Current-Therapy-in-Pain.pdf

1600 John F. Kennedy Boulevard Ste 1800 Philadelphia, PA 19103-2899

CURRENT THERAPY IN PAIN

ISBN: 978-1-4160-4836-7

Copyright ! 2009 by Saunders, an imprint of Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Permissions may be sought directly from Elsevier’s Rights Department: phone: (+1) 215 239 3804 (US) or (+44) 1865 843830 (UK); fax: (+44) 1865 853333; e-mail: [email protected]. You may also complete your request on-line via the Elsevier website at http:// www.elsevier.com/permissions.

Notice Knowledge and best practice in this field are constantly changing. As new research and experience broaden our knowledge, changes in practice, treatment, and drug therapy may become necessary or appropriate. Readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of the practitioner, relying on his or her own experience and knowledge of the patient, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the publisher nor the author assumes any liability for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this book. The Publisher Library of Congress Cataloging-in-Publication Data Current therapy in pain / [edited by] Howard S. Smith. – 1st ed. p. ; cm. Includes bibliographical references and index. ISBN 978-1-4160-4836-7 1. Pain–Treatment. I. Smith, Howard S., 1956[DNLM: 1. Pain–therapy. WL 704 C9758 2009] RB127.C92 2009 616’.0472–dc22 2008008166

Executive Publisher: Natasha Andjelkovic Editorial Assistant: Isabel Trudeau Design Direction: Steven Stave

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I would like to dedicate this book to the memory of my mother, Arlene; to my wife Joan, and our children, Alyssa, Joshua, Benjamin, and Eric; and to my father Nathan, and stepmother Priscilla.

Contributors

Salahadin Abdi, MD, PhD Professor and Chief, University of Miami Pain Center, Department of Anesthesiology, Perioperative Medicine and Pain Management, University of Miami Miller School of Medicine, Miami, Florida PAINFUL DIABETIC PERIPHERAL NEUROPATHY; PAIN IN CHILDREN; BOTULINUM TOXINS FORTHE TREATMENT OF PAIN; EPIDURAL STEROID INJECTIONS; RADIOFREQUENCY TREATMENT; CRYOANALGESIA FOR CHRONIC PAIN

Joseph F. Audette, MA, MD Assistant Professor, Department of Physical Medicine and Rehabilitation, Harvard Medical School, Boston, Massachusetts COMPLEMENTARYAND ALTERNATIVE MEDICINE FOR NONCANCER PAIN

Janet Abrahm, MD Associate Professor of Medicine, Harvard Medical School; Director, Pain and Palliative Care Program, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, and Division Chief, Palliative Care, Dana-Farber Cancer Institute, Boston, Massachusetts PAIN IN THE PALLIATIVE CARE POPULATION

Misha-Miroslav Backonja, MD Professor, Department of Neurology, Anesthesiology and Rehabilitation Medicine, University of Wisconsin School of Medicine and Public Health; Professor, University of Wisconsin Hospital and Clinics, Madison, Wisconsin NEUROPATHIC PAIN-DEFINITION, IDENTIFICATION, AND IMPLICATIONS FOR RESEARCH ANDTHERAPY

Sanjeev Agarwal, MD Assistant Professor, and Director, Interventional Physiatry, SUNY Downstate Medical Center, Brooklyn, New York STEROIDS; SYMPATHETIC BLOCKADE Phillip J. Albrecht, PhD Assistant Professor, Center for Neuropharmacology and Neuroscience, Albany Medical College; Integrated Tissue Dynamics, LLC, Albany New York COMPLEX REGIONAL PAIN SYNDROME PATHOPHYSIOLOGY Catalina Apostol, MD Resident in Pain/Anesthesiology, Department of Anesthesiology, University of Miami, Miami, Florida BOTULINUM TOXINS FORTHE TREATMENT OF PAIN Charles E. Argoff, MD Professor of Neurology, Albany Medical College; Director, Comprehensive Pain Program, Albany Medical Center, Albany, New York NEUROPATHIC PAIN-DEFINITION, IDENTIFICATION, AND IMPLICATIONS FOR RESEARCH ANDTHERAPY; ANTIDEPRESSANTS; BOTULINUM TOXINS FORTHE TREATMENT OF PAIN

Mark L. Baccei, PhD Research Assistant Professor, Department of Anesthesiology, University of Cincinnati College of Medicine, Cincinnati, Ohio PATHOPHYSIOLOGY OF PAIN

Zahid H. Bajwa, MD Assistant Professor of Anesthesia and Neurology, Harvard Medical School; Director, Education and Clinical Pain Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts HEADACHES OTHERTHAN MIGRAINE; TRIGEMINAL NEURALGIA Jeffrey R. Basford, MD, PhD Professor of Physical Medicine and Rehabilitation, Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, Minnesota TRANSCUTANEOUS ELECTRICAL NERVE STIMULATION Allison Baum, DPT Spinal Cord Injury Peer Mentor Coordinator, St. Charles Hospital and Rehabilitation Center, Port Jefferson, New York PHYSICAL MEDICINE APPROACHES TO PAIN MANAGEMENT Joseph M. Bellapianta, MD, MS Department of Orthopaedic Surgery, Albany Medical Center, Albany, New York HAND PAIN; FOOT PAIN

Rafael Benoliel, BDS, LDS, RCS (Eng) Professor and Chairman, Department of Oral Medicine, Faculty of Dental Medicine, Hadassah Hebrew University, Jerusalem, Israel OROFACIAL PAIN Karen Bjoro, PhD(c), RN Doctoral Student, The University of Iowa, Iowa City, Iowa; Nurse Researcher, Department of Orthopedics, Neurology and Neurosurgery, Ulleval University Hospital, Oslo, Norway ASSESSMENT OF PAIN IN THE NONVERBAL AND/OR COGNITIVELY IMPAIRED OLDER ADULT Didier Bouhassira, MD Universite´ de Versailles Saint Quentin, Versailles; Research Director, INSERM (U 792), Centre d’Evaluation et de Traitement de la Douleur, Hoˆpital Ambroise Pare´, Boulogne, France BRAIN IMAGING IN PAINFUL STATES: EXPERIMENTAL AND CLINICAL PAIN Daniel Brookoff, MD, PhD Director, Center for Medical Pain Management, Presbyterian/St. Luke’s Medical Center, Denver, Colorado GENITOURINARY PAIN SYNDROMES: INTERSTITIAL CYSTITIS, CHRONIC PROSTATITIS, PELVIC FLOOR DYSFUNCTION, AND RELATED DISORDERS; SICKLE CELL ANEMIA Patricia Bruckenthal, PhD, RN, ANP-C Clinical Associate Professor, Stony Brook University School of Nursing; Nurse Practitioner, Pain and Headache Treatment Center, Department of Neurology, North Shore/Long Island Jewish Health System, Manhasset, New York ASSESSMENT OF PAIN IN OLDER ADULTS Sean Burgest, MD Medical Director, The Burgest Clinic, Austin, Texas FAILED BACK SURGERY SYNDROME

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CONTRIBUTORS

Allen L. Carl, MD Professor of Orthopaedic Surgery and Pediatrics, Albany Medical College, Albany, New York BACK PAIN

Daniel Clayton, MD, PhD Resident, Division of Neurosurgery, Duke University Medical Center, Durham, North Carolina NEUROSURGICALTREATMENT OF PAIN

Juan Cata, MD Resident, Institute of Anesthesiology, Critical Care, and Comprehensive Pain Management, Cleveland Clinic, Cleveland, Ohio INTERPLEURAL ANALGESIA

Steven P. Cohen, MD Associate Professor, Department of Anesthesiology, and Director of Medical Education, Johns Hopkins University School of Medicine, Baltimore, Maryland; Director of Pain Research and Colonel, United States Army, Walter Reed Army Medical Center, Washington, DC SPINAL ANALGESIA

Brian D. Cauley, MD, MPH Resident, Department of Anesthesiology and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts POSTHERPETIC NEURALGIA Lucy Chen, MD Instructor, Harvard Medical School; Attending Physician, Massachusetts General Hospital, Boston, Massachusetts OPIOIDTOLERANCE, DEPENDENCE, AND HYPERALGESIA Jianguo Cheng, MD, PhD Staff, Department of Pain Management, Institute of Anesthesiology, Critical Care, and Comprehensive Pain Management, Cleveland Clinic, Cleveland, Ohio INTERPLEURAL ANALGESIA Pradeep Chopra, MD, MHCM Assistant Professor (Clinical), Brown Medical School, Providence, Rhode Island; Assistant Professor (Adjunct), Boston University Medical Center, Boston, Massachusetts THORACIC PAIN Paul J. Christo, MD, MBA Assistant Professor, Johns Hopkins University School of Medicine; Director, Multidisciplinary Pain Fellowship, and Director, Pain Treatment Center, The Johns Hopkins Hospital, Baltimore, Maryland PELVIC PAIN; POSTHERPETIC NEURALGIA; COMPLEX REGIONAL PAIN SYNDROME: TREATMENTAPPROACHES Daniel Ciampi de Andrade, MD Universite´ de Versailles Saint Quentin, Versailles; Clinical Fellow, INSERM (U 792), Centre d’Evaluation et de Traitement de la Douleur, Hoˆpital Ambroise Pare´, Boulogne, France BRAIN IMAGING IN PAINFUL STATES: EXPERIMENTAL AND CLINICAL PAIN Eli Cianciolo, MD Clinical Instructor and Pain Medicine Fellow, Harvard Medical School, and Massachusetts General Hospital, Boston, Massachusetts NONSTEROIDAL ANTI-INFLAMMATORY DRUGS AND CYCLOOXYGENASE-2 INHIBITORS

Alane B. Costanzo, MD Anesthesiology Resident, University of Miami Miller School of Medicine, Jackson Memorial Hospital, Miami, Florida EPIDURAL STEROID INJECTIONS Sukdeb Datta, MD, DABIPP, FIPP Associate Professor, and Program Director, Vanderbilt University Pain Medicine Fellowship, Vanderbilt University Medical Center; Director, Vanderbilt University Interventional Pain Center, Nashville, Tennessee EPIDURAL ADHESIOLYSIS Emily A. Davis, MSN, ACNP Division of Neurosurgery, Duke University Medical Center, Durham, North Carolina SPINAL CORD STIMULATION FORTHE TREATMENT OF CHRONIC INTRACTABLE PAIN; NEUROSURGICALTREATMENT OF PAIN Timothy R. Deer, MD President and Chief Executive Officer, The Center for Pain Relief; Clinical Professor, West Virginia University, Charleston, West Virginia EPIDEMIOLOGY OF COMPLICATIONS IN INTERVENTIONAL PAIN MANAGEMENT Martin L. DeRuyter, MD Associate Professor of Anesthesiology and Staff Anesthesiologist, University of Kansas Medical Center, University of Kansas School of Medicine, Kansas City, Kansas PERIOPERATIVE EPIDURAL ANALGESIA; CONTINUOUS PERIPHERAL NERVE CATHETERTECHNIQUES Anthony Dragovich, MD Director, Pain Management Center, Womack Army Medical Center, Fort Bragg, North Carolina; Assistant Professor, Department of Anesthesiology, Uniformed Services University of the Health Sciences, Bethesda, Maryland SPINAL ANALGESIA

Andrew Dubin, MD, MS Associate Professor of Physical Medicine and Rehabilitation, Albany Medical College; Attending Physician, Albany Medical Center Hospital; Medical Director, Capital Region Spine, Albany, New York POST AMPUTATION PAIN DISORDERS; POSTSTROKE PAIN Demetri Economedes, DO Department of Orthopaedic Surgery, Albany Medical Center, Albany, New York HAND PAIN Eli Eliav, DMD, PhD Professor and Director, Division of Orofacial Pain, and Susan and Robert Carmel Endowed Chair in Algesiology, University of Medicine and Dentistry of New Jersey-New Jersey Dental School, Newark, New Jersey OROFACIAL PAIN Jennifer A. Elliott, MD Assistant Professor, Department of Anesthesiology, University of MissouriKansas City School of Medicine; Staff Pain Physician, Saint Luke’s Hospital, Kansas City, Missouri PATIENT-CONTROLLED ANALGESIA; 2-AGONISTS Nasr Enany, MD Assistant Professor and Attending Anesthesiologist, University of Cincinnati, Cincinnati, Ohio SYMPATHETIC BLOCKADE Jonathan Epstein, MD, MA Fellow, Obstetric Anesthesia, Mount Sinai Medical Center, New York, New York TRAMADOL Ike Eriator, MD, MPH Associate Professor, University of Mississippi School of Medicine; Chief, Pain Management Services, University of Mississippi Medical Center, Jackson, Mississippi CANCER PAIN MANAGEMENT David Euler, LicAc Co-Director, Continuing Medical Education Course, Harvard Medical School, Boston, Massachusetts COMPLEMENTARYAND ALTERNATIVE MEDICINE FOR NONCANCER PAIN Vania E. Fernandez, MD Assistant Professor of Anesthesiology, University of Miami School of Medicine; Pain Management Fellow, Department of Anesthesiology, Perioperative Medicine and Pain Management, Jackson Memorial Hospital, Miami, Florida PAINFUL DIABETIC PERIPHERAL NEUROPATHY

CONTRIBUTORS

Richard Field, MD Pain Fellow, Massachusetts General Hospital, and Harvard Medical School, Boston, Massachusetts RADIOFREQUENCY TREATMENT Nanna Brix Finnerup, MD Associate Research Professor, Aarhus University, Aarhus, Denmark SPINAL CORD INJURY Colleen M. Fitzgerald, MD Assistant Professor, Feinberg School of Medicine, Northwestern University; Medical Director, Women’s Health Rehabilitation, Rehabilitation Institute of Chicago, Chicago, Illinois FEMALE PERINEAL/PELVIC PAIN:THE REHABILITATION APPROACH Marc D. Fuchs, MD Associative Clinical Professor, Department of Orthopaedic Surgery, Albany Medical College, Albany, New York HIP PAIN Aimee Furdyna, BS Department of Orthopaedic Surgery, Albany Medical Center, Albany, New York BACK PAIN Christine Gallati, BS Research Assistant, Pharmaceutical Research Institute at Albany College of Pharamacy, Albany, New York PAIN AND SLEEP Padma Gulur, MD Pain Specialist, Center for Pain Medicine, Massachusetts General Hospital; Instructor in Anesthesia, Harvard Medical School, Boston, Massachusetts PAIN IN CHILDREN Payam Hadian, BA College of Arts and Sciences, University of Rochester, Rochester, New York DIAGNOSIS ANDTREATMENT OF FACET-MEDIATED CHRONIC LOW BACK PAIN R. Norman Harden, MD Director, Center for Pain Studies, and Addison Chair, Rehabilitation Institute of Chicago; Associate Professor, Feinberg School of Medicine, Northwestern University, Chicago, Illinois INTERDISCIPLINARY MANAGEMENT FOR COMPLEX REGIONAL PAIN SYNDROME Keela Herr, PhD, RN, FAAN, AGSF Professor and Chair, Adult and Gerontology, The University of Iowa College of Nursing, Iowa City, Iowa ASSESSMENT OF PAIN IN THE NONVERBAL AND/OR COGNITIVELY IMPAIRED OLDER ADULT

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Greg Hobelmann, MD Postdoctoral Fellow, Division of Pain Medicine, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore; Pain Medicine Specialists, P.A., Towson, Maryland PELVIC PAIN

Clete A. Kushida, MD, PhD, RPSGT Director, Stanford University Center for Human Sleep Research; Associate Professor, Stanford University Medical Center, Stanford University Center of Excellence for Sleep Disorders, Stanford, California PAIN AND SLEEP

Steven H. Horowitz, MD Clinical Professor of Neurology, University of Vermont College of Medicine, Burlington, Vermont; Assistant in Neurology, Massachusetts General Hospital, Boston, Massachusetts NEUROPATHIC PAIN: IS THE EMPEROR WEARING CLOTHES?

Elizabeth Demers Lavelle, MD Assistant Professor, SUNY Upstate Medical University, Syracuse, New York HAND PAIN; BACK PAIN; HIP PAIN; KNEE PAIN; FOOT PAIN; RHEUMATOID ARTHRITIS; MYOFASCIALTRIGGER POINTS; INTRAARTICULAR INJECTIONS

Christina K. Hynes, MD Clinical Instructor, Feinberg School of Medicine, Northwestern University; Attending Physician, Rehabilitation Institute of Chicago, Chicago, Illinois FEMALE PERINEAL/PELVIC PAIN:THE REHABILITATION APPROACH Kenneth C. Jackson, II, PharmD Associate Professor, Pacific University School of Pharmacy; Associate Editor, Journal of Pain and Palliative Care Pharmacotherapy, Hillsboro, Oregon OPIOID PHARMACOTHERAPY ChaunceyT. Jones, MD Resident, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland COMPLEX REGIONAL PAIN SYNDROME: TREATMENTAPPROACHES Douglas Keene, MD Director of Pain Management, Department of Anesthesia, Milton Hospital, Milton, Massachusetts; Co-founder, Boston PainCare, Waltham, Massachusetts RADIOFREQUENCY TREATMENT Kenneth L. Kirsh, PhD Assistant Professor, Pharmacy Practice and Science, University of Kentucky; Attending Clinical Psychologist, The Pain Treatment Center of the Bluegrass, Lexington, Kentucky POTENTIAL DOCUMENTATION TOOLS FOR OPIOIDTHERAPY; PAIN IN THE SUBSTANCE ABUSE POPULATION Jan Kraemer, MD Clinical Fellow, Harvard Medical School, Boston, Massachusetts HEADACHES OTHERTHAN MIGRAINE Michael A. Krieves, BS Department of Orthopaedic Surgery, Albany Medical Center, Albany, New York HIP PAIN; KNEE PAIN

Lori A. Lavelle, DO Staff Physician, Altoona Arthritis and Osteoporosis Center, Duncansville, Pennsylvania RHEUMATOID ARTHRITIS; INTRA-ARTICULAR INJECTIONS William F. Lavelle, MD Assistant Professor, Department of Orthopaedic Surgery, SUNY Upstate Medical University, Syracuse, New York HAND PAIN; BACK PAIN; HIP PAIN; KNEE PAIN; FOOT PAIN; RHEUMATOID ARTHRITIS; MYOFASCIALTRIGGER POINTS; INTRAARTICULAR INJECTIONS Andrew Linn, MD Clinical Fellow in Anesthesia, Harvard Medical School, and Beth Israel Deaconess Medical Center, Boston, Massachusetts TRIGEMINAL NEURALGIA Dave Loomba, MD Assistant Professor, University of California, Davis, Sacramento; Anesthesiologist, Enloe Medical Center, Chico, California SACROILIAC JOINT PAIN Karan Madan, MBBS, MPH Instructor in Anaesthesia, Harvard Medical School; Staff, Pain Management Center, Department of Anesthesia, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Boston, Massachusetts PAIN AND PAIN MANAGEMENT RELATEDTO HIV INFECTION Gagan Mahajan, MD Associate Professor, and Director, Fellowship in Pain Medicine, University of California, Davis, Sacramento, California SACROILIAC JOINT PAIN Jianren Mao, MD, PhD Associate Professor, Harvard Medical School; Attending Physician, Massachusetts General Hospital, Boston, Massachusetts OPIOIDTOLERANCE, DEPENDENCE, AND HYPERALGESIA

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CONTRIBUTORS

John D. Markman, MD Director, Neuromedicine Pain Management Center and Translational Pain Research, Department of Neurosurgery, University of Rochester School of Medicine and Dentistry, Rochester, New York LUMBAR SPINAL STENOSIS: CURRENT THERAPYAND FUTURE DIRECTIONS; DIAGNOSIS ANDTREATMENT OF FACETMEDIATED CHRONIC LOW BACK PAIN Eric M. May, MD Assistant Professor of Anesthesiology, University of Missouri-Kansas City; Staff Anesthesiologist, Saint Luke’s Hospital, Kansas City, Missouri CONTINUOUS PERIPHERAL NERVE CATHETERTECHNIQUES Gary McCleane, MD, FFARCSI Consultant in Pain Management, Rampark Pain Centre, Lurgan, Northern Ireland, United Kingdom PAIN IN THE ELDERLY; OPIOIDS ISSUES; ANTIEPILEPTIC DRUGS; LOCAL ANESTHETICS; MUSCLE RELAXANTS; TOPICAL ANALGESIC AGENTS James McLean, MDy Pain Fellow, Rehabilitation Institute of Chicago; Department of Physical Medicine and Rehabilitation, Feinberg School of Medicine, Northwestern University, Chicago, Illinois PHYSICAL MEDICINE APPROACHES TO PAIN MANAGEMENT Sangeeta R. Mehendale, MD, PhD Research Associate, Department of Anesthesia and Critical Care, Pritzker School of Medicine, University of Chicago, Chicago, Illinois GASTROINTESTINAL DYSFUNCTION WITH OPIOID USE Harold Merskey, DM, FRCPC, FRCPsych Professor Emeritus of Psychiatry, University of Western Ontario, London, Ontario, Canada THE TAXONOMY OF PAIN Tobias Moeller-Bertram, MD Assistant Clinical Professor, Department of Anesthesiology, University of California, San Diego, La Jolla, California BOTULINUM TOXINS FORTHE TREATMENT OF PAIN

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Deceased

Mila Mogilevsky, DO, PT Resident Physician, Rehabilitation Institute of Chicago, Department of Physical Medicine and Rehabilitation, Northwestern University, Chicago, Illinois PHYSICAL MEDICINE APPROACHES TO PAIN MANAGEMENT Xavier Moisset, MD Universite´ de Versailles Saint Quentin, Versailles; Clinical Fellow, INSERM (U 792), Centre d’Evaluation et de Traitement de la Douleur, Hoˆpital Ambroise Pare´, Boulogne, France BRAIN IMAGING IN PAINFUL STATES: EXPERIMENTAL AND CLINICAL PAIN Muhammad A. Munir, MD Chairman, Southwest Ohio Pain Institute, West Chester, Ohio STEROIDS; NONSTEROIDAL ANTI-INFLAMMATORY DRUGS AND CYCLOOXYGENASE-2 INHIBITORS; SYMPATHETIC BLOCKADE Beth B. Murinson, MS, MD, PhD Assistant Professor of Neurology, Johns Hopkins University School of Medicine; Active Staff, Johns Hopkins Medical Institutions, The Johns Hopkins Hospital, Baltimore, Maryland A MECHANISM-BASED APPROACH TO PAIN PHARMACOTHERAPY:TARGETING PAIN MODALITIES FOR OPTIMALTREATMENT EFFICACY Lida Nabati, MD Instructor of Medicine, Harvard Medical School; Attending Physician, Division of Palliative Care, Dana-Farber Cancer Institute, Boston, Massachusetts PAIN IN THE PALLIATIVE CARE POPULATION Srdjan S. Nedeljkovic¤, MD Fellowship Director, Pain Medicine Program, and Staff, Pain Management Center, Department of Anesthesia, Perioperative and Pain Medicine, Brigham and Women’s Hospital; Assistant Professor of Anaesthesia, Harvard Medical School, Boston, Massachusetts PAIN AND PAIN MANAGEMENT RELATEDTO HIV INFECTION Lisa J. Norelli, MD, MPH, MRCPsych Assistant Professor of Psychiatry, Albany Medical College; Director of Psychiatry, Capital District Psychiatric Center, Albany, New York HYPNOTIC ANALGESIA Akiko Okifuji, PhD Professor of Anesthesiology, and Attending Psychologist, Pain Management Center, University of Utah, Salt Lake City, Utah PSYCHOLOGICAL ASPECTS OF PAIN

Ike Onyedika, BS Department of Orthopaedic Surgery, Albany Medical Center, Albany, New York HAND PAIN Susan Elizabeth Opper, MD Assistant Professor of Medicine, University of Missouri-Kansas City School of Medicine; Director, Pain Management Services, Saint Luke’s Hospital, Kansas City, Missouri NECK PAIN Richard K.Osenbach, MD Director, Neurosurgical Services, Cape Fear Valley Medical Center, Fayetteville, North Carolina SPINAL CORD STIMULATION FORTHE TREATMENT OF CHRONIC INTRACTABLE PAIN; NEUROSURGICALTREATMENT OF PAIN Joshua Pal, MD Clinical Fellow, Harvard Medical School, Boston, Massachusetts HEADACHES OTHERTHAN MIGRAINE Marco Pappagallo, MD Professor, Department of Anesthesiology, Mount Sinai School of Medicine; Director, Pain Medicine Research and Development, Mount Sinai Medical Center, New York, New York NEUROPATHIC PAIN-DEFINITION, IDENTIFICATION, AND IMPLICATIONS FOR RESEARCH ANDTHERAPY;TRAMADOL Amar Parikh Research Assistant, Albany Medical College, Albany, New York POST AMPUTATION PAIN DISORDERS Winston C.V. Parris, MD, FACPM Professor of Anesthesiology, and Director, Pain Programs, Duke University Medical Center; Division Chief, Duke Pain and Palliative Care Center, Duke University Hospital, Durham, North Carolina CANCER PAIN MANAGEMENT Steven D. Passik, PhD Associate Professor of Psychiatry, Weill College of Medicine, Cornell University Medical Center; Associate Attending Psychologist, Memorial Sloan Kettering Cancer Center, New York, New York PAIN IN THE SUBSTANCE ABUSE POPULATION Gira Patel, LicAc Clinical Associate, Osher Integrative Care Center, Harvard Medical School Osher Institute; Division for Research and Education in Complementary and Integrative Medical Therapies, Arnold Pain Clinic, Beth Israel Deaconess Hospital, Boston, Massachusetts COMPLEMENTARYAND ALTERNATIVE MEDICINE FOR NONCANCER PAIN

CONTRIBUTORS

Eric M. Pearlman, MD, PhD Director, Pediatric Education, and Assistant Professor of Pediatrics, Mercer University School of Medicine; Savannah Neurology, P.C., Savannah, Georgia MIGRAINE HEADACHES

Scott S. Reuben, MD Professor of Anesthesiology and Pain Medicine, Tufts University School of Medicine, Boston; Director, Acute Pain Service, Baystate Medical Center, Springfield, Massachusetts PERIOPERATIVE USE OF COX-2 AGENTS

Richard A. Pertes, DDS Clinical Professor, Division of Orofacial Pain, University of Medicine and Dentistry of New Jersey-New Jersey Dental School, Newark, New Jersey OROFACIAL PAIN

Frank L. Rice, PhD Professor, Center for Neuropharmacology and Neuroscience, Albany Medical College; Integrated Tissue Dynamics, LLC, Albany, New York COMPLEX REGIONAL PAIN SYNDROME PATHOPHYSIOLOGY

Annie Philip, MD Assistant Professor, Department of Anesthesiology, University of Rochester School of Medicine and Dentistry, Rochester, New York DIAGNOSIS ANDTREATMENT OF FACET-MEDIATED CHRONIC LOW BACK PAIN Mark Anthony Quintero, MD Pain Management Fellow, Department of Anesthesiology, Perioperative Medicine and Pain Management, University of Miami Miller School of Medicine, Jackson Memorial Hospital, Miami, Florida CRYOANALGESIA FOR CHRONIC PAIN Lynn Rader, MD Clinical Instructor, Feinberg School of Medicine, Northwestern University; Attending Physician, Rehabilitation Institute of Chicago, Chicago, Illinois PHYSICAL MEDICINE APPROACHES TO PAIN MANAGEMENT Lakshmi Raghavan, PhD Associate Director, Research and Development, Vyteris Corporation, Inc. Fair Lawn, New Jersey PAIN IN CHILDREN Rakesh Ramakrishnan, BS Department of Orthopaedic Surgery, Albany Medical Center, Albany, New York HIP PAIN; KNEE PAIN Alan M. Rapoport, MD Clinical Professor of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California; Founder and Director Emeritus, The New England Center for Headache, P.C., Stamford, Connecticut MIGRAINE HEADACHES Rahul Rastogi, MD Assistant Professor, Washington University in St. Louis; Assistant Professor and Attending Anesthesiologist, Barnes-Jewish Hospital, St. Louis, Missouri SYMPATHETIC BLOCKADE

Melissa A. Rockford, MD Assistant Professor of Anesthesiology, University of Kansas Medical Center, University of Kansas School of Medicine, Kansas City, Kansas PERIOPERATIVE EPIDURAL ANALGESIA Carl Rosati, MD Associate Professor of Surgery, Albany Medical College; Trauma Director, Albany Medical Center, Albany, New York ABDOMINAL PAIN Mike A. Royal, MD, JD, MBA Vice President, Clinical Development Analgesics, Cadence Pharmaceuticals, Inc., San Diego, California ACETAMINOPHEN Christine N. Sang, MD, MPH Director, Translational Pain Research, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts GLUTAMATE RECEPTOR ANTAGONISTS Nalini Sehgal, MD, FABPMR Associate Professor, Department of Orthopedics and Rehabilitation, University of Wisconsin School of Medicine and Public Health; Medical Director, Interventional Pain Program, and Pain Fellowship Program Director, University of Wisconsin Hospital and Clinics, Madison, Wisconsin CRYOANALGESIA FOR CHRONIC PAIN Ashutosh Sharma, PhD Chief Strategic Officer, Vyteris, Inc., Fair Lawn, New Jersey PAIN IN CHILDREN Lee S. Simon, MD Associate Clinical Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, Massachusetts OSTEOARTHRITIS: ETIOLOGY, PATHOGENESIS, ANDTREATMENT

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ThomasT. Simopoulos, MD Instructor in Anaesthesia, Harvard Medical School; Director of Interventional Pain Management, Beth Israel Deaconess Medical Center, Boston, Massachusetts FAILED BACK SURGERY SYNDROME Jeremy C. Sinkin, BA Department of Neurosurgery, University of Rochester School of Medicine and Dentistry, Rochester, New York LUMBAR SPINAL STENOSIS: CURRENT THERAPYAND FUTURE DIRECTIONS David J. Skinner, MD Assistant Professor, Departments of Anesthesiology and Pain Management, Mount Sinai School of Medicine; Assistant Professor, Mount Sinai Medical Center, New York, New York TRAMADOL Michelle Skinner, MS Graduate Student, Department of Psychology, University of Utah, Salt Lake City, Utah PSYCHOLOGICAL ASPECTS OF PAIN Howard S. Smith, MD, FACP, FACNP Associate Professor of Anesthesiology, Internal Medicine, Physical Medicine and Rehabilitation, Albany Medical College, Academic Director of Pain Management, Department of Anesthesiology, Albany Medical Center, Assistant Director of Clinical Research at The Pharmaceutical Research Institute, Albany College of Pharmacy, Albany, New York NEUROPATHIC PAINçDEFINITION, IDENTIFICATION, AND IMPLICATIONS FOR RESEARCH ANDTHERAPY; POTENTIAL DOCUMENTATION TOOLS FOR OPIOID THERAPY; POST AMPUTATION PAIN DISORDERS; COMPLEX REGIONAL PAIN SYNDROME PATHOPHYSIOLOGY; PAIN AND SLEEP; OPIOIDS ISSUES; ACETAMINOPHEN; ANTIDEPRESSANTS; GLUTAMATE RECEPTOR ANTAGONISTS; BOTULINUM TOXINS FOR THE TREATMENT OF PAIN; CRYOANALGESIA FOR CHRONIC PAIN Paul E. Spurgas, MD Associate Professor of Neurosurgery, Division of Neurosurgery, Albany Medical Center, Albany, New York; Temple University, Philadelphia, Pennsylvania VERTEBROPLASTYAND KYPHOPLASTY Steven C. Stain, MD Neil Lempert Professor, and Chair, Department of Surgery, Albany Medical College; Chief of Surgery, Albany Medical Center Hospital, Albany, New York ABDOMINAL PAIN

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CONTRIBUTORS

Steven Stanos, DO Assistant Professor, Feinberg School of Medicine, Northwestern University; Medical Director, Rehabilitation Institute of Chicago, Chicago, Illinois PHYSICAL MEDICINE APPROACHES TO PAIN MANAGEMENT Roland Staud, MD Professor of Medicine, University of Florida, Gainesville, Florida FIBROMYALGIA SYNDROME Richard L.Uhl, MD Professor of Surgery, Albany Medical College, Albany; Adjunct Professor of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy; Chief, Orthopaedic Surgery, Albany Medical Center Hospital, Albany, New York SHOULDER PAIN; ELBOW PAIN Mark Wallace, MD Professor of Clinical Anesthesiology, and Program Director, Center for Pain Medicine, Department of Anesthesiology, University of California, San Diego, La Jolla, California BOTULINUM TOXINS FORTHE TREATMENT OF PAIN Deirdre M.Walsh, DPhil, BPhysio Professor of Rehabilitation Research, Health and Rehabilitation Sciences Research Institute, University of Ulster, Newtownabbey, County Antrim, Northern Ireland, United Kingdom TRANSCUTANEOUS ELECTRICAL NERVE STIMULATION

Chris Warfield, BA Research Assistant, Arnold Pain Management Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts COGNITIVE THERAPY FOR CHRONIC PAIN

James P.Wymer, MD, PhD Assistant Professor of Neurology, Albany Medical College; Upstate Clinical Research, Albany, New York GLUTAMATE RECEPTOR ANTAGONISTS

Ajay D.Wasan, MD, MSc Assistant Professor, Harvard Medical School; Departments of Anesthesiology and Psychiatry, Brigham and Women’s Hospital, Boston, Massachusetts ANTIDEPRESSANTS

Chun-SuYuan, MD, PhD Cyrus Tang Professor, Department of Anesthesia and Critical Care, Pritzker School of Medicine, University of Chicago, Chicago, Illinois GASTROINTESTINAL DYSFUNCTION WITH OPIOID USE

Lynn R.Webster, MD, FACPM, FASAM Medical Director, Lifetree Clinical Research and Pain Clinic, Salt Lake City, Utah PAIN AND SLEEP Richard Whipple, MD Assistant Clinical Professor, Department of Orthopaedic Surgery, Albany Medical College, Albany, New York HAND PAIN Joshua Wootton, MDiv, PhD Assistant Professor, Department of Anaesthesia, Harvard Medical School; Director of Pain Psychology, Arnold Pain Management Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts COGNITIVE THERAPY FOR CHRONIC PAIN

Jun-Ming Zhang, MD, MSc Associate Professor and Director of Research, Department of Anesthesiology, University of Cincinnati College of Medicine, Cincinnati, Ohio PATHOPHYSIOLOGY OF PAIN; STEROIDS; NONSTEROIDAL ANTI-INFLAMMATORY DRUGS AND CYCLOOXYGENASE-2 INHIBITORS YiLi Zhou, MD, PhD Courtesy Clinical Assistant Professor, University of Florida; Medical Director, Comprehensive Pain Management of North Florida, Gainesville, Florida DIAGNOSIS AND MINIMALLY INVASIVE TREATMENT OF LUMBAR DISCOGENIC PAIN

Preface

The International Association for the Study of Pain (IASP) has defined pain as ‘‘an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or defined in terms of such damage’’. Donald Price in his 1999 book Psychological Mechanisms of Pain and Analgesia by IASP Press proposed an alternative definition, arguing that the IASP definition does not emphasize the experiential nature of pain. He holds that pain is a ‘somatic perception containing (1) a bodily sensation with qualities like those reported during tissue-damaging stimulation, (2) an experienced threat associated with this sensation, (3) a feeling of unpleasantness or other negative emotion based on this experienced threat’. In 1931, the French medical missionary, Dr. Albert Schweitzer wrote ‘‘Pain is a more terrible lord of mankind than even death itself’’. These words emphasize the scope of total human suffering due to pain which may dramatically affect a person’s life/quality of life. Pain remains among one of the most debilitating symptoms as well as one of the most common symptoms which patients report. Blair Smith and Nicole Torrance have addressed the Epidemiology of Chronic Pain as a chapter in the book, Systematic Reviews in Pain Research: Methodology Refined edited by Henry J. McQuay, Eija Kalso, and R. Andrew Moore and published by IASP Press in 2008. They write that it seems that up to half of the adult population suffers from chronic pain as defined by the broad IASP definition and that 10-20% experience chronic pain when measures of clinical significance are added to the definition. They further state that the incidence of chronic pain (though difficult to estimate) may be between 5% and 10% per year and is associated with poor health-related quality of life in all studies that measured this variable. Numerous potential therapeutic targets exist which may modulate nociceptive processing including: ion channels, TRP channels, ASIC channels, stretch-activated channels, signaling molecules/casades (pERK, p38MAPK protein kinases), neurotrophins (BDNF, GDNF, NGF) inflammatory mediators, cytokines, adhesion molecules, immune cells/glia, neurotransmitters (SP, NK1, CCK), adrenergic receptors, purinergic receptors, toll-like receptors, and glutamate receptors. Furthermore, it is not uncommon that opposing antiinflammatory processes may exist for certain pro-inflammatory/ pro-nociceptive processes (e.g., acetylation of MKP-1 promotes the interaction of MKP-1 with its substrate p38 MAPK, which results in dephosphorylation of p38 MAPK). However, some of these targets do not have clinically available agents to specifically enhance or inhibit their function and even if these agents existed, clinicians would not know which agents to utilize for a specific individual patient’s pain complaints. Furthermore, analgesics, modalities, neuromodulation, and interventional techniques, etc. should not be used ‘‘in a vacuum’’, but rather optimally in conjunction with physical medicine, behavioral medicine, and other techniques as part of an interdisciplinary team approach. Additionally, it is conceivable that some pain

complaints in some patients may need therapies targeting peripheral, spinal, as well as supraspinal mechanisms in efforts to fully address their issues. Despite an explosion of basic science pain research, the translation of these advances into tangible and clinically useful diagnostic and therapeutic measures to identify and ameliorate various human painful conditions has lagged. Unfortunately, despite valiant efforts, too many people continue to exist with horrific pain and suffering, some who have been helped a little, and some who have not been helped at all. The field of Pain Medicine is still relatively in its infancy, but continues to gradually mature. Thus, it was heartening to learn that as we approach the tail end of the ‘‘decade of pain’’; Elsevier is adding the book ‘‘Current Therapy in Pain’’ to its critically acclaimed ‘‘Current Therapy’’ series. Perhaps one of the best known books in this series is Conn’s Current Therapy, which was initially published in 1943 and has been revised yearly since. After 65 years, Current Therapy in Pain has surfaced in efforts to deliver a source of current information on the field of pain medicine which will be updated reasonably frequently. In keeping with the style of the series ‘‘Current Therapy in Pain’’ is clinically oriented. However, in contrast to other Current Therapy texts, ‘‘Current Therapy in Pain’’ does not present all chapters without references. Although I initially set out with the intention to keep this format, which is seen in some chapters, it became apparent that it would be challenging to have all the chapters without references, largely due to the immaturity and dynamic nature of the field of pain medicine. The text is organized to initially present background information on pain —taxonomy, pathophysiology and assessment. Various treatment strategies for acute pain are then presented. The next sections deal with a number of conditions/syndromes/ issues which are painful or may interface with pain. Section IV is devoted to Pain in Special Populations. Finally, Sections VII through XIII deal with treatment approaches to pain (pharmacologic, behavioral medicine, physical medicine and rehabilitation, neuromodulation, complementary and alternative medicine, neurosurgical, and interventional). The text, although not comprehensive of all pain-relieving strategies, is felt to present a reasonable representation of available therapeutic options which may help alleviate pain. Furthermore, because of the dynamic nature of pain and the attempt to present current information, it is not intended that all treatment strategies presented in the text are ‘‘tried and true’’ therapies which have stood the test of time, but only that they are or may be available options for certain circumstances, now or in the future. It is hoped that the experts who contributed to this text have presented information which may be helpful/educational to clinicians and/or patients and that future editions continue to present current and useful information related to the ever-changing field of pain medicine. HOWARD S. SMITH, MD

xiii

Acknowledgments

The editor would like to thank and acknowledge the enormous efforts of Pya Seidner who helped to bring this project to fruition. The editor would like to acknowledge and thank the Reflex Sympathetic Dystrophy Association (RSDA) for the use of Dr. R. Norman Harden’s chapter which was initially written for RSDA.

The editor would also like to acknowledge and thank Dr. Kevin W. Roberts, Chairman of the Department of Anesthesiology for Albany Medical College, for his continued support throughout this project.

xv

Foreword

I distinctly remember the moment, more than 25 years ago. It is frozen in my memory as if it occurred yesterday. With eyes closed, my senses recall the dim lighting, the squeaking of aged and rarely waxed tongue-and-groove flooring underfoot, the musty smell of weathered paper, dried binding glue and dust. This was the library in the teaching hospital that served as my ‘‘home away from home’’ as a neophyte physician. And that was where I went to seek help when I began to steadily encounter patients with pain problems. And there were, it seemed, so many . . . yet, on whose behalf my attending physicians shrugged their collective shoulders and skillfully redirected the stream of discussion to more discernible pathology. There was no malice, just discomfort, and I discovered why. No one knew anything. The library shelves were devoid of journals and texts on the subject. Fast forward to 2008, and there is such an outpouring of painrelated literature, I have to purposefully block out my schedule every Friday afternoon to peruse what comes across my desk just to keep up before the week ends. Sure, I have learned that it’s okay to say ‘‘I don’t know’’, but there will be no shoulder-shrugging or

avoidance of the subject when medical trainees ask me those difficult questions about the most common problem experienced by people seeking medical care: pain! But how can most clinicians— who have so many areas of medicine to keep up on—also keep up on all the advances in pain assessment and management? The answer lies between the covers of this well-written, comprehensive yet pointedly practical text. In this new addition to the highly valued ‘‘Current Therapy’’ series, Dr. Howard Smith has assembled many of the leading authorities in this rapidly-evolving field to do that all-important and selfless work: write a book that really can, and will, help to improve peoples’ lives. Would that I could have discovered such a gem when I went searching, way back in ‘‘the dark ages’’ of the late 20th century! PERRY G. FINE, MD Professor of Anesthesiology Pain Research Center University of Utah School of Medicine Salt Lake City, Utah

xvii

I PAIN BACKGROUND

Chapter 1

THE TAXONOMY OF PAIN Harold Merskey

INTRODUCTION Taxonomy is the theory and practice of classification. For an ideal classification, each item to be considered should be independent of all other items so that it stands in its own place in the classification. For example, if we wish to classify peoples’ names for a telephone directory, each name must represent a separate and distinguishable item. The classification must also be comprehensive (Box 1—1). If two or more people have names such as John A. Smith, then an additional criterion must be used to distinguish each John A. Smith and this can be done by adding a street address. If there are two John A. Smiths, each with his own telephone number at exactly the same address—most likely father and son, or if there are three, grandfather, father, and son—they may use a numeric superscript or a numeric postscript as John A. Smith1, John A. Smith2, John A. Smith.3 That provides a perfect classification useful for the purpose for which it is intended and of little or no interest besides. Natural classifications such as animal, vegetable, or mineral are more exciting and even sometimes intellectually beautiful, for example, the periodic table in chemistry. Nearly always (apart perhaps from some isotopes made by people) this meets the highest standards of classification also. Each element has a place of its own into which it fits and no other element with which it can be confused. Evolutionary classifications of flora and fauna similarly achieve great success, although disputes may arise in marginal cases (Box 1—2). Medical classification lacks the rigor of either the telephone directory or the periodic table. It is exceptionally untidy, but it is taken to reflect in some way ‘‘the absolute truth’’ or at least the wonderful truth, as known to the best practitioners. Accordingly, physicians endeavor to create true descriptions of individual ‘‘true’’ disorders, each helping to some extent to improve upon the worth of the previous ones. Classification may then be bedeviled by an argument about the criteria that apply to a particular diagnosis, for example, what is Cervicogenic Headache? What is the difference after an injury between that and Migraine if Migraine occurs with photophobia or phonophobia and nausea? Are there two or more disorders, each with its essential characteristics?

These disputes form an interesting adjunct to classification and may or may not be illuminating, but resolving them is not part of the primary function of a classificatory system. Classification is not a means of reaching an absolute truth but rather a means of establishing ways to code data that can be shared and compared between different practitioners or investigators. The main task of the classifier is simply to make sure that individuals can identify and locate types of objects or events. The classifier is not required to establish a true ‘‘meaning.’’1 Thus, if physicians in different parts of the world wish to exchange information about headache, it is not necessarily important to resolve, first, whether Migraine should or should not include phonophobia in its classification. Rather, it is important to identify headaches that are unilateral or bilateral, and then whether photophobia, phonophobia, nausea, and vomiting occur together with varying durations of the event. Thus, data can be collected for comparison between different groups with respect to the items used to identify particular events, and any consequences that we wish to suppose follow from them, such as loss of response to different treatments and so forth. Of course, this does mean that one has to have some sort of idea about which criteria one wishes to put together in one classificatory slot and which criteria go into another classificatory slot. We are not really interested in comparing cases of headache with cases of elephantiasis. That separation is easily made. Separations between types of headache become a topic for study within the framework of an overall definition. It is just as well that classification can be used in the way just mentioned. Were that not the case, we would be left with irreconcilable arguments and spend all our time trying to determine whether all physical illnesses were hereditary and secondary to psychological status, or whether some physical illnesses certainly were due to environmental causes and others resulted from ill treatment in childhood. A workable system of classification needs to proceed on the basis of information that is largely agreed and to define areas of disagreement so that these can be further explored. This is a reasonable way to avoid controversy about medical diagnoses and to pursue knowledge.

EXISTING MEDICAL CLASSIFICATIONS Existing medical classifications vary enormously but are all, or nearly all, illogical. In the International Classification of Diseases and Related Health Problems, 10th edition (ICD-10),2 for example, we find that conditions are classified by causal agent (e.g., infectious diseases or neoplasms); by systems of the body (e.g., gastrointestinal or genitourinary); or by symptom pattern and type of psychiatric illnesses (including affective psychosis, schizophrenic psychosis, organic psychoses, depressive and anxiety disorders, and personality disorders) (Box 1—3). 1

2

Chapter 1  THE TAXONOMY OF PAIN

Box 1—1 IDEAL CLASSIFICATION

Box 1—3 MEDICAL CLASSIFICATION

 Comprehensive  Specific place for each item

By Cause Bacteria By Organ Pneumonia

All of the psychiatric conditions just mentioned, except for Personality Disorders, are segregated into a category known in the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders in several editions (DSM-IV TR, at present3) as ‘‘Axis I Type Disorders,’’ and Personality Disorders are classified in an additional axis (Axis II). Patients may have any number of disorders from Axis I (e.g., Major Depressive Disorder plus Post-Traumatic Stress Disorder), and another diagnosis as well on Axis II (e.g., 301.4 Obsessive Compulsive Personality Disorder) (Box 1—4). Medical diagnoses can also be classified by time of occurrence in relation to stages of life, for instance, congenital anomalies, conditions originating in the perinatal period, or presenile and senile disorders. At the lowest level of classification, that is, the simplest and least complex description of phenomena, conditions used to be classified simply as ‘‘Symptoms, Signs and Ill-Defined Conditions’’ and are now classified as Symptoms and Signs, which actually constitute a group on their own in the ICD-10.2 Not only illness is classified in medical lists. There was also a code in ICD-94: ICD650 for delivery in a completely normal case of pregnancy. The nearest to this now appears in ICD-10 as Single Spontaneous Delivery. Within the major medical groups of ICD-9 and -10 and particularly the neurologic section, there are subdivisions by symptom pattern (e.g., epilepsy or migraine), by the presence of hereditary or degenerative disease (e.g., cerebral degenerations that may be manifest in childhood or adult life), and by symptom pattern (e.g., Parkinson’s disease, chorea, and types of cellular change). Accordingly, there are also diagnoses by location (e.g., spinocerebellar disease) and by infectious causes within the neurologic group (which is defined first by location, e.g., meningitis). If we look at pain disorders, there are codes in the ICD-10 for ‘‘Migraine’’ (G43) and 9 subtypes, and separately for ‘‘Other Headache Syndromes’’ (G44) with 10 subcategories. There are codes for ‘‘Juvenile Ankylosing Spondylitis’’ (M081) and for ‘‘Ankylosing Spondylitis in adults’’ (M45), as for ‘‘Seropositive Rheumatoid Arthritis’’ (M05) with 6 subordinate categories and for ‘‘Other Rheumatoid Arthritis’’ with 9 subordinate categories (M06). Among Symptoms and Signs, we find ‘‘Headache’’ (R51). In the Cardiologic section, R07 includes precordial pain in the anterior chest wall (NOS); this may be pain in the musculoskeletal system or refer to a neuralgic type of pain and precordial pain, which may well not be cardiac. If we look at Endocrinology, we may simply diagnose ‘‘Diabetes,’’ which was once one disorder but is now defined in terms of 5 subtypes on a biochemical and therapeutic basis. Among Musculoskeletal conditions, we have ‘‘Fibromyalgia’’ defined by a distribution of pain and tender points and not by what might be its supposed innermost essence, and ‘‘Repetitive Strain Syndrome’’ is diagnosed, whether rightly wrongly, on the basis of pain in parts that are overused. To resolve some of the problems of comparing these illnesses, the American Psychiatric Association’s DSM-III5 provided at least

By System Pneumonia Parkinson’s Disease By Site Low back pain By Symptom Headache

five different Axes on which conditions might be classified including Axis I: Clinical Disorders; Axis II: Personality Disorders, Mental Retardation, or Specific Development Disorders; Axis III: General Medical Conditions; Axis IV: Psychosocial and Environmental Problems; and Axis V: Global Assessment of Functioning. This system allows us to classify both symptom patterns and people, an interesting conclusion, although the classification of people is notoriously unreliable whether by psychiatrists or by anyone else in the medical context. To add to these hazards, we can also note that we may diagnose psychiatric conditions from serology (e.g., genetics [e.g., Huntington’s chorea]), symptom pattern (e.g., schizophrenia, depression, bipolar illness), reported mechanism (e.g., tension headache), and even the presence or the absence of irrational behavior (e.g., psychosis vs. neurosis, although the latter term is not much used nowadays and was dropped from DSM-III onward). One of the obvious responses in a situation in which classification cannot be provided on a theoretical basis is to provide agreed operational definitions. This brings us back to the starting point of this discussion at which it was pointed out that only two things really matter in a classification system, one is a distinction between A, B, and C and the other is that everything from A to Z will be included that is part of the material to be classified. Thus, it follows that even within medicine, the range of classificatory systems can be enormous. There are highly specialized and valuable classifications that will code the varieties and degrees of a single diagnostic category such as stroke,6 and there are also classifications that cover not just the type of illness or condition examined but simply the reason for consultation. Thus, the ICCPC, the International Classification of Conditions in Primary Care7 does not classify diseases but rather the reason for contact between the family practitioner and her or his patient. Such a classification will include the reason for a patient being in the doctor’s office (e.g., advice on a symptom, review of treatment, completion of a referral form, and completion of an insurance company form).

Box 1—4 AMERICAN PSYCHIATRIC ASSOCIATION DIAGNOSTIC AND STATISTICAL MANUAL OF MENTAL DISORDERS

Box 1—2 TYPES OF CLASSIFICATION Natural Mineral Vegetable Artificial Telephone directory

From American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV).Washington, DC: APA Press, 2000.

I PAIN BACKGROUND

All these items are classifiable and can be examined for whatever statistical purpose desired. The one thing classification does not do is provide a statement of absolute truth about the ultimate meaning of all medical disorders—or even one.

CLASSIFICATIONOF PAIN In 1983, citing others, it was said that, ‘‘There has long been a need for classification in the field of pain.’’1 A classification of pain was prepared originally for the International Association for the Study of Pain, and first published in 1986,8 with a second edition in 1994. The aim of the classification is described in the introduction to the 1994 volume9 as being to classify the major causes of chronic pain and to organize descriptions of the syndromes. It turned out slightly differently. At first, it was not felt possible nor desirable to classify all painful conditions. A good classification of pain was principally required for practitioners who were specializing in the treatment of painful disorders and who needed to distinguish them from other disorders and disabilities. Thus, it was inappropriate to include the pain of appendicitis or tonsillectomy in a classification of chronic pain, but it was desirable to have a systematic arrangement of conditions that commonly caused chronic pain. Any attempt to do otherwise would, of course, have amounted to writing an extensive textbook of medicine. The purpose of such a classification would be to provide a means of communication between specialists in the field of pain, enable them to know that when one published a report on, for example, sprain injuries, the same disorders would be at least broadly similar to that which a different person would call by the same name, even internationally. A few types of acute pain were admitted to the classification for comparative purposes and because they frequently gave rise to chronic pain (e.g., postherpetic neuralgia). The Taxonomy of Chronic Pain, which was produced by the Task Force on Taxonomy of the International Association for the Study of Pain (IASP), known as the Sub-Committee, thus attempted to cover the major causes of chronic pain and some illustrative examples of acute pain. That being easily decided, the most difficult problem was to determine the best approach to organizing pain syndromes. It is obviously theoretically possible to arrange pain syndromes by region of the body or by organ system (e.g., cardiac pains, musculoskeletal pains, and pain due to neurologic illness, and so forth). Alternatively, one might arrange pain syndromes by their purported causes (e.g., postherpetic neuralgia, which it is immediately obvious also could come under the Neurologic rubric.

THE IASP CLASSIFICATION The Task Force on Taxonomy of the IASP decided, after some vigorous discussion, that it would be unwise to classify on the basis of etiology. Etiology is the topic that most concerns practitioners because we think that it leads us to make the most useful diagnoses. Diagnosis is seen as the avenue to correct treatment. To give up the idea that we can classify by etiology first means recognizing that the empirical methods of medicine are not yet good enough to provide etiologic classification, at least in the field of pain. An attempt was made by a group at the National Institutes for Dental Research in the late 1970s to classify orofacial pain by etiology. The IASP subcommittee concluded that, although the classification was detailed and well worked out, there was insufficient agreement on etiology to make that approach satisfactory for pain as a whole. An impressive classification had actually been developed by the late Dr. John Bonica in his classic work, The Management of Pain.10 Bonica had started with regions of the body and turned to diagnosis only after he had arranged the subject by region. The committee was unanimous that the best way to start was by

3

region of the body because this was the least controversial and should be the first basis for classification. The next step was to look at whether systems, patterns of pain, or etiology should come next. Etiology again lost out. The system involved seemed to be the next obvious agreed basis for arranging observations on pain. Not only was etiology displaced from the first position and the second position, but there was also agreement that it should be left to the end to work out what we could best do about it. Accordingly, the next part of the classification system focused upon the temporal characteristics of pain and the pattern of occurrence for which coding was provided. Everyone was comfortable after that in grading the pain according to its intensity, and so, the first four Axes of a pain classification had emerged as regions, systems, temporal characteristics, and intensity combined with duration since onset. Finally, room was left for etiology, and that was classified as genetic or congenital: trauma; surgery; infective or parasitic; inflammatory but with no known infective agent and immune reactions; neoplasm; toxic; metabolic; degenerative; dysfunctional (including psychophysiologic); unknown or other; and lastly, psychological origins. Each of these codings acquired a number from 0 to 9 (Box 1—5). As an example of how the coding system works, consider common migraine. Migraine was coded 4 in the third Axis on the basis the pattern of occurrence being one of recurring irregularly. A period is inserted for convenience of citing extra numbers. Axis IV reflects the patient’s statement of intensity and time since the onset of pain, so that a mild pain present for 1 month or less was coded at.1, and a severe pain present for more than 6 months was coded at.9. Because this criterion can vary from case to case within the same diagnostic category, the letter X was placed to reflect the fourth Axis and to signify that each case would have its features determined on the occasion of coding and not arbitrarily beforehand. Code 7 concerning Migraine was a statement indicating modesty about knowledge of the exact origins of the condition. Thus, the initially constructed code for Common Migraine ran 004.X7. However, Classical Migraine also satisfies these criteria, and therefore, Classical Migraine was coded as 004.X7a and Common Migraine was coded as 004.X7b. A code of 0 is given for the head, face, and mouth; 0 for the nervous system, whether central, peripheral autonomi,c or special senses. As indicated, the X code symbol was used to permit the clinician to determine the features of that particular case in accordance with whether the intensity was mild, medium, or severe, and the duration was less than 1 month, between 1 month and 6 months, or more than 6 months. Thus, mild intensity of more than 6 months was rated as 3, medium intensity of more than 6 months was rated as 6, severe intensity equal to or more than 1 month but less than 6 months was rated at 8, and so on. Lastly as indicated, codes were given for etiology. Despite using five places organized at a default sequence of XXX.XX which in the case of common migraine, as just discussed, was shown as 004.X7b, a number of classifications could theoretically use these additional codes. In order to discriminate between conditions occupying the same five Axis locations, additional letters were required, namely a, b, c, and d, so that Classical and Common Migraine were coded as 0004.X7a and 004.X7b, respectively.

Box 1—5 IASP CLASSIFICATION I. II. III. IV. V.

Site System Pattern of Pain Intensity and Duration of Pain Etiology

IASP, International Association for the Study of Pain.8

4

Chapter 2  PATHOPHYSIOLOGY OF PAIN

Box 1—6 USES OF CLASSIFICATION SYSTEMS Communication Uniform standards of diagnosis Statistical Service delivery Financial Billing and planning

This system of coding by special characteristics is intended to allow comparisons between groups of cases. To the best of my knowledge, it has not been used a lot in clinical practice or in research investigations. However, a number of the diagnostic categories have been popular, clinicians frequently referring to the descriptions and characteristics provided for them. This particularly applies to fibromyalgia and complex regional pain syndrome, conditions in which there was more doubt about the traditional appreciation of the disorder. The section on Back Pain is also used by some. As well, occasional rare syndromes that appeared in the classification were conveniently identified through it by members of the IASP who were able to refer to relevant sections of the classification in order to assist a diagnosis. This was noted, for example, with the fairly rare syndrome of painful legs and moving toes, which sometimes also involves the arms and which is due to dorsal ganglion or spinal cord damage. This is a condition that was on occasion previously treated as ‘‘hysteria.’’

THE USES OF CLASSIFICATION The uses of classification are thus essentially pragmatic (Box 1—6). It is important to understand that issues as to what a ‘‘real illness’’ is or what constitutes ‘‘a genuine syndrome’’ are not easily solved and should not get in the way of the diagnosis and treatment of patients.

Chapter 2

PATHOPHYSIOLOGY OF PAIN Jun-Ming Zhang and Mark L. Baccei

Rather, it is necessary to have a structured method of characterizing syndromes, whether or not this describes their supposed true essence or is in accordance with particular claims about etiology or significance. Given the structured method, we can proceed to identify the subordinate phenomena that may lead to a more refined diagnosis. Even when there is a refined diagnosis, it still may not be something that can be called an absolute truth but rather a step on the way to improved management, which is what clinical medicine is actually about. Such a modest aim nevertheless does not inhibit clinical description from proceeding to more fundamental analyses by interested scientists who may or may not be the clinicians.

REFERENCES 1. Merskey H. Development of a universal language of pain syndromes. In Bonica JJ (ed): Advances in Pain Research and Therapy, Vol 5. New York: Raven, 1983; pp 37—52. 2. World Health Organization. International Classification of Diseases and Related Health Problems, 10th rev. (ICD-10). Geneva: WHO, 1992. 3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV). Washington, DC: APA Press, 2000. 4. World Health Organization: International Classification of Diseases and Related Health Problems, 9th rev. (ICD-9). Geneva: WHO, 1978. 5. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 3rd ed. (DSM-III). Washington, DC: APA Press, 1980. 6. Capildeo R, Haberman S, Rose FC. New classification of stroke. Preliminary communication. Br Med J 1977;2:1578—1580. 7. Lamberts H, Wood M. International Classification of Primary Care. Oxford: Oxford University Press, 1989. (Reprinted with corrections, 1989.) 8. Merskey H (ed): Classification of chronic pain: descriptions of chronic pain syndromes and definitions of pain terms. Monograph for the Sub-Committee on Taxonomy, International Association for the Study of Pain. Pain (suppl 3). Amsterdam: Elsevier Science, 1986. 9. Merskey H, Bogduk N (eds): Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms, 2nd ed. Seattle: IASP Press, 1994. 10. Bonica JJ. The Management of Pain. Philadelphia: Lippincott, 1953.

severe tissue damage, chronic and/or neuropathic pain is persistent and maladaptive.

CLASSIFICATIONOF PAIN Pain involves sensory, emotional, and cognitive components. Although it may be classified in many ways, pain can often be categorized as nociceptive, neuropathic, mixed, or idiopathic pain.

Nociceptive Pain

INTRODUCTION Pain is defined as ‘‘an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.’’ Under normal physiologic conditions, pain is elicited by the activation of specific nociceptors (nociceptive pain). However, it may also result from a lesion or dysfunction of peripheral afferent fibers or the central nervous system (CNS) itself (neuropathic pain). Although acute nociceptive pain serves as a warning signal regarding possible

Pain is termed nociceptive when the clinical evaluation suggests that it is sustained primarily by the nociceptive system. Nociceptive pain is pain that is proportionate to the degree of actual tissue damage. A more severe injury results in a pain that is perceived to be greater than that caused by a less severe injury. Such pain serves a protective function. Sensing a noxious stimulus, a person behaves in certain ways to reduce the injury and promote healing (e.g., pulling his or her finger away from a hot object). This ‘‘good’’ pain serves a positive function. Examples of nociceptive pain include acute burns, bone fracture, and other somatic and visceral pains.

4

Chapter 2  PATHOPHYSIOLOGY OF PAIN

Box 1—6 USES OF CLASSIFICATION SYSTEMS Communication Uniform standards of diagnosis Statistical Service delivery Financial Billing and planning

This system of coding by special characteristics is intended to allow comparisons between groups of cases. To the best of my knowledge, it has not been used a lot in clinical practice or in research investigations. However, a number of the diagnostic categories have been popular, clinicians frequently referring to the descriptions and characteristics provided for them. This particularly applies to fibromyalgia and complex regional pain syndrome, conditions in which there was more doubt about the traditional appreciation of the disorder. The section on Back Pain is also used by some. As well, occasional rare syndromes that appeared in the classification were conveniently identified through it by members of the IASP who were able to refer to relevant sections of the classification in order to assist a diagnosis. This was noted, for example, with the fairly rare syndrome of painful legs and moving toes, which sometimes also involves the arms and which is due to dorsal ganglion or spinal cord damage. This is a condition that was on occasion previously treated as ‘‘hysteria.’’

THE USES OF CLASSIFICATION The uses of classification are thus essentially pragmatic (Box 1—6). It is important to understand that issues as to what a ‘‘real illness’’ is or what constitutes ‘‘a genuine syndrome’’ are not easily solved and should not get in the way of the diagnosis and treatment of patients.

Chapter 2

PATHOPHYSIOLOGY OF PAIN Jun-Ming Zhang and Mark L. Baccei

Rather, it is necessary to have a structured method of characterizing syndromes, whether or not this describes their supposed true essence or is in accordance with particular claims about etiology or significance. Given the structured method, we can proceed to identify the subordinate phenomena that may lead to a more refined diagnosis. Even when there is a refined diagnosis, it still may not be something that can be called an absolute truth but rather a step on the way to improved management, which is what clinical medicine is actually about. Such a modest aim nevertheless does not inhibit clinical description from proceeding to more fundamental analyses by interested scientists who may or may not be the clinicians.

REFERENCES 1. Merskey H. Development of a universal language of pain syndromes. In Bonica JJ (ed): Advances in Pain Research and Therapy, Vol 5. New York: Raven, 1983; pp 37—52. 2. World Health Organization. International Classification of Diseases and Related Health Problems, 10th rev. (ICD-10). Geneva: WHO, 1992. 3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV). Washington, DC: APA Press, 2000. 4. World Health Organization: International Classification of Diseases and Related Health Problems, 9th rev. (ICD-9). Geneva: WHO, 1978. 5. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 3rd ed. (DSM-III). Washington, DC: APA Press, 1980. 6. Capildeo R, Haberman S, Rose FC. New classification of stroke. Preliminary communication. Br Med J 1977;2:1578—1580. 7. Lamberts H, Wood M. International Classification of Primary Care. Oxford: Oxford University Press, 1989. (Reprinted with corrections, 1989.) 8. Merskey H (ed): Classification of chronic pain: descriptions of chronic pain syndromes and definitions of pain terms. Monograph for the Sub-Committee on Taxonomy, International Association for the Study of Pain. Pain (suppl 3). Amsterdam: Elsevier Science, 1986. 9. Merskey H, Bogduk N (eds): Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms, 2nd ed. Seattle: IASP Press, 1994. 10. Bonica JJ. The Management of Pain. Philadelphia: Lippincott, 1953.

severe tissue damage, chronic and/or neuropathic pain is persistent and maladaptive.

CLASSIFICATIONOF PAIN Pain involves sensory, emotional, and cognitive components. Although it may be classified in many ways, pain can often be categorized as nociceptive, neuropathic, mixed, or idiopathic pain.

Nociceptive Pain

INTRODUCTION Pain is defined as ‘‘an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.’’ Under normal physiologic conditions, pain is elicited by the activation of specific nociceptors (nociceptive pain). However, it may also result from a lesion or dysfunction of peripheral afferent fibers or the central nervous system (CNS) itself (neuropathic pain). Although acute nociceptive pain serves as a warning signal regarding possible

Pain is termed nociceptive when the clinical evaluation suggests that it is sustained primarily by the nociceptive system. Nociceptive pain is pain that is proportionate to the degree of actual tissue damage. A more severe injury results in a pain that is perceived to be greater than that caused by a less severe injury. Such pain serves a protective function. Sensing a noxious stimulus, a person behaves in certain ways to reduce the injury and promote healing (e.g., pulling his or her finger away from a hot object). This ‘‘good’’ pain serves a positive function. Examples of nociceptive pain include acute burns, bone fracture, and other somatic and visceral pains.

I PAIN BACKGROUND

Table 2—1. Comparison of ‘‘Good’’ Pain and ‘‘Bad’’ Pain Nociceptive Pain

Neuropathic Pain

 Warns of acute or potential damage  Protective function  Can be differentiated from touch  Transient  Well localized  C- and Ad-fiber—mediated  Increased activity, wide dynamic range neurons  Opioid sensitive

        

Pain caused by nerve injury Spontaneous, evoked activity Develops in days or months Associated with inflammation, neuropathy Associated with peripheral and central sensitization Pain outlasts duration of the stimulus Pain sensed in noninjured areas Elicited by Ab (?) as well as C and Ad fibers Opioid insensitive

Neuropathic Pain Unlike nociceptive pain, neuropathic pain occurs through peripheral nervous system (PNS) changes, such as neuroma formation, generation of ectopic discharge from the injured axons or the somata of the dorsal root ganglion (DRG) neurons, or through CNS changes that can lead to enhanced excitability of central pain networks (termed central sensitization) in patients with a prolonged exposure to noxious stimuli or nerve injury. It is disproportionate to the degree of tissue damage and can also persist in the absence of continued noxious stimulation (i.e., the pathophysiologic changes become independent of the inciting event). Thus, neuropathic pain serves no protective function and provides no benefit to the overall health of the person. The underlying causes of neuropathic pain are discussed in a later section (Table 2—1).

Mixed Pain In a given patient, components of continued nociceptive pain may coexist with a component of neuropathic pain. Patients with persistent back and leg pain after lumbar spine surgery (failed low back surgery syndrome) represent a common example. Some patients with complex regional pain syndrome (CRPS; reflex sympathetic dystrophy or causalgia) may develop painful complications that are nociceptive (e.g., joint ankylosis, myofascial pain) and that coexist with the underlying neuropathic pain.

Idiopathic Pain Idiopathic pain may be defined as pain that persists without any identifiable organic lesions or that is disproportionate to the degree of tissue damage.

PERIPHERAL AND CENTRAL MECHANISMS OF NOCICEPTIVE PAIN Understanding the pathophysiology of abnormal or nonphysiologic pain requires basic knowledge of the pathways mediating the perception of somatosensory stimuli under normal conditions. The first step in this process involves the transduction of the sensory stimulus (which can be mechanical, thermal, or chemical) into an electrical potential by first-order afferent neurons in the DRG located external to the spinal cord. These neurons express specialized receptors at their distal ends that respond to specific types of external (e.g., the skin) or internal (e.g., visceral organs such as the

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liver) sensory stimuli by opening ion channels in their membrane. This results in a depolarization of the sensory neuron, which can trigger the generation of an action potential that propagates to the dorsal horn of the spinal cord. It is now clear that the size of the sensory neuron can provide significant clues as to its function. Large-diameter DRG neurons possess large myelinated axons with rapid conduction velocities in the Ab range (>30 m/sec) and generally transmit information about innocuous mechanosensation (e.g., touch, vibration). Noxious stimulation is transmitted via small-diameter DRG neurons that give rise to either thin myelinated Ad fibers (which conduct impulses at 2—30 m/sec) or small unmyelinated C-fibers (with conduction velocities of < 2 m/sec). The signals carried by all three types of sensory afferents are integrated by the synaptic network within the spinal dorsal horn, which consists of both local circuit interneurons and second-order projection neurons that transmit impulses from the spinal cord to higher brain areas (including the thalamus) predominantly via the spinothalamic tract (STT). The output of these STT neurons depends on the net balance between inhibitory and facilitatory mechanisms within the dorsal horn. For example, repetitive stimulation of tactile Ab mechanoreceptive inputs can activate spinal interneurons and inhibit the response of STT neurons by decreasing the amount of glutamate released from the presynaptic terminals of nociceptive C-fibers in the dorsal horn. This is believed to underlie the effectiveness of both transcutaneous electrical nerve stimulation (TENS) and dorsal column stimulation as clinically therapeutic interventions for patients with pain. In contrast, responses of STT neurons to nociceptive stimuli can be facilitated if they have been subjected to long-term excessive input from C-fiber nociceptive neurons (sensitization), which can be caused by chronic inflammation or other chronic noxious stimulation of C-fibers. The excitability of STT neurons is also modulated by descending projections to the spinal cord from higher areas of the CNS (such as the rostral medulla), which can cause both facilitation and inhibition under different conditions. The activation of third-order neurons in the thalamus by STT inputs allows the transmission of the noxious information to the cerebral cortex, where the perception of pain is generated. Evidence exists that numerous supraspinal control areas—including the reticular formation, midbrain, thalamus, hypothalamus, the limbic system of the amygdala and the cingulate cortex, basal ganglia, and cerebral cortex—modulate the sensation of pain (Table 2—2).

PERIPHERAL AND CENTRAL MECHANISMS OF PATHOLOGIC PAIN Pathologic pain occurs when prolonged nociception continues to drive pain that outlasts its physiologic usefulness (as a signal to avoid harm and promote healing) and when pain-processing mechanisms themselves function abnormally. The latter occurs in neuropathic pain syndromes, such as postherpetic neuralgia and central pain due to stroke (Table 2—3). The mechanisms underlying neuropathic pain involve both peripheral and central components. Although a comprehensive summary of the changes that occur in the nervous system after peripheral nerve injury is outside the scope of the present chapter, we highlight some key mechanisms later.

Peripheral Mechanisms Altered Expression of Ion Channels in Axotomized Sensory Neurons Spontaneous activity originating from the somata is rarely observed in DRG cells with normal, uninjured axons.1 However, this is a common phenomenon after the peripheral axons are injured and reflects underlying alterations in the complement of voltage-gated

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Chapter 2  PATHOPHYSIOLOGY OF PAIN

Table 2—2. Spinocerebral Ascending Pathways Spinothalamic pathway

Crosses the midline and ascends on the opposite side of the spinal cord to the ventral posterolateral nucleus of the thalamus. This nucleus is subdivided for specific areas of the body, and each area projects to its own section of the primary sensory cortex—a thin band of cortex in the parietal lobe just posterior to the central sulcus. This discriminative pathway transmits to consciousness precise information about the location of pain. Spinoreticular pathway Ascends on both sides of the spinal cord to the intralaminar nuclei of both the right and the left thalamus. From there, the next neuron in the chain takes the information to many areas of the brain—e.g., the anterior part of the cingulate gyrus (emotion), the amygdala (memory and emotion), and the hypothalamus (emotion and the vascular response to emotion). Dorsal column pathway Transmits visceral nociception (as well as somatic touch and position sense) to the thalamus. Spinomesencephalic Travels with the spinotectal tract to the periaqueductal gray matter and superior colliculus of the midbrain. This tract may be the same as, or related to, the pathway traveling to the parabrachial nucleus in the brainstem—which in turn projects to the amygdala, hypothalamus, and other limbic system structures in the forebrain. Spinohypothalamic A recently described route; does not synapse in the reticular formation. It carries information of emotional pathway significance from the skin, lips, sex organs, gastrointestinal tract, intracranial blood vessels, tongue, and cornea directly to the hypothalamus. ion channels expressed by DRG neurons.2-10 There is now compelling evidence that the expression of sodium channel subtypes (e.g., Nav1.3, Nav1.7, Nav1.8, and Nav1.9) is dramatically altered by nerve injury and may account for the increased excitability of neuropathic DRG neurons in models of chronic pain.11-13 The accumulation of Nav1.3 channels in the injured DRG somata and neuroma may play a significant role in the development and maintenance of ectopic discharges. Meanwhile, the loss of sodium currents mediated by the Nav1.8, and Nav1.9 subtypes in injured DRG neurons leads to a hyperpolarization of the resting membrane potential. Paradoxically, this may contribute to the enhanced excitability of these neurons by relieving the steady-state inactivation of other Na+ channel subtypes (such as Nav1.3), thus increasing the size of overall Na+ influx and the likelihood of action potential discharge. A reduction in the density of potassium channels (or an alteration in their functional properties) after axotomy may also increase the excitability of sensory neurons. Indeed, it has been shown that K+ conductance is decreased significantly in nerveinjured DRG cells. This is also supported by observations that mexiletine, which can lead to an attenuation of neuropathic pain, also facilitates K+ currents in DRG neurons. Previous work has also demonstrated that peripheral nerve injury causes alterations in the expression of voltage-sensitive Ca2+ channels in DRG neurons. Because these channels (particularly N-type)

Table 2—3. Clinical Causes of Neuropathic Pain Nerve injury

Dorsal root ganglion

Spinal cord, brainstem, thalamus, cortex

 Nerve compression (entrapment neuropathies, tumors)  Nerve crush, stretching, incomplete transection (trauma)  Neuropathy (diabetes, irradiation, ischemia, toxic)  Neuroma (amputation, nerve transection)  Compression (disk, tumor, scar tissue)  Root avulsion  Inflammation (postherpetic neuralgia)  Spinal cord, brainstem, thalamus, cortex  Infarction, tumors, trauma

are involved in controlling the release of neurotransmitters from the terminals of sensory, central, and sympathetic neurons in the spinal cord, these alterations have significant implications for nociceptive processing under pathologic conditions. In fact, the ability of anticonvulsants (carbemazepine and gabapentin) to reduce mechanical allodynia (both in the clinic and in experimental models of neuropathic pain) may involve, among other mechanisms, an interaction with Ca2+ channels localized on the injured DRG neurons.

Sympathetic Excitation of Injured Sensory Neurons CRPS II (causalgia) is a classic example of sympathetically maintained pain (SMP) associated with PNS injury. It is characterized by a distal burning sensation that is exacerbated by cold and gentle mechanical stimulation.14 Clinically, SMP appears to be a significant component of various painful conditions such as CRPS, phantom pain, neuralgias, and herpes zoster. Clinical observations and animal studies have shown that coupling of the activated sympathetic nervous system and the sensitized sensory nervous system is important for development of SMP. Under normal physiologic conditions, the afferent sensory nervous system and the efferent sympathetic nervous system are anatomically separated and functionally independent of each other. There is evidence, however, that an abnormally enhanced communication between these two systems may occur under pathologic conditions. For example, sympathetic stimulation may excite sensory neurons in animals with inflamed peripheral tissue or after peripheral nerve injury. Chemical or surgical sympathectomy may relieve allodynia and hyperalgesia and improve chronic pain behavior. These observations suggest that increased activity of the sympathetic nervous system may be involved in the sensitization of sensory neurons toward the development of neuropathic pain. Sympathetic-sensory coupling may occur either centrally or peripherally. The DRG has been identified as an important site for peripheral sympathetic-sensory coupling. Within the normal DRG, sympathetic axons are only found accompanying blood vessels. After peripheral nerve injury, sympathetic efferent fibers extensively sprout into both DRG and spinal nerves. Sprouting fibers sometime form distinctive basket-like webs (sympathetic baskets) or rings wrapping around medium and large DRG neurons.15 Although it is currently unclear what triggers the sprouting of sympathetic nerve fibers in the ganglia, recent studies16 suggest that sympathetic sprouting is associated with the inflammatory responses within the axotomized DRG and may be mediated by abnormal spontaneous activity of the DRG neurons.

I PAIN BACKGROUND

Inflammatory Cytokines and Chemokines Proinflammatory cytokines such as tumor necrosis factor-a (TNF-a), interleukin (IL)-1 and IL-6, and chemokines (e.g., monocyte chemoattractant protein-1 [MCP-1]) may be produced in and by peripheral nerve tissue during physiologic and pathologic processes by resident and recruited macrophages, mast cells, endothelial cells, Schwann cells, and neurons. After PNS injury, macrophages and Schwann cells that gather around the nerve injury site secrete cytokines and specific growth factors required for nerve regeneration. The cytokines may be synthesized in the DRG or may be transported in a retrograde fashion from the periphery, via axonal or nonaxonal mechanisms, to the DRG and dorsal horn of the spinal cord, where they can have profound effects on neuronal activity and pain sensitivity.

Spinal Mechanisms: Central Sensitization After peripheral nerve injury, strong activation of nociceptive afferents, particularly C-fiber nociceptors, may lead to sensitization of dorsal horn neurons (i.e., ‘‘central sensitization’’).17 This can result in the following alterations in the physiologic properties of dorsal horn neurons: (1) increased size of the receptive field (i.e., the area of the body that, when stimulated, evokes action potential firing in the cell); (2) lower thresholds; neurons begin to fire in response to low-threshold afferent inputs that were previously too weak to evoke action potential discharge; (3) increased magnitude of action potential discharge in response to nociceptive inputs; and (4) increased spontaneous impulse activity. These alterations are believed to significantly contribute to the hyperalgesia, allodynia, and spontaneous pain that result from peripheral nerve injury. As a result, the mechanisms underlying central sensitization have been intensely studied, and the most relevant findings are briefly summarized later.

Long-term Potentiation of Nociceptive Inputs in the Dorsal Horn The repetitive activation of high-threshold C-fibers (as might occur at the time of a peripheral nerve injury) can result in a prolonged increase in the strength of their synaptic connections with dorsal horn neurons. The result is that a given impulse traveling along the nociceptive fiber can produce a greater depolarization of the second-order neurons in the spinal cord. This may reflect the insertion of additional glutamate receptors at the postsynaptic site or by altering the function of receptors that already exist at the synapse. Importantly, in lamina I of the dorsal horn, this potentiation of synaptic efficacy occurs selectively on spinal projection neurons (i.e., the output cells of the dorsal horn). Thus, strong activation of nociceptive sensory afferents can lead to a greater synaptic drive onto spinal projection neurons and a subsequent facilitation of pain transmission from the spinal cord to the brain. Additional work has demonstrated that the activation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor is necessary to induce long-term potentiation (LTP) at nociceptive synapses in the superficial dorsal horn. Within lamina I of the spinal cord, the activation of the substance P receptor (NK1) is also required. Both of these receptors likely contribute to LTP by elevating the levels of intracellular calcium in the dorsal horn neuron and thus activating downstream signaling cascades involving protein kinases. Animal studies have confirmed that both NMDA and NK1 receptors are involved in the induction and maintenance of the central sensitization produced by high-threshold nociceptive afferent inputs at the behavioral level. Because central sensitization is likely to contribute to the postinjury pain hypersensitivity states in humans,18 these data have a bearing on the potential importance of NMDA and NK1 antagonists for preemptive analgesia and the treatment of established pain states. However, it

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should be noted that other types of receptors (e.g., metabotropic glutamate receptors, TrkB receptors) are also capable of inducing synaptic plasticity in the dorsal horn.

Loss of Central Inhibition Much attention has been given to the possibility that the hyperexcitability of spinal neurons after nerve injury reflects a loss of synaptic inhibition in the dorsal horn. This has emerged from previous experiments showing that the blockade of spinal g-aminobutyric acidAreceptor (GABAAR) and glycine receptor (GlyR) (the two major inhibitory neurotransmitter receptors in the spinal cord) mimics the signs of central sensitization. More recent studies have shown that such a reduction in inhibitory strength can indeed occur in the dorsal horn through a variety of mechanisms. For example, peripheral nerve injury induces a marked reduction in the amplitude of GABAAR-mediated synaptic currents in superficial dorsal horn neurons and a corresponding increase in the fraction of cells that receive no GABAergic input at all. This is accompanied by a reduction in the expression of the GAD65 enzyme, which is largely responsible for the synthesis of GABA in the dorsal horn. These changes are believed to result from the selective death of GABAergic interneurons in the region after nerve damage, but the mechanisms underlying this cell death are not yet clear. The inhibition of neuronal excitability that normally results from the activation of GABAAR and GlyR reflects the influx of Cl— across the cell membrane. The magnitude (and direction) of this flow depends on the relative concentration of Cl— inside versus outside the neuron. Recent work has shown that sciatic nerve injury leads to a decrease in the expression of the Cl— transporter KCC2 (which serves to pump Cl— out of the cell) in dorsal horn neurons and a subsequent build-up in the concentration of intracellular Cl—, thereby reducing the electrochemical force normally driving the Cl— ions into the cell. Thus, after nerve injury, less Cl— enters the cell through an open GABAAR (or GlyR), which translates into weaker synaptic inhibition. Under normal conditions, the production of pain from the activation of nociceptors with mechanical stimuli is inhibited in the spinal dorsal horn by the concurrent activation of Ab mechanoreceptive afferents. This occurs in large part through the activation of inhibitory spinal interneurons by Ab sensory fibers. However, given the previously discussed reductions in the efficacy of GABAergic and glycinergic transmission, this mechanism will be much less effective after peripheral nerve injury, allowing for greater firing in the STT output cells in the spinal cord. This likely contributes to the allodynia/hyperalgesia in patients with peripheral nerve damage.

Spinal Glial Activation There is now significant evidence showing that glial activation in the spinal cord appears to be important for both the initiation and the maintenance of pathologic pain. Astrocytes and microglia are activated by neuronal signals including substance P, glutamate, and fractalkine. Fractalkine is a chemotactic cytokine (chemokine) that is constitutively expressed in the nervous system where it is tethered to the extracellular membrane surface of primary afferent neurons in an inactive form via a mucin stalk. After nerve insult, the mucin stalk breaks, releasing fractalkine in an active state, which is then free to bind to the CX3C receptor-1 (CX3CR-1) on glia, resulting in glial activation. Activation of glia by these substances leads to the release of mediators that then may act on other glia and spinal neurons. These include proinflammatory cytokines (IL-1b), TNF-a, IL-6, adenosine triphosphate (ATP), nitric oxide, and excitatory amino acids released from microglia and astrocytes. These cytokines have been shown to be critical mediators of allodynia. Evidence also points to a role for spinal microglia in the weakening of GABAergic inhibition that is observed after nerve injury. Activation of microglia with ATP results in the release of brain-derived neurotrophic factor (BDNF) from these cells.

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Chapter 2  PATHOPHYSIOLOGY OF PAIN

The subsequent binding of BDNF to its receptor TrkB localized on dorsal horn neurons causes an increase in the intracellular Cl— concentration and a subsequent decrease in the efficacy of GABAergic inhibition, as described earlier. Importantly, blocking BDNF release from microglia prevented both the reduction in GABAergic strength and the development of mechanical hypersensitivity after nerve injury, suggesting that targeting the glia-neuron signaling pathway may prove to be an effective strategy for treating neuropathic pain.

Supraspinal Mechanisms: Pain Modulation Descending connections between higher brain centers and the spinal cord can either amplify or inhibit the transmission of painrelated signals. Mounting evidence suggests that these descending systems are involved in the maintenance of neuropathic pain. Injections of the local anesthetic lidocaine into the rostral ventromedial medulla (RVM) given 6 to 12 days after a nerve injury abolished the observed tactile and thermal hypersensitivity. A similar effect was seen if the dorsolateral funiculus, the main pathway from the RVM to the dorsal horn, was lesioned prior to the nerve injury. These effects suggest that peripheral nerve injury results in the strengthening of the descending facilitatory pathways from the RVM, producing an enhanced excitability of the dorsal horn and a subsequent increase in the sensitivity to pain The enhanced descending facilitation after nerve injury may reflect increased activation of ‘‘ON’’ cells in the RVM. As first described by Fields,19 this subtype of neuron in the RVM increases its rate of action potential firing immediately before the tail-flick in response to a heat stimulus and may increase the transmission of pain-related information to the brain. In contrast, a second group of neurons in the RVM (the ‘‘OFF’’ cells) reduce their spontaneous firing rate immediately prior to the rat’s moving its tail away from a noxious heat stimulus and is believed to inhibit the transmission of pain-related information to the brain. A better understanding of the interaction between the brainstem and the spinal cord after peripheral nerve injury will greatly aid efforts to treat neuropathic pain.

CONCLUSION Understanding the pathophysiology of pain requires knowledge of the underlying neuronal plasticity at the levels of the nociceptive neurons, spinal cord, and brain. Modulatory effects at the nociceptor, sympathetically mediated pain, central sensitization, and alterations in ascending/descending CNS pathways are all involved in the perception of pain as well as the related pain motivations and behaviors. Despite great advances in unraveling the complexities of the pathophysiology of pain, much remains to be discovered that will hopefully lead to better therapies.

REFERENCES 1. Wall PD, Devor M. Sensory afferent impulse originate from dorsal root ganglia as well as from the periphery in normal and nerve injury rats. Pain 1983;17:321—339. 2. Amir R, Kocsis JD, Devor M. Multiple interacting sites of ectopic spike electrogenesis in primary sensory neurons. J Neurosci 2005;25:2576—2585. 3. Burchiel KJ. Effects of electrical and mechanical stimulation on two foci of spontaneous activity which develop in primary afferent neurons after peripheral axotomy. Pain 1984;18:249—265. 4. Burchiel KJ. Spontaneous impulse generation in normal and denervated dorsal root ganglia: sensitivity to alpha-adrenergic stimulation and hypoxia. Exp Neurol 1984;85:257—272. 5. DeSantis M, Duckworth JW. Properties of primary afferent neurons from muscle which are spontaneously active after a lesion of their peripheral processes. Exp Neurol 1982;75:261—264.

6. Kajander KC, Wakisaka S, Bennett GJ. Spontaneous discharge originates in the dorsal root ganglion at the onset of a painful peripheral neuropathy in the rat. Neurosci Lett 1992;138:225—228. 7. Kirk EJ. Impulses in dorsal spinal nerve rootlets in cat and rabbit arising from dorsal root ganglia isolated from the periphery. J Comp Neurol 1970;139:307—320. 8. Song XJ, Hu SJ, Greenquist KW, et al. Mechanical and thermal hyperalgesia and ectopic neuronal discharge after chronic compression of dorsal root ganglia. J Neurophysiol 1999;82:3347—3358. 9. Xie Y, Zhang J-M, Petersen M, LaMotte RH. Functional changes in dorsal root ganglion cells after chronic nerve constriction in the rat. J Neurophysiol 1995;73:1811—1820. 10. Zhang J-M, Song XJ, LaMotte RH. Enhanced excitability of sensory neurons in rats with cutaneous hyperalgesia produced by chronic compression of the dorsal root ganglion. J Neurophysiol 1999;82:3359—3366. 11. Devor M, Govrin-Lippmann R, Angelides K. Na+ channel immunolocalization in peripheral mammalian axons and changes following nerve injury and neuroma formation. J Neurosci 1993;13:1976—1992. 12. Rizzo MA, Kocsis JD, Waxman SG. Selective loss of slow and enhancement of fast Na+ currents in cutaneous afferent dorsal root ganglion neurons following axotomy. Neurobiol Dis 1995;2:87—96. 13. Zhang J-M, Song XJ, LaMotte RH. An in vitro study of ectopic discharge generation and adrenergic sensitivity in the intact, nerve-injured rat dorsal root ganglion. Pain 1997;72:51—57. 14. Scadding JW. Complex regional pain syndrome. In Wall PD, Melzack R (eds.): Textbook of Pain. Edinburgh, New York: Churchill Livingstone, 1999; pp 835—849. 15. McLachlan EM, Jang W, Devor M, Michaelis M. Peripheral nerve injury triggers noradrenergic sprouting within dorsal root ganglia. Nature 1993;363:543—546. 16. Xie WR, Deng H, Li H, et al. Robust increase of cutaneous sensitivity cytokine production and sympathetic sprouting in rats with localized inflammatory irritation of the spinal ganglia. Neuroscience 2006;142:809—822. 17. Dubner R, Basbaum A. Spinal dorsal horn plasticity following tissue or nerve injury. In Wall PD, Melzack R (eds.): Textbook of Pain. Edinburgh: Churchill Livingstone, 1994; pp 225—241. 18. Woolf CJ, Salter MW. Plasticity and pain: role of the dorsal horn. In McMahon S, Koltzenburg M (eds.): The Textbook of Pain. London: Elsevier, 2005; pp 91—105. 19. Fields HL, Bry J, Hentall I, Zorman G. The activity of neurons in the rostral medulla of the rat during withdrawal from noxious heat. J Neurosci 1983;3:2545—2552.

SUGGESTED READINGS Dubner R, Basbaum A. Spinal dorsal horn plasticity following tissue or nerve injury. In Wall PD, Melzack R (eds): Textbook of Pain, 3rd ed. Edinburgh: Churchill Livingstone, 1994; pp 225—241. Fitzgerald M, Woolf CJ: Axon transport and sensory C fibre function. In Chahl LA, Szolcsanyi J, Lembeck F (eds): Antidromic Vasodilation and Neurogenic Inflammation, Budapest: Akademiai Kiado, 1984; pp 119—140. Galer BS, Dworkin RH. Pathophysiology of neuropathic pain. In Galer BS, Dworkin RH (eds): A Clinical Guide to Neuropathic Pain, Minneapolis, MN: Healthcare Information Programs, a division of McGraw-Hill Healthcare Information, 2000; pp 33—36. Hirshberg RM, Al-Chaer ED, Lawand NB, et al: Is there a pathway in the posterior funiculus that signals visceral pain? Pain 1996;67:291—305. McCleskey EW, Gold MS. Ion channels of nociception. Annu Rev Physiol 1999;61:835—856. Merskey HM, Bogduk N. Classification of Chronic Pain, 2nd ed. Seattle, IASP Press, 1994; p 211. Roberts WJ: A hypothesis on the physiological basis for causalgia and related pains. Pain 1986;24:297—311. Watkins LR, Maier SF: Immune regulation of central nervous system functions: from sickness responses to pathological pain, J Intern Med 2005;257:139—155. Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science 2000;288:1765—1769. Zhang J-M, Li H, Munir MA. Decreasing sprouting of noradrenergic sympathetic fibers in pathologic sensory ganglia: new mechanism and approach for treating neuropathic pain using local anesthetics. Pain 2004;109:143—149.

II ASSESSMENT OF PAIN AND ITS TREATMENT

Chapter 3

NEUROPATHIC PAIN: IS THE EMPEROR WEARING CLOTHES? Steven H. Horowitz

INTRODUCTION Current concepts of acute and chronic pain disorders distinguish ‘‘nociceptive,’’ ‘‘inflammatory,’’ ‘‘functional,’’ and ‘‘neuropathic’’ pains.1 Nociceptive pain is the most common pain experienced when pain receptors (nociceptors) are activated, as in tissue injury. Inflammatory pain also involves nociceptor activation as a consequence of inflammation. Transduction, conduction, and transmission of nociceptor activity to conscious awareness involves peripheral and central nervous system pain pathways that, when intact, function in a protective and adaptive manner.1 Damage to, or dysfunction of, these pain (somatosensory) pathways, peripherally or centrally, can result in a different, less frequent, but nevertheless important pain picture—that of neuropathic pain. Neuropathic pain confers no functional benefit and may be considered a ‘‘maladaptive’’ response of the nervous system to the primary pathology.1 After earlier periods of debate and uncertainty, the International Association for the Study of Pain (IASP), in 1986 and then in 1994, sought to codify the concept of neuropathic pain as ‘‘pain initiated or caused by a primary lesion or dysfunction of the nervous system.’’2 Spirited attacks arose thereafter and have continued unabated, mostly over the terms ‘‘lesion’’ and ‘‘dysfunction.’’ The definition has been considered narrow if the pain relates to a lesion and broad if it relates to dysfunction.3 Either way, it presupposes a demonstrable abnormality exclusive to the nervous system; not the result of ongoing tissue injury elsewhere.4 It is the word ‘‘demonstrable’’ that is operative in this chapter. The definition also presupposes underlying pathophysiologic mechanisms affecting somatosensory components that are responsible for this special type of pain and are common to multiple nervous system disorders. It further assumes, given the limitations of human experimentation, that animal models are reasonable correlates of the human pain condition and pain mechanisms

discovered therein have clinical relevance (with exceptions).5—7 Such mechanisms include spontaneous and ectopic afferent discharges, alterations in ion channel expression, peripheral collateral sprouting of afferent neurons, sprouting of sympathetic neurons into dorsal root ganglia, nociceptor sensitization, recruitment of silent nociceptors, dorsal horn deafferentation, central sensitization with changes in receptive field properties, decreased descending inhibition, and cerebral cortical reorganization, among others.1,5—10 The disorders associated with neuropathic pain include polyneuropathies such as those secondary to diabetes mellitus, alcoholism, and amyloidosis; idiopathic small fiber neuropathy; hereditary neuropathies; mononeuropathies, or neuronopathies such as trigeminal, glossopharyngeal, and postherpetic neuralgias; entrapment neuropathies; and traumatic nerve injuries producing complex regional pain syndrome (CRPS) type II. CRPS type I is also considered a neuropathic pain disorder, although evidence for nerve damage and/or dysfunction is more controversial. Neuropathic pain can occur in central nervous system conditions, especially spinal cord injury, multiple sclerosis, and cerebrovascular lesions involving the brainstem and thalamus. In reality, the diagnosis of neuropathic pain is often problematic. Clinically, a distinction between nociceptive, inflammatory, and neuropathic pains is not precise, and conditions such as diabetes mellitus, cancer, and neurologic diseases with dystonia or spasticity can produce mixed pain pictures suggestive of multiple pathophysiologic mechanisms.8 As with other pains, the perception of neuropathic pain is purely subjective, not easily described nor directly measured. Also, pain pathway responses to damage are not static, but dynamic; signs and symptoms change with pathway activation and responsiveness and with chronicity. Further, the multiplicity of disorders that have neuropathic pain as a component of their clinical presentations makes a single underlying pain mechanism unlikely. More than one type of pain, and therefore, very likely more than one mechanism, may occur in a single patient, and the same symptoms can be caused by disparate mechanisms.8—10 For these and other reasons, including the failure of etiology-based or anatomy-based classifications to be therapeutically helpful, a mechanistic approach to neuropathic pain management is currently advocated.1 Ideally, specific mechanisms or combinations of mechanisms would relate to specific signs and symptoms (specific somatosensory phenotypes) and, ultimately, specific therapies.11 Unfortunately, no objective methods of diagnosing underlying pain mechanisms exist at present.12 Should such methods be developed, diseases-based symptom palliation strategies can be supplemented with ‘‘targeted’’ mechanism-specific pharmacologic management.13 9

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Chapter 3  NEUROPATHIC PAIN: IS THE EMPEROR WEARING CLOTHES?

PATIENT HISTORYAND SYMPTOMS Despite these complexities, there are several features to the clinical presentation of neuropathic pain that support its diagnosis and should be sought during history taking. In the case of mononeuropathies secondary to trauma, the severity of the pain often exceeds the severity of the inciting injury and the pain extends past the healing period. CRPS can follow minor skin or joint trauma, bone fractures, or injections. The pain is stimulus-independent and described as ‘‘burning,’’ ‘‘lancinating,’’ ‘‘electric shock—like,’’ ‘‘jabbing,’’ and/or ‘‘cramping’’; it is often accompanied by pinsand-needles sensations and sometimes by intractable itching (positive symptoms). These symptoms do not adhere to specific peripheral nerve distributions and often begin and remain most pronounced distally. The pain may be worse at night when activity ceases and/or during cold, damp weather, and it is exacerbated by movement of the affected limb. Multiple types of pain (constant pain with paroxysms and stimulus-evoked pains) can be experienced simultaneously. It is useful to separate stimulus-independent and stimulus-evoked pains to differentiate ongoing from provoked activities.6,9 Spread of symptoms outside the initial site of injury is common; in the case of unilateral pain, there may be spread to homologous sites in the opposite limb (mirror pain). Positive and negative (numbness, loss of sensation) symptoms can occur concurrently, sometimes accompanied by autonomic symptoms. Spontaneous pain, often without complaints of sensory loss, is a feature of the cranial mononeuralgias—trigeminal, glossopharyngeal, and postherpetic. Of course, location, intensity, and duration of pain are extremely important. In generalized polyneuropathies, rapid progression solely affecting sensory fibers is more likely to be painful, especially if inflammation and ischemia are prominent, as in the vasculitidies.8 In painful polyneuropathies, for example, idiopathic small fiber neuropathy and diabetic polyneuropathy with predominant small fiber (Ad- and C-fibers) damage, the burning, lancinating, jabbing pains with pins-and-needles sensations are nerve-length—dependent and bilaterally symmetrical, beginning distally in the feet. Over time, symptoms ascend more proximally in the lower extremities and may eventually affect the hands. This centripetal progression also occurs in intercostal nerve distributions, beginning anteriorly over the midline of the torso with later symmetrical lateral extension to the flanks. In patients with painful polyneuropathies, Otto and coworkers14 found that 88% complained of deep aching pain, 86% of paresthesias, 69% pain on pressure (as when walking), and 59% of paroxysmal pain. Autonomic complaints, for example, abnormal sweating, impotence, orthostatic hypotension, and gastrointestinal and bladder symptoms, are frequent.

CLINICAL EXAMINATION Among the more common and important clinical signs in neuropathic pain disorders are positive sensations—stimulus-evoked hypersensitivities such as allodynia to innocuous stimuli (e.g., light touch and cold) and hyperalgesia to noxious stimuli (e.g., pinprick). They occur focally in mononeuropathies and distally and symmetrically in polyneuropathies. Various forms of hyperalgesia include touch-evoked (or static) mechanical hyperalgesia to gentle pressure, pinprick hyperalgesia, bluntpressure hyperalgesia, and punctate hyperalgesia that increases with repetitive stimulation (windup-like pain).8,9 Paradoxically, these hypersensitivities can occur in areas in which the patient also complains of and demonstrates loss of sensation. Persistence of stimulus-evoked pain after stimulus withdrawal (aftersensation) can occur in the same anatomic distributions. As with symptoms, spread of allodynia and hyperalgesia outside the original site of injury is common and may extend to homologous sites in the opposite limb. Focal autonomic abnormalities after

nerve injury, especially of sweating, skin temperature, and skin color, in conjunction with the aforementioned pain, fulfill the diagnostic criteria of CRPS (discussed below). With chronicity, trophic changes of the skin and nails may develop, as well as motor signs such as weakness, tremor, and dystonia. Nerve percussion at points of compression, entrapment, or irritation can elicit pins-and-needles or ‘‘electrical’’ sensations (Tinel’s sign) in the territory of the nerve percussed. In small fiber neuropathies, deficits occur in thermal and pain perceptions and sometimes touch, whereas large fiber functions (e.g., muscle strength, reflexes, and perception of vibratory and proprioceptive stimuli) are normal. In combined large and smallfiber polyneuropathies, all these functions are compromised. Symmetrical distal autonomic dysfunction is often present but rarely severe. In patients with significant neuropathic pain, clinical neurologic deficits are demonstrable in many conditions, but not in others, for example, trigeminal and glossopharyngeal neuralgias and, more than occasionally, postherpetic neuralgia. Patients with small fiber mono- or polyneuropathies, despite describing typical neuropathic pain symptoms, may have normal examinations. There is the temptation to attribute their pain complaints to functional or psychogenic causes; however, at least from a logical perspective, that cannot always be the case, and if they are known to have a particular disease such as diabetes or suffered an injury in which nerve damage is likely, pain may be their only manifestation of neural dysfunction. In such situations and in cases in which further diagnostic information would be helpful, ancillary testing can be employed.

ANCILLARY TESTS Any consideration of the utility of ancillary tests to support the diagnosis of specific neuropathic pain mechanisms must take into account several factors: 1. Currently, available tests only evaluate nervous system structures and functions presumed germane to pain perception and transmission; from their results, the presence, extent, and mechanisms of neuropathic pain are, at best, inferred. This situation is similar to testing for diabetes mellitus using peripheral nerve, ophthalmologic, and renal studies without the availability of plasma glucose levels. 2. There is a spectrum of clinical and pathophysiologic manifestations of neural injury within each disorder, and chronic pain exists in only a small percentage of affected patients. For example, neuropathic pain develops in approximately 16% of patients with diabetes mellitus and a third of patients with diabetic neuropathy15; Postherpetic neuralgia, defined as chronic pain present 4 or more months after resolution of the acute herpes zoster (shingles) rash, occurs in 13% to 20% of shingles patients16; and after direct nerve injury during phlebotomy, persistent pain is rare, perhaps present after 1:1,500,000 procedures.17 3. The presence of pain is presumed to reflect damage to the small myelinated (Ad-) and unmyelinated (C-) nociceptive fibers within peripheral nerves.8 Because these fiber types also mediate certain clinical functions that are measurable (e.g., perception of noxious and temperature stimuli and autonomic activity), many tests have focused on demonstrating defects in these modalities to verify Ad- or C-fiber damage and invoke a basis for the pain.

Clinical Neurophysiology Neurophysiologic testing, principally nerve conduction studies and electromyography (EMG), are frequently employed in suspected

II ASSESSMENT OF PAIN AND ITS TREAT MENT

disorders of the peripheral nervous system. The usual techniques, with surface electrodes for nerve stimulation and evoked potential recording, measure activity of the largest and fastest conducting sensory and motor myelinated nerve fibers (Aab-). The most significant measured parameters are maximum nerve conduction velocity (NCV), for the segment of nerve between the stimulating and the recording electrodes, and amplitude and configuration of the resulting signals—the compound motor action potential (CMAP) evoked from motor fibers and the sensory nerve action potential (SNAP) evoked from sensory fibers. For central nervous system or proximal peripheral nerve disorders, somatosensory and magnetic evoked potential studies can be helpful. EMG is the needle examination of muscles and evaluates muscle and motor nerve fiber activities. Unfortunately, Ad- and C-fiber activities cannot be tested with these techniques. Slowing in maximum NCVs and/or loss of CMAP or SNAP amplitudes occur as a consequence of large fiber dysfunction. Abnormal EMG features such as acute and chronic denervation indicate involvement of large motor nerve fibers from the anterior horn cell distally. If present in a patient with neuropathic pain, these abnormalities can corroborate the clinical impression of peripheral nerve damage either individually or in general as in a polyneuropathy (e.g., diabetic or alcoholic neuropathy). However, painful polyneuropathies or focal nerve lesions with exclusive or predominant small fiber involvement can have normal NCVs and EMG. Nerve conduction studies may be of value in the serial investigation of patients who present with painful small fiber neuropathies, because there is indirect electrodiagnostic evidence of progression to large fiber involvement 5 to 10 years after the onset of pain. However, some patients had preserved large fiber functions over a 10-year period.18

Quantitative SensoryTesting Quantitative sensory testing (QST), used with increasing frequency especially in clinical therapeutic trials, measures sensory thresholds for pain, touch, vibration, and hot and cold temperature sensations. Commercially available devices range from hand-held tools to sophisticated computerized equipment with complicated testing algorithms, standardization of stimulation and recording procedures, and comparisons with age- and gender-matched control values. With this technology, specific fiber functions can be assessed: Ad-fibers with cold, cold-pain, and mechanical pain detection thresholds; C-fibers with heat and heat-pain detection thresholds; and large fiber (Aab-) functions with vibration detection thresholds and mechanical detection thresholds to von Frey hairs.11,19 Elevated sensory thresholds correlate with sensory loss; lowered thresholds occur in allodynia and hyperalgesia.19 Certain QST findings may relate to specific pathophysiologic mechanisms associated with neuropathic pain: heat hyperalgesia to peripheral sensitization and static mechanical hyperalgesia or dynamic mechanical allodynia to central sensitization.11 In generalized polyneuropathies, when all quantitative sensory thresholds are elevated, it is inferred that all fiber types are affected, whereas if a dissociation exists wherein vibration thresholds are normal but the other thresholds are elevated, a small fiber neuropathy is suspected. In asymptomatic patients, abnormal QST thresholds suggest subclinical nerve damage. The quantitation of an individual patient’s sensory perceptions, when compared with normative values, gives a clearer distinction between normal and abnormal responses and allows for analyses across patient and disease groups and for baseline standards in longitudinal studies. Further, certain patterns of QST data may have pathophysiologic significance. In two patients with postherpetic neuralgia and similar levels of chronic pain, the QST results suggested peripheral and central sensitization (heat hyperalgesia, mechanical hyperalgesia to pinprick and blunt stimuli, allodynia

11

to light touch) in one, and hyperactive deafferentation of spinal cord neurons (thermal and mechanical hypoesthesia without hyperalgesia or allodynia) in the other.11 The shortcomings of QST are: (1) It has never been used to differentiate between neuropathic and nonneuropathic pains, and QST abnormalities occur in nonneuropathic pain conditions.3 (2) Abnormal findings are not specific for peripheral nerve dysfunction; central nervous system disorders will also affect sensory thresholds. (3) Most significant, QST is a subjective psychophysical test entirely dependent upon patient motivation, alertness, and concentration. Patients can willingly perform poorly, and even when not doing so, there are large intra- and interindividual variations.

Autonomic FunctionTesting The evaluation of autonomic functions in patients with suspected neuropathic pain can be clinically useful because of anatomic similarities between pain and autonomic fibers outside the central nervous system and because disorders associated with neuropathic pain frequently have signs and symptoms of autonomic dysfunction (e.g., dry eyes or mouth, skin temperature and color changes, sweating abnormalities, orthostatic hypotension, heart rate responses to deep breathing, edema). The majority of autonomic tests study skin temperature and sudomotor, baroreceptor, vasomotor, and cardiovagal functions; they have been extensively reviewed.20,21 A semiquantitative composite autonomic symptoms score (CASS), composed of the results of sudomotor, cardiovagal, and adrenergic testing, has been devised.22 Pupillary, gastrointestinal, and sexual function tests are occasionally helpful. The value of autonomic testing in a generalized neuropathic pain disorder, small fiber neuropathy with burning feet, has been demonstrated in several studies of patients with normal or only mildly abnormal electrophysiologic (NCVs/EMG) findings.23,24 Autonomic abnormalities were seen in greater than 90% of patients, the most useful tests being the quantitative sudomotor axon reflex test (QSART), thermoregulatory sweat test, heart rate responses to deep breathing, Valsalva ratio, and surface skin temperature.23,24 However, in a recent study of patients with diabetic polyneuropathy, discordance was noted between efferent C-fiber responses in sudomotor tests (QSART and sweat imprint) and primary afferent (nociceptor) C-fiber axon-reflex flare responses. These findings indicate that these two C-fiber subclasses can be differentially damaged or may have different patterns of regeneration and reinnervation.25 Abnormal autonomic functions can also occur in painless peripheral neuropathies. The relationship between autonomic dysfunction and pain is more complicated in CRPS in which focal sudomotor and vasomotor abnormalities occurring at some point in time are essential for the diagnosis,2, pp 39—43 and sympathetic blockade has been a mainstay of diagnosis and therapy for decades. As would be expected, the vast majority of CRPS patients have autonomic abnormalities, particularly involving sweating and skin temperature.26 However, there are patients with identical focal pain, but no clinical evidence of autonomic dysfunction. These patients do not meet the current definition of CRPS and their condition has been termed ‘‘posttraumatic neuralgia.’’27 Their autonomic functions have not been well studied.

Skin Biopsy Since the mid 1990s, the histologic analysis of unmyelinated cutaneous axons has grown in importance in the diagnosis of peripheral nerve disorders, both generalized and focal, including those associated with neuropathic pain. When a skin punch biopsy is exposed to certain antibodies—most frequently, protein gene product (PGP) 9.5—epidermal fibers are labeled and can be

12

Chapter 3  NEUROPATHIC PAIN: IS THE EMPEROR WEARING CLOTHES?

visualized at light-microscopic magnifications.28,29 Intraepidermal nerve fiber (IENF) density and morphology (e.g., tortuosity, complex ramifications, clustering, and axon swellings) can be quantified28,29 and compared with control values.30 A reduced IENF density is seen in idiopathic small fiber neuropathies,31 diabetic neuropathy, and impaired glucose tolerance neuropathy,32 each of which is associated with neuropathic pain. In one study, skin biopsy findings were found to be a more sensitive measure than QSART or QST in diagnosing neuropathy in patients with burning feet and normal NCVs.33 Conversely, disorders with severe loss of pain sensation such as congenital insensitivity to pain with anhidrosis (hereditary sensory and autonomic neuropathy IV [HSAN IV]) and familial dysautonomia with sensory loss (Riley-Day syndrome [HSAN III]) also have severe loss of intraepidermal fibers, as does a predominantly large fiber neuropathy, Friedreich’s ataxia, in which pain is unusual.28,29 Thus, the loss of IENFs is not specific for the presence of neuropathic pain. A recent study suggests that the presence of large axonal swellings (>5 times the nerve fiber diameter) on an initial skin biopsy may predict progression of small fiber neuropathies, because this finding was associated with decreases in IENF densities on subsequent biopsies. Also, those patients with these large axon swellings were more likely to present with paresthesias (tingling or pins and needles) than with burning or ‘‘lightning’’ pains.34 Additional tests of potential diagnostic value in patients with neuropathic pain, particularly in focal pain syndromes such as CRPS, are bone scintigraphy, bone densitometry, and nerve or sympathetic ganglion blockade. Serum immunoelectrophoresis can be helpful in painful polyneuropathies associated with monoclonal gammopathies and acquired amyloid polyneuropathy. Specific serum antibody tests are valuable in painful neuropathies associated with neoplasia, celiac disease, and human immunodeficiency virus.35 Cruccu and associates3 also noted that nociceptive reflex testing, laser-evoked potentials, and functional neuroimaging may be helpful in assessing function in nociceptive pathways but are not widely used at this time. The latter two technologies may have great value in the future.

DISCUSSION Determining the causes of neuropathic pain is more than an epistemologic exercise. At its essence, it is a quest to identify mechanisms of dysfunction through which treatment strategies can be created to reduce, ameliorate, or eliminate symptomatology. To date, predictors of which patients will develop neuropathic pain or who will respond to specific therapies are lacking, and present therapies have been developed mainly through trial and error.36 Our current inability to make therapeutically meaningful decisions based on ancillary test data and defined mechanisms is illustrated by the following: 1. In assessing the response of patients with painful distal sensory neuropathies to the 5% lidocaine patch, no relationship could be established between treatment response and distal leg skin biopsy, QST, or sensory nerve conduction study results.36 From a mechanistic perspective, the hypothesis that the lidocaine patch would be most effective in patients with relatively intact epidermal innervation, whose neuropathic pain is presumed due to ‘‘irritable nociceptors,’’ and least effective in patients with few surviving epidermal nociceptors, presumably with ‘‘deafferentation pain,’’ was unproved.36 2. In Fabry’s disease, in which small fibers are exclusively affected,37 enzyme replacement therapy failed to influence IENF density, had mixed effects on cold and warm QST thresholds, and had beneficial effects on sudomotor findings.38,39 This occurred in the presence of clinical improvement as manifested in modest reductions in pain scores and in pain interference in daily life.39

3. In a study of IENF density in diabetic patients with and without bilateral symmetrical chronic neuropathic foot pain, ‘‘small fiber dropout does not always parallel large fiber function and in fact differs between people with or without pain depending upon the degree of sensory loss . . .. In individuals with little objective sign of neuropathy, abnormalities of small nerve fibers are more likely to play a central role in the genesis of pain. In those with severe objective signs of neuropathy, a role of small fiber dysfunction in causing pain is still possible but less certain, as there is a great deal of overlap in IENF [density] in those with or without pain.’’40 The authors conclude that IENF loss ‘‘cannot explain pain in all cases, suggesting that different mechanisms underpin the genesis of pain at various stages of neuropathy.’’40 4. These same authors also report in diabetic patients that whereas QST is useful in detecting the presence of neuropathy, and those with neuropathic pain had greater sensory loss than those without pain, the abnormalities detected by QST do not predict the presence of pain in diabetic neuropathy. They specifically state that whereas the cold detection threshold is a sensitive indicator of neuropathy, it is not a sensitive indicator for the presence of pain, and heat perception was even less so.41 Along with the disparity in C-fiber subtype involvement in diabetic small fiber neuropathy,25 these results indicate that the specificity of ancillary testing and our attempts to target mechanism-specific therapies in neuropathic pain are inadequate at present and reinforce the aforementioned caveats about inferential conclusions from indirect data. The diagnosis of neuropathic pain mechanisms is in its nascent stages and ancillary testing remains ‘‘subordinate,’’ ‘‘subsidiary,’’ ‘‘auxiliary’’ (as defined in Webster’s Third New International Dictionary) to history and clinical examination. Because of these difficulties and the lack of a diagnostic ‘‘gold standard,’’42—44 there has been renewed interest in patient symptoms and signs with the intent of establishing clinical parameters indicative of neuropathic pain. Several questionnaires and scales have been developed,4,12,42—48 each using descriptors of the types discussed in the ‘‘History’’ section, earlier, and based on several premises: 1. Determination of which chronic pain patients have neuropathic pain is predicated upon observer interpretation of evidence of nervous system injury, for example, ‘‘The clinical diagnosis was classified by the . . . clinician as nociceptive or neuropathic pain based on clinical features, known pathology and radiological or electrophysiological evidence’’12; ‘‘suspicion of neuropathic pain (by the referring physician)’’43; ‘‘pain . . . which could be clearly attributed to a peripheral or central nervous system injury . . . based on medical history, physical examination and electromyography, laboratory tests and/or imaging when indicated.’’46,47 2. There is a relationship between nervous system damage or dysfunction and a special (neuropathic) pain with unique features. In these conditions, the clinical features are not attributable to other etiologies. 3. The questionnaires and scales have the potential to isolate certain symptoms and signs, which when present indicate that the pain is neuropathic. In their absence, the pain is nonneuropathic in origin. One immediate concern with this approach is the potential for circular reasoning—the criteria for classifying patients into neuropathic or nonneuropathic pain groups include some of the outcome variables,43 thereby making the results self-fulfilling and logically inconsistent. The results obviously vary from study to study, but one clear finding is that no single or group of pain descriptors was dispositive for neuropathic pain. At its best, in the Bennett and colleagues’ studies,12,44,48 this approach attained 75% to 82% success in correctly classifying pain type (sensitivity and specificity), with other studies reporting less than 73% accuracy.42,43,45—47 Even in the bestresults studies,12,44,48 individual descriptors thought specific for

II ASSESSMENT OF PAIN AND ITS TREAT MENT

neuropathic pain (e.g., hot-burning, stabbing-shooting sensations) occurred in only 60% to 85% of definite neuropathic pain patients, and some of these same descriptors were seen in up to one third of nonneuropathic pain patients. As a consequence, various authors of these neuropathic pain questionnaires and scales have opined: ‘‘the overall picture is that there are surprisingly few clusters of symptoms and signs in chronic pain patients with either definite or possible neuropathic pain, which are different from those that are unlikely to have neuropathic pain.’’43 Also, ‘‘despite the ability of the S-LANSS to classify patients, around 20% to 25%. . . were incorrectly classified; some patients with nociceptive pain appear to have a number of features of neuropathic pain and some patients with neuropathic pain appear to have few. . . . it seems from the literature that at least 20% of patients with neuropathic pain are not identified by any existing tool that relies on assessment of clinical features.’’44 Recognizing this enigma, Attal and Bouhassira49 and Bennett and his colleagues48 hypothesized (and provided data in support) that chronic pain can be more or less neuropathic on a spectrum between ‘‘likely,’’ ‘‘possible,’’ and ‘‘unlikely,’’ based on patient responses on neuropathic pain symptom scales, when compared with specialist pain physician certainty of neuropathic pain on a 100-mm visual analog scale. The symptoms most associated with neuropathic pain were dysesthesias, evoked pain, paroxysmal pain, thermal pain, autonomic complaints, and descriptions of the pain as being ‘‘sharp,’’ ‘‘hot,’’ ‘‘cold,’’ with high sensitivity. Higher scores for these symptoms correlated with greater clinician certainty of neuropathic pain mechanisms. There is, again, the logical conundrum of circular reasoning at play here. There is also the surrender of the concept that neuropathic pain is a unique phenomenon separate and distinct from other types of pain. It remains to be seen whether considering each individual patient’s chronic pain as being somewhere on a continuum between ‘‘purely nociceptive’’ and ‘‘purely neuropathic’’ has diagnostic and therapeutic relevance.

CONCLUSIONS Taken together, the clinical findings and ancillary test results in patients suspected of having neuropathic pain have suggested to Hansson10 that: ‘‘Currently we lack operational criteria for translating clinical symptoms and signs into identified distinct pathophysiological mechanisms. Due to this shortcoming,. . . we are not in a position to extrapolate and make a safe bridging between clinical phenomenology and pathophysiological mechanisms in animals. Therefore, a detailed mechanism-based classification is currently not feasible.’’ I agree. We have moved from the point at which we separated neuropathic pain from other types of pain by recognizing similarities in the pain of patients with varied neurologic conditions, to realizing that neuropathic pain is, itself, highly heterogeneous46,47 and multifactorial. Now, it may be beneficial to abandon the concept of neuropathic pain as a single entity. The situation resembles that of Hans Christian Andersen’s metaphorical child who, when watching the emperor’s processional, revealed what all could see but none would admit.

REFERENCES 1. Woolf CJ. Pain: moving from symptom control toward mechanismspecific pharmacologic management. Ann Intern Med 2004;140:441—451. 2. Merskey H, Bogduk N. Classification of chronic pain: descriptions of chronic pain syndromes and definitions of pain terms. In Merskey H, Bogduk N (eds): Task Force on Taxonomy of the International Association for the Study of Pain. Seattle: IASP Press, 1994. 3. Cruccu G, Anand P, Attal N, et al. EFNS guidelines on neuropathic pain assessment. Eur J Neurol 2004;11:153—162. 4. Galer BS, Jensen MP. Development and preliminary validation of a pain measure specific to neuropathic pain: The Neuropathic Pain Scale. Neurology 1997;48:332—338.

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5. Horowitz SH. Venipuncture-induced neuropathic pain: the clinical syndrome, with comparison to experimental nerve injury models. Pain 2001;94;225—229. 6. Backonja M-M. Defining neuropathic pain. Anesth Analg 2003;97:785—790. 7. Klein T, Magerl W, Rolke R, Treede R-D. Human surrogate models of neuropathic pain. Pain 2005;115:227—233. 8. Scadding JW, Koltzenburg M. Painful peripheral neuropathies. In McMahon SB, Koltzenburg M (eds): Wall and Melzack’s Textbook of Pain, 5th ed. Philadelphia: Elsevier Churchill Livingstone, 2006; pp 973—999. 9. Jensen TS, Baron R. Translation of symptoms and signs into mechanisms of neuropathic pain. Pain 2003;102:1—8. 10. Hansson P. Difficulties in stratifying neuropathic pain by mechanisms. Eur J Pain 2003;353—357. 11. Rolke R, Baron R, Maier C, et al. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): standardized protocol and reference values. Pain 2006;123:231—243. 12. Bennett M. The LANSS Pain Scale: the Leeds assessment of neuropathic symptoms and signs. Pain 2001;92:147—157. 13. Smith HS, Sang CN. The evolving nature of neuropathic pain: individualizing treatment. Eur J Pain 2002;6(suppl B):13—18. 14. Otto M, Bak S, Bach FW, et al. Pain phenomena and possible mechanisms in patients with painful polyneuropathy. Pain 2003;101:187—192. 15. Daousi C, MacFarlane IA, Woodward A, et al. Chronic painful peripheral neuropathy in an urban community: a controlled comparison of people with and without diabetes. Diabet Med 2004;21:976—982. 16. Jung BF, Johnson RW, Griffin DRJ, Dworkin RH. Risk factors for postherpetic neuralgia in patients with herpes zoster. Neurology 2004;62:1545—1551. 17. Newman BH. Venipuncture nerve injuries after whole-blood donation. Transfusion 2001;41:571. 18. Walk D, Zaretskaya M, Parry GJ. Symptom duration and clinical features in painful sensory neuropathy with and without nerve conduction abnormalities. J Neurol Sci 2003;214:3—6. 19. Suarez GA, Dyck PJ. Quantitative sensory assessment. In Dyck PJ, Thomas PK (eds): Diabetic Neuropathy, 2nd ed. Philadelphia: WB Saunders, 1999; pp 151—169. 20. Low PA, Mathias CJ. Quantitation of autonomic impairment. In Dyck PJ, Thomas PK (eds): Peripheral Neuropathy, 4th ed. Philadelphia: Elsevier Saunders, 2005; pp 1103—1133. 21. Hilz MJ, Dutsch M. Quantitative studies of autonomic dysfunction. Muscle Nerve 2006;34:6—20. 22. Low PA. Composite autonomic scoring scale for laboratory quantification of generalized autonomic failure. Mayo Clin Proc 1993;68.748—752. 23. Novak V, Freimer ML, Kissel JT, et al. Autonomic impairment in painful neuropathy. Neurology 2001;56:861—868. 24. Low VA, Sandroni P, Fealey RD, Low PA. Detection of small-fiber neuropathy by sudomotor testing. Muscle Nerve 2006;34:57—61. 25. Berghoff M, Kilo S, Hilz MJ, Freeman R. Differential impairment of the sudomotor and nociceptor axon-reflex in diabetic peripheral neuropathy. Muscle Nerve 2006;33:494—499. 26. Chelimsky TC, Low PA, Naessens JM, et al. Value of autonomic testing in reflex sympathetic dystrophy. Mayo Clin Proc 1995;70:1029—1040. 27. Wasner G, Schattschneider J, Binder A, Baron R. Complex regional pain syndrome—diagnostic, mechanisms, CNS involvement and therapy. Spinal Cord 2003;41:61—75. 28. Kennedy WR. Opportunities afforded by the study of unmyelinated nerves in skin and other organs. Muscle Nerve 2004;29:756—767. 29. Kennedy WR, Wendelschafer-Crabb G, Polydefkis M, McArthur JC. Pathology and quantitation of cutaneous innervation. In Dyck PJ, Thomas PK (eds): Peripheral Neuropathy, 4th ed. Philadelphia: Elsevier Saunders, 2005; pp 869—895. 30. Umapathi T, Tan WL, Tan NCK, Chan YH. Determinants of epidermal nerve fiber density in normal individuals. Muscle Nerve 2006;33:742—746. 31. Holland NR, Stocks A, Hauer P, et al. Intraepidermal nerve fiber density in patients with painful sensory neuropathy. Neurology 1997;48:708—711. 32. Polydefkis M, Griffin JW, McArthur J. New insights into diabetic polyneuropathy. JAMA 2003;290:1371—1376. 33. Periquet MI, Novak V, Callino MP, et al. Painful sensory neuropathy: prospective evaluation using skin biopsy. Neurology 1999;53:1641—1647.

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Chapter 4  ASSESSMENT OF PAIN IN OLDER ADULTS

34. Gibbons CH, Griffin JW, Polydefkis M, et al. The utility of skin biopsy for prediction of suspected small fiber neuropathy. Neurology 2006;66:256—258. 35. Mendell JR, Sahenk Z. Painful sensory neuropathy. N Engl J Med 2003;348:1243—1255. 36. Herrmann DN, Pannoni V, Barbano RL, et al. Skin biopsy and quantitative sensory testing do not predict response to lidocaine patch in painful neuropathies. Muscle Nerve 2006;33:42—48. 37. Scott LJC, Griffin JW, Luciano C, et al. Quantitative analysis of epidermal innervation in Fabry disease. Neurology 1999;52:1249—1254. 38. Schiffmann R, Hauer P, Freeman B, et al. Enzyme replacement therapy and intraepidermal innervation density in Fabry disease. Muscle Nerve 2006;34:53—56. 39. Schiffmann R, Floeter MK, Dambrosia JM, et al. Enzyme replacement therapy improves peripheral nerve and sweat function in Fabry disease. Muscle Nerve 2003;28:703—710. 40. Sorensen L, Molyneaux L, Yue DK. The relationship among pain, sensory loss, and small nerve fibers in diabetes. Diabetes Care 2006;29:883—887. 41. Sorensen L, Molyneaux L, Yue DK. The level of small nerve fiber dysfunction does not predict pain in diabetic neuropathy; a study using quantitative sensory testing. Clin J Pain 2006;22:261—265.

42. Krause SJ, Backonja M-M. Development of a neuropathic pain questionnaire. Clin J Pain 2003;19:306—314. 43. Rasmussen PV, Sindrup SH, Jensen TS, Bach FW. Symptoms and signs in patients with suspected neuropathic pain. Pain 2004;110:461—469. 44. Bennett MI, Smith BH, Torrance N, Potter J. The S-LANSS score for identifying pain of predominantly neuropathic origin: validation for use in clinical and postal research. J Pain 2005;6:149—158. 45. Backonja M-M, Krause SJ. Neuropathic pain questionnaire—short form. Clin J Pain 2003;19:315—316. 46. Bouhassira D, Attal N, Fermanian J, et al. Development and validation of the Neuropathic Pain Symptom Inventory. Pain 2004;108:248—257. 47. Bouhassira D, Attal N, Alchaar H, et al. Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4). Pain 2005;114:29—36. 48. Bennett MI, Smith BH, Torrance N, Lee AJ. Can pain be more or less neuropathic? Comparison of symptom assessment tools with ratings of certainty by clinicians. Pain 2006;122:289—294. 49. Attal N, Bouhassira D. Can pain be more or less neuropathic? Pain 2004;110:510—511.

Chapter 4

the older adults reside in a nursing home, 45% to 80%1,2 or are community dwelling. The range reported for community-dwelling elders is 25% to 50%.3,4 Pain continues to be an under-assessed and under-treated condition in this population.5,6 Lack of familiarity of common age-related changes and common painful conditions among the elderly may contribute to the underrecognition of the problem. Many times, diagnostic imaging studies are poorly correlated with the clinical expressions of pain. This may lead to confusion on the part of the examining clinician and the potential for undervaluing the self-report of the patient and poor treatment planning. A list of pain syndromes common in older adults is presented in Box 4—1. Musculoskeletal pain is one of the most common types of pain experienced by community-dwelling older adults.7—9 The underlying disorders responsible for chronic low back pain (CLBP) are varied and require specific physical examination techniques. For example, of 111 older adults with CLBP, 84% reported sacroiliac joint pain, 19% reported pain consistent with fibromyalgia, 96% myofacial pain, and 48% hip pain.10 Rheumatic diseases, characterized by inflammation, degeneration, or metabolic disorders, are the most common diseases reported by older adults residing in long-term care (LTC) facilities.11 Specific examination techniques for musculoskeletal disorders are discussed later. Functional, cognitive, emotional, and societal consequences have been associated with unrelieved pain in older adults. Decreased activity due to pain can lead to myofacial deconditioning and gait disturbances, which in turn, can result in injuries from falls. Appetite impairment has been reported in communitydwelling adults with pain intensity scores higher than in those without appetite impairment.12 Pain in the elderly has been associated with increased sleep disturbances.13 These consequences can lead to less than optimal participation in rehabilitation efforts and decreased quality of life in general. Increased costs due to health care utilization have also been implicated as a result of unrelieved pain in the elderly.14 Consideration of the unique characteristics included in the history and physical assessment for pain in older adults will assist clinicians in the development and implementation of an individualized treatment plan that will optimize successful outcomes.

ASSESSMENT OF PAIN OLDER ADULTS

IN

Patricia Bruckenthal

INTRODUCTION Older adults often have multiple comorbidities that affect the pain presentation. Whereas the goals of a clinical assessment for pain in the older adult may be similar to those established for younger patients, certain characteristics of aging make this assessment more challenging for clinicians. These characteristics include reluctance of older individuals to report pain, the assumption that pain is a normal part of aging, sensory and cognitive impairments, and fear of the consequences of acknowledging pain, such as expensive testing or hospitalization. The pain experience can influence mood, physical functioning, and social interactions and indicates that pain assessment in older adults is multidimensional and often a multidisciplinary responsibility. The purpose of this chapter is to provide the clinician with the foundation to perform a successful pain assessment for older adults who are able to communicate by self-report. This will provide a comprehensive base on which to build a relevant plan of care. Pain assessment for those with cognitive impairment is the focus of Section II, Chapter 5, Assessment of Pain in the Nonverbal and/ or Cognitively Impaired Older Adult.

PREVALENCE OF PAIN INOLDER ADULTS Prevalence statistics for persistent pain in older adults range from 25% to 80%. Pain prevalence reports vary depending on whether

14

Chapter 4  ASSESSMENT OF PAIN IN OLDER ADULTS

34. Gibbons CH, Griffin JW, Polydefkis M, et al. The utility of skin biopsy for prediction of suspected small fiber neuropathy. Neurology 2006;66:256—258. 35. Mendell JR, Sahenk Z. Painful sensory neuropathy. N Engl J Med 2003;348:1243—1255. 36. Herrmann DN, Pannoni V, Barbano RL, et al. Skin biopsy and quantitative sensory testing do not predict response to lidocaine patch in painful neuropathies. Muscle Nerve 2006;33:42—48. 37. Scott LJC, Griffin JW, Luciano C, et al. Quantitative analysis of epidermal innervation in Fabry disease. Neurology 1999;52:1249—1254. 38. Schiffmann R, Hauer P, Freeman B, et al. Enzyme replacement therapy and intraepidermal innervation density in Fabry disease. Muscle Nerve 2006;34:53—56. 39. Schiffmann R, Floeter MK, Dambrosia JM, et al. Enzyme replacement therapy improves peripheral nerve and sweat function in Fabry disease. Muscle Nerve 2003;28:703—710. 40. Sorensen L, Molyneaux L, Yue DK. The relationship among pain, sensory loss, and small nerve fibers in diabetes. Diabetes Care 2006;29:883—887. 41. Sorensen L, Molyneaux L, Yue DK. The level of small nerve fiber dysfunction does not predict pain in diabetic neuropathy; a study using quantitative sensory testing. Clin J Pain 2006;22:261—265.

42. Krause SJ, Backonja M-M. Development of a neuropathic pain questionnaire. Clin J Pain 2003;19:306—314. 43. Rasmussen PV, Sindrup SH, Jensen TS, Bach FW. Symptoms and signs in patients with suspected neuropathic pain. Pain 2004;110:461—469. 44. Bennett MI, Smith BH, Torrance N, Potter J. The S-LANSS score for identifying pain of predominantly neuropathic origin: validation for use in clinical and postal research. J Pain 2005;6:149—158. 45. Backonja M-M, Krause SJ. Neuropathic pain questionnaire—short form. Clin J Pain 2003;19:315—316. 46. Bouhassira D, Attal N, Fermanian J, et al. Development and validation of the Neuropathic Pain Symptom Inventory. Pain 2004;108:248—257. 47. Bouhassira D, Attal N, Alchaar H, et al. Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4). Pain 2005;114:29—36. 48. Bennett MI, Smith BH, Torrance N, Lee AJ. Can pain be more or less neuropathic? Comparison of symptom assessment tools with ratings of certainty by clinicians. Pain 2006;122:289—294. 49. Attal N, Bouhassira D. Can pain be more or less neuropathic? Pain 2004;110:510—511.

Chapter 4

the older adults reside in a nursing home, 45% to 80%1,2 or are community dwelling. The range reported for community-dwelling elders is 25% to 50%.3,4 Pain continues to be an under-assessed and under-treated condition in this population.5,6 Lack of familiarity of common age-related changes and common painful conditions among the elderly may contribute to the underrecognition of the problem. Many times, diagnostic imaging studies are poorly correlated with the clinical expressions of pain. This may lead to confusion on the part of the examining clinician and the potential for undervaluing the self-report of the patient and poor treatment planning. A list of pain syndromes common in older adults is presented in Box 4—1. Musculoskeletal pain is one of the most common types of pain experienced by community-dwelling older adults.7—9 The underlying disorders responsible for chronic low back pain (CLBP) are varied and require specific physical examination techniques. For example, of 111 older adults with CLBP, 84% reported sacroiliac joint pain, 19% reported pain consistent with fibromyalgia, 96% myofacial pain, and 48% hip pain.10 Rheumatic diseases, characterized by inflammation, degeneration, or metabolic disorders, are the most common diseases reported by older adults residing in long-term care (LTC) facilities.11 Specific examination techniques for musculoskeletal disorders are discussed later. Functional, cognitive, emotional, and societal consequences have been associated with unrelieved pain in older adults. Decreased activity due to pain can lead to myofacial deconditioning and gait disturbances, which in turn, can result in injuries from falls. Appetite impairment has been reported in communitydwelling adults with pain intensity scores higher than in those without appetite impairment.12 Pain in the elderly has been associated with increased sleep disturbances.13 These consequences can lead to less than optimal participation in rehabilitation efforts and decreased quality of life in general. Increased costs due to health care utilization have also been implicated as a result of unrelieved pain in the elderly.14 Consideration of the unique characteristics included in the history and physical assessment for pain in older adults will assist clinicians in the development and implementation of an individualized treatment plan that will optimize successful outcomes.

ASSESSMENT OF PAIN OLDER ADULTS

IN

Patricia Bruckenthal

INTRODUCTION Older adults often have multiple comorbidities that affect the pain presentation. Whereas the goals of a clinical assessment for pain in the older adult may be similar to those established for younger patients, certain characteristics of aging make this assessment more challenging for clinicians. These characteristics include reluctance of older individuals to report pain, the assumption that pain is a normal part of aging, sensory and cognitive impairments, and fear of the consequences of acknowledging pain, such as expensive testing or hospitalization. The pain experience can influence mood, physical functioning, and social interactions and indicates that pain assessment in older adults is multidimensional and often a multidisciplinary responsibility. The purpose of this chapter is to provide the clinician with the foundation to perform a successful pain assessment for older adults who are able to communicate by self-report. This will provide a comprehensive base on which to build a relevant plan of care. Pain assessment for those with cognitive impairment is the focus of Section II, Chapter 5, Assessment of Pain in the Nonverbal and/ or Cognitively Impaired Older Adult.

PREVALENCE OF PAIN INOLDER ADULTS Prevalence statistics for persistent pain in older adults range from 25% to 80%. Pain prevalence reports vary depending on whether

II ASSESSMENT OF PAIN AND ITS TREAT MENT

Box 4—1 CURRENT PAIN SYNDROMES IN OLDER ADULTS Musculoskeletal Conditions  Osteoarthritis  Degenerative disk disease  Osteoporosis and fractures  Gout Neuropathic Conditions  Diabetic neuropathy  Postherpetic neuralgia  Trigeminal neuralgia  Central poststroke pain  Radicular pain secondary to degenerative disease of the spine Rheumatologic Conditions  Rheumatoid arthritis  Polymyalgia rheumatica  Fibromyalgia Adapted from HadjistavropoulosT, Herr K, Turk DC, et al. An interdisciplinary expert consensus statement on assessment of pain in older persons. Clin J Pain 2007;23(1 suppl):S1—S43; and Hanks-Bell, et al, 2004.

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Present Pain Complaint Assessment of the pain characteristics includes a detailed description of the onset, duration, frequency, intensity, location, and contributing factors. For a variety of reasons, older adults may not be forthcoming regarding reports of pain. They also may use descriptions other than pain to describe what they are experiencing. It is common for older adults to use terms such as ‘‘aching,’’ ‘‘soreness,’’ ‘‘hurting,’’ ‘‘discomfort,’’20,21 or other descriptors. The onset and timing are important considerations. Wheras degenerative musculoskeletal disorders generally have an insidious onset, a change in character from a less severe to a more intense pain may indicate a progression of disease or a new-onset fracture. Pain that is more intense in the morning is a feature of cancerous bone pain. Tools to evaluate pain intensity specific to the geriatric population have been identified and are outlined later. Older persons are able to utilize a body pain map or diagram to indicate the location(s) of their pain.22,23 Sometimes, the pain, although not present during rest, will manifest itself during activities and, therefore, this too should be explored with the patient. A useful structured interview technique that will elicit information on the present pain complaint for older adults who can communicate is suggested in Box 4—2. Associated symptoms, such as paresthesias, may indicate radicular involvement of an extremity in pain. Fever or weight loss may herald more ominous diagnoses including infection or malignancy.

ELEMENTS OF A COMPREHENSIVE ASSESSMENT A comprehensive, multidimensional pain assessment in older adults will ultimately lead to a more successful individualized plan of care. Regardless of whether the pain is acute, postoperative, or chronic, the goal of the assessment is to identify the cause of pain, conduct a thorough history of comorbid medical and psychosocial conditions, and perform an appropriate physical examination and diagnostic work-up. Often, a multidisciplinary approach may be needed, and after the initial assessment, the clinician may determine that referral to an appropriate specialist is necessary for specialized services or skilled procedures. For example, a mental health professional may be able to optimize a plan to treat depression or a substance abuse disorder or a physical therapist may be consulted for evaluation of a conditioning program. A review of existing medical records is also beneficial to the assessment process.

History of the Pain Complaint Several elements are recognized as essential for a comprehensive assessment of pain at any age. One such schema recommended for guiding a comprehensive pain assessment in older adults is outlined in detail in the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) project.15—18 Included in this review are necessary elements such as nuances specific to older adults to assist the clinician in the assessment process. Techniques for assessing these age-specific elements are described later. Self-report of pain is still considered the most reliable source for the cognitively intact and communicative older adult’s pain complaint.19 Sensory deficits in vision, hearing, and cognition are common in this population and need to be identified prior to beginning the interview. These may affect the patient’s ability to complete the assessment process, and adjustments to accommodate for deficits need to be considered. This may become especially relevant when selecting appropriate pain assessment instruments. It also may be beneficial to query other family members or caregivers for additional perspectives on medical history, predominant mood and affect, and physical and social functioning.

Past Medical History This review should include a history of past medical, surgical, and psychiatric conditions, as well as accidents/injuries. Dates of onset, current and past treatments, and treating practitioners should be obtained. Eliciting this information is important for several reasons. The existence of certain comorbid conditions will affect treatment decisions for pain. For example, nonsteroidal anti-inflammatory agents may be of limited use in those with a history of heart disease or hypertension. Patients with liver disease will need to use acetaminophen cautiously. Preexisting renal disease will affect the use of medications as well. Identification and documentation of preexisting conditions will facilitate treatment planning.

Box 4—2 ASSESSMENT OF BRIEF PAIN IMPACT FOR VERBAL PATIENTS 1. How strong is your pain (right now, worst/average over past week)? 2. How many days over the past week have you been unable to do what you would like to do because of your pain? 3. Over the past week, how often has pain interfered with your ability to take care of yourself, for example with bathing, eating, dressing, and going to the toilet? 4. Over the past week, how often has pain interfered with your ability to take care of your home-related chores such as going grocery shopping, preparing meals, paying bills, and driving? 5. How often do you participate in pleasurable activities such as hobbies, socializing with friends, and travel? Over the past week, how often has pain interfered with these activities? 6. How often do you do some sort of exercise? Over the past week, how often has pain interfered with your ability to exercise? 7. Does pain interfere with your ability to think clearly? 8. Does pain interfere with your appetite? Have you lost weight? 9. Does pain interfere with your sleep? How often over the past week? 10. Has pain interfered with your energy, mood, personality, or relationship with other people? 11. Over the past week, how often have you taken pain medications? 12. How would you rate your health at the present time? Reprinted with permission from Weiner D, Herr K. Comprehensive interdisciplinary assessment and treatment planning: an integrative overview. In Weiner D, Herr K, Rudy T (eds): Persistent Pain in Older Adults: An Interdisciplinary Guide forTreatment.NewYork: Springer, 2002; pp18—57.

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Chapter 4  ASSESSMENT OF PAIN IN OLDER ADULTS

Knowledge of the pattern of certain preexisting conditions can also help with anticipatory planning. Sensory distal polyneuropathy is the most common neurologic presentation in patients with diabetes mellitus. Although most polyneuropathies are painless, 7.5% of patients report unpleasant sensations of pain.24 Clinicians should be alert to evolving sensory complaints in diabetic patients, especially those with poor glycemic control. Musculoskeletal disorders that have changed in presentation may signal progression of disease and may require more intense investigation. Finally, results of any previous laboratory and diagnostic tests should be reviewed not only to guide future treatment decisions but also to avoid unnecessary repeat testing.

Medication History A careful medication history must be inclusive of all current and past medications, dosages, side effects, and response. This consists of prescribed, over-the-counter, and herbal supplements. Alcohol use should be specific to frequency and amount. Tobacco products and illicit drug use are important elements of inquiry as well. It is important to obtain the name and phone number of the current pharmacy(ies) used.

Functional Assessment Essential elements of a functional assessment are broad and include cognitive, physical, and psychosocial dimensions. Data from these aspects of the assessment establish a baseline to enable the clinician to determine specific goals, the extent to which the patient can participate, and response to the treatment plan. Cognition is grossly assessed during the process of the health interview. Some areas of cognitive decline, such as fluid reasoning, processing speed, and short-term memory, are part of the normal aging process.25,26 Factors other than dementia that should be considered as causative in cognitive decline include poor nutritional status, medication effect, depression, living environment,25 and pain.27 The Mini-Mental State Examination (MMSE)28 can be used to assess cognition, but it may not be able to pick up subtle changes. A more complete discussion on pain assessment in the cognitively impaired adult is addressed in detail in Section II, Chapter 5, Assessment of Pain in the Nonverbal and/or Cognitively Impaired Older Adult. Physical function incorporates the assessment of mobility, activities of daily living (ADLs), sleep pattern, and appetite. The clinician should ascertain the current level of physical activity and mobility the patient is capable of. This includes an assessment of the level at which basic ADLs are being performed. It is helpful to identify activities previously preformed that the pain prohibits the patient from doing currently. Ask if the patient engages in a regular exercise program. These assessment parameters should establish the baseline of current physical function. Questions regarding sleep patterns are asked to evaluate whether restorative sleep is being attained. Poor sleep may be the result of the aging process, depression, or pain. Identifying the cause will assist in developing an appropriate intervention for improving sleep. Appetite suppression has been associated with a higher pain intensity level in community-dwelling adults.12 Poor nutrition can contribute to fatigue and diminished function and well-being. By reviewing all the pertinent aspects of function, the clinician and patient can begin to establish realistic treatment goals in this domain.

Psychosocial Assessment Mood, social support systems, recreational involvement, and financial resources are important to the psychosocial assessment. These factors all influence the pain experience and how the patient in pain functions in these domains as well as responds to various treatments.

Depressive disorders are prevalent in people with chronic pain.13,29—31 Patients who are depressed may exhibit decreased energy and engagement in treatment modalities or avoidance of pleasant diversional activities. The Geriatric Depression Scale (GDS)32 is one instrument that can be used to determine whether further evaluation for depression is indicated. This instrument is of particular benefit in residential care elders, whereas the Center for Epidemiological Studies Depression Scale (CESD)33,34 is more suited for community-dwelling elders.35 Anxiety has also been closely associated with pain36,37 and often coexists with depression in this population. Anxiety may play a part in fear-related behavior that might inhibit participation in physical rehabilitation efforts. It may be useful for the clinician under these circumstances to evaluate this disorder in more detail. The Beck Anxiety Inventory38 is a brief screening tool that has been used in the elderly for evaluating anxiety symptoms. A distinction can be made between a situational anxiety response and the more enduring personality anxiety trait, and these can be evaluated using the State-Trait Anxiety Inventory.39 While eliciting trait versus state anxiety traits, it may be noted that in pain patients, the relationship between transient and enduring emotional responses to pain and outcomes to treatment intervention need to be further explored. Emotional responses of depression and anxiety, however, do have an impact on the overall pain experience and are essential to the overall assessment. Assessment of the social support network and economic status for older people in pain is important on several levels. Involvement with family and friends can provide pleasurable experiences and diversion away from a constant focus on pain. Supportive social contacts can provide transportation to clinic and treatment appointments. Osteoarthritis patients who participated in spouse-assisted pain-coping skills training had a greater reduction on pain and disability outcomes that those who participated in conventional nonspousal participant training.40 In addition to the availability of social support, the type of relationship should be assessed. Negative social reinforcement may present in the form of overly solicitous family members who encourage sedentary behavior. Other negative effects are likely if long-term caregivers become resentful of their support role. Finally, economic resources have a great impact on access to potential treatment options and must be identified.

Beliefs and Attitudes about Pain The context in which older adults perceive pain is relevant to the overall assessment. Pain can signify loss of independence or debilitating illness or be regarded as a general consequence of the aging process and therefore be underreported. Better treatment satisfaction and outcomes are reported when there is greater agreement between patient beliefs about the nature and treatment of pain and the treatment received.41 Multiple constructs associated with beliefs and attitudes about pain have been studied and have an impact on the total pain experience and outcomes. Many of these are interrelated, such as coping, self-efficacy, catastrophizing, and pain-related fears. Coping and self-efficacy are discussed later. Two simplistic models of coping have been described as active versus passive42—44 and adaptive versus maladaptive coping.45,46 Patients use a variety of coping skills for managing pain. For example, task persistence, activity pacing, and use of coping selfstatements were coping strategies most frequently used by a group of predominantly female older adults living in retirement facilities.47 Prayer is often utilized by older adult women as a coping mechanism for pain.48 Identifying coping skills among the elderly is important so that the clinician can encourage the use of previously successful skills or modify treatment interventions to incorporate teaching effective coping skills. Patients with passive or

II ASSESSMENT OF PAIN AND ITS TREAT MENT

maladaptive coping styles would likely benefit from psychological interventions49 that would focus on more effective ways of coping. Self-efficacy refers to the belief that one can control or manage certain outcomes of one’s life.50,51 Beliefs about the degree of control and self-efficacy in being able to manage pain have been well studied52,53 and are related to types of coping strategies used to manage pain.54 Participation in cognitive-behavioral pain-coping skills interventions can increase self-efficacy beliefs and have been shown to decrease pain intensity, disability, and depression.40,55—57 Patients who are identified as having poor beliefs regarding their ability to manage pain may benefit from coping skills training aimed at increasing self-efficacy. Examples of instruments that measure one’s perceived ability to manage pain are listed in Table 4—1.

Pain Assessment Measurement Instruments An abundance of reliable and valid instruments are available to assist in the assessment of pain. The choice of which to use will depend on factors including purpose of the tool, clinical setting, and time constraints. Some instruments measure a single pain construct whereas others are multidimensional. Clinicians are encouraged to find instruments that are useful to their clinical needs and encompass the broad pain assessment domains covered in this chapter. Table 4—1 represents a sample of pain assessment instruments that were extrapolated from reviews by Hadjistavropoulos and coworkers,18 Gibson and Weiner,58 and Herr and Garand.59 Many of these are self-assessment/self-report instruments and can be administered prior to the history and examination portion of the pain assessment and reviewed by the clinician with the patient. The choice of tools can be overwhelming. As a pragmatic yet comprehensive approach, Hadjistavropoulos and coworkers18 recommended the administration of the Brief Pain Inventory (BPI)60 and the Short-Form McGill Pain Questionnaire (SF-MPQ)61 as suitable for most cognitively intact older adults. These cover the multidimensional nature of the pain assessment and can be completed in approximately 10 minutes. Instruments that measure pain in cognitively impaired elders are covered in Section II, Chapter 5, Assessment of Pain in the Nonverbal and/or Cognitively Impaired Older Adult.

Physical Assessment General The focus of the physical assessment will vary depending on whether the pain complaint is acute or chronic. In general, inflammation, traumatic injury, and cancer-related conditions are associated with acute pain, whereas neurologic and musculoskeletal etiologies cause more chronic pain conditions. This section focuses on the latter assessment and suggestions for the former are included in the discussion of assessment of specific painful conditions. All patients should have a brief examination of general health status, including vision and hearing, cardiovascular, respiratory, and gastrointestinal systems, prior to the more focused examination. When the painful region is examined, inspection is focused on signs of inflammation, trophic changes, joint deformity, and vascular signs such as paleness, cyanosis, or mottled appearance.

Musculoskeletal Examination Assessment of the musculoskeletal system focuses on inspection of any joint deformities and disuse signs such as asymmetry of muscular bulk and tone. Note any spinal deformity including kyphosis, lordosis, or scoliosis. Palpation includes the spinous processes and paraspinal muscles, sacroiliac joint, piriformis, or the fibromyalgia tender points for more generalized pain complaints. During range

17

of motion of the cervical spine, lumbar spine, and hip, the quality, quantity, and elicitation of pain should be noted. Specific examination maneuvers can offer clues to the etiology of the pain complaint. Straight leg raising, Lase`gue’s sign, is indicative of nerve root compression. Crossed straight leg raising, exacerbation of leg pain when the contralateral leg is raised, may suggest lumbar disk herniation. Fabere maneuvers (Patrick’s test) include flexion, extension, abduction, and external rotation of the hip. Pain during these movements is suggestive of degenerative joint disease of the hip, but it may also occur with sacroiliac pathology. Pain radiating down the arm produced by lateral tilt or rotation of the head (Spurling’s sign) in patients complaining of neck pain may indicate cervical nerve root compression. Lhermitte’s sign is an electric shock—like sensation in the torso or extremities associated with cervical flexion and may be suggestive of a cervical cord lesion.62

Mobility/Balance Pain is a contributing factor of mobility impairment and falls in the elderly and warrants an assessment of gait and balance. Gait changes associated with aging include decreased step length, walking speed, ankle range of motion, and the ability to push-off with the toes. The ability to rise unassisted from a seated position to standing, timed and averaged for 5 repetitions,63 and the timed ‘‘up and go’’ test64 are simple, quick measures of basic functional mobility.

Neurologic When conducting a focused neurologic examination, strength, sensation, and deep tendon reflexes are assessed. In general, a sensory dermatomal level usually correlates with the anatomic level of the lesion. Hyperalgesia, hyperpathia, and hypoesthesia can be tested by pinprick. Allodynia is tested using a cotton swab or paintbrush. Hyporeflexia may indicate nerve root compression whereas hyperreflexia may be indicative of myelopathy from spinal cord compression. Decreased vibratory sensation and hyporeflexia are signs consistent with peripheral neuropathy. The physical assessment is important to help confirm etiology and identify level of impairment, to determine level of function, and to elicit emergent conditions in the older population. Ongoing physical assessment continues to be imperative in order to evaluate the effectiveness of treatment, exacerbation of identified conditions, or the emergence of new problems that need attention. Therefore, a follow-up physical examination guided by the medical history should take place at each subsequent visit.

ASSESSMENT CONSIDERATIONS FOR SPECIFIC PAINFUL CONDITIONS Trigeminal Neuralgia Trigeminal neuralgia is characterized by severe, unilateral facial pain described as lancinating, electric shock—like jolts in one or more distributions of the trigeminal nerve. The maxillary and mandibular divisions are most commonly affected. The causes vary by age. In the elderly, compression of the trigeminal root by an artery or vein or both is the cause about 80% of the time. Intracranial tumors and demyelinating disease have also been implicated. The characteristic jabs of pain last from 2 to 120 seconds and are often precipitated by activities such as brushing, chewing, or talking. The paroxysms of pain are separated by pain-free intervals. Because there are no cranial nerve deficits, the diagnosis of tumor may be delayed. Careful clinical evaluation and magnetic resonance imaging (MRI) are recommended for all patients presenting with trigeminal neuralgia.65

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Table 4^1. Selected Instruments for Pain Assessment in Older Adults Instrument

Instrument Characteristics

Pain intensity

Numerical rating scale (NRS)

Available in a variety of scale ranges including 0—5, 0—10, 0—20, and 0—100.

Acute care Subacute care Pain clinic Long-term care (LTC) Assisted living Community dwelling

 Preferred by many older adults  Verbal version may be difficult for elders with cognitive impairment  Vertical orientation of scale easier to use for elders

Verbal descriptor scale (VDS)

Available in a variety of scale types including 5-Point Verbal Rating Scale Pain Thermometer77 Present Pain Inventory (PPI)78 Graphic Rating Scale79

 Most preferred by older adults  Requires abstract thought  Thermometer adaptation may assist with tool understanding80

Pictorial Pain Scales

Facial pain scales tested in older adults: Faces Pain Scale (FPS)81 Wong-Baker FACES Scale82

Acute care Subacute care Pain clinic LTC Assisted living Community dwelling Acute care Subacute care Pain clinic LTC Assisted living Community dwelling Community dwelling Pain clinic Acute care Multiple settings including cancer, chronic pain conditions, postoperative pain, and older adults Community dwelling Chronic pain

Multidimensional Short-Form McGill pain assessment Pain Questionnaire (SF-MPQ)61 Brief Pain Inventory (BPI)60

Pain Disability Index (PDI)83

15 Pain quality words rated on a Likert scale, plus a visual analog scale (VAS) of pain intensity, plus a PPI 11-Item instrument that gathers information on pain severity and level of pain interference on seven key aspects of function

Multidimensional Pain Inventory (MPI)85

Seven items using 11-point scale to measure perceived pain interference with the performance of seven areas of daily function 24-item questionnaire measuring five clusters of components: Pain Intensity, Disengagement, Pain with Ambulation, Pain with Strenuous Activities, and Pain with Other Activities 61 Items, made up of 13 subscales across three sections

Functional Pain Scale (FPS)86

0—5 Scored tool that combines pain severity and function and rates ability to tolerate activity

Geriatric Pain Measure (GPM)84

Ambulatory geriatric clinic

Multiple settings Pain clinic

Community dwelling

Comments

   

Preferred by many older adults Validated in white, African American, and Spanish Does not require language Requires abstract thinking

 Measures sensory and affective dimensions  Not recommended for illiterate or cognitively impaired  Measures intensity and pain interference  Does not measure quality or affective dimensions of pain  Available in over 30 languages  Measures pain-related disability  Short and easy to use  Needs further study for utility in outcomes measures  Measures intensity, interference, disengagement, and pain with activity  Limited evaluation data  Measures pain intensity, interference, significant other support, general activity  Cross-culturally validated  Identifies adaptation styles and response to treatment  Lengthy to complete, approximately 20 min  Limited psychometric study in the elderly  Measures intensity and function  Limited by indicators that measure interference based on ability to watch TV, read, and use a telephone

Chapter 4  ASSESSMENT OF PAIN IN OLDER ADULTS

Psychometrics Established by Setting

Domain

Functional status Functional Status Index (FSI)87

Site-specific disability

Cognitive processes; pain specific

19

Continued

II ASSESSMENT OF PAIN AND ITS TREAT MENT

Affective processes

Two self-administered subscales: pain and Acute care  Measures basic activities of daily living (ADLs) and difficulty; difficulty subscale focuses attention on Primary care instrumental ADLs  Takes approximately 8 min to administer task performance rather than amount of pain experienced while performing the task  Measures basic, instrumental, and advanced ADLs Physical Activity Scale88 Measures levels of physical activity in past week in Community dwelling  8 min to complete areas of leisure, occupation, and household activities Oswestry Disability 10 Items measuring level of pain and interference Primary care  Evaluates low back pain Scale89 with physical activities, sleep, self-care, sex life,  Measures basic, instrumental, and advanced ADL’s social life, and travel  5 min to complete Rowland Morris 24-Item instrument derived from the Sickness Includes, but not specific to,  Evaluates low back pain Disability Index77 Impact Profile in which the phrase ‘‘because of older adults  Measures basic and instrumental ADLs my back’’ was added to each statement, making it  5 min to complete disease specific Western Ontario And 24-Item instrument assesses pain, disability, and Includes, but not specific to,  Evaluates hip and knee pain McMaster Universities joint stiffness older adults  8 min to complete Osteoarthritis Index (WOMAC)90 Neck Pain and Disability 20-Item instrument designed to measure intensity Includes, but not specific to,  Evaluates neck pain of pain and interference with vocational, older adults  5 min to complete Index91 recreational, social, and self-care activities as well as emotions Adults with rheumatoid 48 Vignettes assessing four depression-related Cognitive Errors arthritis, including, but not cognitive disorders: catastrophizing, Questionnaire92 specific to, older adults overgeneralization, personalization, and selective abstraction; half of the vignettes use chronic pain as the stimulus for the situation Inventory of Negative 21 5-Point items made up of three subscales: Includes, but not specific to, Thoughts in Response negative self-statements, negative social older adults to Pain93 cognitions, and self-blame  Age-related increase in degree of reticence to pain, Pain Attitudes 27 Items load on four factors representing stoicism Community dwelling self-doubt, and reluctance to label a sensation as Questionnaire94 (superiority, reticence) and cautiousness (selfpainful was found doubt, reluctance) Pain Catastrophizing 13 Items made up of three subscales describing Not known Scale95 catastrophizing thinking: helplessness, rumination, and magnification Arthritis Helplessness 5 Items tapping perceived (un)controllability of Includes, but not specific to,  Helplessness correlated with greater age, lesser Index96 arthritis symptoms older adults education, lower self-esteem, lower internal health locus of control, higher anxiety and depression, and impairment in performing ADLs Arthritis Self-efficacy 20 Items measuring self-efficacy in three domains: Primary care  Health outcomes and self-efficacy scores improved Scale97 pain, function, and other symptoms Community dwelling when patients participated in the Arthritis SelfManagement Course Pain Anxiety Symptoms Multidisciplinary pain clinic Scale98

Instrument

Beck Anxiety Inventory38 Tampa Scale of Kinesiophobia99

Survey of Activities and Fear of Falling in the Elderly102 Geriatric Depression Scale (GDS)32

Coping skills

Instrument Characteristics

62 Items made up of four subscales: fear of pain, cognitive anxiety, somatic anxiety, escape and avoidance 21 Items answered on a 4-point scale 17 Items addressing fears about pain and re(injury)

Psychometrics Established by Setting

Not known

11 Items, subscales include activity, restriction, fear of falling, and activity level 30 Yes/no items; omits somatic and other depressive symptoms possibly confounded with aging 20 4-Point items

Comments

Includes, but not specific to,  May be useful in the continued study of fear of older adults pain and its contribution to the development and maintenance of pain behaviors

Community dwelling LTC facility

Center for Community dwelling Epidemiological Studies LTC facility Depression Scale (CESD)33 Coping Strategies 42 Items assess seven strategies (making coping Questionnaire103 self-statements, ignoring pain sensations, reinterpreting pain sensations, praying/hoping, catastrophizing, diverting attention, and increasing activities), but various factor structures have emerged Chronic Pain Coping 65 Items assess behavioral coping strategies in 11 Inventory104 domains Vanderbilt Pain Separate active (11 items) and passive (7 items) Management subscales Inventory42 54 Items made up of six subscales: cognitive Includes, but not specific Coping with Chronic restructuring, emotional expression, wishto, older adults Illness105,106 fulfilling fantasy, self-blame, information seeking, and threat minimizing Ways of Coping Scale 66 Items made up of numerous subscales and two (Revised)107 higher-order factors: problem-focused and emotion-focused coping. Revised

 For older chronic pain patients, a stronger mediating role for pain-related fear was supported100  Items may represent catastrophic thinking rather than fear of movement101  May be able to differentiate fear of falling that leads to activity restriction from fear of falling that accompanies activity  Short form available  Performed better than the CESD in residential settings for elders  Performed better than the GDS in community dwelling elders

 Widely used in older adults, especially those with osteoarthritis

 Short form available  Has been used, but not validated in older adults

 Not pain specific

 Not pain specific

Adapted from Hadjistavropoulos T, Herr K, Turk DC, et al. An interdisciplinary expert consensus statement on assessment of pain in older persons. Clin J Pain 2007;23(1 suppl):S1—S43; Gibson SJ, Weiner DK. Pain in Older Persons. Seattle: IASP Press, 2005; and Herr KA, Garand L. Assessment and measurement of pain in older adults. Clin Geriatr Med 2001;17:457—478, vi.

Chapter 4  ASSESSMENT OF PAIN IN OLDER ADULTS

Domain

20

Table 4^1. Selected Instruments for Pain Assessment in Older Adultsçcont’d

II ASSESSMENT OF PAIN AND ITS TREAT MENT

Postherpetic Neuralgia Postherpetic neuralgia (PHN) is a frequent complication after an outbreak of herpes zoster in the elderly. Sensory findings include allodynia or hyperalgesia in the associated dermatomal region, the thoracic being more common than the facial. Patients with allodynia complain of the wind or a piece of clothing causing pain. Hyperalgesic patients describe provocation of pain by a relatively mild stimulus, such as bumping up against a piece of furniture. Tingling, severe itching, burning, or steady throbbing pain have also been described. Pain associated with PHN can interfere with ADLs and quality of life, and therefore, identification and intervention are crucial.65

Poststroke Pain Poststroke pain, an underrecognized consequence after stroke, occurs in 33% to 40% of patients who have had a stroke. The pain may present as shoulder pain in the paretic limb or present as central poststroke pain (CPSP). CPSP is characterized as pain that is severe and persistent with accompanying sensory abnormalities.66,67

Metastatic Bone Pain Bone pain that is worse at night, when lying down, or not associated with acute injury should raise suspicion of metastatic disease. Also, pains that gradually but rapidly increase in intensity or with weight bearing or activity are suspicious. Frequent sites of metastatic pain include the hip, vertebrae, femur, ribs, and skull. Examination includes palpation of the affected site.

Temporal Arteritis Greater than 95% of the cases of temporal arteritis occur in patients over 50 years old. Presentation includes complaints of new-onset headache, malaise, scalp tenderness, and jaw claudication. Physical examination reveals an indurated temporal artery that is tender with a diminished or absent pulse. Because irreversible blindness is a consequence if untreated, timely assessment and treatment are essential.68 Generally, patients are started on glucocorticoids while awaiting temporal artery biopsy.

SETTING OF THE PAIN ASSESSMENT Much of the current literature on pain assessment and information provided in this chapter seem most suited for elders with chronic rather than acute pain. Psychosocial factors are more closely associated with chronic pain states and have been studied more intensely. The nature of the pain being evaluated and the setting of the evaluation will dictate which assessment techniques are warranted. Whereas scales that measure pain intensity can be administered rapidly and are suitable for any setting, others require more time and are more likely to be helpful in the primary care office/clinic or LTC facility. Some distinctions regarding the setting and type of pain are provided later.

Acute Pain Older adults who present with acute pain require a rapid assessment including a self-report of pain intensity and other descriptors of the present pain complaint. Past pain history and medication history are also essential. Completion of a more comprehensive assessment can be delayed until the etiology and treatment of the pain has been

21

initiated. Ongoing monitoring of the pain intensity, duration, and effects of treatment should take place every 2 to 4 hours initially. Once every 8 hours is appropriate once the pain is well controlled.69 Older adults may use terms other than pain, so questions that relate to discomfort and hurting may need to be asked.20 The patient should be observed during an activity such as ambulation, transfers, or repositioning, because behavior and pain levels may not be equal during different activities.20 Autonomic responses such as increased heart rate and blood pressure and altered respiratory rate are generally associated with acute pain. The clinician should be cautioned that the absence of these signs does not indicate that pain is not present.70 In fact, no statistically significant differences were seen between self-reported pain scores and heart rate, blood pressure, or respiratory rate in adult patients presenting to an emergency department for a variety of acute painful conditions.71 Clinicians should not rely on vital signs as the sole indicator for the presence or degree of acute pain. Patient self-report of pain remains the ‘‘gold standard.’’

LTC Facility Pain assessment in nursing homes continues to be a challenge. Common themes regarding pain assessment in LTC facilities persist. Two studies illustrate the significance of this problem. Clark and colleagues72 conducted a qualitative study using focus groups in 12 nursing homes in Colorado. They identified that within nursing homes (1) there is an uncertainty in pain assessment, (2) that relationship-centered cues to residents’ pain are a solution to limitations of formal assessment, (3) cues to pain are behavioral changes and observable physical changes, and (4) specific residents’ characteristics, such as attitudes or being perceived as ‘‘difficult,’’ made pain assessment more challenging. These findings have implications for practice. Education of staff regarding the complex nature of chronic pain and its psychosocial domains may help clarify the ambiguity expressed regarding assessment. Acknowledging the importance of family members’ and certified nursing assistants’ reports of behavioral and physical changes is essential to the process. The use of pain assessment tools appropriate for difficult patients or patients with communication impairment is helpful. It has been reported that the availability of various assessment tools to suit patient preferences will increase the frequency of diagnosing pain in nursing home residents.73 Similarly, Kaasalainen and coworkers74 found that pain assessment was problematic in nursing homes and that appropriate pain assessment strategies were closely linked to effective pain management. Common themes emerged of negative myths about pain and aging, inadequacy of current tools used in practice, and the inability to discriminate between pain and problems such as dementia and delirium. This lack of confidence in assessment was reflected in the ways that pain was treated. These findings suggest that engaging in a process committed to pain assessment at all levels in the LTC facility will have positive implications for management of pain in this setting. Two useful resources to facilitate implementing an institutional plan are described in the American Geriatric Society Panel on Persistent Pain in Older Adults19 and the American Medical Directors Association Chronic Pain Management in the Long Term Care Setting guidelines.75 These evidence-based interdisciplinary guidelines form a basis for a comprehensive pain management program that includes recognition, assessment, treatment, and monitoring recommendations.

CONCLUSION An accurate assessment of pain provides the foundation for a successful treatment plan in the older adult. This assessment is often

22 Chapter 4  ASSESSMENT OF PAIN IN OLDER ADULTS complex and multidimensional and varies depending on the practice setting in which the patient is encountered. Self-report remains the most reliable measure of the painful complaint. Self-report should be supplemented with existing medical records, information from family members and caregivers when possible, and the utilization of additional instruments available to measures pain-related constructs. The sheer range and choice of pain-related measurement instruments can be daunting for the clinician. In many cases, particularly when evaluating an older adult with a chronic pain complaint, the process can be time consuming. Many assessment instruments can be given to the patient prior to the evaluation process and reviewed with the patient during the examination. One suggestion toward a rational approach to assessment is described earlier and includes self-report, the BPI, and the SF-MPQ. Other assessment instruments can be added depending on particular needs of specific populations common to a practice setting. The objective is to make sure the assessment is comprehensive and includes an evaluation of the multidimensional facets of pain in older adults. The initial evaluation is only the beginning of the assessment process. Ongoing clinical monitoring of treatment outcomes or the development of new clinical findings includes reassessment at appropriate intervals, documentation, and communication of findings to all members of the health team involved in care. By implementing a systematic process in pain assessment, clinicians can develop goals and treatment protocols that will ultimately optimize pain management in older adults.

REFERENCES 1. Proctor WR, Hirdes JP. Pain and cognitive status among nursing home residents in Canada. Pain Res Manage 2001;6:119—125. 2. Bernabei R, Gambassi G, Lapane K, et al. Management of pain in elderly patients with cancer. SAGE Study Group. Systematic Assessment of Geriatric Drug Use via Epidemiology. JAMA 1998;279:1877—1882. 3. Helme R, Gibson SJ. Pain in older people. In Crombie I, Croft P, Linton S, et al (eds): Epidemiology of Pain, Seattle: IASP Press, 1999; pp 103—112. 4. Blyth FM, March LM, Brnabic AJ, et al. Chronic pain in Australia: a prevalence study. Pain 2001;89:127—134. 5. Martin R, Williams J, Hadjistavropoulos T, et al. A qualitative investigation of seniors’ and caregivers’ views on pain assessment and management. Can J Nurs Res 2005;37:142—164. 6. Sengstaken EA, King SA. The problems of pain and its detection among geriatric nursing home residents. J Am Geriatr Soc 1993;41:541—544. 7. Helme RD, Gibson SJ. The epidemiology of pain in elderly people. Clin Geriatr Med 2001;17:417—431. 8. Leveille SG. Musculoskeletal aging. Curr Opin Rheumatol 2004;16:114—118. 9. Weiner DK, Haggerty CL, Kritchevsky SB, et al. How does low back pain impact physical function in independent, well-functioning older adults? Evidence from the Health ABC Cohort and implications for the future. Pain Med 2003;4:311—320. 10. Weiner DK, Sakamoto S, Perera S, Breuer P. Chronic low back pain in older adults: prevalence, reliability, and validity of physical examination findings. J Am Geriatr Soc 2006;54:11—20. 11. McCarberg BH. Rheumatic diseases in the elderly: dealing with rheumatic pain in extended care facilities. Rheum Dis Clin North Am 2007;33:87—108. 12. Bosley BN, Weiner DK, Rudy TE, Granieri E. Is chronic nonmalignant pain associated with decreased appetite in older adults? Preliminary evidence. J Am Geriatr Soc 2004;52:247—251. 13. Magni G, Marchetti M, Moreschi C, et al. Chronic musculoskeletal pain and depressive symptoms in the National Health and Nutrition Examination. I. Epidemiologic follow-up study. Pain 1993;53:163—168. 14. Gallagher RM, Verma S, Mossey J. Chronic pain. Sources of late-life pain and risk factors for disability. Geriatrics 2000;55:40—44. 15. Dworkin RH, Turk DC, Farrar JT, et al. Core outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain 2005;113:9—19.

16. Turk DC, Dworkin RH, Allen RR, et al. Core outcome domains for chronic pain clinical trials: IMMPACT recommendations. Pain 2003;106:337—345. 17. Turk DC, Dworkin RH, Burke LB, et al. Developing patient-reported outcome measures for pain clinical trials: IMMPACT recommendations. Pain 2006;125:208—215. 18. Hadjistavropoulos T, Herr K, Turk DC, et al. An interdisciplinary expert consensus statement on assessment of pain in older persons. Clin J Pain 2007;23(1 suppl):S1—S43. 19. AGS Panel on Persistent Pain in Older Persons. The management of persistent pain in older persons. American Geriatrics Society. J Am Geriatr Soc 2002;50:S205—S224. 20. Feldt KS, Ryden MB, Miles S. Treatment of pain in cognitively impaired compared with cognitively intact older patients with hipfracture. J Am Geriatr Soc 1998;46:1079—1085. 21. Closs SJ, Briggs M. Patients’ verbal descriptions of pain and discomfort following orthopaedic surgery. Int J Nurs Stud 2002;39:563—572. 22. Weiner D, Peterson B, Keefe F. Evaluating persistent pain in long term care residents: what role for pain maps? Pain 1998;76:249—257. 23. Wynne CF, Ling SM, Remsburg R. Comparison of pain assessment instruments in cognitively intact and cognitively impaired nursing home residents. Geriatr Nurs 2000;21:20—23. 24. Shanker V. Neurological complications of systemic disease: GI and endrocrine. In Sirven J, Malamut B (eds): Clinical Neurology of the Older Adult, Philadelphia: Lippincott Williams & Wilkins, 2002; pp 395—404. 25. Pickholtz J, Malamut B. Cognitive changes associated with normal aging. In Sirven J, Malamut B (eds): Clinical Neurology of the Older Adult, Philadelphia: Lippincott Williams & Wilkins, 2002; pp 56—64. 26. Sirven J, Malamut B: Cognitive Changes Associated with Normal Aging. Philadelphia: Lippincott Williams & Wilkins, 2002. 27. Herr K. Pain assessment in the older adult with verbal communication skills. In Gibson SJ, Weiner DK (eds): Progress in Pain Research and Managment: Pain in Older Adults, Vol 35. Seattle: IASP Press, 2005; pp 111—133. 28. Folstein MF, Folstein SE, McHugh PR. "Mini-mental state." A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189—198. 29. Herr KA, Mobily PR, Smith C. Depression and the experience of chronic back pain: a study of related variables and age differences. Clin J Pain 1993;9:104—114. 30. Turk DC, Okifuji A, Scharff L. Chronic pain and depression: role of perceived impact and perceived control in different age cohorts. Pain 1995;61:93—101. 31. Parmelee PA, Katz IR, Lawton MP. The relation of pain to depression among institutionalized aged. J Gerontol 1991;46:P15—P21. 32. Yesavage J, Brink T, Rose T, et al. Development and validation of a geriatric depression scale: A preliminary report. J Psychiatr Res 1983;17:37—49. 33. Radloff L. The CES-D Scale: a self-report depression scale for research in the general population. Appl Psychol Meas 1977;1:385—401. 34. Radloff L, Teri L. The use of CESD with older adults. Clin Gerontol 1986;5:119—135. 35. Parmelee PA. Measuring mood and psychological function associated with pain in late life. In Gibson SJ, Weiner DK (eds): Pain in Older Persons, Progress in Pain Research and Management, Vol 35. Seattle: IASP Press, 2005; pp 175—202. 36. McWilliams LA, Cox BJ, Enns MW. Mood and anxiety disorders associated with chronic pain: an examination in a nationally representative sample. Pain 2003;106:127—133. 37. Von Korff M, Crane P, Lane M, et al. Chronic spinal pain and physical-mental comorbidity in the United States: results from the national comorbidity survey replication. Pain 2005;113:331—339. 38. Beck AT, Epstein N, Brown G, Steer RA. An inventory for measuring clinical anxiety: psychometric properties. J Consult Clin Psychol 1988;56:893—897. 39. Spielberger C, Gorsuch R, Lushene R. Manual for the State-Trait Anxiety Inventory, Palo Alto, CA: Consulting Psychologists Press, 1970. 40. Keefe FJ, Caldwell DS, Baucom D, et al. Spouse-assisted coping skills training in the management of osteoarthritic knee pain. Arthritis Care Res 1996;9:279—291. 41. Turner JA, Jensen MP, Romano JM. Do beliefs, coping, and catastrophizing independently predict functioning in patients with chronic pain? Pain 2000;85:115—125.

II ASSESSMENT OF PAIN AND ITS TREAT MENT 42. Brown GK, Nicassio PM. Development of a questionnaire for the assessment of active and passive coping strategies in chronic pain patients. Pain 1987;31:53—64. 43. Snow-Turek AL, Norris MP, Tan G. Active and passive coping strategies in chronic pain patients. Pain 1996;64:455—462. 44. Covic T, Adamson B, Hough M. The impact of passive coping on rheumatoid arthritis pain. Rheumatology (Oxford) 2000;39:1027—1030. 45. Keefe FJ, Williams DA. A comparison of coping strategies in chronic pain patients in different age groups. J Gerontol 1990;45:P161—P165. 46. Keefe FJ, Caldwell DS, Martinez S, et al. Analyzing pain in rheumatoid arthritis patients. Pain coping strategies in patients who have had knee replacement surgery. Pain 1991;46:153—160. 47. Ersek M, Turner JA, Kemp CA. Use of the chronic pain coping inventory to assess older adults’ pain coping strategies. J Pain 2006;7:833—842. 48. Dunn K, Horgas A. Religious and nonreligious coping in older adults experiencing chronic pain. Pain Manage Nurs 2004;5:19—28. 49. Keefe FJ, Dunsmore J, Burnett R. Behavioral and cognitive-behavioral approaches to chronic pain: recent advances and future directions. J Consult Clin Psychol 1992;60:528—536. 50. Bandura A. Self-efficacy mechanism in human agency. Am Psychol 1987;37:122—147. 51. Bandura A. Self-Efficacy: The Exercise of Control. New York: Freeman, 1997. 52. Barry LC, Guo Z, Kerns RD, et al. Functional self-efficacy and painrelated disability among older veterans with chronic pain in a primary care setting. Pain 2003;104:131—137. 53. Reid MC, Williams CS, Gill TM. The relationship between psychological factors and disabling musculoskeletal pain in community-dwelling older persons. J Am Geriatr Soc 2003;51:1092-1098. 54. Turner JA, Ersek M, Kemp C. Self-efficacy for managing pain is associated with disability, depression, and pain coping among retirement community residents with chronic pain. J Pain 2005;6:471—479. 55. Keefe F, Blumenthal J, Baucom D, et al. Effects of spouse-assisted coping skills training and exercise training in patients with osteoarthritic knee pain: a randomized controlled study. Pain 2004;110:539—549. 56. Keefe F, Caldwell D, Baucom D, et al. Spouse-assisted coping skills training in the management of osteoarthritic knee pain: long term follow up results. Arthritis Care Res 1999;12:101—111. 57. Ersek M, Turner JA, McCurry SM, et al. Efficacy of a selfmanagement group intervention for elderly persons with chronic pain. Clin J Pain 2003;19:156—167. 58. Gibson SJ, Weiner DK. Pain in Older Persons. Seattle: IASP Press, 2005. 59. Herr KA, Garand L. Assessment and measurement of pain in older adults. Clin Geriatr Med 2001;17:457—478, vi. 60. Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singapore 1994;23:129—138. 61. Melzack R. The Short-Form McGill Pain Questionnaire. Pain 1987;30:191—197. 62. Deen G. Back and neck pain. In Sirven J, Malamut B (eds): Clinical Neurology of the Older Adult, Philadelphia: Lippincott Williams & Wilkins, 2002; pp 191—199. 63. Tinetti ME. Performance-oriented assessment of mobility problems in elderly patients. J Am Geriatr Soc 1986;34:119—126. 64. Podsiadlo D, Richardson S. The timed "Up & Go": a test of basic functional mobility for frail elderly persons. J Am Geriatr Soc 1991;39:142—148. 65. Dodick D, Capobianco D. Headaches. In Sirven J, Malamut B (eds): Clinical Neurology of the Older Adult. Philadelphia: Lippincott Williams & Wilkins, 2002; pp 176—190. 66. Andersen G, Vestergaard K, Ingeman-Nielsen M, Jensen TS. Incidence of central post-stroke pain. Pain 1995;61:187—193. 67. Benrud-Larson LM, Wegener ST. Chronic pain in neurorehabilitation populations: prevalence, severity and impact. Neurorehabilitation 2000;14:127—137. 68. Spiera R, Spiera H. Inflammatory disease in older adults. Cranial arteritis. Geriatrics 2004;59:25—29; quiz 30. 69. Ardery G, Herr KA, Titler MG, et al. Assessing and managing acute pain in older adults: a research base to guide practice. Medsurg Nurs 2003;12:7—18; quiz 19. 70. Pasaro C, Reed B, McCaffery M. Pain in the Elderly, 2nd ed. St. Louis: Mosby, 1999.

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71. Marco CA, Plewa MC, Buderer N, et al. Self-reported pain scores in the emergency department: lack of association with vital signs. Acad Emerg Med 2006;13:974—979. 72. Clark L, Jones K, Pennington K. Pain assessment practices with nursing home residents. West J Nurs Res 2004;26:733—750. 73. Kamel HK, Phlavan M, Malekgoudarzi B, et al. Utilizing pain assessment scales increases the frequency of diagnosing pain among elderly nursing home residents. J Pain Symptom Manage 2001;21:450—455. 74. Kaasalainen S, Coker E, Dolovich L, et al. Pain management decision making among long-term care physicians and nurses. West J Nurs Res 2007;29:561—580. 75. American Medical Directors Association (AMDA). Chronic Pain Management in the Long Term Care Setting. Columbia, MD: American Medical Doctors Association, 2003. 76. Weiner D, Herr K. Comprehensive interdisciplinary assessment and treatment planning: an integrative overview. In Weiner D, Herr K, Rudy T (eds): Persistent Pain in Older Adults: An Interdisciplinary Guide for Treatment. New York: Springer, 2002; pp 18—57. 77. Roland M, Morris R. A study of the natural history of back pain. Part I: development of a reliable and sensitive measure of disability in lowback pain. Spine 1983;8:141—144. 78. Melzack R. The McGill pain questionnaire: major properties and scoring methods. Pain 1975;1:277. 79. Bergh I, Sjostrom B, Oden A, Steen B. An application of pain rating scales in geriatric patients. Aging Clin Exp Res 2000;12:380—387. 80. Herr K, Mobily PR. Comparison of selected pain assessment tools for use with the elderly. Appl Nurs Res 1993;6:39—46. 81. Bieri D, Reeve R, Champion G, et al. The Faces Pain Scale for the self-assessment of the severity of pain experienced by children: initial validation and preliminary investigation for ratio scale properties. Pain 1990;41:139—150. 82. Wong D, Baker C. Pain in children: comparison of assessment scales. Pediatr Nurse 1988;14:9—17. 83. Tait RC, Chibnall JT, Krause S. The Pain Disability Index: psychometric properties. Pain 1990;40:171—182. 84. Ferrell BA, Stein WM, Beck JC. The Geriatric Pain Measure: validity, reliability and factor analysis. J Am Geriatr Soc 2000;48:1669—1673. 85. Kerns RD, Turk DC, Rudy T. The West Haven—Yale Multidimensional Pain Inventory (WHYMPI). Pain 1985;23:345—356. 86. Gloth F, Scheve A, Stober C, et al. The Functional Pain Scale: reliability, validity and responsiveness in an elderly population. J Am Med Dir Assoc 2001;2:110—114. 87. Jette A. The Functional Status Index: reliability and validity of a selfreport functional disability measure. J Rheumatol Suppl 1987;14(suppl 15):15—21. 88. Washburn RA, Smith KW, Jette AM, Janney CA. The Physical Activity Scale for the Elderly (PASE): development and evaluation. J Clin Epidemiol 1993;46:153—162. 89. Fairback JC, Couper J, Davies JB, O’Brien JP. The Oswestry Low Back Pain Disability Questionnaire. Physiotherapy 1980;66:271—273. 90. McConnell S, Kolopack P, Davis AM. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC): a review of its utility and measurement properties. Arthritis Rheum 2001;45:453—461. 91. Wheeler AH, Goolkasian P, Baird AC, Darden BV 2nd. Development of the Neck Pain and Disability Scale. Item analysis, face, and criterion-related validity. Spine 1999;24:1290—1294. 92. Lefebvre M. Cognitive distortion and cognitive errors in depressed psychiatric and low back pain patients. J Consult Clin Psychol 1981;49:517—525. 93. Gil K, Williams D, Keefe F, Beckham J. The relationship of negative thoughts to pain and psychological distress. Behav Ther 1990;21:349-362. 94. Yong HH, Gibson SJ, Horne DJ, Helme RD. Development of a pain attitudes questionnaire to assess stoicism and cautiousness for possible age differences. J Gerontol B Psychol Sci Soc Sci 2001;56:P279—P284. 95. Sullivan M, Bishop S, Pivik J. The Pain Catastrophizing Scale: development and validation. Psychol Assess 1995;7:524—532. 96. Nicassio PM, Wallston KA, Callahan LF, et al. The measurement of helplessness in rheumatoid arthritis. The development of the arthritis helplessness index. J Rheumatol 1985;12:462—467. 97. Lorig K, Chastain RL, Ung E, et al. Development and evaluation of a scale to measure perceived self-efficacy in people with arthritis. Arthritis Rheum 1989;32:37—44.

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Chapter 5  ASSESSMENT OF PAIN IN THE NONVERBAL AND/OR COGNITIVELY IMPAIRED OLDER ADULT

98. McCracken LM, Zayfert C, Gross RT. The Pain Anxiety Symptoms Scale: development and validation of a scale to measure fear of pain. Pain 1992;50:67—73. 99. Kori S, Miller R, Todd D. Kinesiophobia: a new view of chronic pain behavior. Pain Manage 1990;3:35—43. 100. Cook AJ, Brawer PA, Vowles KE. The fear-avoidance model of chronic pain: validation and age analysis using structural equation modeling. Pain 2006;121:195—206. 101. Burwinkle T, Robinson JP, Turk DC. Fear of movement: factor structure of the Tampa scale of kinesiophobia in patients with fibromyalgia syndrome. J Pain 2005;6:384—391. 102. Lachman ME, Howland J, Tennstedt S, et al. Fear of falling and activity restriction: the survey of activities and fear of falling in the elderly (SAFE). J Gerontol B Psychol Sci Soc Sci 1998;53:43—50.

Chapter 5

ASSESSMENT OF PAIN IN THE NONVERBAL AND/OR COGNITIVELY IMPAIRED OLDER ADULT Karen Bjoro and Keela Herr

INTRODUCTION Pain is a highly subjective and personal experience. Self-report is widely accepted as the most reliable source of information on an individual’s pain experience and is considered to be the ‘‘gold standard’’ in most populations.1,2 Yet, older adults with severe cognitive impairment or who are unconscious and/or intubated during an episode of severe critical illness are unable to communicate their pain experience. The inability to use verbal language represents a major barrier to pain assessment and treatment. For these individuals, alternative approaches to pain assessment, involving observation of pain behaviors and proxy pain reports, are necessary. The ability to use language is a comprehensive and complex behavior acquired in early childhood. The primary faculties of language include speaking, signing, and language comprehension, whereas reading and writing are secondary abilities.3 With language impairment (e.g., aphasia, dysphasia), the ability to communicate orally, through signs, or in writing or the ability to understand such communications may be severely compromised. Language impairment (e.g., aphasia, dysphasia) is associated with many medical illnesses and clinical states (Box 5—1). The loss of ability to communicate is a core feature of many types of cognitive impairment (e.g., dementia, delirium) and occurs frequently with severe critical illness as well as at the end of life, with the naturally occurring deterioration in cognition resulting from ensuing death and/or sedation. The purpose of this chapter is to review the current basis for pain assessment in three nonverbal populations: those with advanced dementia, those with delirium, and those experiencing

103. Rosenstiel AK, Keefe FJ. The use of coping strategies in chronic low back pain patients: relationship to patient characteristics and current adjustment. Pain 1983;17:33—44. 104. Jensen MP, Turner JA, Romano JM, Strom SE. The Chronic Pain Coping Inventory: development and preliminary validation. Pain 1995;60:203—216. 105. Felton BJ, Revenson TA. Coping with chronic illness: a study of illness controllability and the influence of coping strategies on psychological adjustment. J Consult Clin Psychol 1984;52:343—353. 106. Felton BJ, Revenson TA, Hinrichsen GA. Stress and coping in the explanation of psychological adjustment among chronically ill adults. Soc Sci Med 1984;18:889—898. 107. Folkman S, Lazarus RS. If it changes it must be a process: study of emotion and coping during three stages of a college examination. J Pers Soc Psychol 1985;48:150—170.

an episode of critical illness who are unable to communicate owing to an unconscious state or the presence of an endotracheal tube. General principles of pain assessment and specific recommendations for pain assessment of nonverbal older adults are discussed. Finally, a selection of behavioral pain assessment tools for use with these nonverbal older adults is critiqued.

CHALLENGE OF DEMENTIA FOR PAIN ASSESSMENT Dementia is one of the most frequent causes of cognitive impairment in older adults, with a forecast worldwide increase in incidence from 25 million in 2000 to 114 million by 2050.4 Dementia involves the development of multiple cognitive deficits manifested by impaired memory and involving cognitive disturbances and the loss of language, the ability to recognize or identify objects, and executive function.5 As dementia progresses to advanced stages, individuals become increasingly dependent in all activities of daily living, often requiring skilled nursing care. The burden of dementia in the older adult population is compounded by a considerable pain burden.6 In institutionalized older adults with dementia, pain or potentially painful conditions are common, with prevalence estimates ranging between 49% and 83%.7,8 One large-scale nursing home study documented that half of the residents reported having pain in the past week and a fourth experienced pain daily.9 Moreover, a similar prevalence of pain was documented in subgroups of cognitively intact and impaired residents. The most common pain-associated conditions in the cognitively impaired residents were arthritis, previous hip fracture, osteoporosis, pressure ulcers, depression, and a history of a recent fall, unsteady gait, and verbally abusive behavior.9 The severity of cognitive impairment and the progression of language deficit vary by type and stage of disease, environmental factors, and individual characteristics. In Alzheimer’s disease (AD), which accounts for over half of dementia cases, memory deficit is the presenting symptom, with language impairments developing gradually over the course of the illness.10 Typically, AD patients are fluent until the middle to late stages of the disease, whereas global language disturbance and mutism are generally present in the end stage of AD. With vascular dementia, the second most prevalent type, the trajectory of language impairment resembles that observed in AD.11 By comparison, individuals with frontotemporal dementia (behavioral type) and primary progressive aphasia show earlier onset of language impairment and more rapid decline.10 The subtype of dementia also appears to affect pain

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Chapter 5  ASSESSMENT OF PAIN IN THE NONVERBAL AND/OR COGNITIVELY IMPAIRED OLDER ADULT

98. McCracken LM, Zayfert C, Gross RT. The Pain Anxiety Symptoms Scale: development and validation of a scale to measure fear of pain. Pain 1992;50:67—73. 99. Kori S, Miller R, Todd D. Kinesiophobia: a new view of chronic pain behavior. Pain Manage 1990;3:35—43. 100. Cook AJ, Brawer PA, Vowles KE. The fear-avoidance model of chronic pain: validation and age analysis using structural equation modeling. Pain 2006;121:195—206. 101. Burwinkle T, Robinson JP, Turk DC. Fear of movement: factor structure of the Tampa scale of kinesiophobia in patients with fibromyalgia syndrome. J Pain 2005;6:384—391. 102. Lachman ME, Howland J, Tennstedt S, et al. Fear of falling and activity restriction: the survey of activities and fear of falling in the elderly (SAFE). J Gerontol B Psychol Sci Soc Sci 1998;53:43—50.

Chapter 5

ASSESSMENT OF PAIN IN THE NONVERBAL AND/OR COGNITIVELY IMPAIRED OLDER ADULT Karen Bjoro and Keela Herr

INTRODUCTION Pain is a highly subjective and personal experience. Self-report is widely accepted as the most reliable source of information on an individual’s pain experience and is considered to be the ‘‘gold standard’’ in most populations.1,2 Yet, older adults with severe cognitive impairment or who are unconscious and/or intubated during an episode of severe critical illness are unable to communicate their pain experience. The inability to use verbal language represents a major barrier to pain assessment and treatment. For these individuals, alternative approaches to pain assessment, involving observation of pain behaviors and proxy pain reports, are necessary. The ability to use language is a comprehensive and complex behavior acquired in early childhood. The primary faculties of language include speaking, signing, and language comprehension, whereas reading and writing are secondary abilities.3 With language impairment (e.g., aphasia, dysphasia), the ability to communicate orally, through signs, or in writing or the ability to understand such communications may be severely compromised. Language impairment (e.g., aphasia, dysphasia) is associated with many medical illnesses and clinical states (Box 5—1). The loss of ability to communicate is a core feature of many types of cognitive impairment (e.g., dementia, delirium) and occurs frequently with severe critical illness as well as at the end of life, with the naturally occurring deterioration in cognition resulting from ensuing death and/or sedation. The purpose of this chapter is to review the current basis for pain assessment in three nonverbal populations: those with advanced dementia, those with delirium, and those experiencing

103. Rosenstiel AK, Keefe FJ. The use of coping strategies in chronic low back pain patients: relationship to patient characteristics and current adjustment. Pain 1983;17:33—44. 104. Jensen MP, Turner JA, Romano JM, Strom SE. The Chronic Pain Coping Inventory: development and preliminary validation. Pain 1995;60:203—216. 105. Felton BJ, Revenson TA. Coping with chronic illness: a study of illness controllability and the influence of coping strategies on psychological adjustment. J Consult Clin Psychol 1984;52:343—353. 106. Felton BJ, Revenson TA, Hinrichsen GA. Stress and coping in the explanation of psychological adjustment among chronically ill adults. Soc Sci Med 1984;18:889—898. 107. Folkman S, Lazarus RS. If it changes it must be a process: study of emotion and coping during three stages of a college examination. J Pers Soc Psychol 1985;48:150—170.

an episode of critical illness who are unable to communicate owing to an unconscious state or the presence of an endotracheal tube. General principles of pain assessment and specific recommendations for pain assessment of nonverbal older adults are discussed. Finally, a selection of behavioral pain assessment tools for use with these nonverbal older adults is critiqued.

CHALLENGE OF DEMENTIA FOR PAIN ASSESSMENT Dementia is one of the most frequent causes of cognitive impairment in older adults, with a forecast worldwide increase in incidence from 25 million in 2000 to 114 million by 2050.4 Dementia involves the development of multiple cognitive deficits manifested by impaired memory and involving cognitive disturbances and the loss of language, the ability to recognize or identify objects, and executive function.5 As dementia progresses to advanced stages, individuals become increasingly dependent in all activities of daily living, often requiring skilled nursing care. The burden of dementia in the older adult population is compounded by a considerable pain burden.6 In institutionalized older adults with dementia, pain or potentially painful conditions are common, with prevalence estimates ranging between 49% and 83%.7,8 One large-scale nursing home study documented that half of the residents reported having pain in the past week and a fourth experienced pain daily.9 Moreover, a similar prevalence of pain was documented in subgroups of cognitively intact and impaired residents. The most common pain-associated conditions in the cognitively impaired residents were arthritis, previous hip fracture, osteoporosis, pressure ulcers, depression, and a history of a recent fall, unsteady gait, and verbally abusive behavior.9 The severity of cognitive impairment and the progression of language deficit vary by type and stage of disease, environmental factors, and individual characteristics. In Alzheimer’s disease (AD), which accounts for over half of dementia cases, memory deficit is the presenting symptom, with language impairments developing gradually over the course of the illness.10 Typically, AD patients are fluent until the middle to late stages of the disease, whereas global language disturbance and mutism are generally present in the end stage of AD. With vascular dementia, the second most prevalent type, the trajectory of language impairment resembles that observed in AD.11 By comparison, individuals with frontotemporal dementia (behavioral type) and primary progressive aphasia show earlier onset of language impairment and more rapid decline.10 The subtype of dementia also appears to affect pain

II ASSESSMENT OF PAIN AND ITS TREAT MENT

Box 5^1 CLINICAL STATES IN OLDER ADULTS ASSOCIATED WITH INABILITY TO COMMUNICATE VERBALLY          

Dementias Delirium Cerebrovascular accident State of unconsciousness/advanced life support/intubation Severe depression Psychosis Mental disability Coma, persistent vegetative state Encephalopathy Terminal illness

response. In frontotemporal dementia, a decrease in affective pain response has been documented that could be explained by atrophy of the prefrontal cortex. In contrast, with vascular dementia, an increase in affective response is reported that may be related to white matter lesions and deafferentiation in these patients.12 Neuropathologic processes in dementia seriously affect the ability of those with advanced stages of disease to communicate pain. However, only a few studies have investigated the relationship between dementia and the neuropathology of pain, and these are limited to experimental pain studies in individuals with AD. Whereas sensory discriminatory aspects of pain are processed in the lateral pain system (e.g., lateral thalamus), motivational affective aspects are processed in the medial pain system (e.g., anterior cingulate gyrus, hippocampus).13,14 Noxious stimuli transmitted via the lateral pain system are interpreted in the somatosensory cortex, involving areas of the brain that are relatively unaffected by AD neuropathology. This explains the finding that sensory aspects of pain remain intact in individuals with AD. Nevertheless, the lateral pain system does show some functional decline, as evidenced by an elevated pain threshold and reports of less intense pain in those with AD. By contrast, the medial pain system is severely affected by pathologic processes in AD.12,15 The affective pain response (e.g., pain tolerance) was significantly increased in individuals with AD compared with those without dementia.12 Thus, empirical studies indicate that older adults with dementia are not less sensitive to pain but they may fail to interpret sensations as painful. Despite these findings, evidence suggests that older adults with advanced dementia underreport pain compared with those who are cognitively intact. Research studies have documented a decrease in the number of pain complaints with increasing severity of cognitive impairment in older adults with dementia.16,17 Inability to communicate is a major barrier to adequate pain assessment and treatment in older adults with advanced dementia. Cognitively impaired older adults hospitalized with a hip fracture received significantly less opioid analgesia than those with less or no impairment.18,19 In the nursing home setting, pain is documented less frequently in residents unable to communicate their pain, even though they have a similar number of painful diagnoses.9,20,21 Moreover, less analgesia is prescribed and administered for cognitively impaired nursing home residents, even when the impaired residents have numbers of painful diagnoses similar to those in cognitively intact residents.22,23 Thus, the inability to communicate in older adults with dementia is a major barrier to both assessment and treatment. Language impairment is also common in delirium.

CHALLENGE OF DELIRIUM FOR PAIN ASSESSMENT Delirium is a form of transient cognitive impairment often accompanied by loss of the ability to communicate effectively. The incidence of delirium in older adults ranges from 16% to 62% with hip fracture,24 62% in the intensive care unit (ICU),25 25% to 45%

25

in older cancer patients,26 and approximately 22% in nursing home residents.27 Delirium is characterized by recent onset of fluctuating awareness and an inability to focus attention, a change in cognition (e.g., memory deficit, disorientation) or perceptual disturbance, and the presence of an underlying organic illness.5 There are three clinical subtypes of delirium: hyperactive, hypoactive, and mixed.28 Language disturbance in delirium is characteristically manifested by an impaired ability to articulate, name objects, write, or even speak. Speech may be rambling and irrelevant or pressured and incoherent, with unpredictable shifting from subject to subject.5 Thus, although older adults with delirium may be able to speak, the content may be incomprehensible. Although the pathophysiology of delirium remains unclear, there is general agreement that delirium etiology is multifactorial.29,30 Inouye and Charpentier29 proposed that delirium may develop in a vulnerable individual owing to the interaction of predisposing and precipitating risk factors. Predisposing factors (e.g., high age, dementia, multiple chronic diseases) increase the vulnerability of an individual to noxious factors that interact with the underlying predisposing factors to precipitate the onset of delirium. Whereas many potential precipitating factors have been identified (e.g., dehydration, electrolyte disturbance, polypharmacy, infection, hypoxia), delirium onset has also been linked to antecedent pain in hip fracture patients,31 medical patients,32 and older adults undergoing elective surgery.33,34 However, many of the analgesics (e.g., meperidine31,35) and other adjuvant medications used to treat pain (e.g., benzodiazepine35) can also trigger the onset of delirium. The relationship between pain, pain treatment, and delirium is complex and unclear. Pain assessment in older adults with delirium is extremely challenging. No diagnostic tests exist to determine the presence of either pain or delirium. Identification of pain in nonverbal older adults and of delirium both rely on observation of behavioral presentation. Moreover, there is considerable overlap between delirium behaviors and nonverbal pain behaviors. Liptzin and Levkoff36 used behavioral items on the Delirium Symptom Interview37 to observe hypoactive and hyperactive behaviors of patients with delirium (Table 5—1). Interestingly, many behavioral symptoms of delirium also occur on a comprehensive list of nonverbal pain behaviors (Table 5—2) (e.g., wandering, verbally abusive behavior, resistiveness to care). Few studies have investigated pain assessment in older adults with ongoing delirium. One study showed that physicians and nurses were likely to misinterpret agitation as an expression of pain in patients with agitated delirium in whom the pain was well controlled before and after the delirium episode.38 Further, it is unclear whether available behavioral pain tools may assist in pain detection in older adults during episodes of delirium. Only one pain assessment tool has been developed for use with this particular patient population; however, initial testing of the tool was conducted in cognitively intact older adults undergoing orthopedic surgery and not in those with cognitive impairments.39 Thus, the relationships between pain and delirium are complex and unclear. Although improved pain treatment may reduce the occurrence of delirium in older adults, there is a gap in the literature regarding assessment of pain in patients with delirium. It may not be possible to identify pain definitively by behavioral presentation in patients with delirium and may require alternative approaches to pain assessment, such as analgesic trial, addressed in later sections of this chapter.

CHALLENGE OF SEVERE CRITICAL ILLNESS FOR PAIN ASSESSMENT Older adults have an increased prevalence of comorbid illness and trauma and account for more than 60% of all ICU days.40 During episodes of severe critical illness, older people may lose the ability to

26

Chapter 5  ASSESSMENT OF PAIN IN THE NONVERBAL AND/OR COGNITIVELY IMPAIRED OLDER ADULT

Table 5^1. Delirium Subtype and Associated Potential Behavioral Symptoms

Table 5^2. Common Pain Behaviors in Cognitively Impaired Older Persons

Delirium Subtype

Behavioral Symptoms

Behavior

Examples

Hyperactive

Hypervigilance Restlessness Fast or loud speech Irritability Combativeness Impatience Swearing Singing Laughing Uncooperative Euphoric Anger Wandering Easy startling Fast motor responses Distractability Tangentiality Nightmares Persistent thoughts Unawareness Decreased alertness Sparse or slow speech Lethargic Slowed movements Staring Apathy

Facial expressions

Slight frown, sad, frightened face Grimacing, wrinkled forehead, closed or tightened eyes Any distorted expression Rapid blinking Sighing, moaning, groaning Grunting, chanting, calling out Noisy breathing Asking for help Verbal abusiveness Rigid, tense body posture; guarding Fidgeting Increased pacing, rocking Restricted movement Gait or mobility changes Aggressive, combative, resists care Decreased social interactions Socially inappropriate, disruptive Withdrawn Refusing food, appetite change Increase in rest periods Sleep, rest pattern changes Sudden cessation of common routines Increased wandering Crying or tears Increased confusion Irritability or distress

Hypoactive

Based on Liptzin B, Levkoff SE. An empirical study of delirium subtypes. Br J Psychiatry 1992;161:843—845. speak owing to an unconscious state, the presence of an endotracheal tube, or fatigue. Many older adults die in the ICU.41 However, patients able to report the ICU experience in retrospect indicated that endotracheal intubation, mechanical ventilation, and the consequent inability to speak are extremely stressful events.41—43 Pain and the inability to speak were reported to be moderately to extremely bothersome. Endotracheal suctioning is a particularly painful procedure, and the stressful experience associated with the endotracheal tube was strongly associated with the subjects’ experiencing spells of terror.42 Sources of pain during episodes of critical illness include existing an medical condition, traumatic injuries, the surgical/medical procedure, invasive instrumentation, blood draws, and other routine care such as turning, positioning, drain and catheter removal, and wound care.44—46 Adult patients described the experience of pain in critical illness as a constant baseline aching pain with intermittent procedure-related pain that is experienced as sharp, stinging, stabbing, shooting, and awful pain.45 Although most studies have been conducted with younger patients, it should be assumed that nonverbal older adults also experience these sensations. Identification of pain in nonverbal older patients who are unable to communicate their pain and discomfort owing to critical illness requires astute observational skill. Moreover, the complexity of detecting pain is confounded by the overhanging threat of delirium that occurs in approximately 62% of older adults in the ICU.25

Summary The inability of nonverbal populations to communicate pain and discomfort represents a major barrier to adequate pain assessment

Verbalizations, vocalizations

Body movements

Changes in interpersonal interactions Changes in activity patterns or routines

Mental status changes

From American Geriatrics Society (AGS) Panel on Persistent Pain in Older Persons. The management of persistent pain in older persons. J Am Geriatr Soc 2002;50:S211. Used with permission. and treatment. The evidence indicates the urgent need to improve methods of detecting and managing pain in these vulnerable populations and is addressed in the following section.

APPROACHES TO PAIN ASSESSMENT IN NONVERBALOLDER ADULTS Assessment of pain is a critical component of a comprehensive approach to pain management in all populations. The purpose of pain assessment is to detect the presence and source of pain, identify any comorbidities requiring attention, determine the effect of pain on function, and collect data on which to base individual treatment plans.6 Achievement of these goals is challenging in nonverbal older adults. Nevertheless, general principles can guide approaches to pain identification, measurement, and continuous monitoring, as well as selection of specific pain assessment strategies in nonverbal older adults. The American Society for Pain Management Nursing (ASPMN) recently published recommendations for pain assessment in nonverbal individuals.47 This comprehensive, hierarchical strategy includes five key principles to guide pain assessment in nonverbal populations: (1) obtain a self-report if at all possible, (2) investigate for possible pathologies that could produce pain, (3) observe for behaviors that may indicate pain, (4) solicit a surrogate report, and (5) use analgesics to evaluate whether pain management causes a reduction in the behavioral indicators believed to be related

II ASSESSMENT OF PAIN AND ITS TREAT MENT

27

Is pain behavior present during movement?* Yes

No

Is pain behavior present that is not associated with movement?**

No

Yes

No

Do pain behaviors persist?

Are basic comfort needs being met?†

Yes

No

Yes

Provide for basic comfort needs Is there evidence of pathology (e.g., fracture, infection, constipation)?

No Empirical trial of analgesic

Yes

Yes Treat cause of the pathology

to pain.47 These principles reflect a decision making process, illustrated in Figure 5—1, that may guide and support health care clinicians and are discussed in greater depth in the following section.

Obtain a Self-report Attempts should be made to obtain a self-report of pain from all patients. The ability of cognitively impaired patients to report their pain consistently and accurately varies widely across levels of cognitive impairment.48 Research indicates that individuals with mild and moderate dementia and even some with severe dementia are able to self-report.7,48—50 Even a limited yes/no response to a query regarding pain presence is important information regarding the patient’s own pain experience. With increasing cognitive impairment, the ability to reliably use self-report instruments wanes. Although no clear method has been identified to address reliability in using self-report instruments, Buffum and colleagues51 described a Pain Screening Tool, an approach developed for evaluating cognitive ability to reliably complete pain intensity scales. Patients are asked to provide a number from 0 to 3 and a word to describe their pain. After 1 minute of

Do pain behaviors persist?

No

Maintain vigilance: monitor symptoms and response to therapy.

Maintain vigilance: monitor symptoms and response to therapy.

Search for pathology and treat Also try: • Medication before provocative movement • Strategies to alter pain-inducing movement • Reassurance for fear-related behavior

Figure 5^1. Pain assessment in elders with severe cognitive impairment. *For example, grimacing, guarding, combativeness, groaning with movement; resisting care; **for example, agitation, fidgeting, sleep disturbance, diminished appetite, irritability, reclusiveness, disruptive behavior, rigidity, rapid blinking; {for example, toileting, thirst, hunger, visual or hearing impairment. (From Reuben DB, Herr KA, Pacala JT, et al.Geriatrics At Your Fingertips: 2007—2008 Edition. New York:The American Geriatrics Society, 2007. Used with permission.)

distracting conversation, the respondent is asked to recall the number and the word. Patients receive one point each for being able to provide an initial number and word and one half point each for recalling the number and the word. Only respondents who score a three are identified as providing reliable pain reports. Strategies that increase the likelihood of obtaining a self-report of pain from a cognitively impaired individual may include use of a modified verbal rating scale with a limited number of descriptors, careful instruction on tool use and repetition, focus on the individual’s current pain rather than past pain experience, and adaptation of tools to compensate for possible sensory impairments.48,52 However, despite these efforts, many patients’ impairments will be severe enough to require alternative approaches to assessment.

Search for Potential Causes of Pain Pathologic conditions should be considered as a potential cause of pain and discomfort in the assessment process. History and general physical evaluation, examination of any painful regions, as well as consideration of any pain medication regimen provide essential information for clinical decisions. Musculoskeletal and neurologic

28 Chapter 5  ASSESSMENT OF PAIN IN THE NONVERBAL AND/OR COGNITIVELY IMPAIRED OLDER ADULT conditions are among the most common causes of pain in older adults and should be given priority in the clinical examination. Moreover, evaluation of the patient’s cognitive status is a crucial element of geriatric focused-pain assessment because both acute and chronic pain can affect cognition. When pain-associated pathologies are identified, the presence of pain may be assumed and appropriate pain intervention strategies should be implemented. Pain should be treated preemptively prior to initiation of any procedures known to cause pain.1,47 A change in behavior should initiate a search for any acute problems as a source of pain or discomfort (e.g., pneumonia, urinary tract infection, a recent fall). Detailed guidelines with recommendations for assessment of pain pathology in older adults are available.6

Observe for Behaviors that May Indicate Pain When older adults are unable to communicate the presence of pain owing to cognitive impairments, unconsciousness, or severe critical illness, reliance on external signs of pain, such as nonverbal behaviors and physiologic changes, becomes a necessary approach to pain detection. The American Geriatrics Society (AGS) Panel on Persistent Pain in Older Persons2 compiled a comprehensive list of nonverbal behaviors observed in older adults with cognitive impairment with six categories of pain behavioral indicators: facial expressions, verbalizations/vocalizations, body movements, changes in interpersonal interactions, changes in activity patterns or routines, and mental status change (see Table 5—2). This framework provides a valuable resource for evaluating the relevance and comprehensiveness of behaviors included on a particular behavioral pain tool for use with older adults.53 Observational approaches to pain assessment rely on interpretation of behaviors. The inherent subjectivity involved in observational approaches represents challenges to the reliability and validity

of pain assessments. Important issues for consideration when using behavioral observation to detect pain or when selecting a behavioral pain tool are summarized in Table 5—3. In the following section, we provide recommendations that may maximize observational pain assessment approaches in nonverbal older adults. Behavioral indicators for pain assessment must be appropriate to the patient population, setting, and type of pain problems encountered. The shorter behavioral pain tools tend to be direct observation—focused including specific behaviors that may be observed in a direct encounter by trained observers (e.g., grimacing, guarding, restlessness, moaning, fighting the ventilator).54,55 The patient may be observed for a specified period and activity for the presence or absence, intensity, or frequency of pain behaviors.54,56 Shorter behavioral tools require no previous history with the patient, an advantage in the acute care setting. Longer pain scales are more comprehensive including more subtle behavioral indicators in addition to those commonly observed. Items such as changes in activity patterns or routines, interpersonal interactions, or mental status require involvement of family and caregivers familiar with the patient’s baseline or typical behaviors. Thus, longer tools may be more appropriate in the long-term care (LTC) setting in which patients may be observed over time while performing everyday activities. With chronic pain states, changes in physiologic indicators are often not observed. In acute pain situations, physiologic and behavioral indicators may increase temporarily, but these changes may be attributed to underlying physiologic conditions and medications. Thus, changes in vital signs are not reliable as single indicators of pain, but changes in physiologic indicators (e.g., blood pressure, pulse, oxygen saturation) should be considered a cue to begin further assessment for pain or other stressors. Moreover, an absence of increased vital signs does not indicate an absence of pain.57,58 The conditions of behavioral observation are also important to ensure reliability of assessments. Observation of behaviors should

Table 5^3. Key Issues in Behavioral Pain Assessment in Older Adults with Cognitive Impairment Issue

Key Considerations

Specific vs. subtle behaviors

 Specific behaviors are obvious and commonly observed in pain states (e.g. facial expressions, verbalizations/ vocalizations, body movements)2  Subtle behaviors reflect change from usual individual behavioral pattern and are less obvious pain indicators (e.g., changes in interpersonal interactions, activity patterns or mental status)2  Subtle behaviors require interpretation and validation that pain is the etiology  Specific, obvious indicators may be observed directly; no prior history with the patient is required  Subtle behaviors of change from baseline require reassessment over time by individuals familiar with the patient  Use of surrogate reporting requires caution due to evidence of disagreements between self-report of pain by cognitively impaired individuals and proxy report84—87  Patient self-report and proxy report of pain severity show increasing disagreement with increasing severity of cognitive impairment50  Evidence documents surrogate/proxy ability to recognized pain presence but not intensity84  Professional caregivers tend to underestimate patient pain severity84,86,88  Family members tend to overestimate patient pain severity and level of discomfort89  A behavioral pain tool score is not the same as a pain intensity rating; pain behavior tool score and score on pain intensity ratings should not be compared90  A comprehensive indicator set including obvious and less obvious pain behaviors increases sensitivity of behavioral tools to detect pain when present91  A narrow indicator set with only obvious indicators increases specificity of behavioral tools to rule out pain when pain is not present, but are less sensitive in detecting pain in those with less obvious pain presentation91  Behavioral pain assessment may assist in screening for presence of pain, but does not provide diagnostic certainty regarding exact nature and cause of possible pain to guide treatment64—66,68  In situations in which uncertainty prevails, an empirical analgesic trial is warranted as a pain assessment strategy1,6,47

Direct observation vs. surrogate report Pain presence vs. severity

Sensitivity vs. specificity

Screening vs. diagnostic certainty

II ASSESSMENT OF PAIN AND ITS TREAT MENT

occur during movement or activity that is likely to elicit a pain response if pain is present. Studies have demonstrated that observation of pain behaviors at rest is misleading and can result in false judgments that pain is absent, leading to underdetection and undertreatment.18,54,59,60 Moreover, serial observations should be performed under similar circumstances (e.g., time of day, activity performed) to ensure comparability of behavioral pain assessments over time.

Solicit Support of Surrogate Reporters In the absence of pain self-report, surrogate observation is an important source of information. Family members or others who know the patient well (e.g., spouse, child, caregiver) should be encouraged to provide information regarding usual and past behaviors as well as to assist in the identification of subtle, less obvious changes in behavior that may indicate pain presence. In LTC, the certified nursing assistant is a key health care provider who has been shown to be effective in recognizing the presence of pain.61,62 In settings in which health care providers do not have a history with the patient, family members are likely to be the caregivers with the most familiarity with typical pain behaviors or changes in usual activities that might suggest pain presence. A family member’s report of their impression of a patient’s pain and response to an intervention should be included as one component of pain assessment that encompasses multiple sources of information. When engaging multiple care providers and surrogates in pain screening procedures, training is important to safeguard the reliability of behavioral observations. Moreover, when introducing new behavioral tools to the clinical setting, interrater reliability between caregivers should be established initially as well as on a regular basis to calibrate observations, thus reducing subjectivity and the potential for bias associated with this method.

Conduct an AnalgesicTrial If, after following the initial steps in this multifaceted approach to pain assessment, behaviors persist that may indicate pain, an analgesic trial is warranted. The underlying supposition is that any reduction in behaviors after analgesic intervention is related to improved pain control. Early unblinded trials provided preliminary support for this approach.63 Buffum and coworkers64 did not demonstrate significant changes in agitated behavior believed to be pain related in persons with advanced dementia; however, the acetaminophen dose was only 1500 mg/day. In a randomized, controlled trial (RCT) evaluating low-dose opioids in persons with dementia, Manfredi and associates65 reported decreased agitation in the over-85 age group and suggested that less response in the younger old group could be related to low dosing of analgesic. In a recent double-blind crossover RCT with patients with dementia receiving 3000 mg/day of acetaminophen, Chibnall and colleagues66 demonstrated increased levels of social activity and interaction compared with the times the patients were receiving placebo. An analgesic trial is an integrated component of the Serial Trial Intervention (STI), a clinical protocol developed by Kovach and colleagues,67 that uses a systematic method for assessing and treating potential pain-related behaviors in patients with severe dementia. A recent RCT of the STI demonstrated significantly less discomfort and behavioral symptoms returning to baseline more frequently in the treatment group and has been shown to be effective in increasing recognition and treatment of pain in persons with dementia.68 Although an analgesic trial is a promising approach, selecting and titrating analgesics for this purpose have not been clearly explicated or studied. The use of an analgesic trial as a means to evaluate pain as the cause of potential pain-related behaviors requires further investigation but is likely an important step in the process of

29

recognizing and validating pain in those presenting with atypical pain behaviors.

Summary This section has outlined key components of a comprehensive approach to pain assessment in nonverbal older adults. A multifaceted approach is recommended that combines direct observation of behaviors, family/caregiver input, and evaluation of response to treatment. A standardized behavioral pain tool may be used as one component of a comprehensive approach to pain assessment and is addressed in the following section.

BEHAVIORAL PAIN ASSESSMENT TOOLS FORUSE WITHOLDER ADULTS Since the late 1990s, a number of standardized tools for pain assessment based on observation of behaviors have been developed for use with nonverbal older adult populations. Several reviews of available tools53,69—72 have indicated that, although there are tools with potential, currently no tool has sufficiently strong reliability and validity to support recommendation for broad adoption in clinical practice. Moreover, reviews have called for further tool testing in larger samples and/or in diverse clinical settings. In an earlier comprehensive review, Herr and associates53 critiqued 10 tools for use with nonverbal adults with advanced dementia based on published reports of psychometric data. Since the publication of this review, some tools have undergone further testing and development. In the following discussion, a selection of tools is presented with updated critiques. Further, we have included two recently developed tools for use with critically ill adult patients who are unconscious and/or intubated that have not previously been critiqued for relevance, reliability, and validity for use with this patient population. Table 5—4 provides an overview of characteristics of the selected tools with presentation of tool items and scoring range, reliability, validity, and clinical utility.

The Checklist of Nonverbal Pain Indicators18,54 The Checklist of Nonverbal Pain Indicators (CNPI), developed to measure pain in cognitively impaired older adults, includes six conceptually sound behavioral items commonly observed in direct observation situations. Initial tool testing supports the reliability and validity of this tool for use in acute care, although internal consistencies were low, suggesting a need for further testing. In a tool evaluation in Norwegian nursing homes, the test-retest and interrater reliabilities reported were low to moderate when administered by various categories of nursing personnel as an element of daily care, and moreover, concurrent validity was supported.73 In another recent study in LTC,91 sensitivity of the CNPI was moderate, while at the same time, nearly half the residents who reported having pain showed no pain behaviors on the CNPI, thus giving rise to concerns about the ability of the tool to detect pain in those unable to report. Because the CNPI lacks indicators of subtle behaviors, the tool’s ability to detect pain in those with less obvious behavioral presentation is questioned. Thus, this tool may be more appropriate for use in acute care. However, additional testing in larger and more acute care samples is needed.

The Doloplus 274 The Doloplus 2 is a French tool developed for multidimensional assessment of pain in nonverbal older adults. Psychometric

Tool Name

Items/Scoring Range

Reliability

Tools for Nonverbal Older Adults with Advanced Dementia Internal consistency: CNPI18,54,73,91 6 items, including nonverbal vocalizations, 0.54—0.64 Interrater reliability: facial grimacing or k = 0.62—0.82 wincing, bracing, 74%—94% rubbing, restlessness, k = 0.45—0.69 vocal complaints. Test-retest: Items scored present or 34%—41% absent at rest and on k = 0.23—0.66 movement Total score range 0—12

Doloplus 249,74—76

10 items; three dimensions of somatic (n = 5), psychomotor (n = 2), psychosocial (n = 3) Score range: 0—30 Reflects progression of experienced pain, not current pain experience

Internal consistency: Total scale: 0.82 Subscales: Somatic: 0.63—0.7 Psychomotor: 0.7—0.8 Psychosocial: 0.58—0.63 Interrater reliability: Not established Test-retest: Not established

PACSLAC75,77

60 items, four dimensions:

Internal consistency: Retrospective data: 0.85

Validity

Feasibility/Utility

Summary

Moderate discriminant validity supported by higher scores on movement vs. at rest Convergent validity supported by moderate correlations with VDS with movement, but only weak correlation at rest In LTC: Sensitivity: 55% Specificity: 85% Convergent validity supported by significant positive relationship between selfreport of pain intensity and CNPI score Concurrent validity supported by positive correlation with nurse-rated VAS Convergent validity supported by moderate positive correlations with self-report of pain on VAS (r = 0.65) and on VAS, VRS, and FPS (r = 0.31— 0.40). Predictive validity supported by significant prediction of expert rated NRS-11 score; four items explained 62% of the expert score; four items explained 68% of the variance of the expert-rated pain score Sensitivity: 71% Specificity: 76% Concurrent validity indicated by moderate correlations with PACSLAC, PAINAD, a nurserated VAS, and an expertrated VAS Discriminant validity supported by

Language of original: English Translations: Norwegian and Dutch Easy to use Scoring instructions provided Score interpretation unclear Tested in acute care and long-term care

CNPI includes only common obvious behaviors observed by direct observation Tool appears to lack ability to detect pain in individuals with less common pain presentation (e.g., nursing home residents) CNPI appears more appropriate for pain assessment in acute care and procedural pain situations

Language of original: French Translations: Dutch, Norwegian, English English translation issues are evident and English version is not tested Estimated time to complete 5 minutes Tool manual is clear Tool evaluation by nurses shows the tool is difficult to score and interpret

Psychosocial subscale appears to need revision based on psychometric results Nurses report tool is difficult to score and interpret English tool version needs testing in English-speaking population

Language of original: English

30 Chapter 5  ASSESSMENT OF PAIN IN THE NONVERBAL AND/OR COGNITIVELY IMPAIRED OLDER ADULT

Table 5^4. Characteristics of Selected Behavioral Pain Assessment Tools for Nonverbal Older Adults with Dementia or Severe Critical Illness (Unconscious/Intubated)

PACSLAC-D-Revised92

PAINAD75,78—80,93—96

Total tool: 0.62—0.84 Subscales: 0.12—0.76 Interrater reliability: 0.92 Test-retest: Good intrarater reliabilities

24 items; three subscales: facial and vocal expressions (n = 10) resistance/defense (n = 6) social-emotional aspects/ mood (n = 8) Score range: 0—24 5 items: breathing, negative vocalizations, facial expression, body language, consolability Score range: 0—10

Internal consistency: Total tool: 0.82—0.86 Subscales: 0.72—0.82 Interrater reliability: Not yet established Test-retest: Not yet evaluated Internal consistency: 0.50—0.67 0.69—0.74 Interrater reliability: r = 0.82—0.97 0.75—0.81 Test-retest: r = 0.90 (P < .001) Time interval: morning/ evening shift scores r = 0.88 (interval: 15 days) r = 0.89

Translations: Dutch Appears easy to use; estimated time to complete 5 min Nurses report that some items on the tool are redundant

Tool most preferred by nurses when compared with PAINAD and Doloplus 2 Promising tool but item reduction and subscale revisions needed

Available in Dutch and English translation Clinical utility not yet evaluated

Promising preliminary tool needs prospective testing in independent sample Testing in English-speaking population needed

Discriminant validity supported by 1. Moderate ability to differentiate pleasant and aversive activities 2. Before and after pain medication 3. Ability to differentiate levels of pain: at rest, during influenza vaccination, and during mobilization/bathing Ability to detect change before and after pain medication in treatment group vs. controls; moderate effect size Convergent validity indicated by positive correlations with DS-DAT, PACSLAC and nurse-rated VAS Scores on the DS-DAT decreased following pain intervention Divergent validity indicated by no correlation with MMSE and GDS and Cornell Depression Scale and AMT score

Language of original: English Translations: Dutch, German, Italian Requires 5 minute observation period Uncertainty about when to implement consolability item Nurses evaluate tool as too concise

Actual interval time for testretest not reported Measurement of pain severity via observation of behaviors not supported in the literature, although tool appears to discriminate between levels of pain Usefulness of breathing and consolability items for pain detection is questioned Concerning validity. there was no indication as to whether raters were blind to the intervention, and subjects were not randomly allocated to treatment or control group

31

 Moderate ability to differentiate between pain, calm, and distress events based on rater memory  Ability to differentiate levels of pain: at rest, during influenza vaccination, and during mobilization/bathing Congruent validity supported by significant positive correlations with PAINAD, self-report, and proxy rating on VAS Correlation with original PACSLAC suggests validity is retained

II ASSESSMENT OF PAIN AND ITS TREAT MENT

Facial expression (n = 13) Activity/body movements (n = 20) Social/personality/mood (n = 12) Physiologic/eating/ sleeping/vocal (n = 15) Score range: 0—60

Continued

32

Tool Name

Items/Scoring Range

Reliability

Validity

Tools for Nonverbal Older Adults with Severe Critical Illness (unconscious/intubated) Discriminant validity indicated BPS81—83 Three behavioral items: Interrater reliability: by significantly higher BPS facial expression, 0.64—0.72 scores during painful movements of upper Interrater reliability: procedure (repositioning) limbs, compliance with k = 0.74 (P < .01) compared with rest periods ventilation Good interrater reliability and nonsignificant increase in Scoring range: 3—12 (r2 = 0.91—0.89) average BPS during a less Percent agreement: painful procedure (eye care) 36%—91% The higher the sedation/ Test-retest: analgesia administered, the Not established lower the BPS value as well as BPS change Factor analysis supports content validity in adults Support for tool ability to detect change in clinical status and detect painful procedures is indicated by large effect size for both subscale scores and for total BPS scores Despite significant increase in physiologic variables (HR and mean arterial BP) between rest and painful procedure times, correlations among BPS score and HR/BP were not significant. Significant negative correlations with Ramsay sedation scale; the higher the sedation level, the lower the BPS scores

Feasibility/Utility

Summary

Language of original: French Translation: English Appears easy to use; requires 4 min, on average, to complete Reported less difficulty agreeing on pain level when pain level was low, but greater when assessing increased pain level Interpretation of tool score unclear

Psychometric evaluation largely based on observations as unit of analysis rather than patients Internal consistency is variable; interrater reliability varies widely across studies Tool not evaluated in sample of older adults

Chapter 5  ASSESSMENT OF PAIN IN THE NONVERBAL AND/OR COGNITIVELY IMPAIRED OLDER ADULT

Table 5^4. Characteristics of Selected Behavioral Pain Assessment Tools for Nonverbal Older Adults with Dementia or Severe Critical Illness (Unconscious/Intubated)çcont’d

CPOT55

4 items, including facial expression, body movements, muscle tension, compliance to ventilator if the patient is intubated or vocalization if extubated Scoring range: 0—8

Internal consistency: Not established Interrater reliability: k = 0.52—0.88 Test-retest: Not established

Criterion validity with intubated/conscious patients indicated by significantly higher CPOT scores for patients reporting pain presence compared with lack of pain during positioning, at rest, and recovery postprocedure Moderate criterion validity in extubated conscious patients indicated by moderate correlations between CPOT scores and self-reported pain intensity scores during positioning, at rest and recovery post-procedure Moderate ability to discriminate pain indicated by significantly higher CPOT scores during positioning than during rest in three situations: (1) intubated and unconscious, (2) intubated and conscious, and (3) extubated and conscious

Language of original tool: French Requires 1-min observation period Interpretation of score unclear

Evidence of internal consistency is needed Evaluation of French tool conducted in French-speaking population Evaluation in English is needed Tool evaluation in older adult samples is warranted Tool evaluation in larger samples and with a variety of conditions is needed

II ASSESSMENT OF PAIN AND ITS TREAT MENT

BP, blood pressure; BPS, Behavioral Pain Scale; CNPI, Checklist of Nonverbal Pain Indicators; CPOT, Critical Care Pain Observation Tool; FPS, Faces Pain Scale; GDS, Geriatric Depression Scale; HR, heart rate; LTC, long-term care; MMSE, Mini-Mental State; NRS, numerical rating scale; PACSLAC, Pain Assessment Checklist for Seniors with Limited Ability to Communicate; PAINAD, Pain in Advanced Dementia; VAS, visual analog scale; VDS, verbal descriptor scale.

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Chapter 5  ASSESSMENT OF PAIN IN THE NONVERBAL AND/OR COGNITIVELY IMPAIRED OLDER ADULT

evaluations are available based on French-, Dutch-, and Norwegianspeaking populations, but not on English-speaking ones. The Doloplus 2 addresses many key indicators noted in the literature and AGS Guidelines. Doloplus reflects the progression of experienced pain, not current pain experience; thus, intrarater and interrater reliabilities of the tool represent a particular challenge and have not yet been adequately established. Although internal consistencies for the total scale and the psychomotor reactions subscale were strong, reliabilities for somatic reactions and psychosocial reactions subscales were low.75 Moreover, a Norwegian study demonstrated that the four most informative tool items explained 68% of the variance of the expert score, with the psychosocial reactions subscale contributing little to the tool.76 Thus, despite evidence to support validity,49,75,76 there is indication of need for a tool revision. Moreover, although clinicians report the ctool manual is clear, in clinical testing, nurses reported that the tool is difficult to score and interpret.75,76

The Pain Assessment Checklist for Seniors with Severe Dementia77 The Pain Assessment Checklist for Seniors with Severe Dementia (PACSLAC), developed by a Canadian team, is a conceptually sound comprehensive checklist of pain behaviors that addresses all six pain behavioral categories included in the AGS Guidelines. In preliminary testing, the PACSLAC showed initial reliability and validity based on retrospective judgments. In recent prospective testing of a Dutch version of the tool, interrater and intrarater reliabilities were high.75 The tool includes 60 behavioral items; however, nearly half the items were not observed in over 90% of the study subjects, suggesting a need for item reduction. Moreover, although internal consistency for total tool score was good, results for subscale scores were poor to moderate, suggesting a need for tool revision. PACSLAC also showed good construct and congruent validity and was rated the most preferred behavioral pain tool by Dutch nurses. Thus, the Dutch research team found the PACSLAC to be the most promising tool for further development.75

The Pain Assessment Checklist for Seniors with Severe DementiaçDutch-Revised75 The PACSLAC—Dutch-Revised (PACSLAC-D-Revised) is a 24item preliminary tool with three subscales derived from the original PACSLAC based on factor analysis. Internal consistencies of the total tool and revised subscales are good. Moreover, the reduced version of the scale correlated highly with the original tool, suggesting that validity is retained. However, further prospective, confirmatory testing in an independent sample is needed.

The Pain Assessment in Advanced Dementia Scale78 The Pain Assessment in Advanced Dementia (PAINAD) scale was developed as a short, easy-to-use observation tool for behavioral pain assessment in nonverbal older adults with advanced dementia. Originally developed in English, the PAINAD has been translated and tested in Italian,79 Dutch,75 and German.80 Although interrater75,78—80 and test-retest75,79,80 reliabilities have been supported, internal consistency is only moderate, with the breathing item scoring persistently low.75 Evidence currently supports several types of validity. However, despite mounting evidence of reliability and validity, issues persist. The PAINAD attempts to measure severity based on scoring of behaviors that has not been substantiated in the literature. Moreover, in clinical testing, nurses report experiencing

the PAINAD as too concise, with too few pain cues included.75 In one study, raters did not use the breathing item in painful situations in over 80% of participants with pain.75 In another study, nurses expressed uncertainty regarding the consolability item.80 Thus, the limited number of items restricts the ability of the PAINAD to detect pain in persons with dementia with more subtle behavioral presentation.

Behavioral Pain Scale81 The Behavioral Pain Scale (BPS) is a French tool developed for critically ill, sedated adult patients undergoing mechanical ventilation. Initial reports of tool testing in trauma and postoperative ICUs in France81 and Morocco82 appear to provide initial support for reliability and validity; however, results are largely based on the total number of observations rather than on individual patients. Initial validation studies were conducted with younger adults; thus, testing in older adult populations is needed. An English version of the BPS was tested in Australia in unconscious medical and surgical ICU patients, including some older patients (median age 64 yr, range 16—82).83 Reported reliabilities were variable, suggesting a need for further testing under more tightly controlled conditions. Data were skewed toward the lower end of the BPS, which may indicate inaccurate scaling of items. Patients were not assessed for delirium in any of these three BPS studies. Thus, further testing of the BPS is needed to establish reliability and validity using patients as the unit of analysis, and moreover, testing in older adults is needed.

Critical Care Pain ObservationTool55 The Critical Care Pain Observation Tool (CPOT) is a French tool developed by a Canadian team for assessment of pain behaviors in critically ill patients unable to communicate verbally. The CPOT attempts to measure pain intensity via behavioral observation, which has not been substantiated in the literature. Initial tool testing was conducted in cognitively intact adult surgical patients with no delirium while unconscious, conscious, intubated, and after extubation. Internal consistency was not reported, and interrater reliability was only moderate; thus, further testing is necessary to establish reliability. Initial tool validity was supported. Although this tool shows promise, tool testing in critically ill older adult samples as well as testing in English-speaking populations are needed.

Summary This review demonstrates progress is being made in the development and validation of behavioral pain tools for use with nonverbal older adults. Yet, despite advances, no single pain behavioral tool has been shown to be superior for use with older adults who are unable to communicate verbally owing to dementia or to unconscious state and/or intubation. Continued and concerted effort is needed to develop and validate tools for nonverbal populations.

CONCLUSION Pain is an important health problem for nonverbal older adults with dementia and delirium and during episodes of severe critical illness requiring appropriate strategies for these vulnerable populations. A comprehensive approach to assessment is advocated, including multiple sources of information to ensure a valid and reliable basis on which to make treatment decisions. Behavioral observation and surrogate report are essential components of a

II ASSESSMENT OF PAIN AND ITS TREAT MENT

multifaceted approach to assessment that may include standardized behavioral pain tools. Although some currently available tools for behavioral assessment in nonverbal older adults show promise, there is currently no single tool with sufficient validity and reliability to warrant recommendation for broad adoption in clinical practice.

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25. McNicoll L, Pisani MA, Zhang Y, et al. Delirium in the intensive care unit: occurrence and clinical course in older patients. J Am Geriatr Soc 2003;51:591—598. 26. Goy E, Ganzini L. Delirium, anxiety, and depression. In Morrison RS, Meier DE (eds): Geriatric Palliative Care. New York: Oxford University Press, 2003; pp 286—303. 27. Culp KR, Wakefield B, Dyck MJ, et al. Bioelectrical impedance analysis and other hydration parameters as risk factors for delirium in rural nursing home residents. J Gerontol A Biol Sci Med Sci 2004;59:813—817. 28. Lipowski ZJ: Delirium: Acute Confusional States. New York: Oxford University Press, 1990. 29. Inouye SK, Charpentier PA. Precipitating factors for delirium in hospitalized elderly persons: predictive model and interrelationship with baseline vulnerability. JAMA 1996;275:852—857. 30. Young J, Inouye SK. Delirium in older people. BMJ 2007;334:842—846. 31. Morrison RS, Magaziner J, Gilbert M, et al. Relationship between pain and opioid analgesics on the development of delirium following hip fracture. J Gerontol A Biol Sci Med Sci 2003;58:76—81. 32. Schor JD, Levkoff SE, Lipsitz LA, et al. Risk factors for delirium in hospitalized elderly. JAMA 1992;267:827—831. 33. Duggleby W, Lander J. Cognitive status and postoperative pain: older adults. J Pain Symptom Manage 1994;9:19—27. 34. Lynch EP, Lazor MA, Gellis JE, et al. The impact of postoperative pain on the development of postoperative delirium. Anesth Analg 1998;86:781—785. 35. Marcantonio ER, Juarez G, Goldman L, et al. The relationship of postoperative delirium with psychoactive medications. JAMA 1994;272:1518—1522. 36. Liptzin B, Levkoff SE. An empirical study of delirium subtypes. Br J Psychiatry 1992;161:843—845. 37. Albert MS, Levkoff SE, Reilly C, et al. The Delirium Symptom Interview: an interview for the detection of delirium symptoms in hospitalized patients. J Geriatr Psychiatry Neurol 1992;5:14—21. 38. Bruera E, Fainsinger RL, Miller MJ, Kuehn N. The assessment of pain intensity in patients with cognitive failure: a preliminary report. J Pain Symptom Manage 1992;7:267—270. 39. Decker SA, Perry AG. The development and testing of the PATCOA to assess pain in confused older adults. Pain Manage Nurs 2003;4:77—86. 40. Angus DC, Kelley MA, Schmitz RJ, et al. Caring for the critically ill patient. Current and projected workforce requirements for care of the critically ill and patients with pulmonary disease: can we meet the requirements of an aging population? JAMA 2000;284:2762—2770. 41. Nelson JE, Meier DE, Oei EJ, et al. Self-reported symptom experience of critically ill cancer patients receiving intensive care. Crit Care Med 2001;29:277—282. 42. Rotondi AJ, Chelluri L, Sirio C, et al. Patients’ recollections of stressful experiences while receiving prolonged mechanical ventilation in an intensive care unit. Crit Care Med 2002;30:746—752. 43. Pennock BE, Crawshaw L, Maher T, et al. Distressful events in the ICU as perceived by patients recovering from coronary artery bypass surgery. Heart Lung 1994;23:323—327. 44. Puntillo KA, Morris AB, Thompson CL, et al. Pain behaviors observed during six common procedures: results from Thunder Project II. Crit Care Med 2004;32:421—427. 45. Puntillo KA, White C, Morris AB, et al. Patients’ perceptions and responses to procedural pain: results from Thunder Project II. Am J Crit Care 2001;10:238—251. 46. Jacobi J, Fraser G, Coursin DB, et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med 2002;30:119—141. 47. Herr K, Coyne PJ, Key T, et al. Pain assessment in the nonverbal patient: position statement with clinical practice recommendations. Pain Manage Nurs 2006;7:44—52. 48. Closs SJ, Barr B, Briggs M, et al. A comparison of five pain assessment scales for nursing home residents with varying degrees of cognitive impairment. J Pain Symptom Manage 2004;27:196—205. 49. Pautex S, Herrmann F, Le Lous P, et al. Feasibility and reliability of four pain self-assessment scales and correlation with an observational rating scale in hospitalized elderly demented patients. J Gerontol A Biol Sci Med Sci 2005;60:524—529. 50. Pautex S, Michon A, Guedira M, et al. Pain in severe dementia: self-assessment or observational scales? J Am Geriatr Soc 2006;54:1040—1045.

36 Chapter 5  ASSESSMENT OF PAIN IN THE NONVERBAL AND/OR COGNITIVELY IMPAIRED OLDER ADULT 51. Buffum MD, Miaskowski C, Sands L, Brod M. A pilot study of the relationship between discomfort and agitation in patients with dementia. Geriatr Nurs 2001;22:80—85. 52. Herr K, Garand L. Assessment and measurement of pain in older adults. Clin Geriatr Med 2001;17:457—478, vi. 53. Herr K, Bjoro K, Decker S. Tools for assessment of pain in nonverbal older adults with dementia: a state-of-the-science review. J Pain Symptom Manage 2006;31:170—192. 54. Feldt KS. The Checklist of Nonverbal Pain Indicators (CNPI). Pain Manage Nurs 2000;1:13—21. 55. Gelinas C, Fillion L, Puntillo KA, et al. Validation of the CriticalCare Pain Observation Tool in adult patients. Am J Crit Care 2006;15:420—427. 56. Hurley AC, Volicer BJ, Hanrahan PA, et al. Assessment of discomfort in advanced Alzheimer patients. Res Nurs Health 1992;15:369—377. 57. Pasero C, McCaffery M. Pain in the critically ill. Am J Nurs 2002;102:59—60. 58. McCaffery M, Pasero C: Pain: Clinical Manual, 2nd ed. St. Louis: Mosby, 1999. 59. Bell ML. Postoperative pain management for the cognitively impaired older adult. Semin Perioper Nurs 1997;6:37—41. 60. Hadjistavropoulos T, LaChapelle DL, MacLeod FK, et al. Measuring movement-exacerbated pain in cognitively impaired frail elders. Clin J Pain 2000;16:54—63. 61. Mentes JC, Teer J, Cadogan MP. The pain experience of cognitively impaired nursing home residents: perceptions of family members and certified nursing assistants. Pain Manage Nurs 2004;5:118—125. 62. Nygaard HA, Jarland M. Chronic pain in nursing home residents—patients’ self-report and nurses’ assessment. Tidsskr Nor Laegeforen 2005;125:1349—1351. 63. Kovach CR, Weissman DE, Griffie J, et al. Assessment and treatment of discomfort for people with late-stage dementia. J Pain Symptom Manage 1999;18:412—419. 64. Buffum MD, Sands L, Miaskowski C, et al. A clinical trial of the effectiveness of regularly scheduled versus as-needed administration of acetaminophen in the management of discomfort in older adults with dementia. J Am Geriatr Soc 2004;52:1093—1097. 65. Manfredi PL, Breuer B, Wallenstein S, et al. Opioid treatment for agitation in patients with advanced dementia. Int J Geriatr Psychiatry 2003;18:700—705. 66. Chibnall JT, Tait RC, Harman B, Luebbert RA. Effect of acetaminophen on behavior, well-being, and psychotropic medication use in nursing home residents with moderate-to-severe dementia. J Am Geriatr Soc 2005;53:1921—1929. 67. Kovach CR, Noonan PE, Griffie J, et al. Use of the Assessment of Discomfort in Dementia protocol. Appl Nurs Res 2001;14:193—200. 68. Kovach CR, Noonan PE, Schlidt AM, et al. The Serial Trial Intervention: an innovative approach to meeting needs of individuals with dementia. J Gerontol Nurs 2006;32:18—25. 69. Hadjistavropoulos T. Assessing pain in older persons with severe limitations in ability to communicate. In Gibson SJ, Weiner DK (eds): Pain in Older Persons. Seattle: IASP Press, 2005; pp 135-151. 70. Stolee P, Hillier LM, Esbaugh J, et al. Instruments for the assessment of pain in older persons with cognitive impairment. J Am Geriatr Soc 2005;53:319—326. 71. Zwakhalen SM, Hamers JP, Abu-Saad HH, Berger MP. Pain in elderly people with severe dementia: a systematic review of behavioural pain assessment tools. BMC Geriatr 2006;6:3. 72. van Herk R, van Dijk M, Baar FP, et al. Observation scales for pain assessment in older adults with cognitive impairments or communication difficulties. Nurs Res 2007;56:34—43. 73. Nygaard HA, Jarland M. The Checklist of Nonverbal Pain Indicators (CNPI): testing of reliability and validity in Norwegian nursing homes. Age Ageing 2006;35:79—81. 74. Lefebvre-Chapiro S, The Doloplus group. The Doloplus 2 scale—evaluating pain in the elderly. Eur J Palliat Care 2001;8:191-194. 75. Zwakhalen SM, Hamers JP, Berger MP. The psychometric quality and clinical usefulness of three pain assessment tools for elderly people with dementia. Pain 2006;126:210—220. 76. Holen JC, Saltvedt I, Fayers PM, et al. The Norwegian Doloplus-2, a tool for behavioural pain assessment: translation and pilotvalidation in nursing home patients with cognitive impairment. Palliat Med 2005;19:411—417.

77. Fuchs-Lacelle S, Hadjistavropoulos T. Development and preliminary validation of the Pain Assessment Checklist for Seniors with Limited Ability to Communicate (PACSLAC). Pain Manag Nurs 2004;5:37—49. 78. Warden V, Hurley AC, Volicer L. Development and psychometric evaluation of the Pain Assessment in Advanced Dementia (PAINAD) scale. J Am Med Dir Assoc 2003;4:9—15. 79. Costardi D, Rozzini L, Costanzi C, et al. The Italian version of the Pain Assessment in Advanced Dementia (PAINAD) scale. Arch Gerontol Geriatr 2007;44:175—180. 80. Schuler MS, Becker S, Kaspar R, et al. Psychometric properties of the German Pain Assessment in Advanced Dementia scale (PAINAD-G) in nursing home residents. J Am Med Dir Assoc 2007;8:388—395. 81. Payen JF, Bru O, Bosson JL, et al. Assessing pain in critically ill sedated patients by using a behavioral pain scale. Crit Care Med 2001;29:2258—2263. 82. Aissaoui Y, Zeggwagh AA, Zekraoui A, et al. Validation of a behavioral pain scale in critically ill, sedated, and mechanically ventilated patients. Anesth Analg 2005;101:1470—1476. 83. Young J, Siffleet J, Nikoletti S, Shaw T. Use of a behavioural pain scale to assess pain in ventilated, unconscious and/or sedated patients. Intensive Crit Care Nurs 2006;22:32—39. 84. Manfredi PL, Breuer B, Meier DE, Libow L. Pain assessment in elderly patients with severe dementia. J Pain Symptom Manage 2003;25:48—52. 85. Cohen-Mansfield J, Creedon M. Nursing staff members’ perceptions of pain indicators in persons with severe dementia. Clin J Pain 2002;18:64—73. 86. Cohen-Mansfield J, Lipson S. Pain in cognitively impaired nursing home residents: how well are physicians diagnosing it? J Am Geriatr Soc 2002;50:1039—1044. 87. Horgas AL, Dunn K. Pain in nursing home residents. Comparison of residents’ self-report and nursing assistants’ perceptions. incongruencies exist in resident and caregiver reports of pain; therefore, pain management education is needed to prevent suffering. J Gerontol Nurs 2001;27:44—53. 88. Cohen-Mansfield J. Nursing staff members’ assessments of pain in cognitively impaired nursing home residents. Pain Manage Nurs 2005;6:68—75. 89. Cohen-Mansfield J. Relatives’ assessment of pain in cognitively impaired nursing home residents. J Pain Symptom Manage 2002;24:562—571. 90. Pasero C, McCaffery M. No self-report means no pain-intensity rating. Am J Nurs 2005;105:50—53. 91. Jones KR, Fink R, Hutt E, et al. Measuring pain intensity in nursing home residents. J Pain Symptom Manage 2005;30:519—527. 92. Zwakhalen SMG, Hamers JPH, Berger MPF. Improving the clinical usefulness of a behavioural pain scale for older people with dementia. J Adv Nurs 2007;58:493—502. 93. Lane P, Kuntupis M, MacDonald S, et al. A pain assessment tool for people with advanced Alzheimer’s and other progressive dementias. Home Healthc Nurse 2003;21:32—37. 94. Basler HD, Huger D, Kunz R, et al. Assessment of pain in advanced dementia. Construct validity of the German PAINAD. Schmerz 2006;20:519—526. 95. Leong IY, Chong MS, Gibson SJ. The use of a self-reported pain measure, a nurse-reported pain measure and the PAINAD in nursing home residents with moderate and severe dementia: a validation study. Age Ageing 2006;35:252—256. 96. Leong IY, Nuo TH. Prevalence of pain in nursing home residents with different cognitive and communicative abilities. Clin J Pain 2007;23:119—127.

SUGGESTED READINGS American Geriatric Society (AGS) Panel on Persistent Pain in Older Persons. The management of persistent pain in older persons. J Am Geriatr Soc 2002;50:S205—S224. Closs SJ, Barr B, Briggs M, et al. A comparison of five pain assessment scales for nursing home residents with varying degrees of cognitive impairment. J Pain Symptom Manage 2004;27:196—205. Hadjistavropoulos T, Herr K, Turk DC, et al. An interdisciplinary expert consensus statement on assessment of pain in older persons. Clin J Pain 2007;23:S1—S43.

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37

Herr K, Bjoro K, Decker S. Tools for assessment of pain in nonverbal older adults with dementia: a state-of-the-science review. J Pain Symptom Manage 2006;31:170—192. Herr K, Coyne PJ, Key T, et al. Pain assessment in the nonverbal patient: position statement with clinical practice recommendations. Pain Manage Nurs 2006;7:44—52. McNicoll L, Pisani MA, Zhang Y, et al. Delirium in the intensive care unit: occurrence and clinical course in older patients. J Am Geriatr Soc 2003;51:591—598.

Proctor WR, Hirdes JP. Pain and cognitive status among nursing home residents in Canada. Pain Res Manage 2001;6:119—125. Scherder E, Oosterman J, Swaab D, et al. Recent developments in pain in dementia. BMJ 2005;330:461—464. Zwakhalen SM, Hamers JP, Berger MP. The psychometric quality and clinical usefulness of three pain assessment tools for elderly people with dementia. Pain 2006;126:210—220.

Chapter 6

from the IASP definition and proposed that the definition for NP be ‘‘pain initiated or caused by a primary lesion of the nervous system.’’ Conversely, Jensen and coworkers3 opined that going back to a pure neuroanatomic description of NP overlooks the plasticity of the nervous system and its continuous modulation, which may change after activation or injury. In 2002, Merskey4 noted that without the word ‘‘dysfunction’’ in the definition of NP, the entity of trigeminal neuralgia may require two subcategories, one neuropathic with a definable lesion and one not. In 2006, Gary Bennett suggested that given the present level of understanding, a clean separation between inflammatory pain and NP may not be realistic in many patients, and a satisfying definition of NP may not be currently possible. A clinically acceptable definition of NP is vitally important because effective treatment of NP remains a challenge and the number of patients with NP is significant and growing. A group consisting of neurologists, neuroscientists, clinical neurophysiologists, and neurosurgeons established a task force in collaboration with the IASP Special Interest Group on Neuropathic Pain (NeuPSIG) and put forth a revised definition and grading system for NP.5 Treede and associates5 proposed that NP be redefined/reworded as ‘‘pain arising as a direct consequence of a lesion or disease affecting the somatosensory system.’’ Peripheral NP and central NP are proposed to refer to lesions/disease of the peripheral nervous system (PNS) and central nervous system (CNS), respectively.5 The NP grading system is used to decide on the level of certainty with which the presence or absence of NP can be determined in an individual patient.5 The grading of certainty for the presence of NP consists of

NEUROPATHIC PAIN—DEFINITION, IDENTIFICATION, AND IMPLICATIONS FOR RESEARCH AND THERAPY Howard S. Smith, Misha-Miroslav Marco Pappagallo and Charles E. Argoff

Backonja,

INTRODUCTION Neuropathic pain (NP) presents a puzzle to patients and a challenge to clinicians because it manifests simultaneously with seemingly contradictory positive (pain) and negative (lack of sensation) sensory phenomena. The lack of a conceptual framework within which progress in the science of pain can translate into improvement in clinical care and vice versa presents additional difficulty when addressing NP. Derasari1 stated that the main impact of effective taxonomy is the framework for the interpretation of the differences and similarities in living organisms in light of comparative genetics, biochemistry, physiology, embryology, behavior, and etiology. Commonly accepted terminology and classifications of pain have recently come under scrutiny as our understanding of central and peripheral pathophysiologic processes has continued to grow. One key example has been NP. Simple distinctions such as that of nociceptive pain versus NP are woefully inadequate. The term nociceptive pain refers to pain that is transmitted under laboratory conditions of pain stimulation that do not truly exist in any clinical situation. More importantly, the lack of specificity of the term as proposed by the International Association for the Study of Pain (IASP) is contradictory to the preferred approach—the mechanism-based diagnosis and treatment of all painful conditions. NP remains a significant challenge to diagnose and treat effectively. Perhaps, this is in part related to the difficulty in defining NP. The IASP defined NP as ‘‘pain initiated or caused by a primary lesion or dysfunction in the nervous system.’’ Controversy exists regarding the definition of NP and what it entails. Max2 argued for removal of the words ‘‘or dysfunction’’

Definite NP: all (1—4). Probable NP: 1 and 2, plus either 3 or 4. Possible NP: 1 and 2, without confirmatory evidence from 3 or 4. The levels ‘‘definite’’ and ‘‘probable’’ indicate that the presence of this condition has been established. The level ‘‘possible’’ indicates that the presence of this condition has not yet been established, which should instigate additional investigations in this patient, either immediately or during follow-up. If a patient does not fulfill the criteria for any of these three levels, it is considered unlikely that this patient has NP.5 The criteria to be evaluated for each patient are 1. Pain with a distinct neuroanatomically plausible distribution.* 2. A history suggestive of a relevant lesion or disease affecting the peripheral or central somatosensory system.{

*A region corresponding to a peripheral innervation territory or to the topographic representation of a body part in the CNS. { The suspected lesion or disease is reported to be associated with pain, including a temporal relationship typical for the condition.

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Herr K, Bjoro K, Decker S. Tools for assessment of pain in nonverbal older adults with dementia: a state-of-the-science review. J Pain Symptom Manage 2006;31:170—192. Herr K, Coyne PJ, Key T, et al. Pain assessment in the nonverbal patient: position statement with clinical practice recommendations. Pain Manage Nurs 2006;7:44—52. McNicoll L, Pisani MA, Zhang Y, et al. Delirium in the intensive care unit: occurrence and clinical course in older patients. J Am Geriatr Soc 2003;51:591—598.

Proctor WR, Hirdes JP. Pain and cognitive status among nursing home residents in Canada. Pain Res Manage 2001;6:119—125. Scherder E, Oosterman J, Swaab D, et al. Recent developments in pain in dementia. BMJ 2005;330:461—464. Zwakhalen SM, Hamers JP, Berger MP. The psychometric quality and clinical usefulness of three pain assessment tools for elderly people with dementia. Pain 2006;126:210—220.

Chapter 6

from the IASP definition and proposed that the definition for NP be ‘‘pain initiated or caused by a primary lesion of the nervous system.’’ Conversely, Jensen and coworkers3 opined that going back to a pure neuroanatomic description of NP overlooks the plasticity of the nervous system and its continuous modulation, which may change after activation or injury. In 2002, Merskey4 noted that without the word ‘‘dysfunction’’ in the definition of NP, the entity of trigeminal neuralgia may require two subcategories, one neuropathic with a definable lesion and one not. In 2006, Gary Bennett suggested that given the present level of understanding, a clean separation between inflammatory pain and NP may not be realistic in many patients, and a satisfying definition of NP may not be currently possible. A clinically acceptable definition of NP is vitally important because effective treatment of NP remains a challenge and the number of patients with NP is significant and growing. A group consisting of neurologists, neuroscientists, clinical neurophysiologists, and neurosurgeons established a task force in collaboration with the IASP Special Interest Group on Neuropathic Pain (NeuPSIG) and put forth a revised definition and grading system for NP.5 Treede and associates5 proposed that NP be redefined/reworded as ‘‘pain arising as a direct consequence of a lesion or disease affecting the somatosensory system.’’ Peripheral NP and central NP are proposed to refer to lesions/disease of the peripheral nervous system (PNS) and central nervous system (CNS), respectively.5 The NP grading system is used to decide on the level of certainty with which the presence or absence of NP can be determined in an individual patient.5 The grading of certainty for the presence of NP consists of

NEUROPATHIC PAIN—DEFINITION, IDENTIFICATION, AND IMPLICATIONS FOR RESEARCH AND THERAPY Howard S. Smith, Misha-Miroslav Marco Pappagallo and Charles E. Argoff

Backonja,

INTRODUCTION Neuropathic pain (NP) presents a puzzle to patients and a challenge to clinicians because it manifests simultaneously with seemingly contradictory positive (pain) and negative (lack of sensation) sensory phenomena. The lack of a conceptual framework within which progress in the science of pain can translate into improvement in clinical care and vice versa presents additional difficulty when addressing NP. Derasari1 stated that the main impact of effective taxonomy is the framework for the interpretation of the differences and similarities in living organisms in light of comparative genetics, biochemistry, physiology, embryology, behavior, and etiology. Commonly accepted terminology and classifications of pain have recently come under scrutiny as our understanding of central and peripheral pathophysiologic processes has continued to grow. One key example has been NP. Simple distinctions such as that of nociceptive pain versus NP are woefully inadequate. The term nociceptive pain refers to pain that is transmitted under laboratory conditions of pain stimulation that do not truly exist in any clinical situation. More importantly, the lack of specificity of the term as proposed by the International Association for the Study of Pain (IASP) is contradictory to the preferred approach—the mechanism-based diagnosis and treatment of all painful conditions. NP remains a significant challenge to diagnose and treat effectively. Perhaps, this is in part related to the difficulty in defining NP. The IASP defined NP as ‘‘pain initiated or caused by a primary lesion or dysfunction in the nervous system.’’ Controversy exists regarding the definition of NP and what it entails. Max2 argued for removal of the words ‘‘or dysfunction’’

Definite NP: all (1—4). Probable NP: 1 and 2, plus either 3 or 4. Possible NP: 1 and 2, without confirmatory evidence from 3 or 4. The levels ‘‘definite’’ and ‘‘probable’’ indicate that the presence of this condition has been established. The level ‘‘possible’’ indicates that the presence of this condition has not yet been established, which should instigate additional investigations in this patient, either immediately or during follow-up. If a patient does not fulfill the criteria for any of these three levels, it is considered unlikely that this patient has NP.5 The criteria to be evaluated for each patient are 1. Pain with a distinct neuroanatomically plausible distribution.* 2. A history suggestive of a relevant lesion or disease affecting the peripheral or central somatosensory system.{

*A region corresponding to a peripheral innervation territory or to the topographic representation of a body part in the CNS. { The suspected lesion or disease is reported to be associated with pain, including a temporal relationship typical for the condition.

38 Chapter 6  NEUROPATHIC PAIN ç DEFINITION, IDENTIFICATION, AND IMPLICATIONS FOR RESEARCH AND THER APY

Table 6^1. Comparison of Items within Five Neuropathic ScreeningTools* LANSS{

DN4{

NPQ

painDETECT

ID Pain

Symptoms Pricking, tingling, pins and needles Electric shocks or shooting Hot or burning Numbness Pain evoked by light touching Painful cold or freezing pain Pain evoked by mild pressure Pain evoked by heat or cold Pain evoked by changes in weather Pain limited to joints{ Itching Temporal patterns Radiation of pain Autonomic changes

  

   

 

     

    

    

       

Clinical Examination Brush allodynia Raised soft touch threshold Raised pinprick threshold

 

  

DN4, Douleur Neuropathic 4 Questions; LANSS, Leeds Assessment of Neuropathic Symptoms and Signs; NPQ, Neuropathic Pain Questionnaire. *Shaded areas highlight features shared by two or more tools. { Tools that involve clinical examination. { Used to identify nonneuropathic pain.

From Bennett MI, Attal N, Backonja MM, et al. Using screening tools to identify neuropathic pain. Pain 2007;127:199—203.

3. Demonstration of the distinct neuroanatomically plausible distribution by at least one confirmatory test.{ 4. Demonstration of the relevant lesion or disease by at least one confirmatory test.§5 Treede and associates5 pointed out that controversy over whether diseases such as complex regional pain syndrome I constitute NP will not be resolved by their proposed definition. However, it is conceivable that future tools/research may help sort this out. This new definition and criteria will likely yield a lower sensitivity but higher specificity than the IASP definition for the identification of NP. Although the precise incidence of NP in the general population is unknown, it appears that NP exists in a significant portion of the population and, thus, presents a major clinical problem. Torrance and colleagues mailed a questionnaire (which included the Selfcomplete Leeds Assessment of Neuropathic Symptoms and Signs [S-LANSS] and the Neuropathic Pain Scale [NPS]; described later) to six family practices in three U.K. cities and found that chronic pain with neuropathic features appears to be more common in the general population than previously suggested.

CURRENT SCREENING TOOLS FOR NP Multiple measurement tools exist to assess the intensity of pain, however. In 1997, Galer and Jensen6 published the NPS in efforts to assess the intensity of, specifically, NP. The NPS is essentially a measurement tool of NP severity. The NPS was designed to assess distinct pain qualities associated with NP.6 In 2005, Jensen and colleagues7 proposed that the NPS may have utility in assessing changes in pain qualities after analgesic treatments (e.g., lidocaine 5% patch). NP presents some unique issues, and it may be difficult at times to correctly recognize the neuropathic qualities of various painful complaints by patients. In 2007, Bennett and coworkers8 reviewed five screening tools used to identify NP (with up to 80% sensitivity and specificity) (Table 6—1). It can be appreciated that the first three items (‘‘pricking, tingling, pins and needles,’’ ‘‘electric shocks or shooting,’’ and ‘‘hot or burning’’) are present in all tools, with the next two items (‘‘numbness’’ and ‘‘pain evoked by light touching’’) present in 80% of the tools in Table 6—1.

Leeds Assessment of Neuropathic Symptoms and Signs {

As part of the neurologic examination, these tests confirmed the presence of negative or positive neurologic signs concordant with the supplemented by laboratory and objective tests to uncover subclinical abnormalities. § As part of the neurologic examination, these tests confirm the diagnosis of the suspected lesion or disease. These confirmatory tests depend on which lesion or disease is causing NP.5

In 2001, Bennett9 published the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS), which contains five symptom and two clinical examination items and is easy to score within clinical settings. In 2005, Bennett and associates10 validated a self-report tool, the S-LANSS. The original LANSS was developed in a sample of 60 patients with chronic nociceptive pain or NP and validated in a further sample of 40 patients. Sensitivity and

II ASSESSMENT OF PAIN AND ITS TREAT MENT

specificity in the latter group were 85% and 80%, respectively, compared with clinical diagnosis. The LANSS has subsequently been tested and validated in several settings. Although the LANSS was not designed as a measurement tool, Khedr and colleagues11 showed sensitivity to treatment effects.

Douleur Neuropathique 4 Questions In 2005, Bouhassira and coworkers12 published a comparison of pain syndromes associated with nervous or somatic lesions utilizing a new NP diagnostic questionnaire. The French Neuropathic Pain Group developed a clinician-administered questionnaire called DN4, which stands for ‘‘douleur neuropathique 4 questions’’ (i.e., ‘‘neuropathic pain four questions,’’ in French). The DN4 was validated in 160 patients with either NP or nociceptive pain. The most common etiologies of NP (n = 89) were traumatic nerve injury, postherpetic neuralgia (PHN), and poststroke pain. Nonneurologic conditions included osteoarthritis, inflammatory arthropathies, and mechanical low back pain. It consists of 7 items related to symptoms and 3 related to clinical examination.

Box 6^1 COMPARISON OF PAIN SYNDROMES ASSOCIATED WITH NERVOUS OR SOMATIC LESIONS AND DEVELOPMENT OF A NEW NEUROPATHIC PAIN DIAGNOSTICS QUESTIONNAIRE (DN4) Please complete this questionnaire by ticking one answer for each item in the 4 questions below: INTERVIEW OF THE PATIENT

39

A score of 1 is given to each positive item and a score of 0 is given to each negative item. The total score is the sum of the 10 items. The DN4 is easy to score, and a total score of 4 or more out of 10 suggests NP. The DN4 showed 83% sensitivity and 90% specificity when compared with clinical diagnosis in the development study. The first 7 sensory descriptors (based solely on patient interview) can be used as a self-report questionnaire with similar results (Box 6—1). DN4 is complementary to the NPS or the Neuropathic Pain Symptom Inventory (NPSI). In 2004, Bouhassira and associates13 published the NPSI for the evaluation of different symptoms and dimensions of NP. The final version of the NPSI includes 10 descriptors (plus 2 temporal items) that allow discrimination and quantification of five distinct clinically relevant dimensions of NP syndromes. It has been suggested that NPSI is particularly suitable to assess treatment outcome.

Neuropathic Pain Questionnaire In 2003, Krause and Backonja14 published the Neuropathic Pain Questionnaire (NPQ), which consists of 12 items, including 10 related to sensations or sensory responses and 2 related to affect. It was developed in 382 patients with a broad range of chronic pain diagnoses. The discriminant function was initially calculated on a random sample of 75% of the patients and then cross-validated in the remaining 25%. The NPQ demonstrated 66% sensitivity and 74% specificity compared with clinical diagnosis in the validation sample. Backonja and Krause15 also published a short form of the NPQ, which maintained similar discriminative properties with only 3 items: (1) positive sensory phenomena (‘‘increased pain due to touch’’); (2) negative sensory phenomena (‘‘numbness’’); and (3) phenomena suggestive of paresthesia and dysesthesia (‘‘tingling’’).

painDETECT

Question 1: Does the pain have one or more of the following characteristics? yes

no

1 - Burning 2 - Painful cold 3 - Electric shocks Question 2: Is the pain associated with one or more of the following symptoms in the same area? yes

no

4 - Tingling 5 - Pins and needles 6 - Numbness 7 - Itching EXAMINATION OF THE PATIENT Question 3: Is the pain located in an area where the physical examination may reveal one or more of the following characteristics? yes

no

8 - Hypoesthesia to touch 9 - Hypoesthesia to prick Question 4: In the painful area, can the pain be caused or increased by: yes

no

10-Brushing From Bouhassira D, Attal N, Alchaar H, et al.Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4). Pain 2005;114:29—36.

In 2005, Freynhagen and colleagues16 published the screening tool referred to as painDETECT, which was developed and validated in German. painDETECT incorporated an easy-to-use, patient-based (self-report) questionnaire with nine items that do not require a clinical examination. There are seven weighted sensory descriptor items (‘‘never’’ to ‘‘very strongly’’) and two items relating to the spatial (‘‘radiating’’) and temporal characteristics of the individual pain pattern. The painDETECT questionnaire (PD-Q) was developed in cooperation with the German Research Network on Neuropathic Pain; validated in a prospective, multicenter study of 392 patients with either NP (n = 167) or nociceptive pain (n = 225); and subsequently applied to a population of roughly 8000 patients with low back pain. The tool correctly classified 83% of patients to their diagnostic group with a sensitivity of 85% and a specificity of 80%. It is also available in English.

ID Pain In 2006, Portenoy17 published the ID Pain, which consists of five sensory descriptor items and one item relating to whether pain is located in the joints (used to identify nociceptive pain). It also does not require a clinical examination (Table 6—2). The tool was developed in a multicenter study of 586 patients with chronic pain of nociceptive, mixed, or neuropathic etiology and validated in a multicenter study of 308 patients with similar pain classifications. The tool was designed to screen for the likely presence of a neuropathic component to the patient’s pain. In the validation study, 22% of the nociceptive group, 39% of the mixed group, and 58% of the neuropathic group scored above 3 points, the recommended cut-off score.

40 Chapter 6  NEUROPATHIC PAIN ç DEFINITION, IDENTIFICATION, AND IMPLICATIONS FOR RESEARCH AND THER APY Neuropathic pain mechanisms

Table 6^2. ID Pain Questionnaire None

Severe

Inflammatory pain mechanisms

OA PHN CRPS PDN

CATEGORIZING NP Traditionally, neurologic research and practice have followed a distinction between the PNS and the CNS, and in many regards, this division has served the field of neurology very well—for example, clearly distinct clinical courses have been mapped for demyelinating disorders of the PNS (e.g., inflammatory demyelinating polyradiculoneuropathy) and of the CNS (e.g., demyelinating disorder of multiple sclerosis), although both can be progressive and, as part of presentation, have chronic pain. Conversely, pain does not necessarily respect that distinction between the PNS and the CNS because any time a painful event occurs, the whole system is activated, from nociception, to modulation, to perception—leading to a reaction to pain. Petersen and coworkers18 shed light on the fact that NP, even though it may appear ‘‘centralized,’’ may still exhibit ongoing nociceptive input from the periphery. A further conceptual challenge for NP is that, although the clinical course and expression of the disorder are under the influence of the underlying disease process (e.g., painful diabetic peripheral neuropathy vs. spinal cord injury), most of its phenomenologic manifestations including ongoing pain, pain paroxysms, and various types of hyperalgesia are frequently similar, regardless of whether injury occurs to the PNS or the CNS. The nature and the extent of the nervous system injury and the natural course of repair that follows with involvement of inflammatory processes all add to the complexity and dynamic nature of NP in each particular case. NP has its own signature characteristics. There are books (Pappagallo M [ed]. The Neurological Basis of Pain. New York: McGraw-Hill, 2005), journals (The Journal of Neuropathic Pain and Symptom Palliation), and groups (the NeuPSIG of the IASP) largely devoted specifically to NP. Modern neuroimaging methods (position-emission tomography [PET] and functional magnetic resonance imaging [fMRI]) have overall indicated that acute physiologic pain and NP have distinct, although overlapping, brain activation patterns but that there is no unique ‘‘neuropathic pain matrix’’ or ‘‘allodynia network.’’19 The distinction between inflammatory pain and NP in many regards is arbitrary, but on a practical level, the distinction may have direct implications for the diagnostic steps and therapeutic planning in addition to the natural course of the disease for each type of pain. Insult or irritation of nerves may promote inflammation and inflammation may affect neural function. In fact, even in the basic sciences, various animal models may not be ‘‘black and white.’’ Although the air pouch model appears to be largely inflammatory and the chronic constriction injury model appears largely neuropathic, injection of formalin into the rodent hind paw (traditionally considered an inflammatory model) may actually be

CIDP

Severe

RA

From Portenoy R. Development and testing of a neuropathic pain screening questionnaire: ID Pain. Curr Med Res Opin 2006;22:1555—1565.

Phantom pain (post trauma)

Figure 6^1. Spectrum of pathophysiologic mechanisms, neuropathic and inflammatory, and their influence on common painful disorders. CIDP, chronic inflammatory diabetic polyneuropathy; CRPS, complex regional pain syndrome; OA, osteoarthritis; PDN, painful diabetic neuropathy; PHN, postherpetic neuralgia; RA, rheumatoid arthritis.

more of a ‘‘mixed picture’’ and the specific type of insults appears to be somewhat dose-dependent. The systematically obtained clinical and experimental data would then determine whether a particular pain disorder is neuropathic or whether it presents a transitional form (i.e., at the overlapping borders of NP and other pain processes) (Fig. 6—1). Conventional older classifications have divided persistent pain into two mutually exclusive categories: nociceptive and neuropathic. Clinicians later realized that in practice, pain complaints were not strictly black and white, and they considered a categorization of persistent pain as (1) neuropathic, (2) nonneuropathic (e.g., nociceptive), or (3) nonneuropathic with neuropathic features/qualities/ characteristics or a neuropathic component. This third category refers to a single pain complaint that contains a mix of nonneuropathic pain with a neuropathic component. Rasmussen and associates20 examined whether symptoms and signs cluster in patients with increasing evidence of NP. They used three categories of NP (‘‘definite,’’ ‘‘possible,’’ and ‘‘unlikely’’) based on detailed sensory examination and found a considerable overlap of symptoms and signs between the categories, using the Short-form McGill Pain Questionnaire (SF-MPQ).21 Distinguishing NP from nonneuropathic pain in a specific patient’s complaint is an interesting challenge because in many patients there is a likely mix. A single pain complaint from a patient may represent a fusion or mesh of NP and inflammatory pain. Attempts to ‘‘tease out’’ ‘‘how much’’ (if any) of the pain complaint is neuropathic in nature may potentially be worthwhile because it may affect medical decision making regarding the planning of treatment strategies. Backonja and Stacey22 evaluated NP relative to overall pain rating. Intensity of symptoms as rated by NPQ and NPS items varied widely, with the least intense being ‘‘itch and cold sensation’’ on NPS and ‘‘heat and emotional upset’’ on NPQ. The most intense ratings were ‘‘unpleasant and sharp’’ on NPS and ‘‘distressing and stabbing’’ on NPQ (Fig. 6—2). Smith and colleagues23 sent the S-LANSS questionnaire to 6000 adults from general practices in the United Kingdom, along with chronic pain identification and severity questions, the Brief Pain Inventory (BPI), the NPS, and the SF-MPQ general health questionnaires. The chronic Pain of Predominantly Neuropathic Origin (POPNO) group reported higher pain severity and had significantly poorer scores for all interference items of the BPI than those with chronic pain (non-POPNO).23 Mean scores from the NPS were also

II ASSESSMENT OF PAIN AND ITS TREAT MENT

INTENSITY OF SYMPTOMS AS RATED ON NPQ 95% Bonferroni CI for the Mean 10

Intensity rating

8 6 4 2

t

l

Em

H

ot io

ea

na

ch

d ol

To u

C

Sh o

Bu r

ni

ng

ot in g St ab bi n N um g bn es s Ti ng lin D g is tre ss in g

0

INTENSITY OF SYMPTOMS AS RATED ON NPQ 95% CI for the Mean 10

Intensity rating

8 6 4 2

ce

ee

rfa Su

D

as le np

p

t an

hy Itc U

C

ns Se

PS N

iti

ol

ve

d

l ul D

ot H

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ar

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0

Figure 6^2. Intensity of neuropathic pain symptoms as rates on the

Neuropathic Pain Questionnaire (NPQ) and the Neuropathic Pain Scale (NPS). (Reproduced from Backonja MM, Stacey B. Neuropathic pain symptoms relative to overall pain rating.J Pain 2004;5:491—497.).

significantly higher for the chronic POPNO group reporting the worst health.23 After adjusting for pain severity, age, and sex, the chronic POPNO group was still found to have poorer scores than the non-POPNO group in all domains of the SF-MPQ and all interference items in the BPI, indicating poorer health and greater disability.23 This study supports the importance of identifying NP in the community and the need for multidimensional management strategies that address all aspects of health.23 Postal surveys were carried out in large community samples from the United Kingdom23,24 and France25 in attempts to gain information regarding the epidemiology of NP in the general population. Although different NP questionnaires were used (i.e., S-LANSS in the United Kingdom and DN4 in France), similar estimates of the prevalence of chronic pain with neuropathic characteristics were reported in the general population, around 7% to 8%.26 Interestingly, these population-based studies showed that the subset of respondents with NP features had several associated clinical characteristics that differed from other respondents with chronic pain, even after controlling for pain severity. These characteristics include significantly worse quality of life, greater interference from pain, and pain of longer duration.26 One limitation inherent to this approach is the lack of direct information regarding the etiology of pain. In other words, how sure can we be that a positive responder to a postal screening tool would be diagnosed with NP if seen by a pain specialist in a clinic? Weingarten and coworkers27 addressed this very question and reported on a community validation study of the S-LANSS in an

41

issue of Pain. Weingarten and coworkers27 mailed a short questionnaire that included questions on pain and, specifically, the S-LANSS to nearly 6000 community adults and received over 3500 replies.10 A subsample of these respondents were invited for clinical assessment, and finally, a comparison was made between clinical assessment and responses to S-LANSS after a gap of 3 to 12 months.26 Weingarten and coworkers27 asked subjects only for ‘‘any pain in the last 3 months as opposed to pain lasting for more than 3 months.’’26 The prevalence of NP derived from the survey of Weingarten and coworkers27 (8.8%) is very close to that reported by Torrance and associates.24 Patient’s symptoms remain the cornerstone of pain assessment; however, patients’ complaints should not be the sole determinant in categorizing NP. NP needs to be carefully assessed by trained pain specialists, starting with a complete and thorough history and physical examination. This would include assessing mechanical and thermal hyperalgesia/allodynia as well as a detailed, more traditional neurologic examination. The combination of history, physical examination, and ancillary confirmatory testing, although providing enough information to categorize NP based on the criteria of Treede and associates,5 is not sufficient to precisely dissect all patient’s pain complaints into neuropathic, nonneuropathic, or mixed. Ideally, a valid specific tool for the examination of patients with chronic pain will be developed that will allow the examiner at the conclusion to be able to accurately predict whether or not NP is present. Or perhaps testing may be developed that could be used in conjunction with data from the history and physical examinations to aid in the identification of an NP component. Furthermore, when appropriate, this information may be supplemented with various laboratory testing, imaging, electrodiagnostic testing, quantitative sensory testing (QST), as well as specific testing of the skin such as provocative or challenge testing, assessing whether various agents (e.g., capsaicin) exacerbate, alleviate, or do not affect preexisting spontaneous pain, and analysis of skin punch biopsies. In addition, the future information from PET imaging or fMRI may be useful to supplement these data. Over the last 2 decades, QST has been developed to complement traditional neurologic bedside examination in the analysis of somatosensory aberrations.28 This approach, derived from experimental psychophysics, consists of measuring the responses (i.e., nonpainful sensations and pain) evoked by mechanical and thermal stimuli, the intensity of which is controlled by automated devices.29 QST is based on precise definition of the stimulus properties (modality, intensity, spatial, and temporal characteristics), analysis of the quality of evoked sensation, and quantification of its intensity.29 In addition to the evaluation of sensory thresholds (i.e., the detection threshold for innocuous stimuli and pain threshold), QST includes the assessment of sensations evoked by suprathreshold stimuli.30—32 The German Research Network on Neuropathic Pain (DFNS) developed a comprehensive QST protocol consisting of 7 tests measuring 13 parameters and defined a set of normative data for thermal and mechanical detection and pain thresholds for the hand, foot, and face in healthy volunteers.33 The expected role of QST in the definition of a mechanismsbased approach to NP has not yet been met. QST has helped to determine selective roles for different peripheral fibers or ascending pathways in specific conditions.34—36 However, there are probably no simple relationships between the pattern of sensory deficits and NP symptoms37; and the ultimate aim of marrying clinical symptoms and signs with pain pathophysiology still has to be accomplished.29 Max38 stated that small academic clinical trials so far have failed to identify obvious differences in the response to various drugs of different pain symptoms in the same condition. In contrast, there are clear differences in the analgesic responses of patient groups distinguished on the basis of etiology or tissue origin of pain, factors that tend to be associated with groups of mechanisms.38

42 Chapter 6  NEUROPATHIC PAIN ç DEFINITION, IDENTIFICATION, AND IMPLICATIONS FOR RESEARCH AND THER APY An emphasis has been on supplementing a disease-based treatment approach with one based on symptoms (used as an indicator) and their underlying putative mechanisms.39 This approach accounts for the observation that patients with one disease entity (e.g., diabetic neuropathy) may have vastly different symptoms arising from different mechanisms and that patients with different diseases may have similar symptoms arising from the same mechanism.40 Treatment of NP should be supplemented by the signs and symptoms manifested by the patient as well as by any pertinent ancillary data including history and physical examination information challenge testing, imaging electrodiagnostic studies, QST, and skin biopsies. By specifically targeting the mechanisms underlying these symptoms, an improved therapeutic response may be realized.41 The clinician may need to explore ‘‘rational polypharmacotherapy’’ on a case-by-case basis when a single agent is ineffective in relieving a patient’s reported symptoms.41

between anxiety and pain in humans. The influence of pain on psychiatric comorbidities and vice versa are extremely complex and far from clear. The availability of many specific assessment tools for human as well as bench research provides ample opportunities to study those relationships. Backonja and Argoff42 proposed a framework to assist in obtaining a complete clinical picture about each individual patient. The suggested multidimensional assessment approach (Table 6—3) provides the means of assessing critical dimensions of chronic pain specifically and, on the basis of that assessment, rank-ordering components that contribute to the patient’s presentation at any given time.42 It provides for the complexity as well as the dynamic nature of pain. Certainly, use of validated pain-intensity rating scales are still considered the ‘‘gold standards’’ for pain-intensity assessment, but use of a more comprehensive approach may provide insight into how any particular component of pain, including multiple components of NP, behave in time and respond to treatments.

CLINICAL IMPLICATIONS The challenge for NP diagnosis and assessment is the complexity not only of the primary manifestation of symptoms but also the many other manifestations of NP as a disease that crosses more than one domain. For this complexity to be captured and communicated, a model of Multidimensional Pain Assessment (MDPA) has been proposed by Backonja and Argoff.42 The clinical implications of NP and challenges for the diagnosis and assessment originate from the fact that the inciting illness or injury may have many consequences in addition to pain. As discussed previously, each illness, be it PHN or diabetes mellitus, has a specific clinical course and associated comorbidities. Those comorbidities may be medical, such as hypertension and hypothyroidism, or psychiatric, such as depression and anxiety. Medical and psychiatric comorbidities may or may not further affect NP. Even though many comorbidities do not have direct effects on the clinical manifestations of NP, some comorbidities may indirectly affect it (e.g., as hypothyroidism, which if untreated, can contribute to worsening of neuropathy and consequently pain). Psychiatric comorbidities and pain, in general, may pose an even bigger challenge. In this regard, NP is perhaps most complicated because of its severity, chronicity, and lack of response to traditional treatments. Ploghaus and coworkers,43 through advances in neuroimaging, elegantly demonstrated a neural basis for the relationship

Table 6^3. The Multiple Dimensions of Neuropathic Pain

Dimension

I Medical etiology

Specific Parameters

Specific etiology and medical comorbidities II Pain Neuropathic, mechanisms inflammatory, myofascial, incidence, other III Psychiatric Psychiatric comorbidity comorbidities and coping skills IV Function, QOL Disabilities, impaired QOL QOL, quality of life.

Severity Rating (None, Mild, Moderate, Severe) or (0—4)

MDPA I. Medical etiology related to pain (e.g., diabetes) and medical comorbidities that could influence manifestation of pain symptoms (e.g., hypothyroidism). II. Pain mechanisms, such as neuropathic, inflammatory, myofascial. III. Psychiatric comorbidity (e.g., depression, anxiety), patients’ coping skills, and tendency to catastrophize. IV. Impact of pain on ability to function (with loss of function comes the disabilities) and quality of life. The most significant implication of applying this approach is the ability to comprehensively assess pain and to prioritize necessary steps of treatment. Assessment should be made for each dimension and each dimension should be rated as ‘‘none,’’ ‘‘mild,’’ ‘‘moderate,’’ or ‘‘severe’’ to allow ranking. The severity of items for each particular dimension would determine the order of further diagnostic investigations and treatment steps. Clinical experience points to the fact that most, if not all, patients with chronic painful disorders have diagnoses on each of these dimensions. It is tempting to concentrate on one component with which the clinician is most comfortable and to ignore others or to see all of the components as separate and isolated entities. However, it is crucial to remember that these components interact constantly and have to be considered together. SAFE (measuring social functioning, analgesia or pain relief, physical functioning, and emotional functioning) is another multidimensional tool (not specific to NP) that can be used to assess various domains of functioning in patients with persistent pain.44 Similarly, other investigators have addressed the need for a multidimensional assessment of persistent pain not only at baseline but also during follow-up in efforts to interpret treatment outcomes. A consensus meeting of the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) provided recommendations for interpreting clinical importance of treatment outcomes in clinical trials of the efficacy and effectiveness of chronic pain treatments. A group of 40 participants from universities, governmental agencies, a patient self-help organization, and the pharmaceutical industry considered methodologic issues and research results relevant to determining the clinical importance of changes in the specific outcome measures recommended assessing four core chronic pain outcome domains: (1) Pain intensity, assessed by a 0 to 10 numerical rating scale; (2) physical functioning, assessed by the Multidimensional Pain Inventory and BPI interference scales; (3) emotional functioning, assessed by the Beck Depression Inventory and Profile of Mood States; and (4) participant ratings of overall

II ASSESSMENT OF PAIN AND ITS TREAT MENT

43

Table 6^4. Provisional Clinical Trial Outcome Measures Type of Improvement*

Method{

Change

Minimally important Moderately important Substantial

Anchor Anchor Anchor

10%—20% decrease 30% decrease 50% decrease

2. Physical functioning Multidimensional Pain Inventory Interference Scale46 Brief Pain Inventory Interference Scale47

Clinically important Minimally important

Distribution Distribution

0.6-point decrease 1-point decrease

3. Emotional functioning Beck Depression Inventory48, 49 Profile of Mood States50 Total Mood Disturbance51 Specific subscales51

Clinically important Clinically important Clinically important

Distribution Distribution Distribution

5-point decrease 10—15-point decrease 2—12-point change{

Minimally important Moderately important Substantial

Anchor Anchor Anchor

Minimally improved Much improved Very much improved

Outcome Domain and Measure

1. Pain intensity 0—10 Numerical rating scale

4. Global rating of improvement Patient Global Impression of Change52

*Because few studies have examined the importance of worsening on these measures, benchmarks are only provided for improvement in scores. { Specific method used in determining benchmark provided in final column; distribution-based methods were based on use of 0.5 standard deviation or 1.0 standard error of the mean or both. { The magnitude of a clinically important change depends on the specific subscale, as does the direction of change that reflects an improvement.

Reproduced with modification from Dworkin RH, Oconnor AB, Backonja M, et al. Pharamacologic management of neuropathic pain: evidence-based recommendations. Pain 2007;132:237—251. improvement, assessed by the Patient Global Impression of Change scale (all four domains being assessed by two or more different methods)45 (Table 6—4). Finally, although this chapter does not address treatment strategies, a stepwise pharmacologic management algorithm in

the approach to NP is included in order to illustrate current conventional strategies (Box 6—2). However, even adhering to these strategies, existing pharmacologic treatments for NP are limited, with no more than 40% to 60% of patients obtaining partial relief of their pain.45

Box 6^2 STEPWISE PHARMACOLOGIC MANAGEMENT OF NEUROPATHIC PAIN Step 1 Assess pain and establish the diagnosis of NP53,54; if uncertain about the diagnosis, refer to a pain specialist or neurologist. Establish and treat the cause of NP; if uncertain about availability of treatments addressing NP etiology, refer to appropriate specialist. Identify relevant comorbidities (e.g., cardiac, renal, or hepatic disease, depression, gait instability) that might be relieved or exacerbated by NP treatment or that might require dosage adjustment or additional monitoring of therapy. Explain the diagnosis and treatment plan to the patient and establish realistic expectations. Step 2 Initiate therapy of the disease causing NP, if applicable. Initiate symptom treatment with one or more of the following:  A second aryamineTCA (nortriptyline, desipramine) or an SSNRI (duloxetine, venlafaxine).  A calcium channel a2d ligand, either gabapentin or pregabalin.  For patients with localized peripheral NP: topical lidocaine used alone or in combination with one of the other first-line therapies.  For patients with acute NP, neuropathic cancer pain, or episodic exacerbations of severe pain, and when prompt pain relief during titration of a first-line medication to an efficacious dosage is required, opioid analgesics or tramadol may be used alone or in combination with one of the first-line therapies. Evaluate patient for nonpharmacologic treatments, and initiate if appropriate. Step 3 Reassess pain and health-related quality of life frequently. If substantial pain relief (e.g., average pain reduced to  3/10) and tolerable side effects, continue treatment. If partial pain relief (e.g., average pain remains  4/10) after an adequate trial, add one of the other first-line medications. If no or inadequate pain relief (e.g., 8–12 mg or total daily doses > 24–36 mg)

Time to peak effect

T= 1

2

Route of metabolism/ elimination Dosage

60 min 1 hr (fasted state) 1.5–3 hr (fed state) 2–2.5 hr

Distribution: 6 min Elimination: 2 hr Hepatic (nearly 100%) Loading: 1 mcg/kg Maintenance: 0.2–0.7 mcg/ kg/hr

478 Chapter 65  a2 -AGONISTS

Clonidine Extensive scientific literature documents the utility of clonidine in the management of a variety of painful conditions. Clonidine has been frequently used for the management of pain in the perioperative period and treatment of intractable cancer associated pain, especially that neuropathic in nature. Other conditions for which clonidine has been effective include complex regional pain syndrome, postherpetic neuralgia, trigeminal neuralgia, and chronic headaches. Clonidine has been utilized with benefit in peripheral nerve blocks, retrobulbar blocks, plexus anesthesia, intravenous regional anesthesia, labor analgesia, intra-articular administration after arthroscopy, and topically for neuropathies. Clonidine has also demonstrated opioid-sparing effects and synergistic action with opioids, local anesthetics, glutamate receptor antagonists, and gabapentin. Use of oral clonidine in conjunction with epidural or intrathecal morphine has enhanced analgesia in the postoperative period. It is clear, however, that the greatest degree of analgesia occurs with neuraxial administration of clonidine. In fact, one study using epidural clonidine as the sole analgesic agent intraoperatively and in the first 12 hours postoperatively demonstrated that administration of a clonidine bolus of 8 mcg/kg/hr followed by a continuous infusion of 2 mcg/kg/hr provided substantial analgesia. Another study compared the use of epidural clonidine or bupivacaine as the sole analgesic agent during and after abdominal surgery. In this study, high-dose epidural clonidine exhibited analgesia superior to two dosing regimens of epidural bupivacaine. The potency of clonidine when administered intrathecally is approximately 10 times that of epidural clonidine when used to treat acute thermal pain, whereas it is approximately twice as potent when used to manage mechanical hyperalgesia and allodynia. In addition to its beneficial effects on acute postoperative pain, intrathecal clonidine has been demonstrated to reduce postoperative secondary hyperalgesia as determined in a group of patients undergoing colonic resection. It was noted that the area of hyperalgesia around the incision site was much smaller in diameter in patients receiving 300 mcg of intrathecal clonidine than in those receiving saline. The patients given intrathecal clonidine as part of their perioperative anesthetic also had less residual pain in their surgical wounds and surrounding tissue at 2 weeks, 1 month, and 6 months than those patients who had received intrathecal saline placebo. Intrathecal clonidine is also being used with regularity in the treatment of chronic nonmalignant pain and intractable cancer pain, typically in combination with an opioid with or without a local anesthetic, and supplied via an implanted intrathecal drug delivery system.

Tizanidine Tizanidine had been used predominantly in the management of spasticity; however, it has also proved useful for a variety of painful conditions. As to its efficacy in the management of spasticity, tizanidine compares favorably with both baclofen and diazepam and seems to cause less muscle weakness than baclofen and a lower incidence of sedation than diazepam. In treating spasticity related to multiple sclerosis and cerebrovascular disorders such as stroke, tizanidine doses of approximately 24 mg/day are average, with maximal doses in the range of 32 to 36 mg daily. It appears that muscle strength is fairly well preserved in patients taking tizanidine for spasticity or muscle spasm, because less weakness is associated with use of this drug compared with baclofen or diazepam. Tizanidine has been successfully used in the treatment of paravertebral muscle spasm in association with acute low back pain as well and is frequently employed in the management of myofascial pain. Another major indication for the use of tizanidine is in the management of headache disorders. Tizanidine has been found effective in the treatment of chronic daily headache and has been given as

part of a detoxification regimen to assist with analgesic withdrawal in patients exhibiting analgesic rebound headaches. Based on animal studies, it also appears that tizanidine may provide benefit in the perioperative period and in the management of neuropathic pain, in accordance with the effects of clonidine under similar circumstances. One study in humans demonstrated a nearly 20% decrease in the minimum alveolar concentration of sevoflurane when 4 mg of oral tizanidine was administered preoperatively. This, in conjunction with the fact that tizanidine is not as potent as clonidine in its antihypertensive effects, may allow for more widespread use than clonidine. Use of tizanidine for perioperative anesthetic and analgesic-sparing effects may prove especially beneficial if it becomes available for neuraxial use in humans.

Dexmedetomidine Dexmedetomidine is currently U.S. Food and Drug Administration (FDA) approved for use in short-term (< 24 hr) sedation in the intensive care unit in the mechanically ventilated patient. Aside from its use in sedation of the critically ill patient, it has also been evaluated for use perioperatively and in the management of pain. Dexmedetomidine has been used as an anesthetic adjunct for a variety of surgical procedures and has demonstrated reduction in the hemodynamic responses associated with procedures such as tracheal intubation and surgical incision. This is desirable because the tachycardia and hypertension that often accompany such stimuli may induce myocardial ischemia in susceptible individuals, such as patients with underlying coronary artery disease. Because dexmedetomidine also allows for sedation without significant impact on respiration, it has been employed in the perioperative management of patients at risk of opioid-induced respiratory depression, such as the morbidly obese. Several studies have shown a reduction in perioperative opioid requirements when dexmedetomidine was incorporated into the anesthetic plan, further indicating the potential utility of this agent in selected patient populations such as those with obstructive sleep apnea. In addition, dexmedetomidine does not create the central nervous system disinhibition typically seen with other sedative agents such as propofol. Instead, because of its action on the locus ceruleus, the sedation seen with dexmedetomidine resembles that seen during normal sleep. This property allows for rapid patient arousal and cooperation, which may be important especially when intraoperative assessment of neurologic function is essential. Situations in which this drug might be particularly beneficial include use during awake carotid endarterectomy or craniotomy. Many studies have shown reduction in anesthetic requirements when dexmedetomidine is used intraoperatively, including reduced needs for thiopental, isoflurane, and fentanyl. At this point, a few case studies exist in which dexmedetomidine has been used for longer than 24 hours, the manufacturer’s maximum recommended duration of infusion. Thus far, no reports of significant withdrawal phenomena have been reported with prolonged dexmedetomidine use, but this remains a concern and must be considered when contemplating use divergent from its labeled indications.

PRECAUTIONS AND ADVERSE EFFECTS ASSOCIATED WITH a2-AGONIST THERAPY a2-Agonists appear to have beneficial effects on hemodynamics in patients at risk for myocardial ischemia, especially in the perioperative period. However, because hypotension is a frequent side effect of these agents, caution must be observed when using them in patients with cerebrovascular disease, chronic renal insufficiency, and in those who have had a recent myocardial infarction. Use of

VII PHARMACOLOGIC APPROACHES TO PAIN MANAGEMENT 479

these drugs in the elderly also warrants care because there may be an increased incidence of orthostatic hypotension in this patient population. Orthostatic hypotension can result in syncope with attendant fall-related injuries such as fractures. Use of a2-agonists in combination with b-blockers, calcium channel blockers, or digitalis may increase the potential for significant bradycardia or atrioventricular block. Some cases of sinus arrest have occurred with rapid infusion of dexmedetomidine. It may be advisable to avoid these drugs in patients with preexisting cardiac conduction defects. All the a2-agonists currently available for clinical use are considered category C drugs for use in pregnancy. Common adverse effects seen with administration of all of the a2-agonists include dry mouth, sedation, dizziness, fever, and nausea. New-onset or exacerbation of preexisting depression may occur with use of clonidine and tizanidine. Asthenia is a fairly frequent side effect of tizanidine, whereas hallucinations have been infrequently reported with this drug. Of most significant concern with the use of tizanidine is the potential for hepatotoxicity. Approximately 5% of patients who receive this drug will manifest increases in liver function tests (aspartate transaminase [AST]/alanine aminotransferase [ALT]) to greater than three times the upper limit of normal. Most of these cases have been asymptomatic, and the abnormalities in liver function tests resolved rapidly after discontinuation of tizanidine. There have been, however, several fatalities related to fulminant hepatic failure in patients on tizanidine therapy. It is, therefore, recommended that liver function tests be monitored at initiation of treatment with tizanidine and at 1, 3, and 6 months after it is started. Additional monitoring of liver function tests on a periodic basis thereafter may also be necessary, depending on clinical indicators. Lastly, a withdrawal syndrome has been reported with abrupt discontinuation of clonidine, even after epidural administration.

This may manifest as severe hypertension and can result in myocardial or cerebral infarction in some patients. It is recommended that clonidine doses be gradually tapered prior to its discontinuation. Thus far, no reports of similar withdrawal phenomena have been reported for tizanidine or dexmedetomidine (Table 65–2).

FUTURE DEVELOPMENTS IN a2-AGONIST THERAPY The use of a2-agonists in pain management may expand in the future, especially as newer agents become available that demonstrate reduced adverse effects such as undesired sedation. In addition, dexmedetomidine and tizanidine may have expanded applications in the treatment of pain in the future if they are made available for neuraxial administration. Two a2-agonists undergoing study in animal models of pain show promise for future use in humans. Moxonidine, like clonidine, has been found to provide analgesic synergy when administered with morphine intrathecally in an animal model and appears to be less sedating than clonidine. Moxonidine may act at a different a-receptor subtype than clonidine. It is possible that combinations of a2-agonists that exert their effects at different receptor subtypes may further enhance analgesic synergism and may thereby allow reduction in total analgesic requirements and attendant side effects. Moxonidine is available outside the United States for the management of hypertension. Radolmidine, another a2-agonist in development, has been compared with dexmedetomidine to evaluate antinociceptive properties when administered intrathecally in a rat model. It was demonstrated that these two agents were equipotent in antinociceptive effects, but radolmidine resulted in less reduction in rat locomotor

Table 65^2. Current Therapy: Drug Interactions, Precautions, and Adverse Effects of a2-Agonists Drug interactions

Precautions

Adverse effects

General: Sedatives (enhanced sedation); b-blockers, calcium channel blockers, digitalis (increased risk of heart block) Clonidine: Local anesthetics (prolonged sensory and motor block); cyclosporine (increased serum levels of cyclosporine/cyclosporine toxicity); tricyclic antidepressants (decreased antihypertensive action of clonidine) Tizanidine: Oral contraceptives, fluvoxamine, ciprofloxacin, zileuton, amiodarone, mexiletine, propafenone, verapamil, cimetidine, famotidine, acyclovir, ticlopidine (increased serum tizanidine levels, decreased tizanidine clearance owing to CYP1A2 inhibition) Dexmedetomidine: No specific interactions (except as above in general drug interactions with a2-agonists) General: Pregnancy (category C), use in patients with known cardiac conduction defects Clonidine: Potential for rebound hypertension with abrupt discontinuation regardless of route of administration; cautious use in obstetric patients owing to potential for hypotension; cautious use in patients with cerebrovascular disease, chronic renal failure, coronary artery disease, or recent myocardial infarction (owing to potential for hypotension)* Tizanidine: Dose reduction is advised in patients using oral contraceptives, renal insufficiency (owing to decreased clearance of tizanidine); avoid use in the presence of liver disease (owing to risk of hepatotoxicity) Dexmedetomidine: Use for periods exceeding 24 hr is not recommended (although several reports of use for longer periods have been described); owing to its ability to blunt sympathetically mediated blood pressure and heart rate responses, may be increased risk of failure to detect signs of awareness under anesthesia if this drug is incorporated into an anesthetic regimen General: Hypotension, bradycardia, heart block, sedation, dizziness, dry mouth, asthenia, orthostasis, rash, nausea Clonidine: Depression, constipation, nervousness/agitation Tizanidine: elevation of LFTs (5%) with rare incidence of fulminant hepatic failure, hallucinations, muscle spasm, fever, abdominal pain, diarrhea, dyspepsia, depression Dexmedetomidine: Sinus arrest, hypertension (with rapid infusion or loading dose administration); fever, tachycardia, anemia, hypoxia, atrial fibrillation

*This may apply to a2-agonists in general, but it is especially relevant to the use of clonidine. CYP, cytochrome P-450; LFTs, liver function tests.

480 Chapter 66  GLUTAMATE RECEPTOR ANTAGONISTS activity, suggesting that it causes less sedation than dexmedetomidine. This effect was possibly related to the inability of radolmidine to cross the blood-brain barrier, thus resulting in fewer central effects. Thus, it appears that if radolmidine becomes available for human use in the future, it may allow for substantial analgesia in the absence of significant effects on consciousness.

CONCLUSION The use of a2-agonists has expanded into the fields of anesthesia and pain management over the past few decades. These agents provide analgesia and can be administered by a variety of routes. a2-Agonists have provided benefit in the treatment of acute pain related to surgery, cancer-associated pain, headaches, neuropathies, complex regional pain syndromes, myofascial pain, and spasticity. They also provide analgesic synergy and opioid- and anestheticsparing effects. Clonidine is the oldest and most widely used of the a2-agonists. Tizanidine has found a role in the treatment of spasticity and associated muscle pain, whereas dexmedetomidine demonstrates utility in the perioperative and critical care patient populations. Newer agents such as moxonidine and radolmidine are being evaluated for future use in pain-management applications in humans and appear to show promise with regards to reduction in dose-limiting side effects. It, therefore, appears that the role of a2-agonists in anesthesia and pain management will continue to broaden in the future.

SUGGESTED READINGS Aantaa R, Jalonen J. Perioperative use of alpha2-adrenoceptor agonists and the cardiac patient. Eur J Anesthesiol 2006;23:361–372. Arain SR, Ruehlow RM, Uhrich TD, Ebert TJ. The efficacy of dexmedetomidine versus morphine for postoperative analgesia after major inpatient surgery. Anesth Analg 2004;98:153–158. De Kock M, Gautier P, Pavlopoulou A, et al. Epidural clonidine or bupivacaine as the sole analgesic agent during and after abdominal surgery. Anesthesiology 1999;90:1354–1362. De Kock M, Lavand’homme P, Waterloos H. The short-lasting analgesia and long-term antihyperalgesic effect of intrathecal clonidine in patients undergoing colonic surgery. Anesth Analg 2005;101:566–572.

Chapter 66

GLUTAMATE RECEPTOR ANTAGONISTS Howard S. Smith, James P. Wymer, and Christine N. Sang

INTRODUCTION Confirming the preclinical data that show a role for glutamate in neuropathic pain has proved to be a significant clinical challenge.

De Kock M, Wiederkher P, Laghmiche A, Scholtes J-L. Epidural clonidine as the sole analgesic during and after abdominal surgery. Anesthesiology 1997;86:285–292. Dunbar SA. Alpha2-adrenoceptor agonists in the management of chronic pain. Baillieres Clin Anesthesiol 2000;14:471–481. Eisenach JC, DuPen S, Dubois M, et al. Epidural clonidine analgesia for intractable cancer pain. Pain 1995;61:391–399. Eisenach JC, Hood DD, Curry R. Relative potency of epidural to intrathecal clonidine differs between acute thermal pain and capsaicininduced allodynia. Pain 2000;84:57–64. Gabriel JS, Gordin V. Alpha 2 agonists in regional anesthesia and analgesia. Curr Opin Anesthesiol 2001;14:751–753. Hall JE, Uhrich TD, Barney JA, et al. Sedative, amnestic, and analgesic properties of small-dose dexmedetomidine infusions. Anesth Analg 2000;90:699–705. Khan ZP, Ferguson CN, Jones RM. Alpha-2 and imidazoline receptor agonists: their pharmacology and therapeutic role. Anaesthesia 1999;54:146–165. Lataste X, Emre M, Davis C, Groves L. Comparative profile of tizanidine in the management of spasticity. Neurology 1994;44(suppl 9):S53–S59. Saper JR, Winner PK, Lake AE III. An open-label dose-titration study of the efficacy and tolerability of tizanidine hydrochloride tablets in the prophylaxis of chronic daily headache. Headache 2001;41:357–368. Semenchuk MR, Sherman S. Effectiveness of tizanidine in neuropathic pain: an open-label study. J Pain 2000;1:285–292. Smith H, Elliott J. Alpha2 receptors and agonists in pain management. Curr Opin Anesthesiol 2001;14:513–518. Smith TR. Low-dose tizanidine with nonsteroidal anti-inflammatory drugs for detoxification from analgesic rebound headache. Headache 2002;42:175–177. Unlugenc H, Gunduz M, Guler T, et al. The effect of pre-anesthetic administration of intravenous dexmedetomidine on postoperative pain in patients receiving patient-controlled morphine. Eur J Anesthesiol 2005;22:386–391. Wajima Z, Yoshikawa T, Ogura A, et al. Oral tizanidine, an alpha2adrenoceptor agonist, reduces the minimum alveolar concentration of sevoflurane in human adults. Anesth Analg 2002;95:393–396. Waldman SD. Recent advances in analgesic therapy—tizanidine. Pain Dig 1999;9:40–43. Yildiz M, Tavlan A, Reisli R, et al. Effect of dexmedetomidine on haemodynamic responses to laryngoscopy and intubation. Drugs 2006;7:43–52.

This is in part due to glutamate’s contribution to the normal function of physiology and processes as diverse as cognition, sensation, and memory.1 However, excessive activation by glutamate is believed to contribute to neuronal damage in a variety of neurologic disorders ranging from acute hypoxic-ischemic brain injury and spinal cord injury to diseases such as Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis. This dual role of glutamate significantly affects therapeutic strategies for neuropathic pain and diseases. Disruption of abnormal glutamate function must be achieved without interference with normal neuronal processes. The glutamate receptors are classified into two major groups based on action: ionotropic and metabotropic. The ionotropic receptors function as ion channels and are named after the agonists that selectively bind to them. This group includes Nmethyl-D-aspartate (NMDA), a-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), and kainate receptors The metabotropic receptors are directly coupled to intracellular signal transduction systems via G proteins such as protein kinase C and cyclic

480 Chapter 66  GLUTAMATE RECEPTOR ANTAGONISTS activity, suggesting that it causes less sedation than dexmedetomidine. This effect was possibly related to the inability of radolmidine to cross the blood-brain barrier, thus resulting in fewer central effects. Thus, it appears that if radolmidine becomes available for human use in the future, it may allow for substantial analgesia in the absence of significant effects on consciousness.

CONCLUSION The use of a2-agonists has expanded into the fields of anesthesia and pain management over the past few decades. These agents provide analgesia and can be administered by a variety of routes. a2-Agonists have provided benefit in the treatment of acute pain related to surgery, cancer-associated pain, headaches, neuropathies, complex regional pain syndromes, myofascial pain, and spasticity. They also provide analgesic synergy and opioid- and anestheticsparing effects. Clonidine is the oldest and most widely used of the a2-agonists. Tizanidine has found a role in the treatment of spasticity and associated muscle pain, whereas dexmedetomidine demonstrates utility in the perioperative and critical care patient populations. Newer agents such as moxonidine and radolmidine are being evaluated for future use in pain-management applications in humans and appear to show promise with regards to reduction in dose-limiting side effects. It, therefore, appears that the role of a2-agonists in anesthesia and pain management will continue to broaden in the future.

SUGGESTED READINGS Aantaa R, Jalonen J. Perioperative use of alpha2-adrenoceptor agonists and the cardiac patient. Eur J Anesthesiol 2006;23:361–372. Arain SR, Ruehlow RM, Uhrich TD, Ebert TJ. The efficacy of dexmedetomidine versus morphine for postoperative analgesia after major inpatient surgery. Anesth Analg 2004;98:153–158. De Kock M, Gautier P, Pavlopoulou A, et al. Epidural clonidine or bupivacaine as the sole analgesic agent during and after abdominal surgery. Anesthesiology 1999;90:1354–1362. De Kock M, Lavand’homme P, Waterloos H. The short-lasting analgesia and long-term antihyperalgesic effect of intrathecal clonidine in patients undergoing colonic surgery. Anesth Analg 2005;101:566–572.

Chapter 66

GLUTAMATE RECEPTOR ANTAGONISTS Howard S. Smith, James P. Wymer, and Christine N. Sang

INTRODUCTION Confirming the preclinical data that show a role for glutamate in neuropathic pain has proved to be a significant clinical challenge.

De Kock M, Wiederkher P, Laghmiche A, Scholtes J-L. Epidural clonidine as the sole analgesic during and after abdominal surgery. Anesthesiology 1997;86:285–292. Dunbar SA. Alpha2-adrenoceptor agonists in the management of chronic pain. Baillieres Clin Anesthesiol 2000;14:471–481. Eisenach JC, DuPen S, Dubois M, et al. Epidural clonidine analgesia for intractable cancer pain. Pain 1995;61:391–399. Eisenach JC, Hood DD, Curry R. Relative potency of epidural to intrathecal clonidine differs between acute thermal pain and capsaicininduced allodynia. Pain 2000;84:57–64. Gabriel JS, Gordin V. Alpha 2 agonists in regional anesthesia and analgesia. Curr Opin Anesthesiol 2001;14:751–753. Hall JE, Uhrich TD, Barney JA, et al. Sedative, amnestic, and analgesic properties of small-dose dexmedetomidine infusions. Anesth Analg 2000;90:699–705. Khan ZP, Ferguson CN, Jones RM. Alpha-2 and imidazoline receptor agonists: their pharmacology and therapeutic role. Anaesthesia 1999;54:146–165. Lataste X, Emre M, Davis C, Groves L. Comparative profile of tizanidine in the management of spasticity. Neurology 1994;44(suppl 9):S53–S59. Saper JR, Winner PK, Lake AE III. An open-label dose-titration study of the efficacy and tolerability of tizanidine hydrochloride tablets in the prophylaxis of chronic daily headache. Headache 2001;41:357–368. Semenchuk MR, Sherman S. Effectiveness of tizanidine in neuropathic pain: an open-label study. J Pain 2000;1:285–292. Smith H, Elliott J. Alpha2 receptors and agonists in pain management. Curr Opin Anesthesiol 2001;14:513–518. Smith TR. Low-dose tizanidine with nonsteroidal anti-inflammatory drugs for detoxification from analgesic rebound headache. Headache 2002;42:175–177. Unlugenc H, Gunduz M, Guler T, et al. The effect of pre-anesthetic administration of intravenous dexmedetomidine on postoperative pain in patients receiving patient-controlled morphine. Eur J Anesthesiol 2005;22:386–391. Wajima Z, Yoshikawa T, Ogura A, et al. Oral tizanidine, an alpha2adrenoceptor agonist, reduces the minimum alveolar concentration of sevoflurane in human adults. Anesth Analg 2002;95:393–396. Waldman SD. Recent advances in analgesic therapy—tizanidine. Pain Dig 1999;9:40–43. Yildiz M, Tavlan A, Reisli R, et al. Effect of dexmedetomidine on haemodynamic responses to laryngoscopy and intubation. Drugs 2006;7:43–52.

This is in part due to glutamate’s contribution to the normal function of physiology and processes as diverse as cognition, sensation, and memory.1 However, excessive activation by glutamate is believed to contribute to neuronal damage in a variety of neurologic disorders ranging from acute hypoxic-ischemic brain injury and spinal cord injury to diseases such as Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis. This dual role of glutamate significantly affects therapeutic strategies for neuropathic pain and diseases. Disruption of abnormal glutamate function must be achieved without interference with normal neuronal processes. The glutamate receptors are classified into two major groups based on action: ionotropic and metabotropic. The ionotropic receptors function as ion channels and are named after the agonists that selectively bind to them. This group includes Nmethyl-D-aspartate (NMDA), a-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), and kainate receptors The metabotropic receptors are directly coupled to intracellular signal transduction systems via G proteins such as protein kinase C and cyclic

VII PHARMACOLOGIC APPROACHES TO PAIN MANAGEMENT 481

adenosine monophosphate.2 In this chapter, we review currently available data on the role of antagonism at the NMDA, AMPA/ kainate, and metabotropic sites in neuropathic pain.

THE NMDA RECEPTOR NMDA receptors (NMDARs) are composed of subunits known as NR1, NR2 (A, B, C, D), and NR3 (A and B). The NR1 binds glycine, and NR2 binds glutamate. Normally, the NMDAR has a resting membrane potential of –65 mV, and the NMDAR is blocked by magnesium ion and is thus unresponsive to glutamate. After a significant depolarization of the AMPA or kainate receptors by glutamate, at the neurokinin-1 receptor by substance P, at the neurokinin-2 receptor by neurokinin A, or at the trkB receptor by brain-derived neurotropic factor (BDNF), the NMDAR becomes responsive to glutamate.

NMDAR ANTAGONISTS In neuropathic pain, prolonged firing of peripheral C-fiber nociceptors causes the release of glutamate centrally, which then acts on NMDARs in the spinal cord dorsal horn. Activation of these receptors then triggers influx of calcium into the cell and initiates a number of events that enhance secondary messenger pathways, causes rearrangement of receptors in the spinal cord, and alters the transcription of genes. Ultimately, this process will alter the

neuron’s response to subsequent stimuli.3,4 These events are believed to at least partially contribute to the development of mechanical hyperalgesia that may follow peripheral nerve injury or tissue inflammation.5 Antagonism of the NMDA channel can be categorized pharmacologically according to the site of action on the receptor-channel complex (Fig. 66–1). These include drugs acting at the agonist (NMDA) or coagonist (glycine) sites, the channel pore site, and the modulatory sites. Competitive NMDA and glycine antagonists are effective in models of glutamate-mediated neurotoxicity.3–5 Moreover, systemic administration of NMDAR antagonists in patients with neuropathic pain can reduce spontaneous pain and hyperalgesia in experimental,6 acute postoperative,7 and chronic neuropathic pain.8,9 Unfortunately, however, memory impairment, sedation, psychotomimetic effects, ataxia, and motor incoordination are also potential results with the potential to effectively limit maximal doses achievable in patients.10 This is because glutamate is also responsible for processes important to normal cognition. Functional inhibition of the NMDAR complex can be achieved through indirect actions at the channel pore sites (phencyclidine [PCP]; polyamine site [NR2B selective], and magnesium), and modulatory sites such as the S-nitrosylation site where nitric oxide (NO) reacts with critical cysteine thiol groups (see Fig. 66–1). Some investigations suggest that targeting the channel pore and modulatory sites may provide superior analgesia with the potential of a better side effect profile, especially in patients with neuropathic pain. Selective antagonists to the NR2B subunit have become available and also may open new therapeutic opportunities

NMDA RECEPTOR COMPLEX Glycine site

Outer membrane surface

NMDA site

Polyamine site

Zn ++

SNO

SNO-cysteine sulfhydral group (-SH) reacting with nitrogen oxide species NO-Nitric Oxide ROS-Reactive Oxygen Species nNOS neuronal Nitric oxide synthase LA Local Anesthetic BDNF Brain derived neurotrophic factor

Ca++ Na++

K+

PCP site Membrane

NR2

NR1

Mg++ Inner membrane surface Tyr

Mitochondria Ca++

ROS ERK

PKC

1472

NMDA Zn++ Mg++ PCP Na++ K+ Ca++ P

= Inhibitory = Facilatory = N-methyl-D-aspartate = Zinc = Magnesium = Phencyclidine = Sodium ions = Potassium ions = Calcium ions

Fyn kinase EP1

Src nNOS

TrkB BDNF

Figure 66^1. N-methyl-D-aspartate receptor (NMDAR) complex.

LA

PGE 2

482 Chapter 66  GLUTAMATE RECEPTOR ANTAGONISTS in the clinical management of pain.11 Currently available NMDAR antagonists include ketamine, dextromethorphan (DM), amantadine, memantine, magnesium sulfate, and certain opioids such as methadone. Drugs of other classes, such as amitriptyline, also have affinity for the NMDA channels,12,13 and different antidepressants may have differing affinities.14 However, these agents are not discussed. Spinal interleukin-1b (IL-1b) produced by astrocytes enhances NR1 phosphorylation to promote inflammatory pain.15 IL-1 receptor antagonists (IL-1ras) produce antiallodynic effects in rat models of neuropathic pain16,17 and attenuate inflammatory hyperalgesia likely via inhibiting NR1 phosphorylation15 (perhaps by inhibiting the activation [i.e., phosphorylation] of extracellular receptor–activated kinase [ERK]).18 This may be similar to one of the potential postsynaptic mechanisms by which bupivacaine produces analgesia.18,19

ketamine may have a better therapeutic ratio for analgesia than parenteral ketamine.47–49 Oral ketamine, however, has been associated with hepatic damages, gastric ulcer, and memory impairment50 and may have problems related to tolerance with long-term administration.

Ketamine

Neuraxial Ketamine

Ketamine is a phencyclidine-like drug with noncompetitive NMDAR antagonist activity. It inhibits the NMDA receptor by binding to the PCP site in the open state and thus provides usedependent blockade of the NMDA channel.20 Ketamine exhibits a phenomenon called ‘‘trapping’’ of NMDA blockade, which produces accumulation of the antagonist, resulting in supramaximal blockade (in situations in which there is repetitive NMDAR stimulation) and correlating with a narrow therapeutic index.21 In addition to this, ketamine may function via secondary effects of enhanced peripheral monoaminergic transmission, inhibition of central and peripheral cholinergic transmission, and possibly, effects on voltage-gated calcium currents Animal analgesic studies suggest that ketamine reduces nociceptive behaviors and spinal dorsal horn neuronal activity in response to tissue injury.22–25 In humans, ketamine has been reported to relieve glossopharyngeal and neuralgia and cancer pain in subanesthetic doses.8,26,27 Placebo-controlled trials in patients suffering from postherpetic neuralgia,28,29 acute postoperative hyperalgesia,7,29 phantom pain,30 acute and chronic orofacial pain,31 spinal cord injury,32 chronic post-traumatic pain,33 chronic ischemic pain,34 and mixed neuropathic pain syndromes8,28 have shown that ketamine can relieve neuropathic pain and hyperalgesia. In most cases, however, appreciable symptomatic relief from ketamine develops only after the onset of unpleasant psychotomimetic side effects. Ketamine administered by the subcutaneous and intravenous routes causes dose-dependent nausea, confusion, hallucinations, visual disturbances, unpleasant dreams, delirium, and other psychotomimetic adverse effects.35 The activity of ketamine in the cortex and limbic systems has been implicated in the development of such symptoms. Ketamine has anecdotally been administered for the treatment of refractory complex regional pain syndrome.36,37 Although some studies are unable to find significant utility to support the perioperative use of ketamine,38 multiple studies exist that support a perioperative benefit to ketamine administration.39–42

He and coworkers demonstrated that the combined injection of ketamine and clonidine can produce synergistic analgesia without obvious side effects when compared with ketmaine alone in the chronic construction injury (CCI) rate model.52 Case reports and case series suggest that the administration of intrathecal and epidural ketamine is effective for the treatment of pain. However, ketamine has been associated with histopathologic changes of the spinal cord. Stotz and associates53 reported a patient with intractable cancer pain who obtained pain relief after ketamine was added to an intrathecal mixture of bupivacaine, morphine, and clonidine. Although the patients did not develop neurologic deficits, focal lymphocytic vasculitis was observed close to the intrathecal catheter postmortem. Karpinski and colleagues54 reported postmortem changes of subpial spinal cord vacuolation in a terminally ill cancer patient who developed a wide-based gait after receiving a continuous infusion of intrathecal ketamine for pain control. Murali Krishna and coworkers55 concluded that low doses of midazolam and ketamine with bupivacaine intrathecally result in prolonged analgesia and fewer hemodynamic fluctuations.

Oral Ketamine A number of case reports and case series have shown the successful use of oral ketamine in experimental ischemic arm pain, postherpetic neuralgia, neuropathic pain, and postamputation pain.43–46 The administration of oral ketamine results in higher serum concentrations of norketamine, the main metabolite of ketamine. Norketamine is a noncompetitive NMDAR antagonist and is equipotent to its parent drug in the second phase of the formalin test. The potency of norketamine, the shorter duration of psychomotor effects of oral ketamine, and the relatively high levels of norketamine in the brain (the norketamine-to-ketamine area under the curve [AUC] ratio in the brain may reach 2.9) suggest that oral

Nasal Ketamine Carr and coworkers51 reported a small, double-blind, randomized, controlled, cross-over trial of intranasal ketamine as rapid delivery for systemic administration for the management of breakthrough pain. Intranasal ketamine was found to produce reasonably effective analgesia (more effective than placebo) with an onset of analgesia within 10 minutes. The peak effect of analgesia occurred at 40 minutes, with an analgesia duration of over an hour. The predominant adverse effects included fatigue, dizziness, altered taste, and feelings of unreality.

3 -(2-Carboxypiperazin- 4 -yl) propyl-1-phosphonic Acid 3-(2-Carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) is a potent and selective competitive antagonist of the NMDAR. CPP is not clinically available, and there is little evidence supporting its use for the management of clinical pain. Kristensen and associates56 described the use of CPP in on patient with intractable neuropathic pain. In this patient, intrathecal administration of CPP abolished the spread of pain evoked by low-threshold mechanical and thermal stimuli to areas outside the territory of the injured nerve. However, continuous deep pain and allodynia in the territory of the injured nerve were unchanged. The authors suggested that CPP modulates pathologic pain at the spinal level. The patient developed psychotoimimetic ketamine-like side effects, which were attributed to the hydrophilicity and rostral spread of CPP.

LOW-AFFINITYCHANNEL BLOCKING NMDAR ANTAGONISTS Low-affinity NMDAR antagonists such as DM, dextrorphan (DX), remacemide, amantadine, memantine, and other adamantine analogues produce fewer neuropsychologic side effects than the higheraffinity antagonists. The improved side effect profile of these compounds has been attributed to their low micromolar affinity

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for the NMDAR. The faster rates of block and unblock contribute in part to their more-favorable toxicity profile.20

showed that DM prevented the development of tolerance to the antinociceptive effects of morphine and attenuated signs of naloxone-precipitated physical dependence on morphine.

DM DM is a dextrorotatory analogue of levorphanol, a low-affinity noncompetitive antagonist of the NMDA-sensitive ionotropic glutamate receptor. In addition, it is also a sigma-1 receptor agonist, suppressing the release of excitatory,8 and may act on the N-type calcium channel. Unlike ketamine, DX (and likely DM) interacts with NMDA-binding sites that are distinct from that of ketamine or MK801, and ability to the bind to a closed channel exists (with DX and probably DM).57 Initial human studies yielded conflicting results,22,58–60 probably due to inadequate dosing. McQuay and colleagues29 found that DM did not relieve pain in patients with different chronic neuropathic pain syndromes at doses of 81 mg/day. Duedahl and colleagues61 administered intravenous DM in normal volunteers and found significantly reduced areas of secondary hyperalgesia after both capsaicin and thermal stimulation. Nelson and coworkers9 compared high doses of DM and DX to placebo in patients with diabetic neuropathy and postherpetic neuralgia. Patients with diabetic neuropathy, but not postherpetic neuralgia, reported better pain relief with DM. Sang and associates62 compared DM with the active placebo lorazepam and obtained similar results to those of Nelson’s group,9 using doses as high as 920 mg/day (mean doses 400 mg/day). DM produces dose-dependent side effects, depending on the rate of titration and cytochrome P-450 (CYP) 2D6 metabolizer status. Single, overthe-counter doses of 30 to 60 mg produce mild side effects in fewer than 10% of patients. Reported adverse effects to DM include dizziness, fatigue, confusion, lightheadedness, depression, gastrointestinal disturbances, and nystagmus. DM is extensively metabolized to DX, primarily by CYP2D6 and is rapidly protein bound. The disposition of DM is, therefore, substantially influenced by the CYP2D6 enzyme. Seven percent to 10% of whites and 1% of Asians have mutations in both copies of the CYP2D6 gene. These patients accumulate higher DM levels than normal (poor metabolizers). Most patients have two normal copies of the CYP 2D6 gene (extensive metabolizers), and some patients may have multiple copies of the intact genes (ultrarapid metabolizers). The median elimination half-life is 2.4 hours in extensive metabolizers and 19.1 hours in poor metabolizers.63–66 Patients can be pharmacologically converted to poor metabolizer status by administering drugs such as quinidine, which is a potent CYP2D6 inhibitor.67 However, the parent drug, DM, has a higher affinity for the sigma-1 opioid receptor than DX, which may contribute to differences in effects between the parent drug and its metabolite. In an open-label study of subjects with painful diabetic peripheral neuropathy, quinidine in combination with antitussive doses of DM (30 and 120 mg/day) was well tolerated in patients with pain associated with diabetic peripheral neuropathy. Twenty-three of 33 subjects were able to tolerate 120 mg of DM in combination with 120 mg of quinidine. The most commonly reported adverse events were nausea (27.8%), dizziness (25.0%), and headache (25.0%). Studies that have compared the effects of either single doses68 or chronic oral dosing69 in poor and rapid metabolizers show that high doses of DM are better tolerated in rapid metabolizers than in poor metabolizers. Moreover, Carlsson and colleagues68 found a differential effect of DM efficacy in favor of rapid metabolizers that correlated with higher plasma DX concentrations. Finally, animal and human studies have suggested that the combination of DM with opiate analgesics may be useful for preventing opiate tolerance and dependence while enhancing both peak and duration of opioid analgesia, even at subanalgesic doses of DM. Mao and coworkers,70 in a study to evaluate the practical feasibility of the combined oral administration of morphine sulfate with DM,

Amantadine Amantadine has been used as an antiviral agent and for the treatment of Parkinson’s disease. Until recently, the mechanism of action of amantadine was speculated to be related to dopaminergic and anticholinergic activity. Several human postmortem and in vitro studies have demonstrated that memantine may produce its pharmacologic effects through noncompetitive binding to the PCP site of the NMDAR complex.71–74 Investigations of the analgesic efficacy of amantadine have yielded conflicting results. Eisenberg and Pud75 reported three patients in whom a single dose of intravenous amantadine resulted in the complete resolution of spontaneous pain, mechanical allodynia, and hyperalgesia. Pud and associates76 also randomized 25 cancer patients with surgical neuropathic pain to receive either placebo or 200 mg of intravenous amantadine. Mean pain intensity remained significantly lower during the 48 hours after amantadine treatment compared with the 48 hours prior to treatment, whereas no such effect was found with the placebo. However, amantadine was not analgesic in subsequent studies by Medrik-Goldberg and colleagues77 and Taira78 in patients with sciatica and different types of neuropathic pain. Amantadine produces fewer psychotomimetic side effects than ketamine and is usually well tolerated. Dose-dependent side effects include dizziness, lethargy, sleep disturbances, headache, hallucinations, and nausea and vomiting.

Memantine Memantine has been used for the treatment of dementia and Parkinson’s disease.79 A number of studies have looked at memantine for the treatment of different neuropathic pain syndromes. Sang and associates62 compared memantine with the active placebo lorazepam for the treatment of diabetic neuropathy and postherpetic neuralgia and were unable to detect a treatment effect. Eisenberg and coworkers,80 in a double-blind, randomized, placebo-controlled trial, administered memantine at a dose of 10 mg/day and 20 mg/day to patients with postherpetic neuralgia. Reduction in spontaneous pain, mechanical and cold allodynia, mechanical hyperalgesia, and wind-up–like pain was found in both groups, but there were no significant differences between the placebo and the treatment group. Schifitto and associates81 studied 45 subjects with human immunodeficiency virus (HIV)–associated symptomatic DSP (SDSP) in a randomized, multicenter, 16-week, placebo-controlled study of memantine. Memantine was well tolerated; however, no trend toward clinical benefit was observed. Results were similar to those of other pilot studies of memantine for neuropathic pain unrelated to HIV, suggesting that memantine is ineffective for the symptomatic treatment of HIV-associated SDSP.81 In spite of these studies, certain clinicians believe that patients exist with difficult-to-treat pain syndromes often associated with cortical reorganization (e.g., phantom limb syndrome, complex regional pain syndrome) that may benefit from memantine therapy.82–85 Memantine is associated with dizziness, lethargy, sleep disturbances, headache, nausea, and vomiting. In addition, taking advantage of memantine’s preferential binding to open channels and the fact that excessive NMDAR activity can be down-regulated by S-nitrosylation, combination drugs called NitroMemantines have been developed.86 These drugs use memantine as a homing signal to target NO to hyperactivated NMDARs in order to avoid systemic side effects of NO such as hypotension (low blood pressure). These second-generation mematine derivatives, although not currently available, are designed as pathologically

484 Chapter 66  GLUTAMATE RECEPTOR ANTAGONISTS activated therapeutics and, in preliminary studies, appear to have even-greater neuroprotective properties than memantine.86

Numerous investigators have described the successful use of methadone in the treatment of cancer pain, especially for pain refractory to high doses of other opioids.101–106

Magnesium A number of investigators have suggested that the administration of magnesium might be useful as an analgesic.87 Magnesium ions prevent extracellular calcium ions from entering the cell by blocking the ion channel coupled to the NMDAR. Dubray and colleagues88 showed that dietary restriction of magnesium decreased mechanical nociceptive thresholds in rats. In the same study, decreased pain threshold was reversed by the administration of MK-801, an NMDAR antagonist. Xiao and Bennett89 demonstrated that spinal or subcutaneous administration of magnesium significantly reduces heat hyperalgesia and mechanical allodynia in a model of neuropathic pain. In another animal study, Takano and coworkers87 found that intrathecal administration of magnesium sulfate caused a dose-dependent suppression of phase 2 of the formalin test. Koinig and associates,90 in a randomized, double-blind study, administered magnesium to patients undergoing arthroscopic knee surgery and found that intravenous magnesium sulfate administration reduced intraoperative and postoperative analgesic requirements. However, Felsby and colleagues28 were unable to demonstrate a statistically significant reduction of pain and allodynia in patients with peripheral neuropathic pain. Acute and chronic administration of magnesium is well tolerated. Reported adverse effects include a flushed feeling, heat sensation and pain at the injection site, and sedation.

Riluzole Riluzole has been used for the treatment of amyotrophic lateral sclerosis. The exact mechanism of action of riluzole noncompetitively inhibits the NMDAR and kainite receptor91 as well as sodium channels.92 Analgesic studies with riluzole have not been encouraging. Hammer and coworkers93 examined the acute analgesic effect of riluzole in a human model of inflammatory pain induced by a thermal injury in 20 healthy volunteers. Riluzole had no acute analgesic effects in normal or hyperalgesic skin.

OPIOIDS WITHNMDAR ACTIVITY Methadone, dextropropoxyphene, and meperidine have demonstrated low affinity for the PCP site of the NMDAR.94–97 The dual action of this opioid over the NMDAR and m-receptors might have important clinical implications in the treatment of neuropathic pain. Because of its long half-life, excellent bioavailability, and low cost, methadone has received particular attention in recent years.

Methadone Methadone is a racemic mixture of levorotatory (L) and dextrorotatory (D) methadone. Animal studies have shown that both D- and L-methadone have NMDAR antagonist and that both isomers bind specifically to the noncompetitive site of the NMDAR. However, D-methadone does not produce opioid-like locomotor activity in mice,98 is inactive after intraventricular administration in rats,99 and is a 50-fold less potent analgesic in humans than L-methadone. These findings suggest that D-methadone does not have opioid analgesic properties and that its analgesic activity might be mediated through the NMDAR. Besides its NMDAR activity, methadone differs from other opioids because of its long half-life, excellent absorption after oral and rectal administration, and lack of known active metabolites.100

NMDAR 2B SUBUNITANTAGONISTS The NMDAR complex encompasses many protein subunits, including NMDA R1 (NR1) and NR 3 (NR2A-NR2D). Spinal NMDAR 2B (NR2B) subunit–increased expression plays an important role in the facilitation and maintenance of the persistent pain state due to peripheral nerve injury.107 Animal studies have demonstrated that the NR2B subunit is restricted to the forebrain and distributed in the laminae I and II of the spinal cord dorsal horn and, therefore, might induce antinociception without motor dysfunction. Rivat and associates108 reported that a polyamine-deficient (PD) diet for 7 days prevented the enhancement of tyrosine phosphorylation of the spinal NR2B subunit–containing NMDAR associated with inflammation in rats. A PD diet strongly reduced long-lasting hyperalgesia induced by inflammation or incision, especially in fentanyl-treated rats. Moreover, a PD diet also prevented the exaggerated hyperalgesia induced by a second inflammation performed 7 days after the first one. A PD diet also opposed paradoxical hyperalgesia induced by nonnociceptive environmental stress in rats with pain and opioid experiences. A PD diet reversed pain hypersensitivity associated with monoarthritis or neuropathy and restored the analgesic effect of morphine.108 CP101,606 [(1S, 2S)-2-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol], a selective NR2B subunit antagonist, was demonstrated to be antihyperalgesic in neuropathic rats without impairing rotarod performance.109 Nakazato and colleagues110 suggested that the antiallodynia effect of CP-101,606 is ascribable to blockade of NR2B receptors at the brain, but not the spinal cord. In contrast, intrathecal injection of a nonselective NMDA antagonist, memantine, significantly inhibited CCI-induced mechanical allodynia at a dose of 300 nmol, indicating the difference in the site of action between the nonselective NMDA antagonist and the NR2B-specific NMDA antagonist.110 Spinal administration of the NMDA-2B receptor antagonist Ro 25-6981 had a clear antinociceptive effect at the spinal level after high-frequency stimulation (HFS) (P < .05, C-fiber–evoked responses in baseline).111 Moreover, spinal administration of this antagonist clearly attenuated the magnitude of spinal cord long-term potentiation (LTP) after HFS conditioning (P < .05, C-fiber–evoked responses after HFS vs. C-fiber–evoked responses after 8 mm Ro 25-6981 + HFS.111 (–)-6-[2-[4-(3-Fluorophenyl)-4-hydroxy-1-piperidinyl]1-hydroxyethyl]-3, 4-dihydro-2(1H)-quinolinone was identified as an orally active NR2B subunit–selective NMDAR antagonist.112 It has very high selectivity for NR2B subunits containing NMDARs versus the HERG-channel inhibition (therapeutic index = 4200 vs. NR2B binding inhibitory concentration of 50% [IC50]). This compound has improved pharmacokinetic properties compared with the prototype CP-101,606.112 In fact, it is theoretically conceivable and has been proposed113 that the analgesic effects of intrathecal glucocorticoids in certain pain states114 may be due in part to their ability to induce significant up-regulation of neuronal NO synthase and NR2B subunit expression in the spinal dorsal horn.115 Wang and colleagues107 showed the feasibility of oral immunization with rAd5/NR2B in efforts to potentially prevent neuropathic pain.

NON-NMDAR ANTAGONISTS Evidence has been accumulating that the AMPA channels also play a role in the development and maintenance of neuropathic pain. During the sensitization process, excessive C-fiber stimulation enhances influx through AMPA as well as NMDA. With AMPA

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channels known to show dense expression in the superficial lamina of the spinal cord, they are a potential site of intervention. The anticonvulsant topiramate inhibits activity of glutamate at AMPA/ kainate receptors with no effect on NMDA-evoked currents. Topiramate blocks kainate-evoked currents in patch clamp studies of hippocampal neurons by allosterically modulating channel conductance116–119 likely by binding to phosphorylation sites on AMPA and kainate receptors in their dephosphorylated states.120 It has been U.S. Food and Drug Administration (FDA) approved for use in migraine prophylaxis, and in three open-label studies, 44 subjects with mixed peripheral neuropathies received topiramate doses of 250 to 300 mg/day and demonstrated reduction in visual analog score (VAS) of 65%, 30%, and 60% in 14, 8, and 22 subjects, respectively.116 Placebo-controlled trials have had less success.121 AMPA-specific antagonists have been developed, and in the experimental animal CCI model, these agents have shown antiallodynic activity. Human trials of AMPA-specific agents have had limited benefit in migraines but are currently under way for other types of pain. Kainate receptors have been associated with pain pathways.122,123 Recent studies in humans suggest that the mixed AMPA/kainate antagonist LY293558 can prevent capsaicin-induced hyperalgesia and allodynia with no effect on physiologic nociception.124 Similar results were reported in animal studies in which formalin-induced,125 but not acute physiologic,126 nociceptive responses were reduced by kainite/GluR5-selective decahydrosioquinolines. In a randomized, controlled clinical trial, Gilron and coworkers compared the analgesic efficacy of the AMPA/kainite antagonist LY293558 with that of intravenous ketorolac trimethamine and placebo after oral surgery. Study drugs were administered at the onset of moderate pain; pain intensity and relief were measured for 240 minutes. LY293558 and ketorolac trimethamine were superior to placebo for pain evoked by mouth opening and in one of several measures of spontaneous pain. The potential therapeutic value of non-NMDAR depends on the continued development of subtype-selective non-NMDAR antagonists.

METABOTROPIC GLUTAMATE ANTAGONISTS The metabotropic glutamate receptor antagonists (mGluRs) represent G protein–coupled receptors. Eight mGluR subtypes have been cloned to date and are classified into groups I (mGluRs 1 and 5), II (mGluRs 2 and 3), and III (mGluRs 4, 6, 7, and 8) based on their sequence, signal transduction mechanisms, and pharmacologic profile.127–129 mGluRs modulate nociceptive processing at various levels of the nervous system and are involved in both peripheral and central pain sensitization. Other investigations suggest that antagonists at group I and agonists at group II may be useful drugs to downregulate the transmission and processing of nociceptive signals. The recent discovery of peripheral mGluRs involved in nociception may lead to peripherally acting analgesics devoid of central side effects. mGluR5 antagonists have significant antinociceptive effects at the spinal cord level, in the thalamus and amygdala. Noticeably, group II mGluR agonists have no effect on normal transmission in the spinal cord but reverse pain-related central sensitization. mGluRs block secondary thermal hyperalgesia in rats with knee joint inflammation.11 Spinal infusion of group I mGluRs LY393053 [(±)-2-amino-2-(3-cis and trans-carboxycyclobutyl-3-(9-thioxanthyl) propionic acid], LY367385 [(S)-(+)–amino-4-crboxy2-methylbenzeneacetic acid], or AIDA [(R,S)-1-aminoindan-1, 5-dicarboxylic acid/UPF 523] before a knee joint injection of kaolin and carrageenan significantly reduced the development of secondary thermal hyperalgesia suggestive of sensitization of spinal neurons.130

Selective mGluR5 antagonists, such as 2-methyl-6-(phenylethynyl)-pyridine (MPEP) and 3-[(2-methyl-1, 2-thiazol-4-yl)ethynyl] pyridine (MTEP), have shown analgesic properties in several animal modes of inflammatory and neuropathic somatic pain.131–139 Lindstro¨m and associates140 concluded that mGluR5 antagonists (e.g., MPEP and MTEP) inhibit colorectal distention–evoked visceromotor and cardiovascular changes in conscious rats through an effect, at least in part, at peripheral afferent mechanically evoked visceral nociception in the gastrointestinal tract. Lee and colleagues141 demonstrated that intra-articular MPEP is more effective than AIDA on nonevoked pain as well as mechanical hyperalgesia in both the induction and the maintenance phase in knee joint inflammation. Both preoperative and postoperative administration of 10 mg/kg–1 MPEP blocked mechanical hypersensitivity induced by abdominal surgery (P < .01 vs. vehicle treatment).142

CONCLUSIONS The NMDAR complex has been implicated to play a crucial role in wind-up phenomena and activity-dependent central sensitization of nociceptive afferent input into the spinal cord dorsal horn. Thus, it seemed to follow that the NMDAR complex may be involved in the development and/or maintenance of many persistent pain states. However, the clinical use of NMDAR antagonists as sole analgesics or coanalgesics has not been found to be as effective as had originally been hoped. This discrepancy is probably due in part to the relatively low potency of clinically available agents at the NMDAR complex and the relative low doses of NMDAR antagonists utilized. This is largely due to the unfavorable side effect profile (PCPlike cognitive effects [e.g., feelings of intoxication or delirum, dissociative effects, and/or vivid dreams]) seen with clinically available NMDAR antagonists when used at higher doses. Despite the concerns previously raised, many patients have achieved adequate analgesia with NMDA antagonists alone or in combination with other analgesic agents (e.g., opioids, a2-adrenergic receptor agonists) in certain neuropathic pain states. Among clinically available oral NMDA antagonists utilized for persistent pain, DM appears to be the most useful agent for analgesia, especially when titrated slowly to higher doses in combination with other analgesics. Future research in this area may aim for developing oral NMDA antagonists with higher potency and a more favorable side effect profile (perhaps by focusing on selective agents targeting specific NMDA subunit sites).

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Chapter 67

BOTULINUM TOXINS FOR TREATMENT OF PAIN

THE

Catalina Apostol, Salahadin Abdi,Tobias Moeller-Bertram, Howard S. Smith,Charles E. Argoff, and Mark Wallace

INTRODUCTION Botulinum toxins (BTXs) have been used to relax muscles with severe abnormal spasticity or increased tone but appear to possess independent analgesic qualities as well. Major uses of BTXs for painful conditions include headache, low back pain, and painful myofascial and muscle disorders. This chapter gives an overview of the use of BTX in various painful conditions.

HISTORICAL PERSPECTIVE Historically, the existence of Clostridium botulinum has been known for centuries. Its application as a treatment for skeletal disorders started in 1817 when Christian Andreas Justinius Kerner first recognized the toxin’s ability to paralyze skeletal muscle. Purified forms were developed through research by Dr. Herman Sommer in the 1920s and later by Dr. Edward J. Schantz in 1946. In 1950, Dr. Vernon Brooks discovered that BTX-A injected in hyperactive muscle stops the release of acetylcholine (Ach). In the 1960s. Dr. Allan B. Scott, MD, of the Smith-Kettlewell Eye Research Foundation, injected BTX in ocular muscles of monkeys and humans and observed that he was able to correct strabismus. Allergan acquired rights to distribute Dr, Scott’s product, Oculinum, in 1989 and started conducting clinical trials of the drug’s effectiveness for other indications. In 1989, the U.S. Food and Drug Administration (FDA) approved BTX-A (Botox) for treatment of strabismus, essential blepharospasm, and hemifascial spasm in patients 12 years or older.

STRUCTURE AND MECHANISM BTX is produced by the gram-negative anaerobic bacterium C. botulinum. The bacterium culture is fermented in order to liberate a toxin that is further precipitated, purified, and crystallized. The resulting complex contains a single-chained 150-kDa peptide and associated proteins. This form has low potency and requires modification of its tertiary structure before it can inhibit exocytosis of Ach from vesicles at the neuromuscular junction. There are seven distinct neurotoxin types (A through G) that share a general structure and function but differ in potency and duration. BTX-A and -B are the only forms approved by the FDA after they were shown to be safe and effective in double-blind clinical trials for the treatment of dystonia. BTX-A is marketed in the United States as Botox by Allergan and in Europe as Dysport by

Speywood, United Kingdom. The BTX-B formulation is named Myobloc in the United States and Neurobloc in Europe (Elan Pharmaceuticals). Although the clinical effects of BTX-A and -B are similar, types -A and -B toxins are distinct antigenically. Neutralizing antibodies to BTX-A do not block type B toxin effects. This allows patients who develop neutralizing antibodies to BTX-A and no longer obtain satisfactory muscle relaxation to continue treatment with the immunologically different BTX-B. At least 4% and perhaps more than 7% of patients treated with BTX-A may develop neutralizing antibodies to it.1 BTX inhibits the release of Ach from cholinergic terminals of motor neurons, leading to a temporary flaccid muscle paralysis, and also inhibits release of Ach from preganglion sympathetic and parasympathetic neurons and postganglionic parasympathetic nerves.2 Understanding how Ach works in the autonomic system and skeletal muscle is important in appreciating the wide potential of clinical applications for BTX. Normally, Ach binds to nicotinic receptors on skeletal muscles to increase intracellular calcium and produce contraction. BTX cleaves a synaptosomal protein of 25 kDa that mediates the fusion of Ach vesicles with the axon terminal. A potent biologic substance, BTX inhibits proteins that mediate the fusion of Ach vesicles with the axon terminal and thus interferes with vesicle exocytosis. Inhibition of the release of glutamate, substance P, and calcitonin gene–related peptide, reduced afferent input to the central nervous system through effects of the toxins on muscle spindles, and other possible effects on pain transmission independent of the effect on cholinergic transmission of these neurotoxins have been proposed based upon the results of many laboratory experiments.3–5 The inhibition of neurotransmitter release by BTX occurs in a multistep process that is initiated when the heavy chain of BTX binds to specific acceptors/receptors on cholinergic neurons.6,7 Each serotype appears to require different acceptors, and each acceptor comprises a ganglioside and a protein component.8–19 For serotypes B and G, the protein component of the acceptor has been identified as synaptotagmin,19–23 but the target protein for serotype A has not been fully characterized nor confirmed. Fernandex-Salas and coworkers24 tentatively identified FGFR3 as the putative protein component for the serotype A receptor. However, it is not known whether this protein associates with any soluble N-ethylmaleimide–sensitive factor attachment protein receptor (SNARE) proteins,25–27 or other membrane proteins, to form a complex that would work with the ganglioside to provide high-affinity binding of BTX-A. BTXs share a common structure, being di-chain proteins of 150 kDa, consisting of a heavy chain (HC) of 100 kDa covalently joined by a single disulfide bond to a light chain (LC) of 50 kDa.28 The HC consists of two domains, each of 50 kDa. The C-terminal domain (HC) is required for the high-affinity neuronal binding,29,30 whereas the N-terminal domain (HN) is proposed to be involved in membrane translocation.31 The LC is a zincdependent metalloprotease responsible for the cleavage of the substrate SNARE protein.32 BTX is believed to gain access to SNARE proteins and block vesicle exocytosis at the neuromuscular junction via a three-stage process: (1) an initial binding stage leading to internalization via endocytosis; (2) a membrane translocation stage; and (3) a secretion blockade stage (Fig. 67–1).33 Lectins from the leguminous Erythrina species have been identified to bind such galactose-containing carbohydrates and the lectin from E. cristagalli (ECL) was selected to test the hypothesis that BTX endopeptidases could be retargeted selectively to nociceptive afferents.34,35 After intrathecal administration of the

490 Chapter 67  BOTULINUM TOXINS FOR THE TREAT MENT OF PAIN 3

H⫹ 4 Vesicle 2

5 SNARE complex

1

Pre-synaptic membrane Figure 67^1. Schematic of neurotoxin action at presynaptic

nerve terminal. (1) Botulinum neurotoxin binds to receptor(s) at the presynaptic membrane via (Hc) (providing very selective target specificity). (2) Receptor with bound neurotoxin undergoes endocytosis. (3) Endosome acidifies, leading to insertion of neurotoxin heavy chain (HN) into the membrane and translocation of the neurotoxin into the neuronal cytosol. (4) Neurotoxin, or light chain, in the cytosol. (5) Neurotoxin light chain cleaves specific soluble N-ethylmaleimide ^ sensitive factor attachment protein receptor (SNARE) protein at unique peptide bond. (From Foster KA. A new wrinkle on pain relief: re-engineering clostridial neurotoxins for analgesics. Drug Discov 2005;10:563^569.)

ECL-LHN/A conjugate into the lumbar region of the spinal cord of rats, sensory inputs by primary nociceptive afferents were significantly attenuated.34,35 The ability of ECL-LHN/A to block neurotransmitter release from nociceptive afferent neurons for prolonged periods in vitro is, therefore, retained in vivo. Intrathecal administration of ECL-LHN/A into the lumbar region of the spinal cord of mice resulted in a prolonged withdrawal latency in a model of thermal pain, thus demonstrating the analgesic activity of the conjugate.36 This effect was sustained for more than 30 days postadministration of the conjugate, whereas morphine in the same model ceased to demonstrate analgesic activity within less than a day. The ECL-LHN/A conjugate, intrathecal or subcutaneous, has also been shown to inhibit phase II inflammatory pain in the rat formalin model.37 Specifically, a novel protein consisting of the LHN domains of BTX-C and epidermal growth factor (EGF) that is able to inhibit secretion of mucus from epithelial cells is reported. Such a molecule has the potential to prevent mucus hypersecretion in asthma and chronic obstructive pulmonary disease.38 BTX is internalized by the cell through an energy-dependent process and the LC is translocated across the vesicle membrane into the cytosol.6,7,39 The translocation domain may form a channel to facilitate the release of the LC from the endosome.40–42 In the cytoplasm, the LC of the BTX-A molecule acts as an enzyme, cleaving a specific bond on synaptosomal-associated protein of 25 kDa (SNAP-25), one of the proteins essential for the exocytosis of Ach. The LCs of each of the seven BTX serotypes (and that of tetanus toxin) cleave a distinct peptide bond on one or more SNARE proteins such that no two serotypes act at exactly the same target substrate site. Once in the cytosol, clostridial neurotoxin (CNT) LCs exploit their catalytic activity, which was revealed following the discovery that they contain the His-Glu-Xaa-Xaa-His zinc-binding motif of zinc endopeptidases.43–45 BTXs and TeNT are remarkably specific proteases that recognize and cleave only three proteins, the so-called SNARE proteins, which form the core of the

neuroexocytosis machinery.46,47 BTXs and TeNT, BTX-B, BTX-D, BTX-F and BTX-G cleave vesicle-associated membrane protein (VAMP), a protein of the synaptic vesicle membrane, at different single peptide bonds; BTX-C cleaves both syntaxin and SNAP-25, two proteins of the presynaptic membrane; BTX-A and BTX-E cleave SNAP-25 at different sites within the COOH-terminus.47,48 The core of the membrane fusion machinery is the SNARE complex, which consists of three major proteins, including N-ethylmaleimide–sensitive factor (NSF), a-soluble NSF attachment protein (a-SNAP), synaptobrevin/VAMP, and syntaxin 1A (syntaxin). SNAREs function at both constitutive and regulated stages in the secretory pathway, for example, in both the constitutive transport required for cell growth and the highly regulated release of neurotransmitters on stimulation by an action potential. They are present on vesicle (v-SNAREs) and target membranes (t-SNAREs) and form a parallel four-helical bundle complex (with two SNAP-25 proteins, synaptobrevin/VAMP, and syntaxin) that bridges the membranes inside the cell.49 In the neuron, the SNAREs are synaptobrevin/ VAMP on the synaptic vesicle membrane and syntaxin 1A and SNAP-25 on the presynaptic plasma membrane. Assembly of SNARE complexes requires exquisite spatial and temporal regulation to prevent inappropriate membrane fusion. Synaptotagmin I (synaptotagmin) is the main Ca2+ sensor in neurons, where it is essential for the fast, synchronous fusion of synaptic vesicles after Ca2+ influx.50–53 Synaptotagmins generally consist of an amino-terminal transmembrane domain and two Ca2+-binding conserved region 2 of protein kinase C (C2) domains.54–56 SNARE complexes assemble when synaptic vesicles dock at the presynaptic membrane. Complexin is believed to clamp SNARE complexes and prevent membrane fusion. Synaptotagmin recognizes and binds to the complexin–SNARE complex in the absence of Ca2+. After Ca2+ influx, synaptotagmin binds to both Ca2+ and membranes, leading to conformational changes that release complexin, and the shape of the membrane-inserted, Ca2+–synaptotagmin–SNARE complex might buckle the membranes outward to complete fusion.57–60 Owing to its ability to interfere with exocytosis of cholinergic vesicles, BTX produces a temporary chemodenervation of 3 to 4 months that reduces muscle tone, clonus, and other forms of muscle overreactivity. Antonucci and associates61 demonstrated that catalytically active BTX-A is retrogradely transported by central neurons and motoneurons and is then transcytosed to afferent synapses, in which it cleaves SNAP-25.61 Also, SNAP-25 cleavage by BTX-A was observed in the contralateral hemisphere after unilateral BTX-A delivery to the hippocampus. However, they did not demonstrate that this was a specific uptake. It is known from cell culture studies that you can ‘‘force’’ uptake by increasing the concentration and exposure time (Roger Aoki, personal communication). In preclinical pain models, in vivo, pretreatment with BTX-A (3.5–30 U/kg subcutaneously) prevents formalin-induced pain (in phase 2 only) and the release of glutamate from the rat hindpaw.62,63 BTX-A pretreatment also prevents the development of thermal hyperalgesia, mechanical allodynia, increased blood flow, WDR activation, and Fos-like immunoreactivity (Fos-LI) [as measure of fos protein expression].64,65 In addition, BTX-A (15 U/kg subcutaneously) reversed established allodynia in a diabetic rat model.64 Multiple studies have evaluated the antinociceptive effects of BTX-A in human experimental models of pain, with mixed results.66–71 One study, from the Arendt-Nielson laboratory, demonstrated a positive antinociceptive effect with BTX-A.71 Cui and colleagues62 proposed a BTX antinociceptive hypothesis that BTX-A is expected to prevent peripheral nerve sensitization induced by neurotransmitter (neuromodulator) release and, due to an agent or stimulus, indirectly attenuate central sensitization (e.g., allodynia and/or hyperalgesia). The inhibition of the release of pronociceptive transmitters is also the proposed mechanism behind pain reduction seen from

VII PHARMACOLOGIC APPROACHES TO PAIN MANAGEMENT 491

intra-articular injections described for knee, shoulder, hip, and sacroiliac joints.72,73

PHARMACODYNAMICS Peak effect is seen within 2 weeks from injection. Duration is limited to 3 months when neuronal sprouting and molecular turnover at the neuromuscular junction return. Function is completely restored within 6 months. The long-term efficacy of BTX was evaluated by Mejia and coworkers74 in a study of 45 patients who had received BTX treatment for at least 12 consecutive years for dystonia or blepharospasm. The peak effect and duration of response did not change over time. The dose per visit did increase, as did the duration of response. Twenty-two patients exhibited less than satisfactory response to BTX-A and were tested for antibodies. Only 4 patients had confirmed blocking antibodies and started treatment with BTX-B. Sixteen patients were antibody-negative and responded to dose adjustments of BTX-A. Two antibody-negative patients were nonrespondent to dose changes in BTX-A and underwent treatment with BTX-B or BTX-F. It has been observed that if immunoresistance to BTX-A is going to develop, it occurs within the first 4 years of treatment.

APPLICATIONS In 1989, the FDA approved BTX-A for treatment of strabismus, blepharospasm, and hemifacial spasm. Numerous other off-label uses of BTX have been published, including achalasia, anismus, cervical dystonia, detrussor sphincter abnormalities, dysynergia, essential tremor, and hyperhydrosis. Novel uses for BTX continue to evolve and include its preliminary research use in newborns with CHARGE (coloboma, heart disease, atresia choanae, retarded growth and retarded development and/or central nervous system abnormalities, genital hyperplasia, and ear anomalies and/or deafness) syndrome in efforts to facilitate extubation and avoid tracheotomy.75 CHARGE syndrome may be associated with hyperstimulated salivary glands, which may secrete excessive fluids/saliva with the potential for aspiration. Injection of BTX may block nerve activity in the nerves stimulating the salivary glands, thereby reducing salivary gland secretions to a normal level.75 BTX has also been employed for its cosmetic properties as a temporary treatment of facial wrinkles. Some of the popular uses of BTX are discussed in more detail.

Treatment of Headache The antinociceptive effect of BTX for the treatment of headaches may be due to the ability of BTX-A to block substance P release, demonstrated using an in vitro culture system (20%). Other studies showed that BTX-A can inhibit the release of glutamate and other neurotransmitters, including neuropeptides, from synaptosomes.76 BTX-A has also been shown to decrease peripheral sensitization of nociceptive sensory nerve fibers by inhibiting the release of glutamate and substance P.77 Furthermore, BTX-A was shown to suppress the secretion of calcitonin gene–related peptide, a neuropeptide involved in migraine pathophysiology, from rat trigeminal ganglia neurons.78 Oshinsky79 demonstrated that injection of BTX-A into the foreheads of rodents prevents central sensitization of wide dynamic range neurons in the trigeminal nucleus caudalis induced by administering an ‘‘inflammatory soup’’ onto the dura. A double-blind, placebo-controlled clinical study of 123 patients with a history of two to eight moderate to severe episodic migraine (EM) headaches per month were randomly divided into groups that received a single injection of either 25 or 75 U of BTX or the

vehicle-placebo.80 Injection sites were standardized and located in the bilateral frontalis, glabellar, and temporalis muscles. Patients kept daily diaries recording migraine frequency, severity, and occurrence of migraine-associated symptoms. In the second study month, the 25-U BTX-A group showed significant reductions in EM frequency and severity, acute medication use, and associated vomiting symptoms when compared with the placebo group. Additional improvements were observed in EM frequency in both treatment groups when these parameters were measured at 3 months. Although the 25-U group seemed to derive a greater degree of benefit, the 75-U BTX-A group showed significant improvement in global assessment scores at month 2 when compared with placebo. Treatment-related adverse effects included blepharoptosis, diplopia, and injection site weakness. These adverse effects were all transient and may have been initially and primarily related to injector inexperience and technique, which reportedly improved.80

Clinical Studies BTX-A for theTreatment of EM Evers and associates81 examined the effect of BTX-A on headache frequency and other migraine-related parameters in 60 patients with migraine. This relatively small study population was divided into three groups: one group was given BTX-A to the frontalis and temporalis muscles at a total dose of 16 U; one group was given BTX-A to the cranial muscles, with additional injections to the neck muscles, for a total dose of 100 U; and the third was given placebo. Patients were allowed to receive migraine-preventive drugs throughout the study period. At 3 months, there were no significant differences in the reduction of migraine headache frequency or in the use of acute pain medications between the groups. The only significant effect of BTX-A was in reducing migraine-associated symptoms in the 16-U BTX-A group. Possible explanations for the mostly negative results of this study are the small number of patients and the low BTX-A doses given to the cranial muscles (although no study to date has shown a dose-dependent effect of BTX-A on headache). In a large multicenter trial by Aurora and colleagues and the Botox North American Episodic Migraine Study Group,82 809 adult EM patients were screened with 369 randomized to placebo or BTX-A. The mean BTX-A dose was 190.5 U. The BTX-A group had a mean change from baseline of -4.0 headache episodes at day 180 compared with -1.9 headache episodes in the placebo group (P = .048). Both BTX-A and placebo groups experienced a reduced number of headaches, but BTX-A was not superior to placebo. A European migraine study by Relja and coworkers83 evaluated BTX-A in 495 adults in a randomized, double-blind, placebo-controlled design. The doses used were 75, 150, or 225 U. At 180 days, the mean number of migraine events was decreased in all groups including placebo, with no statistically significant differences noted between groups. Saper and associates84 conducted a randomized, double-blind, placebo-controlled study of 232 patients with a history of four to eight moderate to severe migraines per month, with or without aura. Patients were randomized to placebo or one of four BTX-A groups that received injections into different muscle regions: frontal (10 U), temporal (6 U), glabellar (9 U), or all three areas (total dose 25 U).84 For 3 months after a single treatment, patients recorded migraine-related variables in a daily diary.84 BTX-A and placebo produced comparable decreases from baseline in the frequency of migraines (P .411).84

BTX-A for theTreatment of Chronic Daily Headache The evidence that BTX helps patients with chronic daily headache (CDH) is reasonable but not robust. Mathew and colleagues85 evaluated the effect of BTX-A on 355 patients with CDH in a

492 Chapter 67  BOTULINUM TOXINS FOR THE TREAT MENT OF PAIN randomized, placebo-controlled study using the ‘‘follow-the-pain’’ approach. Patients were injected three times at 3-month intervals. Injections of BTX-A were associated with a significant decrease in headache frequency compared with placebo (at day 180 –7.1 vs. –3.7 headache days per month with BTX-A and with placebo, respectively). Fifty-four percent of patients treated with BTX-A reported at least a 50% decrease from baseline in migraine headache frequency at day 180 compared with 38% of placebo-treated patients. Injections of BTX-A nonsignificantly increased the number of headache-free days from baseline and decreased the use of acute pain medications more than placebo. A subgroup analysis of these study results for patients who were not taking other migrainepreventive drugs showed a significantly greater decrease in headache frequency (–7.8 vs. –4.5 headache days per month on day 180) and in mean headache severity in the BTX-A group compared with placebo.86 The number of headache-free days per month increased significantly more in the BTX-A group compared with placebo (+10.0 vs. +6.7 days, respectively).86 Only 4 of the patients discontinued BTX-A because of adverse effects, which were mild and generally consisted of localized pain at the injection site.86 Ondo and coworkers87 studied the effect of BTX-A on 60 patients with CDH. Using the follow-the-pain approach, patients were given 200 U of BTX-A or placebo at different sites. Between weeks 8 and 12, a significantly higher increase in headache-free days occurred in the BTX-A group than in the placebo group, and there was a strong tendency for this effect to continue over the entire study period. Both subjects’ and investigators’ global impressions were significantly better for the BTX-A group compared than for the placebo group. Women tended to respond better than men to BTX-A. An open-label extension of the study showed a possible cumulative beneficial effect of BTX-A on headache. In a randomized, placebo-controlled study of 702 patients, Silberstein and associates88 studied the efficacy and tolerability of BTX-A for CDH prevention using a ‘‘fixed-site’’ protocol at a total dose of 75 U, 150 U, or 225 U. Patients were given three BTX-A treatments over a 9-month period. Patients overused pain medication 42% of the time. Patients received additional masked treatments at 90 and 180 days. Patients were assessed every 30 days for 9 months. The primary efficacy end-point was a mean change from baseline in frequency of headache-free days at day 180 compared with the placebo nonresponder group. This primary efficacy end-point was not met; all groups responded to treatment. However, the 225- and 150-U groups experienced a greater decrease in headache frequency than the placebo group at day 240.88 Pooled analysis showed that at day 240, patients who received 225-U BTXA and 150-U BTX-A had significantly fewer headaches than those who received placebo. A subgroup analysis was done of 231 patients (33%) who at baseline had (1) no concurrent headache-preventive medications; (2) 15 days or longer with headache lasting 4 or more continuous hours per day; (3) 50% or more of the headache days as migraine/probable migraine days; and (4) 4 or more headache episodes per month that lasted 4 or more continuous hours. A reduction in headache days favoring the three BTX-A treatment arms was seen at all post-treatment time points with significant differences observed at several time points.89

and interventional therapies, including oral antidepressants, membrane stabilizers, opioids, and traditional occipital nerve blocks without significant relief. This group then underwent occipital nerve blocks using the BTX-A 50 U for each block (100 U if bilateral).95 Significant decreases in pain on visual analog scale (VAS) scores and improvement in Pain Disability Index (PDI) were observed at 4 weeks follow-up in five out of six patients after BTX-A occipital nerve block. The mean VAS score changed from 8 ± 1.8 (median score of 8.5) to 2 ± 2.7 (median score of 1), whereas PDI improved from 51.5 ± 17.6 (median 56) to 19.5 ± 21 (median 17.5), and the duration of the pain relief increased to an average of 16.3 ± 3.2 weeks (median 16) from an average of 1.9 ± 0.5 weeks (median 2) compared with diagnostic 0.5% bupivacaine block.95 After block resolution, the average VAS scores and PDIs returned to levels similar to those before BTX-A block. Kapural and colleagues95 concluded that BTX-A occipital nerve blocks provided a much longer duration of analgesia than diagnostic local anesthetics. The functional capacity improvement measured by PDI was profound enough in the majority of the patients to allow them to resume their regular daily activities for a period of time.95

ChronicTension-type Headache

Several anecdotal reports exist of the utility of BTX in treating trigeminal neuralgia.99–104 In these various reports, injection of the BTX is targeted peripherally at the region surrounding the trigger zone for the neuralgic pain or into the region of the zygomatic arch101 with a variable dose (e.g., 100 U101). Although some authors seem optimistic, the results have been promising but not definitive. One major side effect of treatment with BTX is the weakening of muscles of facial expression proximate to the injected trigger zones, resulting in a temporary cosmetic paresis. In cases of intractable pain that is unresponsive to first-line oral medications, BTX may offer a safe and logical next therapeutic option owing to its reversibility.

No good evidence exists for the efficacy of BTX-A in the treatment of chronic tension-type headache (CTTH). In fact, four placebocontrolled studies that examined its efficacy in CTTH were negative, and one study showed a beneficial effect of BTX-A only on a secondary outcome measure.90–94

Occipital Neuralgia Kapural and colleagues95 retrospectively describes a series of six patients with severe occipital neuralgia who received conservative

Whiplash Injuries Two randomized, placebo-controlled trials showed that BTX was not clinically beneficial for the treatment of neck pain and whiplash (WI)–associated disorders. Statistically significant effects were not achieved in a study of 15 participants.96 In a subsequent study of 25 participants, no specific benefits could be identified. Participants treated with normal saline showed outcomes comparable with those treated with BTX over 4 months.97 However, Braker and coworkers98 studied 20 patients with cervical myofascial pain, 2 to 48 weeks after WI, who were randomly assigned to receive either 200 U of BTX-A or placebo at four tender points and were seen during the follow-ups at 3, 6, 9, 12, and 24 weeks after the injections. Outcome measures included the intensity of pain as evaluated by a 10-cm VAS and a 5-point verbal rating scale (VRS), quality of life as evaluated by the Short Form 36-item (SF-36) questionnaire, treatment efficacy as per the global assessment of the physician and patient, intensity of pain in response to mechanical pressure, range of cervical motion, and use of other therapies and their adverse effects.98 A time-dependent improvement in all the parameters was found in both groups, which was consistently larger in the BTX-A–treated group but mostly not at a significant level.98 Significant differences between the groups were found only in the percentages of patients who achieved 50% or more of reduction in intensity (VAS and average VRS) at 24 weeks (50% vs. 0%, P > .05 and 70% vs. 11%, P > .05, respectively).98 Thus, Braker and coworkers98 suggested that BTX-A treatment has some efficacy when administered within 1 year of the WI; however, a large, well-designed clinical trial is needed to draw final conclusions.

Facial Pain

VII PHARMACOLOGIC APPROACHES TO PAIN MANAGEMENT 493

The most significant joint of the face is the temporomandibular joint (TMJ). This joint can exhibit a multitude of pathologic conditions collectively referred to as temporomandibular disorders (TMD). These pathologic conditions involve pathology of various components of the TMJ, as for any joint in the body. Many of these disorders are painful, and some have reportedly been treated successfully with BTX.105 A potential mechanism for diminishing inflammation of a joint secondary to trauma is via decreasing joint loading. The muscles of mastication are primarily jaw-closing muscles. The masseter, temporalis, and medial (internal) pterygoid muscles are the largest and most powerful facial muscles. Reducing the strength of contraction of these muscles with BTX over a prolonged period of time may lead to decreased joint loading and thus, diminished inflammation, joint pain, and joint damage. The dual benefit of muscle injection of BTX in TMD lies in its ability to diminish primary muscle pain associated with muscle hyperactivity as well as to potentially diminish TMJ inflammation.105 BTX dosing is dependent on the size of the muscle, with typical range for each masseter muscle from 25 to 50 U and for the temporalis muscle from 12.5 to 25 U.106,107

Interstitial Cystitis A total of 19 patients with interstitial cystitis (IC) were treated with 100 U or 200 U of intravesical BTX-A injections followed by cystoscopic hydrodistention 2 weeks later. Bladder mucosa biopsies were performed before BTX-A injection and immediately after hydrodilation and in 12 controls. At 3 months, 14 patients had symptomatic improvement (responders) and 5 did not (nonresponders). The nerve growth factor (NGF) mRNA levels at baseline in the overall IC patient group were significantly greater than those in the controls (0.65 ± 0.33 vs. 0.42 ± 0.25, P = .046). At 2 weeks after BTX-A treatment, the NGF mRNA levels had decreased to 0.47 ± 0.23 (P = .002, compared with baseline) and were no longer significantly different from those of the controls. The NGF mRNA levels decreased significantly in responders and were significantly decreased after BTX-A in 11 patients with a VAS reduction of 2 or more. The immunoreactivity study of bladder tissue from patients with IC showed greater NGF density at baseline compared with controls, but the difference was no longer significant after successful BTX-A treatment. Intravesical BTX-A injections plus hydrodistetsion reduce bladder pain in patients with IC.108 Three men and 12 women were prospectively given injections of 200 U commercially available BTX-A diluted in 20 ml 0.9% saline submucosally in the bladder trigone and lateral walls under cystoscopic guidance.109 A voiding chart and the VAS for pain were used, and urodynamics were performed before treatment and 1, 3, 5, and 12 months later. Overall, 13 patients (86.6%) reported subjective improvement at the 1- and 3-month follow-ups. The mean VAS score and daytime and nighttime urinary frequency were significantly decreased (P < .05, < .01, and < .05, respectively).109 At the 5-month follow-up, the beneficial effects persisted in 26.6% of cases, but increased daytime and nighttime urinary frequency and an increased VAS score were observed compared with baseline. At 12 months after treatment, pain recurred in all patients. Giannantoni and associates109 concluded that intravesically injected BTX-A is effective for short-term management of refractory painful bladder syndrome.

Low Back Pain Foster and colleagues110 studied 31 consecutive patients with chronic low back pain, with 15 patients receiving a total of 200 U of BTX-A 40 U/site at five lumbar paravertebral levels on the side of maximum discomfort and another 16 patients receiving the same volume of normal saline. The mean duration of pain was 8.1 years for the

BTX-A group and 5.7 years for the control group (range 6 mo–30 yr). Each patient’s baseline level of pain and degree of disability were documented using the VAS and the Oswestry Low Back Pain Questionnaire (OLBPQ) and reevaluated at 3 and 8 weeks (VAS) and at 8 weeks (OLBPQ). At 3 weeks, 11 of 15 patients who received BTX (73.3%) had greater than 50% pain relief versus 4 of 16 (25%) in the control group (P = .012). At 8 weeks, 9 of 15 (60%) in the BTX group and 2 of 16 (12.5%) in control group had relief (P = .009). Repeat OLBPQ at 8 weeks showed improvement in 10 of 15 (66.7%) in the BTX group versus 3 of 16 (18.8%) in the control group (P = .011). None of the patients experienced any side effects. Foster and colleagues110 concluded that paraspinal administration of BTX-A in patients with chronic low back pain can relieve pain and improve function at 3 and 8 weeks after treatment.110 Jabbari and coworkers111 prospectively studied the effect of BTX-A on 75 patients with chronic low back pain refractory to medical or surgical treatment over a period of 14 months. Patients with bilateral low back pain were also included in this study. The patients had a mean age of 46.1 years (range 21–79) and a mean pain duration of 9.2 years (range 7 mo–50 yr). Twenty-one of 75 patients were female, and 84% of the entire cohort had bilateral pain. Other factors noted among the cohort were previous back surgery (n = 14), root pain (n = 20), epidural steroids injections (n = 19), and opioid analgesic use (n = 36). Magnetic resonance imaging (MRI) showed a variety of low back pathology but mostly chronic degeneration of the spine, canal stenosis, and chronic disk protrusions. Patients were instructed not to change their analgesic medications and to continue with their physical therapy during the course of the study. Pain intensity (VAS), pain frequency (pain days measured by the Pain Impact Questionnaire [PIQ]), and perceived functional status by patients (OLBPQ) were assessed at baseline and at 3 weeks and 2, 4, 6, 8, 10, 12 and 14 months. BTX-A was injected into the paraspinal muscles at four to five levels (between L1 and S1) unilaterally or bilaterally, and an extra dose was administered laterally into the bulk of the erector muscles at the level of most discomfort. The dose per site varied from 40 to 50 U. The total dose per session ranged from 200 to 500 U. Reinjections were performed at 4 months if pain returned. Most patients had reinjections every 4 months.111 At 3 weeks 40 patients (53%) and at 2 months 39 patients (52%) reported significant pain relief.111 The change in mean VAS, mean OLBPQ score, and mean pain days was significant compared with baseline at 2 months after each injection period (P < .005) and remained so over subsequent treatments.111 Among initial responders, 91% continued to be responders over the length of the study. In 9 of 20 patients (45%) with ‘‘root’’ (radicular) pain, the pain improved significantly after BTX treatment of the paraspinal muscle. After the first treatment, 3 patients (4%), had mild flulike symptoms that lasted 2 to 5 days.111 No other side effects were noted.111 Eighteen women and 42 men, ages 21 to 79 years (mean 46.6 yr), with low back pain of a mean duration of 9.1 years, were injected in the lower back with BTX-A and followed prospectively over 6 months.112 Significant improvement in back and radicular pain occurred at 3 weeks in 60% and at 2 months in 58% of the cohort. Beneficial clinical response to the first injection predicted response to reinjection in 94%. A significant minority of patients had a sustained beneficial effect from the first injection at 4 (16.6%) and 6 (8.3%) months. Two patients had a transient flulike reaction after the initial treatment.112 The patient’s response to BTX-A was considered beneficial and significant when improvement occurred in least two of the following ratings: (1) VAS (average) showed 50% or more decrease in pain intensity; (2) OBLPQ showed a two-grade or more improvement in the pain subset and one or more of the functional subsets; and (3) CLBPQ showed a 30% or more decrease in the number of pain days from baseline.112 BTX-A, concentrated at 100 U/ml, was injected with a 1-ml tuberculin syringe through a 0.75- or 1.5-inch needle, depending

494 Chapter 67  BOTULINUM TOXINS FOR THE TREAT MENT OF PAIN on the degree of subject adiposity. Four or five injection sites per side from L2 to S1 were determined by the physician and the patient based on deep finger pressure to locate trigger points or muscle spasm. Injections were done without electromyographic guidance owing to the size of the muscles involved, the additional expense and equipment costs, and the relative ease of clinically determining painful or overactive sites of paravertebral muscles. The dose per site was 40 to 50 U, and the total dose per session did not exceed 500 U for bilateral pain.112 BTX injections were to occur at the time of entry into the study. The duration of effect was assumed to decline by 4 months. A second set of injections would be given at 4 months if the patient had a significant beneficial response at 2 months. Patients with continued clinical benefit past 4 months would be allowed to defer reinjection. Follow-up was to occur at 3 weeks after the initial injection and at 2-month intervals thereafter. Failure to respond at 3 weeks or 2 months warranted no further follow-up.112 Overall, the number needed to treat for BTX for low back pain is 2.1.113

Musculoskeletal/Myofascial Disorders Muscle Spasm Muscle spasm refers to pain after muscle injury. Commonly known as a muscle cramp, muscle spasm starts as an involuntary contraction triggered by irritable muscle spindles or secondary to electrolyte imbalance seen with dehydration or exercise. Chronic forms of muscle spasm such as paraspinal muscle spasm account for some forms of low back pain. BTX injection into these muscles reduced pain for a period of 6 to 12 weeks according to a study by Knusel and associates.114

Dystonia Dystonia is another type of movement disorder in which involuntary muscular contraction results in bizarre twisting postures. Unlike spasticity, it is not linked with upper motor neuron disorders. Up to 70% of cervical dystonia patients experience pain.115 In a study by Janovic and Schwartz,116 76.4% of patients with cervical dystonia had complete relief after BTX injections. Surprisingly, clinical observation indicates that in patients with cervical dystonia, pain relief due to BTX outweighs the benefit obtained from motor block of affected muscles.116

Piriformis Syndrome Piriformis syndrome is considered to be a reversible compression of the sciatic nerve by the piriformis muscle that may lead to deep and severe pain in the buttock, hip, and sciatic nerve, with radiation into the thigh, leg, foot, and toes. Pirformis muscular tension could compress the sciatic nerve anteriorly and inferiorly against the sharp tendinous edge of other muscles (e.g., gemellus superior, obturator internus), which may result in peripheral nerve insult.117 Diagnostic signs include tenderness in the buttock between the medial edge of the greater sciatic foramen and the greater trochanter,118 weakness in resisted abduction of the flexed thigh,119 pain on passive adduction and internal rotation of the extended thigh,120 buttock pain with passive adduction of the flexed thigh,121 and pain in voluntary flexion adduction and internal rotation of the hip.117,122 Furthermore, electromyographic testing may help to support the diagnosis of PS if the flexion, adduction, and internal rotation position (the FAIR test) brings more than a 3–standard deviation delay of the H-reflex (1.86 msec).117 A significant component of treatment involves physical therapy approaches. Interventional approaches include injection of steroid and local anesthetic (e.g.,

triamcinolone acetonide 30 mg with 1.5 ml of 2% lidocaine) into the motor point of the piriformis muscle. The electromyography (EMG)-guided injection of BTXs (300 U BTX-A or 12,500 U BTXB) may have advantages over traditional local anesthetic and steroid injections that may include more pain relief faster, longer duration, fewer relapses, fewer side effects (especially in diabetic and immunocompromised patients).123,124

Plantar Fasciitis The plantar fascia runs from the medial tubercle of the calcaneus to the transverse ligaments of the metatarsal heads of the foot. Because the plantar fascia is relatively rigid in nature, repetitive stretching/ overuse insult may lead to microtears at its origin.125 These and other processes may result in myxoid degeneration with fibrocyte necrosis, chondroid metaplasia, and angiofibroblastic proliferation, replacing the normal cellular matrix.125 This degenerative thickened fascia is mechanically inefficient and contracts during the night as the foot rests in the equinus position. The first step out of bed in the morning stretches the fascia acutely, leading the irritation and pain. The pain of plantar fasciitis generally diminishes with activity but may be reaggravated after prolonged sitting, standing, or walking long distances.125 Other findings that may be associated with plantar fasciitis include taut, tender muscle structures around the arch; decreased ankle or hallux dorsiflexion; aggravation with heel raises or toewalking; heel spurs (about 70%); and heel pain reproduced with passive dorsiflexion of the toes (especially while the patient is weight-bearing).125 The differential diagnosis may include stress fracture, retrocalcaneal bursitis, plantar fascia rupture, calcaneal apophysitis (in adolescents [Sever’s disease]), sacral radiculopathy, fat pad necrosis, tarsal tunnel syndrome, entrapment of the medial calcaneal branch of the posterior tibial nerve, and irritation of the nerve to the abductor digiti quinti.125 Treatment of plantar fasciitis may include physical medicine techniques (stretching and strengthening exercises [e.g., ankle dorsiflexion stretch, great toe stretch, wall stretches, gastrocnemius stretch, soleous stretch, can roll, towel curl]). Cold therapy (ice massage) can be employed. Anti-inflammatory agents perhaps with analgesic adjuncts may be used. Orthotics including heel cups and night splints may help certain patients. Some clinicians have used steroid injections, iontophorosis with glucocorticoids and/or acetic acid, surgery, or extracorporeal shock wave therapy in refractory cases.125 Babcock and colleagues126 studied the effects of BTX-A injection for refractory plantar fasciitis in a randomized, placebo-controlled, prospective, short-term clinical trial. They used a 27-gauge 0.75inch needle to inject group A with 40 U (0.4 ml) in the tender region of the heel medial to the base of the plantar fascia insertion and 30 U (0.3 ml) in the most tender point of the arch of the foot (between an inch anterior to the heel and the middle of the foot); group B received injections of saline in the same sites.126 Main outcome measures included pain VASs, Maryland foot score, pain relief VAS, and pressure algometry response. Patients were assessed prior to injection and at 3 and 8 weeks. Compared with saline, the BTX-A group showed statistically significant improvements in all measures: pain VAS (P < .005), Maryland foot score (P = .001), pain relief VAS (P < .0005), and pressure algometry response (P = .003); without significant side effects.126

Myofascial Pain Syndrome Myofascial pain syndrome (MPS) presents as acute or chronic skeletal muscle pain that originates in specific trigger points and affects surrounding soft tissue and fascia. Although the etiology of MPS is still unclear, muscle spasm resulting from increased release of Ach

VII PHARMACOLOGIC APPROACHES TO PAIN MANAGEMENT 495

at dysfunctional end motor plates may play a fundamental role. Contracted fibers cannot relax, leading to pain, stiffness, and fatigue. Symptoms are reported by up to 21% of patients presenting to orthopedic clinics and 85% to 93% of patients seen in pain-management centers.127 The high incidence of MPS and the growing body of evidence linking this disorder to excessive muscle spasm have made BTX a promising treatment (Table 67–1). BTX allows taut muscle bands to regress to a latent, asymptomatic phase by inhibiting Ach release at motor nerve endings. This has led to FDA approval of BTX-A in 1989 for conditions involving abnormal muscle contraction such as essential blepharospasm and hemifacial spasm. Its use in MPSs, however, remains off label, and currently, no definitive studies have established the efficacy of BTX for the treatment of MPS or fibromyalgia.128

Evaluation Unlike the diagnosis of fibromyalgia, an international diagnostic criteria for MPS does not exist. However, identification of trigger points is an important first step. Trigger points are found by gentle palpation in the direction of the muscle fibers. They have a characteristic nodularity, and palpation is extremely painful. Clinical reliability in identifying trigger point varies considerably unless examiners are consistently trained. In a study by Sciotti and coworkers,129 four blinded examiners who were trained together were able to agree up to 80% of the time on the location of trigger points in the upper trapezius muscle.

Management Adjunct Therapies Traditional therapies for MPS include, but are not limited to, pharamacotherapy and injection therapies. Nonsteroidal anti-inflammatory drugs, steroids antidepressants, a-adrenergic agonists, vasodilators, skeletal muscle relaxants, and opioids in conjunction with massage, physical therapy, and transcutaneous electrical nerve stimulation have been employed with some success. Injection therapy with local anesthetics, with or without steroids, or simply dry needling has been shown to be beneficial. BTX has only recently been introduced as a possible treatment modality for MPS. Injection Protocols. Therapy with BTX is individualized according to specific patient indications. There is variation between injection techniques, dosing, and number of injections. Ultimately, the technique should be adapted to the patient’s specific situation. Injections into deep compartments of the back generally require the use of special imaging techniques and/or electromyographic guidance, whereas superficial injections can be undertaken without monitoring (Figs. 67–2 to 67–4). EMG. EMG or motor point stimulation is useful for monitoring the injection of limb muscles, such as the small forearm muscles. EMG is a useful guide in identifying the anatomy of the muscles to be injected. It is based on the observation that trigger points are found in the proximity of motor endplates. Motor endplates occur predictably in bands throughout the muscle where small motor nerves terminate. EMG is typically connected to a needle electrode that is used to search for the characteristic noise of the motor endplate. Upon finding the motor endplate, a low-voltage (10–40 mV) increase in the baseline will occur, and the EMG device produces a sound similar to that heard in a seashell held up to one’s ear. There are irregularly firing spikes, and the patient experiences a deep pain over these points. Motor endplates coincide with motor points, the areas at which motor nerves terminate in the muscles and where phenol and alcohol blocks typically take place. If a motor endplate cannot

be localized with EMG, electrical stimulation can be used to find motor points and injection can be undertaken because the two usually coincide. Motor points may be localized with peripheral nerve stimulators whose electrodes are connected over the muscle belly and when 5 to 10 mA and 0.5 sec duration are applied.130

Dosage The severity and chronicity of disease, number of muscles involved, previous response, and coexisting conditions affect the dosing. Optimally, BTX is used in the least amount needed to achieve muscle relaxation and improve range of motion without causing weakness or other side effects. Administration is proportionate to body mass. Potency is expressed in mouse units (MU) that were determined according to a standard Swiss-Webster mouse of 20 g. Generally, 1 MU is the median lethal dose (LD50) that has been determined across several animal species. No specific studies were done in humans. Human LD50 is approximately 3000 MU for a 70kg adult. Large muscle groups receive anywhere between 60 and 400 MU per treatment, although the recommended ceiling dose is closer to 360 MU given 12 weeks apart.131

Preparations BOTOX is dispensed in 100U vials, whereas Dysport contains 500 U. The potency of the two forms differs with a 1:4 conversion rate for BOTOX to Dysport. Most practitioners dilute BOTOX with 1 to 4 ml of preservative-free saline for a concentration of 2.5 to 10 U/ 0.1 ml. The preparation is best used within 4 hours of reconstitution. The pH should be maintained from 4.2 to 6.8, and the temperature kept at less than 208C. BTX-B is available in vials of various volumes, each at a concentration of 5000 U/ml. It is recommended that this be stored at between 28C and 88C.

Complications and Side Effects Owing to its specific mechanism of action, specific side effects are uncommon and systemic effects are even less common. Short-lived flulike symptoms of soreness, headache, fever, chills, lightheadedness, hypertension, diarrhea, and abdominal pain have been reported. Muscular weakness, however, remains the predominant side effect that patients should be made aware of prior to BTX injections. Clinicians should have a clear understanding of the functional consequence of injecting particular muscles when these muscles serve crucial functions such as swallowing (Table 67–2). Recently, some reports of adverse events including death have been linked to the use of BTX in children, leading to a warning by the FDA.132 According to the FDA, adverse events suggesting botulism and felt to be potentially associated with distant spread generally occurred at relatively high dosages of 100 to 700 U in BTX-A recipients and 10,000 to 20,000 U in BTX-B recipients.132 Botulism cases in children younger than 16 years, who were treated for limb muscle spasticity associated with cerebral palsy, were associated with adverse events including dysphagia, respiratory insufficiency requiring use of gastric feeding tubes and ventilatory support, hospitalization, and death. Doses in these cases ranged from 6.25 to 32 U/kg for BTX-A (some > 20 U/kg max) and from 388 to 625 U/kg for BTX-B. Public Citizen, a consumer advocacy group, stated that its investigation of the FDA’s adverse event database indicates that 16 BTX recipients (the majority receiving BTX-B), including 4 children, died after being injected with the products; although the FDA has not determined whether these deaths were caused by the use of the products or were attributable to other causes.132

Absolute Contraindications BTX-A is contraindicated in the presence of infection at the proposed site of injection or hypersensitivity to any ingredient in the

496 Chapter 67  BOTULINUM TOXINS FOR THE TREAT MENT OF PAIN

Table 67^1. Medline Search for ‘‘Myofascial Pain’’ and ‘‘BTX’’ Spanning 1966^2006 StudiesThat Show No Significant Pain Improvement after BTX Treatment Muscles Reference Study N Affected Outcome Measures Doses BTX-A

Infraspinatus

50 U vs. saline EMG control Pressure algometry Flexibility tests

31

Neck, shoulder

Grabowski Randomized, et al137 double-blind

17

Neck, shoulder, hip, back

Ferrante et al138

132

Cervical/shoulder

Pressure point 15–35 U threshold (dolorimeter) questionnaires Likert format VAS 25 U vs. 0.5% bupivacaine questionnaires (cost estimations) VAS 10, 25, 50 U Pressure algometry BTX-A Need for rescue medications

Querama et al135

30 Double-blind, placebo-controlled, parallel

Tuula et al136

Double-blind, randomized, controlled

Randomized, double-blind, placebo-controlled

StudiesThat Show a Decrease in Myofascial Pain after BTX Treatment Outcome Reference Study N Muscles Affected Measures

29 Lew et al139 Randomized, double-blind, placebo-controlled, single-center, prospective

Neck and upper back VAS for pain NDI SF-36

De Andres Open-label, et al140 interventional, prospective

Various muscles

Lang141

Argoff142

Foster et al143

77

91 Retrospective, open-label, single-center, chart review, comparing BTX-A vs. BTX-B Observational study 11 of CRPS patients who also have myofascial pain Randomized, 28 double-blind

Porta144

Single-center, randomized

Wheeler et al145

Randomized, double- 33 blind, prospective

40

VAS EMG Oswestry Questionnaire

Levator muscle, VAS splenius capitis, Patient global semispinalis capitis, assessment piriformis

Results

BTX-A decreases motor endplate activity and influences EMG pattern but does not change pain level No difference between small BTX doses and saline injections P =0.3 BTX VAS 2.705 ± 3.31 Bupivacaine 0.5% 2 ± 2.03 Improved pain with placebo and BTX but no increased benefit from BTX vs. saline

Doses BTX

Results

BTX-A (50 U) per site (not exceeding 200 U per treatment and 100 U per side) vs. saline 10–20 U BTX-A vs. 1 ml 0.5% lidocaine vs. control: dry needling VAS BTX-A (100–600 U) VAS BTX-B (9000 U)

Minimally positive study improved SF-36 bodily pain scale at 2 and 4 mo and mental health scale at 1 mo Baseline VAS of 8.1 improved to 6.47 at 15 days after BTX; VAS at 30 days: 5.84 VAS at 90 days: 5.97 BTX-A VAS down by 2.7 (better pain relief than BTX-B and longer pain relief) BTX-B VAS down by 1.8 Improved burning and dysesthesia Normalization of skin color

Sternocleidomastoid, Questionnaire 25–50 U trapezius, splenius capitis, levator scapular, etc. 40 U Pain relief at 3 and 8 wk Paravertebral VAS Oswestry Low Back Questionnaire Iliopsoas VAS BTX-A 80-150 U + Results at 30 days: Piriformis bupivacaine 0.5% vs. nonsignificant at 60 days: Scalenus anterior methylprednisolone VAS decreased by 5.5 for BTX vs. 2.5 for steroid 80 mg + 0.5% bupivacaine Cervicothoracic BTX-A 50 U vs. All groups with pain relief paraspinal muscles 100 U vs. saline but no difference among BTX and saline (UNLESS a second 100-U injection is done, then improvement seen with BTX)

VII PHARMACOLOGIC APPROACHES TO PAIN MANAGEMENT 497

Table 67^1. Medline Search for ‘‘Myofascial Pain’’ and ‘‘BTX’’ Spanning 1966^2006çcont’d Reference

Study

N

Cheshire et al146

Randomized, double- 6 blind, placebocontrolled, crossover

Muscles Affected

Cervical paraspinal muscles Shoulder girdle muscles

Outcome Measures

Doses BTX

50 U BTX-A VAS Verbal pain descriptors (Gracely) Pressure algometry

Results

>30% improvement with BTX-A but not with saline

BTX, botulinum toxin; CRPS, complex regional pain syndrome; EMG, electromyographic; N, number of patients; NDI, Neck Disability Index; SF-36, Short Form 36-item questionnaire (Medical Outcomes Study); VAS, visual analog scale.

BTX formulation. Hypersensitivity reactions are rare but may be accompanied by serious reactions such as anaphylaxis, soft tissue edema, and dyspnea. If a hypersensitivity reaction is suspected, BTX-A injection should be discontinued immediately and appropriate medical intervention instituted.

transmission (e.g., tubocurarine, tetracyclines, lincomycin) or drugs that interfere with the intraneuronal concentrations of calcium.133,134

CONCLUSION Relative Contraindications Relative contraindications are administration to individuals who cannot understand the risks and benefits of BTX-A and treatment in patients with neuromuscular disorders or myopathies characterized by generalized muscle weakness. Patients with amyotrophic lateral sclerosis, myasthenia gravis, or Lambert-Eaton syndrome should receive BTX treatment only with caution. The toxin may be potentiated by aminoglycoside antibiotics, spectinomycin, or any other drug that might interfere with the neuromuscular

Recent advances in understanding the antinoniceptive properties of BTX, its inhibition of substance P, and its ability to inhibit muscle spasm have made this product a credible treatment for MPS. Lacking FDA guidelines for its use in MPS, BTX continues to be used clinically by practitioners. Based on current published studies,

Figure 67^3. Biceps muscle injection. Muscle function: primary Figure 67^2. Sternocleidomastoid muscle injection. Muscle

function: contralateral neck torsion, anterior flexion. Recommended botulinum toxin (BTX) dose: 50 mouse units (MU).

function is to move the forearm toward the shoulder (elbow flexion). The secondary function is supination of the forearm (turning the hand from a palms-down to a palms-up position). Recommended BTX dose: 100 MU in 2 ml saline injected at two sites.

498 Chapter 67  BOTULINUM TOXINS FOR THE TREAT MENT OF PAIN

REFERENCES

Figure 67^4. Trapezius muscle injection. Muscle function:

scapular elevation (shrugging up), scapular adduction (drawing the shoulder blades together) and scapular depression (pulling the shoulder blades down). Recommended BTX dose: 10 ^15 MU/trigger point (50 MU total).

therapy needs to be individualized and specific injection techniques and dosing applied according to the patient’s particular situation. Intramuscular injection demands a clear understanding of the functional consequences of blocking contraction in a particular muscle and its effects on crucial functions. Furthermore, the dose technique and approach for each specific BTX injection need to be carefully considered before the procedure. A significant number of BTX injections may benefit from electromyographic guidance.

Table 67^2. Exercise Caution When InjectingThese Muscles

From Childers MK, Wilson JW, Simison D. Equipment and injection techniques. In Childers MK, Wilson JW, Simison D (eds): Use of Botulinum Toxin Type A in Pain Management. New York: Demos Medical Publishing, 1999; pp 64–92.

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Chapter 68

TOPICAL ANALGESIC AGENTS Gary McCleane

INTRODUCTION As medical science progresses, physicians seem to become more and more specialized and to utilize increasingly invasive techniques in attempts to achieve therapeutic goals. One cannot help but be impressed by the technological advances that allow access, visualization, and opportunity for treatment in areas of the body long considered too delicate or inaccessible for intervention. But this does not mean that the more complex interventions are necessarily more efficacious than simpler ones. Nothing is fundamentally wrong with utilizing the simplest modalities of treatment and reserving the more complex treatments for situations in which therapeutic failure has occurred with less complex treatments. Therefore, we cannot forget about simple methods of administration of drugs and should remember that, in many cases, their use is founded not only on solid scientific evidence of effectiveness but also, in some cases, on generations’ worth of clinical use. When drugs are applied to the skin, they may either have a local effect (topical analgesics) or be absorbed transdermally but have a systemic mode of action. In this chapter, our consideration is on the former. When these topical analgesics are considered, they may be long-established topical agents, old pharmaceutical entities that have recently been shown to have a peripheral mode of action, or entirely new and novel agents. That the pharmaceutical industry still sees the merit in producing topical and transdermal analgesic agents is a

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reflection of its perception of market potential and patient preference. To many patients, it seems logical and sensible to put the painkiller where the pain is, rather than ingesting a substance that travels everywhere even though the pain is felt in a relatively small and well-defined area. Fortunately, we are now often in a position to rationalize why many topically applied agents achieve their therapeutic effect. This more detailed understanding of the pathophysiology and pharmacology of pain has also allowed some to suggest novel, topically applied treatments. Examples are provided later of some old drugs, previously systemically administered, but now known to have a peripheral mode of action. This does not, unfortunately, mean that they will become prominent in pain practice. Being old drugs, the patent protection surrounding their use—and allowing the pharmaceutical companies to invest in their verification and licensing while protecting the financial investment—has long since expired. Therefore, it is unlikely that the companies will invest resources in seeking an indication for the topical use of these drugs.

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS A bewildering array of topical nonsteroidal anti-inflammatory agents (NSAIDs) is available for purchase either over the counter or through medical prescription. These agents are known to reduce the production of prostaglandins that sensitize nerve endings at the site of injury. This effect occurs through inhibition of the cyclooxygenase (COX) enzyme that converts arachidonic acid, liberated from the phospholipid membrane by phospholipases, to prostanoids such as prostaglandin. At least two forms of COX are believed to be important. COX-1 is normally expressed in tissues such as those of the stomach and kidneys and plays a physiologic role in maintaining tissue integrity. A second form, COX-2, plays a role in pain and inflammation. The analgesic effects of NSAIDs can be dissociated from their anti-inflammatory effects, and this may

VII PHARMACOLOGIC APPROACHES TO PAIN MANAGEMENT 501 129. Sciotti VM, Mittak VL, et al. Clinical precision of myofascial trigger point location in the trapezius muscle. Pain 2001;93:259–266. 130. Childers MK, Wilson JW, Simison D. Equipment and injection techniques. In Childers MK, Wilson JW, Simison D (eds): Use of Botulinum Toxin Type A in Pain Management. New York: Demos Medical Publishing, 1999; pp 64–92. 131. Brin MF, Lew MF, Adier CH, et al. Safety and efficacy of NeuroBloc (botulinum toxin type B) in type A-resistant cervical dystonia. Neurology 1999;53:1431–1438. 132. U.S. Food and Drug Administration (2008;February 10). Botox linked to respiratory failure and death, FDA advises. Science Daily. Available at http://www.sciencedaily.com-/releases/2008/02/ 080209090530.htm (retrieved April 10, 2008). 133. Dysport [Product information]. Glen Waverly, Victoria, Australia: IPSEN Pty Ltd. 134. Botox [Product information]. Gordon, New South Wales, Australia: Allergan Australia Pty Ltd, 2002. 135. Querama E, Fuglsang-Frederiksen A, et al. A double-blind, controlled study of botulinum toxin A in chronic myofascial pain. Neurology 2006;67:241–245. 136. Tuula O, Arokoski JPA, et al. The effect of small doses of botulinum toxin A on neck-shoulder myofascial pain syndrome: a double-blind, randomized, and controlled crossover trial. Clin J Pain 2006;1:90–96. 137. Grabowski CL, Gray DS, et al. Botulinum toxin A versus bupivicaine trigger point injections for the treatment of myofascial pain syndrome: a randomized double blind crossover study. Pain 2005;118:170–175.

Chapter 68

TOPICAL ANALGESIC AGENTS Gary McCleane

INTRODUCTION As medical science progresses, physicians seem to become more and more specialized and to utilize increasingly invasive techniques in attempts to achieve therapeutic goals. One cannot help but be impressed by the technological advances that allow access, visualization, and opportunity for treatment in areas of the body long considered too delicate or inaccessible for intervention. But this does not mean that the more complex interventions are necessarily more efficacious than simpler ones. Nothing is fundamentally wrong with utilizing the simplest modalities of treatment and reserving the more complex treatments for situations in which therapeutic failure has occurred with less complex treatments. Therefore, we cannot forget about simple methods of administration of drugs and should remember that, in many cases, their use is founded not only on solid scientific evidence of effectiveness but also, in some cases, on generations’ worth of clinical use. When drugs are applied to the skin, they may either have a local effect (topical analgesics) or be absorbed transdermally but have a systemic mode of action. In this chapter, our consideration is on the former. When these topical analgesics are considered, they may be long-established topical agents, old pharmaceutical entities that have recently been shown to have a peripheral mode of action, or entirely new and novel agents. That the pharmaceutical industry still sees the merit in producing topical and transdermal analgesic agents is a

138. Ferrante FM, Bern L, et al. Evidence against trigger point injection technique for the treatment of cervicothoracic myofascial pain with botulinum toxin type A. Anesthesiology 2005;103:377–383. 139. Lew HL, Lee EH, Castaneda A, et al. Therapeutic use of botulinum toxin type A in treating neck and upper-back pain of myofascial origin: a pilot study. Arch Phys Med Rehabil 2008;89:75–80. 140. De Andres J, Cerda-Olmedo G, et al. Use of botulinum toxin in the treatment of chronic myofascial pain. Clin J Pain 2003;19:269–275. 141. Lang AM. A preliminary comparison of the efficacy and tolerability of botulinum toxin serotypes A and B in the treatment of myofascial pain syndrome: a retrospective, open-label chart review. Clin Ther 2003;25:2268–2278. 142. Argoff C. A focused review of the use of botulinum toxins for neuropathic pain. Clin J Pain 2002;18:S177–S181. 143. Foster L, Clapp L, et al. Botulinum toxin A and chronic low back pain, a randomized, double blind study. Neurology 2001;56:1290–1293. 144. Porta M. A comparative trial of botulinum toxin type A in and methylprednisolone for the treatment of myofascial pain syndrome and pain from chronic muscle spasm. Pain 2000;85:101–105. 145. Wheeler AH, Goolkasian P, et al. A randomized, double-blind, prospective pilot study of botulinum toxin injection for refractory, unilateral, cervicothoracic, paraspinal myofascial pain syndrome. Spine 1998;23:1662–1666. 146. Cheshire WP, Abashian S, et al. Botulinum toxin in the treatment of myofascial pain syndrome. Pain 1994;59:65–69.

reflection of its perception of market potential and patient preference. To many patients, it seems logical and sensible to put the painkiller where the pain is, rather than ingesting a substance that travels everywhere even though the pain is felt in a relatively small and well-defined area. Fortunately, we are now often in a position to rationalize why many topically applied agents achieve their therapeutic effect. This more detailed understanding of the pathophysiology and pharmacology of pain has also allowed some to suggest novel, topically applied treatments. Examples are provided later of some old drugs, previously systemically administered, but now known to have a peripheral mode of action. This does not, unfortunately, mean that they will become prominent in pain practice. Being old drugs, the patent protection surrounding their use—and allowing the pharmaceutical companies to invest in their verification and licensing while protecting the financial investment—has long since expired. Therefore, it is unlikely that the companies will invest resources in seeking an indication for the topical use of these drugs.

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS A bewildering array of topical nonsteroidal anti-inflammatory agents (NSAIDs) is available for purchase either over the counter or through medical prescription. These agents are known to reduce the production of prostaglandins that sensitize nerve endings at the site of injury. This effect occurs through inhibition of the cyclooxygenase (COX) enzyme that converts arachidonic acid, liberated from the phospholipid membrane by phospholipases, to prostanoids such as prostaglandin. At least two forms of COX are believed to be important. COX-1 is normally expressed in tissues such as those of the stomach and kidneys and plays a physiologic role in maintaining tissue integrity. A second form, COX-2, plays a role in pain and inflammation. The analgesic effects of NSAIDs can be dissociated from their anti-inflammatory effects, and this may

502 Chapter 68  TOPICAL ANALGESIC AGENTS reflect additional spinal and supraspinal actions of NSAIDs to inhibit various aspects of central pain processing. Recent evidence suggests that a third COX, COX-3, which is predominantly centrally distributed, may also have a significant role in NSAID action. When NSAIDs are applied topically, bioavailability and plasma concentrations are 5% to 15% of those achieved by systemic delivery. In human experimental pain models, topically applied NSAIDs produce analgesia in models of cutaneous pain and muscle pain. In terms of clinical use, three major reviews—one examining use in musculoskeletal and soft tissue pain, another reviewing data accrued in over 10,000 patients in 86 trials, and the third looking primarily at chronic rheumatic disease—all concluded that there was clear and significant evidence that topical NSAIDs do have pain-relieving properties. When NSAIDs are applied topically, relatively high concentrations occur in the dermis, whereas levels in adjacent muscle are as high as when the agent is given systemically. Gastrointestinal side effects occur less frequently than when the drug is given orally but are still more likely in patients who have previously demonstrated such responses to oral medication. Work is ongoing to develop alternative formulations of various NSAIDs that will give enhanced dermal penetration, provide a more measured dose, or be easier to use. For example, Mazieres and coworkers1 reported the study of the use of a topical ketoprofen patch in the treatment of tendinitis. They found a 56% reduction in pain with its use versus a 37% reduction with a placebo patch. Adverse effects were reported in approximately equal numbers in both the active- and the placebo-treatment groups. A topical diclofenac patch is also under investigation, with Allessandri and associates2 reporting that it gives significantly more pain relief than a placebo patch in patients undergoing laparoscopic gynecologic surgery. Niethard and colleagues3 reported that topical diclofenac diethylamine gel was effective in the treatment of osteoarthritis of the knee. Spacca and coworkers4 reported that the use of topical diclofenac epolamine was efficacious in the treatment of lateral epicondylitis and shoulder periarthritis. They suggested that this diclofenac salt has enhanced potential for cutaneous penetration and that it is carried by a lecithin gel, which also aids penetration. Unfortunately, with both these studies, an inactive placebo was used. More insight could have been gained if they had used conventional diclofenac gel and investigated whether their study preparations did offer benefit over currently available formulations. A multicenter, randomized, placebo-controlled, double-blind study of patients (N = 134) with minor ankle sprain was conducted using a Flector Patch or placebo patch for 7 consecutive days. The primary efficacy variable was pain on active mobilization, self-evaluated on a visual analog scale (VAS). The mean pain score revealed 78% improvement at day 3 over baseline in the treatment group compared with a 59% improvement in the placebo group (P < .0001). The mean pain score revealed an 88% improvement at day 7 over baseline in the treatment group compared with a 74% improvement in the placebo group (P < .0001). Another multicenter, randomized, double-blind, placebo-controlled study of patients (N = 418) with a variety of soft tissue injuries was performed. Patients applied dictofenac epolamine topical patches (1.3%) twice daily for 14 days or until pain resolution. The primary end-point was self-evaluated pain on a VAS assessed twice daily. The mean pain score revealed a 41% improvement at day 3 versus Vaseline in the treatment group compared with a 33% improvement in the placebo group. The mean pain score revealed a 79% improvement over the entire treatment period over baseline in the treatment group compared with a 73% improvement in the placebo group (P = .009). Perhaps the greatest danger of topical NSAID use is the risk of polypharmacy. A number of over-the-counter topical and oral NSAIDs are now available, and the risk of overdosing with several different preparations taken at the same time, all of which contain an NSAID, is very real.

NITRATES Conventionally used in the treatment of ischemic heart disease, it now seems that nitrates have potent analgesic and anti-inflammatory effects as well. It is known that exogenous nitrates stimulate the release of nitric oxide (NO). This substance is known to be a potent mediator in a wide variety of cellular systems such as the endothelium and both the peripheral and the central nervous systems. NO is released from the endothelium and from neutrophils and macrophages, all known to be intimately involved in the inflammatory process. It appears that NO exerts its effect by stimulating increases in guanylate cyclase, thereby increasing levels of cyclic guanidine monophosphate. Cholinergic drugs, such as acetylcholine, produce analgesia in a similar fashion by releasing NO and increasing NO at the nociceptor level. In addition to this action, NO may activate adenosine triphosphate–sensitive potassium channels and peripheral antinociception. Endogenous NO levels may be increased if glutamate levels are increased. Glutamate is known to be an excitatory amino acid that activates N-methyl-D-aspartate (NMDA) receptors, thereby initiating sensitization and protracting the pain process. Topical nitrate, in the form of glyceryl trinitrate (GTN), has been shown to effectively reduce the pain of osteoarthritis, supraspinatus tendinitis, Achilles tendinopathy, extensor tendinosis of the elbow, and infusion-related thrombophlebitis. In addition, GTN may reduce the pain and inflammation caused by sclerosant treatment of varicose veins and may even be useful in the treatment of vulvar pain. A number of reports suggested that topical nitrates may enhance the analgesic effectiveness of strong opioids, but it is likely that this effect is due to systemic absorption of the nitrate and a consequent central action. From a practical perspective, GTN can be considered for any relatively well-localized inflammatory condition. Therefore, in addition to the conditions mentioned previously, GTN can be used with effect in any joint pain (e.g., osteoarthritis, rheumatoid arthritis), tenosynovitis, enthetic pain, muscle pain, fracture pain (e.g., fractured rib, finger), around painful skin ulcers, and even in the management of postoperative pain. In this latter situation, the patch or segments of patch are placed close to the operative wound. Presumably, in addition to reducing inflammation and pain, the patch can enhance low tissue blood flow with all the benefits that can bring in terms of wound healing. The predominant side effect associated with topical nitrate use is headache. Currently, patch formulations deliver a relatively large amount of nitrate, and therefore, the incidence of headache is high. Should lower-dose patches become available, the utility of this treatment would be increased. GTN is also available in an ointment formulation. The measurement and consistency of dosing are problematic with the ointment formulation, and because there is only a small difference between a potentially analgesic dose and one that causes headache, GTN ointment is less practical than the patch. Topical nitrate can, therefore, be considered when pain is localized and particularly in those patients in whom NSAIDs are contraindicated. Topical nitrate is devoid of the renal, gastrointestinal, and hematologic side effects of NSAIDs.

LOCAL ANESTHETICS Gels/Creams Several topical local anesthetic preparations are available in gel, cream, and patch forms. Amethocaine is available as a gel, and lidocaine/prilocaine is provided as EMLA cream. EMLA cream contains a eutectic mixture of lidocaine and prilocaine; it has been used to anesthetize skin prior to cannula insertion. It also has

VII PHARMACOLOGIC APPROACHES TO PAIN MANAGEMENT 503

demonstrable benefit in reducing the pain of other procedures including lumbar puncture, intramuscular injections, and circumcision. Although EMLA cream is not U.S. Food and Drug Administration (FDA) approved for any neuropathic pain condition, several studies have been undertaken in patients with postherpetic neuralgia (PHN). Two of these were uncontrolled and showed a pain-reducing effect, whereas a randomized, controlled study in the same condition failed to show any benefit. Caution should be taken with long-term use of this preparation because prilocaine has been associated with the onset of methemoglobinemia.

conditions. Their pain-relieving effect is independent of their antidepressant effect. Unfortunately, their use is also associated with a significant risk of side effects, including dry mouth, sedation, urinary retention, and weight gain, which reduces compliance. In contrast, when TCAs are applied topically, side effects are relatively rare and a very real chance of pain relief exists. Any relief obtained by topical TCA use can be offset by their possible peripheral actions (Table 68–1).

Adenosine Receptors Patches Lidocaine is available in a topically applied patch in a 5% strength (Lidoderm). Lidoderm is approved by the FDA for the treatment of PHN. Its efficacy in this pain condition is supported by several trials that also confirm that it is well tolerated. Not only can pain levels in patients with PHN be reduced, but measures of quality of life also show improvement. In one study of patients with PHN, 66% of subjects reported reduced pain intensity when up to three Lidoderm patches were used for 12 hours each day. Whereas Lidoderm is indicated for use in PHN, it may also be efficacious in other pain conditions. One controlled study confirmed a pain-reducing effectin the treatment of focal neuropathic pain conditions, such as mononeuropathies and intercostal and ilioinguinal neuralgia. In an open-label study of 16 patients with ‘‘refractory’’ neuropathic pain (including post-thoracotomy pain, complex regional pain syndrome, postamputation pain, neuroma pain, painful diabetic neuropathy, meralgia parasthetica, and postmastectomy pain), 81% of subjects experienced notable pain relief. Refractory was defined in those patients who had either failed to gain pain relief or experienced unacceptable side effects with opiates, anticonvulsants, antidepressants, or antiarrhythmic agents. Lidoderm patches, therefore, offer a low-risk strategy for the treatment of a variety of conditions. Many other pain conditions could probably be effectively treated with Lidoderm patches. One wonders how the postoperative pain may respond if the patch is applied over the operative wound and changed on an intermittent basis.

CAPSAICIN Capsaicin achieves its pain-relieving effect by reversibly depleting sensory nerve endings of substance P and by reducing the density of epidermal nerve fibers, again in a reversible fashion. When capsaicin is used clinically, the major impediment to better compliance is the intense burning sensation associated with use. This is generally reduced with repeated administration, although if capsaicin cream is applied outside the normal area of application, discomfort will once again be apparent. Coadministration of GTN can reduce the discomfort associated with application and enhance the analgesic effect of capsaicin. Alternatively, preapplication of EMLA cream can also reduce application-associated discomfort. Occasional patients experience bouts of sneezing when capsaicin is used. Normally, this is caused by overapplication, drying of the cream on the skin, and nasal inhalation of the capsaicin dust from the application site. Care always needs to be taken that capsaicin is not applied to moist areas because this is associated with an increased burning sensation.

TRICYCLIC ANTIDEPRESSANTS Tricyclic antidepressants (TCAs) taken orally have a long history in pain management. Their use is established for a broad range of pain

At peripheral nerve terminals in rodents, adenosine A1-receptor activation produces antinociception by decreasing, while adenosine A2-receptor activation produces, pronociception by increasing cyclic adenosine monophosphate levels in the sensory nerve terminals. Adenosine A3-receptor activation produces pain behaviors through the release of histamine and serotonin from mast cells and subsequent actions on the sensory nerve terminal. Caffeine acts as a nonspecific adenosine receptor antagonist. When systemic caffeine is administered with systemic amitriptyline, the normal effect on thermal hyperalgesia is blocked. When amitriptyline is administered into a paw with neuropathic pain, an antihyperalgesic effect is recorded (but not when it is given into the contralateral paw). This antihyperalgesic effect is blocked by caffeine, suggesting that at least part of the effect of peripherally applied amitriptyline is mediated through peripheral adenosine receptors.

Sodium Channels Sudoh and associates5 administered various TCAs by a single injection into rat sciatic notches. They measured the duration of complete sciatic nerve blockade and compared it with that of bupivicaine. They found that amitriptyline, doxepin, and imipramine produced a longer complete sciatic nerve block than bupivicaine, whereas trimipramine and desipramine produced a shorter block. Nortriptyline and maprotiline failed to produce any block. The topical application of amitriptyline produced longer cutaneous analgesia than lidocaine. Similarly, Gerner and colleagues6 found that intrathecal doxepin was not significantly different in its motor or proprioceptive effects from those of intrathecal bupivicaine at a concentration of 0.75%. These studies suggest that from a mode-of-action perspective, peripherally applied TCAs could have an analgesic effect.

Table 68^1. Modes of Action of Tricyclic Antidepressants Central

Peripheral

Serotonergic effect Adenosine receptor effect Noradrenergic effect Sodium channel blocking effect Adenosine receptor effect ?? Opioidergic effect Sodium channel blocking effect Opioidergic effect NMDA receptor effect Calcium channel effect NMDA, N-methyl-D-aspartate.

504 Chapter 68  TOPICAL ANALGESIC AGENTS

Animal Evidence of an Antinociceptive Effect of Peripherally Applied TCAs Neuropathic Pain Amitriptyline applied to rodent paws made neuropathic by a chronic nerve constriction injury produced an antinociceptive effect. When amitriptyline was applied to the contralateral paw, no antinociceptive effect was observed in the paw on the injured side. When desipramine and the selective serotonin reuptake inhibitor fluoxetine were studied, desipramine had a similar antinociceptive effect when applied topically, whereas fluoxetine did not.

FormalinTest When amitriptyline and desipramine are coadministered peripherally with formalin, both the first- and the second-phase responses are reduced. When amitriptyline is administered peripherally along with formalin, Fos immunoreactivity in the dorsal region of the spinal cord is significantly lower than in animals in which formalin is administered alone.

Visceral Pain Using a noxious colorectal distention model in the rat, Su and Gebhart7 showed that the TCAs imipramine, desipramine, and clomipramine reduced the response to noxious colorectal distention by 20%, 22%, and 46%, respectively, compared with control-treated animals.

Thermal Injury Thermal hyperalgesia is produced by exposing a rodent hindpaw to 528C for 45 seconds. Locally applied amitriptyline at the time of thermal injury produces both antihyperalgesic and analgesic effects, depending on the concentration. When the amitriptyline is applied after the injury, the analgesic, but not the antihyperalgesic, effect is retained.

Human Pain Human evidence of an analgesic effect with the topical application of TCAs is limited. A small randomized, placebo-controlled trial of 40 subjects with neuropathic pain of mixed etiology produced a reduction of 1.18 on a 0 to 10 linear VAS relative to placebo use with the application of doxepin 5% cream. Minor side effects were seen in only 3 subjects. A larger randomized, controlled trial involving 200 subjects, again with neuropathic pain of mixed etiology, suggested that 5% doxepin cream reduced the linear VAS by approximately 1 relative to placebo and that the time to effect was about 2 weeks. Again, side effects were minor and infrequent. A pilot study examining the effect of topical amitriptyline application failed to produce any pain relief, but the maximum therapy duration was 7 days; therefore, the study may have been terminated before the time to maximal effect had been reached. Case studies have provided results of a useful reduction in pain when 5% doxepin cream was applied topically in subjects with complex regional pain syndrome type I and when doxepin was used as an oral rinse in patients with oral pain as a result of cancer or cancer therapy. Whereas the human evidence of an analgesic effect with topical doxepin is interesting, more study is needed to verify this and other TCA effects for this route of administration. The evidence suggests that the effect of topically applied doxepin is local and that the consequences of systemic administration and, hence, systemic side effects can be substantially reduced. Doxepin in a 5% cream formulation is currently available as Zonalon, which is indicated for the treatment of itch associated with eczema.

GLUTAMATE RECEPTOR ANTAGONISTS It has recently become apparent that glutamate receptors are expressed on peripheral nerve terminals and that these may contribute to peripheral nociceptive signalling. Both ionotropic and metabotropic glutamate receptors are present on membranes of unmyelinated peripheral axons and axon terminals in the skin, and peripheral inflammation increases the proportions of both unmyelinated and myelinated nerves expressing ionotropic glutamate receptors. Local injections of NMDA and non-NMDA glutamate receptor agonists to the rat hindpaw or knee joint enhance pain behaviors, generating hyperalgesia and allodynia. Injections of metabotropic glutamate receptor agonists produce similar actions. Conversely, local application of glutamate receptor antagonists inhibits pain behavior after formalin application. In humans, ketamine, a noncompetitive NMDA receptor antagonist, enhances the local anesthetic and analgesic effects of bupivicaine in acute postoperative pain by a peripheral mechanism. When a thermal injury was inflicted on volunteers, one study suggested that subcutaneous injection of ketamine produces long-lasting reduction in hyperalgesia, whereas another failed to confirm this result. That said, any analgesic effect produced by peripheral ketamine application may be due to more than its glutamate receptor activity. Ketamine can also block voltage-sensitive calcium channels, alter cholinergic and monoaminergic actions, and interfere with opioid receptors. Isolated case reports suggest that topical ketamine can reduce sympathetically maintained pain and pain of malignant origin, again suggesting that glutamate receptor antagonists may have some analgesic effect when applied topically. A study by Poyhia and Vainio8 reported that topically administered ketamine reduces capsaicin-evoked mechanical hyperalgesia, although they suggested that the effect they observed was due to a reduction in central sensitization caused by systemic ketamine absorption.

a-ADRENORECEPTOR ANTAGONISTS Clonidine, an a2-adrenoreceptor agonist, is available in both cream and patch formulations. It can have both a peripheral and a central action when applied topically. Clonidine patches have been reported to reduce the hyperalgesia associated with sympathetically maintained pain, but not that in patients with sympathetically independent pain. Clonidine cream may also have some painrelieving effect in orofacial neuralgia–like pain. The effect of clonidine in sympathetically maintained pain may be related to its effect of reducing presynaptic norepinephrine release from sympathetic nerves. In patients with sympathetically maintained pain and in those with peripheral nerve injury and postherpetic neuralgia, localized norepinephrine injection worsens the mechanical and thermal hyperalgesia in some patients. When clonidine is injected into the knee joint after arthroscopy, pain relief can be observed. When injected in combination with bupivicaine and morphine, the analgesic effect of these drugs are enhanced.

CANNABINOIDS Cannabinoids can act at peripheral sites to produce analgesia by virtue of their effect on cannabinoid (CB) CB1 and CB2 receptors. In animal models, peripheral administration of agents selective for CB1 receptors produces local analgesia in the formalin test, the carrageenan hyperalgesia model, and the nerve injury model. This effect may be obtained because of the action of these agents on the sensory nerve terminal to inhibit release of calcitonin gene–related peptide or by inhibiting effects of nerve growth factor. CB2 receptor mechanisms may play a prominent role in inflammatory pain.

VII PHARMACOLOGIC APPROACHES TO PAIN MANAGEMENT 505

OPIOIDS The analgesic effect of systemic opioids are well established and beyond question. Recently, transdermal formulations of fentanyl and buprenorphine have been introduced. Although they are applied to skin, it is likely that their predominant effect is central. Opioid receptors are not located exclusively in the central nervous system. It appears that opioid receptors are synthesized in dorsal root ganglia and transported into peripheral terminals of primary afferent neurons. Both m and d opioid receptors can be identified in fine cutaneous nerves in opioid-naı¨ve animals. When a ligature is placed on the rat sciatic nerve, b-endorphin binding sites accumulate both proximally and distally to the ligature site. When inflammation is induced, the number of b-endorphin binding sites on both sides of the ligature massively increases. From the human clinical perspective, a number of reports suggest that the knowledge of a peripheral representation of opioid receptors may have practical application. Topical morphine, provided as an oral rinse, has been shown to reduce mucositis-related pain in patients undergoing chemotherapy for head and neck carcinomas, whereas other case reports suggest that topical opioids may reduce pain from skin ulcers. In patients undergoing dental extractions, mixed results have been obtained, with some reports of enhanced relief when morphine is applied locally after dental extraction, and others reporting no such effect. It has also been suggested that intravesical strong opioids can reduce painful bladder spasms. Despite these suggestions from the literature, two systematic reviews failed to find any evidence of a pain-relieving effect when morphine was used by peripheral application.

CONCLUSIONS In the majority of cases, pain is generated by damage that occurs in the periphery, and although central processes can have a great effect on its intensity and duration, the stimulation and irritation of peripheral nociceptors initiates the process. Whereas we can influence the activity of these peripheral receptors and those neural structures that affect their activity by systemic administration of drugs, there is much logic and significant patient acceptance for the targeting of these structures by the topical, peripheral application of drugs. Therefore, the use of topical analgesics is not based on a simplistic view of pain treatment, but rather, on a logical appreciation of those peripheral factors that govern the generation, propagation, and control of pain. Concomitant with our increased understanding of the pathophysiology of pain is the availability of new pharmacologic entities that can target peripheral receptors and neural pathways and the realization that other drugs, previously shown to be effective when administered by different routes of administration or for differing indications, can also have analgesic effects when applied topically. With advances in pharmacologic technology, it is possible that the future will see a wider spectrum of drugs used in topical formulations as the ability to enhance the dermal penetration of drugs allows more medications to be used in this fashion.

REFERENCES Nonsteroidal Anti-inflammatory Drugs 1. Mazieres B, Rouanet S, Guillon Y, et al. Topical ketoprofen patch in the treatment of tendinitis: a randomized, double-blind, placebocontrolled study. J Rheumatol 2005;32:1563–1570. 2. Alessandri F, Lijoi D, Mistrangelo E, et al. Topical diclofenac patch for postoperative wound pain in laparoscopic gynaecologic surgery: a randomized study. J Minim Invasive Gynecol 2006;13:195–200.

3. Niethard FU, Gold MS, Solomon GS, et al. Efficacy of topical diclofenac diethylamine gel in osteoarthritis of the knee. J Rheumatol 2005;32:2384–2392. 4. Spacca G, Cacchio A, Forgacs A, et al. Analgesic efficacy of a lecithinvehiculated diclofenac epolamine gel in shoulder periarthritis and lateral epicondylitis: a placebo-controlled, multicenter, randomized, double-blind clinical trial. Drugs Exp Clin Res 2005;31:147–154. Tricyclic Antidepressants 5. Sudoh Y, Cahoon EE, Gerner P, Wang GK. Tricyclic antidepressant as long acting local anesthetics. Pain 2003;103:49–55. 6. Gerner P, Srinivasa V, Zizza AM, et al. Doxepin by topical application and intrathecal route in rats. Anesth Analg 2006;102:283–287. 7. Su X, Gebhart GF. Effects of tricyclic antidepressants on mechanosensitive pelvic nerve afferent fibers innervating the rat colon. Pain 1998;76:105–114. Glutamate Receptor Antagonists 8. Poyhia R, Vainio A. Topically administered ketamine reduces capsaicin-evoked mechanical hyperalgesia. Clin J Pain 2006;22:32–36.

SUGGESTED READINGS Nonsteroidal Anti-inflammatory Drugs Chandrasekharan NV, Dai H, Roos KL, et al. COX-3, a cyclo-oxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs. Cloning, structure and expression. Proc Natl Acad Sci U S A 2002;99:13926–13931. Heyneman CA, Lawless-Liday C, Wall GC. Oral versus topical NSAIDs in rheumatic diseases. A Comparison. Drugs 2000;60:555–574. Kress M, Reeh PW. Chemical excitation and sensitization in nociceptors. In Cavero F, Belmonte C (eds): Neurobiology and Nociceptors. Oxford, UK: Oxford University Press, 1996; pp 258–297. Mazieres B. Topical ketoprofen patch. Drugs R D 2005;6:337–344. Moore RA, Tramer MR, Carrol D, et al. Quantitative systematic review of topically applied non-steroidal anti-inflammatory drugs. BMJ 1998;316:333–338. Schmelz M, Kress M. Topical acetylsalicylate attenuates capsaicin induced pain, flare and allodynia but not thermal hyperalgesia. Neurosci Lett 1996;214:72–74. Steen KH, Reeh PW, Kreysel HW. Dose-dependent competitive block by topical acetylsalicylic acid and salicylic acid of low pH-induced cutaneous pain. Pain 2001;64:71–82. Steen KH, Reeh PW, Kreysel HW. Topical acetylsalicylic, salicylic acid and indomethacin suppresses pain from experimental tissue acidosis in human skin. Pain 1995;62:339–347. Steen KH, Wegner H, Meller ST. Analgesic profile of peroral and topical ketoprofen upon low pH-induced muscle pain. Pain 2001;93:23–33. Vaile JH, Davis P. Topical NSAIDs for musculoskeletal conditions. A review of the literature. Drugs 1998;56:783–799. Vane JR, Bakhle YS, Botting J. Cyclo-oxygenase 1 and 2. Annu Rev Pharmacol Toxicol 1998;38:97–120. Yaksh TL, Dirig DM, Malmberg AB. Mechanisms of action of nonsteroidal anti-inflammatory drugs. Cancer Invest 1998;16:509–527. Nitrates Berrazueta JR, Fleitas M, Salas E, et al. Local transdermal glyceryl trinitrate has an anti-inflammatory action on thrombophlebitis induced by sclerosis of leg varicose veins. Angiology 1994;45:347–351. Berrazueta JR, Losada A, Poveda J, et al. Successful treatment of shoulder pain syndrome due to supraspinatus tendonitis with transdermal nitroglycerin. A double-blind study. Pain 1996;66:63–67. Berrazeuta JR, Poveda JJ, Ochoteco JA, et al. The anti-inflammatory and analgesic action of transdermal glyceryl trinitrate in the treatment of infusion related thrombophlebitis. Postgrad Med J 1993;69:37–40. Duarte ID, Lorenzetti BB, Ferreira SH. Acetylcholine induces peripheral analgesia by the release of nitric oxide. In Moncada S, Higgs A (eds): Nitric oxide from L-arginine. A bioregulatory system. Amsterdam: Elsevier, 1990; pp 165–170. Feelisch M, Noack EA. Correlation between nitric oxide formation during degradation of organic nitrates and activation of guanylate cyclase. Eur J Pharmacol 1987;139:19–30. Hunte G, Lloyd-Smith R. Topical glyceryl trinitrate for chronic Achilles tendinopathy. Clin J Sport Med 2005;15:116–117. Knowles RG, Palacios M, Palmer RM, Moncada S. Formation of nitric oxide from L-arginine in the central nervous system: a transduction mechanism for stimulation of soluble guanylate cyclase. Proc Natl Acad Sci U S A 1989;86:5159–5162.

506 Chapter 68  TOPICAL ANALGESIC AGENTS Lauretti GR, de Oliveira R, Reis MP, et al. Transdermal nitroglycerine enhances spinal sufentanil postoperative analgesia following orthopaedic surgery. Anesthesiology 1999;90:734–739. Lauretti GR, Lima IC, Reis MP, et al. Oral ketamine and transdermal nitroglycerin as analgesic adjuvants to oral morphine therapy for cancer pain management. Anesthesiology 1999;90:1528–1533. Lauretti GR, Perez MV, Reis MP, Pereira NL. Double-blind evaluation of transdermal nitroglycerine as an adjuvant to oral morphine for cancer pain management. J Clin Anesth 2002;14:83–86. McCleane GJ. The addition of piroxicam to topically applied glyceryl trinitrate enhances its analgesic effect in musculoskeletal pain: a randomised, double-blind, placebo-controlled study. Pain Clin 2000;12:113–116. Okuda K, Sakurada C, Takahashi M, et al. Characterization of nociceptive responses and spinal release of nitric oxide metabolites and glutamate evoked by different concentrations of formalin in rats. Pain 2001;92:107–115. Paoloni JA, Appleyard RC, Nelson J, Murrell GA. Topical glyceryl trinitrate treatment of chronic noninsertional achilles tendinopathy. A randomized, double-blind, placebo-controlled trial. J Bone Joint Surg Am 2004;86:916–922. Paoloni JA, Appleyard RC, Nelson J, Murrell GA. Topical nitric oxide application in the treatment of chronic extensor tendinosis at the elbow: a randomized, double-blind, placebo-controlled clinical trial. Am J Sports Med 2003;31:915–920. Soares A, Leite R, Patsuo M, Duarte I. Activation of ATP sensitive K channels: mechanisms of peripheral antinociceptive action of the nitric oxide donor, sodium nitroprusside. Eur J Pharmacol 2000;14:67–71. Walsh KE, Berman JR, Berman LA, Vierregger K. Safety and efficacy of topical nitroglycerin for treatment of vulvar pain in women with vulvodynia: a pilot study. J Gend Specif Med 2002;5:21–27. Local Anesthetics Attal N, Brasseur L, Chauvin M. Effects of single and repeated applications of a eutectic mixture of local anesthetics (EMLAÕ ) cream on spontaneous and evoked pain in post-herpetic neuralgia. Pain 1999;81:203–209. Devers A, Galer BS. Topical lidocaine patch relieves a variety of neuropathic pain conditions: an open-label study. Clin J Pain 2000;16:205–208. Galer BS. Topical medications. In Loeser JD (ed): Bonica’s Management of Pain. Philadelphia: Lippincott Williams & Wilkins, 2001; pp 1736–1741. Galer BS, Rowbotham MC, Perander J, et al. Topical lidocaine patch relieves post-herpetic neuralgia more effectively than vehicle patch: results of an enriched enrolment study. Pain 1999;80:533–538. Katz NP, Davis MW, Dworkin RH. Topical lidocaine patch produces a significant improvement in mean pain scores and pain relief in treated PHN patients: results of a multicenter open-label trial. J Pain 2001;2:9–18. Litman SJ, Vitkun SA, Poppers PJ. Use of EMLAÕ cream in the treatment of post-herpetic neuralgia. J Clin Anesth 1996;8:54–57. Lycka BA, Watson CP, Nevin K, et al. EMLAÕ cream for the treatment of pain caused by post-herpetic neuralgia: a double-blind, placebo controlled study. Abstract. In Proceedings of the Annual Meeting of the American Pain Society, Washington, DC, November 14–17, 1996; A111. Meier T, Wasner G, Faust M, et al. Efficacy of lidocaine 5% patch in treatment of focal peripheral neuropathic pain syndromes: a randomized, double-blind, placebo-controlled study. Pain 2003;106:151–158. Rowbotham MC, Davies PS, Verkempinck C, et al. Lidocaine patch: double-blind controlled study of a new treatment method for postherpetic neuralgia. Pain 1996;65:39–44. Capsaicin Altman RD, Aven A, Holmburg CE, et al. Capsaicin cream 0.025% as monotherapy for osteoarthritis: a double-blind study. Semin Arthritis Rheum 1994;23S:25–33. Bernstein JE, Korman NJ, Bickers DR, et al. Topical capsaicin treatment of chronic postherpetic neuralgia. J Am Acad Dermatol 1989;21:265–270. Capsaicin Study Group. Effect of treatment with capsaicin on daily activities of patients with painful diabetic neuropathy. Diabetes Care 1992;15:159–165. Capsaicin Study Group. Treatment of painful diabetic neuropathy with topical capsaicin. Arch Intern Med 1991;151:2225–2229. Chad DA, Aronin N, Lundstorm R, et al. Does capsaicin relieve the pain of diabetic neuropathy? Pain 1990;42:387–388.

Deal CL. The use of topical capsaicin in managing arthritis pain: a clinician’s perspective. Semin Arthritis Rheum 1994;23S:48–52. Deal CL, Schnitzer TJ, Lipstein E, et al. Treatment of arthritis with topical capsaicin: a double-blind trial. Clin Ther 1991;13:383–395. Ellison N, Loprinzi CL, Kugler J, et al. Phase III placebo-controlled trial of capsaicin cream in the management of surgical neuropathic pain in cancer patients. J Clin Oncol 1997;15:2974–2980. Epstein JB, Marcoe JH. Topical application of capsaicin for treatment of oral neuropathic pain and trigeminal neuralgia. Oral Surg Oral Med Oral Pathol 1994;77:135–140. Fitzgerald M. Capsaicin and sensory neurones. Pain 1983;15:109–130. Low PA, Opfer-Gehrking TL, Dyck PJ, et al. Double-blind, placebocontrolled study of the application of capsaicin cream in chronic distal painful polyneuropathy. Pain 1995;45:163–168. Mathias BJ, Dillingham TR, Zeigler DN, et al. Topical capsaicin for chronic neck pain. Am J Phys Med Rehabil 1995;74:39–44. McCarthy GM, McCarty DJ. Effect of topical capsaicin in the therapy of painful osteoarthritis of the hands. J Rheumatol 1992;19:604–607. McCleane GJ. The analgesic efficacy of topical capsaicin in enhanced by glyceryl trinitrate in painful osteoarthritis: a randomized, double-blind, placebo-controlled study. Eur J Pain 2000;4:355–360. McCleane GJ, McLaughlin M. The addition of GTN to capsaicin cream reduces the discomfort associated with application of capsaicin alone. A volunteer study. Pain 1998;78:149–151. Morgenlander JC, Hurwitz BJ, Massey EW. Capsaicin for the treatment of pain in Guillain-Barre´ syndrome. Ann Neurol 1990;12:199. Nolano M, Simone DA, Wendelschafer-Crabb G, et al. Topical capsaicin in humans: parallel loss of epidermal nerve fibers and pain sensation. Pain 1999;81:135–141. Rains C, Bryson HM. Topical capsaicin. A review of its pharmacological properties and therapeutic potential in post herpetic neuralgia, diabetic neuropathy and osteoarthritis. Drugs Aging 1995;7:317–328. Schnitzer T, Morton C, Coker S. Topical capsaicin therapy for osteoarthritis pain: achieving a maintenance regimen. Semin Arthritis Rheum 1994;23S:34–40. Tandan R, Lewis GA, Krusinski PB, et al. Topical capsaicin in painful diabetic neuropathy. Diabetes Care 1992;15:8–13. Turnbull A. Tincture of capsicum as a remedy for chilblains and toothache. Dublin Med Press 1850;95–96. Watson CP, Evans R, Watt VR. Post herpetic neuralgia and topical capsaicin. Pain 1988;33:333–340. Walker RA, McCleane GJ. The addition of glyceryl trinitrate to capsaicin cream reduces the thermal allodynia associated with the use of capsaicin in humans. Neurosci Lett 2002;323:78–80. Watson CP, Tyler KL, Bickers DR, et al. A randomized vehicle-controlled trial of topical capsaicin in the treatment of postherpetic neuralgia. Clin Ther 1993;15:510–526. Yosipovitch G, Mailback HI, Rowbotham MC. Effect of EMLA pretreatment on capsaicin-induced burning and hyperalgesia. Acta Derm Venereol 1999;79:118–121. Tricyclic Antidepressants Epstein JB, Truelove EL, Oien H, et al. Oral topical doxepin rinse: analgesic effect in patients with oral mucosal pain due to cancer or cancer therapy. Oral Oncol 2001;37:632–637. Esser MJ, Chase T, Allen GV, Sawynok J. Chronic administration of amitriptyline and caffeine in a rat model of neuropathic pain: multiple interactions. Eur J Pharmacol 2001;430:211–218. Esser MJ, Sawynok J. Acute amitriptyline in a rat model of neuropathic pain: differential symptom and route effects. Pain 1999;80:643–653. Esser MJ, Sawynok MJ. Caffeine blockade of the thermal antihyperalgesic effect of acute amitriptyline in a rat model of neuropathic pain. Eur J Pharmacol 2000;399:131–139. Haderer A, Gerner P, Kao G, et al. Cutaneous analgesia after transdermal application of amitriptyline versus lidocaine in rats. Anesth Analg 2003;96:1707–1710. Heughan CE, Allen GV, Chase TD, Sawynok J. Peripheral amitriptyline suppresses formalin-induced Fos expression in the rat spinal cord. Anesth Analg 2002;94:427–431. Lynch ME, Clarke AJ, Sawynok J. A pilot study examining topical amitriptyline, ketamine, and a combination of both in the treatment of neuropathic pain. Clin J Pain 2003;19:323–328. McCleane GJ. Topical application of doxepin hydrochloride can reduce the symptoms of complex regional pain syndrome: a case report. Injury 2002;33:88–89.

VII PHARMACOLOGIC APPROACHES TO PAIN MANAGEMENT 507 McCleane GJ. Topical application of doxepin hydrochloride, capsaicin and a combination of both produces analgesia in chronic human neuropathic pain: a randomized, double-blind, placebo-controlled study. Br J Clin Pharmacol 2000;49:574–579. McCleane GJ. Topical doxepin hydrochloride reduces neuropathic pain: a randomized, double-blind, placebo-controlled study. Pain Clin 1999;12:47–50. Oatway M, Reid A, Sawynok J. Peripheral antihyperalgesic and analgesic actions of ketamine and amitriptyline in a model of mild thermal injury in the rat. Anesth Analg 2003;97:168–173. Sawynok J. Adenosine receptor activation and nociception. Eur J Pharmacol 1998;317:1–11. Sawynok J, Esser MJ, Reid AR. Peripheral antinociceptive actions of desipramine and fluoxetine in an inflammatory and neuropathic pain test in the rat. Pain 1999;82:149–158. Sawynok J, Reid A. Peripheral interactions between dextromethorphan, ketamine and amitriptyline on formalin-evoked behaviours and paw edema in rats. Pain 2003;102:179–186. Sawynok J, Reid AR, Esser MJ. Peripheral antinociceptive action of amitriptyline in the rat formalin test: involvement of adenosine. Pain 1999;80:45–55. Glutamate Receptor Antagonists Carlton SM, Coggeshall RE. Inflammation-induced changes in peripheral glutamate receptor populations. Brain Res 1999;820:63–70. Carlton SM, Hargett GL, Coggeshall RE. Localization and activation of glutamate receptors in unmyelinated axons of rat glabrous skin. Neurosci Lett 1995;197:25–28. Crowley KL, Flores JA, Hughes CN, Iacono RP. Clinical application of ketamine ointment in the treatment of sympathetically maintained pain. Int J Pharm Compd 1998;2:122–127. Hirota K, Lambert DG. Ketamine: its mechanism(s) of action and unusual clinical uses. Br J Anaesth 1996;77:441–444. Jackson DL, Graff CB, Richardson JD, Hargreaves KM. Glutamate participates in the peripheral modulation of thermal hyperalgesia in rats. Eur J Pharmacol 1995;284:321–325. Lawland NB, Willis WD, Westlund KN. Excitatory amino acid receptor involvement in peripheral nociceptive transmission in rats. Eur J Pharmacol 1997;324:169–177. Meller ST. Ketamine: relief from chronic pain through actions at the NMDA receptor? Pain 1996;68:435–436. Pedersen JL, Galle TS, Kehlet H. Peripheral analgesic effects of ketamine in acute inflammatory pain. Anesthesiology 1998;89:58–66. Sawynok J, Reid AR. Modulation of formalin-induced behaviours and edema by local and systemic administration of dextromethorphan, memantine and ketamine. Eur J Pharmacol 2002;450:115–121. Tverskoy M, Oren M, Vaskovich M, et al. Ketamine enhances local anesthetic and analgesic effects of bupivicaine by a peripheral mechanism: a study in postoperative patients. Neurosci Lett 1996;215:5–8. Walker K, Reeve A, Bowes M, et al. mGlu5 receptors and nociceptive function II. mGlu5 receptors functionally expressed on peripheral sensory neurones mediate inflammatory hyperalgesia. Neuropharmacology 2001;40:10–19. Warncke T, Jørum E, Stubhaug A. Local treatment with the N-methylD-aspartate receptor antagonist ketamine, inhibits development of secondary hyperalgesia in man by a peripheral action. Neurosci Lett 1997;227:1–4. Wood RM. Ketamine for pain in hospice patients. Int J Pharm Compd 2000;4:253–254. Zhou S, Bonasera L, Carlton SM. Peripheral administration of NMDA, AMPA or KA results in pain behaviour in rats. Neuroreport 1996;7:895–900. Zhou S, Komak S, Du J, Carlton SM. Metabotropic glutamate 10 receptors on peripheral primary afferent fibers: their role in nociception. Brain Res 2001;913:18–26. a-Adrenoreceptor Antagonists Ali Z, Raja SN, Wesselmann U, et al. Intradermal injection of norepinephrine evokes pain in patients with sympathetically maintained pain. Pain 2000;88:161–168. Buerkle H, Huge V, Wolfgart M, et al. Intra-articular clonidine analgesia after knee arthroscopy. Eur J Anaesthesiol 2000;17:295–299. Chabal C, Jacobson L, Mariano A, et al. The use of oral mexiletine for the treatment of pain after peripheral nerve injury. Anesthesiology 1992;76:513–517.

Choi B, Rowbotham MC. Effect of adrenergic receptor activation on post-herpetic neuralgia pain and sensory disturbances. Pain 1997;69:55–63. Davis CL, Treede RD, Raja SN, et al. Topical application of clonidine relieves hyperalgesia in patients with sympathetically maintained pain. Pain 1991;47:309–317. Epstein JB, Grushka M, Le N. Topical clonidine for orofacial pain: a pilot study. J Orofac Pain 1997;11:346–352. Gentili M, Houssel P, Osman H, et al. Intra-articular morphine and clonidine produce comparable analgesia but the combination is not more effective. Br J Anaesth 1997;79:660–661. Gentili M, Juhel A, Bonnet F. Peripheral analgesic effect of intra-articular clonidine. Pain 1996;64:593–596. Joshi M, Reuben SS, Kilaru PR, et al. Postoperative analgesia for outpatient arthroscopic knee surgery with intra-articular clonidine and/ or morphine. Anesth Analg 2000;90:1102–1106. Reuben SS, Connelly NR. Postoperative analgesia for outpatient arthroscopic knee surgery with intra-articular clonidine. Anesth Analg 1999;88:729–733. Torebjo¨rk E. Noradrenaline-evoked pain in neuralgia. Pain 1995;63:11–20. Cannabinoids Calignano A, La Ranna G, Giuffrida A, Piomelli D. Control of pain initiation by endogenous cannabinoids. Nature (Lond) 1998;394:277–281. Fox A, Kesingland A, Gentry C, et al. The role of central and peripheral cannabinoid1 receptors in the antihyperalgesic activity of cannabinoids in a model of neuropathic pain. Pain 2001;92:91–100. Rice AS, Farquhar-Smith WP, Nagy I. Endocannabinoids and pain: spinal and peripheral analgesia in inflammation and neuropathy. Prostaglandins Leukot Essent Fatty Acids 2002;66:243–256. Richardson JD, Kilo S, Hargreaves KM. Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors. Pain 1998;75:111–119. Opioids Cerchietti LC, Navigante AH, Bonomi MR, et al. Effect of topical morphine for mucositis-associated pain following concomitant chemoradiotherapy for head and neck carcinoma. Cancer 2002;95:2230–2236. Cerchietti LC, Navigante AH, Ko¨rte MW, et al. Potential utility of the peripheral analgesic properties of morphine in stomatitis-related pain: a pilot study. Pain 2003;105:265–273. Coggeshall RE, Zhou S, Carlton SM. Opioid receptors on peripheral sensory axons. Brain Res 1997;764:126–132. Duckett JW, Cangiano T, Cubina M, et al. Intravesical morphine analgesia after bladder surgery. J Urol 1997;157:1407–1409. Gupta A, Bodin L, Holmstrom B, Berggren L. A systematic review of the peripheral analgesic effects of intra-articular morphine. Anesth Analg 2001;93:761–770. Hassan AH, Ableitner A, Stein C, Herz A. Inflammation of the rat paw enhances axonal transport of opioid receptors in the sciatic nerve and increases their density in the inflamed tissue. Neuroscience 1993;55:185–195. Krajnik M, Zylicz Z, Finlay I, et al. Potential uses of topical opioids in palliative care—report of 6 cases. Pain 1999;80:121–125. Likar R, Koppert W, Blatnig H, et al. Efficacy of peripheral morphine analgesia in inflamed, non-inflamed perineural tissue of dental surgery patients. J Pain Symptom Manage 2001;21:330–337. Likar R, Sittl R, Gragger K, et al. Peripheral morphine analgesia in dental surgery. Pain 1998;76:145–150. McCoubrie R, Jeffrey D. Intravesical diamorphine for bladder spasm. J Pain Symptom Manage 2003;25:1–2. Moore RJ, Seymour RA, Gilro J, Rawlins MD. The efficacy of locally applied morphine in post-operative pain after bilateral third molar surgery. Br J Clin Pharmacol 1994;37:227–230. Picard PR, Tramer MR, McQuay HJ, Moore RA. Analgesic efficacy of peripheral opioids (all except intra-articular): a qualitative systematic review of randomised controlled trials. Pain 1997;72:309–318. Stein C, Schafer H, Hassan AH. Peripheral opioid receptors. Ann Med 1995;27:219–221. Twillman RK, Long TD, Cathers TA, Mueller DW. Treatment of painful skin ulcers with topical opioids. J Pain Symptom Manage 1999;17:288–292. Zhou L, Zhang Q, Stein C, Schafer M. Contribution of opioid receptors on primary afferent versus sympathetic neurons to peripheral opioid analgesia. J Pharmacol Exp Ther 1998;286:1000–1006.

508 Chapter 69  TR AMADOL

Chapter 69

Tramadol David J. Skinner, Jonathan Epstein, and Marco Pappagallo

INTRODUCTION The rungs of the World Health Organization (WHO) analgesic ladder provide the guidelines for the selection of ‘‘weak or strong’’ opioids according to the severity of cancer pain. The ladder has been used by many practitioners not only in the management of cancer pain but also in the care of noncancer pain. On the second rung are the so-called weak opioids such as tramadol, hydrocodone, and codeine. Tramadol, despite being classified with other opioids, is an atypical member of this group. It is a unique analgesic compound that demonstrates a dual mechanism of action with both opioid and monoaminergic actions. It generally has fewer side effects and better tolerability than oral nonsteroidal antiinflammatory drugs (NSAIDs) or traditional opioids. Tramadol was introduced to the U.S. market in 1995 as an alternative to NSAIDs. It was developed in 1962 by the German pharmaceutical company Grunenthal and entered the West German market in 1977 under the trade name Tramal. Since that time, it has been used by over 100 million patients and is available in 100 countries. Tramadol is usually marketed as the hydrochloride salt (tramadol hydrochloride) and is available in injectable (intravenous and/or intramuscular), oral, and rectally administered preparations. In the United States, however, only the oral formulation is available for use. It is available in 50- and 100-mg tablets as well as a 37.5-mg tramadol/acetaminophen combination. There is also a 24-hour, sustained-release preparation produced in 100-, 200-, and 300-mg strengths. The immediate-release forms are marketed as Ultram and Ultracet and the extended-release form as Ultram-ER (OrthoMcNeil).

PHARMACOLOGY Tramadol is a racemic mixture of two enantiomers with different pharmacologic properties composed of 50% (–)-tramadol and 50% (+)-tramadol. Each enantiomer displays differing affinities for varying receptors. The (+) enantiomer shows a greater affinity for the m-receptor and increases serotonin levels. The (–) enantiomer preferentially stimulates a2-receptors, resulting in higher levels of norepinephrine.

Mechanism of Action Tramadol is a synthetic medication that is structurally related to codeine and morphine, with an incompletely understood mechanism of action (Fig. 69–1). It is believed to work primarily in the central nervous system via two distinct mechanisms. Tramadol functions as a weak opioid approximately one fourth to one fifth as potent as morphine with affinity for the m-receptor but little to

none for k- or d-receptors. The reported affinity for the m-receptor is 10 times less than that of codeine and 6000 times less than that of morphine. The major active metabolite M1 (O-desmethyl-tramadol) has a modestly higher affinity at 300 times less than morphine (Fig. 69–2). The affinities for tramadol and its metabolites compared with other opioids are listed in Table 69–1. Alone, the opioidrelated activity of tramadol would not be expected to produce a significant analgesic effect. In addition, the administration of the opioid antagonist naloxone can only partially reverse the analgesic effects of tramadol. The other mechanism of action of tramadol is inhibition of the neuronal reuptake of the neurotransmitters norepinephrine and serotonin. This activity modulates the normal descending inhibitory pathways of pain. Of note is that tramadol analgesia can be decreased by ondansetron, an antiemetic that is a selective serotonin-3 (5-HT3)–receptor antagonist and has actions in both central and peripheral sites. The (+) enantiomer has an approximately fourfold greater effect on serotonin reuptake, whereas the (–) enantiomer has a greater effect on norepinephrine reuptake. Evidence has also shown that the (+) enantiomer and (±) tramadol increase the presynaptic efflux of serotonin in the central nervous system. It is known that medications causing reuptake inhibition of these neurotransmitters, such as the tricyclic antidepressants (TCAs), are effective for pain. The analgesic effects of tramadol are also completely reversed by coadministration of naloxone and the a2-adrenoceptor antagonist yohimbine. Therefore, the reduction in pain produced by tramadol is the result of the complementary and synergistic actions of its enantiomers.

Absorption, Distribution, Metabolism, and Elimination Tramadol has an oral absorption of 100%, with a mean bioavailability of 70% owing to a 20% to 30% first-pass metabolism after a single oral dose. After multiple oral dosing, the bioavailability may increase to 90% to 100%, which may be the result of a saturated first-pass hepatic metabolism. The bioavailability of tramadol after food intake, although increased, does not seem to be clinically relevant. The time to peak plasma concentration after an oral dose of the immediate-release tramadol is 1.6 to 1.9 hours. The time to peak plasma concentrations for the extended-release tramadol UltramER is 12 hours. Tramadol is rapidly distributed after oral intake with peak brain concentrations occurring at 10 minutes and at 20 to 60 minutes for its major active metabolite, O-desmethyl-tramadol (M1). The binding of tramadol to human plasma proteins is approximately 20%. After absorption and distribution, tramadol is extensively metabolized by the liver primarily via N- and O-demthylation and conjugation of O-demethylated compounds. The cytochrome P-450 (CYP450) system (CYP2D6 and CYP3A4 enzymes) appears to be much involved in the metabolism of tramadol, with alteration of tramadol pharmacokinetics seen in populations with varied amounts of CYP2D6 activity. In total, 23 metabolites have been identified in humans (11 phase I metabolites and 12 conjugates). The major active metabolite is M1, which displays a m-opioid receptor affinity 300 times greater than that of the parent drug, tramadol (see Table 69–1). The pharmacologic properties of many of the other metabolites have not been extensively studied but appear to have similar elimination half-lives and excretion via the kidneys. Elimination of tramadol

VII PHARMACOLOGIC APPROACHES TO PAIN MANAGEMENT 509

HO

H3CO

OCH3 N Me

O

O

HO N

H H

A HO

B

CH3

CH3

H

C

N CH3

HO

Figure 69^1. Chemical structures of morphine, tramadol, and codeine.

and its metabolites occurs mostly through the kidneys (90%), with a negligible amount excreted in the bile and feces. The elimination half-life of tramadol is 5 to 6 hours, with that of M1 being slightly longer. Elimination and metabolism, processes heavily dependent upon renal and hepatic mechanisms, are expected to be affected by changes in renal and/or hepatic function. The elimination half-life is not excessively prolonged, however, as long as one of the two excretion organs is virtually intact. In patients with severe cirrhosis of the liver, the elimination half-life of tramadol was extended to a mean of 13 hours and a maximum of 22 hours. The manufacturer (Ortho-McNeil) has recommended that its use be avoided in patients with liver failure. In patients with renal failure (creatinine clearance < 5 ml/min), the mean elimination half-life was prolonged to about 11 hours, with a maximum of 19 hours. Dialysis does not have a significant effect on the plasma concentrations of tramadol. The total amount of tramadol and M1 removed after a 4-hour dialysis period (hemodialysis, intermittent or continuous hemofiltration, or peritoneal dialysis) was less than 7% of the administered dose.

INDICATIONS The unique combination of m-opioid agonism with norepinephrine and serotonin reuptake inhibition allows tramadol to be a particularly effective drug across a wide spectrum of painful conditions. It is currently used to alleviate many types of musculoskeletal, neuropathic, and cancer pain syndromes.

Musculoskeletal Pain A wealth of data supports the use of tramadol in musculoskeletal pain. A favorable side effect profile allows this medication to be an attractive choice for practitioners treating musculoskeletal and arthritic conditions in particular. As chronic usage of analgesics becomes more prevalent with an aging population, it is imperative that physicians find methods of treatment with mild side effect profiles, minimal risk for drug interactions, and resistance to tolerance. Tramadol is a viable alternative, or adjuvant, to NSAIDs, particularly among patients with an increased risk for gastrointestinal bleeding or other conditions that limit or prevent NSAID use. In 2003, Mullins and Wild,1 in an analysis of the O

OH

CH3

OH

H3C N CH3

H3C O-demethylation

OH N CH3

Tramadol O-Desmethyl tramadol Figure 69^2. O-Demethylation of tramadol to the M1

metabolite.

treatment of nonmalignant pain in the elderly at a long-term facility, found decreases in pain and an improvement in intestinal function. In the same study, they also noted a decrease in falls, loss of weight, behavioral symptoms, depression, and in overall consumption of analgesics. These changes were accompanied by an increase in activity levels. In a 2006 Cochrane Review on the use of tramadol in osteoarthritis,2 data from 11 randomized, controlled trials involving nearly 2000 patients was examined. The authors concluded that tramadol decreases pain intensity, produces symptom relief, and improves function, but that these benefits were small. Tramadol has also been proven to be useful in the notoriously difficult to treat condition of chronic low back pain. A review paper published in 2005 by Mattia and Coluzzi3 examined specifically the usefulness of tramadol in musculoskeletal and neuropathic pain. Tramadol, in both the immediate- and the controlled-release forms, was found to be effective in reducing pain and improving function in patients with low back pain, while providing a lower incidence of side effects. This review also described significant reductions in NSAID requirements for patients who had previously required high doses of NSAIDs for pain control.3 The 2006 market release of a sustained-release formulation in the United States is likely to make tramadol a more attractive option for both patient and practitioner. A controlled trial involving over 1000 patients investigating the efficacy and safety of this extended-release tramadol versus placebo in the treatment of osteoarthritis pain was recently published by Gana and coworkers.4 The findings showed statistically significant improvements in pain and physical function. Advantages of the sustaine-release version include improved adherence to a treatment regimen, avoidances of plasma peaks that seem to be associated with increased side effects, and greater therapeutic options. Reported adverse events were generally mild to moderate in severity and were consistent with the established safety profile of immediate-release tramadol in the treatment of osteoarthritis pain. Whereas first-line pharmacologic treatments of musculoskeletal pain continue to be acetaminophen and NSAIDs, tramadol offers an

Table 69^1. Affinities of Opioids with Active Metabolites at k-Opioid Receptors, Given as Ki Values (Lower Value Denotes Higher Affinity) Substance

Ki value (kM)

Morphine Codeine Tramadol (+)-Tramadol ()-Tramadol O-Desmethyltramadol

0.00049 ± 0.00003 0.59 ± 0.0017 17 15.7 28.8 3.19

Adapted from Lotsch J. Opioid metabolites. J Pain Sympton Manage 2005;29:S10–S24.

510 Chapter 69  TR AMADOL analgesic alternative with an acceptably small risk of side effects. This is especially true for those patients who either fail to achieve adequate analgesia via traditional treatments or have contraindications to traditional therapies.

Cancer Pain The use of tramadol in cancer pain has also been well documented. A significant amount of the literature investigating tramadol for use in cancer pain involves the comparison of tramadol with morphine and other opioids traditionally used for treatment of cancer pain. Leppert and Luczak5 reviewed data from more than 10 comparative and noncomparative studies on the use of tramadol for cancer pain. These studies suggested that tramadol is an effective analgesic for mild to moderate pain, with a greatly reduced side effect profile compared with that of morphine. It has also been consistently noted that the utility of tramadol is especially apparent when treating those who were particularly sensitive to the side effects of the stronger opioids, such as sedation, constipation, and fatigue, symptoms commonly present in patients with cancer owing to disease. Morphine and the stronger opioids remain the first-line drugs to treat cancer pain owing to superior analgesia. However, side effects, often severe with traditional opioids, are usually more frequent and often lead to decreases in dosage and resultant increases in pain. Tramadol, with a more attractive side effect profile and proven efficacy, should be considered a first-line approach to cancer pain of mild to moderate severity.

Neuropathic Pain Neuropathic pain is often the result of injury or damage to neural structures in the central and/or the peripheral nervous systems. It has a wide range of symptoms, typically including burning pain, tingling, shooting sensations, abnormal sensitivity to painless stimuli, and increased sensitivity to painful stimuli. It is widely believed to be the type of pain that is most refractory to treatment. For reasons that remain unclear, reduction of neuropathic pain has been best achieved with medications such as the antiepileptics and the TCAs. Unfortunately, optimal use of these classes of medications is often limited by intolerable side effects, which can include cardiac dysrhythmias resulting from increased levels of catecholamines, antimuscarinic effects, orthostatic hypotension, rapid tolerance (TCAs), and central nervous system depression. Opioids, although proven efficacious for neuropathic pain at high doses, are also limited by an extensive side effect profile. Tramadol has become an important medication in the management of neuropathic pain. A Cochrane Library Review published in 20046 examined the efficacy of tramadol in neuropathic pain tested against placebo (three trials), clomipramine (a TCA) (one trial), and morphine (one trial). The review found that the number needed to treat with tramadol versus placebo was 3.5 in order to achieve at least 50% pain relief. Data were insufficient to draw conclusions about the effectiveness of tramadol compared with clomipramine or morphine. Based on this review, the authors concluded that tramadol is an effective treatment for neuropathic pain.6 The recommendations reflected not only an apparent efficacy but also a markedly reduced side effect profile compared with other treatments.

ADVERSE EFFECTS Much has been made about the side effect profile of tramadol compared with other methods of treatment. However, as with any drug, adverse side effects are noted with tramadol usage. In 1997, Cossman and associates7 produced an extensive summary of

drug safety data concerning the use of tramadol. Information from phases II to IV clinical studies, postmarketing surveillance studies (covering safety data from a total of more than 21,000 patients), and the spontaneous reporting system was taken into consideration. The most frequent adverse events were nausea (6.1%), dizziness (4.6%), drowsiness (2.4%), tiredness/fatigue (2.3%), sweating (1.9%), vomiting (1.7%), and dry mouth (1.6%). These incidences, however, varied according to administration route, with intravenous doses producing higher incidences of side effects. Adverse events published in the package insert for the sustainedrelease formulation, Ultram-ER, were from two 12-week, placebocontrolled studies in patients with moderate to moderately severe chronic pain. Events occurred more frequently than in the data published by Cossmann and associates,7 and were dose dependent. The most common were dizziness (15.9%–28.2%), nausea (15.1%–26.2%), constipation (12.2%–29.7%), and somnolence (8.2%–20.3%). This difference may be due to duration of therapy or to the more stringent conditions inherent with controlled studies. Respiratory depression, a common and potentially life-threatening side effect of other opioids, is very rarely observed with tramadol. The few cases of respiratory depression reported occurred after large intravenous doses or in patients with severe renal disease. The incidence of adverse effects is believed to be less common and those effects less severe when dosages are gradually increased. In 2000, Pavelka8 published a schedule for tramadol dosing that he found effective in decreasing side effects. Patients are given 50 mg/ day for the first 3 days and then increased every 3 days by 50 mg until 200 mg/day is reached. Doses of 50 to 100 mg every 4 to 6 hours as needed are allowed up to 400 mg/day. A schedule similar to this is also recommended by the manufacturer. Another potentially serious complication concerns the risk of seizures. Medications such as TCAs, monoamine oxidase inhibitors (MAOIs), selective serotonin uptake inhibitors (SSRIs), neuroleptics, and opioids, which can similarly alter levels of neurotransmitters, have been shown to increase the risk of seizure when taken with together with tramadol. A multicenter, prospective case series by Spiller and colleagues9 reviewed reports of tramadol exposure from regional poison control centers. The lowest dose associated with seizure was 500 mg, with a mean of 3.2 g. In a cohort of 9218 adult tramadol users, fewer than 1% had a presumed incident seizure. Risk was highest among those aged 25 to 54 years, those with more than four tramadol prescriptions, and those with history of alcohol abuse, stroke, or head injury. An evaluation of a general practice research database in Germany identified 21 cases of idiopathic seizures in 11383 subjects. Of those cases, 3 patients were exposed to tramadol, 10 to other opioids, 3 to both tramadol and other opioids, 1 to other analgesics, and 4 to no analgesics. The risk of idiopathic seizures in these patients was similarly elevated in each analgesic exposure category compared with nonusers, suggesting that the risk for patients taking tramadol was not increased compared with other analgesics. In general, tramadol should be avoided in patients with a history of seizures because increases in occurrence may follow. Caution and risk disclosure is advised when prescribing to those patients with a history of substance abuse, stroke, or head injury. The serotonin syndrome, characterized by clonus, hyperreflexia, hyperthermia, and agitation, is another rare but serious potential complication associated with the use of tramadol when combined with other agents that can increase central nervous system levels of serotonin such as SSRIs and MAOIs. In a review on serotonin syndrome, Gillman10 concluded that tramadol, which causes a weak serotonin reuptake inhibition, may infrequently precipitate dose-dependant serotonin toxicity (when administered in conjunction with any type of MAOI) but perhaps only in large doses or susceptible individuals. Treatment of this condition includes medication cessation, symptom management, and antiserotonergic drugs such as cyproheptadine or chlorpromazine.

VII PHARMACOLOGIC APPROACHES TO PAIN MANAGEMENT 511

Tramadol is an opioid and, thus, has the potential to be abused. This potential, however, is exceeding low, with estimations at 1 case per 100,000 patients. In those cases, 97% were found to occur in those patients with a prior history of substance abuse. Further evidence for the low abuse potential of tramadol is provided from a double-blind, placebo-controlled study in volunteers who were previous addicts. Patients were given morphine (15 and 30 mg) and tramadol in varied doses. Morphine produced typical subjective effects, opioid identification, and miosis. Tramadol 75 mg and 150 mg was no different from placebo. Tramadol at 300 mg was identified as an opioid but produced no other opioid-like effects. A mild abstinence syndrome similar to that seen with other opioids can occur with abrupt cessation, but the rate is reported as only 1 per month per 100,000 cases and can easily be treated by reinstitution of tramadol.

DRUG INTERACTIONS Tramadol is extensively metabolized by the CYP450 system and may interact with medications metabolized by that same system (e.g., fluoxetine, sertraline, paroxitene, ranitidine, cimetidine). Cimetidine, a typical CYP450 enzyme inducer, can increase both plasma concentration and elimination half-life, but the clinical significance of this is unclear. Carbamazepine, a CYP3A4 inducer, has been shown to increase the metabolism and decrease the elimination half-life of tramadol, thus potentially requiring dose adjustment with concomitant use. The use of any other medication with the potential to cause central nervous system depression with tramadol may also require dose adjustment.

DOSAGE AND ADMINISTRATION The current recommendations for dosing from the manufacturer are on a conservatively slow titration schedule. It is begun with 25 mg daily and increased every 3 days by 25 mg until 100 to 200 mg daily in divided doses is achieved. Then, tramadol may be administered 50 to 100 mg every 6 hours on an as-needed basis up to 400 mg per day. This dosing schedule requires 16 days while the schedule published by Pavelka8 requires 10 days. These dose titrations, although appropriate for chronic pain, may not be desirable for the treatment of acute pain. In the setting of acute pain, a more aggressive schedule may be needed. Oral tramadol is generally regarded to be approximately one fourth the potency of oral morphine. Potencies compared with other opioids are listed in Table 69–2. Despite being generally well tolerated, the gastrointestinal and nervous system side effects of tramdaol are troublesome enough for 19% to 30% of patients to discontinue therapy. Some authors advocate the use of the antiemetic metoclopramide during

Table 69^2. Relative Potency of Oral Tramadol Compared with Other Common Opioids Substance

Potency

Codeine Meperidine Morphine Oxycodone Hydromorphone Fentanyl (transdermal) Methadone

1:1 1:1 4–5:1 10:1 40:1 500–75:1 20:1

the initial portion of treatment to decrease the incidence of nausea and vomiting. It has been demonstrated in several studies that slower titration rates led to improved tolerance. The manufacturer’s recommended maximum daily dose, which is much debated, is 400 mg/day. In contrast, doses up to 800 mg/day have been safely and effectively used in the treatment of cancer pain. Outside of the United States, tramadol has been successfully and routinely administered via intravenous, intramuscular, and rectal routes. It has also been administered, to a lesser extent, for epidural anesthesia and as a component of peripheral regional anesthesia. For patients with renal disease and a creatinine clearance of less than 30 ml/min, a 12-hour dosing interval should be used to a maximum of 200 mg/day, as recommended by the manufacturer. Owing to the possibility of a prolonged elimination half-life for patients older than 75 years of age, the maximum recommended daily dose of tramadol in those patients is 300 mg. Although tramadol is uncommonly used in the pediatric population, its pharmacodynamics have been studied. After intravenous injection of tramadol 2 mg/kg in nine children aged 1 to 7 years (median 2.4), the mean plasma concentrations of tramadol and M1 were only slightly higher than those in adults, with no significant differences in pharmacokinetics noted from those in healthy adult volunteers. The safety and dosing of tramadol in nursing and pregnant mothers have not been fully established. The U.S. Food and Drug Administration (FDA) classifies tramadol as pregnancy risk factor C. Several studies, however, have been published using tramadol as a labor analgesic that show adequate analgesia with no significant neonatal respiratory depression.

CONCLUSION Tramadol is a unique analgesic that has been safely used for nearly 30 years in many parts of the world. The synergistic and complementary mechanisms of action involving opioid receptor antagonism and serotonin and norepinephrine modulation provide a therapeutic modality that can be useful in treating pain from a broad variety of conditions. It has been used effectively for pain relief in a multitude of disorders of both malignant and nonmalignant origin. The benefits include a much lower risk of physical dependence and abuse, lower incidences of respiratory depression, constipation, and sedation compared with traditional opioids and a nonscheduled status allowing for less-complicated prescribing practices. Despite its benefits for mild to moderate pain, tramadol may be underutilized. This is likely due to undesirable side effects secondary to aggressive titration schedules and fear of the severe but rare adverse reactions such as seizures and the serotonin syndrome. There is also, unlike other opioids, an analgesic ceiling effect owing to a dose-related toxicity. With both immediate-release and sustained-release formulations available, the therapeutic options for tramadol are more variable and may be suited to individual patient needs. Tramadol remains a safe and effective therapy for a multitude of pain types when used in appropriate patient populations.

REFERENCES 1. Mullins CR, Wild TL. Pain management in a long-term care facility: compliance with JCAHO standards. J Pain Palliat Care 2003;17:63–70. 2. Cepeda MS, Carmargo F, Zea C, Valencia L. Tramadol for osteoarthritis. Cochrane Database Syst Rev 2006;3:CD005522. 3. Mattia C, Coluzzi F. Tramadol: focus on musculoskeletal and neuropathic pain. Minerva Anestesiol 2005;71:565–584. 4. Gana TJ, Pascual ML, Fleming RR, et al. Extended-release tramadol in the treatment of osteoarthritis: a multi-center, randomized, doubleblind, placebo controlled clinical trial. Curr Med Res Opin 2006;22:1391–1401.

512 Chapter 69  TR AMADOL 5. Leppert W, Luczak J. The role of tramadol in cancer pain treatmenta review. Support Care Cancer 2005;13:5–17. 6. Duhmke RM, Cornblath DD, Hollingshead JRF. Tramadol for neuropathic pain. Cochrane Database Syst Rev 2004;2:CD003726. 7. Cossmann M, Kohnen C, Langford R, McCartney C. Tolerance and safety of tramadol use. Results of international studies and data from drug surveillance. Drugs 1997;53(suppl 2):50–62. 8. Pavelka K. Treatment of pain in osteoarthritis. Eur J Pain 2000;4(suppl A):23–30. 9. Spiller HA, Gorman SE, Villalobos D, et al. Prospective multi-center evaluation of tramadol exposure. J Toxicol Clin Toxicol 1997;35:361–364. 10. Gillman PK. Monoamine oxides inhibitors, opioid analgesics, and seratonin toxicity. Br J Anaesth 2005;95:434–441.

SUGGESTED READINGS Arcioni R, della Rocca M, Romano S, et al. Ondansetron inhibits the analgesic effects of tramadol: a possible 5-HT(3) spinal receptor involvement in acute pain in humans. Anesth Analg 2002;94:1553–1557. Bamigbade TA, Davidson C, Langford RM, et al. Actions of tramadol, its enantiomers and principal metabolite O-desmethyltramadol, on serotonin (5-HT) efflux and uptake in the rat dorsal raphe nucleus. Br J Anaesth 1997;79:352–356. Cicero JC, Adams EH, Geller A, et al. A post-marketing surveillance program to monitor Ultram (tramadol hydrochloride) abuse in the United States. Drug Alcohol Depend 1999;57:7–22. Desmeules JA, Piguet V, Collart L, et al. Contribution of monoaminergic modulation to the analgesic effect of tramadol. Br J Clin Pharmacol 1996;41:7–12. De Witte JL, Schoenmaekers B, Sessler DI, Deloof T. The analgesic efficacy of tramadol is impaired by concurrent administration of ondansetron. Anesth Analg 2001;92:1319–1321. Gardner JS, Blough D, Drinkard CR, et al. Tramadol and seizures: a surveillance study in a managed care population. Pharmacotherapy 2000;20:1423–1431.

Gasse C, Derby L, Vasilakis-Scaramozza C, et al. Incidence of first time idiopathic seizures in users of tramadol. Pharmacotherapy 2000;20:629–634. Ground S, Sablotzki A. Clinical pharmacology of rramadol. Clin Pharmacol 2004;43:879–923. Grond S, Radbruch L, Meuser T, et al. High-dose tramadol in comparison to low-dose morphine for cancer pain relief. J Pain Symptom Manage 1999;18:174–179. Hennies HH, Friderichs E, Schneider J. Receptor binding, analgesic and antitussive potency of tramadol and other selected opioids. Arzneimittelforschung 1988;38:877–880. Hernandez-Diaz S, Garcia-Rodriguez LA. Epidemiologic assessment of the safety of conventional nonsteroidal anti-inflammatory drugs. Am J Med 2000;110(suppl 3A):20S–27S. Lee CR, McTavish D, Sorkin EM. Tramadol: a preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in acute and chronic pain states. Drugs 1993;46:313–340. Lotsch J. Opioid metabolites. J Pain Symptom Manage 2005;29:S10–S24. Murthy BV, Pandya KS, Booker PD, et al. Pharmacokinetics of tramadol in children after i.v. or caudal epidural administration. Br J Anaesth 2000;84:346–349. Preston KL, Jasinski DR, Testa M. Abuse potential and pharmacological comparison of tramadol and morphine. Drug Alcohol Depend 1991;27:7–17. Raffa RB, Friderichs E, Reimann W, et al. Opioid and non-opioid components independently contribute to the mechanism of action of tramadol, an ‘‘atypical’’ opioid analgesic. J Pharmacol Exp Ther 1992;260:275–285. Raffa RB, Nayak RK, Liao S, et al. The mechanism(s) of action and pharmacokinetics of tramadol hydrochloride. Rev Contemp Pharmacother 1995;6:485–497. Roux PJ, Coetzee JF. Tramadol today. Curr Opin Anaesthesiol 2000;13:457–461. Wu WN, McKown LA, Liao S. Metabolism of the analgesic drug Ultram (tramadol hydrochloride) in humans: API-MS and MS/MS characterization of metabolites. Xenobiotica 2002;32:411–425.

VIII BEHAVIORAL MEDICINE APPROACHES TO PAIN MANAGEMENT

Chapter 70

PSYCHOLOGICAL ASPECTS PAIN

OF

Akiko Okifuji and Michelle Skinner

INTRODUCTION Pain is a common human experience. Most pain we experience is a relatively minor event and generally remits without any medical intervention or with over-the-counter analgesics. Yet, some forms of pain require much medical attention. Some pain is associated with specific pathology, such as cancer or tissue damages. Some pain is persistent, failing to remit over and beyond the expected healing period. Historically, the psychological factors were considered important only if the pain was ‘‘functional’’ or ‘‘psychogenic,’’ that is, the presence and extent of pain could not be explained by physical findings. However, over the past 3 decades, research has repeatedly and consistently demonstrated that pain is not a mere sensory experience but represents a complex biopsychosocial phenomenon. A range of cognitive, behavioral, and affective factors has been identified as essential aspects of understanding and treating pain patients, particularly those with chronic pain. In this chapter, we briefly review cognitive and behavioral concepts that are known to be significant contributors of chronic pain experience, provide an overview of a psychological assessment of chronic pain patients, and discuss psychological treatment approaches to chronic pain.

Pain behavior: Verbal or nonverbal actions understood by observers to indicate that a person may be experiencing pain and suffering, such as audible complaints, facial expressions, abnormal postures or gait, use of prosthetic devices, avoidance of activities, and verbal complaints of pain. Self-efficacy: A personal conviction that one can successfully execute a course of action (i.e., perform required behaviors) to produce a desired outcome in a given situation. Coping: Ways of thinking or acting directed at resolving or mitigating a problematic situation. Operant conditioning: A behavioral principle in which a likelihood of a specific behavior recurring increases (i.e., is reinforced) if the behavior is followed by a rewarding consequence or avoidance of negative consequence. The likelihood decreases as the behavior leads to a negative consequence.

EPIDEMIOLOGY A discussion of epidemiology for most of the psychosocial factors does not make much sense, because those factors are not pathology categories. We thus focus only on the prevalence of psychopathology in this section. Psychopathology, particularly depression and anxiety disorders, are quite common in chronic pain, estimated to range from 50% to 87%1,2 with a lifetime prevalence of 32%.3 A recent large-scale study yielded a 35% prevalence of anxiety disorders in chronic pain.4

CLINICAL FEATURES Affective Features

TAXONOMY (DEFINITIONS) Pain: An unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage. Chronic pain: A state of pain that, in general, extends for a long period of time and/or represents low levels of underlying pathology that explain the presence and extent of pain.

Pain is, by definition, an unpleasant experience, and thus, all chronic pain patients are bound to experience some affective distress. Many, as noted previously, do meet the diagnostic criteria for a specific mood/anxiety disorder. Others show significant reduction in emotional resources, leading to increased irritability as well as dysphoria. Many patients suffer from chronic fatigue and low energy. These features tend to lead to a further reduction in life activities and enjoyment. Fear of reinjury or pain exacerbation is 513

514 Chapter 70  PSYCHOLOGICAL ASPECTS OF PAIN also common; such fear often is a significant barrier for activating therapy.

Cognitive Features Patients’ attitudes, beliefs, and expectancies about various aspects of their plight, their own coping capacity, and the health care system influence the reports of pain, activity, disability, and response to treatment. Some patients consistently show maladaptive beliefs and expectations about pain that compromise their coping resources. Box 70–1 lists common types of maladaptive cognitions. Maladaptive beliefs are often not based upon facts, but rather are emotionally driven, leading to a sense of helplessness and low selfefficacy. As a consequence, many pain patients find that their ability to adaptively cope with chronic pain and disability is substantially compromised. Some patients may also exhibit a strong belief that their pain should be ‘‘cured.’’ This passive approach may be expressed as resistance to activating therapies and self-management skill training.

Behavioral Features One of the common behavioral deficits in chronic pain patients is deactivation. Pervasive limitations in daily chores, recreational and social activities, and work lead to an extremely sedentary lifestyle. Those patients spend most of their days staying home and resting, thereby severely restricting the opportunity to derive life enjoyment and compromising the quality of life (QOL). Another important behavioral issue is pain behaviors. Pain behaviors are often used to communicate patients’ pain and distress and may become a determining factor for the interpersonal dynamics in the family. An overly solicitous environment, for example, may actually keep the patient from engaging in tasks that could be therapeutic. Conversely, a punishing environment in which patients’ pain behaviors meet disapproval tends to make them feel alienated and emotionally distressed.

EVALUATION (HISTORY, PHYSICAL EXAMINATION, LABORATORY TESTING, AND IMAGING) Clinical Interview The interview is critical in understanding the historical and current psychosocial and behavioral factors relevant to the patient’s pain

Box 70^1 EXAMPLES OF NEGATIVE COGNITIVE PATTERNS Polarizing pattern: Black-and-white thinking. If a patient’s performance falls short of perfect, he or she sees himself or herself as a total failure, leading to a high expectation that is often unattainable. Overgeneralization pattern: A patient generalizes beyond the specific facts of a situation and sees a single negative experience as a neverending pattern of defeat. Catastrophizing pattern: A patient consistently assumes the worst possible outcomes. Her or his understanding of her or his own plight is extremely negative, and she or he tends to interpret relatively minor problems as major catastrophes. Filtering pattern: A patient focuses upon a single negative detail, rather than a whole picture, of the event and lets the single detail characterize the entire experience. Emotional reasoning pattern: A patient assumes that his or her negative emotions reflect the reality.‘‘I really feel it, therefore, this must be true.’’

and disability (Table 70–1). The interview can be divided into three parts.

Part I: History of Present Illness Many chronic pain patients are nervous in the unfamiliar, psychological interview process. Starting with pain assessment in the psychological evaluation may be helpful because it breaks the ice and gets them to feel comfortable. The pain assessment consists of a history of the pain problem and current pain parameters (intensity, quality, duration, aggravating and relieving factors, time course) as well as relevant medical and surgical history. The patient’s functional levels should be assessed in multiple domains including daily chores; social, recreational, and occupational activities; sleep; and sexual and interpersonal functioning to determine the extent of pain interfering with them. In the process, it is also good to get a sense of how the patient perceives her or his chronic pain and related disability, the underlying causes of pain, whether she or he believes adequate diagnostic work has been done, and the expectation of how her or his pain should be treated.

Part II: Psychosocial History In this section, the patient’s background and adjustment history are assessed to evaluate how the patient has historically coped with illness and stress and the current life resources that may

Table 70^1. Current Diagnosis: Psychosocial and Behavioral Factors Relevant to Chronic Pain Symptoms/Features

Affective Aspects Depression Dysphoria Chronic fatigue, low motivation, lethargy Anhedonia Irritability Cognitive decline (concentration, memory) Social withdrawal Decline in self-care Sleep disturbance (insomnia, hypersomnia) Suicidal ideation Appetite change (anorexia, overeating, binge eating) Anxiety Panic-like symptoms: overwhelming feelings of wanting to ‘‘get out,’’ hyperventilation, tachycardia, shakiness, dizziness, gastrointestinal disturbance, sweatiness Pervasive edginess Inability to rest and relax Avoidance of activities for fear of ‘‘reinjuring’’ or exacerbating pain Hypervigilance Cognitive Aspects Negative thought patterns (see Box 70–1) Low self-efficacy Passive attitude to pain management Behavioral Aspects Deactivated and sedentary lifestyle Excessive pain behaviors

VIII BEHAVIOR AL MEDICINE APPROACHES TO PAIN MANAGEMENT 515

influence rehabilitation. This includes a family and personal history of psychiatric illness, substance abuse (including inappropriate use of prescribed medications), and abuse and trauma. In addition, education, marital and occupational history, litigation, and disability issues are discussed.

Part III: Psychological Examination In this section, the patient’s current mental status, mood functions, and other maladaptive behavioral patterns are evaluated. As noted earlier, mood disorders are prevalent in chronic pain patients, and it is often the case that a psychiatric illness presents a potential confound in the interdisciplinary pain care. It is critical that the psychological evaluation provides a clear picture of how these factors contribute to the current dysfunction of the person and guide the treatment plan as to how the process of rehabilitation will incorporate the relevant psychological issues.

Testing A wide range of self-report inventories is available to complement the clinical assessment. They include questionnaires to assess pain and related dysfunction (e.g., McGill Pain Questionnaires,5 Multidimensional Pain Inventories6), mood (Center for the Epidemiological Depression Scale7), pain-related disability (Oswestry Disability Index8), and health-related QOL (Short Form 36-item Medical Outcomes Study questionnaire [SF-36]9). Most have demonstrated adequate psychometric properties and can be useful in evaluating the patient and monitoring the treatment progress. However, it should be noted that the reliability of measures are estimated in a large number of people, and the measurement errors are expected to be much greater when the inventory is used on an individual basis. Given this, it is best to use the instruments at multiple time points, rather than just pre- and posttreatment, to monitor the slope of change as an indicator of treatment progress.

MANAGEMENT Cognitive-Behavioral Approach Cognitive-behavioral therapy (CBT) is widely used to treat chronic pain patients as a part of comprehensive pain care. The rationale behind the approach is that (1) patients’ own appraisal of internal (e.g., physiologic events) and external events significantly contributes to the sense of well-being and (2) acquisition of adequate behavioral skills facilitates adaptive coping.

Patient Education Patient education is essential in the cognitive-behavioral approach to pain management. Well-educated and ‘‘pain-literal’’ patients are likely to become efficient in self-management for their pain. The education program should be developed to increase the patient’s understanding of how the psychological and behavioral factors interact with the neurophysiology of pain, stress, mood, and sleep. In addition, knowledge related to the behavioral principles, such as conditioning, reinforcement, pain/illness behaviors, and how those principles interact with pain and disability, can also help patients prepare for the behavioral skill–training phase.

Behavioral Skill^Training Relaxation and controlled breathing exercises are especially useful for chronic pain patients because (1) most patients can readily learn these skills, (2) these skills are helpful in managing stress, one of the

most potent exacerbating factors for pain, and (3) the application of the specific, tangible technique often leads to a greater sense of selfefficacy in pain management. A variety of relaxation techniques is available, and the therapist and patient should review some techniques to determine what might work best for the particular individual. No matter which technique they decided to pursue, the main focus should be for the patient to behaviorally manipulate the arousal, thereby altering his or her physiological states. It is important that the patient learn to actively engage in relaxation, rather than passively listening to music or watching images. In other words, relaxation training should enable the person to actively monitor and alter the physiologic state. The most commonly used physiologic avenue for relaxation includes controlling muscle tension, body temperature, heart rate, and sense of heaviness. Another common behavioral approach is attentional training. Attention plays a major role in pain perception. Some pain patients may also be attuned to any bodily sensation, leading to the amplification of pain experience. Because our attentional resource is limited, increasing one’s attention to nonpainful stimuli should help reduce excessive attention to pain. Attentional control may be attained via helping the patient actively engage in pain-noncompatible activities. These may be overt behaviors (e.g., breathing exercise, hobby) or covert activities such as mental imagery. Guided imagery is not necessarily helpful to all patients; whether imagery can successfully alter the attentional process depends upon the patient’s imaginative ability, sensory involvement, and absorption in using imageries. Stressful imageries can be used as a part of a covert behavioral rehearsal strategy. Such guided imagery requires the therapist and patient to create a hierarchy of stress/pain-related situations that are realistic enough to provoke actual anxiety responses. Then, the therapist will assist the patient in pairing each of the situations with a relaxation exercise, starting from the least difficult one. The premise of this exercise is to psychophysiologically desensitize the patient to the known stressful situations and to help her or him attain a greater managing ability over her or his anxiety responses. As a variation, the same imageries can be used to explore various problem-solving behaviors and help the patient to mentally rehearse the execution of the adaptive coping. Behavioral strategy can be used to address functional disability of the patient. Behavioral activation has been found to be helpful in patients who exhibit symptoms of depression such as inertia, social withdrawal, and reduced activity.10 The premise for behavioral activation strategies is a learning model and suggests that people are actively trying to cope with overwhelming life circumstances, and by coping ineffectively (e.g., activity reduction, social withdrawal), people effectively reduce the opportunity for rewards in the environment. The same premise can be applied to chronic pain patients whose lives are often characterized by depressive symptomatology such as avoidance patterns of reduced social, recreational, and employment activities. Thus, a functional analysis of behavioral patterns, activity monitoring, and planned activation is often employed for patients who have come to live sedentary lifestyles. The therapist may work in conjunction with the physical therapist to employ a graded exercise program that includes a psychological component of charting mood and thoughts during exercise. Planning goals for recreational and enjoyment activities may also provide an opportunity for increased rewards in the patient’s environment. A variety of other behavioral skill training can be added to meet patients’ clinical needs. For example, interpersonal stress is a major contributor for pain flares and stress for some patients. Behavioral techniques such as communication skill and problem-solving training can be beneficial for these patients. In communication skill training, patients learn their own communication style and how it leads to certain consequences. Some patients are not accustomed to express themselves effectively, often driven by overly emotional expression or inhibited by fear of interpersonal rejection.

516 Chapter 70  PSYCHOLOGICAL ASPECTS OF PAIN The therapist provides a safe context in which patients can practice adequate communication patterns. Similarly, in problem-solving training, the therapist helps patients recognize optional responses, other than what they think is the ‘‘natural response’’ to stressors. The therapist guides the patient to define the problem and goal as well as to delineate reasonable and executable options. A range of options can be stratified by their desirability and feasibility; the patient can start executing the plan from the most desirable and feasible. The results are reviewed, and success should be reinforced. It should be noted that there is no one way to provide behavioral skills sets to patients. It is important to remember that behavioral skill training is not limited to a mere application of specific behavioral techniques. A wide variety of techniques are available for chronic pain patients (Table 70–2). The key aspect of the behavioral therapy plan is to apply the behavioral concept to the idiosyncratic problems of a specific patient. The therapist must work in conjunction with the patient to identify skill sets that work the best for him or her.

Cognitive Skill Training One of the critical basics for using cognitive training for chronic pain is to understand that one’s cognition modulates physiologic and emotional responses, both of which serve as impetuses for behaviors. This relationship is reciprocal in that the physiologic and emotional states can alter the cognitive process as well. As can be seen in Section VIII, Chapter 72, Cognitive Therapy for Chronic Pain, by Dr. Wootton, the cognitive therapy is an integrated part of the psychological approach to pain.

Cognitive Restructuring Typical cognitive training for pain management begins with helping patients understand their own cognitive response system. Patients can learn to identify and monitor their thoughts triggered by painful or stressful situations and to understand how the thoughts lead to subsequent emotions, behaviors, and physiologic responses. Particular attention should be paid to negative thought patterns

Table 70^2. Current Therapy TherapyTarget

Approach

Depression

Cognitive restructuring Behavioral activation Breathing exercise Relaxation exercise Imagery-guided behavioral rehearsal/ desensitization Attentional control training Education Cognitive restructuring Graded behavioral activation Problem-solving training Communication skill training Attentional control training Education Behavioral activation Motivation enhancement therapy Family education on operant learning Motivation enhancement therapy

Anxiety

Maladaptive Thoughts Self-efficacy

Deactivation

Pain behaviors Lack of compliance

that are known to adversely affect the rehabilitation effort.11 Some of the common negative cognitions are listed in Box 70–1. In cognitive training and restructuring, the therapist helps the patient become aware of her or his tendency to think negatively about situations. The therapist then collaborates with the patient to explore adaptive alternatives. This often entails examining the patient’s belief about pain and stress and directly challenging longstanding maladaptive beliefs.

Coping Effective self-management of pain depends upon the individual’s specific ways of dealing with pain, adapting to chronic pain and disability, and minimizing pain-related distress through the use of coping strategies. Coping strategies can be passive (e.g., withdrawing from activities, depending upon others for help) or active (employing a strategy to help oneself by engaging in activity and maintaining a positive frame of mind). Active coping tends to be associated with adaptive functioning, and passive coping tends to lead to greater pain-related disability and health care utilization in chronic pain,12 although no one particular strategy seems to work on all people.13 The extent to which a patient is able to identify and employ effective strategies depends largely on various personal (e.g., self-efficacy beliefs), situational (e.g., work, living arrangements), and psychosocial factors (e.g., family history of pain, level of support). Interaction between coping strategies and personal and situational factors may be a critical factor in how coping strategies are implemented. Clinicians need to understand how patients interpret their world through the use of their cognitive systems (e.g., self-talk, self-efficacy beliefs, instrumentality). In coping skill training, self-efficacy beliefs are particularly important in treatment. Pain patients’ self-efficacy beliefs are largely influenced by their own past success/failure at performing tasks to manage their pain. In the course of treatment, the patient must be engaged in activities that provide experiences of success and mastery through the patient’s effective performance. This task can be accomplished by appropriately giving small and relatively easy behavioral tasks to complete that gradually increase in difficulty. Early success in treatment and provision of tasks that increases patients’ self-efficacy for pain management can increase treatment adherence. Further, early success can help the patient to gradually be able to cope when the demands of the situation no longer exceed the patient’s beliefs about his or her ability to effectively manage.

FAMILY PERSPECTIVES Chronic pain certainly affects the QOL of those who are afflicted with persistent pain and disability. It is also common that chronic pain adversely affects their family. Pain and distress are behaviorally expressed. It is hard for the family to see their loved ones suffer despite medications and therapies. Often not intentionally, however, patients’ communication of pain and pain behaviors is subjected to reinforcement by the behaviors of the family members in response. According to the operant principle, any behaviors that are immediately followed by rewarding behaviors from others are likely to recur (i.e., positive reinforcement). Similarly, behaviors that lead to avoidance of unpleasant events (i.e., negative reinforcement) also reinforce such behaviors. Pain behaviors are no exception to this rule. Therapeutic efforts can be extended to address how the interaction between the patient and her or his significant other (SO) affects chronic pain. Although often well intended, the SO may reinforce pain behaviors by responding solicitously. Solicitous responses are associated with perceived support; however, they may not help patients to become active in life. Thus, it is important for the patient and SO to understand that solicitous support may present a double-edged sword that may increase functional disability.

VIII BEHAVIOR AL MEDICINE APPROACHES TO PAIN MANAGEMENT 517

Helping the SO to engage in enabling behaviors requires the clinician to address the SO’s beliefs about chronic pain, and the application of the CBT approaches described previously can be helpful. It is also helpful to include the SO in setting treatment goals and encouraging the SO to participate in behavioral rehearsal of coping skills. The activation plan may work more effectively if activities that they can engage in together are included. In addition, the sessions for both the patient and the SO can address effective communication by helping them increase straightforward language and requests for support rather than relying on behaviors as cues and assuming what the patient is trying to communicate. The inclusion of the SO in these particular aspects of treatment has been shown to increase patient levels of self-efficacy for pain management and perceived ability to control pain and to decrease pain-catastrophizing thinking.14 Further, these benefits appear to be maintained for up to a year after treatment.

MOTIVATIONAL INTERVENTION Motivation is an essential aspect of self-management therapies, because adherence to a daily activating regimen is required for successful rehabilitation for chronic pain. Historically, noncompliant patients are considered as failing to respond to treatment. However, as we are faced with greater needs to manage chronic illnesses, the issue of how motivation can be addressed through the therapeutic process has become of great importance. Motivation enhancement therapy (MET) is a problem-focused, therapist-directed approach aiming to help patients enhance their readiness to commit and engage in activating self-management. The basic aims of MET are to help patients (1) identify the discrepancy between what they want (goals) and where they are (current status), (2) delineate how the discrepancy can be reduced, (3) understand the cost-benefit ratio of engaging (and not engaging) in adaptive and maladaptive behaviors, and (4) internalize motivational thoughts via improved self-efficacy. In order to achieve MET goals, clinicians engage in empathetic listening, reflecting patients’ negative emotion in a nonjudgmental manner. Rather than telling patients what to do or what not to do, clinicians need to ‘‘roll with resistance.’’ One of the easy pitfalls we all fall into is to press on with what we consider as adaptive coping and activation while patients resist and present why they should not engage in those activities. Efforts should be made to form a therapeutic alliance by staying on the same side of the argument, which is critical to increase patients’ motivation to change. As a part of the MET process, the clinician helps patients to identify specific discrepancies between their treatment goals (e.g., ‘‘I want to play golf’’) and what they actually do (e.g., ‘‘I don’t exercise because I am afraid it may flare my pain’’). By focusing on the discrepancy, patients gain insight that their maladaptive behaviors and attitudes are actually preventing them from obtaining their goals. Similarly, patients benefit greatly from engaging in ‘‘decisional balance analysis’’ of their own behaviors. For example, patients list a ‘‘benefit’’ for regular exercise as well as for not exercising and a ‘‘cost’’ for exercising as well as for not exercising. These can be incorporated into the discussion of the discrepancy between the patient’s goals and actions. The decisional balance analysis helps patients gain a better awareness of their own role in maintaining maladaptive behaviors as well as identifying strategies to engage in more adaptive behaviors. Another essential feature of MET is to provide a supportive environment to nurture a sense of self-efficacy and, ultimately, a patient’s ability to change her or his behaviors. By understanding that change is a process that the patient has control over, she or he realizes that change is possible. With increased self-efficacy beliefs come a sense of responsibility and an awareness that it is the patients themselves who will choose to engage in therapeutic efforts and execute them. MET is a clinician-directed approach

that is heavily patient-centered. Detailed descriptions of the specific MET approach are beyond the scope of this paper. Interested readers may find the comprehensive book by Miller and Rollnick15 helpful.

COMPLICATIONS/OUTCOMES A large volume of studies has been published reporting on the efficacy of CBT for chronic pain. Typically, CBT is incorporated into a multidisciplinary pain care program. Outcomes on measures of pain reduction, improved mood, medication adjustment, health care utilization, increased activity, and return to work—multidisciplinary programs that include CBT—have been shown to be highly effective, yet there is very little, if any, concern for iatrogenic complications.16 Moreover, when the results have been evaluated to determine the cost-effectiveness, multidisciplinary programs that incorporate CBT can save a significant amount of money in medical expenditures and indemnity costs.17

CONCLUSIONS In this chapter, we reviewed the psychological approaches to the assessment and treatment of chronic pain. Research in the past 3 decades has delineated a range of psychosocial and behavioral factors relevant to chronic pain and related disability. The application of CBT and MET that targets to those relevant psychological factors has been consistently shown to help patients better manage pain, mood, and function, particularly as an integrated part of a comprehensive pain rehabilitation program. Although we focused in this chapter on the role of psychological factors in chronic pain, we believe that these same factors may play a role in acute pain states as well. We believe that medical, psychosocial, and behavioral factors are all important in the experience of pain per se. The relative weight of these factors may vary, however, with medical factors making a larger contribution in acute pain states than in chronic pain states and psychological factors making a more significant contribution in chronic pain than in acute pain. In each of these instances, however, attention should be given to the range of factors that contribute to the total experience of pain.

REFERENCES 1. Katon W. The epidemiology of depression in medical care. Int J Psychiatry Med 1987;17:93–112. 2. Romano JM, Turner JA. Chronic pain and depression: does the evidence support a relationship? Psychol Bull 1985;97:18–34. 3. Atkinson JH, Slater MA, Patterson TL, et al. Prevalence, onset, and risk of psychiatric disorders in men with chronic low back pain: a controlled study. Pain 1991;45:111–121. 4. McWilliams LA, Cox BJ, Enns MW. Mood and anxiety disorders associated with chronic pain: an examination in a nationally representative sample. Pain 2003;106:127–133. 5. Melzack R. The McGill Pain Questionnaire: major properties and scoring methods. Pain 1975;1:277–299. 6. Kerns RD, Turk DC, Rudy TE. The West Haven-Yale Multidimensional Pain Inventory (WHYMPI). Pain 1985;23:345–356. 7. Radloff L. A self-report depression scale for research in the general population. Appl Psychol Meas 1977;1:385–392. 8. Fairbank JC, Couper J, Davies JB, O’Brien JP. The Oswestry low back pain disability questionnaire. Physiotherapy 1980;66:271–273. 9. Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care 1992;30:473–483. 10. Jacobon N, Martell C, Dimidjian S. Behavioral activation for depressions: returning to contextual roots. Clin Psychol Res Pract 2001;8:255–271. 11. Cook AJ, Degood DE. The cognitive risk profile for pain: development of a self-report inventory for identifying beliefs and

518 Chapter 71  HYPNOTIC ANALGESIA attitudes that interfere with pain management. Clin J Pain 2006;22:332–345. 12. Blyth FM, March LM, Nicholas MK, Cousins MJ. Self-management of chronic pain: a population-based study. Pain 2005;113:285–292. 13. Fernandez E, Turk DC. The utility of cognitive coping strategies for altering pain perception: a meta-analysis. Pain 1989;38:123–135. 14. Flor H, Fydrich T, Turk DC. Efficacy of multidisciplinary pain treatment centers: a meta-analytic review. Pain 1992;49:221–230.

Chapter 71

HYPNOTIC ANALGESIA Lisa J. Norelli

INTRODUCTION For thousands of years, the significance of the mind-body connection in health and disease has been recognized by many healing systems. Hippocrates acknowledged the importance of emotional and spiritual attitude on health, and central to his medical practice was the notion that the body has the power to heal itself.1 In more contemporary times, the predominance (and, some would argue, overreliance upon) technological approaches has skewed modern medical practice toward less humanistic treatment methods at the expense of a holistic approach to health and wellness. With the recent rediscovery of the importance of the mind-body connection, alternative and complementary treatments are the subject of increasing study and integration into medical practice. Hypnosis, one example of the mind-body healing approach, has been used successfully in the treatment of many medical conditions and particularly in the management of acute and chronic pain.2 Hypnotic analgesia during and after medical procedures has been shown to result in significant cost savings, decreased pain severity, and a reduction in the required dose and duration of pain medications.3 Despite demonstrated effectiveness in a wide variety of clinical pain scenarios and at virtually no risk to the patient, hypnosis has been used infrequently compared with other behavioral interventions.4 For over a hundred years, hypnosis practice and training has been endorsed by the medical establishment, yet it is not uniformly available in clinical settings. In the United States, this is partly a reflection of the inconsistent availability of hypnosis training opportunities in psychology and medical education programs.5,6 In the late 18th century, Franz Anton Mesmer proposed the idea that universal fluid energy mediated hypnotic phenomena. Mesmer’s theory was scientifically discredited, and it was not until nearly a century later that the concept of medical hypnosis was officially accepted.7,8 The practice of medical hypnosis reemerged in the 1840s, revitalized by the scientific and clinical observations of Scottish physician James Braid.9 In 1892, a committee commissioned by the British Medical Association (BMA) investigated the science and practice of hypnosis and found it effective for, among other things, relieving pain.10 The BMA reiterated its approval of medical hypnosis in 1955.11 The American Medical

15. Miller W, Rollnick S. Motivational Interviewing: Preparing People for Change. New York: Guilford, 1991. 16. Flor H, Turk DC, Rudy TE. Relationship of pain impact and significant other reinforcement of pain behaviors: the mediating role of gender, marital status and marital satisfaction. Pain 1989; 38:45–50. 17. Okifuji A. Interdisciplinary pain management with pain patients: evidence for its effectiveness. Semin Pain Med 2003;1:110–119.

Association agreed with the BMA in a report published in 1958 by the Council on Mental Health,12 which stated that there are ‘‘definite and proper uses of hypnosis in medical and dental practice’’ and recommended the establishment of training facilities in the United States. In 1961, the American Psychiatric Association issued a position statement confirming that hypnosis has definite clinical applications across different medical fields.13 Two years later, the American Psychological Association endorsed hypnotherapy as a branch of psychology. In 1996, a National Institutes of Health panel14 issued a statement indicating that there was strong evidence for the use of hypnosis in alleviating chronic pain associated with cancer and other chronic pain conditions. Despite growing evidence, the routine inclusion of hypnosis in the medical armamentarium against pain has been sporadic.

DEFINITIONS Broadly defined, hypnosis is an induced state of passive, selective attention often attained through the use of relaxation and imagery techniques. During the induction phase of a session, patients are guided into a state of mental (and often physical) ease, along with sustained focus on an object or mental image of attention. Through the induction process of relaxation and selective focus, the patient becomes absorbed in her or his inner experiences and, with practice, develops a state of passive attention and reduced range of attention to the environment. This state of mind contributes to a decreased monitoring of the environment and the blocking out of some perceptual experiences. If the induction process is successful, the patient accepts suggestions without censorship and, thus, is more receptive to verbal and nonverbal communications (suggestions) without reflection. For pain, the hypnotic suggestions would be tailored to alter the person’s perception of or behavioral response to the painful sensations. For example, one could suggest a lack of sensation or that the painful sensation will be experienced as only warmth or coolness.15 Participation in a series of hypnosis sessions can reinforce the suggestions and teach methods for sustaining the analgesic effects. If possible, patients are taught to master the techniques and use self-hypnosis for pain control independent of formal sessions. With regular practice, many patients become adept at selfhypnosis. Repetition and self-hypnosis have been shown to enhance analgesic effects and impart a greater sense of self-agency and mastery over pain management.16

MECHANISM OF ACTION Pain is a complex phenomenon incorporating sensory and affective dimensions. The sensory features of pain (e.g., intensity, temporal pattern, quality) and the affective features (e.g., attention, expectation, emotional response) are interrelated via spinal pathways and

518 Chapter 71  HYPNOTIC ANALGESIA attitudes that interfere with pain management. Clin J Pain 2006;22:332–345. 12. Blyth FM, March LM, Nicholas MK, Cousins MJ. Self-management of chronic pain: a population-based study. Pain 2005;113:285–292. 13. Fernandez E, Turk DC. The utility of cognitive coping strategies for altering pain perception: a meta-analysis. Pain 1989;38:123–135. 14. Flor H, Fydrich T, Turk DC. Efficacy of multidisciplinary pain treatment centers: a meta-analytic review. Pain 1992;49:221–230.

Chapter 71

HYPNOTIC ANALGESIA Lisa J. Norelli

INTRODUCTION For thousands of years, the significance of the mind-body connection in health and disease has been recognized by many healing systems. Hippocrates acknowledged the importance of emotional and spiritual attitude on health, and central to his medical practice was the notion that the body has the power to heal itself.1 In more contemporary times, the predominance (and, some would argue, overreliance upon) technological approaches has skewed modern medical practice toward less humanistic treatment methods at the expense of a holistic approach to health and wellness. With the recent rediscovery of the importance of the mind-body connection, alternative and complementary treatments are the subject of increasing study and integration into medical practice. Hypnosis, one example of the mind-body healing approach, has been used successfully in the treatment of many medical conditions and particularly in the management of acute and chronic pain.2 Hypnotic analgesia during and after medical procedures has been shown to result in significant cost savings, decreased pain severity, and a reduction in the required dose and duration of pain medications.3 Despite demonstrated effectiveness in a wide variety of clinical pain scenarios and at virtually no risk to the patient, hypnosis has been used infrequently compared with other behavioral interventions.4 For over a hundred years, hypnosis practice and training has been endorsed by the medical establishment, yet it is not uniformly available in clinical settings. In the United States, this is partly a reflection of the inconsistent availability of hypnosis training opportunities in psychology and medical education programs.5,6 In the late 18th century, Franz Anton Mesmer proposed the idea that universal fluid energy mediated hypnotic phenomena. Mesmer’s theory was scientifically discredited, and it was not until nearly a century later that the concept of medical hypnosis was officially accepted.7,8 The practice of medical hypnosis reemerged in the 1840s, revitalized by the scientific and clinical observations of Scottish physician James Braid.9 In 1892, a committee commissioned by the British Medical Association (BMA) investigated the science and practice of hypnosis and found it effective for, among other things, relieving pain.10 The BMA reiterated its approval of medical hypnosis in 1955.11 The American Medical

15. Miller W, Rollnick S. Motivational Interviewing: Preparing People for Change. New York: Guilford, 1991. 16. Flor H, Turk DC, Rudy TE. Relationship of pain impact and significant other reinforcement of pain behaviors: the mediating role of gender, marital status and marital satisfaction. Pain 1989; 38:45–50. 17. Okifuji A. Interdisciplinary pain management with pain patients: evidence for its effectiveness. Semin Pain Med 2003;1:110–119.

Association agreed with the BMA in a report published in 1958 by the Council on Mental Health,12 which stated that there are ‘‘definite and proper uses of hypnosis in medical and dental practice’’ and recommended the establishment of training facilities in the United States. In 1961, the American Psychiatric Association issued a position statement confirming that hypnosis has definite clinical applications across different medical fields.13 Two years later, the American Psychological Association endorsed hypnotherapy as a branch of psychology. In 1996, a National Institutes of Health panel14 issued a statement indicating that there was strong evidence for the use of hypnosis in alleviating chronic pain associated with cancer and other chronic pain conditions. Despite growing evidence, the routine inclusion of hypnosis in the medical armamentarium against pain has been sporadic.

DEFINITIONS Broadly defined, hypnosis is an induced state of passive, selective attention often attained through the use of relaxation and imagery techniques. During the induction phase of a session, patients are guided into a state of mental (and often physical) ease, along with sustained focus on an object or mental image of attention. Through the induction process of relaxation and selective focus, the patient becomes absorbed in her or his inner experiences and, with practice, develops a state of passive attention and reduced range of attention to the environment. This state of mind contributes to a decreased monitoring of the environment and the blocking out of some perceptual experiences. If the induction process is successful, the patient accepts suggestions without censorship and, thus, is more receptive to verbal and nonverbal communications (suggestions) without reflection. For pain, the hypnotic suggestions would be tailored to alter the person’s perception of or behavioral response to the painful sensations. For example, one could suggest a lack of sensation or that the painful sensation will be experienced as only warmth or coolness.15 Participation in a series of hypnosis sessions can reinforce the suggestions and teach methods for sustaining the analgesic effects. If possible, patients are taught to master the techniques and use self-hypnosis for pain control independent of formal sessions. With regular practice, many patients become adept at selfhypnosis. Repetition and self-hypnosis have been shown to enhance analgesic effects and impart a greater sense of self-agency and mastery over pain management.16

MECHANISM OF ACTION Pain is a complex phenomenon incorporating sensory and affective dimensions. The sensory features of pain (e.g., intensity, temporal pattern, quality) and the affective features (e.g., attention, expectation, emotional response) are interrelated via spinal pathways and

VIII BEHAVIOR AL MEDICINE APPROACHES TO PAIN MANAGEMENT 519

central brain regions. Painful stimuli ascend spinal pathways to the ventral thalamus, somatosensory cortex (SSC) and the corticolimbic system (anterior cingulate cortex [ACC], insula). These systems are involved in emotional response and cognitive mediation of pain. Other spinal pathways project to the amygdala, hypothalamus, reticular formation, medial thalamus, and limbic structures. These are involved in arousal, autonomic regulation, and affective response to pain. Hypnotic analgesia is associated with changes in the neural activity in many of these known pain pathways, including higher-order central mechanisms that modulate pain through cognitive factors such as anticipation and attention.17,18 First, it has been demonstrated that hypnosis promotes relaxation, known to decrease anxiety and increase the pain threshold. Second, it alters the perception of pain, decreasing unpleasantness. Third, it distracts from pain by reducing the attention paid to the painful sensation and focusing attention elsewhere.16,19,20 The accumulating data from physiologic, imaging, and psychological research has illuminated a more comprehensive neuropsychophysiologic picture of hypnotic analgesia. An integrative model asserts that hypnosis is a state of sustained attention that activates the cortical and subcortical brain dynamics.21 In hypnotic analgesia, research has shown that the process requires sustained effort and activates specific attentional and inhibitory feedback circuits that modulate thalamic and cortical areas involved in pain.22,23 Kiernan and coworkers24 have provided research evidence in support of at least three underlying mechanisms responsible for hypnotic analgesia: spinal cord nociceptive reflex attenuation, reduction in awareness (perceived intensity) of pain, and the selective reduction in the affective component (unpleasantness) of pain sensation. Research employing functional testing has helped to localize the effects of hypnotic analgesia in specific brain regions. Electroencephalographic studies have demonstrated enhanced anterior temporal theta activity during hypnotic analgesia.21–23 In addition, functional magnetic resonance imaging and positron-emission tomography studies have demonstrated that modulation of different pain attributes s associated with specific changes in cortical activity associated with hypnosis. In these studies, modulation of pain unpleasantness was associated with changes in the ACC, whereas changes in pain intensity were associated with primary SSC activity.25–28

CLINICAL APPLICATIONS Hypnosis has been used successfully as a primary and an adjunctive treatment modality for both acute and chronic pain in children and adults.29–31 One meta-analysis of 18 studies confirmed a moderate to large hypnoanalgesic effect size.32 Given its demonstrated effectiveness, it can be argued that hypnotic analgesia should be routinely available for an integrated biopsychological approach to clinical pain. When compared with other psychological interventions, hypnosis has been found to be equally or more effective.33,34 The main factor that influences the effectiveness of hypnotic analgesia is hypnotizability or hypnotic susceptibility. Despite this observation, some clinical studies suggest that even low-hypnotizable patients can achieve some pain relief with hypnosis. These findings include increased pain threshold with repeated suggestions of analgesia and increased pain threshold and pain tolerance with ongoing skills training.16 Several instruments have been developed to assess a patient’s hypnotizability, although in practice, many clinical hypnotists rely instead on individual assessment of responsiveness in the context of the treatment interaction.35–37 Hypnotic analgesia has demonstrated efficacy in ameliorating acute pain, for example, during dental procedures,38 biopsies, other invasive medical procedures,39–41 and labor and delivery.42,43 A prospective, randomized study of women undergoing large-core breast biopsy showed those patients using self-hypnosis techniques

had decreased procedural pain and less anxiety compared with women who received treatment as usual or an empathetic intervention.40 In another study, patients undergoing invasive renal and vascular procedures who employed self-hypnosis not only had less pain and anxiety but also were more hemodynamically stable than patients who received standard treatment or more directed attention.41 Hypnosis has also shown benefit in the treatment and management of chronic pain, for example, pain arising from malignancy or burn wounds.44–46 When offered, hypnosis is usually provided along with cognitive-behavioral or psychotherapeutic techniques to holistically address other issues associated with pain such as depression, secondary gain, and social and functional withdrawal.16

COMPLICATIONS Hypnosis is a safe and well-tolerated intervention that can be used in a wide variety of clinical pain situations in both children and adults. Uncommonly, there are negative effects. MacHovec47 defines hypnosis complications as ‘‘unexpected, unwanted thoughts, feelings or behaviors during or after hypnosis which are inconsistent with the goals of treatment and interfere with the hypnotic process by impairing optimal mental function.’’ Untoward reactions are typically mild and transient such as nausea, dizziness, and headaches; rarely, there have been reports of panic or difficulties awakening from hypnosis.48,49 Negative effects have been attributed to failure of technique, failure of the hypnotist to adequately prepare the patient, and undetected preexisting severe psychopathology or personality factors. These potential problems can be minimized by careful patient screening, appropriate hypnotist training, and careful attention to the treatment environment. It is recommended that the hypnotist monitor the patient’s reactions during and after the treatment to detect and obviate negative reactions.50,51

CONCLUSIONS Hypnotic analgesia is an effective, safe, noninvasive intervention for the reduction of the sensory and affective components of acute and chronic pain. The intervention has been used successfully in both children and adults. It should have a wider, complementary role in the treatment and management of acute and chronic pain within medical settings. It may be a preferred treatment modality in patients for whom pain medications are poorly tolerated or pose a high risk of side effects. Those patients at higher risk of untoward side effects, such as children and elderly, are particularly likely to benefit from nonpharmacologic approaches to pain. Patients with pain should have access to an integrative medical and psychological approach. This strategy would not only include analgesic medication but also incorporate psychological interventions such as hypnosis, cognitive-behavioral techniques, psychotherapy, and relaxation. Hypnosis training programs should be offered routinely during the education of physicians, psychologists, and other health professionals to foster more widespread availability of expertise in this modality across clinical treatment settings.

Key Points n Clinicians should approach the patient with clinical pain holi-

stically, integrating both medical and psychological ‘‘mindbody’’ interventions. n Hypnotic analgesia is a safe, well-tolerated intervention for a wide array of acute and chronic pain situations. n This modality can be effective for a range of patients, from children to adults, including those who are less receptive to hypnosis.

520 Chapter 71  HYPNOTIC ANALGESIA n Hypnosis has been shown to reduce the severity of anxiety and

suffering associated with pain, increase pain tolerance, and reduce the use of pain medication. n Hypnotic analgesia modulates pain via central and peripheral pain pathways and decreases the intensity and unpleasantness of pain.

REFERENCES 1. Garrison FH. History of Medicine. Philadelphia: WB Saunders, 1966. 2. Chaves JF, Dworkin SF. Hypnotic control of pain: historical perspectives and future prospects. Int J Clin Exp Hypn 1997;45:356–373. 3. Lang EV, Benotsch EG, Fick LJ, et al. Adjunctive nonpharmacological analgesia for invasive medical procedures: a randomized trial. Lancet 2000;355:1486–1490. 4. Malone MD, Strube MJ. Meta-analysis of non-medical treatment for chronic pain. Pain 1988;34:231–234. 5. Walling DP, Baker JM. Hypnosis training in psychology intern programs. Am J Clin Hypn 1996;38:219–223. 6. Walling DP, Baker JM, Dott SG. A national survey of hypnosis training—its status in psychiatric residency programs: a brief communication. Int J Clin Exp Hypn 1996;44:184–188. 7. Salas C, Salas D. The first scientific investigation of the paranormal ever conducted: testing the claims of Mesmerism. Skeptic 1996;4:66–83. 8. Price DD, Rainville P. The neurophenomenology of hypnosis and hypnotic analgesia. In Price DD, Bushnell MC (eds): Psychological Methods of Pain Control: Basic Science and Clinical Perspectives Vol. 29. Seattle: IASP Press, 2004; pp 236–237. 9. Kravis NM. James Braid’s psychophysiology: a turning point in the history of dynamic psychiatry. Am J Psychiatry 1988;145:1191–1206. 10. British Medical Association. Statement of 1892 by a Committee appointed by the Council of the BMA. Supplement to the BMJ 1955;(suppl):190–193. 11. British Medical Association. Medical use of hypnotism: report of a Subcommittee appointed by the Psychological Medicine Group Committee of the British Medical Association. BMJ 1955;(suppl):190–193. 12. Council on Mental Health. Medical use of hypnosis. JAMA 1958;168:186–189. 13. American Psychiatric Association. Regarding Hypnosis Position Statement, approved by the Council February 15, 1961. Available at www.psych.org/public_info/libr_publ/position.cfm (accessibility verified February 1, 2007). 14. National Institutes of Health (NIH) Technology Assessment Panel on Integration of Behavioral and Relaxation Approaches into the Treatment of Chronic Pain and Insomnia. Integration of behavioral and relaxation approaches into the treatment of chronic pain and insomnia. JAMA 1996;276:313–318. 15. Rainville P, Price DD. The neurophenomenology of hypnosis and hypnotic analgesia. In Price DD, Bushnell MC (eds): Psychological Methods of Pain Control: Basic Science and Clinical Perspectives, Vol 29. Seattle: IASP Press, 2004; p 248. 16. Holroyd J. Hypnosis treatment of clinical pain: understanding why hypnosis is useful. Int J Clin Exp Hypn 1996;44:33–51. 17. Price DD. Psychological and neural mechanisms of the affective dimension of pain. Science 2000;288:1769–1772. 18. Price DD. Central neural mechanisms that interrelate sensory and affective dimensions of pain. Mol Interventions 2002;2:392–402. 19. Hilgard ER. The problem of divided consciousness: a neodissociation interpretation. Ann N Y Acad Sci 1977;296:48–59. 20. Patterson DR, Jensen MP. Hypnosis and clinical pain. Psychol Bull 2003;129:495–521. 21. Crawford HJ. Brain dynamics and hypnosis: attentional and dysattentional processes. Int J Clin Exp Hypn 1994;42:204–232. 22. Crawford HJ, Birbaumer N, Elbert T, et al. Slow potentials of the cerebral cortex and behavior. Physiol Rev 1990;70:1–41. 23. Gruzelier JH, Brow TD. Psychophysiological evidence for a state theory of hypnosis and susceptibility. J Psychosom Res 1985;29:287–382.

24. Kiernan BD, Dane JR, Phillips LH, Price DD. Hypnotic analgesia reduced R-III nociceptive reflex: further evidence concerning the multifactorial nature of hypnotic analgesia. Pain 1995;60:39–47. 25. Rainville P. Pain affect encoded in human anterior cingulate but not somatosensory cortex. Science 1997;277:968–971. 26. Hofbauer RK, Rainville P, Duncan GH, Bushnell MC. Cortical representation of the sensory dimension of pain. J Neurophysiol 2001;86:402–411. 27. Faymonville ME, Laureys S, Degueldre C, et al. Neural mechanisms of antinociceptive effects of hypnosis. Anesthesiology 2000;92:1257–1267. 28. Schulz-Stubner S, Krings T, Meister IG, et al. Clinical hypnosis modulates functional magnetic resonance imaging signal intensities and pain perception in a thermal stimulation paradigm. Reg Anesth Pain Med 2004;29:549–556. 29. Lynn SJ, Kirsch I, Barabasz A, et al. Hypnosis as an empirically supported clinical intervention: the state of the evidence and a look to the future. Int J Clin Exp Hypn 2000;48:239–259. 30. Pinnell CM, Covino NA. Empirical findings on the use of hypnosis in medicine: a critical review. Int J Clin Exp Hypn 2000;48:170–194. 31. Tsao JC, Zeltzer LK. Complementary and alternative medicine approaches for pediatric pain: a review of the state-of-the-science. Evid Based Complement Alternat Med 2005;2:149–159. 32. Montgomery GH, DuHamel KN, Redd WH. A meta-analysis of hypnotically induced analgesia: how effective is hypnosis? Int J Clin Exp Hypn 2000;48:138–153. 33. Malone MD, Strube MJ. Meta-analysis of non-medical treatment for chronic pain. Pain 1988;34:231–234. 34. Spinhoven P. Similarities and dissimilarities in hypnotic and nonhypnotic procedures for headache control: a review. Am J Clin Hypn 1988;30:183–194. 35. Weitzenhoffer AM, Hilgard ER. Stanford Hypnotic Susceptibility Scale. Palo Alto, CA: Consulting Psychologists Press, 1959. 36. Shor RE, Orne EC. Harvard Group Scale of Hypnotic Susceptibility. Palo Alto, CA: Consulting Psychologists Press, 1963. 37. Spiegel DB, Spiegel H, Nee JC. The Hypnotic Induction Profile: normative observations, reliability and validity. Am J Clin Hypn 1978-1979;21:109–133. 38. Barber J, Mayer D. Evaluation of the efficacy and neural mechanism of a hypnotic analgesia procedure in experimental and clinical dental pain. Pain 1977;4:41–48. 39. Zeltzer L, LeBarron S. Hypnosis and nonhypnotic techniques for reduction of pain and anxiety during painful procedures in children and adolescents with cancer. J Pediatr 1982;101:1032–1035. 40. Lang EV, Berbaum KS, Faintuch S, et al. Adjunctive self-hypnotic relaxation for outpatient medical procedures: a prospective randomized trial with women undergoing large core breast biopsy. Pain 2006;126:155–164. 41. Lang EV, Benotsch EG, Fick LJ, et al. Adjunctive nonpharmacological analgesia for invasive medical procedures: a randomized trial. Lancet 2000;355:1486–1490. 42. Freeman RM, MacCauley AJ, Eve L, Chamberlain GVP. Randomized trial of self-hypnosis for analgesia in labour. BMJ 1986;292:657–658. 43. Jenkins MW, Pritchard MH. Hypnosis: practical applications and theoretical considerations in normal labor. Br J Obstet Gynaecol 1993;100:221–226. 44. Hilgard JR, LeBaron S. Relief of anxiety and pain in children and adolescents with cancer: quantitative measures and clinical observations. Int J Clin Exp Hypn 1982;32:417–442. 45. Cangello VW. The use of the hypnotic suggestion for relief in malignant disease. Int J Clin Exp Hypn 1961;9:17–22. 46. Patterson DR, Goldberg ML, Ehde DM. Hypnosis in the treatment of patients with severe burns. Am J Clin Hypn 1996;38:200–212. 47. MacHovec F. Hypnosis complications, risk factors, and prevention. Am J Clin Hypn 1988;31:40–49. 48. Coe WC, Ryken K, Hypnosis and risks to human subjects. Am Psychol 1979;34:673–681. 49. Judd FK, Burrows GD, Dennerstein L. Dangers of hypnosis: a review. Aust J Clin Exp Hypn 1985;13:1–15. 50. Lynn SJ, Martin DJ, Does hypnosis pose special risks for negative effects? A master class commentary. Int J Clin Exp Hypn 1996;44:7–19. 51. Kleinhauz M, Beran B. Misuse of hypnosis: a factor in psychopathology. Am J Clin Hypn 1984;26:283–290.

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Chapter 72

COGNITIVE THERAPY CHRONIC PAIN

FOR

Joshua Wootton and Chris Warfield

INTRODUCTION Although pain may not be psychological in origin, how we respond to it is. The quality, intensity, and duration of pain are influenced by a host of psychosocial factors; and while these may not have arisen in the context of pain, they are no less consequential than the actual or potential tissue damage that gave rise to pain in the first place. By the time pain has become chronic, it represents the product of conflict between the original sensory stimulus and the whole person. As pain interferes with one’s work and livelihood, recreational pursuits, relationships with family and friends, and even sexual intimacy and spiritual expression, it can come to be a powerful influence on self-esteem and the ways in which one views oneself as a man or woman, husband or wife, father or mother, friend, citizen, and spiritual being. Chronic pain will always require some level of adaptation and adjustment from those who experience it, but the intrusion of chronic pain is frequently accompanied by obstacles to this process of adjustment that make the experience a complex, subjective phenomenon, uniquely molded by the environment and the individual’s personality, characteristic strategies for coping, and core beliefs about herself or himself and the world. Consider the patient in the following case study.

Case Study Jonathan, a 40-year-old married man with two adolescent children, was referred to the pain-management center, 14 months after a work-related injury to his lower spine. His pain had remained intractable to multiple surgical interventions, medications, and physical therapy and, if anything, had become more severe over time. His physicians supported his claim to disability, but his Workman’s Compensation carrier’s independent medical examiner insisted that he could return to work. Imagining his previously comfortable life and hopes for the future slipping away, he turned from those whom he believed he was disappointing and began to seek solace in the abuse of alcohol and prescription medications. Withdrawn, irritable, and depressed, he described a household dominated by marital discord and complained that his children no longer respected him. In the middle of his examination, he broke down, becoming tearful and sobbing, ‘‘I’m never going to get better . . .. There’s nothing I can do to help myself. . .. I can’t take care of my family. . .. I’m a complete failure.’’ It is at this point that many pain physicians and other medical providers experience the helplessness and hopelessness of their chronic pain patients most intensely. We ourselves can easily feel overwhelmed in the face of such profound despair. In Jonathan’s case, his pain physician showed an appropriately

empathic appreciation for the patient’s dilemma but focused, not on sympathizing with the patient’s feelings, but rather on addressing his thoughts and beliefs: Jonathan, it has taken you a long time to reach this point of frustration and grief, and it will take some time to begin to turn back from it, but that is exactly what I and your other providers here are dedicated to helping you do. I would like you to meet with our psychologist—not because I believe your pain is in your head but rather because I see first-hand the terrible toll your pain has taken and how it has led you to believe there is no hope for you. We believe that, if we ignore this part of your pain, we are simply giving in to it. Reassured that his pain physician would continue to move ahead with attempts to provide medical treatment, the patient— nevertheless, with some apprehension—arranged for a first appointment with the pain psychologist, a cognitive therapist.

THE BASIS OF COGNITIVE THERAPY It is a natural and understandable human tendency for family members, friends, colleagues, and even medical providers to sympathize with the patient in chronic pain, echoing his or her feelings and allowing themselves to feel, in some measure, the emotional distress of the patient. Even many approaches to psychotherapy—including psychoanalytic psychotherapy and many other forms of insightoriented and supportive treatment—concentrate on the primacy of emotions as the path to healing and adjustment. The principal arguments against taking this tack with patients in chronic pain are that (1) these approaches are typically long-term and may require many months, if not years, to result in meaningful insight and progress, (2) they may lead the patient to an uncritical acceptance of his or her feelings, further entrenching the negative emotions associated with his or her maladaptive response to pain, and (3) the principal obstacles to successful adjustment to chronic pain can usually be more fairly characterized as cognitions, not emotions. In the 1960s, the type of psychotherapy known as cognitive therapy was developed by the psychologist Aaron Beck, who believed there is a quicker path toward achieving results in the treatment of certain psychological problems than the often laborious and painstaking examination and interpretation of the largely unconscious basis of conflicts and drives. Beck based his approach on the observation that how we think (cognition), how we feel (emotion), and how we act (behavior) are all inseparably bound and interrelated and that it is our thoughts that influence and often determine our feelings and actions. In other words, negative and unrealistic thinking is behind much of our distress and maladaptive behavior. In Jonathan’s case, then, his thoughts, images, and beliefs about his not being able to provide for his family gave rise to his distress and led to the maladaptive responses—self-medication, defensive outbursts, and social withdrawal—that only further entrenched his pain and the myriad psychosocial stressors now associated with it. In the cognitive model of chronic pain, negative cognitions arising within the context of the unremitting sensory stimulus of pain exert a correspondingly negative influence on emotions, behaviors, and reciprocally, even the perception of pain. The negative thoughts, images, and beliefs developing as a result can, therefore, maintain or even exacerbate the experience of pain by promoting musculoskeletal tension and autonomic arousal. In the face of sustained or escalating pain, the resulting negative thinking can also lead to changes in mood states—anxiety and depression—as well as

522 Chapter 72  COGNITIVE THER APY FOR CHRONIC PAIN self-defeating behaviors often associated with chronic pain and disability. The picture of chronic pain portrayed in Jonathan’s case is one of agitated and anxious depression in which a patient has turned for consolation to behaviors that, in the end, can only worsen his problems and make his situation more dire. When the signal of pain is processed and interpreted in the brain, certain thoughts and images become activated in the somatosensory cortex, and certain emotions are cued in the limbic structures. When Jonathan, for example, rises from his bed in the morning, he experiences a sharp, lancinating sensation in his lower back and legs. Emotionally, he experiences frustration and helplessness, while he thinks, ‘‘This is ridiculous. I can’t even get out of bed without hurting myself. How can I ever work or live my life like this?’’ As his experience of pain becomes more generalized, he develops persistent images of himself as disabled; and these thoughts, in turn, begin to modulate his every signal of pain negatively, intensifying his frustration and helplessness and leading to depression and generalized anxiety. Recent functional magnetic resonance imaging (fMRI) studies suggest that the maintenance of negative cognitions and their emotional burden can even amplify pain signals—in effect, altering the neurologic circuitry associated with the experience of pain. In this way, maladaptive patterns of responding to pain can become firmly entrenched over time, unless the negative cognitions behind them are addressed. At least one study suggests that cognitive therapy might be further refined and improved through real-time monitoring of fMRI patterns. In cognitive therapy, patients are led to examine whether, in the process of trying to make sense of their pain and what is happening in their lives as a result of pain, they may be making fundamental errors in their thinking and relying upon or developing mistaken beliefs. Jonathan had concluded that life, for him, was essentially over—that he was only a burden to his family and could no longer hope for satisfying and meaningful relationships, pursuits, or goals. His cognitive therapist’s task is first to help him identify the thoughts and beliefs that led him to this conclusion, to examine critically their value and veracity, and to assist him in restructuring his thinking to admit and consider all the possibilities and choices he may actually have within his grasp. Of course, some of the patient’s negative thoughts and beliefs may be accurate. He may never, for example, be able to resume his amateur golfing career or even play pick-up basketball on the playground with his children. Here, the aim of therapy would be to help the patient identify the negative generalization—that he can never again enjoy sports or time with his children—and offer new solutions—that he can still enjoy other recreational endeavors and still have fun and satisfying time with his family through other pursuits. He may not be able to return to his old job, but he may still remain active and, if he chooses, pursue other professional or occupational directions and goals.

OUTLINE OF TREATMENT IN COGNITIVE THERAPY Cognitive therapy is structurally flexible and can be refined and individualized to meet a particular patient’s or group of patients’ needs. In most cases, however, the approach to treatment in the context of chronic pain will include (1) an individual intake during which a thorough anamnesis is recorded and the patient’s history of coping with stress and pain is examined, followed by (2) typically 8 to 12 sessions or modules of individual or group therapy, progressively building toward (3) a final session or termination, during which the goals are reviewed and the patient’s progress is consolidated. The therapy sessions are often divided into an examination phase, during which patients identify and learn to self-monitor their negative cognitions, and a cognitive restructuring phase, during which they learn to restructure their thinking toward more adaptive cognitive coping. In addition,

(4) intermittent refresher or booster sessions are sometimes offered at longer intervals—3 to 5 months—to ensure that patients remain on track with their cognitive skills.

Intake and the Introduction to the Stress-Pain Cycle During the intake, the cognitive therapist attempts to assess the background of the patient’s chronic pain, along with the range of associated stressors—personal, family, social, and occupational— now impinging on the patient’s life. Some of these stressors may be longstanding and premorbid to her or his pain, but others will have developed out of the experience of chronic pain. In either case, stress can render pain less tractable to treatment and introduce exacerbations and still other complications and sources of stress. For this reason, the discussion during the intake, as well as during the first few sessions of therapy, will often focus on the patient’s characteristic strategies, both conscious and unconscious, for addressing and responding to the stressors in her or his life.

Case Study Ellen, a 32-year-old single woman was referred to the pain-management center, 1 year after the development of chronic daily headache with migrainous features. Her headaches had become progressively worse, despite multiple trials of medications and physical therapy, and once or twice a week, she was forced to spend several hours in a quiet, darkened room to manage her pain and nausea. She had continued to work as an administrative assistant and editorin-training at a publishing firm but now faced the possibility of losing her ‘‘dream job’’ because of absenteeism. Fearing that she would soon ‘‘lose everything,’’ the patient began to overuse her medication in anticipation of developing a headache, ultimately leading her to double and triple her prescribed dosages once she inevitably developed headache pain. She arrived at the pain center, desperate for a new medication or new treatment that would allow her to function at her workplace and pursue her career. Here, recognizing and learning about the stress-pain cycle become paramount to the success of the treatment. Once the patient acknowledges that stress can play a role in the experience of pain—and that pain itself can become a major stressor—the way is opened to an examination of what can be done to correct and ameliorate this cycle. In the case of Ellen, a number of stressors appeared to trigger her headache pain; and chronic headache pain itself became a source of stress that precipitated further headaches. Just thinking about her busy schedule would lead the patient to become anxious and ask herself, ‘‘But what if I get a headache and can’t do everything that needs to get done?’’ This anxiety would result in her becoming overly vigilant to the physical and situational cues of her pain, often leading her, in turn, to take medication at the first sign of trouble or even in anticipation of her pain. Her situation progressively worsened with the overuse of her medications and the eventual development of rebound headaches.

Identifying AutomaticThoughts and Core Beliefs During the 8 to 12 sessions or modules of treatment, the therapist’s goal is to assist the patient toward an understanding that situations are ordinarily neutral, until we interpret or assign meaning to them. Typically, a portion of each session will be devoted to identifying and examining the automatic thoughts and core beliefs that influence patients’ interpretation of their experience. We are often unaware of this step of assigning meaning because we do not usually

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stop to examine the thoughts and beliefs that give rise to our emotional responses to certain situations—and, even when we do, we may not consider the accuracy of these thoughts and beliefs. The essence of the cognitive model of treatment suggests that much of our emotional distress and self-defeating behavior is simply based upon inaccurate thinking and that, once our attention is drawn to the relationship between our distress and these upsetting thoughts and beliefs, we can test their value and veracity to see whether they form an appropriate basis for our emotions and actions or reactions. If not, then changing our thinking to correspond more accurately with reality may result in a change in mood and behavior, as well as in the perception of pain itself. In the case of Ellen, several automatic thoughts appeared to predominate in her interpretation of her experience. Whenever she felt the first twinge of pain, she would immediately think, ‘‘Oh, no, here it comes again! The rest of the day is ruined!’’ A variation of this occurred whenever she faced a particularly challenging or packed daily schedule. Just looking at her daily calendar would lead her to think, ‘‘What if I get a headache? I’ll never be able to do my job!’’ All too often, her perception of her pain would quickly move from just noticeable all the way to unbearable, leading her to flee her office in tears after only an hour or two in the morning. Her pattern of overusing her medications would continue to escalate, and her mounting dissatisfaction with her physicians’ solutions would propel her to renew her search for a doctor who could ‘‘fix’’ her. Such automatic thinking is associated with escalating pain and emotional distress, the overuse of medication, and as the pattern spirals out of control, with greater functional impairment and disability. In Ellen’s case, however, certain core beliefs tended to complicate her situation even further. These underlying views and attitudes about herself left her even more vulnerable to the triggering events of her pain and provided a platform for her maladaptive automatic thinking. As a child, she had had often endured the anger and impatience of a mother who, herself, was overburdened and often overwhelmed with her responsibilities. Ellen grew up with the idea that she could never be strong enough or competent enough to negotiate life successfully and that she was therefore weak and undeserving. For the patient, her pain and visions of impending failure were simply expressions of this deeply held core belief that she could never succeed, and her inability to control or manage her pain was further proof of her weakness and the belief that she did not deserve a challenging, responsible job.

not bad now, and I can continue working, while I see what happens.’’ With this simple cognitive restructuring, the patient was able to remain at work and actually miss far fewer days accommodating to her pain. Ellen’s anxiety—expressed in the fear, ‘‘What if I get a headache?’’—became a more rational and adaptive response: ‘‘Well, if I do, I’ll wait and see what happens. If it’s not bad, I can continue working. If it becomes severe and I have to leave, I’ll take some work home, in case it improves, and shuffle my priorities on tomorrow’s schedule.’’ Within a few weeks, she was reporting that her pain seemed more manageable; she was using less medication, and she was clearly less distressed and overwhelmed. Addressing patients’ automatic thoughts is critical to assisting them with the management of their pain, but their core beliefs are typically more influential where their motivation, identity, and selfesteem are concerned. In Ellen’s case, her idea that she was weak and undeserving quickly allowed the negative event of the development of her headaches to be interpreted and supported by an image of herself that was vulnerable and impaired. All too quickly, it made sense to her that her pain would become overwhelming and that she would ‘‘lose everything’’—her ‘‘dream job’’ and her hopes for success. Patients often face greater difficulty addressing the core beliefs supporting their pain and disability precisely because these beliefs are fundamental to their self-image and their view of the world. Not all core beliefs are negative, but those that are dysfunctional can quickly become the foundation of a patient’s view of himself or herself as impaired or disabled. In Ellen’s case, once the dysfunctional core belief was identified, her therapist gently encouraged her to examine the evidence for and against it. Although she could point to a deteriorating pattern in her life, since the onset of her headaches, she acknowledged that she had successfully completed school, landed a good job, and subsequently been promoted to her current position, all because of her talent and hard work. In fact, when she examined her situation carefully, she could see that, not only had she worked hard, but she had also overcome much adversity in her struggle to succeed— an achievement that, she agreed, did not sound reminiscent of weakness at all. As her pain became better managed through the cognitive restructuring of her maladaptive automatic thoughts, she began to see herself not as weak and undeserving but as strong and empowered—a woman who can succeed despite obstacles and setbacks.

Final Session and Intermittent Refreshers Cognitive Restructuring: Constructing Alternative Responses Once patients have become mindful of the stress-pain cycle and once the automatic thoughts and core beliefs that influence the cycle have been identified, then challenging those thoughts and beliefs and constructing alternative responses becomes the focus of treatment. Where automatic thoughts are concerned, the therapist often assists patients with the construction of a list of facts supporting and refuting each thought in order to reveal the distortion involved and open the door to considering a more realistic alternative. In Ellen’s case, her therapist encouraged her to examine the evidence for and against her thinking. Did the first hint of pain actually mean that her day was ruined where work was concerned? Her evidence that the thought was true depended upon her perception of a consistency that, when she evaluated her situation, turned out not to be true. Her headaches varied considerably—sometimes severe but just as frequently, quite mild—and she realized that she usually assumed the worst, leaving her office, when her pain was sometimes still quite manageable. Constructing an alternative to her previously maladaptive automatic thought led the patient to evaluate her situation more realistically. ‘‘I seem to be getting a headache, but it’s

During the final session, the therapist’s work is to review and reinforce what the patient has learned during the course of treatment and to emphasize that the newly acquired cognitive skills—identifying, evaluating, and challenging automatic thoughts and core beliefs and constructing more realistic and adaptive alternatives—must continually be applied, even after the work of formal therapy is concluded. Not to do so risks returning to the role of ‘‘chronic pain patient’’ and surrendering to disability. The irony is that patients who accept their pain as chronic—along with the implied limitations—tend to have lower levels of perceived pain, less distress and depression, and higher levels of functioning than those who remain focused on finding a cure or being rescued by a new medical approach. ‘‘Chronic pain patients’’ typically find the limitations of their pain to be intolerable and the emotional burden of their pain, unbearable; whereas patients who accept their pain take satisfaction in negotiating their limitations and pacing their activities, enabling a higher quality of life. Refresher sessions may be offered individually or in small groups to support the ongoing cognitive work of the patient and to reinforce the self-help perspective of this approach to treatment. Usually offered at 1-, 3-, and 6-month intervals, refresher sessions are intended to consolidate the gains of the formal therapy, while providing assistance with the development of ongoing self-help

524 Chapter 72  COGNITIVE THER APY FOR CHRONIC PAIN plans. In the case of group cognitive therapy, members of the group sometimes agree to continue meeting monthly without the therapist to support each other in their individual efforts at addressing stress and pain. In individual treatment, the therapist must remain available for refresher sessions, especially in the first few months after the original course of treatment, to ensure that patients’ cognitive skills remain sharp and their motivation high.

MILIEUAND MODE IN COGNITIVE THERAPY There is a broad array of selection criteria that psychotherapists must consider when evaluating patients for cognitive therapy. These include both the intrinsic impediments and resistances toward this form of treatment and the indications of which milieu and mode of therapy—clinic-based or private, group or individual—is likely to promote the greatest chance of success. Every psychotherapist who is regularly engaged in offering group therapy, for example, has had the experience of particular patients derailing or redirecting the attention and work of the group to address their own idiosyncratic needs or to conform to their own maladaptive defensive strategies. Even highly skilled group therapists have seen how the dynamic of a group can begin to shift to support the pathology its members, rather than to encourage them to progress toward more adaptive and better-adjusted perspectives. Many physicians and psychotherapists have also encountered failures in treatment that have resulted from poor communication or even lack of communication between providers. In the treatment of chronic pain, the physician’s or psychotherapist’s lament, ‘‘I wish I’d known that sooner,’’ often foreshadows a less than optimal end.

Clinic-based versus Private Milieu For some patients, dividing their treatment among several providers—even a highly coordinated multidisciplinary team—can lead to a confusion of boundaries. Psychotherapists are frequently asked highly technical questions regarding medical and surgical interventions; while physicians, nurses, and physical therapists sometimes become important confidants regarding patients’ personal lives and even their appraisals of their progress in psychotherapy. Generally speaking, the greater the geographic distance between providers, the greater the challenges become to maintaining an interdisciplinary understanding of the patient’s individual needs and responses to treatment. A multidisciplinary pain center, in which the providers remain in close proximity, tends to foster a setting in which patients and can feel reassured that critical and appropriate information is freely shared and that a comfortably collaborative perspective on treatment is maintained. This does not mean that, in situations in which outside and private referrals for particular treatments are necessary or more expedient, patient care need be compromised. However, it does suggest that frequent communication and consultation among all providers may prove essential to quality of care. Patients may be sensitive to sharing some disclosures with all their providers, so negotiating what to share and how to share it may become critical to the success of the multidisciplinary enterprise. When a patient asks a psychotherapist for specifically medical information or for a medical opinion, not only is it important to consider why the psychotherapist is being asked, but it may also prove most helpful to respond, ‘‘That’s a good question. Shall we ask your doctor?’’ or even ‘‘Would you ask you doctor and let me know what she says?’’ Similarly, when personal and psychosocial revelations are presented to the physician or nurse, responding, ‘‘I didn’t realize that. Are you and your psychotherapist working on that?’’ reminds the patient of the need to be forthcoming in the milieu of psychotherapy. Taking the further step of negotiating consultation between providers

with the patient can also serve as a useful reminder that, in a multidisciplinary approach to care, everyone is focused on the goal of recovery. Asking, for example, ‘‘Would you mind if I shared that with your doctor?’’ can pave the way for an interdisciplinary understanding of the patient’s situation that can prove critical to wellmanaged and successful care.

Individual versus GroupTreatment While no significant differences in outcome and effectiveness have been found between individual and group cognitive therapy, several basic impediments may rule out some patients for group cognitive therapy and pose certain obstacles even for individual cognitive treatment. Because the critical feature of cognitive therapy is psychoeducational, much depends upon the individual patient’s background with and attitudes toward this approach. Belowaverage intelligence, deficits in education, and lack of facility with spoken or written English may suggest that certain patients can easily feel overwhelmed in a group environment and become quickly discouraged. For these patients, a more tailored approach is required to meet their individual needs and to ensure that they are not awash or lost in the group dynamic. Similarly, certain highly sensitive patients who tend to resist personal disclosure may find that a group environment poses too many risks and dangers to their sense of privacy and personal integrity. Still others with rigid or primitive personality structures may find a group dynamic too threatening, unless it conforms to their own cognitive distortions and meets their extraordinary needs for unqualified acceptance. Because one of the characteristic features of the cognitive approach to treatment is to challenge patients’ interpretations of events and question their appraisals, thoughts, and beliefs about their pain, the sometimes arduous work of treatment is usually best approached in an atmosphere in which they can feel less threatened and more accommodated and reassured by the psychotherapist’s individual attention. Some attention, too, must be given to an assessment of each patient’s readiness for change, according to the transtheoretical model. Patients who come to treatment with a passive attitude—‘‘You’re the doctor; you fix me!’’—are often unwilling to consider an active role for themselves in their own treatment and recovery. When patients remain unconvinced that anything they can do will make a difference to their experience of pain, then the remedial step of encouraging a more empowered and collaborative relationship with their medical providers becomes a necessary preliminary intervention.

EFFICACYOF COGNITIVE THERAPY There is considerable evidence in the literature of psychological and medical research that cognitive therapy is an effective approach to the management of chronic pain. Many studies of this form of therapy support its supplementary and complementary roles as a multidisciplinary intervention, when undertaken with pharmacologic and other medical interventions and physical therapies. One difficulty in establishing a more central role for cognitive therapy is that it is typically combined in empirical research with behavioral techniques, such as relaxation skills and behavioral pacing techniques, and studied as cognitive-behavioral treatment. In a variety of settings, cognitive-behavioral therapy and behavioral therapy, when combined with other treatments in a multidisciplinary approach, have been shown to be more efficacious than unimodal medical treatment or no treatment. In direct comparisons, cognitive-behavioral treatment was shown to be just as effective, and in some studies, more effective than behavioral therapy alone. Problems emerge with drawing more generalizable conclusions because of variability across studies as to what is considered a specifically cognitive intervention and what is a behavioral

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intervention. There is the further difficulty that the term cognitive therapy embraces a variety of specific techniques, not all of which are utilized or combined in every study. The broadest application of cognitive therapy would include not only cognitive restructuring, or the identification and modification of maladaptive cognitions, but training in cognitive coping skills as well, which would include distraction techniques, positive self-statements, and imaging or visualization techniques. In the most empirically rigorous research to date, cognitive restructuring leading to positive changes in cognitions was demonstrated to occur prior to reductions in emotional distress and the perception of pain, suggesting that cognitive therapy can lead to improved pain management.

SUGGESTED READINGS Burns JW, Kubilus A, Bruehl S, et al. Do changes in cognitive factors influence outcome following multidisciplinary treatment for chronic pain? A cross-lagged panel analysis. J Consult Clin Psychol 2003;71:81–91. Caudill M. Managing Pain Before It Manages You, rev. ed. New York: Guilford, 2002. deCharms RC, Maeda F, Glover GH, et al. Control over brain activation and pain learned by using real-time functional MRI. Proc Natl Acad Sci U S A 2005;102:18626–18631.

McCracken LM, Turk DC. Behavioral and cognitive-behavioral treatment for chronic pain. Spine 2002;27:2564–2573. Morley S, Eccleston C, Williams A. Systematic review and meta-analysis of randomized controlled trials of cognitive behaviour therapy and behaviour therapy for chronic pain in adults, excluding headache. Pain 1999;80:1–13. Prochaska JO, Norcross JC, DiClemente CC. Changing for Good. New York: William Morrow, 1994. Thorn BE. Cognitive Therapy for Chronic Pain. New York: Guilford, 2004. Turk DS. Cognitive-behavioral approach to the treatment of chronic pain patients. Reg Anesth Pain Med 2003;28:573–579. Turner-Stokes L, Erkeller-Yuksel F, Miles A, et al. Outpatient cognitivebehavioral pain management programs: a randomized comparison of a group-based multidisciplinary versus an individual therapy model. Arch Phys Med Rehabil 2003;84:781–788. Vlaeyen JWS, Morley S. Cognitive behavioral treatments for chronic pain: what works for whom? Clin J Pain 2005;21:1–8. Winterowd C, Beck AT, Gruener D. Cognitive Therapy with Chronic Pain Patients. New York: Springer, 2003. Wootton RJ, Caudill-Slosberg MA, Frank JB. Psychotherapeutic management of chronic pain. In Warfield CA, Bajwa ZH (eds): Principles and Practice of Pain Medicine. 2nd ed. New York: McGraw-Hill, 2004; pp 157–169.

IX PHYSICAL MEDICINE APPROACHES TO PAIN MANAGEMENT

Chapter 73

PHYSICAL MEDICINE APPROACHES TO PAIN MANAGEMENT Steven Stanos, Mila Mogilevsky, Lynn Rader, James McLean, and Allison Baum

the patient is managed through a patient-centered, multidisciplinary approach in which the specialists of various disciplines (e.g., physician, occupational therapist [OT] and physical therapist [PT], psychologist, nurse, social worker) contribute their expertise to an ongoing patient’s care.2 This chapter provides a description of acute and chronic pain syndromes together with a discussion of the basic framework of approaching pain conditions from a global physiatric standpoint. The basic concepts of obtaining a functional history and assessing gait pattern, posture, strength, and balance (as it relates to a painful condition) are explained. Various assessment techniques and treatment strategies are discussed. Finally, the role of each member of the interdisciplinary team is highlighted.

PAIN: GENERAL CONSIDERATIONS INTRODUCTION Physical medicine and rehabilitation, also referred as physiatry or rehabilitation medicine, is a discipline concerned with the evaluation, treatment, and coordination of care for persons with multiple musculoskeletal injuries, pain syndromes, and/or other physical and cognitive impairment and disabilities. The primary focus is on maximal restoration of physical and psychological function and on alleviation of pain (adapted from definitions by the American Board of Medical Specialties and the American Board of Physical Medicine and Rehabilitation). The physiatric model of care and, in particular, pain management is based on fundamental understanding of the individuals’ unique conditions as it relates to the concept of impairment, disability and handicap.1 Impairment is the loss or abnormality from psychological, physiologic, and functional perspectives that results from acquiring a painful condition. Disability is a restriction and/or lack of ability to perform activities owing to an impairment (e.g., pain). Handicap is a disadvantage that an individual possesses due to the impairment and disability that affects his or her role in society. Physical medicine and rehabilitation (physiatry) offers a unique approach to pain management in which the treatment is focused on a whole patient rather than an isolated painful condition. As such,

The International Association for the Study of Pain (IASP) describes pain as ‘‘an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.’’

Differences between Acute and Chronic Pain Pain is usually described as acute or chronic. The distinction between the two types of pain has to do with the duration of symptoms as well as the physiologic response of the person (Table 73–1).

Acute Pain Syndromes and Their Management In acute pain syndrome, the experience of pain is often directly related to an underlying tissue injury. For example, an acute episode of low back pain may be due to a herniated lumbar disk. Receptors in the annulus fibrosis of the disk and surrounding neural tissue transmit signals to the dorsal horn, where the signal is modulated.3 The signal then ascends to higher brain levels, where the multidimensional experience of pain is perceived.4 In treating such patients, the medical rehabilitation team focuses on acute symptomatic improvement, promotion of the healing process, and patient education. For patients with an acute herniated disk, the initial management may include several days of relative rest, ice, and anti-inflammatory medications. Bracing, corticosteroid injections, 527

528 Chapter 73  PHYSICAL MEDICINE APPROACHES TO PAIN MANAGEMENT

Table 73^1. Differences between Acute and Chronic Pain Acute Pain

Chronic Pain

Elicited by immediate tissue Persists after tissue injury has injury resolved or healed Serves as a ‘‘warning’’ of tissue Serves no obvious useful function damage or injury; protective of further injury Activates nociceptors Involves central sensitization and permanent structural abnormalities of the central nervous system Activates sympathetic nervous Physiologic adaptation system Limits duration Prolonged duration Remits with resolution and Persists long after resolution healing of injury and healing of injury Directly associated with injury, Remotely associates with postoperative conditions, and injury, trauma, or surgical disease processes procedures Responds to treatment Resistant to treatment

THE ROLE OF THE PHYSICIAN The first role of the physician in the management of a patient with pain is to establish a complete and accurate diagnostic assessment and determine and coordinate other specialists involved in the patient’s case. Arriving at the specific diagnosis involves a complete history, a comprehensive physical assessment, and appropriate use of laboratory and diagnostic tests. Once a diagnosis is reached, the physician will develop a comprehensive plan of care, which will include short- and long-term goals, pharmacologic interventions, physical and occupational therapy, cognitive and behavioral treatments, vocational rehabilitation, and patient education.

Physiatric Assessment

and therapeutic modalities such as ultrasound/electrical stimulation can be used to reduce inflammation and muscle spasm in selected patients. As the patient’s symptoms gradually improve, normalization of range of motion and emphasizing postures that will unload the herniated disk are taught. Finally, common biomechanical impairments, such as weakness in core musculature (e.g., abdominals, gluteus muscle groups), lower limb contracture (e.g., hip, hamstring), and poor lifting techniques, will be the focus of physical and occupational therapy. At the conclusion of treatment, the patient will be given recommendations about exercises and lifestyle modifications.

The diverse nature of any pain condition requires a comprehensive assessment in order to design a tailored treatment plan. Identifying the onset of pain, understanding the mechanism of injury, and analyzing pain-related functional changes are the main components of physiatric assessment. The analysis of function and the goal setting can vary dramatically based on the patient’s functional expectations. For example, a treatment plan for a marathon runner may focus entirely on returning the athlete to a previous level of competitive running. Conversely, a 70-year-old sedentary woman with a thoracic compression fracture might best benefit from the activities that focus on negotiating basic daily living tasks (e.g., dressing, hygiene, and meal preparation). Often, a functional assessment will be performed before and after therapy sessions to determine the level of patient’s progress. The Functional Independent Measure (FIM) scores, although commonly used in the acute inpatient rehabilitation arena, can be applied to stratify the level of function with various activities of daily living (Box 73–2). A physiatrist musculoskeletal examination comprises a complete examination of the pain area including bony structures, cartilages, joints, ligaments, tendons, bursae, nerves, and skin. Equally important is a more global evaluation of posture, core strength, balance, and gait (Box 73–3). Performing a proficient physical examination is a fundamental part of identifying pain generators, diagnosing and identifying potential areas of dysfunction, narrowing the clinical differential diagnosis, and establishing a rational treatment plan.

Chronic Pain Syndromes and Their Management

Posture and Postural Abnormalities

Multidisciplinary and interdisciplinary functional restoration programs based on cognitive and behavioral principles and active physical and occupational therapy have been increasingly used in the treatment of chronic pain. A biopsychosocial focus is an important part of the assessment and ongoing treatment program. The collaborative rehabilitation team typically comprises a physiatrist or pain medicine specialist; PTs, OTs, and recreation therapists (RTs); pain psychologists; relaxation therapists; social workers; vocational counselors; and nurse educators (Box 73–1).

Posture is defined as the position of the body at one point in time and is influenced by each of the joints of the body. Proper posture is

Adapted from Twanddle M, Cooke K. Assessment of pain and common pain syndromes. In Van Roenn JH, Price JA, Preodor ME (eds): Currrent Diagnosis and Treatment of Pain. New York: Lange/McGraw-Hill, 2006.

Box 73^2 LEVELS OF FUNCTIONAL INDEPENDENCE BY THE FUNCTIONAL INDEPENDENCE MEASURE

Box 73^1 MEMBERS OF A COMPREHENSIVE MULTIDISCIPLINARY PAIN TREATMENT TEAM         

Physiatrist (or pain specialist) Physical therapist Occupational therapist Pain psychologist Biofeedback and relaxation training specialist Therapeutic recreation therapist Social worker Vocational counselor Nurse facilitator/educator

From Stanos S. Developing an interdisciplinary multidisciplinary chronic pain management program: nuts and bolts. In Schutman M, Campbell A (eds): Chronic Pain Management: Guidelines for Multidisciplinary Program Development. New York: Informa Healthcare, 2007.

From Ottenbacher KJ,Christiansen C: Occupational performance assessment. In Christiansen C, Baum C (eds): Occupational Therapy Enabling Function and Well-being, 2nd ed. Thorofare, NJ: Slack,1997.

IX PHYSICAL MEDICINE APPROACHES TO PAIN MANAGEMENT 529

Box 73^3 COMPONENTS OF PHYSIATRIST ASSESSMENT       

Pain behavior, affect Posture Motor strength and muscle firing patterns Balance Range of motion Core assessment Gait assessment

achieved when the body is aligned in such a way that the least amount of stress and muscle activation is possible. In standing, normal posture includes a mild cervical and lumbar lordosis and a thoracic kyphosis. Posture should be observed directly (physical examination) and indirectly during the patient interview. One may assess for shoulder height asymmetry (as it relates to a limb dominance), head position, positioning of the pelvis (resting position of the iliac crests), and positioning of the feet (flat or arched midfoot, internally or externally rotated in relation to the tibia). It is important to evaluate the patient in her or his normal sitting position. Poor sitting posture may place excessive strain on multiple structures including soft tissues; cervical, thoracic, and lumbar spine; intervertebral disks; and facet joints.5

Range of Motion, Muscle Strength, and Muscle Imbalances Active and passive range of motion should be assessed for each joint (painful joints should be assessed last). The examiner should note general hyper- or hypomobility of the joint, side-to-side differences in range of motion, and movements that result in pain. The findings of range of motion testing combined with manual muscle testing may lead to objective findings of muscle imbalances around the joint. This concept has been described by Jull and Janda6 as the upper crossed and pelvic crossed syndromes. An upper crossed syndrome is characterized by tight upper postural muscles (pectoralis major and upper trapezius) and lengthened phasic muscles (rhomboids and serratus anterior, middle and lower trapezius). Motor strength assessment is based on the Canadian classification system in which the strength of a limb is analyzed on a scale of 0 to 5, where 0 is the absence of any visible muscle activity and 5 is normal strength, comparable with the strength of the examiner (Box 73–4).

Core Strength Evaluation The core is often visualized as a box with the abdominal muscles in the front, the diaphragm as the roof, and the pelvic floor and hip muscles at the bottom. It includes more than 20 pairs of muscle groups that stabilize spinal structures and the pelvis and coordinate movements during the functional tasks such as bending, lifting, and squatting. The outer, more superficial group of muscles is composed primarily of fast-twitch fibers, which are capable of producing large torque forces, greater speed, and larger areas of motion. The deeper muscles lay closer to the spine and are

Box 73^4 MOTOR STRENGTH: MANUAL MUSCLE TESTING

From Cutter NC, Kevorkian CG. Handbook of Manual MuscleTesting. New York: McGraw-Hill, 1999.

composed predominantly of slow-twitch muscle fibers, which help control segmental motion and maintain the mechanical stiffness of the spine.

Balance and Stability A concept closely related to core strength is balance and stability. Patient with weak core musculature will often demonstrate weakness in that area. These deficits may lead to increased stress in other parts of the body and an increased risk of injury. Tissue injury may in turn lead to more core weakness and the vicious circle will be established. Bermark7 studied patients with low back pain and demonstrated decreased core strength and postural stability compared with those without low back pain. Balance can be assessed and described as static or dynamic. Static balance is assessed in the sitting or standing position without introducing external perturbations. The patient is asked to perform simple activities such as sitting or standing without support. If the task is achieved without difficulty, he or she may be asked to stand on one leg. Further assessment involves asking the patient to close his or her eyes, reach across the room, or catch a ball while standing on one leg. The amount of sway and degree of pain during the maneuver is noted, as well as the utilization of compensatory movements during the task. Dynamic balance involves maintaining the center of mass over the base of support when the base of support is moving (i.e., sitting on an exercise ball) or external pertubations are applied.8

Gait Assessment Normal gait may be described in two phases and seven parameters (Box 73–5).9 Understanding the normal gait cycle helps the physician to identify gait deviations that are seen in common pathologic conditions. In normal individuals, the stance phase (foot on the ground) represents 60% of the gait cycle, whereas the swing phase represents 40% of the gait cycle. The notion of an antalgic gait commonly refers to shortening of one cycle and lengthening of the other. On the affected, painful side, less time is spent in the stance phase and more in the swing phase. The opposite is true for the contralateral side that tends to compensate for the involved extremity. Thus, when assessing the painful side, particular attention should be paid to the ‘‘uninvolved’’ hip, knee, and ankle because these joints may become problematic in the future. Gait can be assessed when the patient first enters the examination room. This ‘‘quick scan’’ allows the examiner to form a general impression of the patient’s gait while assessing for pain behaviors. The examiner should note the positions of the head, shoulders, and pelvis during the gait. Observation of arm swing, foot strike, and foot clearance should be done, assessing for inconsistencies. Special attention should be paid to compensatory patterns of movements,

Box 73^5 PHASES OF GAIT AND GAIT PARAMETERS Phases of Gait Stance: 60% of the walking cycle; shortened on the painful side Swing: 40% of the walking cycle; lengthened of the painful side Important Parameters of Gait Width of support: Distance between feet; normally 2^ 4 inches; larger when pathology of the dorsal columns or an ataxic gait is present; assess for peripheral neuropathic conditions, vitamin B12 deficiency Stride length: Distance between sequential corresponding points of contact by the same foot, normally 30 inches Step length: Shortened on the pain-free side Pelvic and trunk rotation: Helps to elongate the leg, increasing step length and stride length Cadence: Number of steps per minute, normally 100 steps/min Center of gravity: 2 inches anterior to the second sacral vertebra From Esquenazi A, Talaty M. Gait analysis: technology and clinical applications. In Braddom RL (ed): Physical Medicine and Rehabilitation, 3rd ed. Philadelphia: Saunders, Elsevier, 2007; pp 93-110.

530 Chapter 73  PHYSICAL MEDICINE APPROACHES TO PAIN MANAGEMENT such as leaning to one side, circumducting a leg, or holding an arm in a protective manner

Table 73^2. Rehabilitation Professionals and Their Areas of Expertise

Kinetic Chain After the completion of musculoskeletal assessment, having a firm understanding of the kinetic chain helps the clinician to summarize all the findings, interpret the patient’s deficits, and develop a comprehensive treatment plan. The kinetic chain concept is based on the fundamental premises that for functional movement in place, each link of the body must move in a coordinated pattern. The sequence of the links and the interrelationship of muscle activation and translation of forces within the body are referred to as a kinetic chain.10 Each link of the system creates a force and energy that is transferred from the proximal core-stabilizing link to the distal peripheral link. Distal links, in turn, will compensate for the proximal link, and the added stresses and loads will result in further injury. For instance, if the patient develops a painful hip, the knee will have to absorb more forces during the gait. If the patient also has a tendency to overpronate (flat-foot position) the foot, the forces at the knee are further increased. This malalignment of the foot may lead to changes at the knee, such as excessive patellofemoral joint pressures (knee joint degeneration and narrowing) and abnormal patellar tracking. Hence, proper rehabilitation of the patellofemoral joint pain must address factors along the kinetic chain, that is, proximal to the knee (pain control of the hip and strengthening of the hip abductors, extensors, and quadriceps muscles) and more distally (correcting pronated positioning and strengthening intrinsic muscle strength and balance at the ankle).11

THE ROLE OF THERAPISTS PTs and OTs PTs and OTs are an important part of the treatment team. PTs and OTs utilize therapeutic exercise, physical modalities, and manual techniques to improve pain control and optimize flexibility, strength, and endurance of the patient. In addition, they are responsible for ongoing reevaluation and modification of the treatment program set up at the initial evaluation. Whereas there are similarities between these fields, there are also some differences in the treatment approach that PTs and OTs use that make their contribution both different and complementary to each other (Table 73–2). Traditionally, PTs are trained to focus more on the areas of impairment (such as weakness, pain, poor balance, and gait difficulties), whereas OTs deal more with the disability issues (e.g., manufacturing a splint, ordering home equipment, designing an ergonomically favorable environment, educating a patient). In the environment of interdisciplinary patient management, however, those boundaries are often blurred, and it is not unusual to see either of these disciplines using manual therapy, working on transfers, or educating a patient on proper lifting techniques.

RTs RTs play an invaluable role in managing patients with more complex rehabilitation and chronic pain syndromes. An RT assessment examines the patient’s previous interests, hobbies, and leisure pursuits. It helps the patient to identify barriers to returning to these activities and, ultimately, aids her or him to reincorporate enjoyable activities into her or his life. RTs help to establish and incorporate strategies learned from various disciplines of multidisciplinary treatment into social and community functions.

From Stanos SP, Tyburski M: Rehabilitation issues: Pain control. In Von Roenn JH, Paice JA, Preodor ME (eds): Current Diagnosis and Treatment of Pain. New York: Lange/McGraw Hill, 2006.

TREATMENT Therapeutic Exercise Therapeutic exercise is the systematic implementation of planned physical movements, postures, or activities designed to (1) remediate or prevent impairments; (2) enhance function; and (3) enhance fitness and well-being.12 Therapeutic exercise has traditionally been a cornerstone form of therapy utilized by PTs and OTs (Table 73–3). It is prescribed in the treatment of a variety of clinical conditions and in pain management, in particular. The principle behind the utilization of exercise in pain management is based on the fact that dynamic exercise promotes acute physiologic adjustments in most bodily systems.13 Collectively, these adjustments increase the availability of oxygen and nutrients to the active muscle cells and remove metabolic byproducts, such as carbon dioxide, heat, and lactic acid. The optimal body function is maintained in the appropriate milieu (pH, body fluid, temperature), thus facilitating the healing process. The type, frequency, and duration of exercise are often based on the pain etiology, coexisting medical conditions, and the degree of anticipated physical stress. For example, a patient suffering from an acute rheumatoid arthritis exacerbation may be started on non– weight-bearing, low-impact, and short-duration activities designed to optimize movement and flexibility and minimize joint stress. Conversely, an athlete presenting with a limited painful knee

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Table 73^3. General Components of Therapeutic Exercise Active range of motion

Passive range of motion

Stretching Isometric exercises

Isotonic exercises

Isokinetic exercises

Endurance training

Motor reeducation

Patient moves extremity through arc of motion Designed to promote joint flexibility and strength. Therapist moves patient’s extremity through arc of motion Designed to maintain/improve joint flexibility Done actively and passively; designed to improve range of motion Muscle is contracted without change in length Designed to maintain/improve muscle strength in acute pain states and inflammation Muscle is contracted through the available range while the load remains the same; designed to improve muscle strength within an available range Muscle is contracted through a constant angular velocity; designed to improve muscle power; essential for fast repetitive activities Performance of repetitive contractions with incremental increases of duration of exercise; designed to improve aerobic capacity and long-term performance Introduced and utilized in conjunction with other forms of exercise; designed for postural retraining and changing maladaptive patterns developed as a result of painful condition

movement due to recent knee arthroscopy will be offered aggressive active stretching exercises with dynamic strengthening activities and balance training. In each case, the exercise regimen will be adjusted and modified as the patient progresses through the different stages of healing. In addition to its direct impact on pain management, therapeutic rehabilitation is unique in its ability to provide a patient with tools to be used outside of a therapy office. As part of therapeutic management, the patient is frequently given a home exercise program that he or she is expected to perform. This form of therapy is designed to give the individual a sense of responsibility, thus enabling him or her to take an active role in management of his or her own disease. Besides its physiologic effects on actively contracting muscles, therapeutic exercise offers additional mechanisms for controlling pain symptoms via increasing the levels of endogenous endorphins and enkephalins.14,15 Similarly to many psychostimulant agents, an acute bout of active aerobic exercise and chronic aerobic exercise training has been found to increase the dopamine brain concentration in rats by as much as 80%.16 Although the research in humans is currently at its initial stages, the prospect of therapeutic exercise finding its place in the treatment of not only musculoskeletal pain but also chronic conditions

such as central pain, cancer pain, and human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) pain symptoms is promising. In addition to offering pain relief, therapeutic exercise affects other areas of physiologic adaptation such as n n n n n

Blood pressure. Muscle strength. Aerobic capacity. Hormonal adaptation. Pain threshold.

Blood Pressure Regulation A meta-analysis of aerobic exercise training studies demonstrated an average decrease in systolic and diastolic blood pressures of 7 and 6 mm Hg, respectively, in those patients with hypertension and 3 and 2 mm Hg in systolic and diastolic pressures, respectively, in those with normal blood pressure with aerobic training.17

Muscle Strength Therapeutic exercises involving resistance training have been shown to cause muscle enlargement leading to an increase in muscle strength. Muscle fiber hypertrophy is believed to occur through remodeling of the muscle fiber protein and an increase in the size and number of myofibrils.18 In addition, muscle hyperplasia has been speculated to be a possible adaptive strategy in resistance training. However, the extent of hyperplasia and the exact mechanism of its development remain the subjects of an ongoing debate.19

Aerobic Capacity Therapeutic exercise is known to have a direct impact on the increase in aerobic capacity. Among other factors that affect maximum oxygen consumption (VO2max [an index of aerobic capacity]), are maximal heart rate, gender, and stroke volume. Body composition changes associated with loss of physical activity are found to be detrimental in worsening of aerobic capacity. A systematic review of six randomized clinical trials using aerobic conditioning exercises, such as stationary bicycling, walking, or aquatic exercise, in deconditioned patients with rheumatoid arthritis conducted by the Cochrane Group concluded that therapeutic conditioning exercises were effective in improving aerobic capacity, muscle strength, and joint mobility. An estimated average increase of VO2max with traditional aerobic training program is known to be 15% to 20%.20

Hormonal Adaptation It has been speculated that the endocrine system plays a major role in the adaptational responses of skeletal muscle to exercise (resistance training). Staron and colleagues21 found elevated levels of testosterone concentration within 6 weeks of heavy-resistance training among men and women. Testosterone has been found to be directly involved in stimulating protein synthesis (via alternation of myosin adenosine triphosphatase [ATPase] activity), which leads to muscle enlargement and hypertrophy with a concomitant increase in muscle strength and exercise performance.21

PainThreshold The nociceptive nerve endings that are found in skin, joints, muscles, bone make up an intricate network of pain perception controlled by the human central nervous system. Because muscle afferent nerve pathways and pain afferent nerve pathways both converge on the dorsal horn of the spinal cord, it has been proposed

532 Chapter 73  PHYSICAL MEDICINE APPROACHES TO PAIN MANAGEMENT that pain afferents may be susceptible to some form of selective inhibition as a result of physical activity and exercise training.22 Another hypothesis is that endogenous opioid release may be involved in exercise-induced hypoalgesia. Most likely, exercisedinduced hypoalgesia is caused by a host of interrelated factors that may be partially controlled by the mode and intensity of exercise. Koltyn and coworkers’ study23 demonstrated significant hypoalgesia after maximal isometric gripping exercise in both men and women. These researchers tested 15 males and 16 females under two isometric exercise conditions. Subjects squeezed a hand dynamometer for 2 minutes at two different intensities (40%–50% and 100% of maximal handgrip contractions [MVC]).

Hydrotherapy Hydrotherapy entails the heating via submersion of small or large body surface areas, usually in a small tank or tub. The water temperature usually does not exceed 408C for large body surfaces and 438C when a limb is submerged. The temperature may be adjusted depending on the conditions treated and the effects desired (Table 73–4). Hydrotherapy provides a gravity-eliminated environment that facilitates joint range of motion. The addition of agitation provided by water flow provides sensory input. Traditionally utilized mainly as an adjunct to exercise, hydrotherapy has found a wide use in treatment for acute painful conditions such as rheumatoid arthritis, complex regional pain syndrome, and postoperative pain conditions. The benefits of water exercises include elimination of gravity, positive effect of buoyancy,24 increased muscle relaxation, and decreased joint compression. Hydrostatic forces have been shown to increase venous return, improve stroke volume and cardiac output, and promote a reflexive bradycardia.25,26 With the buoyancy of water, the effective weight of the patient is proportionally decreased as the depth increases. Weight-bearing loads are reduced to 40% of the total body weight when the patient is standing in chest deep water. With floating, the effects of gravity are eliminated. Exercises in water may introduce increased loads to tissue by gradually decreasing the depth at which therapy is performed. Water viscosity provides resistance to movement equal to that of the force exerted by the patient. Resistance varies with the speed of the movement performed.27 Clinically, patients experience reduced levels of pain while performing passive and active range of motion as well as strengthening exercises in water. Patients may perform closed kinetic chain activities when pain or weight-bearing precautions prohibit land-based therapy. Water exercise is often perceived as easier than the same exercise performed on land. Studies have also demonstrated a reduction of pain and an improvement of function in patients participating in hydrotherapy as long as 3 months after initiation of therapy. Hall and associates28 randomly assigned 139 patients with rheumatoid arthritis to receive hydrotherapy, seated immersion, land exercise, or progressive

relaxation. Patients attended 30-minute sessions twice weekly for 4 weeks. Physical and psychological measures were completed before and after intervention and again at a 3-month follow-up. The data revealed conclusively that the hydrotherapy patients showed significantly greater improvement in joint tenderness and in knee range of movement (women only) than the other patients. In addition, at the follow-up measurement, the hydrotherapy patients maintained the improvement in emotional and psychological state.

Passive Physical Modalities Physical modalities are an integral part of the management of acute and chronic pain conditions in a rehabilitation setting. A modality describes any physical agent utilized to produce a physiologic response to a targeted tissue. Commonly prescribed modalities include ice, heat, electrical stimulation, ultrasound, transcutaneous electrical nerve stimulation (TENS), interferential current therapy (ICT), iontophoresis, and phonophoresis. Occasionally, other modalities such as paraffin baths, short-wave diathermy, and laser therapy are incorporated. This section gives a brief overview of each of these modalities.

Cryotherapy Physiology Most forms of cryotherapy (ice, cold packs, vapocoolant spray, cryotherapy-compression units) provide transfer of thermal energy by conduction, with the exception of vapocoolant sprays and whirlpool baths. Common application techniques include use of ice packs, ice massage, or cold-water immersion. The physiologic effect of cold application includes immediate vasoconstriction and reflexive vasodilatation that occurs when cold paralyzed vascular smooth muscle relaxes at about 158C.29 This process ultimately leads to decreased local metabolism and enzymatic activity, decreased nerve conduction, and analgesia.30 Cryotherapy has shown efficacy with acute musculoskeletal pain syndromes, soft tissue pain/inflammation, and muscle pain related to eccentrically activated exercises, a condition known as delayedonset muscle soreness (DOMS), which normally peaks 1 to 2 days after activity, with symptoms continuing for up to 10 days31,32 (Box 73–6). Ice application may help decrease the time to return to participation and sport activity.33,34

Patient selection Indications Because connective tissue stiffness and muscle viscosity are increased with cold application, in general, cryotherapy should be

Box 73^6 INDICATIONS FOR CRYOTHERAPY Table 73^4. AquaticTherapy Very hot (1118F) Hot (1008F) Warm (948F) Neutral (928F) Tepid (808F) Cool (678F) Cold (508F)

Pain reduction Arthritis, increase range of motion Open wounds, de´bridements Circulatory disorders, manual techniques for relaxation Therapeutic exercise Decrease spasticity Inflammation, acute tissue changes

Adapted from Konlian C. Aquatic therapy: making a wave in the treatment of low back injuries. Orthop Nurs 1999;18:11–18.

           

Acute trauma Edema Hemorrhage Pain Muscle spasm Spasticity Reduction of metabolic activity Osteoarthritis Minor burns Acute/chronic pain Myofascial pain Contusion inflammation

Adapted from Weber DC, Hoppe KM. Physical agent modalities. In Braddom RL (ed): Physical Medicine and Rehabilitation, 3rd ed. Philadelphia: Saunders Elsevier, 2007; pp 459- 478.

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used during the first 48 hours after musculoskeletal injury.35 Some studies have suggested that the efficacy of cryotherapy may be greater for limiting swelling and decreasing pain after acute injury or surgery, with less vigorous evidence to support its use for chronic pain conditions.36,37 Contraindications The main contraindications to cryotherapy are cryoglobulinemia, cold hemoglobulinemia, cold hypersensitivity, urticaria, Raynaud’s disease, impaired sensation, paroxysmal cold hemoglobinuria, and ischemia.

Box 73 -7 INDICATIONS FOR HEAT THERAPY       

Chronic inflammation Arthritis Myofascial pain Collagen vascular disease Sprains Strains Contracture thrombophlebitis

Contraindications Heat

Heat therapy should be avoided in acute trauma, inflammation, bleeding disorders, edema, scars, impaired sensation, malignancy, and multiple sclerosis.

Physiology The three commonly used mechanisms of heat transfer are n Conduction: transferring of heat from one surface to another. n Convection: transfer of heat due to movement of air or water

across the surfaces. n Conversion: transformation of energy to heat, which is

involved in various forms of cryotherapy/heat (Table 73–5). Heating of the tissues results in increased blood flow to the surface, vasodilatation, increased oxygenation and leukocytes, indirect muscle relaxation, increased metabolism, increased capillary permeability, and collagen extensibility.

Indications Heat therapy is used to treat pain, contracture, hematoma, chronic inflammation, muscle spasm, and arthritis (Box 73–7).

Table 73^5. Mechanisms of Cryotherapy and Heat Therapy Mechanism

Cold/Cryotherapy

Heat

Conduction: by direct contact

Cold packs, ice Hot packs, massage, cold water paraffin baths (1268F–1308F) immersion, cryocompression Whirlpool Fluidotherapy Convection: (1188F/47.88C) movement of a Whirlpool baths medium Conversion: Ultrasound transformation Short-wave diathermy of energy Microwave IR Radiation: emitted Near IR from surface (wl-770-1500 nm) temperature Far IR (wl-150012,500 nm) Vapocoolant spray Evaporation: transforms liquid to gas Requires thermal energy

IR, infrared; wl, wavelength. Adapted from Weber DC, Brown AW. Physical agent modalities. In Braddom RL (ed): Physical Medicine and Rehabilitation, 2nd ed. Philadelphia: WB Saunders, 2000; pp 440–458.

Different types of heat applications The heat modalities are generally classified as superficial or deep. Superficial heat The most commonly used forms of superficial heat are hydrocollator packs, paraffin baths, hydrotherapy, and heat wraps. n Hydrocollator packs are available in various sizes for cervical,

thoracic, and lumbar areas. They are generally heated in stainless steel containers in water temperatures close to 958C. The common duration of heat treatment is between 15 and 30 minutes. Hot packs are the most commonly used heating modality.38 n Hydrotherapy is used for submerging a body part in heated water. Heat treatment also increases active and passive range of motion of the joint and promotes muscle flexibility. Hydrotherapy is also a common adjunct to the treatment of rheumatoid arthritis, diffuse muscle tension, and spasm. The most commonly used forms of hydrotherapy are whirlpool baths and Hubbard tanks. n Paraffin baths are thermostatically controlled tanks filled with a mixture of mineral oil and paraffin. They are predominantly used in treatment of smaller joints, such as hands, fingers, and feet. The mixture of heat and paraffin oil provides increased thermal release over that of water. Temperatures range from 458C to 528C degrees for lower extremities and 528C to 588C degrees for upper extremities. Care must be taken with patients with peripheral neuropathies and vasculo-occlusive diseases.39 n Heat wraps are disposable clothlike patches that, when exposed to the air, heat up to approximately 1048F within 30 minutes and last for at least 8 hours (ThermaCare, Proctor and Gamble Co., Cincinnati, OH). Deep heat The most commonly used forms of deep heat are diathermy (ultrasound, short-wave diathermy, and microwave diathermy), phonophoresis, and iontophoresis. DIATHERMY The three diathermy agents are ultrasound, short-wave diathermy, and microwave diathermy. n Ultrasound. Ultrasound is commonly used in the treatment

of decreased range of motion, contractures, subacute trauma, and chronic degenerative osteoarthritis. Ultrasound is often used as an adjunct to stretching exercises prior to aggressive joint manipulation (Box 73–8). Ultrasound is defined as an acoustic vibration with an audible range of 20,000 Hz. The heat is produced as a result of the conversion of electrical

534 Chapter 73  PHYSICAL MEDICINE APPROACHES TO PAIN MANAGEMENT

Box 73^8 INDICATIONS AND PRECAUTIONS FOR ULTRASOUND THERAPY

From Stanos SP,Tyburski M: Rehabilitation issues: Pain control.InVon Roenn JH,Price JA,Preodor ME, et al (eds): Current Diagnosis and Treatment of Pain.NewYork: Lange/McGraw Hill, 2006.

current into ultrasound energy through the use of a quartz crystal, which is subsequently converted into heat. Depth of heating may be up to 5 cm below the skin surface, providing a therapeutic benefit to superficial bone, joint capsule, ligament, and scar tissue. The ultrasound dosage is measured in Watts per square centimeter. Intensities of 0.8 to 3.0 W/ cm2 are commonly used.40 The dosage is varied depending on the condition. In subacute painful conditions such as tendinitis and adhesive capsulitis, lower intensities and higher frequencies are used. In more chronic conditions, such as contractures due to scar formations, intensities as high as 3.0 W/cm2 are utilized. Ultrasound may decrease pain and improve range of motion in acute pain disorders and osteoarthritis compared with chronic pain conditions.41 Other studies have found any benefit to be based on empirical experience, lacking support from controlled studies.42 n Short-wave diathermy. Short-wave diathermy uses an oscillating electromagnetic field of high frequency to heat body surface areas. It heats to a tissue depth of 2 to 3 cm. Despite gradual decline in its use, short-wave diathermy still finds its place in treatment of large-surface body areas, such as lower extremities, upper extremities, and back. A study by Garrett and colleagues43 concluded that pulsed short-wave diathermy was more effective than 1-MHz ultrasound in heating a large muscle mass and resulted in the muscles’ retaining heat longer. n Microwave diathermy. Microwave diathermy uses electromagnetic radiation by microwaves and heats to a lesser tissue depth than short-wave diathermy. It is primarily used to heat superficial muscles and joints such as the shoulder. Besides its use in musculoskeletal conditions, this modality has been employed to reduce the potential effects of cancer chemotherapy and radiation treatment.44

Iontophoresis uses electromigration and electroosmosis to increase the permeation of charged and neutral compounds. It is noninvasive and painless and avoids potential side effects and adverse reactions of oral medications or injection therapies (e.g., increased risk for bleeding, intravenous catheter infiltration, and pump malfunction). Penetration may be particularly intense at sweat glands and areas of skin breakdown. Iontophoresis therapy has been applied transdermally in the postoperative pain-management setting. The U.S. Food and Drug Administation (FDA) has recently approved an iontophoretic transdermal fentanyl system.45 The first needle-free, patientactivated analgesic system for acute postoperative pain is a potential alternative to patient-controlled analgesia (PCA). The fentanyl HCl patient-controlled iontophoretic transdermal system (PCITS) uses an imperceptible, low-intensity direct current to deliver fentanyl on demand across the skin and subsequently into the systemic circulation. The quantity of fentanyl delivered is directly proportional to the magnitude of current applied by the device.46 Studies have shown the efficacy of iontophoretic fentanyl over PCA morphine in a number of postoperative pain states.47,48 Indication. Iontophoresis is widely used in the treatment of overuse conditions such as epicondylitis and plantar fasciitis.49,50 Yarrobino and coworkers49 investigated lidocaine iontophoresis (LI) in patients with subacute to chronic epicondylitis using 80 mA/min, low-current, long-duration LI over a 24-hour period. Patients were treated every other day for three treatment sessions and demonstrated improved pain and function.49 Osborne and Allison51 compared 0.4% dexamethasone to placebo and 5% acetic acid along with taping in patients with plantar fasciitis. Six treatments of acetic acid iontophoresis combined with taping provided greater relief from stiffness and greater improvement in morning pain compared with dexamethasone.51 There have been case reports of iontophoretic treatment in postherpetic neuralgia.52 Dowd and associates53 performed a prospective, double-blind, placebo-controlled trial of patients with postherpetic neuralgia. The goal of the study was to determine the effect of iontophoretic administration of vincristine versus saline in patients unresponsive to conservative treatment for postherpetic neuralgia. The patients were randomly divided in two groups; each group received 20 days of vincristine (0.01%) or saline for 1 hour a day for 20 days via iontophoresis. Whereas the response was similar in the vincristine and the saline groups (40% and 55%, respectively, reported moderate to greater improvement after 20 days), the authors concluded that a maintained improvement in both groups (30% with vincristine and 33% with saline) at 3 months follow-up could be attributed to a beneficial effect of iontophoresis.

Electrical Stimulation The most commonly applied electrical modalities in the treatment of pain include TENS and ICT. TENS and ICT involve the transmission of electrical energy to the peripheral nervous system via an external stimulator.

Physiology PHONOPHORESIS Phonophoresis allows delivery of topically applied medications (analgesics, anti-inflammatory agents) into the deeper areas of skin using ultrasound. Phonophoresis is frequently used in the treatment of postinjury conditions (dislocations, joint distortions), rheumatologic and musculoskeletal pain disorders, and spinerelated conditions (nerve root pain, and disk-related pain). IONTOPHORESIS Iontophoresis is the process by which various drugs (e.g., dexamethasone, fentanyl, insulin, or lidocaine) are introduced into a joint or small body area superficially via electrical current.

TENS is based theoretically on the gate-control theory originally proposed by Melzack and Wall.54 The theory is based on the concept of blocking and/or modulating nociceptive transmission at the level of the spinothalamic tract via stimulation of inhibitory interneurons. Activity in large myelinated afferent fibers theoretically activates dorsal horn interneurons that inhibit cephalad transmission in small unmyelinated primary afferent nociceptive fibers and the secondary transmission cells in the lateral spinothalamic tracts. Somatic afferents activate convergent wide-dynamic-range cells deep in the dorsal horn (lamina V), which project in the spinothalamic tract to higher somatosensory processing in the thalamus and cortex.

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Techniques Box 73^9 CONTRAINDICATIONS AND PRECAUTIONS FOR ELECTRICAL STIMULATION THERAPY

n TENS. This treatment is typically applied in two formats: low-

intensity, high-frequency ‘‘conventional’’ TENS (1–2 mA, 50– 100 Hz) and high-intensity, low-frequency ‘‘dense-disperse’’ TENS (15–20 mA, 1–5 Hz). High-frequency TENS is used to achieve a faster onset of analgesia for acute pain states and low-frequency TENS is used for chronic pain conditions. Treatment times range from 30 minutes for slower analgesia affects to 2 to 6 hrs for long-duration analgesia.55 n ICT. A variant of TENS, ICT involves mixing of two sine waves with different frequencies, allowing for summated waveforms and stimulation of deeper tissues with less patient discomfort. The proposed mechanism of action involves direct stimulation of muscle fibers, as opposed to nerve fibers, to achieve increased vasodilatation and improve healing.

Massage

ICT, interferential current therapy; TB, tuberculosis; TENS, transcutaneous electrical nerve stimulation. From Stanos SP,Tyburski M: Rehabilitation issues: Pain control.InVon Roenn JH,Price JA,Preodor ME, et al (eds): Current Diagnosis and Treatment of Pain.NewYork: Lange/McGraw Hill, 2006.

The three routes of neuromodulation include presynaptic inhibition of the spinal cord, direct inhibition of abnormally firing nerves, and facilitation of afferent input. Other mechanisms of analgesia include direct peripheral effects of stimulation as well as increased release of endogenous opioids within the central nervous system. The indications for the use of TENS and ICT are similar, and the decision to use one form over the other is largely based on clinical preference. Contraindications and precautions for electrical stimulation therapy are similar as well (Box 73–9).

Therapeutic massage involves certain manipulations of soft tissue of the body, mostly applied by a practitioner, and can include holding, causing movement, and/or applying pressure to the body. Massage therapy has been difficult to assess with regards to clinical outcomes owing to the variability in techniques, styles, and names. The American Massage Therapy Association publishes a glossary of terms that help to clarify some of these issues. Four basic massage strokes are effleurage, petrissage, friction massage, and tapotement. A proposed taxonomy of massage practice divides therapeutic message into four separate groups: (1) relaxation massage, (2) clinical massage, (3) movement reeducation, and (4) energy work56 (Table 73–6). Relaxation massage focuses on moving body fluids, such as lymph and blood, nourishing cells, removing waste from local tissue, relaxing muscles, and decreasing pain. Swedish message is the most commonly practiced type of relaxation massage and employs five basic strokes (effleurage, petrissage, friction, vibration, and percussion). Clinical massage involves more focused manipulation of muscle and/or surrounding soft tissue or fascia and may incorporate other effected organs including the lymphatic, circulatory, and nervous system as a means of relieving pain and

Table 73^6. Proposed Taxonomy of Massage Practice

From Sherman KJ, Dixon MW, Thompson D, Cherkin DC. Development of a taxonomy to describe massage treatments for musculoskeletal pain. BMC Compl Alternative Med 2006;6:24.

536 Chapter 73  PHYSICAL MEDICINE APPROACHES TO PAIN MANAGEMENT decreasing restricted movement.57 Common types include myofascial trigger point therapy and release and neuromuscular therapy. Movement reeducation focuses on enhancing posture, body awareness, and movement. Energy work is believed to ‘‘assist the flow of energy in the body’’ with light touch or by holding the hands above the skin (e.g., Reiki, Therapeutic Touch).58 A meta-analysis of massage therapy found that a single application of treatment reduced anxiety, blood pressure, and heart rate; it reduced pain only after multiple treatments.59

Massage terminology and techniques: american massage therapy association60 Massage therapy is a profession in which the practitioner applies manual techniques, and may apply adjunctive therapies, with the intention of positively affecting the health and well-being of the client. Massage is a manual soft tissue manipulation and includes holding, causing movement, and/or applying pressure to the body. Deep Tissue releases the chronic patterns of tension in the body through slow strokes and deep finger pressure on the contracted areas, either following or going across the grain of muscles, tendons, and fascia. It is called deep tissue because it also focuses on the deeper layers of muscle tissue. Effleurage is a stroke generally used in a Swedish massage treatment. This smooth, gliding stroke is used to relax soft tissue and is applied using both hands. Friction is the deepest of Swedish massage strokes. This stroke encompasses deep, circular movements applied to soft tissue, causing the underlying layers of tissue to rub against each other. The result is an increase in blood flow to the massaged area. Myofascial release is a form of bodywork that is manipulative in nature and seeks to rebalance the body by releasing tension in the fascia. Long, stretching strokes are utilized to release muscular tension. Petrissage (also called kneading) involves squeezing, rolling, and kneading the muscles; it usually follows effleurage during Swedish massage. Reflexology is massage based around a system of points in the hands and feet thought to correspond, or ‘‘reflex,’’ to all areas of the body. Shiatsu and acupressure are Oriental-based systems of finger-pressure that treat special points along acupuncture ‘‘meridians’’ (the invisible channels of energy flow in the body). Swedish massage is a system of long strokes, kneading, and friction techniques on the more superficial layers of the muscles, combined with active and passive movements of the joints. Tapotement is executed with cupped hands, fingers, or the edge of the hand with short, alternating taps to the client.

LaserTherapy Low-level laser therapy (LLLT) has been investigated and used clinically for over 30 years in Eastern Europe and Asia. It is beginning to gain popularity in Canada. Its use is based on its ability to nonthermaly and nondestructively alter cellular function. This phenomenon, known as laser biostimulation, is the basis for its use in treatment of many rheumatologic, neural, and soft tissue conditions. LLLT uses low outputs levels (15,100 mW), short treatment times (10–240 sec), and low energy levels (1–4 J/cm2). The mechanism and effectiveness of LLLT have been compared with ultrasound therapy and could potentially be used as an extension to the accepted physiotherapy modalities that currently utilize parts of the electromagnetic spectrum, such as short waves, microwaves, infrared, and ultraviolet therapy. The proposed mechanism of action includes repairing of crushed or damaged

nerves and improvement of central and peripheral nervous system functioning. The FDA has classified LLLT as class III, nonsignificant risk, and medical device for investigation use only.61

CLINICAL CONDITIONS This section reviews theoretical issues related to underlying mechanism of common pain conditions (osteoarthritis, low back pain, and myofascial pain syndrome) and principles guiding active physical medicine approaches. In many cases, these same principles can be applied to the other acute and chronic pain conditions.

Osteoarthritis As the population ages, the treatment of osteoarthritis and the symptoms associated with it have become a major part of the rehabilitation medicine. Osteoarthritis is a multifactorial disorder resulting from various causes, such as joint degenerative changes, genetic predisposition, obesity, and environmental factors. As the patient progresses through the continuum of the disease, she or he acquires compensatory patterns that often bring her or him to a physiatric’s attention in the first place. Decreased range of motion, muscle imbalance, joint deformities, poor postural adaptation, and pain are some of the presenting signs and symptoms that are managed in the rehabilitation setting. As a rule, a rehabilitation program starts with patient education about the disease and behavior modification techniques. The treatment is then initiated with gentle passive and active range of motion exercises of the involved joints. Active therapy is aimed at restoring range of motion and optimizing joint stability through muscle contraction. A muscular reeducation technique is often used to ‘‘unload ‘‘and protect the joint. Activities, such as active isometric contraction of the quadriceps muscle and reflexive relaxation of the hamstring muscle, have been shown to improve joint position sense and reduce pain and inflammation.62 During acute stages of pain, therapeutic modalities such as TENS, ICT, and low-intensity ultrasound are often utilized. Ultrasound is commonly used prior to exercise performance. Besides acting as an analgesic anti-inflammatory agent, it also serves as a deep-heating modality, thus promoting better stretching and passive movement of the joint. ICT is often used in the middle or toward the end of the therapy session, sometimes in combination with ice, for optimal pain reduction. Occasionally, an external device will be used in conjunction with an active therapy. Joint taping, orthotics, and braces are often utilized in the acute stages of osteoarthritis when pain and joint instability are major limiting factors of the daily activity performance. Braces and taping may also serve as part of proprioceptive training,63 helping to improve the patient’s awareness of his or her joint in space. In addition, foot orthotics such as lateral wedge insoles and shock-absorbing devices are often used for improvement of the biomechanics of gait and cosmetic appearance of the patient’s limbs. General principles for bracing include supporting moving body parts, correcting alignment, limiting excessive motion, and facilitating motion (Box 73–10).

Box 73^10 GENERAL PRINCIPLES OF BRACING     

Support or reorient moving body parts (e.g., joints, tendons) Control or guide direction of movement Align into more stable or less painful position Limit or stop excessive motion Facilitate or correct motion

From Rakel B, Barr JO. Physical modalities in chronic pain management. Nurs Clin North Am 2003;38:477^ 494.

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Aerobic exercises such as walking, swimming, and cycling have a special role in the treatment of osteoarthritis.64 Inability to walk is often the very complaint that brings a patient to the attention of a physiatrist. The well-rounded rehabilitation program, which includes active strengthening, passive analgesic techniques, and appropriate gait-assistive devices, such as canes, crutches, and braces, will often enable the patient to ambulate as early as 1 week after the beginning of rehabilitation treatment. Swimming serves as both an excellent alternative and an adjunct to ambulation. As described previously, water can act as an anti-inflammatory modality and soothing device for the patient with acute pain. It also provides an adequate resistance to joint movement without the stress of weight-bearing. Stationary cycling can often be started on the first day of treatment. The stationary bicycle can be used as an active and a passive stretching/range of motion device as well as a dynamic strengthening tool.65 The different degrees of seat elevation and gauge resistance can allow a therapist to train a patient at multiple joint angles while increasing a muscle load.

Low Back Pain: Physical and Occupational Therapy Perspective Back pain is the most common cause of chronic pain in the United States. A number of active physical therapy treatments of spinerelated conditions have demonstrated efficacy in decreasing pain and improving function.66 The possible explanation behind some of the success of physical therapy treatment is an understanding of the heterogeneous nature of spinal conditions and tailoring a treatment plan accordingly. For example, management of low back pain resulting from a sprain/strain is very different from the one of discogenic origin. In addition, owing to the fact that a physical therapy treatment lasts over several sessions, there is often room for an adjustment, reassessment, and trial-and-error approach not often seen in other specialties. Riddle67 cited classification systems that have been used for low back pain. Four main classification systems were determined to be the most appropriate and commonly used by physical therapists and, therefore, were reviewed systematically. Mechanical classification in the McKenzie68 mechanical diagnosis and therapy (MDT) system is based on three different ‘‘syndromes’’ or as ‘‘other.’’ 1. Posture syndrome involves pain arising from abnormal postures and related deformation of normal soft tissues in which the treatment is focused on posture correction. 2. Dysfunction syndrome is the result of end-range stresses of structures that have been shortened, scarred, or adhered. Treatment focuses on exercises in the direction of the dysfunction and the goal of ‘‘remodelling,’’ tissue. Four subgroups of the syndrome include flexion dysfunction, extension dysfunction, side-gliding dysfunction, and adherent nerve root dysfunction. 3. Derangement syndrome represents pain occurring as a result of a disturbance in the normal resting position of joint surfaces (e.g., intervertebral disk in lumbar pain syndromes). This syndrome is classified as either reducible or irreducible based on the patient’s symptomatic and mechanical response to repeated movements or positions as assessed by the therapist or physician. Hence, directional preference rests on the ‘‘patient’s response’’ to the direction of movement. The patient is asked to move through range of motion while the therapist assesses the degree of discomfort. The concept of centralization, recognized by McKenzie,68 is based on the theory by which pain radiating from the cervical, thoracic, and lumbar spine is sequentially abolished, neurologic symptoms are decreased,69 or reduction of discomfort is noted. The direction of movement can vary from extension, flexion, or side-bending. As the patient moves away from discomfort,

her or his pain is described as less bothersome, more localized, and proximal. Positions of centralization usually include extension (standing or supine) followed by lumbar flexion.70 Reducible direction of pain improvement then becomes a guide to patient’s treatment. For example, a patient who finds low back pain relief after repetitive extension movements during the evaluation will most likely benefit from therapeutic exercises focusing on spine extension. The exercises involving this movement are offered in a clinic and as a part of a home exercise program. The successes in treating a patient with this approach rests on the fact that the patient will eventually be able to independently modify her or his symptoms and prevent further spine damage. 4. The fourth category, referred to as ‘‘other,’’ describes those patients who do not meet criteria for a mechanical syndrome) as discussed previously and include conditions related to sacroiliac joint disorders, spinal stenosis, spondylosis, spondylolisthesis, hip pathology, zygapophyseal joint disorders, or postsurgical conditions.71 The Philadelphia Panel72 was one of the largest systematic reviews of randomized, controlled trials focusing on the treatment of low back pain. It looked at specific outcomes including pain, quality of life, return to work, patient global assessment, and function. Interventions for low back pain that were reviewed include therapeutic massage, therapeutic exercises, biofeedback, ultrasound, thermotherapy, TENS, mechanical traction, electrical stimulation, and combined interventions. Specific to chronic low back pain, the Panel recommended extension, flexion, and strengthening therapeutic exercises and therapeutic ultrasound for pain relief due to spasms. Other modalities and treatments could not be recommended for treatment of chronic low back pain secondary to lack of sufficient evidence and availability of comparative studies based on the criteria of strict randomized, controlled trials used by the Philadelphia Panel for the systematic review.

General TherapyTreatment Approach Short- and long-term therapy plans incorporate graded strengthening and stretching exercises as well as postural correction and retraining. As with any acute or chronic condition, success in management of spine-related conditions is dependent on successive advancement through four specific phases including 1. 2. 3. 4.

Pain control. Flexibility and strengthening. Aerobic conditioning. Retraining in sport-specific or activity-related functioning.

Rehabilitation Progression Pain control Whether acute or chronic in origin, pain remains a major limiting factor in a patient’s recovery. If severe, it can compromise not only the physical but also the psychological state of the patient, a factor invaluable in a successful rehabilitation. Thus, aggressive pain management should be started as soon as the first visit (the management of low back pain has been discussed elsewhere in this chapter), the patient should be frequently reassessed, and end goals should be clearly established.

Flexibility and strength Lack of flexibility, imbalance, and weakness of core musculature are commonly seen in patients with low back pain. A basic physical therapy treatment should include stretching of tight or contracted muscles, activating inhibiting muscles, and improving core strength. Exercises are commonly targeted on retraining multifidus and

538 Chapter 73  PHYSICAL MEDICINE APPROACHES TO PAIN MANAGEMENT erector spinae (back muscles) and rectus and transverse abdominus (deep abdominal muscles) along with additional exercises for the pelvic floor and breathing control.73 The therapist will train the patient to contract these (core) muscles independently from the more superficial muscles. As a rule, tight, antagonist muscles commonly seen in patients with low back pain will be addressed simultaneously. Hip flexors, upper paraspinals, and pectoral muscles will be passively (performed by the therapist) and actively (closed kinetic chain exercises, performed by the patient) stretched as the patient progresses through the rehabilitation program. The anticipated result is that the patient will not only have a corrected muscle imbalance but also have acquired a proper posture and biomechanics that will prevent him or her from further injuries.

Balance and aerobic conditioning As the patient progresses through the rehabilitation program, balance and aerobic conditioning become incorporated into the training repertoire. Balance training is achieved through use of Swiss (medicine) balls, balance boards, and TheraBand elastic strips. The patient will generally start with static balance exercises (such as standing with feet together or standing on one leg) and then progress to dynamic balance exercises (such as catching a ball while standing on one leg or raising an arm while sitting on a Swiss ball). Aerobic conditioning training involving walking on a treadmill, swimming, or bicycling is generally offered at the beginning and at the end of therapy sessions. The goal of this type of exercise is to optimize the patient’s cardiovascular and respiratory state as well as to prepare her or himr for anticipated return to her or his previous employment and/or sports-related activities. Some studies suggest that activity in general may itself be therapeutic in reducing pain and improving psychological functioning.74

Sports-specific The sports- and/or task-specific exercise routine has been a subject of increased interest in medical rehabilitation. The idea of preparing a patient to return to sports that often caused or predisposed him or her to injury in the first place has always posed a challenge for physicians and therapists. The concept of Specificity Principle states that training must go from highly general training to highly specific training. The principle of Specificity also implies that in order to become better at a particular exercise or skill, a patient must perform that exercise or skill repeatedly. For example, for a patient who has injured his or her low back while playing golf, the training will be focused on simultaneous activation of rectus abdomini, erector spinae, and transverse abdominal muscles during a swing phase. The number of swing phases will be gradually increased until the patient will be allowed to play a full round. While preparing a patient to return to a specific sport and/or occupational task, a physician needs to understand the athletic profile of the individual. In general, it is recommended that the patients should refrain from competitive activity until near-normal back strength and range of motion as well as pain-free activity have been achieved.75

for myofascial trigger points include postural muscles in the neck, shoulders, pelvic girdle and the upper trapezius, scalene, levator scapulae, quadratus lumborum, and the lumbosacral muscles. Myofascial pain syndrome can be aggravated by multiple causes: acute tissue trauma, repetitive microtrauma, muscle deconditioning, postural abnormalities (in the workplace, home, or during recreational activities), poor sleeping habits, and metabolic issues (including vitamin deficiencies and hypothyroidism). During an evaluation focusing on myofascial pain syndrome, the physiatrist as well as the therapist will focus on posture, body mechanics, dynamic joint function, and location and assessment of myofascial trigger points. When assessing trigger points, the clinician palpates for a rigid, fibrous nodule that is associated with the symptoms mentioned previously. At times, instead of a nodule, the clinician will palpate a defined hypersensitive collection of muscle associated with these symptoms.76 The pain associated with the trigger point will usually travel in a proximal to distal pattern. Localized muscle groups may refer pain in distinct patterns. Common areas of presentation include the cervical and lumbar paraspinals, trapezius, gluteus medius and maximus, and piriformis muscle groups (Table 73–7). Active physical therapy and passive modalities may be combined as part of a comprehensive treatment plan. Physical therapy focuses on improving posture and body mechanics with functional tasks that may be contributing to pain and dysfunction. Therapy is focused on improving function of postural slow-twitch and phasic fast-twitch peripherally located muscles. Postural (type I) muscles are slow-twitch fibers with relatively low stores of glycogen and high myoglobulin and mitochondria, and they characteristically fatigue slowly. Under long-term stress, these muscles shorten, tighten, and demonstrate reasonable endurance. Phasic (type II) or fast-twitch muscles contain relatively high stores of glycogen and low myoglobulin and, under long-term stress, are prone to weaken. Passive modalities may be provided by the therapist as a means of decreasing pain and facilitating therapy. Modalities targeted at deactivating symptomatic trigger points include massage, ultrasound, acupressure, spray and stretch therapy, and TENS (Box 73–11).76 (See the section on ‘‘Passive Physical Modalities,’’ earlier.) Spray-and-stretch therapy is a technique performed by the therapist in which a passive stretch to the affected muscle is applied while concurrently spraying a local soft tissue coolant. This coolant spray contains dichlorodifuoromethane-trichloromonofluoromethane or ethyl chloride with the ability to decrease the temperature of the skin and provide an analgesic effect by blocking the spinal stretch reflex and central sensation of pain. With acupressure, clinicians apply gentle manual pressure over areas based on meridian and acupuncture pressure points.77

Table 73^7. Common Referral Patterns for

Myofascial Pain Syndrome Myofascial pain syndrome is distinguished from other chronic pain syndromes by localized muscle tenderness, referred pain patterns, trigger points, local twitch response, pain in a taut band of muscle, withdrawal to pain when pressure is applied to a myofascial trigger point, and restriction of motion. It can occur in any muscle, asymmetrically, and may be due to one or all of these factors: acute tissue trauma, muscle deconditioning, sensitized nerve foci, postural abnormalities, and repetitive microtrauma. The main locations

Adapted from Simons DG, Travell JG, Simons LS (eds): Travell and Simons Myofascial Pain and Dysfunction, The Trigger Point Manual, Vol.1, 2nd ed. Philadelphia: Lippincott Williams & Wilkins, 1999.

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Box 73^11 TRIGGER POINT DEACTIVATION

From Alvarez PJ, Rockwell PG: Trigger point diagnosis and management. Am Fam Physician 2002;65:653- 660.

SUMMARY As with any comprehensive treatment plan for acute or chronic pain, a physical medicine approach is based on identifying underlying causes of pain, physical impairments, and related disability. The primary focus is on maximal restoration of physical and psychological function and on alleviation of pain. Physical and occupational therapy interventions rely on a basic appreciation for the kinetic chain. Understanding deficits above and below or distal and proximal to the pain region, passive modalities may be used to facilitate a therapeutic exercise program, create short- and longerterm analgesia, and include heat and cold modalities. Low back pain–related conditions, common diagnoses seen in practice, focus on incorporating analgesic, antidepressant, and sleep pharmacotherapy into an active therapeutic exercise program. Physical therapy approaches include stabilization exercises and/or directional preference therapies. Occupational therapy focuses on assessing posture, improving tolerance for activity, and ergonomic assessment. Myofascial pain treatment focuses on similar assessment of posture and muscle impairments with the use of additional modalities (cold stretch, trigger point deactivation). Any rehabilitation approach should individually progress a patient through a logical conditioning and, finally, a gradual return to sports-specific or leisure activity pursuits and/or activities of daily living.

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14. Farrell PA, Gates WK, Maskud MG, et al. Increases in plasma betaendorphin/betalipotropin immunoreactivity after treadmill training in humans. J Appl Physiol 1982;52:1245–1249. 15. Grossman A, Sutton JR. Endorphins: what are they? How are they measured? What is their role in exercise? Med Sci Sports Exerc 1985;17:74–81. 16. Wilson WM, Marsden CA. Extracellular dopamine in the nucleus accumbens of the rat during treadmill running. Acta Physiol Scand 1995;155:465–466. 17. Fagard RH. Exercise characteristics and blood pressure response to dynamic physical training. Med Sci Sports Exerc 2001;33(suppl):S484–S492. 18. McDougal JD. Hypertrophy or hyperplasia. In Komi PV (ed): Strength and Power in Sports. The Encyclopedia in Sports Medicine. Oxford: Blackwell, 1992; pp 230–238. 19. Follard JP, Williams AG. The adaptations to strength training. Morphological and neurological contributions to increased strength. Sports Med 2007;37:145–168. 20. Hoffman MD, Sheldahl LM,. Kramer WJ. Therapeutic exercise. In DeLisa JA, Gans BM (eds): Physical Medicine and Rehabilitation. Principles and Practice, 4th ed, Vol 1. Philadelphia: Lippincott Williams & Wilkins, 2005; p 409. 21. Staron RS, Karapondo DL, Kraemer WJ, et al. Skeletal muscle: adaptations during the early phase of heavy resistance training in men and women. J Appl Physiol 1994;76:1247–1255. 22. Kosek E, Ekholm J. Modulation of pressure pain thresholds during and following isometric contraction. Pain 1995;61:481–486. 23. Koltyn K, Trine M, Stegner A, Tobar D. Effect of isometric exercise on pain perception and blood pressure in men and women. Med Sci Sports Exerc 2001;33:282–290. 24. Konlian C. Aquatic therapy: making a wave in the treatment of low back injuries. Orthop Nurs 1999;18:11–18. 25. Choukroun M, Kays C, Varene P. Effects of water temperature on pulmonary volumes in immersed human subjects. Respir Physiol 1989;75:255–266. 26. Anstey K, Roskell C. Hydrotherapy: detrimental or beneficial to the respiratory system? Physiotherapy 2000;86:5–12. 27. Prins J, Cutner D. Aquatic therapy in the rehabilitation of athletic injuries. Clin Sports Med 1999;18:447–461. 28. Hall J, Skevington SM, Maddison PJ; Chapman K. A randomized and controlled trial of hydrotherapy in rheumatoid arthritis. Arthritis Care Res 1996;9:206–215. 29. Enwemeka CS, Allen C, Avila P, et al. Soft tissue thermodymnamics before, during and after cold pack therapy. Med Sci Sports Exerc 2002;34:45–50. 30. Knight KL. Cryotherapy: Theory, Technique and Physiology. Chattanooga, TN: Chattanooga Corporation, 1985. 31. Howaatson G, Van Someren KA. Ice massage. Effects on exercise-induced muscle damage. J Sports Med Phy Fitness 2003; 43:500–505. 32. Szymanski D. Recommendations for the avoidance of delayed onset muscle soreness. Strength Cond J 2001;23:47–53. 33. Hubbard TJ, Aronson ST, Denegar CR. Does cryotherapy hasten return to participation? A systematic review. J Athl Train 2004;39:88–94. 34. Hubbard TJ, Denegar CR. Does cryotherapy improve outcomes with soft tissue injury? J Athl Train 2004;39:278–279. 35. Knight KL. Ice, compression and elevation for initial injury care. In Knight KL (ed): Cryotherapy: Theory, Technique and Physiology. Chattanooga, TN: Chattanooga Corporation, 1985; pp 53–54. 36. Bleakly C, McDonough S, MacAuley D. The use of ice in the treatment of acute-soft-tissue injury: a systematic review of randomized controlled trials. Am J Sport Med 2004;32:251–261. 37. Melzack R, Jeans ME, Statford JG, et al. Ice massage and transcutaneous electrical stimulation: comparison of treatment for low back pain. Pain 1980;9:209–217. 38. Lindsay DM, Dearness J, McGinley CC. Electrotherapy usage trends in private physiotherapy practice in Alberta. Physiother Can 1995;47:30–34. 39. Oosterveld FG, Rasker JJ. Effects of local heat and cold treatment on surface and articular temperatures of arthritic knees. Arthritis Rheum 1994;31:1578–1582. 40. Bassford JR. Therapeutic physical agents. In DeLisa JA, Gans BM (eds): Physical Medicine and Rehabilitation, Principles and Practice, 4th ed. Philadelphia: Lippincott Williams & Wilkins, 2005; pp 256–257.

540 Chapter 73  PHYSICAL MEDICINE APPROACHES TO PAIN MANAGEMENT 41. Falconer J, Hayes KW, Chang RW. Therapeutic ultrasound in the treatment of musculoskeletal conditions. Arthritis Care Res 1990;3:85–91. 42. Gam AN, Johannsen F. Ultrasound therapy in musculoskeletal disorders: a meta-analysis. Pain 1995;63:85–91. 43. Garrett CL, Draper DO, Knight KL. Heat distribution in the lower leg from pulsed short-wave diathermy and ultrasound treatments. J Athl Train 2000;35:50–55. 44. Lee ER, Sullivan DM, Kapp DS. Potential hazards of radioactive electromagnetic hyperthermia in the presence of multiple metallic surgical clips. J Hypertherm 1992;8:809–817. 45. IONSYS, ALZA Corporation, Mountain View, CA. ALZA Corporation receives FDA approval for IONSYS (fentanyl iontophoretic transdermal system). 46. Mayes S, Ferrone M. Fentanyl HCl patient-iontophoretic transdermal system of the management of acute postoperative pain. Ann Pharmacother 2006;40:2178–2186. 47. Hartrick CT, Bourne MH, Gargiulo K, et al. Fentanyl iontophoretic transdermal system for acute-pain management after orthopedic surgery: a comparative study with morphine intravenous patientcontrolled analgesia. Reg Anesth Pain Med 2006;31:546–554. 48. Viscusi ER, Reynolds L, Chung F, et al. Patient-controlled transdermal fentanyl hydrochloride vs intravenous morphine pump for post-operative pain: a randomized controlled trial. JAMA 2004;291:1333–1341. 49. Yarrobino TE, Kalbfleisch JH, Ferslew KE, Panus PC. Lidocaine iontophoresis mediates analgesia in lateral epicondylalgia treatment. Physiother Res Int 2006;11:152–160. 50. Gudeman SD, Eisele SA, Heidt RS Jr, et al. Treatment of plantar fasciitis by iontophoresis of 0.4% dexamethasone. A randomized, double-blind, placebo-controlled study. Am J Sports Med 1997;25:312–316. 51. Osborne HR, Allison GT. Treatment of plantar fasciitis by low dye tapping and iontophoresis: short-term results of a double-blinded, randomized, placebo-controlled clinical trial of dexamethasone and acetic acid. Br J Sports Med 2006;40:545–549. 52. Ozawa A, Haruki Y, Iwashita K, et al. Follow up of clinical efficacy of iontophoresis therapy in post herpetic neuralgia (PHN). J Dermatol 1999;26:1–10. 53. Dowd NP, Day F, Timon D, et al. Iontophoretic vincristine in the treatment of postherpetic neuralgia: a double-blind, randomized, controlled trial. J Pain Symptom Manage 1999;17:175–180. 54. Melzack R, Wall P. Pain mechanisms: a new theory. Sci Justice 1965;150:971–979. 55. King EW, Audette K, Athman GA, et al. Transcutaneous electrical nerve stimulation activates peripherally located alpha2A adrenergic receptors. Pain 2005;115:364–373. 56. Sherman KJ, Dixon MW, Thompson D, Cherkin DC. Development of a taxonomy to describe massage treatments for musculoskeletal pain. BMC Compl Alternative Med 2006;6:24. 57. Levine AS, Levine VJ. The Bodywork and Massage Sourcebook. Los Angeles: Lowell House, 1999. 58. Barnes JF. The basic science of myofascial release. J Bodywork Movement Ther 1997;1:231–238.

59. Moyer CA, Rounds J, Hannum JW. A meta-analysis of massage therapy research. Psychol Bull 2004;130:3–18. 60. http://www.amtamassage.org/about/terms.html (accessed August 27, 2008). 61. Bastford JR. Low intensity laser therapy: still not an established clinical tool. Laser Surg Med 1995;16:331–342. 62. Van Baar ME, Dekker J, Oostendorp RA, et al. The effectiveness of exercise therapy of the hip and knee: a randomized clinical trial. J Rheumatol 1998;25:2432–2439. 63. Birmingham TB, Kramer JF, Kirkley A, et al. Knee bracing after ACL: effects on postural control and proprioception. Med Sci Sports Exerc 2001;33:1253–1258. 64. Ettinger WHJ, Burns R, Messier SP, et al. A randomized trial comparing aerobic and resistance exercise with a health education program in older adults with knee osteoarthritis. The Fitness Arthritis and Seniors Trials (FAST). JAMA 1997;227:25–31. 65. Mangione KK, McCully K, Gloviak A, et al. The effects of high intensity and low intensity cycle ergometry in older adults with knee osteoarthritis. J Gerontol A Bio Sci Med Sci 2000; 54:M184–M190. 66. Malmivaara A, Hakkinen U, Aro T, et al. The treatment of acute low back pain—bed rest, exercises, or ordinary activity? N Engl J Med 1995;332:351–355. 67. Riddle DL. Classification and low back pain: a review of the literature and critical analysis of selected systems. Phys Ther 1998; 78:708–737. 68. McKenzie R. Mechanical Diagnosis and Therapy of the Lumbar Spine, 1st ed. Waikanae, New Zealand: Spinal Publications, 1981. 69. Fritz JM, Delitto A, Vignovic M, et al. Interrelated reliability of judgments of the centralization phenomenon and status change during movement testing in patients with low back pain. Arch Phys Med Rehabil 2000;81:57–61. 70. Long A, Donelson R, Fung T. Does it matter which exercise? A randomized control trial of exercise for low back pain. Spine 2004;29:2593–2602. 71. Hefford C. McKenzie classification of mechanical spinal pain: profile of syndromes and directions of preference. Man Ther 2008; 13:75–81. 72. Philadelphia Panel. Philadelphia Panel evidence-based clinical practice guidelines on selected rehabilitation interventions for low back pain. Phys Ther 2001;81:1641-1674. 73. Akuthota V, Nadler SF. Core strengthening. Arch Phys Med Rehabil 2004;85(3 suppl 1):S86–S92. 74. Abenhaim L, Rossignol M, Valat JP, et al. The role of activity in the therapeutic management of back pain. Report of the International Paris Task Force on Back Pain. Spine 2000;25(4 suppl):1S–33S. 75. Herring SA, Kibler WB. A framework for rehabilitation. In Kibler WB, Herring SA, Press J (eds): Functional Rehabilitataion of Sports and Musculoskeletal Injuries. Gaithersburg, MD: Aspen Publications, 1998; pp 1–8. 76. Alvarez DJ, Rockwell PG. Trigger points: diagnosis and management. Am Fam Physician 2002;65:653–660. 77. Frost H, Stewart-Brown S. Acupressure for low back pain. BMJ 2006;332:680–681.

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Chapter 74

TRANSCUTANEOUS ELECTRICAL NERVE STIMULATION Deirdre M. Walsh and Jeffrey R. Basford

which it reduces pain are still under investigation. In addition to the pain gate theory described previously, recent animal research findings have indicated that low- and high-frequency TENS analgesia is mediated through the activation of specific opioid receptors, thus suggesting an alternate mechanism of neuromodulation. Although some controversy continues over the effectiveness of TENS, this modality is widely used to treat a variety of painful conditions. Technological advances have resulted in the development of more sophisticated TENS units with an overwhelming range of stimulation parameter choice. Fundamentally, however, little has changed: all essentially consist of a unit powered by a small battery that delivers a specified waveform to the skin via superficial electrodes (Figs. 74–1 and 74–2).

INTRODUCTION Transcutaneous electrical nerve stimulation (TENS) involves the application of low-voltage electrical currents to the skin. Technically, the term TENS can be used to cover a range of stimulation currents such as interferential currents and functional electrical stimulation. For the purposes of this chapter, the term is used to describe the application of a specific type of low-voltage current to the skin for the purposes of pain relief. Natural forms of electricity (such as those produced by electric rays) have been used as a method of pain relief since the Egyptian era. The subsequent development of the battery and the induction coil resulted in early prototypes of TENS units being available by the late 1800s. However, electroanalgesia was poorly accepted until 1965, when Melzack and Wall laid a theoretical foundation for it with their gate theory of pain. This theory proposed that a ‘‘gate’’ existed in the dorsal horn of the spinal cord that could regulate the intensity of nociceptive small-diameter afferent nerve fiber signals that could reach the brain. This gate could effectively be closed by a variety of stimuli (e.g., touch, pressure, and electrical currents) that activated the large-diameter afferent fibers. A number of studies appeared shortly after the theory was published that supported the effective use of percutaneous electrical stimulation for the treatment of chronic neurogenic pain. However, widespread acceptance of transcutaneous electrical stimulation did not occur until Norman Shealy, MD, reported that pain relief with an early version of a TENS unit was an effective means of screening patients being considered for a then-new technique for pain relief, dorsal column stimulation, that involved the surgical implantation of electrodes in the dorsal column of the spinal cord. Despite TENS being used by health professionals for decades, the mechanisms by

STIMULATION PARAMETERS Stimulation parameter choice is fundamental to the effective use of TENS and depends on a basic understanding of human physiology, nerve transmission, and electricity itself. However, in practice, trial and error and intuition remain important also. Stimulation parameters of TENS are described below. Current: TENS devices typically use a pulsed current with a rectangular-shaped waveform (Fig. 74–3). The waveform itself may be symmetrical or asymmetrical. Frequency: The number of pulses per second (measured in Hertz). Pulse duration: The time the pulse is delivered (usually measured in milliseconds or microseconds). Pulse amplitude/intensity: The voltage or current output is measured in millivolts or milliamperes (depending on whether the device is designed to deliver a constant current or a constant voltage). Output: The pattern in which the pulses are delivered; it can be continuous, burst, or modulated (Fig. 74–4). The continuous and burst outputs are self-explanatory. A modulated output is produced by varying pulse duration, frequency, and/or amplitude in a regular and cyclical manner. If the output is set for amplitude modulation, a cyclical modulation in amplitude is produced that increases from 0 to a preset level, then back to 0 again. Modulated outputs are provided by manufacturers in the hope of improving treatment effectiveness by avoiding the accommodation of nerve fibers to a constant stimulus; the reality of its benefits remains debatable. 541

542 Chapter 74  TR ANSCUTANEOUS ELECTRICAL NERVE STIMULATION

Acupuncture-like Acupuncture-like TENS uses stimulation at a low-frequency (usually 1–4 Hz), long-pulse duration (200 msec), and high intensity. With acupuncture-like TENS, the intensity is increased to produce visible nonpainful muscle contractions. Pain relief is believed to be produced by descending pain inhibitory pathways through the release of endogenous opioids. The electrodes should be positioned to produce visible muscle contractions (e.g., over a myotome related to the painful area). The patient will experience paresthesia and muscle contraction (twitching type) with this mode. As muscle contractions occur, additional sensory information is carried from the muscle spindle via muscle afferents (Ad). It is desirable that the patient experiences motor contraction; therefore, the intensity should be increased until the patient feels this. Traditionally, conventional TENS analgesia was associated with gating effects and acupuncture-like TENS analgesia with the release of opioids through descending inhibitory pathways. However, recent animal studies have demonstrated that low- and highfrequency TENS-induced antihyperalgesia is mediated by activation of serotonin, m and d opioid receptors, thus providing an additional mechanism of action for this modality.

Burst

Commercially available TENS units provide the necessary parameter ranges (frequency, pulse duration, intensity settings, and burst versus continuous output) for four modes of stimulation.

Burst TENS is an amalgamation of conventional and acupuncturelike TENS and consists of a combination of a baseline lowfrequency current together with high-frequency trains (see Fig. 74–4). Some texts also refer to this mode of TENS as acupuncture-like TENS. The main difference between burst TENS and acupuncture-like TENS is that the burst mode has high frequency trains of pulses delivered at a low frequency, whereas acupuncturelike TENS has single pulses delivered at a low frequency. Typically, the frequency of the individual pulse bursts (trains) is 1 to 4 Hz, with the internal frequency of the trains around 100 Hz. Some patients prefer this mode to acupuncture-like TENS because the pulse trains produce a more comfortable muscle contraction.

Conventional

Brief IntenseTENS

Conventional TENS involves stimulation at a high-frequency (typically > 100 Hz), short-pulse duration (50–80 msec), and low intensity. Large-diameter afferents (Ab-fibers) are stimulated, thus producing paresthesia under the electrodes. Pain relief is believed to be produced primarily by segmental inhibition (i.e., gating effects).

Brief intense (‘‘counterirritant’’) TENS uses high-frequency (100–150 Hz) and long-duration (150–250 msec) pulses delivered at the patient’s highest tolerable intensity for short periods of time (5 patients per treatment group. 2 studies met inclusion criteria.

Brosseau et al, 2003. Proctor et al, 2002

RA of the hand

Osiri et al, 2000

Knee osteoarthritis

Evidence is inconclusive. Adults with chronic pain of > 3 months. Chronic pain conditions associated with acute episodes, such as angina, tension-type headache, migraine and dysmenorrhea were not considered. Evidence is inconclusive. 18 years or older who had experienced cancer-related pain, unspecified or persistent cancer treatment-related pain, or both, for a minimum of three months after any anti-cancer treatment had been completed. 18 yr with chronic mechanical Available evidence supporting LBP use of TENS as isolated treatment of LBP is limited and conflicting. 18 yr, with clinical and/or Acupuncture-like TENS helps radiologic confirmation of RA decrease hand pain in people of the hand. with RA. High-frequency nerve Inclusion criteria: stimulation may help relieve  Women of reproductive age painful menstrual cramps.  Women with moderate to severe primary dysmenorrhea (severe/ incapacitating pain for at least 1 day of menses).  Women affected by dysmenorrhea in >50% of their menstrual cycles. Exclusion criteria:  Dysmenorrhea associated with pelvic pathology, an IUD.  Mild or infrequent dysmenorrhea. 18 years or older, with clinical TENS and AL-TENS are shown and/or radiological to be effective in pain control over placebo. confirmation of OA of the knee and no history of surgery of the affected knee.

TENS and acupuncture for primary dysmenorrhea

RCTs and controlled clinical trials. 3 studies met inclusion criteria. RCTs comparing TENS or acupuncture to each other, placebo, no treatment, or medical treatment. 9 studies met inclusion criteria.

RCTs and controlled clinical trials that were eligible according to an a priori protocol. 7 studies met the inclusion criteria.

Conclusion

IUD, intrauterine device; LBP, low back pain; RA, rheumatoid arthritis; RCT, randomized, controlled trials; TENS, transcutaneous electrical nerve stimulation.

Placement

more appropriate to place the electrodes proximal to the area of hypersensitivity.

Painful area Placement over a painful area is the most common starting point because it is desirable, with conventional TENS, to achieve a sensation of paresthesia over the painful area. As previously outlined, skin sensation must be assessed to ensure normal innervation of the affected area. Patients with impaired sensation in the affected area may be treated by placing the electrodes over normally innervated skin just proximal to the painful area in order to stimulate the afferent sensory nerves traveling to the spinal cord. There are also occasions when application of electrodes at the painful site would be uncomfortable for the patient, and here again, it may also be

Peripheral nerves The electrodes may also be placed over a peripheral nerve that has a cutaneous distribution in the painful area. A sound knowledge of surface marking and neuroanatomy is required to determine where the peripheral nerves are most superficial and, therefore, most easily accessible for stimulation. For example, pain experienced on the dorsum of the lateral aspect of the hand and the first and second digits can be treated with electrodes placed over the course of the superficial radial nerve as it traverses the lateral aspect of the

546 Chapter 74  TR ANSCUTANEOUS ELECTRICAL NERVE STIMULATION distal forearm. Other examples of superficial points of peripheral nerves are the ulnar groove for the ulnar nerve and the head of the fibula for the common peroneal nerve.

Spinal nerve roots The spinal nerve roots emerge through the intervertebral foramina that lie between the nonpalpable transverse processes of the vertebral column. Placing the electrodes parallel to the vertebral column (paraspinal application) and over the intervertebral foramina will allow for stimulation of the appropriate roots of spinal nerves that supply the affected dermatome or myotome. Acupuncture-like TENS is commonly applied to myotomes segmentally related to the area of pain to produce the desirable muscle contractions associated with this mode of TENS. There is considerable overlap between adjacent dermatomes in a specified body part and, therefore, knowledge of the spinal nerve responsible for the dermatome in question is required in order to accurately select the correct spinal segment for stimulation. A knowledge of the relationship between spinal cord segments, their corresponding spinal nerves, and the spinal vertebral processes is particularly important. For example, there are eight cervical spinal nerves and only seven cervical vertebrae, so the seventh cervical nerve will emerge between the last cervical and the first thoracic vertebrae. It is important to remember that angulation of the posterior spinous processes changes with their position in the vertebral column, and palpation of a specific spinous process does not necessarily result in localization of the corresponding cervical nerve (e.g., the C5 spinous process is palpable at the level of the C6 nerve root). Thus, localization is important. However, the need for extreme accuracy is limited by the fact that areas are frequently innervated by more than one nerve root and the length of standard electrodes (5 cm) allows at least two adjacent roots to be stimulated simultaneously. It is also important that the electrodes are placed parallel to the spinal column to ensure stimulation of a maximum number of roots.

Acupuncture, motor, and trigger points Electrode placement in these categories was directed by the location of pathology or nervous tissue. TENS treatment may also be applied to a number of specific sites: typically acupuncture, motor, and trigger points. Treatment over acupuncture points has an obvious rationale, given the importance of their stimulation in the treatment of disease in traditional Chinese medicine. Treatment at the other sites is more empirical, but it should be noted, for example, that a motor point, defined as the point at which a motor nerve synapses with the fibers of a muscle and is characterized by low skin resistance, should be an optimal location for treatment when the gentle muscle contractions associated with acupuncture-like TENS are desired. Trigger points, conversely, are areas characterized by tenderness on palpation and the production of referred pain; a choice of their treatment also seems intuitively strong.

EVIDENCE BASE Although the evidence base for TENS effectiveness has expanded over recent years, it remains surprisingly equivocal. Evaluations range in quality from well-designed randomized, controlled trials to single case studies. A number of systematic reviews have been published addressing the effectiveness of TENS analgesia for different pain conditions. In particular, the Cochrane Collaboration has produced systematic reviews on primarily chronic pain conditions (Table 74–1). It is obvious that definitive evidence is lacking and that this deficiency is due to a combination of poor trial quality and study heterogeneity. Although the number of randomized, controlled clinical trials on TENS has increased since the late 1990s, further high-quality randomized, controlled trials are necessary in order to provide an evidence base for this pain-management modality.

SUGGESTED READINGS Brosseau L, Yonge KA, Robinson V, et al. Transcutaneous electrical nerve stimulation (TENS) for the treatment of rheumatoid arthritis in the hand. Cochrane Database Syst Rev 2003;(2):CD004377. Johnson MI. Transcutaneous electrical nerve stimulation (TENS). In Watson I (ed): Electrotherapy, Evidence-Based Practice, 12th ed. Edinburgh: Churchill Livingstone, 2008; pp 253–296. Kalra A, Urban MO, Sluka KA. Blockade of opioid receptors in rostral ventral medulla prevents antihyperalgesia produced by transcutaneous electrical nerve stimulation (TENS). J Pharmacol Exp Ther 2001;298:257–263. Khadilkar A, Milne S, Brosseau L, et al. Transcutaneous electrical nerve stimulation (TENS) for chronic low-back pain. Cochrane Database Syst Rev 2005;3:CD003008. Nnoaham KE, Kumbang J. Transcutaneous electrical nerve stimulation (TENS) for chronic pain. Cochrane Database Syst Rev 2008;3:CD003222. Osiri M, Welch V, Brosseau L, et al. Transcutaneous electrical nerve stimulation for knee osteoarthritis. Cochrane Database Syst Rev 2000;4:CD002823. Proctor ML, Smith CA, Farquhar CM, Stones RW. Transcutaneous electrical nerve stimulation and acupuncture for primary dysmenorrhoea. Cochrane Database Syst Rev 2002;1:CD002123. Radhakrishnan R, King EW, Dickman JK, et al. Spinal 5-HT(2) and 5-HT(3) receptors mediate low, but not high, frequency TENS-induced antihyperalgesia in rats. Pain 2003;105:205–213. Robb KA, Bennett MI, Johnson MI, et al. Transcutaneous electric nerve stimulation (TENS) for cancer pain in adults. Cochrane Database Syst Rev 2008;3:CD006276. Sluka KA, Deacon M, Stibal A, et al. Spinal blockade of opioid receptors prevents the analgesia produced by TENS in arthritic rats. J Pharmacol Exp Ther 1999;289:840–846. Sluka KA, Walsh D. TENS: basic science mechanisms and clinical effectiveness. J Pain 2003;4:109–121. Walsh DM. TENS: Clinical Applications and Related Theory. New York: Churchill Livingstone, 1997.

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Chapter 75

SPINAL CORD STIMULATION FOR THE TREATMENT OF CHRONIC INTRACTABLE PAIN Richard K.Osenbach and Emily A. Davis

INTRODUCTION The use of electrical stimulation as a treatment modality for pain is not a new concept. Indeed, the application of electricity for the treatment of illness dates back at least several hundred years. John Wesley, founder of the Methodist Movement, championed the use of electricity as early as the 1700s to treat a variety of pain conditions such as angina, headache, and sciatica. This was obviously long before there was any sort of clear understanding of the physiology of pain transmission and processing. Clearly, the utilization of electricity as a therapeutic ‘‘drug’’ has indeed come a long way. It is also somewhat ironic that the conditions for which Wesley advocated electrical stimulation include some of the more common pain conditions that electrical stimulation is currently employed for. Despite early clinical observations of the beneficial effects of electrical stimulation on pain, it was not until Melzack and Wall1 published the gate control theory of pain transmission in 1965 that the concept of electrical stimulation for the treatment of pain really began to emerge and be better understood. However, the first modern applications of electrical stimulation actually did not originate from the gate control theory. Five years earlier, Mazar and coworkers2 had begun to investigate thalamic sensory stimulation using implanted electrodes as a treatment for chronic neuropathic pain. Mazar and coworkers’ work was based largely on the older theory of Henry Head and Gordon Holmes that chronic pain occurs secondary to an imbalance between the epicritic and the protopathic components of pain. Head and Holmes had postulated the explicit existence of modulatory influences on pain. They suggested that the thalamus is the center for pain perception and that the neocortex exerts a continuous influence on the response of the thalamus to nociceptive input. Mazar and coworkers2 believed that stimulation of the sensory thalamus might compensate for this imbalance by enhancing the epicritic difference. Their work not only preceded the description of the gate control theory but also came long ahead of our current understanding of the concept of neuropathic pain. The gate control theory was the first to incorporate the concept of a descending modulatory control process with local spinal mechanisms of pain processing. In simple terms, the gate control theory postulates that within the dorsal horn of the spinal cord, there exists an action or output system, namely thalamic projection neurons (TPN), that transmits noxious information rostrally to the thalamus. These TPN are locally modulated or ‘‘gated’’ by the relative amount of input from both large myelinated Ab-fibers and the small diameter Ad- and C-fibers. A preponderance of activity in large fibers serves to ‘‘close the gate’’ and inhibit pain transmission,

whereas factors that activate the small fiber system keep the gate ‘‘open’’ and allow transmission of noxious information. In addition, a descending modulatory system exists that also influences the spinal gating mechanism. Because spinal cord stimulation (SCS) is known to activate the large fiber system of the dorsal column (DC), it seemed rather logical to hypothesize that electrical stimulation applied to the DC would result in a closing of the gate and inhibition of pain transmission. In 1967, Shealy and associates3 first tested this theory clinically by implanting electrodes directly on the dorsal surface of the spinal cord; the technique became known as DC stimulation. This was a fairly simplistic if not elegant explanation of the therapeutic effect of SCS. As research on pain transmission and processing and SCS has evolved and knowledge has accumulated, a substantial body of evidence gained since the late 1970s has shown that multiple mechanisms are likely responsible for the analgesic effects of SCS. Notwithstanding the criticisms of the gate theory, its relative simplicity has previously and continues to provide a useful framework for the development of various techniques of electrical stimulation as new treatment modalities. It is readily apparent that SCS has improved considerably since its inception 40 years ago. This evolution can be linked to a number of factors including a better understanding of the mechanisms of SCS, an improved understanding of the concepts and mechanisms underlying neuropathic pain, improvements in equipment and technology, the use of novel electrode placements, and a greater appreciation of the indications and efficacy of SCS. All of these factors have contributed to improved patient selection and, as a result, a direct improvement in outcomes associated with SCS.

MECHANISMS OF SCS Despite the fact the SCS has been employed for over 40 years, our understanding of the exact mechanisms through which this modality produces beneficial effects is still fragmentary and unclear. Experimental animal studies have been performed by relatively few investigators and studies in humans are even more uncommon. A major drawback of animal studies is that the results may not necessarily be directly applicable in humans, particularly when studying pain behavior. Most experimental animal models of pain involve acute, noxious stimuli (e.g., heat, pressure, pinch, and application of algogenic substances), whereas in humans, SCS is utilized clinically for chronic pain. It is also conceivable that the mechanisms of analgesia may be different for neuropathic pain than for ischemic pain. The experimental work in this area is indeed fascinating. Unfortunately, an in-depth discussion of this topic is well beyond the scope of this chapter. The interested reader should consult any number of excellent reviews on this subject.4–8 As discussed previously, one of the original concepts was that SCS produced much of its effect based on the gate control theory. Basically, this theory suggested that nociceptive transmission could be interrupted at the first dorsal horn relay by stimulation of large Ab-fibers in the DC through both orthodromic and antidromic activation of collaterals that project to the corresponding spinal segment. These effects are actually very short lasting when studied in animals, and perhaps even more important, the inhibitory effects were exerted on afferent discharges from Ad- and C-fibers in response to noxious input.5 This observation is actually contrary to many of the clinical observations of SCS. Notwithstanding, the general mechanism of SCS is still understood to some extent in terms of these gating mechanisms in the spinal cord.

548 Chapter 75  SPINAL CORD STIMULATION FOR THE TREAT MENT OF CHRONIC INTR ACTABLE PAIN Spinal and supraspinal mechanisms for SCS have also been suggested. Single-cell activity recorded from the dorsal horn (laminae IV and V) evoked by various noxious stimuli has been shown to be inhibited by SCS applied to the DC. This inhibitory effect is preserved even when the DC has been transected rostral to the level at which SCS has been applied, suggesting that the inhibitory effect is mediated through spinal mechanisms alone.5 Studies of the effects of SCS on spinothalamic tract cells excited by peripheral stimulation using bradykinin or noxious pinch in their respective receptive fields have shown that SCS applied to the ipsilateral DC suppressed their discharge activity, suggesting that SCS may preferentially inhibit high-threshold nociceptive specific cells. Inhibition occurred as an immediate effect of SCS applied with high amplitude and concomitant with the noxious stimulus. Moreover, the inhibitory effects of SCS did not outlast the duration of SCS. Clinically, it is well known that the effects of SCS often persist well beyond the duration of stimulation, and it has been suggested that this prolonged effect may be related to supraspinal influence. Indeed, spinal transaction rostral to the applied stimulation site has been shown to abolish this poststimulatory suppression of wide dynamic range (WDR) neurons in the deep dorsal horns activated by noxious stimuli in intact awake animals.5 Peripheral nerve lesions in animals result in hyperexcitability of WDR neurons in the dorsal horn in animals rendered allodynic compared with those that are nonallodynic. Application of SCS using current ‘‘clinical parameters’’ can induce significant depression of these exaggerated responses in allodynic animals, suggesting that this suppressive action on WDR neurons corresponds to the observed clinical benefit of reduction in tactile allodynia as well as spontaneous neuropathic pain.5 Other mechanisms of SCS for neuropathic pain have been suggested based on animal studies, and entirely different mechanisms have been proposed for ischemic pain. Suffice it to say that SCS likely produces its beneficial effects through multiple mechanisms. Whereas the gate control theory may not fully explain these effects, it does seem clear that, at least based on the experimental data and the clinical importance of paresthesia perception, that the DC does indeed play a central role in the mechanistic effects of SCS.

ELECTROPHYSIOLOGYAND APPLIED ANATOMYOF SCS A general understanding of the basic electrophysiology of SCS is important if not essential for the successful application of this modality. SCS is applied clinically through epidural electrodes that are generally placed over the DC of the spinal cord. When a neuron or axon is made more positive or depolarized, the end result is production of an action potential that is then propagated along the nerve fiber. Clinically, SCS is typically produced by choosing two electrodes that are close together; one electrode functions as a cathode (negative) and the other as an anode (positive). The electrode that effectively produces depolarization is the cathode and. therefore. this is termed a cathodal effect. When the neuron or axon becomes more negatively charged or hyperpolarized, the threshold for activation is increased and the ability to conduct an action potential is reduced. A positively charged electrode or anode produces this type of anodal effect. Practically, with SCS, the active electrode for stimulation is the cathode; in other words, stimulation occurs at the cathode. Although the electrical field may be drawn in the direction of the anode, the anode will practically function to ‘‘shield’’ neuronal structures from stimulation, a concept termed anodal shielding. This is an important concept to understand in order to stimulate certain structures that one desires to stimulate while avoiding producing unwanted stimulation in other structures. The closer the proximity of the anode in relation to the cathode, the more influence it will have over the shape and distribution of the electrical field.

Cerebrospinal fluid (CSF) is the most conductive of all the intraspinal elements, followed in decreasing order by longitudinally oriented white matter, gray matter, epidural fat, dura mater, and bone. Understanding these differences has practical applications for SCS in terms of the neural elements recruited and the power consumption. Because CSF has the highest conductivity, it stands to reason that the depth or thickness of the CSF space will have an influence on the specific structures that may be recruited and the threshold of activation. The larger the width of the dorsal CSF space, the higher the stimulation threshold for both DC and dorsal root (DR) fibers.8,9 Furthermore, the difference between stimulation thresholds of DR and DC fibers becomes greater with increasing CSF width. It has also been shown that DR and DC fibers possess different electrical properties. DR fibers have a stimulation threshold that in some cases is less than 50% of that of DC fibers. This discrepancy is due to several factors.8 First, DR and DC fibers have a different orientation with respect to the spinal electrode and the electrical field that is produced. DR fibers are curved and oriented somewhat differently with respect to the electrode; this has an impact on activation threshold. In general, as the angle between the fiber and the transverse plane increases, the threshold becomes higher. Also, when DR fibers enter the spinal cord, they do so by crossing between a high-conductivity (CSF) and a lowconductivity (spinal cord) interface.10–12 These data correlate well with the observation that initial paresthesias that are perceived with SCS are usually felt at the segmental level of stimulation and then spread to encompass more caudal segments. These differences also explain the clinical observation as to why an electrode placed too far laterally often produces purely segmental stimulation. In addition, the width of the epidural space will have an impact on activation thresholds. The greater the distance between the electrode and the DC, the higher the activation threshold. It can now be easily understood why paresthesia perception thresholds are generally higher in the midthoracic region than in the cervical region where the epidural space is narrowest. An important anatomic concept is the somatotopic organization of the DC. Primary afferent fibers in the DR become segregated as they enter the dorsal horn of the spinal cord. The large-diameter Ab-fibers carrying touch and proprioception destined to enter the DC become segregated more medially at the dorsal root entry zone (DREZ), whereas the smaller nociceptive Ad- and C-fibers are situated more laterally. The large myelinated fibers continue to be displaced medially, and consequently, sacral fibers are located most medially, with lumbar fibers more laterally, and so on. Again, this can sometimes have important practical implications in terms of electrode location and paresthesia production. The stimulation-induced paresthesias produced by SCS reflect activation of the various spinal structures including the DC, DR, dorsal horn, and DREZ.8 Distinguishing DR from DC activation is sometimes feasible, especially if the patient initially perceives unilateral segmental paresthesias at a very low perception threshold or if early motor recruitment occurs. More diffuse bilateral distribution of paresthesias at a slightly higher threshold below the spinal level being stimulated is more indicative of DC activation. It should be understood that with current electrode designs, it is likely that several structures are being stimulated simultaneously. The most effective stimulation for the extremities is generally achieved with an electrode positioned within 3 mm of the physiologic midline. In order to stimulate more midline structures (e.g., axial lower back), the electrode must be positioned in the physiologic midline.8,12 Recalling the somatotopic organization of the DC in the lower thoracic spine, the posterior leg will generally be more easily and consistently stimulated by an electrode directly in the midline, whereas the anterior leg (supplied by more rostral dermatomes) will be covered by slightly more laterally placed electrodes.8 In order to stimulate bilaterally, the electrode must be perfectly positioned in the physiologic midline. The chest and abdominal

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wall will be stimulated by more laterally placed electrodes. The upper extremity can be relatively easily stimulated by either midline or lateral electrodes. As a general rule, the stimulationinduced paresthesias will spread caudal to the level of the electrode and occasionally rostrally. Indeed, some patients may report paresthesias in the upper extremities from a midthoracic electrode, although this is very inconsistent and unpredictable. It is important to remember that the spinal cord may not be perfectly centered within the spinal canal in many patients. Consequently, the physiologic midline may not correspond to the anatomic midline. For example, some patients may report paresthesias in the left leg with an electrode that clearly is positioned anatomically to the right of the midline. It is important to not dismiss the patient’s response as aberrant but rather to make the proper adjustments in electrode position to overcome the problem.

GENERAL PRINCIPLES OF SURGICAL TREATMENTOF CHRONIC PAIN Management of the patient with a chronic pain condition is often a complex and difficult challenge, for both the patient and the health care provider. Successful management of these patients requires a thorough understanding of the pain problem along with a careful and contemplative approach in developing an effective treatment algorithm. Failure to obtain a complete and meticulous history regarding the details of the patient’s pain and previous treatment not uncommonly leads to poor patient selection and failure of the treatment employed. It simply cannot be overemphasized that careful patient selection represents the cornerstone of successful surgical management of chronic pain. This is especially true for patients being considered for SCS or, for that matter, any type of implantable pain therapy. One needs to also recognize and accept that chronic pain is a multidimensional biopsychosocial problem and, in a sense, a chronic disease. Consequently, it must be understood that effective management of most patients with longstanding pain requires a multidisciplinary approach, utilizing all modalities and specialists at one’s disposal. Indeed, the belief on the part of the patient and/or the physician that a surgical procedure alone, such as implantation of a spinal cord stimulator, will provide a ‘‘cure’’ is a foolish thought and will nearly always result in treatment failure and a dissatisfied patient. The successful treatment of chronic pain should follow a logical algorithm, beginning with the most simple and least interventional therapies and progressing to more complex invasive modalities.

PSYCHOLOGICAL SCREENING Because nearly all patients with chronic pain demonstrate at least some degree of psychosocial stress, a baseline neuropsychological evaluation should be completed in every patient as part of the screening process prior to proceeding with a trial of SCS. Evaluation by a skilled pain psychologist is invaluable for identifying factors, such as significant depression and external psychosocial stressors, that might influence the effectiveness of treatment. An experienced pain psychologist is also helpful in reinforcing reasonable expectations regarding effectiveness of a particular treatment and assisting the patient in coping with residual pain not alleviated by procedure. This is extremely important because SCS, or any other pain procedure for that matter, is unlikely to completely eliminate or ‘‘cure’’ the condition(s) for which this therapy is applied. In fact, we have anecdotally noted improved results in patients treated with SCS who participate in various behavioral therapies such as biofeedback, stress relaxation training, and coping skills in addition to receiving their SCS implant. Identification of psychological factors believed to affect the patient’s pain should not necessarily be viewed as a contraindication

to surgery because nearly all patients with chronic pain have some psychological factors that contribute to their overall pain and suffering.13 Virtually all patients with chronic pain suffer at least some element of depression that often improves with better pain control. However, patients with major depression accompanied by suicidal thoughts or gestures require intense psychiatric intervention and are not appropriate candidates for any invasive intervention until these issues have been addressed and brought under control. Other psychosocial stressors such as job dissatisfaction and marital problems should also be addressed because surgery is not going to fundamentally alter those issues. Patients with major personality disorders often do not have favorable outcomes from procedures to treat chronic pain, and one should use caution in selecting these patients for procedures such as SCS. Finally, careful judgment and caution should be exercised in considering implantable pain therapy for patients in whom problems such as alcoholism or drug addiction have been identified as ongoing issues. The presence of these behaviors often portends a poor prognosis with any type of implantable pain therapy.13 Assessing the role of psychological factors can be somewhat complicated. First, there is the need to identify their presence or absence. Most patients show a mixture of depression, somatic focus (e.g., hypocondriasis), anxiety, and/or emotional reactivity (e.g., hysteria). The degree of sensitivity and specificity among various psychological tests to detect these and other psychological states varies.13 Second, the magnitude of psychological factors appears to vary with the complexity of the disorder. It has been shown that patients with multiple areas of pain demonstrate increased levels of psychological distress compared with patients with a single pain complaint. Third, psychological factors may be mediators, modulators, or maintainers of pain. For example, in some patients with a clear-cut pain generator, the degree of psychological distress as measured by the Symptom Checklist 90 (SCL-90) was either reduced or resolved along with the pain, suggesting that the psychological distress was secondary to the pain.13 In contrast, in patients with more generalized diffuse pain of unclear cause, the correlation is not so clear. Patients with histories of physical/sexual abuse were found more likely to develop chronic pain after injury and more recalcitrant to treatment, implying some type of predisposition to pain. Such patients may manifest a differential response to an ‘‘acute’’ procedure such as a brief trial of SCS rather than chronic treatment (e.g., long-term SCS therapy), perhaps explaining the reduced effectiveness after a permanent implant that occurs in some patients. Unfortunately, and perhaps all too commonly, some chronic pain patients and even some physicians harbor the belief that ‘‘if the pain is relieved everything else will be fine.’’ Clearly, it is overly simplistic and frankly foolish for the patient and especially for the treating physician to believe that any surgical procedure is going to correct everything that is wrong in a patient’s life. Application of therapies such as SCS under these circumstances will more often than not result in treatment failures as well as a variety of other problems. It is important to remember that, even under ideal circumstances, not everyone can be helped with an implanted device and the decision not to proceed with a pain procedure—rather than going ahead with an operation in which the risks significantly outweigh the potential benefits—is sometimes in the patient’s best interest.

CLINICAL INDICATIONS, PATIENT SELECTION, AND RESULTS All patients considered for SCS or any implantable pain device should undergo a comprehensive preoperative evaluation and screening including a detailed history of their pain problem and all prior treatments along with a thorough neurologic examination. Imaging studies appropriate to the particular problem should be

550 Chapter 75  SPINAL CORD STIMULATION FOR THE TREAT MENT OF CHRONIC INTR ACTABLE PAIN reviewed to clarify the underlying pathologic process if possible and exclude a potentially correctable primary surgical problem. Evaluation tools such as the McGill Pain Questionnaire (MPQ) and visual analog scale (VAS) are useful in characterizing the type and intensity of pain and should be completed prior to surgery and at fixed postoperative intervals to monitor effectiveness of therapy. Unfortunately, changes in VAS scores alone often do not reflect the true effectiveness of a particular therapy and clearly are inadequate for determining the benefit of a particular therapy on functional capacity, quality of life, and other factors. Indeed, many patients show a significant discrepancy in their reported degree of subjective pain relief (as a percentage of their baseline pain) compared with the absolute reduction in their VAS score postimplant. The use of standardized validated questionnaires such as the Health Status Questionnaire 2.0 (HSQ 2.0) and Quality of Life Inventory (QOLI) (NCS Pearson, Inc.) for assessing the impact of SCS as well as other implantable pain therapies can be very helpful in assessing the impact of a particular treatment on function and quality of life. Although numerous published series in the literature detail the results of SCS, most are retrospective and vary significantly in their methods of data collection and reliability. Indeed, prospective series in general and randomized trials in particular are lacking. One of the major problems in assessing the efficacy of SCS based on the available literature is a lack of uniformity of the definition of a successful outcome and the manner in which outcomes are reported in general. The overall long-term results of SCS vary considerably. The percentage of patients who continue to maintain more than 50% reduction in pain ranges from less than 20% to as high as 75% depending on the clinical series, underlying pain conditions, and length of follow-up.14

Failed Back Surgery Syndrome SCS is currently used for a wide variety of painful conditions (Box 75–1).15–30 In the United States, by far the most common indication for SCS is in patients with so-called failed back surgery syndrome (FBSS). Patients with FBSS represent a heterogeneous group of patients who continue to experience persistent axial back and/or radicular pain after one or more surgical procedures on the spine. Of the more than 600,000 patients who undergo spinal surgery annually, more than 50% involve the lumbosacral spine.

Box 75^1 CURRENT APPLICATIONS OF SCS  Postlaminectomy pain syndrome (i.e., FBSS)  Persistent radiculopathy  Axial low back pain  Adhesive arachnoiditis  Brachial plexitis  Neurogenic thoracic outlet syndrome  CRPS  Type I (i.e., reflex sympathetic dystrophy)  Type II (i.e., causalgia)  Peripheral nerve injury pain  Painful peripheral neuropathy (e.g., diabetic neuropathy)  Ischemic limb pain secondary to peripheral vascular disease  Intractable angina pectoris  Post-thoracotomy pain or intercostal neuralgia  Ilioinguinal neuralgia  Postherpetic neuralgia  Interstitial cystitis  Visceral pain syndromes  Coccydinia  Vulvodynia CRPS, complex regional pain syndrome; FBSS, failed back surgery syndrome; SCS, spinal cord stimulation.

Approximately 30% of these patients continue to report persistent pain in spite of surgical intervention; many of these subsequently undergo repeat surgery that is often similarly unsuccessful. There are multiple reasons for FBSS including failure to correct the original pathology, complications of the surgical procedure such as inadvertent nerve root injury or arachnoiditis, lack of a good indication for the original surgery, and the existence of a condition for which surgery is known to be ineffective. Most patients with FBSS probably suffer from a mixture of both neuropathic and nociceptive pain. Most authors have maintained and continue to maintain that SCS is most effective for neuropathic pain that is predominantly radicular in nature.15 Predominantly axial pain in the lower back or pain that involves other midline regions (e.g., perineum) can be very difficult, although perhaps not impossible, to treat effectively with SCS. Early success rates as high as 90% have been reported in patients with FBSS. Unfortunately, the long-term analgesia has not been as durable as one would desire. Indeed, a gradual decline in efficacy tends to occur over time such that long-term outcomes are considerably less. Kumar and colleagues31 summarized the overall results of 16 series of SCS reported in the literature. Pooled data from 8 of these series that included all types of pain syndromes indicated that of 1261 patients who were screened, 894 (71%) received a permanent implant. Long-term pain relief (i.e., >50%) was achieved in 530 (59%) patients. However, the results for the group of patients with FBSS were less impressive. Collated data from 10 different series showed that the implantation rate was higher in the group with FBSS; 860 (88%) patients were implanted out of 972 who were initially screened. However, in examining the long-term efficacy, only 42% of patients continued to maintain more than a 50% reduction in pain. Overall, the outcomes for SCS in patients with FBSS have been fairly consistent. In looking at multiple clinical series, it can be concluded that about 50% to 60% of patients will derive at least 50% reduction in pain with SCS. Approximately 60% of patients experience improvement in activities of daily living as the result of SCS. Although the effect on medication intake is more variable, some studies report in excess of 80% to 90% of patients who were able to discontinue the use of pain medications. Recently, North and coworkers17 demonstrated a statistically significant benefit of SCS over reoperation for patients with FBSS. Sixty patients judged to be candidates for reoperation were randomly assigned to either a trial of SCS or reoperation. Fifty patients ultimately proceeded to treatment. Six months after the initial treatment, patients were given the option to cross over to other treatment arm. An additional 39 patients who did not consent to randomization underwent reoperation. Fourteen of 26 patients initially assigned to reoperation eventually crossed over to SCS (54%) whereas only 5 of 24 patients who were treated with SCS crossed over to reoperation (21%) (P = .02). Out of 38 nonrandomized patients who underwent reoperation, 14 (37%) ultimately chose to undergo SCS. Among patients available for long-term follow-up, SCS proved significantly more successful than reoperation. Nine of 19 (47%) of patients randomized to SCS achieved at least 50% pain relief and were satisfied with the treatment compared with only 3 of 26 patients (12%) randomized to reoperation (P < .01). When the authors analyzed the results based on the latest treatment (including cross-over), 52% (15 of 29) of patients treated with SCS were considered long-term success whereas the success rate for those whose final treatment was reoperation was 19% (3 of 16). The authors also looked at opioid usage as a secondary outcome measure and found that opioid usage either remained stable or was reduced in 87% of patients treated with SCS compared with 58% who underwent reoperation. Therefore, in the absence of spinal instability or neurologic deficit referable to a compressive lesion, it would appear that the results obtained with SCS are superior to those for patients who undergo further surgery.

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Complex Regional Pain Syndromes Complex regional pain syndrome (CRPS) type I (reflex sympathetic dystrophy) and type II (causalgia) represents another excellent indication for SCS. Unfortunately, the variable nature of the symptomatology in patients with CRPS makes comparison of clinical series somewhat difficult. Kumar and associates32 performed SCS in 12 patients with CRPS type I. Two thirds had undergone a previous sympathectomy without benefit. All patients experienced sufficient pain reduction during a trial of stimulation to justify a permanent implant. All patients experienced either good (50%–75%) or excellent (75%–100%) relief of pain with an average follow-up of 41 months. Kemler and colleagues19 reported the results of a retrospective analysis of SCS in 23 patients with CRPS I. Eighteen (78%) patients had a successful trial and underwent placement of a permanent system. Three patients had the system removed after implantation. Of the remaining patients, mean pain scores decreased from 7.9 to 5.4 with a mean follow-up of 32 months. The same authors have since published their results of a randomized, controlled trial of SCS plus physical therapy (PT) compared with PT alone.20 Patients were randomized 2:1 to receive SCS plus PT versus PT alone. Twenty-four of 36 patients who underwent test stimulation received a permanent implant. Nineteen of 24 patients had a reduction of at least 50% in their baseline VAS score. All patients reported that they were ‘‘much improved’’ using a global perceived-effect score. Based on an intention-to-treat analysis, VAS scores were reduced in the SCS group by an average of 2.4 versus an increase of 0.2 in the group that received PT only (P < .001) after 6 months of follow-up. Of the 24 patients who actually received an implant, the VAS score was reduced by an average of 3.6. Of the 36 patients assigned to the SCS group, 14 (39%) had a global perceived-effect score of 6 (6 = much improved) compared with only a single patient (6%) in the group assigned to PT alone. Similar results have been reported with 2-year follow-up.28 Unfortunately, SCS did not appear to result in any functional improvement.

Angina Mannheimer and coworkers33 using transcutaneous electrical stimulation (TENS) were the first to demonstrate that angina responds favorably to electrical stimulation. SCS has been used to relieve intractable angina pectoris since the late 1980s, primarily in Europe. Indeed, long-term studies of SCS for intractable angina have demonstrated that SCS is effective in more than 80% of patients. However, only recently has SCS been approved by the U.S. Food and Drug Administration (FDA) for clinical trials in the United States. SCS has been shown have a number of benefits in this population of patients (Box 75–2). SCS has clearly been shown to reduce the frequency and severity of anginal attacks and, in some patients, can actually eliminate angina. Angina frequency is reduced at least by 50% on average,

Box 75^2 BENEFITS OF SCS FOR INTRACTABLE ANGINA PECTORIS  Reduction in number and severity of angina attacks  Reduction in short-acting nitrate consumption  Reduction in exercise-induced ischemia and (severity, duration, latency)  Increased latency to onset of exercise-induced angina  Improvement in exercise tolerance  Reduction in number of emergency room visits and admissions for uncontrolled angina  Improved quality of life  Reduction in overall cost of care

and this effect has been shown to be durable over time.34 Consumption of short-acting nitrates is significantly reduced with SCS, sometimes as much as 80%. SCS also results in improved exercise tolerance along with ischemia-induced electrocardiographic changes (i.e., ST depression).5 Additional benefits of SCS on angina are highlighted in Box 75–2. In 1998, Mannheimer and associates35 published the results of the ESBY Study, a prospective, randomized, controlled trial of SCS versus coronary artery bypass grafting (CABG) to determine whether SCS might be an alternative to CABG in high-risk patients. The results in 51 patients who underwent CABG and 53 patients treated with SCS were very similar in regard to reduction in angina frequency (67.9% vs. 69.9%, respectively), reduction in nitrate intake (77.4% vs. 73%, respectively), self-reported symptom relief (79.5% vs. 83.7%, respectively), and overall morbidity. The CABG group did demonstrate a greater reduction in myocardial ischemia at 6 months, although exercise testing was conducted with SCS turned off. However, patients who underwent SCS had a significantly lower mortality (1.9%) compared with those who underwent CABG (13.7%) and only one fourth of the cerebrovascular morbidity experienced in the CABG patients. A more recent study with an average follow-up of nearly 5 years after implant showed Kaplan-Meier curves that paralleled each other, indicating similar survival figures for both groups. Moreover, late quality of life data demonstrated equal benefits in both the SCS and the CABG groups.36 Currently, SCS is indicated for patients with severe chronic intractable angina (New York Heart Association classes III–IV) who have received maximal medical therapy and are not candidates for further coronary revascularization procedures. Comprehensive inclusion and exclusion criteria are outlined in Box 75–3.

Peripheral Vascular Disease SCS has been used for the treatment of tissue ischemia since the mid-1970s. SCS has been shown to produce arterial vasodilatation as measured by plethysmography, Doppler flow studies, and xenon clearance.5,37 Increases in capillary blood flow, limb temperature, and cutaneous oxygen tension, which may be a requirement for

Box 75^3 INCLUSION AND EXCLUSION CRITERIA FOR SCS IN PATIENTS WITH INTRACTABLE ANGINA Inclusion Criteria  Chronic intractable angina  Maximal medical management  b-Blockers, calcium channel agents, nitrates, ASA  Objective reversible myocardial ischemia  Significant coronary artery disease  70% reduction in major vessel with poor run-off  Unsuitable for coronary revascularization  PTCA or CABG  Able to provide informed consent Exclusion Criteria  Inability to accurately describe angina  Myocardial infarction during prior 3 mo  Inability to perform exercise test  Conduction disturbances precluding recognition of ischemia  Patient with ‘‘on-demand’’ pacemaker (relative contraindication)  Inadequate medical therapy  MRI with body coil planned in near future  Spinal pathology precluding SCS placement  Coagulopathy  Dementia  Unwilling or unable to comply with follow-up ASA, acetylsalicylic acid; CABG, coronary artery bypass graft; MRI, magnetic resonance imaging; PTCA, percutaneous transluminal coronary angioplasty.

552 Chapter 75  SPINAL CORD STIMULATION FOR THE TREAT MENT OF CHRONIC INTR ACTABLE PAIN analgesia, have all been shown to occur with SCS. As early as 1976, it had been shown that SCS performed in patients with multiple sclerosis resulted in improvement of lower extremity blood flow.5 It was further postulated that analgesia in patients with peripheral vascular disease (PVD) could be directly correlated with augmentation of limb circulation. It was believed that SCS resulted in improvement in blood flow by suppression of sympathetic vasomotor control and, therefore, might even be more effective in patients with a significant component of vasospastic disease. Based on encouraging reports from several initial studies, the use of SCS for peripheral limb ischemia spread rapidly in Europe. Similar to the results seen in patients with angina, satisfactory pain relief has been reported in 67% to 93% of patients with ischemic pain related to PVD.8 In addition, a limb salvage effect has also been suggested in this group of patients. However, much like angina, this application of SCS has not been widely adopted in the United States despite the seemingly excellent results that have been reported. Peripheral arterial disease may produce several different pain components including a deep aching ischemic pain caused by ischemic ulcers and pain from the border of gangrenous tissue zones. Both are primarily nociceptive and generally respond to opiates. However, with advanced disease, many patients also develop a significant neuropathic pain component that is more opiate-resistant. Despite the fact that ischemic pain has a significant nociceptive component, it still seems to respond quite well to SCS. Indeed, good evidence indicates that one of the primary mechanisms by which SCS alleviates pain in PVD is through resolution of tissue ischemia. SCS is potentially indicated for patients with primary vasospastic diseases such as Raynaud’s, limb ischemia in patients with collagen vascular diseases, degenerative atherosclerotic disease, and diabetic arteriopathy. The largest group of patients with PVD for which SCS is indicated includes those with claudication plus rest and/or night pain who have a life expectancy of at least 3 to 6 months and who lack significant tissue involvement. These patients have exhausted conservative therapy and are not candidates for further revascularization procedures. It has been shown that SCS can in fact result in frank healing of ulcers or at least arrest the progression of tissue loss in an extremity. It has also been suggested by some studies that SCS may reduce the need for or prolong the time to amputation in this population of patients, although whether SCS actually has a significant limb salvage effect is still debatable. Transcutaneous tissue oxygen levels (tcPO2) have been shown to be of prognostic value in determining those who will respond best to SCS.38,39 Patients with baseline preoperative tcPO2 between 10 and 30 mm Hg have been shown to have the best outcomes with SCS. Moreover, within this group of patients, those with successful outcomes had a mean change in tcPO2 of around 45 mm Hg with SCS versus a mean change of 15 mm Hg in those who were failures. It has been further suggested that a comparative evaluation between tcPO2 levels in the supine and sitting positions may provide additional evidence of success.38 A gradient exceeding 15 mm Hg was shown to predict a successful outcome in 88% of patients. SCS has been shown to result in satisfactory pain relief in 68% to 93% of patients. Indeed, the effectiveness of SCS in PVD has been confirmed in a Cochrane meta-analysis of 450 patients.25 In the earliest published series, 102 out of 115 (89%) of patients who underwent a trial of SCS received a permanent implant. Of these patients, good or excellent pain relief was reported in around 80%.24,29,30 Augustinsson and colleagues22 treated 34 patients with SCS and reported significant pain relief in 94%, a 50% ulcer healing rate, and an amputation rate of 38% compared with 90% in a control group followed over 16 months. Horsch and Claeys40 performed SCS in 177 patients with ischemic limb pain including 114 with Fontaine stage III and 63 with stage IV disease.

Overall, they reported more than a 75% reduction in pain in 78% of patients including 102 (89%) with stage III disease and 36 (57%) with stage IV involvement. This initial improvement persisted for at least 6 months in nearly two thirds of the patients. Clearly, patients with stage III disease have better outcomes. However, even a success rate of 57% in stage IV patients is comparable with that achieved in the average patient with FBSS. Kumar and coworkers41 evaluated 46 patients with unilateral ischemic pain for implantation of a SCS. The authors defined their criteria for a successful outcome as greater than a 50% reduction in VAS pain score, doubling of baseline claudication distance, a 50% or greater increase in tcPO2, a 25% or greater increase of peak flow velocity, and a 25% or greater increase in pulse volume recording in calf/foot. Failure was defined by an unsuccessful SCS trial, amputation, or removal of the device after implantation. Thirty-nine of 46 (85%) patients received an implant, and 30 (77%) were determined to be long-term successes with an average follow-up of 21 months. Pain relief was shown to correlate with changes in tcPO2 (P = .016) as well as in peak flow velocity (P = .031).41 As discussed previously, it was originally believed that SCS might have a significant limb salvage effect or, more accurately, a reduction in amputation rates. Whereas this may be true to some extent, the original enthusiasm for this claim probably needs to be tempered. There have been three relatively recent randomized, controlled studies that have failed to show any statistically significant difference in amputation rates with SCS at 12 and 18 months follow-up. However, an ‘‘almost significant’’ limb salvage has been shown in a subgroup of patients with baseline tcPO2 values between 10 and 30 mm Hg measured over the dorsum of the foot. Furthermore, even more recently, Amman and coworkers27 reported a highly significant difference in limb survival in patients with inoperable, stable, critical limb ischemia for those treated with SCS compared with controls. The outcome of SCS in patients with vasospastic disease is generally more promising and Augusstinsson29,37 has even maintained that vasospastic disease may be the best indication for SCS. In addition to Raynaud’s, SCS may also improve outcome in patients with frostbite, Buerger’s disease, and scleroderma. It is therefore somewhat surprising that the number of published cases of this application remains relatively small.

OTHER INDICATIONS There are a number of other indications for SCS. There is probably a well-defined role in patients with painful diabetic peripheral neuropathy who have otherwise exhausted pharmacologic therapy.41,42 The success of SCS in this group of patients may be related to the severity of neuropathy and the degree of large fiber sensory impairment. SCS has been successfully employed in patients with postamputation pain syndromes including both stump pain and phantom pain. Stump pain is the result of a painful neuroma and really represents a peripheral nerve injury. Logic would suggest that this type of pain should in fact respond relatively well to SCS. Conversely, it is curious that phantom pain does in fact respond to SCS in some patients. Interestingly, in patients with phantom pain who are successfully treated with SCS, ‘‘phantom paresthesias’’ are generally perceived overlapping the region of phantom pain. Although the success rate is probably much lower than for other types of neuropathic pain, SCS is worth considering because the other alternatives such as motor cortex stimulation or DREZ lesions are more invasive and have higher morbidity. Finally, SCS has also been suggested for the treatment of conditions such as postherpetic neuralgia and postthoracotomy pain. In the author’s experience (RKO), postherpetic neuralgia responds quite poorly to SCS. The inconsistent results in the literature may be related to the degree of deafferentation that occurs in this condition.

X NEUROMODULATION APPROACHES TO PAIN MANAGEMENT 553

SCREENING TRIAL FOR SCS One of the major advantages of SCS is that a screening trial can be performed to determine effectiveness prior to proceeding with a permanent implant. The primary purpose of a trial is to identify and accurately select patients who will achieve long-term success after implantation of a SCS system. Without exception, every patient who is believed to be a candidate for SCS should have a screening trial performed before implantation of a permanent system. It should be understood that the goals of the trial and criteria for success may not be uniform for all patients; these need to be defined on a case-by-case basis. It is important that the specific goals and criteria for success be discussed and defined by both the physician and the patient before proceeding with the trial. The most obvious, and probably the outcome on which patients are most focused, but sometimes the most overrated goal of any treatment for chronic pain is absolute pain reduction. The ‘‘gold standard’’ that generally has been accepted as the criteria for successful treatment is a 50% reduction in baseline pain. Unfortunately, pain reduction alone does not always translate into a significant or acceptable improvement in a given patient’s condition. This can be described by the concept that ‘‘one man’s junk is another man’s treasure.’’ Some patients may be quite satisfied with a lesser degree of pain reduction and positively translate this into their daily life with increased activity, and the like. Conversely, there are some patients who may not ultimately be satisfied with a pain reduction of 90%. This discrepancy in large measure is a reflection of the psychosocial factors that influence pain and suffering for a given patient. Although pain reduction is certainly important, just as important is a demonstration of functional improvement with treatment. Unfortunately, there are no good standardized tools to measure functional improvement that have been applied to patients undergoing implantable pain therapies. Level of function varies considerably among patients, and what is significant for one may not be significant for another. Other measures of success may include improvements in mood and sleep pattern as well as reductions in medication consumption. Many patients incorrectly assume that an SCS or other implantable device may allow them to discontinue medications. Whereas this is certainly a potential benefit of SCS, in the author’s experience (RKO), most patients continue to require some medications even after what is considered a successful implant. Several methods are available for screening: the temporary percutaneous trial, a percutaneous tunneled trial, or a trial with a surgical or paddle electrode. Each method has advantages and drawbacks, and there is no consensus as to the best method. A pure temporary trial is performed using a percutaneous electrode that is externalized with the intention of removing it at the conclusion of the trial. This is a very simple and straightforward procedure that in many cases can be performed in the outpatient clinic setting. Because the electrode is always removed at the end of the trial, it does not commit the patient to any additional procedures in the event the trial is unsuccessful. This is an ideal technique, particularly in situations in which the clinician may have some doubts as to whether trial will be successful. Furthermore, because the patient also understands that the trial electrode will be removed and there is no anticipation of a staged procedure for a permanent implant, she or he may be less likely to embellish the result and thereby lessen the chances of a false-positive trial. The most significant downside to this method is that occasionally ideal placement of a permanent electrode cannot be replicated during the permanent procedure, although for the experienced implanter this is relatively uncommon. A second method of screening is the percutaneous tunneled trial. With this method, after the electrode(s) is inserted and properly positioned, an incision is made incorporating the wire and the electrode is anchored to the fascia. This is then connected to a temporary extension wire that is brought out through the skin, remote from the surgical incision. If the trial is successful, the temporary

extension is removed, and the original electrode is connected to a permanent power source. However, if the trial is unsuccessful, the patient must be returned to the operating room to remove the electrode. The main advantage of this technique is that it obviates the need to place new electrodes for the permanent implant. This method can be very useful in situations in which placement of the trial electrode was very difficult or it was difficult to position the electrode in a location to obtain adequate paresthesias overlap of the pain pattern. Although many implanters might argue that this method is associated with a higher risk of infection, it has not been the experience of the author (RKO). The third method of screening involves implantation of a surgical lead. Surgical leads can be particularly useful in patients who have undergone extensive multilevel laminectomies, which can make accessing the epidural space with a needle and placement of a percutaneous electrode difficult and, in some cases, impossible. If a surgical lead trial is considered, the process is then identical to that described previously for the tunneled percutaneous trial. There is no general consensus as to the ideal duration for a trial, which can last anywhere from 24 hours to several weeks. Regardless of the method used, the author’s (RKO) personal preference is usually to perform a 10- to 14-day trial. However, in the author’s opinion (RKO), the trial should be no less than 3 days and preferably at least 1 week. Longer trials allow for better assessment of function, give the patient ample opportunity to assess the effects of the stimulation, and provide the opportunity to adjust programming and stimulation parameters to obtain the ideal paresthesia coverage. Moreover, a longer trial allows for dissipation of any potential placebo response that may occur in a given patient. In the author’s opinion (RKO), trialing for analgesia in the operating room with immediate implantation of the permanent system should be discouraged. There are several additional principles of screening central to obtaining accurate information that will eventually lead to a successful permanent implant. With few exceptions, one should generally select the type of electrode configuration for the screening trial that one anticipates will be required for an effective permanent implant. For example, if a dual-electrode system is considered necessary to achieve optimal paresthesia coverage, then dual electrodes should be considered for the trial. It is crucial that an optimal stimulation pattern, that is, 100% coverage of the pain topography, be achieved and consistently maintained with the trial in order to make an accurate judgment as to the therapeutic benefit. Remember, with rare exceptions, for SCS to be effective, the patient must be able to perceive paresthesias that overlap the pain topography. Lastly, one should avoid overstimulation of one area in order to get stimulation into a different area. For example, if a patient has pain restricted to the foot and first perceives stimulation in the thigh, one should avoid simply ramping up the amplitude in order to drive the stimulation more caudally. This may produce painful stimulation in an area that is not part of the pain topography and may cause the patient to dislike the sensation and effectively produce a false-negative trial. Lastly, it is critical for the clinician to remember that a successful trial in no way guarantees long-term success of a permanent implant. This is supported by the observation that as many as 50% of patients who experience battery failure never have their internal pulse generator replaced. The key to long-term success with SCS, as with any other pain procedure, is careful patient selection, education of the patient as to the realistic expectations, and a thorough understanding by the implanting physician of the benefits and limitations of the device.

PERMANENT SCS IMPLANT Following a successful trial by whatever criteria have been set by the patient and implanting physician, a permanent SCS system is implanted. Assuming the trial was performed with a temporary

554 Chapter 75  SPINAL CORD STIMULATION FOR THE TREAT MENT OF CHRONIC INTR ACTABLE PAIN percutaneous electrode, one needs to decide whether to use a percutaneous electrode or a surgical lead for the permanent implant. Some of the considerations for using percutaneous as opposed to surgical leads have been discussed previously. Because most physicians who implant SCS systems are nonsurgeons and lack formal surgical training, they will naturally choose percutaneous electrodes unless they enlist the services of a spine surgeon. Conversely, many surgeons will naturally choose surgical leads because they may not be comfortable with the percutaneous needle techniques required to place percutaneous electrodes. Again, there are both advantages and drawbacks to each type of lead. Percutaneous electrodes are usually fairly easy to place and require only a fairly superficial soft tissue dissection for anchoring. Percutaneous electrodes also provide more flexibility than surgical leads and may be advantageous in patients with complicated pain patterns. Percutaneous leads come in either 1 x 4 or 1 x 8 configurations with a variety of interelectrode distances. It is possible to design a ‘‘custom’’ stimulation system utilizing multiple percutaneous leads. Percutaneous leads are steerable to some degree and allow one to explore a much larger area of the spinal cord in a rostral-caudal direction in order to identify the ‘‘sweet spot’’ for stimulation that will produce the optimum paresthesia coverage. The major downside to percutaneous leads is their propensity to migrate, especially in a rostral-caudal direction. This can be prevented, for the most part, by employing sound anchoring techniques including multiple anchoring points and the use of generous strain relief loops in the electrode. In contrast, placement of surgical leads is generally restricted to the areas immediately rostral or caudal to the level of spinal exposure. Surgical leads do have some advantages. Because of their shape, they are less prone to migration, particularly in the cervical spine where there is significant movement. Indeed, once a surgical lead becomes scarred in place, it will virtually never move with normal activity. Also, because surgical leads are insulated except at the contact, the entire electrical field is directed ventrally at the target, and this may result in better performance in terms of power requirements than percutaneous leads in which the contacts are circumferential. The latter is probably somewhat less important now that the use of rechargeable impedance plethysmographs (IPGs) has become more common. Regardless of what type of electrode is employed, it cannot be overemphasized that the most important aspect of electrode placement is complete capture of the pain area with stimulation-induced paresthesias. Once the electrode has been implanted, it is connected to an internal power source. There are three types of power sources: radiofrequency (RF) receivers, primary cell IPGs, and more recently,

rechargeable IPGs. The choice of the power source depends on a number of factors including the total number of contacts to be connected, the anticipated power requirements, frequency needs, and patient compliance and competence (Table 75–1). For pure convenience, most patients prefer a fully implantable IPG as opposed to an RF system that requires the patient to wear an antenna over the receiver in order to use the stimulator. For the most part, RF systems have been supplanted by primary cell or rechargeable IPGs. However, there are selected circumstances in which an RF system may be useful. Some patients, particularly those with CRPS, sometimes require very high frequency stimulation for analgesic benefit. In such cases, an RF system may be the best option. Unlike IPGs, an RF receiver is merely a passive device and, therefore, never requires replacement unless there is a physical problem with the device. It is worthwhile to mention something regarding anesthetic technique for implantation of a SCS system. In order to achieve optimum electrode position and ensure a successful outcome to the greatest extent possible, it is necessary for the patient to provide accurate feedback during placement of the electrodes. Therefore, with a few specific exceptions, implantation of an SCS system must be performed with the patient awake. This is true whether one is using percutaneous electrodes or a surgical lead. Most implants can be accomplished using local anesthesia combined with light intravenous sedation. Indeed, percutaneous electrodes can usually be placed with relatively little, if any, sedation by liberally employing local anesthetics. It is important to anesthetize not only the superficial tissues but also the deeper tissues including the periosteum. If additional sedation is required, a short-acting, readily reversible agent such as propofol supplemented by a modest dose of intravenous opiate works quite well. The author’s preference (RKO) is to completely avoid giving any benzodiazepines, especially in older patients. These drugs tend to produce more cognitive impairment that sometimes completely prevents the patient from providing an adequate description of the paresthesia coverage. Once the electrode has been properly positioned and securely anchored to prevent migration and intraoperative testing has been completed, the patient can be deeply sedated for tunneling of the wires and creation of the subcutaneous pocket to house the IPG. Another technique that has proved very helpful is the use of spinal anesthesia. One might wonder how the patient can perceive paresthesias in the presence of a complete spinal block. Remember that local anesthetics primarily block root fibers. Activation of the DC is unaffected. Since 2007, the author (RKO) has utilized this technique in approximately 20 patients for implantation of surgical lead SCS systems. In no case was the patient unable to perceive paresthesias. The only difference noted between patients operated

Table 75^1. Power Source Device Selection Matrix Primary Cell IPG

Rechargeable IPG

RF System

Power needs Frequency needs Pain targets Disease state

Low to moderate Low Single Stable

Moderate to high Moderate to high Multiple Stable or likely to progress

Coverage needs Compliance requirements

1 or 2 leads Easiest to use

1, 2, 3, or 4 leads Requires following specific batterymanagement procedures Moderate level required

Very high Very high Multiple Stable or likely to progress to multiple extremities 1, 2, 3, or 4 leads Requires daily effort

Competence (physical or Appropriate for all mental limitations) levels Programming needs (programs Simple, 4 g/day dried ginger and taking anticoagulants. Generally well-tolerated in clinical trials. Rare cases of phototoxicity. Herb-drug interactions due to induction of CYP3A4 and P glycoprotein drug transporter. Theoretically, the risks are similar to those of aspirin, although this is not well-supported by clinical trial data.

See Patel G, Euler D, Audette JF. Complementary and alternative medicine for noncancer pain. Med Clin North Am 2007;91:141–167, for a more detailed review of the literature to support these findings.

562 Chapter 76  COMPLEMENTARY AND ALTERNATIVE MEDICINE FOR NONCANCER PAIN language used for the differential diagnosis differs from that used in Western allopathic medicine.22 The Western approach to herbs for treating pain syndromes is more symptom-oriented and restricted to single-herb functions. Single herbs are often combined to treat one or several symptoms. The single-herb approach is simpler to research and control, but the effects may not be as comprehensive and satisfactory or well-fitted to the individual patient as Chinese herbal formulas. Several herbs were found to have satisfactory analgesic effects, among them Rhizoma curcumae (three species of Curcuma rhizomes are being used, which include C. wenyujin, C. phaeocaulis, and C. kwangsiensis), ginger extract, willow bark, capsaicin, Devil’s claw, boswellia, lavender, and feverfew. Most commonly, these herbal remedies are ingested in capsules that contain concentrated extracts of the herb. The essential oil of these herbs can be ingested, inhaled, and/or rubbed onto the painful area. For a milder effect, one can drink the tea or infusion of these herbs22 (Table 76–4).

CONCLUSIONS In summary, the past several years have shown an increase in the quality of trials examining the clinical efficacy of various CAM modalities for pain conditions. There is still need to raise the quality of the studies from a scientific and methodological point of view in many areas of CAM research by randomizing, choosing the appropriate sample size, blinding, and developing more sophisticated sham procedures. However, much work still has to be done to find ways to preserve the clinical authenticity of CAM treatment methods when they are brought into the light of a research protocol. Recent attempts have been made to find a method of maintaining the standardization and reproducibility of a research protocols while allowing the kind of flexible treatment that would normally be applied in a clinical setting. Other questions that should be answered with future studies include understanding how treatment length influences outcome, whether maintenance treatments are needed for chronic conditions, and cost and risk comparisons with standard pharmacologic treatment. Providing this kind of detail will both assist with reproducibility and help us gain a better understanding about whether certain treatment paradigms are superior to others for specific clinical conditions. Finally, physicians who have an interest in pursuing CAM research should educate themselves both about the methodological issues inherent with the particular area of interest as well as about ways to maintain the authenticity of the CAM treatment protocols so that the literature is not populated with more poorly designed studies. For example, physicians can trial the three species of C. rhizomes being used (which include C. wenyujin, C. phaeocaulis, and C. kwangsiensis) as well as acupuncture at the Harvard Continuing Medical Education course, ‘‘Structural Acupuncture for Physicians.’’ With the emerging interest in integrative medicine comes a growing interest in collaboration, and a greater number of physicians are interested in obtaining training in CAM modalities to help bridge this gap between CAM and conventional clinicians. For example, the American Academy of Medical Acupuncturists has been formed to help as both an educational and a research forum for physician acupuncturists, and the American Holistic Medical Association provides educational exposure to a broader range of integrative and CAM modalities. The future of medicine will likely be integrative, and the more that health care providers can educate themselves about this area of medicine, the better they will be able to provide the highest quality of care to their patients.

REFERENCES 1. National Institutes of Health/National Center for Complementary and Alternative Medicine (NIH/NCCAM). Meditation for health purposes. Available at http://nccam.nih.gov/health/ 2. Han JS. Acupuncture and endorphins. Neurosci Lett 2004;361:258–261. 3. Hui KK, Liu J, Makris N, et al. Acupuncture modulates the limbic system and subcortical gray structures of the human brain: evidence from fMRI studies in normal subjects. Hum Brain Mapp 2000;9: 13–25. 4. Berman BM, Ezzo J, Hadhazy V, Sawyers JP. Is acupuncture effective in the treatment of fibromyalgia? J Fam Pract 1999;48:213–218. 5. Guerra de Hoyas JA, Andre´s Martin Mdel C, Bassas Y Baena de Leon E, et al. Randomised trial of long-term effect of acupuncture for shoulder pain. Pain 2004;112:289–298. 6. Trinh KV, Phillips SD, Ho E, et al. Acupuncture for the alleviation of lateral epicondyle pain: a systematic review. Rheumatology 2004;43:1085–1090. 7. Melchart D, Streng A, Hoppe A, et al. Acupuncture for patients with tension-type headache: randomized control trial. BMJ 2005;331:376–382. 8. Linde K, Streng A, Jurgens S, et al. Acupuncture for patients with migraine: a randomized control trial. JAMA 2005;293:2118–2125. 9. Vickers A, Zollman C, McCarney R, et al. Acupuncture for chronic headache in primary care: large randomized trial. BMJ 2004; 328:744. 10. Backer M, Hammes M, Dander D, et al. Changes of cerebrovascular response to visual stimulation in migraineurs after repetitive session of somatosensory stimulation (acupuncture): a pilot study, headache. J Head Face Pain 2004;44:95. 11. Irnich D, Behrens N, Gleditsh JM, et al. Immediate effects of dry needling and acupuncture at distant points in chronic neck pain: results of a randomized, double-blinded, sham-controlled crossover trial. Pain 2002;99:83–89. 12. Witt C, Jena S, Brinkhaus B, et al. Acupuncture for patients with chronic neck pain. Pain 2006;125:98–106. 13. Elden H, Ladfors L, Fagevik O, et al. Effects of acupuncture and stabilising exercises as adjunct to standard treatment in pregnant women with pelvic girdle pain: randomised single-blind controlled trial. BMJ 2005;330:761. 14. Kvorning N, Holmberg C, Greenert L, et al. Acupuncture relieves pelvic and low back pain in late pregnancy. Acta Obstet Gynecol Scand 2004;83:246–250. 15. Furlan AD, van Tulder MW, Cherkin DC, et al. Acupuncture and dry needling for low back pain. Cochrane Database Syst Rev 2005;(1):CD001351. 16. Manhelmer E, White A, Berman B, et al. Meta-analysis: acupuncture for low back pain. Ann Intern Med 2005;142:651–663. 17. Brinkhaus B, Witt C, Jena S, et al. Acupuncture in patients with chronic low back pain. Arch Intern Med 2006;166:450–457. 18. Molsberger A, Mau J, Pawelec D, Winkler J. Does acupuncture improve the orthopedic management of chronic low back pain?—a randomized, blinded, controlled trial with 3 months follow-up. Pain 2002;99:579–587. 19. Berman BM, Lao L, Langenberg P, et al. Effectiveness of acupuncture as adjunctive therapy in osteoarthritis of the knee. Ann Intern Med 2005;141:901–910. 20. Linde K, Weidenhammer W, Streng A, et al. Acupuncture for osteoarthritic pain: an observational study in routine care. Rheumatology 2006;45:222–227. 21. Vas J, Mendez C, Perea-Milla E, et al. Acupuncture as a complementary therapy to the pharmacological treatment of osteoarthritis of the knee: randomized controlled trial. BMJ 2004;329:1216 doi:10.1136/bmj.38238.601447.3A. 22. Patel G, Euler D, Audette JF. Complementary and alternative medicine for noncancer pain. Med Clin North Am 2007;91:141–167.

XII NEUROSURGICAL APPROACHES TO PAIN MANAGEMENT

Chapter 77

NEUROSURGICAL TREATMENT OF PAIN Daniel Clayton, Emily A. Davis, and Richard K.Osenbach

INTRODUCTION Patients with chronic intractable pain not uncommonly present complex and difficult challenges for the treating physician. Successful management of these complicated patients requires a thorough understanding of the underlying pain condition along with a careful and thoughtful approach to developing an effective treatment algorithm. When considering any surgical intervention for chronic pain, the central importance of careful patient selection to a successful outcome cannot be overemphasized. Remember that chronic pain is a multidimensional biopsychosocial problem; it is truly a chronic disease for which there is generally no cure; and it must necessarily be approached much as would a chronic disease such as diabetes or cancer. Indeed, effective management of most patients with chronic pain requires a multidisciplinary approach, utilizing all modalities and specialists at one’s disposal. The belief on the part of the patient and/or physician that a surgical procedure alone (e.g., spinal cord stimulator implant) will provide a ‘‘cure’’ for the pain is a foolish thought and will nearly always result in treatment failure and a dissatisfied patient. The successful treatment of chronic pain should follow a logical algorithm, beginning with the most simple and least interventional therapies and progressing to more complex invasive modalities. The purpose of this chapter is to present a relatively brief yet comprehensive review of the various neurosurgical treatments currently available for the management of chronic intractable pain in both cancer and noncancer patients. A discussion of spinal cord stimulation (SCS; Box 77–1) has been deliberately omitted because this topic is covered in Section X, Chapter 75. Also, the treatment of trigeminal neuralgia is not addressed because this topic is complete unto itself and cannot be adequately covered in this review.

SURGICAL PROCEDURES Surgical procedures for the treatment of chronic pain can be divided into two general categories: neuromodulation and neuroablation (Box 77–2).1,2 The field of neuromodulation primarily encompasses procedures that utilize techniques of electrical stimulation applied to neural structures and neuraxial drug delivery. Indeed, neuromodulation is currently performed not only for the treatment of pain but also for numerous other medical conditions including movement disorders, epilepsy, psychiatric disorders, gastric motility problems, and urinary incontinence. For patients with nonmalignant pain, taking into consideration the clinical problem, pain topography, and type of pain (nociceptive vs. neuropathic), neuromodulation or some type of nonablative procedure should generally be considered before moving on to an irreversible destructive procedure. Neuromodulation procedures are particularly attractive because they are nondestructive and reversible and can be tested with some degree of certainty as to their potential for effective long-term pain relief.

NEUROABLATIVE PROCEDURES Up until the late 1960s, the management of severe intractable pain primarily involved neurosurgical treatments. Early treatments were nearly all ablative in nature and served as a way of interrupting either the transmission of pain to the central nervous system (CNS) or the perception of pain within the CNS. Indeed, a significant body of knowledge regarding functional neuroanatomy was discovered as a result of applying ablative procedures, and even today, some of these earlier treatments such as cordotomy continue to have contemporary indications. Prior to the introduction of spinal drug delivery, ablative procedures formed the cornerstone of treatment for patients with pain related to cancer and, to a lesser extent, nonmalignant pain syndromes. However, the development and evolution of intrathecal (IT) opiates in the 1980s significantly altered the landscape for the treatment of cancer pain. There is a fairly clear correlation in the decline of ablative procedures with the development of intrathecal drug delivery (ITDD) systems, and certainly since the mid to late 1990s, there has been a radical trend away from the use of ablative procedures. This is rather unfortunate because some of these techniques such as percutaneous cordotomy are highly 563

564 Chapter 77  NEUROSURGICAL TREAT MENT OF PAIN

Box 77^1 CURRENT APPLICATIONS OF SPINAL CORD STIMULATION  Postlaminectomy pain syndrome (i.e., failed back surgery syndrome)  Complex regional pain syndromes * Type I (i.e., reflex sympathetic dystrophy) * Type II (i.e., causalgia)  Peripheral nerve injury pain  Post-thoracotomy pain or intercostal neuralgia  Ilioinguinal neuralgia  Ischemic limb pain secondary to peripheral vascular disease  Intractable angina pectoris  Interstitial cystitis  Coccydynia  Vulvodynia

effective in patients with cancer pain. Indeed, improvements in imaging, stereotactic localization, electrode design, and lesioning techniques have created the potential to make these techniques even safer and more effective than ever before. There are certainly both advantages and disadvantages to destructive pain procedures. On the negative side, destructive

procedures are obviously irreversible and carry the risk of neurologic morbidity. Also, the analgesic efficacy of most destructive procedures cannot be tested with any degree of certainty, as is the case with neuromodulation procedures. On the positive side, ablative techniques can be performed in a single stage and can result in immediate and complete pain relief. An effective ablative procedure allows the patient more freedom by eliminating the requirement of continuous interactions with health care providers that is necessary in the case of spinal drug pumps that require periodic refilling and sometimes frequent reprogramming in order to achieve effective pain control. Moreover, the overall cost of ablative procedures is probably lower because the initial high costs of an implant are avoided. Consequently, the senior author (RKO), as well as other neurosurgeons familiar with these techniques, firmly believes they should continue to play an important role in the management of patients with cancer-related pain. For patients with nonmalignant pain syndromes (albeit with some exceptions [e.g., trigeminal neuralgia]), whenever feasible, a neuroaugmentative approach should generally be attempted because this is more likely to result in long-term success than destructive procedures for which the analgesic effects often fade with time.

Peripheral Neurectomy Box 77^2 NEUROMODULATION AND ABLATIVE PROCEDURES FOR CHRONIC PAIN Neuromodulation  Spinal cord stimulation (i.e., dorsal column stimulation)  Peripheral nerve stimulation * Major extremity nerves (median, ulnar, radial, sciatic, peroneal, tibial) * Occipital nerve stimulation * Spinal nerve root stimulation * Trigeminal nerve stimulation (peripheral)  Spinal drug infusion  Intraventricular opiates  Deep brain stimulation * Endogenous opiate system (periaqueductalgray, periventricular gray) * Lemnisal system (medial lemniscus, sensory thalamus, internal capsule)  Motor cortex stimulation Ablative Procedures  Peripheral procedures * Peripheral neurectomy * Excision of painful neuromas * Sympathetic ganglionectomy * Trigeminal system procedures n Retrogasserian radiofrequency thermal rhizotomy n Percutaneous glycerol rhizolysis n Balloon microcompression  Spinal procedures * Dorsal root ganglionectomy * Dorsal rhizotomy * Anterolateral cordotomy * Midline (commissural) myelotomy * Percutaneous high-cervical cordotomy (C1^2) * Dorsal root entry zone (DREZ) lesion  Brainstem and thalamic procedures * Caudalis DREZ * Medullary tractotomy * Pontine tractotomy * Mesencephalic tractotomy * Medial thalamotomy * Pulvinotomy  Other procedures * Cingulotomy * Pituitary ablation * Hypothalamotomy * Stereotactic radiosurgery

Pain is a common symptom after peripheral nerve injury as well as some diseases of the peripheral nerve, such as diabetic neuropathy. Injury to a major nerve trunk may result in a devastating pain syndrome known as complex regional pain syndrome (CRPS) type II, also known as causalgia. Painful nerve injuries are often complex problems that necessitate commitment and perseverance from both the patient and the physician. Multiple pathophysiologic mechanisms for nerve injury pain have been proposed including sensitization of peripheral nerve terminals, abnormalities in primary afferent fibers, abnormal electrical communication between adjacent axons, and alterations in the circuitry and neurochemistry of the dorsal horn. Much work has been focused on the pathophysiology of neuromas, which have been shown to produce abnormal single-unit electrical discharges, although neuroma formation per se is not necessary to produce abnormal electrical activity within a nerve.3 Peripheral neurectomy (i.e., cutting the nerve) is sometimes beneficial in carefully selected patients with peripheral nerve pain.4 The pain may be related to a traumatic injury (e.g., painful neuroma), a compressive neuropathy (e.g., meralgia paresthetica or tumor invasion of the brachial plexus), or an idiopathic condition (e.g., occipital neuralgia). Peripheral neurectomy has also proved beneficial for a small group of patients with refractory trigeminal neuralgia who, because of significant comorbidity, may not be candidates for more standard therapies such as microvascular decompression or even any of the percutaneous retrogasserian procedures. Supraorbital and infraorbital neurectomy can also be considered in patients with neuropathic pain after traumatic injury to these nerves. Neurectomy of the supra- and infraorbital nerves for firstand second-division pain, respectively, can be performed relatively easily under local anesthesia. Even inferior alveolar neurectomy for third-division pain is feasible, although it is necessary to expose this nerve through a small opening in the mandible. The current indications for peripheral trigeminal branch neurectomy are admittedly few, especially now that stereotactic radiosurgery is accepted as a completely noninvasive treatment for trigeminal neuralgia. Although peripheral trigeminal neurectomy is infrequently indicated, it should be remembered as a viable alternative in selected patients.5 Obviously, peripheral neurectomy is limited to pure sensory nerves or mixed nerves in which there has been complete loss of function (e.g., painful amputation neuroma) without the hope of any return. Neuromas that involve pure sensory nerves including the

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dorsal cutaneous ulnar branch, superficial sensory radial branch, antebrachial cutaneous nerves, and the sural and saphenous nerves are usually best managed with excision without consideration of repair. The sensory territories supplied by these nerves are of low functional importance, and numbness in their distribution is usually preferable to pain, dysesthesias, hyperalgesia, and allodynia. Because recurrent pain and paresthesias may occur with nerve regeneration, the proximal nerve stump should be implanted into either underlying muscle or bone. This technique minimizes the chances of a recurrent superficial mechanically sensitive neuroma in the event there is significant regeneration. Meralgia paresthetica, for example, is a condition that can be successfully treated by sectioning of the lateral femoral cutaneous nerve. A recent operative series showed complete symptomatic relief in 73% and partial relief in 20% of cases.6 Neurectomy has also been advocated for chronic ilioinguinal pain. Some authors have reported success rates exceeding 85% in patients with intractable ilioinguinal neuralgia after hernia repair. However, based on the senior author’s (RKO) personal experience, this seems to be overly optimistic. Occipital neuralgia is another condition that traditionally has been managed with peripheral neurectomy. Unfortunately, recurrence of pain is often the rule, and long-term success rates have not been encouraging. One of the most important prerequisites of peripheral neurectomy is complete relief of pain after repetitive local anesthetic nerve blocks. It is important that these blocks be performed without epinephrine because injured peripheral nerves and neuromas abnormally express adrenergic receptors, which are algogenic when activated and can, therefore, produce a false-negative response to blockade. Several other factors also seem to have prognostic value in predicting a successful result with peripheral neurectomy. Ideally, the pain should be related to a traumatic injury; it should be restricted to the territory of a single peripheral nerve; and Tinel’s sign should be present with percussion over the neuroma. Notwithstanding all of the these criteria, the overall success rate for excision of painful neuromas is probably no higher than 60%.4

Spinal and Paraspinal Procedures Dorsal Rhizotomy and Dorsal Root Ganglionectomy Dorsal rhizotomy has been performed since the late 1890s. Application of dorsal rhizotomy for the relief of pain is based on the law of Bell and Magendie, which states that the dorsal roots subserve afferent and ventral roots efferent function, respectively. Intuitively, destruction of the dorsal roots should eliminate the entry of segmental nociceptive information that normally would enter the spinal dorsal horn at these levels. Unfortunately, the results of dorsal rhizotomy have been variable at best and often unrewarding. Two factors likely contribute to the poor outcomes associated with dorsal rhizotomy. First, dorsal rhizotomy depends on denervation of the area from which the pain is believed to be generated, for example, from an intercostal nerve damaged by a rib fracture or injured during thoracotomy. However, the ability to completely denervate a particular region with this procedure is limited by the high degree of sensory overlap between adjacent dermatomes, especially on the trunk. Indeed, complete denervation of a single thoracic dermatome requires interruption of the segmental afferent input at least two dermatomal levels above and below the segmental level of pain. Second, a substantial body of literature now exists demonstrating that as many as 30% of nociceptive afferent fibers enter the spinal cord through the ventral root, the so-called ventral root afferents. Consequently, intradural dorsal rhizotomy, which is a preganglionic procedure, will fail to interrupt the nociceptive input carried by these ventral root nociceptive afferent fibers Notwithstanding the drawbacks, dorsal rhizotomy may have limited applicability, especially in the treatment of cancer pain in

which the tumor has not spread into an extensive area.7–9 Pain from deep and extensive invasive facial cancer can sometimes be effectively treated by rhizotomy. In such cases, it is necessary to cut the trigeminal nerve, nervus intermedius, glossopharyngeal nerve, and upper third of the vagus, combined with dorsal rhizotomy from C1 (if present) through C4. Rhizotomy from C8 to T4 may be utilized for pain produced by tumors in the upper thoracic and lower cervical region that are limited in size (e.g., Pancoast’s tumor) and that involve the brachial plexus to such an extent that there is irreversible loss of function in the upper extremity. For more extensive tumors in which rhizotomy is required at more rostral levels, a useless, nonfunctional extremity is an absolute prerequisite. Bilateral dorsal rhizotomy has proved effective for pain related to pelvic cancer when the tumor involves the more caudal sacral levels (S2 or S3 and below). Sacrococcygeal rhizotomy may also be useful for perineal pain related to cancer. However, bilateral sacral rhizotomy is contraindicated in patients with normal bladder and bowel control. Not unlike other destructive pain procedures, the application of dorsal rhizotomy in patients with nonmalignant pain is more problematic and demands even more prudent judgment.7–9 Rhizotomy has no role in spontaneous steady neuropathic pain of nonmalignant origin and, in fact, leads to further deafferentation. However, rhizotomy may have a role in relieving hyperpathia limited to a radicular distribution, particularly if the pain is relieved by local anesthetic block, as described previously. In animal studies, it has been shown that removal of the dorsal root ganglion (DRG) leads to degeneration of most of the small unmyelinated high-threshold nociceptive-specific fibers that enter through the ventral root, and horseradish peroxidase–labeling studies have confirmed the origin of these fibers to be the DRG. Based on these observations and the large number of failures with dorsal rhizotomy, dorsal root ganglionectomy is now generally the preferred technique that is expected to produce the best results.7 Aside from improved efficacy, dorsal root ganglionectomy offers several other advantages over intradural dorsal rhizotomy.7,8,10 Ganglionectomy obviates the need for a laminectomy and an intradural exposure and, therefore, reduces the anesthetic time to which a debilitated patient must be exposed. It also significantly reduces the risk of cerebrospinal leak. In addition, each DRG is associated with its corresponding neural foramen, making localization somewhat easier. Dorsal root ganglionectomy may be indicated for pain in the neck, trunk, or abdomen. It is contraindicated for extremity pain because the extent of denervation required to produce the desired effect would result in near-complete loss of tactile and proprioceptive function, thereby rendering the extremity useless. Therefore, the procedure can be applied to the following roots: C1–4, T1–12, and L1–2.7,8,10 Prior to surgery, selective nerve root blocks that result in 100% pain relief may suggest but not unequivocally prove that ganglionectomy might be effective. Conversely, failure to derive any pain relief from local anesthetic blockade may indicate that there is a central component to the pain that will not be helped by ganglionectomy. Although dorsal root ganglionectomy is infrequently performed, it may be effective in a selected number of pain conditions including intractable occipital neuralgia that has not responded to electrical stimulation (either occipital nerve stimulation or high-cervical [C1–2] SCS) or peripheral neurectomy,11 post-thoracotomy or postlaparotomy pain, chest wall pain related to pleural-based malignant tumor invasion, and perineal pain secondary to pelvic malignancy.7,8,10 Previous studies of dorsal root ganglionectomy have failed to show any significant efficacy for persistent radicular pain after failed back surgery syndrome.12 In patients with perineal pain, bilateral interruption of the sacral roots is necessary. Because this may produce a sensory neurogenic bladder, this procedure should be limited to patients who have either already lost control of urinary and rectal sphincter function or who have undergone

566 Chapter 77  NEUROSURGICAL TREAT MENT OF PAIN colostomy and urinary diversion. For patients with preserved sphincter function, midline myelotomy (see later) may be a reasonable alternative.

Sympathectomy Sympathectomy has been in use since the late 1800s for a variety of conditions including hyperhidrosis, epilepsy, spasticity, angina, and various pain conditions, most notably complex CRPS type I, formerly known as reflex sympathetic dystrophy.13,14 At present, the most common indication for sympathectomy is symptomatic hyperhidrosis. As a primary treatment for pain, the major indication for sympathectomy is for the treatment of sympathetically mediated pain (SMP), most commonly associated with the group of painful disorders known as CRPS I and II. However, not all patients with CRPS display SMP. Wheeas many patients with CRPS I or II may have a component of SMP, there is usually also one or more components of sympathetically independent pain (SIP) that will clearly not respond to sympatholysis. It should be kept in mind that many, if not the majority of, patients with longstanding CRPS I do not in fact have a large component of SMP, and this probably explains the general lack of effectiveness of sympathectomy in patients with chronic CRPS. Generally, sympathectomy may be indicated for patients with a component of SMP who respond favorably to temporary chemical sympathetic blockade.15 It is generally best suited for SMP involving the upper extremity. Customarily, at least in the senior author’s (RKO) opinion, several successful sympathetic blocks should be performed in which the patient obtains either complete or nearly complete pain relief before considering a surgical sympathectomy. Selective sympathetic ganglion block can be accomplished through local anesthetic injection of the stellate ganglion (head, neck, and upper extremity), lumbar sympathetic chain (lower extremity), or celiac plexus (abdomen).15 The diagnostic utility of chemical sympathetic blockade depends on the ability to selectively interrupt sympathetic activity while leaving somatic pathways undisturbed. Therefore, it is necessary to perform careful sensory testing in order to conclude that pain relief is not in part related to a subtle somatosensory block, thereby producing a false-positive result. Few accepted standards exist to judge the adequacy of sympathetic blockade. Observation of Horner’s syndrome indicates interruption of the sympathetic fibers to the head but does not ensure blockade of sympathetic efferents to the upper extremity. Generally, effective upper extremity blockade is indicated by a temperature increase of 1.08C to 3.08C, although this may be unreliable if the initial skin temperature is warm.15 Other techniques include microneurography, which is invasive and requires sophisticated equipment, and measurement of skin blood flow using laser Doppler flowmetry. There are a number of problems in interpreting efficacy studies of regional sympathetic blockade for CRPS.15 First, the success rate of actually achieving a complete selective sympathetic block is not known. Second, no randomized, placebo-controlled trials have been published. Finally, the specificity of sympathetic blockade is not known. In other words, inadvertent blockade of somatic nerve fibers from diffusion of local anesthetic may produce pain relief and lead to a false-positive result. Unfortunately, the specificity of chemical sympathetic blockade and its ability to predict the response to permanent surgical sympathectomy are less than ideal. However, in spite of its limitations, sympathetic blockade is still an important adjunct in the treatment of CRPS, especially prior to pursuing surgical sympathectomy as a viable treatment option.

Upper thoracic sympathectomy The sympathetic innervation of the upper extremity is supplied by preganglionic fibers that originate from the intermediolateral

cell column. The second-order sympathetic efferent fibers exit the spinal cord in the ventral roots of T2–10, enter the sympathetic chain via the white rami, and synapse in the paravertebral sympathetic ganglia. Postganglionic sympathetic efferent fibers leave stellate and middle cervical ganglia and join the C5–T1 roots, although the majority of the fibers travel with the C7–T1 roots. According to this schema, resection of the T2 ganglia is usually sufficient to produce near-complete sympathetic denervation of the upper extremity.14 Pupillary fibers originate from T1 and pass through the stellate ganglion to synapse in superior cervical ganglion. If stellate resection is required, Horner’s syndrome is likely to occur. This can sometimes be avoided by resecting only the lower one half of the stellate ganglion. Various alternative efferent pathways have also been described including extraganglionic sympathetic pathways, origin of fibers from the C8 and T1 roots, and intermediate ganglia in the spinal roots of C8–T2. In most cases, it would appear that these pathways are probably not clinically significant, and resection of the T2 ganglion is adequate for near-complete sympatholysis to the arm. It should be noted that, previously, preganglionic sympathectomy (resection of ventral roots, white rami, and sympathetic chain with preservation of the ganglia) was considered preferable to a postganglionic sympathectomy. The rationale for this was that preservation of the ganglia might prevent ‘‘hypersensitivity’’ of target organs to circulating catecholamines. It is now believed that this phenomenon either does not occur at all or has minimal clinical significance. T2 sympathetic ganglionectomy can be performed with a variety of surgical techniques including open procedures (dorsal interscapular transaxillary and supraclavicular),13,14 percutaneous RF techniques,16 and most recently, minimally invasive thoracic endoscopic techniques.17,18 Percutaneous radiofrequency (RF) sympathectomy is a quick and easy method for sympathetic denervation of the upper extremity. Several modifications of the technique since the late 1980s have resulted in improved immediate as well as long-term results.16 The indications are identical to those for both open and endoscopic procedures. The operation can be preformed on an outpatient basis under neuroleptic analgesia. The operation has been described in detail by Wilkinson, who developed the procedure. The advantages of the percutaneous RF technique include avoidance of general anesthesia, the ease of performing bilateral procedures, and the ability to tailor the procedure based on physiologic monitoring. Moreover, the procedure can be easily repeated with good results. The most common complications include pneumothorax and intercostal neuralgia, which is usually transient. The transthoracic endoscopic approach was initially described in the mid-1950s and then reintroduced nearly a quarter century later. The evolution of contemporary video-assisted endoscopic techniques and refinement of endoscopic instrumentation has made video-assisted thoracoscopic sympathectomy (VATS) a relatively easy and safe procedure. VATS is performed through an intercostal approach with deflation of the ipsilateral lung. The lung is manually retracted and the appropriate anatomic landmarks are identified. The sympathetic chain is identified beneath the pleura lying alongside the lateral portion of the vertebral body coursing over the head of each rib. A segment of the sympathetic chain and the associated ganglia are excised. At a minimum, the T2 ganglion is resected, but for a complete denervation of the upper extremity, the sympathetic chain extending from just below the stellate ganglion to T4 should be excised. At the conclusion of the procedure, the lung is reinflated and a chest tube placed. A postoperative x-ray should be obtained to ensure proper inflation of the lung. The most common complication of VATS is persistent pneumothorax. Some patients will complain of local pain at the portal sites, but this is usually rather self-limited and customarily resolves without any specific treatment.

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Splanchnicectomy Visceral afferent fibers have been described that carry nociceptive information from internal organs such as the heart, pancreas, kidneys, and other organs. Pathologic processes that involve the pancreas such as carcinoma and chronic pancreatitis can be a source of intractable pain. Visceral afferents from the pancreas travel exclusively through splanchnic chain and enter the spinal cord primarily through the greater splanchnic nerve (GSN) via the celiac ganglion. In addition to bilateral innervation through the GSN (T4–9), visceral nociceptive afferents may also travel with the lesser splanchnic nerves (LSN) the least splanchnic nerves, and perhaps even from lower portions of the thoracic ganglia and upper lumbar chains. The deep, diffuse, aching pain associated with pancreatic carcinoma or chronic pancreatitis in particular suggests involvement of visceral afferents, whereas radicular pain implies involvement of somatic afferents. The source of pain can often be determined through the use of temporary splanchnic block. In the event that temporary splanchnic blockade produces significant pain relief, splanchnicectomy can be considered. A bilateral operation is usually required to achieve adequate pain relief and involves removal of the T9–12 thoracic ganglia along with the GSN, LSN, and least splanchnic nerves.13

Lumbar sympathectomy The sympathetic efferent outflow to the lower extremity originates from the lower thoracic cord and then passes through the lumbar ganglia, whose efferents leave the spinal canal with the ventral roots of L1 and L2. Customarily, resection of the L2 and L3 sympathetic ganglia should be sufficient to produce relatively complete sympatholysis in the lower extremity. Some sympathetic efferents may originate in L2 or L3 and then course caudally through the sympathetic chain and exit with postganglionic rami of the L4 and L5 roots. Consequently, some authors have advocated additional resection of L4 and L5 to improve long-term results. Lumbar sympathectomy is performed through a muscle-splitting transverse flank incision extending from beneath the costal margin to the lower quadrant.13 Although lumbar sympathectomy is a relatively straightforward operation, a number of pitfalls must be avoided. The ureter must be identified and retracted medially with the kidney, and the vena cava or aorta must be carefully preserved at the extremes of the dissection. Also, care must be exercised not to injure somatic nerves passing through the psoas and quadratus lumborum muscles. It must also be recognized that in males, bilateral sympathectomy is often accompanied by sexual dysfunction.

Results of sympathectomy for pain A survey of the more recent literature regarding the effectiveness of surgical sympathectomy for CRPS indicates variable rates of success ranging from 65% to 100%. For the most part, this is consistent with the older literature. On average, ‘‘long-term’’ successful outcomes have been reported in 70% to 85% of cases.17 In general, upper thoracic sympathectomy is more effective in alleviating upper extremity pain than is lumbar sympathectomy in relieving lower extremity pain. There does not appear to be any major difference in outcomes based on the particular surgical approach. Indeed, although less invasive, the results of VATS are similar to those of open procedures. It has been suggested that an important factor in determining the success of surgical sympathectomy is the duration of symptoms prior to the procedure. In a study of 21 patients with CRPS I followed from 4 months to 12 years, 95% of patients who underwent sympathectomy within 1 year of diagnosis achieved a good result.19 Similarly, Schwartzmann and coworkers20 reported long-term pain relief (follow-up 36–68 mo) for patients with CRPS I who underwent sympathectomy within 12 months. In contrast, only 44% of patients operated on after 12 months had the

same success. Conversely, some studies concluded that timing of surgery has no effect on outcome. Unfortunately, the author’s (RKO) experience with surgical sympathectomy has been less positive than some of the outstanding results reported in the literature. In spite of preoperative positive responses to chemical sympathetic blockade, pain relief exceeding 1 year has been the exception rather than the rule. There are several explanations for failed surgical sympathectomy. First, the diagnosis may have been incorrect, leading to poor patient selection. The difficulty with patient selection based on the response to sympathetic blockade has already been mentioned. There is a high placebo-response rate among patients with chronic pain in general and CRPS in particular. Therefore, multiple blocks that produce unequivocal pain relief for the duration of the anesthetic block are essential. Another reason for failure is inadequate resection of the sympathetic chain. Consequently, to maximize the chance for success, it is imperative to completely interrupt all sympathetic outflow to the involved extremity. Recurrent pain after an initial successful result may result from regeneration of the sympathetic chain, which is well known to occur. Lastly, there are reports of cross-communication of the sympathetic system, more common in the lumbar region, in which anatomic studies have shown cross-over fibers in nearly 30% of specimens. As a result, some patients may develop recurrent pain owing to contralateral sympathetic reinnervation of the affected extremity after an ipsilateral sympathectomy.

Dorsal Root Entry Zone Lesions Lesions of the dorsal root entry zone (DREZ) were first described by Sindou and associates21 in 1974 using small microincisions to interrupt incoming nociceptive afferent fibers. This work was further extended by Nashold and Ostdahl22 (who coined the term DREZ) in 1979 using an RF technique. The most common indication for DREZ lesioning has been in patients with deafferentation pain related to brachial plexus avulsion injuries. It is believed that deafferentation pain develops and is sustained owing to lesions that isolate afferent input from the second-order neurons whose cell bodies reside within the dorsal horn, brachial plexus avulsion being the classic example. Isolation or deafferentation of these second-order neurons is believed to result in abnormal electrochemical signals, thus producing pain. Consequently, it was proposed that destruction of this abnormal neuronal pool in the dorsal horn might produce pain relief, which indeed seems to be the case for certain conditions. Several techniques can be used for performing DREZ lesions, the details of which have been extensively published. Suffice it to say that central to all of these techniques is surgical exposure of the DREZ and destruction of the superficial five layers of Rexed’s laminae. The DREZ operation has been employed and the results evaluated for a number of deafferentation pain conditions. Without question, the best single indication for DREZ lesioning is pain that follows brachial plexus avulsion. Pain relief is usually immediate, although some patients may occasionally be worse for a short time after surgery. Long-term pain relief in excess of 5 years has been reported in approximately 70% of patients who have undergone the DREZ procedure for brachial plexus avulsion.23 Interestingly, DREZ lesioning is ineffective for neuropathic pain that develops after stretch injures of the brachial plexus. Therefore, it is important to be certain that the pain is due to avulsion rather than stretch injury. Although sometimes difficult, there are several ways to differentiate avulsion from a stretch injury. Patients with avulsion of the entire plexus will present with a flail extremity that is completely anesthetic. In patients with avulsion injuries, the onset of pain is almost immediate. It can involve any portion of the extremity, although most patients will relate that the most severe pain is felt in the hand, which is anesthetic. These patients commonly described the pain as though the hand is

568 Chapter 77  NEUROSURGICAL TREAT MENT OF PAIN being crushed in a vice. Other clinical clues to the presence of avulsion include weakness of the rhomboid muscles (supplied by the dorsal scapular nerve, which originates very proximally from the C5 nerve root), winging of the scapula, and the presence of Horner’s syndrome. Because root avulsion is a preganglionic (i.e., DRG) injury, the evoked sensory nerve action potential (SNAP) is still present as opposed to a postganglionic stretch injury in which the SNAP will be lost. Avulsion can also be demonstrated radiographically using either magnetic resonance imaging (MRI) or computed tomography (CT)–myelography. The observation of a pseudomeningocele may suggest an avulsion, although this finding may also be seen in the absence of root avulsion. Moreover, root avulsion is not always associated with a pseudomeningocele. The most accurate finding is the demonstration of the absence of the dorsal roots. In the author’s (RKO) opinion, CT-myelography remains superior to MRI in demonstrating this finding. The procedure is performed with the patient under under general anesthesia. A bilateral cervical laminectomy is performed and the dura opened to expose the spinal cord. Although DREZ can be performed through a hemilaminectomy, the senior author (RKO) prefers a bilateral exposure in order to clearly visualize the contralateral normal side. This can be very helpful for orientation because some patients will develop significant arachnoid scarring and/or rotation of the cord, which can sometimes make clear identification of the affected DREZ difficult. Once the location of the dorsolateral sulcus has been confirmed, DREZ lesions are created from the last intact root caudally to the most rostral intact root. Lesions are created at 1- to 2-mm intervals using a thermocouple temperature-monitoring electrode inserted into the DREZ at a 208 to 308 angle from the vertical. The electrode is designed such that a 15-second lesion made at 758C will produce thermal coagulation of the superficial five layers of the dorsal horn.22 The most significant complications of DREZ lesioning include inadvertent injury to the ipsilateral dorsal columns or corticospinal pathways, which may produce proprioceptive sensory loss and/or lower motor neuron weakness of the ipsilateral lower extremity. The single best indication for DREZ is brachial plexus avulsion. It can also be performed after avulsion injuries of the lower lumbosacral nerve roots, although this injury is far less common than brachial plexus avulsion. Pain relief is similar to that achieved with brachial plexus avulsion. Another good indication for the DREZ procedure is in patients with spinal cord injury who suffer from ‘‘end zone’’ pain. These patients complain of severe bandlike constricting pain at the area of transition from anesthesia to relatively normal sensation. However, DREZ lesioning is ineffective for the diffuse constant burning pain that occurs below the level the injury. DREZ has been used, albeit less successfully, for conditions such as phantom limb pain, postherpetic neuralgia, and peripheral nerve injury pain.22 It is neither indicated nor effective for CRPS I.

Anterolateral Cordotomy The lateral spinothalamic tract, located in the lateral funiculus of the spinal cord, is a crossed pathway that transmits the majority of pain and temperature input in the CNS, and a number of procedures have been described to interrupt this pathway including open or percutaneous cordotomy and commissural or midline myelotomy. Open cordotomy, as first described in 1912 by William Gibson Spiller and Edward Martin, is performed with the patient under general anesthesia through a laminectomy. However, the open procedure has largely been supplanted by percutaneous techniques that are less invasive, generally associated with less morbidity, and consequently usually better tolerated by patients with advanced cancer who may be ill and debilitated.24–28 Mullan and colleagues28 initially described percutaneous C1–2 cordotomy. Although the procedure has evolved considerably since the initial description, it remains an excellent option for the treatment of refractory cancer pain.

In considering a patient for cordotomy, or midline myelotomy for that matter, the severity of the pain should be sufficient to justify the procedure and the attendant risks. In this sense, it is important to attempt to segregate physical pain (biologic) due to the underlying cancer and the emotional suffering related to depression and other socioeconomic and secondary gain issues (psychosocial). Also, as with any destructive procedure, all reasonable noninvasive methods for pain control should have been attempted and failed to provide adequate pain relief. The most common indication for percutaneous cordotomy is in the patient with opiate-resistant or opiate-tolerant cancer pain. Indeed, most candidates for cordotomy have failed to respond adequately to high doses of long-acting oral opiates and/or intraspinal opiates. In some patients, for a variety of reasons, intraspinal opiates may not be a practical or viable option for pain management, in which case percutaneous cordotomy remains an excellent alternative. Percutaneous cordotomy has also been utilized in other pathologic conditions such as spinal cord injury pain, radiation plexitis, postamputation stump pain (phantom pain does not respond to cordotomy), pain from tabes dorsalis, and even in intractable pain from failed back surgery.24 Another important consideration in patient selection is the pathophysiology of the pain. In general, cordotomy is more effective for nociceptive than for neuropathic pain syndromes. Pain generated from continuous activation of peripheral nociceptors such as that produced by involvement of a long bone by cancer and pain from direct compression or infiltration of nerve plexuses represent the two conditions that respond best to percutaneous cordotomy. Central pain and evoked pain with hyperpathia or allodynia may respond to cordotomy but less predictably than the conditions listed previously. Location of the pain is another important consideration. A properly performed C1–2 percutaneous cordotomy will reliably produce analgesia up to and including the C5 dermatome.24 Pain that is consistently rostral to C5 as well as pain in the head is not effectively treated by cordotomy. Also, unilateral localized pain is much more effectively treated than is bilateral or midline pain, which require a bilateral procedure. Unilateral cordotomy is a relatively low-risk procedure whereas a bilateral C1–2 cordotomy carries a significantly higher rate of complications.24,26 Patients considered for cordotomy should have a limited life expectancy, generally less than 12 months, because the analgesic effects of cordotomy are often not permanent. Indeed, the analgesia produced by cordotomy tends to fade with time, and pain concomitantly recurs. Some patients may also develop mirror pain (contralateral pain involving the identical body area as the original pain), which may be difficult to manage. Finally, there should be no medical contraindications to the procedure. Assessment of baseline pulmonary function is important in this regard because percutaneous cordotomy at C1–2 may damage the ipsilateral reticulospinal pathway that lies adjacent to the cervical fibers in the spinothalamic tract. This pathway originates in the respiratory center of the medulla and mediates unconscious or automatic respiration. If both lungs are normal, unilateral damage to this pathway is not clinically significant. However, if there is underlying pulmonary insufficiency, especially of the lung on the side contralateral to the cordotomy, or loss of unconscious respiration from underlying disease such as a Pancoast tumor, then loss of the reticulospinal pathway may lead to life-threatening respiratory compromise and even fatal sleep apnea (Ondine’s curse). Cordotomy is carried out with the patient supine using local anesthesia with light intravenous sedation in order to obtain feedback from the patient.24 Lateral fluoroscopy is used to image the C1–2 level, and a subarachnoid puncture is performed. After confirming flow of CSF, several milliliters of preservative-free contrast are injected to identify the dentate ligament, which defines the horizontal equator of the spinal cord. The spinothalamic pathway is located just ventral to the dentate ligament. A temperature-monitoring cordotomy electrode (similar to the DREZ electrode) is then

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inserted into the spinal cord just ventral to the dentate ligament. Intraoperative stimulation is performed for physiologic localization of the electrode. Keep in mind that the spinothalamic tract is somatotopically organized such that the sacral and lumbar fibers are located more dorsal and laterally whereas the cervical fibers are somewhat more ventral and medial. In general, with the electrode properly positioned, the patient will describe either a painful or a warm sensation in the distribution of the pain. Once the target is confirmed, an RF lesion is made usually for about 60 seconds at 758C to 808C. The end-point is reduction or elimination of pain and temperature sensation overlapping the area of pain and extending several dermatomes rostrally. The most significant complication of unilateral cordotomy is ipsilateral leg weakness due to damage of nearby corticospinal fibers. Other complications include meningitis and postcordotomy dysesthesias (10%–15%). It is difficult, if not impossible, to correlate and compare the results of different authors owing to variability in selection criteria and definitions of outcome in terms of pain relief. Tasker24 reviewed and collated data from 21 published series of unilateral percutaneous cordotomy including his own personal series. Complete pain relief was reported in 63% to 90% of patients, with ‘‘significant’’ pain relief in 59% to 96% of patients. In a series of 136 patients, 72% and 84% of patients had either complete or significant relief of their target pain, respectively. Thus, 28% of patients in Tasker’s personal series had persistent pain in the target area. Ischia and coworkers25 reviewed 69 patients who underwent cordotomy for neoplastic vertebral bone pain. Seventy-one percent of the patients were believed to have benefited from the surgery, obtaining either complete pain relief or a significant reduction in pain amenable to control by analgesics. Ischia and coworkers25 later reported the results of unilateral percutaneous cordotomy in a group of 119 patients with cervicothoracic and thoracic pain secondary to lung cancer who were followed up until death. Approximately one third of the patients enjoyed complete pain relief up to the time of death. However, 81% of patients achieved complete pain control with cordotomy and the addition of analgesic medications. Amano and associates26 compared the results of unilateral with those of bilateral cordotomy in a series of 221 patients.26 Unilateral high-cervical cordotomy was performed in 161 patients with bilateral procedures in 60. Complete or nearly complete pain relief was reported in 95% and 82% of patients who underwent bilateral or unilateral procedures, respectively. Overall, percutaneous cordotomy failed to produce even tolerable pain relief in only 5% of all patients. Finally, Kanpolat and colleagues27 performed CT-guided percutaneous cordotomy in 67 patients with pain due to malignancy. Complete pain control was achieved in 97% of patients. In just over two thirds of the patients, the authors were able to perform a selective cordotomy, meaning that analgesia was produced in an area limited to the distribution of pain. There are a number of explanations for persistent pain after unilateral cordotomy. In general, postcordotomy pain can be classified into three different categories: (1) original pain that is not relieved, (2) original pain that disappears only to recur, and (3) new pain.24 Cordotomy has been shown to consistently reduce nociceptive pain. Therefore, failure to relieve pain may indicate that the pain for which the procedure was done had a significant neuropathic component that is not consistently relieved by cordotomy. Alternatively, the original pain may have been bilateral or had a significant midline component, in which case a bilateral procedure must be considered. Often, the original pain will be relieved only to recur anywhere from several days to several months after cordotomy. In many cases, this is due to regression of the level of analgesia, in which case, the procedure may need to be repeated. Some patients will also develop new pain after cordotomy. For new pain located on the same side above the level of analgesia produced by cordotomy, one must be suspicious of progression of the underlying disease. Progression of disease may also lead to development

of a new neuropathic pain syndrome. The third cause of new pain is the development of postcordotomy dysesthesias. The development of pain on the side of the body opposite the original pain may also signal progression of disease or the development of mirror pain.

Midline (Commissural) Myelotomy Midline or commissural myelotomy is a procedure in which the decussating fibers of the spinothalamic tract are interrupted as they cross in the anterior white commissure of the spinal cord. The lesion is usually created over several spinal cord segments at the lower thoracic level, although lesions at C1 have also been reported. Midline myelotomy is most effective for pain in the lower portion of the body, especially midline or bilateral pain for which cordotomy or other ablative procedures may not be as applicable. The overall efficacy of midline myelotomy has been reported to be on the order of about 70%. Broager29 reported his results of midline myelotomy in 44 patients, of whom 33 had adequate follow-up information available. Forty-one (93%) patients suffered from malignant pain. An excellent result (pain eliminated, no side effects) was initially achieved in 25 patients. Pain recurrence occurred between 1 and 6 months in 9 of these patients. Cook and Kawakami30 summarized their results of midline myelotomy in 24 patients. Most patients achieved initial pain relief. However, in the group of patients with nonmalignant pain related to lumbar arachnoiditis, the procedure was ultimately a total failure because pain uniformly returned. These authors also concluded that pain from pelvic metastases does not respond particularly favorably to myelotomy. Several authors have introduced the concept of a more limited punctuate midline myelotomy, particularly for patients whose pain may be more visceral than somatic in nature.31,32 It is believed that a rather large component of visceral pain is carried in the medial aspect of the dorsal columns in the dorsal column polysynaptic pathway. Therefore, in a limited myelotomy, rather than dividing the crossing fibers of the spinothalamic tract in the anterior white commissure, this procedure is designed to interrupt visceral nociceptive pathways that lie in the deep aspects of the medial dorsal columns. Kim and coworkers32 performed limited high-thoracic (T1–2) myelotomy on eight patients with gastric cancer who suffered from intractable visceral pain. Five of these patients either were pain-free or had residual pain that was adequately managed with either a weak opiate (e.g., codeine) or even nonopiate analgesics. Limited myelotomy has been reported to have a number of advantages over the more classic midline myelotomy. There is a better chance of alleviating visceral pain, the risk of bothersome dysesthesias seems to be less, and the risk of neurologic dysfunction such as loss of proprioception or transient motor weakness, albeit relatively small, is less. Because neither classical nor limited myelotomy is performed with any frequency, more studies are needed to determine the role, particularly of limited myelotomy.

Brainstem and Diencephalic Procedures Caudalis DREZ The nucleus caudalis DREZ operation is an off-shoot of the spinal procedure.33 The nucleus caudalis represents the origin of the second-order afferent neurons that carry nociceptive information from structures of the head and face. It receives afferent nociceptive input from not only the trigeminal but also the facial, glossopharyngeal, and vagus nerves. This structure corresponds to and is contiguous with lamina II or the substantia gelatinosa in the upper cervical spinal cord. The procedure is performed through a small suboccipital craniotomy and C1 laminectomy. A series of RF lesions is made from the level of the C2 dorsal root to the obex in order to destroy the second-order neurons originating in the nucleus

570 Chapter 77  NEUROSURGICAL TREAT MENT OF PAIN caudalis and ascending rostrally to connect with the thalamus and reticular formation. The operation is in some respects similar to the trigeminal tractotomy described by Sjoquist, except that the latter is designed to interrupt the descending spinal trigeminal fibers. The major complication associated with caudalis DREZ lesioning is ipsilateral ataxia owing to injury to the spinocerebellar tract, which overlies the entire length of the nucleus caudalis. A caudalis DREZ operation can be considered in patients with intractable recurrent trigeminal neuralgia who have failed multiple previous operations, postherpetic trigeminal facial pain, and trigeminal neuropathic and deafferentation pain.33 It has also been recommended for selected patients with refractory atypical facial pain, although in the author’s (RKO) opinion, destructive procedures in general should be avoided in this particular condition.

MidbrainTractotomy Mesencephalic or midbrain tractotomy (i.e., mesencephalotomy) is not commonly used in the United States. The procedure depends on destruction of the spinothalamic and/or trigeminothalamic fibers that ascend in the brainstem. The primary indication for midbrain tractotomy is pain in the head, face, neck, or arm that is refractory to pharmacologic management including intraspinal narcotics.34,35 Although C1–2 percutaneous cordotomy may be effective for upper extremity pain, effective analgesia is difficult in patients whose pain is in the shoulder and neck region and cordotomy is ineffective for pain in the head and face. Midbrain tractotomy was first performed as an open procedure in the late 1930s, and about a decade later, stereotactic midbrain tractotomy was introduced by Spiegel and Wycis. At present, improvements in imaging techniques, stereotactic localization, and electrode design have made this procedure much easier and probably safer. Following imaging and target selection, stereotactic midbrain tractotomy is performed with the patient under local anesthesia. The midbrain target, namely the spinothalamic and/or quintothalamic pathway, cannot be directly visualized from the MRI but is calculated based on standard landmarks used for functional neurosurgery. The customary target is located 5 mm behind and 5 mm below the posterior commissure and 5 to 10 mm lateral to the midline.34 The target is roughly in line with the inferior border of the superior colliculus. The target is confirmed with intraoperative physiologic testing (i.e., macrostimulation) before the lesion is made. A lesion or series of lesions is then made, the lesion parameters depending to some extent on the electrode design. The major complications associated with midbrain tractotomy include ocular disturbances and injury to the lemniscal tract, which can produce bothersome dysesthesias. Midbrain tractotomy appears to be of significant benefit in the treatment of patients with cancer pain, in whom 75% pain relief has been reported on both a shortand a long-term basis.34 Based on the available literature, it is difficult to assess the efficacy of midbrain tractotomy for pain related to nonmalignant conditions.

Thalamotomy The multiple connections between the sensory pathways that terminate in the thalamus have made this structure a natural target for the treatment of pain. Discriminative somatotopically arranged sensory information carried by spinothalamic fibers along with the sensory input of the lemniscal pathways projects to and terminates in the ventral caudal (Vc) nucleus, which is the main sensory relay nucleus of the thalamus. Nociceptive information that terminates in the Vc nucleus is considered to be part of the neospinothalamic pathway. Nociceptive information is also projected from the reticular formation through a more medial paleospinothalamic system that has more diffuse projections to nonspecific nuclei (centrum medianum [CM], parafascicular [PF], intralaminar, centrolateral, nucleus submedius). A nociceptive relay, the ventral parvocellular

nucleus (VCpc) has also been identified at the most caudal margin of the Vc nucleus.36 Although Vc thalamotomy has been performed in the past, it is not currently recommended because it is accompanied by a high complication rate such as loss of contralateral sensory modalities and pseudoparesis. Indeed, lesions in the Vc nucleus are associated with a high incidence of dysesthesias and may even produce a fullblown thalamic pain syndrome. It has been reported that selective lesions of the VCpc may offer pain relief by producing a dissociative sensory loss (i.e., interruption of nociceptive information with preservation of lemniscal input). However, the results of selective lesions of this nucleus have produced wide discrepancies in success. There is no consensus as to which nuclei are included in medial thalamotomy.37 Although specific nuclear targets have been described (see earlier), it is somewhat difficult to conceive that, with the current technology, lesions can be produced that respect the physiologic borders of these individual nuclei. In general, medial thalamotomy is generally centered around the CM-PF-intralaminar nuclei, an area in which a lesion produces no detectable neurologic deficit. Intraoperative stimulation in this area likewise produces no characteristic response except at very high intensities at which stimulation may produce paresthesias. The degree of pain relief afforded by medial thalamotomy appears to be superior to that achieved with either Vc or VCpc thalamotomy. Nociceptive pain seems to be treated more effectively than neuropathic or deafferentation pain, and pain in the upper body appears to respond better than that in the lower body and legs. The results of medial thalamotomy vary widely.37,38 However, comparison of results is difficult because of the heterogeneous nature of the clinical series, the nonuniformity of how the procedure is performed (exact target, unilateral vs. bilateral lesions), and the variable methods by which results are conveyed. Young and Rinaldi39 suggested that 65% to 85% of patients with cancer pain whose life expectancy is less than 1 year should obtain lasting pain relief with medial thalamotomy. The authors suggested that for nonmalignant pain, medial thalamotomy carries a 20% immediate failure rate and that pain relief occurs in only 50% to 60% of patients for more than 1 year. More recently with the evolution of stereotactic radiosurgical techniques, there has been a renewed interest in medial thalamotomy. Several groups have reported pain relief in 40% to 50% of patients with cancer-related pain, although there was a latency of 1 to 6 weeks before a positive benefit was achieved.

Other Procedures Cingulotomy for Intractable Pain Surgical interruption of limbic pathways has traditionally been employed in patients with intractable psychiatric illness such as obsessive-compulsive disorder, major refractory depression, bipolar disorder, and even Gilles de la Tourette syndrome. However, in patients with intractable pain due to widespread cancer, especially those with an intolerable component of anxiety, bilateral cingulotomy can provide effective relief of pain and suffering for those with relatively limited life expectancy.40 Indeed, cingulotomy can sometimes provide impressive results in patients for whom more traditional therapies have been ineffective. Cingulotomy is indicated and is most effective for nociceptive pain related to diffuse musculoskeletal metastases, in patients whose life expectancy is less than 6 to 9 months. These patients usually have exhausted all other forms of conventional therapy including surgical resection, radiation, chemotherapy, systemic and/or spinal narcotics, as well as other interventions such as nerve blocks. The cingulum is an integral part of the medial limbic loop or Papez circuit and is believed to play an integral role in pain perception. The procedure is performed stereotactically with the patient under local anesthesia and is usually well-tolerated, even by very

XII NEUROSURGICAL APPROACHES TO PAIN MANAGEMENT 571

debilitated patients. The center of the cingulate gyrus can be located stereotactically 24 mm posterior to tip of the frontal horn of the lateral ventricle, 1.5 mm lateral to the midline, and 15 mm above the roof of the lateral ventricles. The object of the procedure is to produce a lesion, usually by RF thermocoagulation, in as large an area of the cingulate gyri as possible without impinging on surrounding structures. Cingulotomy is contraindicated in patients with intracranial vascular anomalies that would be in the path of the electrode trajectory and in patients with an active calvarial or intracranial infection. The pain relief from cingulotomy is usually immediate and can be dramatic. However, pain relief is not generally durable over a long period, and therefore, patients with a life expectancy much more than 9 months are probably not good candidates. Most patients are able to significantly reduce their intake of oral narcotics and increase activity levels. Several clinical studies of MRI-guided cingulotomy have reported that at least 50% of patients have moderate to complete pain relief 3 months after the procedure.40 Notwithstanding any ethical or technical concerns, for this reason alone, cingulotomy is probably not indicated for the treatment of benign pain conditions. Although repeat lesioning is possible and has been performed for psychiatric applications, there are little data to support the use of repeat cingulotomy for pain. Interestingly, some patients report only modest pain reduction in spite of dramatic reduction in narcotic usage and increased levels of activity. Moreover, these patients respond appropriately to new sources of pain, indicating that there may be a discrepancy in discriminative pain sensation and pain perception

Pituitary Destruction for Cancer Pain Destruction of the pituitary gland for the relief of pain is not new. In fact, pituitary ablation has been employed for several decades.41,42 There appears to be a clear association between the pituitary gland, pain, and analgesia. However, the exact mechanism(s) by which hypophysectomy produces analgesia remains unclear. The initial and most obvious logic was that there was some type of endocrine effect because the treatment is primarily effective for patients with breast or prostate carcinoma. It was believed that the degree of pain relief should correlate with the extent of hormonal depletion. However, there is a well-recognized discrepancy between pain relief, the hypopituitarism produced by the procedure, and tumor regression, and in fact, some authors report a complete absence of correlation between hormonal depletion and analgesia.43 Consequently, other mechanisms have been proposed, including a stress analgesic effect as well as a neurolytic effect because there are connections between the pituitary gland and regions of the hypothalamus that are known to be involved in pain processing. Indeed, there have been reports of stimulationproduced analgesia when electrical stimulation has been applied to the pituitary gland. Whatever the mechanism, pituitary ablation is indicated for patients with very advanced malignancy with intractable pain secondary to widespread metastases. Pituitary destruction can be performed in a variety of ways: (1) transcranial hypophysectomy, (2) transsphenoidal hypophysectomy, (3) radiation-induced hypophysectomy, (4) RF thermal coagulation, (5) cryogenic hypophysectomy, and (6) chemical hypophysectomy using alcohol. Open procedures such as transcranial or transsphenoidal hypophysectomy are major surgical procedures and would now be rarely indicated given the other options available. Radiation-induced pituitary destruction was previously performed by either transsphenoidal implantation of an yttrium screw or external radiation. Although there are little if any data, it might be feasible to now consider stereotactic radiosurgery for this purpose. High doses of radiation can be focused in the pituitary fossa without injuring surrounding structures. The one potential problem with this technique is that

pain relief may be delayed as it commonly is when radiosurgery is used for the treatment of trigeminal neuralgia. This is a significant limitation in this population of patients who are suffering or have a limited life expectancy and for whom immediate pain relief is highly desirable. Perhaps the most useful technique for pituitary ablation is transsphenoidal injection of absolute alcohol into the pituitary fossa. The procedure can be performed with the patient under light general anesthesia using an intravenous neuroleptic and/or inhalation agent. The procedure is performed using C-arm fluoroscopy and involves placing a special cannula with a sharp obturator through the anterior wall of the sella and into the pituitary gland. After confirming that the tip is within the pituitary gland by injection of a small amount contrast agent (0.1–0.2 ml), absolute alcohol is injected at a rate of 0.1 ml/min. During the injection period, one is able to track the ascent of the contrast up the pituitary stalk into the hypothalamus and third ventricle. Customarily, a total of 1 to 2 ml of alcohol is injected. During injection, pupillary size and reaction are carefully observed because there is a risk of damage to the optic pathways. In the event that pupillary changes are observed, Miles41 advocated immediate subarachnoid injection of corticosteroids via a C1–2 puncture. Since the degree of hypopituitarism is unpredictable, all patients should routinely receive pituitary replacement therapy. The pain relief achieved with pituitary destruction is variable, most authors reporting pain relief on the order of 70% to 90%, with nearly two thirds of patients having complete pain relief.41 Patients with hormonally independent tumors achieve pain relief at the lower end of the spectrum whereas those with breast or prostate cancer enjoy pain relief nearer to 90%. The duration of pain relief is somewhat variable but tends to fade rather quickly. Around 65% of patients will experience pain relief for 3 months or less, although long-term relief in excess of a year has certainly been reported. Notwithstanding the more successful cases, it would seem that pituitary destruction is, therefore, primarily indicated for patients with a life expectancy of perhaps 3 to 6 months. Aside from damage to the visual system, other complications include diabetes insipidus (as high as 50% with large volumes of alcohol), ocular palsies, cerebrospinal fluid leakage, and meningitis.

NEUROMODULATION Spinal and Intraventricular Drug Delivery Since the 1980s, intraspinal drug delivery has assumed an increasingly important role in the management of intractable pain. Although the initial application of this therapy was restricted to patients with refractory cancer pain, the use of spinal opiates for nonmalignant pain has now become the primary indication for this therapy. Chronic IT drug infusion has been shown to be effective and has clearly been accepted in patients with cancer pain who cannot gain effective analgesia with systemic opioids without significant side effects. In this group of patients, the treatment has a defined end-point and can produce substantial improvements in quality of life. Even though chronic spinal drug infusion is now well accepted for noncancer pain, there continues to be an element of controversy surrounding its long-term use in this particular patient population. IT opiates should be considered only after less invasive and complex modalities have been attempted and have failed. Again, patient selection, particularly with nonmalignant pain, plays a central role in the success of this therapy. It must be appreciated by the treating physician, other members of the pain treatment team, and the patient that the decision to implant a drug pump represents a huge commitment on the part of all parties. Indeed, for patients

572 Chapter 77  NEUROSURGICAL TREAT MENT OF PAIN with nonmalignant pain, chronic spinal drug infusion is a laborintensive therapy that has no definitive end-point. Several factors should influence the clinician in considering spinal drug infusion including pain topography, type of pain (nociceptive vs. neuropathic), pain response to long-acting oral opiates, prior history of drug abuse, psychological screening, response to a screening trial, and patient access to care. In general, spinal drug infusion, particularly using opioids, is most ideally suited to patients with nociceptive pain that has a more diffuse pattern (e.g., patient with failed back surgery syndrome with primarily diffuse axial lower back pain). Classically, it has been taught that neuropathic pain does not respond to opiates, but this is not true in many instances. Clearly, there are patients with pure neuropathic pain who do, in fact, respond to opiates, albeit perhaps at higher does than might be required for nociceptive pain. This is actually true for both oral and IT opiates. Although spinal infusion may be effective for head and neck pain in selected patients, because of drug properties and factors related to drug distribution in the cerebrospinal fluid, this therapy is best suited to pain that occurs below the upper thoracic dermatomes. In general, the pain should be opiate-responsive, although again, patients whose pain has a significant neuropathic component may show a relative resistance to opiates even at reasonable dose levels that are devoid of systemic side effects. Prior to implantation of a permanent pump for chronic therapy, all patients being considered should undergo a screening trial. Screening can be performed in a variety of ways: single or multiple IT boluses or continuous epidural or IT infusion. Screening can be performed either with or without placebo control. There are advantages and disadvantages of each technique and currently no consensus as to which method best predicts long-term response to therapy. The author’s (RKO) preference is to perform a continuous IT over 3 to 4 days using a tunneled IT catheter. For patients who are opiate tolerant, the daily opiate dose is reduced by half at the beginning of the trial and a short-acting oral agent is prescribed as needed for breakthrough pain. This method most closely replicates the effect that will be derived from a pump and may, in theory, at least partially eliminate the potential placebo response that can occur with a single IT bolus. Moreover, this method allows dose escalation during the trial, which may be important in opiate-tolerant patients who have been receiving exceedingly high doses of oral narcotics. The trial should be conducted using the drug one plans to deliver with the implanted pump. For example, it is not rational to screen a patient with a combination of morphine and clonidine and then begin chronic therapy with morphine alone. Also, catheter position is important, depending on the drug chosen. With hydrophilic drugs such as morphine, catheter position is not critical because the drug will distribute over the entire spinal axis. However, when using drugs such as clonidine or fentanyl, which are more lipophilic, the catheter tip must be positioned within several segments of the dermatomal level of the pain. In the past, IT drug infusion was synonymous with IT opiates. Even at present, morphine is still the only opiate approved by the U.S. Food and Drug Administration (FDA) for ITDD using a programmable pump. Notwithstanding, other opiates (hydromorphone, fentanyl, sufentanyl, meperidine, methadone) as well as a number of nonopiate agents such as bupivicaine and clonidine are currently being used. Indeed, the concept of polyanalgesia has become quite popular insofar as ITDD is concerned. A substantial body of literature details the efficacy of many of these alternative agents and drug combinations, and it would appear based on clinical series that many of these agents and combinations are in fact safe for long-term use.36,44,45 However, one should be cautious about utilizing agents for which animal toxicity data are lacking and/or that have not been shown at least over time to be safe. In 1999, the PolyAnalgesic Consensus Conference was convened in an effort to address some of the crucial issues in the field of spinal

drug delivery. The panel, consisting of 17 internationally recognized experts in the field of spinal drug delivery, critically reviewed the literature on the use of opioids, local anesthetics, adrenergic agents, N-methyl-D-aspartate (NMDA) antagonists, somatostatin analogues, calcium channel blockers, and various other agents36; developed standardized clinical guidelines for spinal analgesia44; and suggested future directions for research and development of alternative agents for IT analgesia.45 Intraventricular drug administration may occasionally be indicated in patients with craniocervical pain due to head and neck cancer with limited survival (usually 50%. Sitting intolerance with good standing tolerance. No other major coexisting pain source such as facet joint pain. Normal psychological background with good motivation for recovery.

For the L4–5 disk, a true AP fluoroscopic view is obtained first. Then, the fluoroscopy tube is rotated in a rostral-caudal direction until the L5 superior endplate parallels the x-ray beam. The fluoroscopy tube is then rotated laterally to the needle insertion side until an optimal oblique angle is achieved when the lateral edge of the superior articular process (SAP) of L5 crosses the lateral one third of the L5 superior endplate. This point of intersection is the skin insertion point of the introducer needle. The side of needle insertion should be opposite to the side of the annular tear. The skin and the subcutaneous needle pathway should be well anesthetized with local anesthetics. A 17-gauge introducer needle is inserted at the skin marker and pushed forward, paralleling the x-ray beam, aiming at the cross-section of the lateral margin of the L5 SAP and the L5 endplate. In an ideal tunnel view, only the tail of the introducer needle should be visualized. The tip of the introducer needle should be within the shadow of the tail (Fig. 85–5). The introducer needle should bypass the lateral edge of the L5 SAP and enter the L4–5 intervertebral disk at the lateral one third of the disk in the axial plane and the most caudal portion of the disk in a rostralcaudal direction to avoid hitting the L4 nerve root. Once the needle enters the disk, the direction of the needle should be adjusted immediately upward until it reaches the target point in the lateral one third of the disk in the AP view and the middle of the disk in the lateral view. This needle tip position will provide a good starting point for the SpineCath. The stylet is removed and the SpineCath is inserted through the introducer needle. The tip of the SpineCath is then pushed forward slowly. The curve at the tip of the SpineCath allows it to travel in the medial edge of the annulus fibrosus and form a circle parallel to the annulus fibrosus (Fig. 85–6). Ideally, the final position of the distal part of the catheter should be in the posterior third of the disk, well across the midline of the posterior wall and centered between the endplates. Technically, there could be two major difficulties in placing the catheter. The first involves inserting the introducer needle into the disk. The key to success is to find an ideal needle entry point with fluoroscopy, as described in the previous paragraph. This point should be decided before the skin is anesthetized. Once the introducer needle is inserted into the skin and muscles, it should be pushed directly through a predetermined pathway with minor adjustments. Repeated pulling and pushing of the large introducer needle inside the patient’s body for the purpose of ‘‘adjustment’’ could cause extra pain and trauma to the patient and should be avoided. The second major obstacle is the navigation of the SpineCath inside the disk. Fissures in the annulus could mislead the catheter in the wrong directions. This could frustrate the physicians performing the procedure. There are no magic rules to avoid this condition, except for gently pulling, pushing, and redirecting the catheter. Excessive force should be avoided to prevent extra damage to the tissue or breaking the catheter. In the most difficult conditions, both the catheter and the introducer needle have to be pulled and reinserted through the opposite side of the disk. Using the pulse

624 Chapter 85  DIAGNOSIS AND MINIMALLY INVASIVE TREAT MENT OF LUMBAR DISCOGENIC PAIN

L4

L5

kVp mA Figure 85^5. Ideal needle insertion direction. The needle is in a

‘‘tunnel view.’’ It is aiming at the junction between the middle and the lateral one third of the L4 ^5 disk in an axial plane and the low part of the disk in the sagittal plane.

model of the fluoroscopy is critical during the process of SpineCath placement. It will help avoid excessive radiation exposure to the patient and the medical professionals. Once the SpineCath is placed appropriately, it is ready to be heated according to the protocol for thermocoagulation. However, it is critical to reconfirm the position of the SpineCath before the

heat generator is turned on. The SpineCath must be inside the disk and not in the epidural space! Otherwise, thermocoagulation of the nerve roots may cause serious nerve root damage, leg weakness, and urinary incontinence. Patients must be continuously monitored when the catheter is heated. The patient should be fully awake, and any increase in pain in the back and leg(s) must be reported and assessed immediately. It is common that the patient may report increased back pain. Thermocoagulation may continue as long as the patient can tolerate it. Some experts suggest that the heating process needs to be discontinued if the patient reports pain in the leg. However, this is controversial. As mentioned previously, stimulation of the L4–5 and L5–S1 disks may cause referred pain in the leg and foot without stimulation of the L5 and S1 nerve roots. It is possible that heating of the L4–5 and L5–S1 disks can induce referred pain in the leg without stimulation of the nerve roots. As long as the needle tip is within the disk as confirmed by lateral fluoroscopy, a feeling of pain in the foot may not be the result of direct thermocoagulation of the L5 or S1 nerve roots. It is up to the physician performing the procedure to decide whether to continue or discontinue the heating process. It is conceivable that early discontinuation of thermocoagulation can avoid the possible damage to the nerve roots. However, this may also decrease the efficacy of the treatment. The clinical efficacy of IDET has been confirmed by clinically controlled studies. Pauza and coworkers7 conducted a randomized, placebo-controlled, prospective trial of IDET for the treatment of discogenic back pain confirmed by diskography. Approximately 40% of the patients achieved greater than 50% pain relief. The number needed to treat, to achieve 75% relief of pain, was five. Pauza and coworkers’ findings7 are supported by the results from multiple independent groups. Appleby and associates8 performed a meta-analysis in 2005. The authors analyzed the results of 17 peerreviewed articles on IDET from 1998 to March 2005. The overall mean improvement in pain intensity was 2.9 points as measured by the visual analog scale. Thus, IDET appears to provide benefit to a small proportion of well-selected patients. However, a recent double-blind study revealed no benefits of IDET over the placebo.9 Thus, more studies are needed to confirm the clinical efficacy of IDET. The main risks related to IDET procedures include intradiskal infection, nerve root damage related to needle entry, and thermocoagulation. Infection can be prevented by using strict sterile techniques. The risks of nerve root damage during the needle entry may be decreased by inserting the introducer needle through the lower part of the disk. Confirming the intradiskal position of the SpineCath before heating, careful monitoring of the patient during thermocoagulation, and appropriate discontinuation of thermocoagulation when the patient starts to complain of radicular pain can decrease the risk of nerve root damage by thermocoagulation. Gentle handling of the SpineCath can alleviate the risks of kinking and breaking inside the disk.

Intradiskal and Epidural Steroid Injection

Figure 85^6. A SpineCath navigates inside the L4^5 disk.

Intradiskal steroid injections have been tried to treat discogenic pain. Steroids may be injected during a discogram if the patient reports a concordant pain. The goal of the treatment is to decrease the intradiskal inflammation. Noncontrolled studies have provided positive results. However, double-blind, clinically controlled studies revealed no benefits from intradiskal steroid injections for discogenic pain.10 Thus, this treatment is not currently suggested. It has not been systemically studied whether a lumbar epidural steroid injection can treat lumbar discogenic pain due to an annular tear. However, in the author’s experience, it seems that epidural steroid injection can decrease back pain in many patients with clinical features of discogenic pain. Discogenic pain is partially related to the epidural inflammation due to the leakage of PLA2 in the

XIII INTERVENTIONAL APPROACHES TO PAIN MANAGEMENT 625

epidural space and a subsequently increased PGE2 level in the epidural space. Theoretically, epidural steroid injections may suppress the PLA2 function and decrease the PGE2 level in the epidural space. Thus, before considering a lumbar discogram, it is less costly and less risky to have trials of lumbar epidural steroid injections for those patients with possible discogenic pain.

JMH PAIN

Intradiskal RF Thermocoagulation Early trials of intradiskal RF thermocoagulation using a straight needle to heat the center of the disk have failed to provide any benefit for discogenic pain, partially owing to technical flaws. Most of the nerve fibers innervating the disks are found in the outer layers of the annulus. Thermocoagulation of the center of the nucleus may not be able to destroy any of the nociceptive fibers in the annulus. Recently, a new intradiskal RF device, discTRODE, has been introduced. The patient selection criteria for discTRODE are similar to those for IDET. The patient should be prepared in the same way as for IDET. For discTRODE, once the thermocoagulation catheter is introduced into the disk, it is immediately turned medially and pushed toward the opposite side inside the posterior portion of annulus fibrosus. Once the catheter is placed, RF energy is used to heat the posterior portion of the annulus. Finch and colleagues11 reported some benefit of pain relief in a case control study of 46 patients. However, more studies are needed to confirm its clinical efficacy.

Needle tip

Ramus Communicans Block Discogenic low back pain should be regarded as a visceral pain with respect to its neural pathways. It has been demonstrated that the lumbar disks are predominantly innervated by upper (L1 and L2) dorsal root ganglion neurons via the sympathetic trunks and rami communicans. Block or destruction of ramus communicans has also been reported to decrease the pain originated from the vertebral body or disks.12 Technically, an L2 ramus communicans block may be achieved by inserting a 5-inch, 25-gauge spine needle and placing its tip on both sides of the L2 vertebral body. In the AP view, the needles should be hugging the middle to lower one third of the waist of the L2 vertebral body on both sides. In the lateral view, the needle tip should be in the middle of the vertebral body in an AP direction and at the middle to lower one third of the vertebral body in a rostral-caudal direction (Fig. 85–7). Once the needle reaches the target point, 0.5 to 1.0 ml of local anesthetic can be injected for the purpose of a ramus conmmicans block. An RF needle can also be placed in the same place to achieve thermocoagulation. Preliminary reports from Oh and Shim12 suggest that RF thermocoagulation of the ramus communicans can provide significant pain relief as well as an improvement in body function for patients with discogenic pain.

Cell Transplantation Loss of cellular function and subsequent death are the key mechanisms in the process of disk degeneration and subsequent annular tear. It has been reported that when mesenchymal stem cells were taken from adult bone marrow and grown and microaggregated in the presence of appropriate growth factors, they formed a cartilage-like structure with a multilayer matrix-rich structure, a chondrocyte-like lacunae, and a hypertrophic phenotype.13 Expression of various key cartilage matrix glycans, matrix proteins, and type II collagen has been demonstrated. Culture-expanded mesenchymal stem cells have demonstrated the ability to repair cartilage defects in animal models. All methods demonstrated improvement in cartilage healing with transplantation of mesenchymal stem cells. The

Figure 85^7. The lateral view of fluoroscopy shows the needle tip position for L2 rami communicans block.

feasibility of using autologous bone marrow–derived mesenchymal stem cells for the repair of cartilage in patients with osteoarthritis, osteogenesis imperfecta, and rheumatioid arthritis has been studied.14 It may be simple to transplant stem cells into the disk, and the likelihood that they remain in the disk is high. However, the transplanted cells may face the harsh environment in the disk such as poor nutrients, low oxygen, low pH, and high hydrostatic pressure. The influence of these factors on the stem cells and its differentiation is unknown. It is yet to be determined whether transplanted stem cells may differentiate into disk cells in the human disk and exert its functions. However, cell transplantation could provide a promising tool for the prevention and treatment of human degenerative disk disease in the future.

CONCLUSION Discogenic low back pain continues to be a challenge to physicians managing the pain. Various promising, minimally invasive disk procedures are currently available. Even though some studies indicate that these procedures are effective and safe, the interventional pain community still lacks adequate convincing literature to justify the routine use of these procedures. It is crucial that further studies are conducted in order to improve the existing minimally invasive procedures or even to offer new treatment options for our patients.

REFERENCES 1. Crock HV. A reappraisal of intervertebral disc lesions. Med J Aust 1970;1:983–989. 2. Videman T, Nurminen M: The occurrence of anular tears and their relation to lifetime back pain history: A cadaveric study using barium sulfate discography. Spine 2004;29:2668-2676.

626 Chapter 86  VERTEBROPLAST Y AND KYPHOPLAST Y 3. Aprill C, Bogduk N. High-intensity zone: a diagnostic sign of painful lumbar disc on magnetic resonance imaging. Br J Radiol 1992;65:361–369. 4. Carragee EJ, Paragioudakis SJ, Khurana S. 2000 Volvo Award winner in clinical studies: lumbar high-intensity zone and discography in subjects without low back problems. Spine 2000;25:2987–2992. 5. Derby R, Howard MW, Grant JM, et al. The ability of pressurecontrolled discography to predict surgical and nonsurgical outcomes. Spine 1999;24:364–371. 6. Sachs BL, Vanharanta H, Spivey MA, et al. Dallas discogram description. A new classification of CT/discography in low-back disorders. Spine 1987;12:287–294. 7. Pauza KJ, Howell S, Dreyfuss P, et al. A randomized, placebocontrolled trial of intradiscal electrothermal therapy for the treatment of discogenic low back pain. Spine J 2004;4:27–35. 8. Appleby D, Andersson G, Totta M. Meta-analysis of the efficacy and safety of intradiscal electrothermal therapy (IDET). Pain Med 2006;7:308–316. 9. Freeman BJ, Fraser RD, Cain CM, et al. A randomized, double-blind, controlled trial: intradiscal electrothermal therapy versus placebo for the treatment of chronic discogenic low back pain. Spine 2005;30:2369–2377. 10. Khot A, Bowditch M, Powell J, Sharp D. The use of intradiscal steroid therapy for lumbar spinal discogenic pain: a randomized controlled trial. Spine 2004;29:833–836.

Chapter 86

VERTEBROPLASTY AND KYPHOPLASTY Paul E. Spurgas

INTRODUCTION Pain is the most common symptom of an osteoporotic vertebral compression fracture (VCF). Current treatments are medical management, surgical fusion, vertebroplasty, and kyphoplasty. Although medical management remains the initial approach, patients with persistent pain that lasts more than 4 weeks should be considered for vertebroplasty or kyphoplasty.

EPIDEMIOLOGY The most common complication of osteoporosis is VCF. The incidence of osteoporotic VCFs is on the rise. It is estimated that 700,000 VCFs per year occur in the United States. Only 40% are recognized and treated. With the active, aging population and increased awareness of osteoporosis, the numbers will continue to grow. VCFs are more common than hip fractures. Also, the 5-year survival of a patient with a VCF is lower than that of a similar patient sustaining a hip fracture. VCFs occur in 25% of women older than 50 years and 40% of those 80 to 85 years. Pain occurs in over one third and will require treatment. The effect of these fractures is not only limited to pain. Women with VCFs have been shown to have a 23% increase in

11. Finch PM, Price LM, Drummond PD. Radiofrequency heating of painful annular disruptions: one-year outcomes. J Spinal Disord Tech 2005;18:6–13. 12. Oh WS, Shim JC. A randomized controlled trial of radiofrequency denervation of the ramus communicans nerve for chronic discogenic low back pain. Clin J Pain 2004;20:55–60. 13. Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999;284:143–147. 14. Moore J, Brooks P, Milliken S, et al. A pilot randomized trial comparing CD34-selected versus unmanipulated hemopoietic stem cell transplantation for severe, refractory rheumatoid arthritis. Arthritis Rheum 2002;46:2301–2309.

SUGGESTED READINGS Mochida J. New strategies for disc repair: novel preclinical trials. J Orthop Sci 2005;10:112–118. Schellhas KP, Pollei SR, Gundry CR, Heithoff KB. Lumbar disc highintensity zone. Correlation of magnetic resonance imaging and discography. Spine 1996;21:79–86. Wilke HJ, Neef P, Caimi M, et al. New in vivo measurements of pressures in the intervertebral disc in daily life. Spine 1999;24:755–762. Zhou Y, Abdi S. Diagnosis and minimally invasive treatment of lumbar discogenic pain: a review of the literature. Clin J Pain 2006;22:468–481.

age-adjusted mortality rate within 5 years. Spinal deformity, kyphosis, pulmonary compromise (one thoracic VCF may lead to enough sagittal kyphosis to result in a 9% loss of forced vital capacity, impaired mobility, and decreased quality of life add to the morbidity. Women are affected three times as often as men, and the onset is 5 to 10 years later in men. Fifteen percent of women and 5% of men can expect to be affected during their lifetime. Osteoporosis is more common in Caucasians and Asians.

PATHOPHYSIOLOGY Osteoporosis is synonymous with decreased bone density. The porosity of the bone lessens its ability to support the body. Fractures occur when the weight of the upper body exceeds the vertebra’s ability to resist this force. This is usually a result of a traumatic event. However, the more severe the osteoporosis, the less force necessary to produce a fracture. The vertebral pedicles are denser than the body; therefore, most fractures are wedge-shaped (Fig. 86–1). If the forces are great enough, the vertebral body collapses completely into a burst fracture, with fragmentation into the spinal canal.

EVALUATION VCF should be considered in any female older than 50 years who presents with the acute onset of back pain (Box 86–1). The pain is over the compressed vertebra. The area is tender to palpation. There may be a bandlike pain distribution with thoracic fractures. A kyphotic deformity (dowager’s hump) may be apparent, especially in those patients with multiple fractures. Most fractures occur in the low thoracic and higher lumbar regions. Patients normally do not have radicular pain, paresthesias, paresis, or bowel or bladder incontinence. In half the patients, VCF is associated with a fall

626 Chapter 86  VERTEBROPLAST Y AND KYPHOPLAST Y 3. Aprill C, Bogduk N. High-intensity zone: a diagnostic sign of painful lumbar disc on magnetic resonance imaging. Br J Radiol 1992;65:361–369. 4. Carragee EJ, Paragioudakis SJ, Khurana S. 2000 Volvo Award winner in clinical studies: lumbar high-intensity zone and discography in subjects without low back problems. Spine 2000;25:2987–2992. 5. Derby R, Howard MW, Grant JM, et al. The ability of pressurecontrolled discography to predict surgical and nonsurgical outcomes. Spine 1999;24:364–371. 6. Sachs BL, Vanharanta H, Spivey MA, et al. Dallas discogram description. A new classification of CT/discography in low-back disorders. Spine 1987;12:287–294. 7. Pauza KJ, Howell S, Dreyfuss P, et al. A randomized, placebocontrolled trial of intradiscal electrothermal therapy for the treatment of discogenic low back pain. Spine J 2004;4:27–35. 8. Appleby D, Andersson G, Totta M. Meta-analysis of the efficacy and safety of intradiscal electrothermal therapy (IDET). Pain Med 2006;7:308–316. 9. Freeman BJ, Fraser RD, Cain CM, et al. A randomized, double-blind, controlled trial: intradiscal electrothermal therapy versus placebo for the treatment of chronic discogenic low back pain. Spine 2005;30:2369–2377. 10. Khot A, Bowditch M, Powell J, Sharp D. The use of intradiscal steroid therapy for lumbar spinal discogenic pain: a randomized controlled trial. Spine 2004;29:833–836.

Chapter 86

VERTEBROPLASTY AND KYPHOPLASTY Paul E. Spurgas

INTRODUCTION Pain is the most common symptom of an osteoporotic vertebral compression fracture (VCF). Current treatments are medical management, surgical fusion, vertebroplasty, and kyphoplasty. Although medical management remains the initial approach, patients with persistent pain that lasts more than 4 weeks should be considered for vertebroplasty or kyphoplasty.

EPIDEMIOLOGY The most common complication of osteoporosis is VCF. The incidence of osteoporotic VCFs is on the rise. It is estimated that 700,000 VCFs per year occur in the United States. Only 40% are recognized and treated. With the active, aging population and increased awareness of osteoporosis, the numbers will continue to grow. VCFs are more common than hip fractures. Also, the 5-year survival of a patient with a VCF is lower than that of a similar patient sustaining a hip fracture. VCFs occur in 25% of women older than 50 years and 40% of those 80 to 85 years. Pain occurs in over one third and will require treatment. The effect of these fractures is not only limited to pain. Women with VCFs have been shown to have a 23% increase in

11. Finch PM, Price LM, Drummond PD. Radiofrequency heating of painful annular disruptions: one-year outcomes. J Spinal Disord Tech 2005;18:6–13. 12. Oh WS, Shim JC. A randomized controlled trial of radiofrequency denervation of the ramus communicans nerve for chronic discogenic low back pain. Clin J Pain 2004;20:55–60. 13. Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999;284:143–147. 14. Moore J, Brooks P, Milliken S, et al. A pilot randomized trial comparing CD34-selected versus unmanipulated hemopoietic stem cell transplantation for severe, refractory rheumatoid arthritis. Arthritis Rheum 2002;46:2301–2309.

SUGGESTED READINGS Mochida J. New strategies for disc repair: novel preclinical trials. J Orthop Sci 2005;10:112–118. Schellhas KP, Pollei SR, Gundry CR, Heithoff KB. Lumbar disc highintensity zone. Correlation of magnetic resonance imaging and discography. Spine 1996;21:79–86. Wilke HJ, Neef P, Caimi M, et al. New in vivo measurements of pressures in the intervertebral disc in daily life. Spine 1999;24:755–762. Zhou Y, Abdi S. Diagnosis and minimally invasive treatment of lumbar discogenic pain: a review of the literature. Clin J Pain 2006;22:468–481.

age-adjusted mortality rate within 5 years. Spinal deformity, kyphosis, pulmonary compromise (one thoracic VCF may lead to enough sagittal kyphosis to result in a 9% loss of forced vital capacity, impaired mobility, and decreased quality of life add to the morbidity. Women are affected three times as often as men, and the onset is 5 to 10 years later in men. Fifteen percent of women and 5% of men can expect to be affected during their lifetime. Osteoporosis is more common in Caucasians and Asians.

PATHOPHYSIOLOGY Osteoporosis is synonymous with decreased bone density. The porosity of the bone lessens its ability to support the body. Fractures occur when the weight of the upper body exceeds the vertebra’s ability to resist this force. This is usually a result of a traumatic event. However, the more severe the osteoporosis, the less force necessary to produce a fracture. The vertebral pedicles are denser than the body; therefore, most fractures are wedge-shaped (Fig. 86–1). If the forces are great enough, the vertebral body collapses completely into a burst fracture, with fragmentation into the spinal canal.

EVALUATION VCF should be considered in any female older than 50 years who presents with the acute onset of back pain (Box 86–1). The pain is over the compressed vertebra. The area is tender to palpation. There may be a bandlike pain distribution with thoracic fractures. A kyphotic deformity (dowager’s hump) may be apparent, especially in those patients with multiple fractures. Most fractures occur in the low thoracic and higher lumbar regions. Patients normally do not have radicular pain, paresthesias, paresis, or bowel or bladder incontinence. In half the patients, VCF is associated with a fall

XIII INTERVENTIONAL APPROACHES TO PAIN MANAGEMENT 627

Box 86^2 CURRENT THERAPY  Bedrest for symptomatic relief of pain.  Exercise program aimed to enhance axial muscle strength.  Analgesics cautiously prescribed to avoid confusion and increased risk of falling.  Bracing thoracolumbosacral orthosis (TLSO).  Open surgery in cases of neurologic deterioration.  Vertebroplasty is minimally invasive.  Kyphoplasty is minimally invasive and may restore height deformity.

MANAGEMENT

Figure 86^1. Compression fracture.

(Courtesy of Kyphon, Inc.)

but can occur with coughing, bending, changing position, or lifting. The pain is improved with lying down and exacerbated by standing, sitting, or exertional activities.

IMAGING STUDIES Plain radiography of the entire spine should be the first test. Lateral and anteroposterior (AP) neutral views along with lateral flexion and extension studies will provide the most useful information. The degree of compression, angle of kyphosis, fracture type, stability, and number of involved segments can be ascertained. Multiple fractures can be seen in 20% of patients. This study will also allow screening for infection or metastatic disease. If a fracture is identified, a magnetic resonance imaging (MRI) study should be performed, focusing on the affected vertebra. It is important to access for spinal canal compromise or posterior bony fragments pushed into the spinal canal. MRI is necessary to access the acuity of the fracture and to determine whether infection or metastatic disease exists. In patients in whom MRI is contraindicated (e.g., those with a pacemaker, claustrophobia, or severe pain), a computed tomography (CT) scan can give similar information.

The mainstay of treatment has been conservative medical management (Box 86–2) with bedrest, bracing, exercise, and analgesics. Bedrest should be limited to 3 to 4 days to control discomfort. Extended bedrest is contraindicated with osteoporosis. Immobility leads to decreased bone density, additional fractures, and thromboembolic events. Pain can be alleviated with analgesics, but these are usually poorly tolerated by the elderly. Confusion and instability can result in falls and further injury. Aggressive use of anti-inflammatory medication can have untoward gastrointestinal consequences. Exercise should be professionally monitored, with the goals being weight-bearing, ambulation, and enhancing axial muscle strength. Thoracolumbosacral (TLSO) bracing is difficult for the patient. To be effective, the brace has to immobilize a large area of the spine. They can be uncomfortable to wear and apply unless expertly fitted. Bracing can prevent progressive deformity and alleviate pain, but patient compliance is poor. Open surgical decompression and instrumented stabilization are limited to those patients with neurologic deterioration or progressive kyphotic deformity. The presenting symptoms of paresis, paresthesias, radiculopathy, and bowel or bladder incontinence suggest spinal cord or nerve root compression, which may be caused by retropulsed bone fragments or extreme kyphosis. Surgery requires not only decompression of the neural contents but also fusion to stabilize the fracture. The soft, porous bone poorly tolerates rigid titanium instrumentation. The result is a high rate of instrument failure. The bone matrix for the fusion has to be harvested from the sacrum or iliac crest, which only increases the patient’s pain. Anesthetic and medical risks of surgery on the elderly compound the risks. Surgery should be avoided if at all possible. Minimally invasive techniques, vertebroplasty and kyphoplasty, became available in the late 1990s. These percutaneous techniques stabilize the VCF and eliminate the pain.

TECHNIQUE Box 86^1 CURRENT DIAGNOSIS  Osteoporosis is a skeletal disease characterized by low bone mass and microarchitectural deterioration that leads to bone fragility and increases the risks for fracture.  Osteoporotic compression fracture is a wedge-shaped fracture, usually of the thoracolumbar area, associated with osteoporosis.  Diagnosis is made by history of acute onset of thoracolumbar pain in a patient over 60 yr. The pain may radiate in a ‘‘bandlike’’ distribution from back to front. Tenderness over the painful area and a kyphotic deformity (dowager’s hump) are also characteristic.  Radiology studies include plain lateral x-ray to show compression and magnetic resonance imaging to further define the pathology.

The initial technique is similar for vertebroplasty and kyphoplasty. Patients are positioned in a prone position on the operating table. Anesthesia is either local or general, depending on the patient’s tolerance and anticipated length of the procedure. The level of the fracture is confirmed. The pedicles of the fractured segment are identified using fluoroscopy in the AP projection. An entry site is measured 1 cm above and 1 cm lateral to the outer margin of the pedicle. A 3-mm incision is made through the skin to allow easy placement of the 11-gauge needle. The needles are directed toward the 10 and 2 o’clock positions of the pedicle (Fig. 86–2). Confirmation using AP and lateral views is imperative. The needle is advanced toward the midposition of the vertebral body. Once the correct position is attained, the technique is repeated on the opposite pedicle. At this point, the procedures differ.

628 Chapter 86  VERTEBROPLAST Y AND KYPHOPLAST Y

Figure 86^2. Anteroposterior (AP) needle placement. (Courtesy of Kyphon, Inc.)

For vertebroplasty, the polymethylmethacrylate (PMMA) is injected while the flow into the vertebral body is observed under fluoroscopy. For kyphoplasty, a drill is passed through the needle and a core of bone removed to make an opening for the balloon catheter. This bone core is also sent for pathology. The balloon catheter is introduced through the needle and inflated under fluoroscopy (Fig. 86–3). The balloon inflation restores vertebral height, compacts the fractured bone, and opens a cavity to receive the PMMA (Fig. 86–4). Once adequate inflation occurs, the balloon is deflated and removed (Fig. 86–5). This is repeated on the opposite side. The PMMA is introduced through the needle into this cavity (Fig. 86–6). The mechanism of analgesia of these procedures is not certain, and although it may relieve mechanical stresses, the PMMA monomer may itself be neurotoxic or may result in thermal necrosis during the exothermic polymerization reaction of the PMMA cement (because temperatures may reach 1228C).

PATIENT SELECTION

(Courtesy of Kyphon, Inc.)

n Pain refractory to medical management. n Fracture less than 12 months old.

Not Candidates n Young patients who sustained a vertebral body fracture in a

major accident. n Patients with a neurologic deficit. n Patients with fractures with fragments in the spinal canal.

PROCEDURAL RISKS n Extravasation of PMMA causing neural compression or embolic

Candidates

events less than 5%. n Allergic reaction to the cement or contrast agent in the cement. n Injury to structures during needle or instrument placement.

n VCF as a result of osteoporosis.

Figure 86^3. The needle is inserted.

Figure 86^4. The balloon is inflated.

(Courtesy of Kyphon, Inc.)

Figure 86^5. Filling the cavity.

(Courtesy of Kyphon, Inc.)

XIII INTERVENTIONAL APPROACHES TO PAIN MANAGEMENT 629

90% of people treated. They lessen the likelihood of additional fractures. The positive effects are seen within a few days. Kyphoplasty has the added benefit of restoration of vertebral body height. These procedures should be considered early if patients are still in pain after 4 weeks of medical management. Several papers have compared vertebroplasty and kyphoplasty, but no prospective, randomized, controlled studies exist. The retrospective studies show similar results with pain relief and fracture stabilization. Vertebroplasty has a slightly higher risk of PMMA extravasation. Kyphoplasty has the benefit of height restoration of the fractured vertebra in one third of the cases treated. The first prospective study of kyphoplasty versus controls proved kyphoplasty to be superior to medical management in pain relief, activities of daily living, and patient satisfaction over a 2-year period.

SELECTED READINGS

Figure 86^6. PMMA completed.

(Courtesy of Kyphon, Inc.)

OUTCOMES Vertebroplasty and Kyphoplasty n Pain relief and fracture stabilization in 90% of patients treated. n Fracture stabilization helps prevent additional fractures.

Kyphoplasty n Restoration of at least 30% fracture height in one third of

patients.

Fourney DR, Schomer DF, Nader R. Percutaneous vertebroplasty and kyphoplasty for painful vertebral body fractures in cancer patients. J Neurosurg 2003;26:1–5. Fribourg D, Tang C, Sra P. Incidence of subsequent vertebral fracture after kyphoplasty. Spine 2004;29:2270–2276. Hadjipavlou AG, Tzermiadianos MN, Katonis PG, Szpalski M. Percutaneous vertebroplasty and balloon kyphoplasty for the treatment of osteoporotic vertebral compression fractures and osteolytic tumours. J Bone Joint Surg Br 2005;87:1595–1604. Ledlie JT, Renfro MB. Kyphoplasty treatment of vertebral fractures: 2-year outcomes show sustained benefits. Spine 2006;31:57–64. Matthis C, Weber U, O’Neill TW. Health impact associated with vertebral deformities: Results from the European Vertebral Osteoporosis Study Group. Osteoporos Int 1999;9:206–213. Ohen JE, Lylyk P, Ceratto R. Percutaneous vertebroplasty: technique and results in 192 procedures. Neurol Res 2004;26:41–49. Papaioannou A, Watts NB, Kendler DL. Diagnosis and management of vertebral compression fractures in elderly adults. Am J Med 2002;113:220–228. Truumees E. Hilibrand A, Vaccaro R. Percutaneous vertebral augmentation. Spine J 2004;4:2.

CONCLUSIONS Vertebroplasty and kyphoplasty are proven, safe, minimally invasive techniques. They provide relief of pain and fracture stabilization in

Chapter 87

EPIDURAL ADHESIOLYSIS Sukdeb Datta

INTRODUCTION Treatment of chronic back pain, specifically for postsurgical patients and those with epidural fibrosis, is challenging. Chronic back pain has a prevalence ranging from 35% to 75% after the initial attack of pain. It is widely held that 90% of low back pain is short-lived and that most patients get better on their own. However, this myth has been dispelled in multiple studies.

Enthoven and coworkers1 found that 52% of primary care patients with neck and back pain still had pain at the end of 5 years, confirming that the pain ‘‘did not just go away.’’ A retrospective review of 182 surgical revisions of patients with failed back surgery revealed that most failures were due to epidural fibrosis, which did not respond well to repeat surgery. Ross and associates2 looked at peridural scar after lumbar diskectomy and found that there was a significant relationship between extensive peridural scarring and recurrent radicular pain. They believed that epidural fibrosis caused pain in failed back surgeries and found that for every 25% increase in scarring, the risk of recurrent radicular pain increased 2.0 times and subjects with extensive peridural scarring were 3.2 times more likely to have recurrent radicular pain. Epidurography was introduced in 1921 by Sicard and Forestier, and identification of ‘‘filling defects’’ is believed to be consistent with epidural fibrosis.3 Fluoroscopically directed lumbar epidural corticosteroid injections have been used in interventional pain management to treat chronic low back pain and lumbar

XIII INTERVENTIONAL APPROACHES TO PAIN MANAGEMENT 629

90% of people treated. They lessen the likelihood of additional fractures. The positive effects are seen within a few days. Kyphoplasty has the added benefit of restoration of vertebral body height. These procedures should be considered early if patients are still in pain after 4 weeks of medical management. Several papers have compared vertebroplasty and kyphoplasty, but no prospective, randomized, controlled studies exist. The retrospective studies show similar results with pain relief and fracture stabilization. Vertebroplasty has a slightly higher risk of PMMA extravasation. Kyphoplasty has the benefit of height restoration of the fractured vertebra in one third of the cases treated. The first prospective study of kyphoplasty versus controls proved kyphoplasty to be superior to medical management in pain relief, activities of daily living, and patient satisfaction over a 2-year period.

SELECTED READINGS

Figure 86^6. PMMA completed.

(Courtesy of Kyphon, Inc.)

OUTCOMES Vertebroplasty and Kyphoplasty n Pain relief and fracture stabilization in 90% of patients treated. n Fracture stabilization helps prevent additional fractures.

Kyphoplasty n Restoration of at least 30% fracture height in one third of

patients.

Fourney DR, Schomer DF, Nader R. Percutaneous vertebroplasty and kyphoplasty for painful vertebral body fractures in cancer patients. J Neurosurg 2003;26:1–5. Fribourg D, Tang C, Sra P. Incidence of subsequent vertebral fracture after kyphoplasty. Spine 2004;29:2270–2276. Hadjipavlou AG, Tzermiadianos MN, Katonis PG, Szpalski M. Percutaneous vertebroplasty and balloon kyphoplasty for the treatment of osteoporotic vertebral compression fractures and osteolytic tumours. J Bone Joint Surg Br 2005;87:1595–1604. Ledlie JT, Renfro MB. Kyphoplasty treatment of vertebral fractures: 2-year outcomes show sustained benefits. Spine 2006;31:57–64. Matthis C, Weber U, O’Neill TW. Health impact associated with vertebral deformities: Results from the European Vertebral Osteoporosis Study Group. Osteoporos Int 1999;9:206–213. Ohen JE, Lylyk P, Ceratto R. Percutaneous vertebroplasty: technique and results in 192 procedures. Neurol Res 2004;26:41–49. Papaioannou A, Watts NB, Kendler DL. Diagnosis and management of vertebral compression fractures in elderly adults. Am J Med 2002;113:220–228. Truumees E. Hilibrand A, Vaccaro R. Percutaneous vertebral augmentation. Spine J 2004;4:2.

CONCLUSIONS Vertebroplasty and kyphoplasty are proven, safe, minimally invasive techniques. They provide relief of pain and fracture stabilization in

Chapter 87

EPIDURAL ADHESIOLYSIS Sukdeb Datta

INTRODUCTION Treatment of chronic back pain, specifically for postsurgical patients and those with epidural fibrosis, is challenging. Chronic back pain has a prevalence ranging from 35% to 75% after the initial attack of pain. It is widely held that 90% of low back pain is short-lived and that most patients get better on their own. However, this myth has been dispelled in multiple studies.

Enthoven and coworkers1 found that 52% of primary care patients with neck and back pain still had pain at the end of 5 years, confirming that the pain ‘‘did not just go away.’’ A retrospective review of 182 surgical revisions of patients with failed back surgery revealed that most failures were due to epidural fibrosis, which did not respond well to repeat surgery. Ross and associates2 looked at peridural scar after lumbar diskectomy and found that there was a significant relationship between extensive peridural scarring and recurrent radicular pain. They believed that epidural fibrosis caused pain in failed back surgeries and found that for every 25% increase in scarring, the risk of recurrent radicular pain increased 2.0 times and subjects with extensive peridural scarring were 3.2 times more likely to have recurrent radicular pain. Epidurography was introduced in 1921 by Sicard and Forestier, and identification of ‘‘filling defects’’ is believed to be consistent with epidural fibrosis.3 Fluoroscopically directed lumbar epidural corticosteroid injections have been used in interventional pain management to treat chronic low back pain and lumbar

630 Chapter 87  EPIDUR AL ADHESIOLYSIS radiculopathy, but epidural adhesions can prevent the flow of medications to the affected areas. Once the filling defects have been identified, adhesiolysis (either percutaneous or endoscopic) can be used to eliminate the deleterious effects of scar, allowing the direct application of drugs to nerves or other tissues to treat chronic back and extremity pain. Percutaneous and endoscopic adhesiolysis is useful in the management of chronic refractory low back and extremity pain. The main purpose of percutaneous epidural lysis of adhesions is to eliminate scar tissue and ensure delivery of high concentrations of injected drugs to target areas. Epidural lysis of adhesions and direct deposition of corticosteroids in the spinal canal are also achieved with a three-dimensional view provided by epiduroscopy or spinal endoscopy.

PATHOPHYSIOLOGY Epidural fibrosis is an inflammatory reaction of the arachnoid. There are many possible etiologies of epidural fibrosis, including a leaking intervertebral disk (annular tear), hematoma, infection, surgical trauma, or intrathecal contrast media. Larocca and McNab4 demonstrated the invasion of fibrous connective tissue into the postoperative hematoma as a cause of epidural fibrosis. McCarron and colleagues5 investigated the irritative effect of material from the nucleus pulposus upon the dural sac, adjacent nerve roots, and nerve root sleeves independent of the influence of direct compression on these structures. Epidural fibrosis is a major contributor to postlaminectomy syndrome (pain after surgical procedures of the spine). It is debatable whether epidural fibrosis causes pain or not. However, it is widely accepted that postoperative scar tissue renders the nerve more susceptible to injury. Subjects with extensive peridural scarring are 3.2 times more likely to experience recurrent radicular pain. Parke and Watnabe6 dissected cadavers in patients with lumbar disk herniation and found significant evidence of adhesions (40% in L4– 5 levels, 36% in L5–S1 levels, and 16% in L3–4 levels). Berger and Davis7 showed that periradicular fibrosis was diagnosed preoperatively in 0.67% and postoperatively in 11%. They also showed that in patients who had multiple operations, the incidence of periradicular fibrosis had risen to 47%. Epidural fibrosis can also occur without previous surgery. Leakage of irritants of the nucleus pulposus into the epidural space has been documented as causing an inflammatory response, producing an increase in fibrocytic deposition, which results in epidural fibrosis. The role of chemical irritation of the nerve roots of the herniated nucleus pulposus was first postulated when it was noticed that removal of the herniated disk did not produce pain relief. Mixter and Ayers8 reported that low back and leg pain may occur without disk herniation and with a normal appearance of the disk. This initiated the concept of noncompressive lesion and irritation of the nerve root, as well as the definition of failed back surgery syndrome. Kuslich and coworkers9 described the role of scar tissue as compounding pain associated with the nerve root by fixing it in one position, thus increasing the susceptibility of the nerve root to tension or compression. In addition, they concluded that sciatica can be reproduced only by direct pressure or stretch on the inflamed, stretched, or compressed nerve root. In spite of the continued debate as to whether epidural fibrosis causes pain, it is widely accepted that postoperative scar tissue renders the nerves susceptible to injury. Scar tissue is generally found in three compartments of the epidural space. Dorsal epidural scar tissue is formed by resorption of surgical hematoma and may be involved in pain generation. In the ventral epidural space, dense scar tissue is formed by ventral defects in the disk, which may persist despite surgical treatment. Finally, the lateral epidural space includes epiradicular structures out of the

root canals, termed sleeves, containing the exiting nerve root and dorsal root ganglia, which are susceptible to lateral disk defects, facet overgrowth, and neuroforaminal stenosis.

CLINICAL FEATURES Epidural adhesions are not readily diagnosed by conventional studies such as myelography, computed tomography, and magnetic resonance imaging. It is believed that epidural adhesions are best diagnosed by an epidurogram, which is most commonly performed via the caudal route. Epidural filling defects have also been seen in a significant number of patients with no prior history of prior surgery. Bogduk and associates10 stated that a volume of 10 ml was sufficient to reach the L5 level. Manchikanti and colleagues3 found that the caudal epidurogram was effective in correlating a filling defect with the patient’s reported level of pain.

INDICATIONS Percutaneous epidural adhesiolysis and hypertonic saline neurolysis are indicated in patients with chronic low back pain who have failed to respond to conservative modalities of treatment, including epidural injections administered under fluoroscopic guidance, and other well-documented therapeutic modalities. Racz and colleagues11 described various conditions in which epidural lysis of adhesions is indicated, including postlaminectomy syndrome, epidural adhesions, disk disruption, traumatic or pathologic vertebral body compression fracture, spinal stenosis, and resistant multilevel degenerative arthritis (Box 87–1).

MANAGEMENT Epidural adhesiolysis can be performed percutaneously by either a catheter or an endoscopic technique.

Percutaneous Catheter Adhesiolysis (Racz Technique) Percutaneous catheter adhesiolysis (Racz technique) can be performed by utilizing a caudal, interlaminar, or transforaminal approach. Entry is performed with a 16-gauge RK needle, followed by advancement of a Racz catheter into the epidural space, with appropriate lysis of adhesions under radiographic control, utilizing nonionic contrast medium. Subsequently, a combination of local anesthetic and steroid is injected into the epidural space through the catheter, following which hypertonic saline neurolysis is carried out by slow and intermittent injection of hypertonic saline. In the classic Racz technique (Box 87–2), the procedure is repeated without steroids on day 2 and day 3. With other modifications (Box 87–3), the catheter is removed after the initial procedure is performed.

Box 87^1 INDICATIONS FOR EPIDURAL ADHESIOLYSIS       

Epidural fibrosis Spinal stenosis Radiculopathy Small herniated disks Fractures of vertebral bodies Vertebral metastases Degenerative diseases

Adapted and modified from Racz GB, Heavner JE, Raj PP. Percutaneous epidural neuroplasty. Prospective one-year follow-up. Pain Dig 1999;9:97^102.

XIII INTERVENTIONAL APPROACHES TO PAIN MANAGEMENT 631

Box 87^2 PERCUTANEOUS EPIDURAL NEUROPLASTY TECHNIQUE

space of a patient with adhesions are usually quite painful because of distention of the affected nerve roots. Although sedation is usually given, it is important that the patient be awake and responsive during the procedure so that the spinal cord is not compromised during the injection. n Fluoroscopy is mandatory for lysis of adhesions. n A water-soluble, nonionic contrast medium is used because of the possibility of unintended subarachnoid injection. Scar tissue may dissect during injection of contrast and enter the subarachnoid space. n Hypertonic saline is used to prolong the pain relief because of its local anesthetic effect.

The Caudal Approach

From Heavner JE, Racz GB, Raj P. Percutaneous epidural neuroplasty: prospective evaluation of 0.9% NaCI versus 10% NaCI with or without hyaluronidase. Reg Anesth pain Med 1999; 24:202-207.

Racz and colleagues11 also recommend using hyaluronidase with the injections.

Indications Percutaneous epidural adhesiolysis is indicated in patients with chronic low back and/or lower extremity pain who have failed to respond to conservative modalities of treatments, including epidural injections administered under fluoroscopic guidance. Racz and colleagues11 (see Box 87–1) described various conditions in which epidural lysis of adhesions is indicated, including postlaminectomy syndrome, epidural adhesions, disk disruption, traumatic or pathologic vertebral body compression fracture, spinal stenosis, and resistant multilevel degenerative arthritis.

General Principles n Intravenous access is recommended. It may be necessary to

sedate the patient. Injections of solutions into the epidural

Box 87^3 PERCUTANEOUS EPIDURAL ADHESIOLYSIS, 1-DAY PROCEDURE In the Operating Room  Place the epidural needle.  Inject contrast and visualize the spread (epidurogram).  After identification of the filling defect corresponding to the area of pain, thread a Racz catheter into the filling defect.  Inject additional contrast to ascertain opening of the scar and the spread of injectate within the epidural space and nerve roots.  Inject preservative saline 10 ^20 ml.  Inject 2% lidocaine 5 ml.  Tape the catheter in place in a sterile fashion. In the Recovery Room  After ascertaining for motor blockade, inject 6 ml of10% saline in two divided doses of 3 ml each,15^30 min after injection of local anesthetic.  Inject 6 ^12 mg of betamethasone or equivalent steroid.  Inject 0.5^1 ml of normal saline and remove the catheter. Modified from Manchikanti L, Pakanati R, Bakhit CE, et al. Role of adhesiolysis and hypertonic saline neurolysis in management of low back pain. Evaluation of modification of the Racz protocol. Pain Digest 1999;9:91-96.

The patient is placed prone with a pillow under the abdomen to straighten the lumbar spine. The sacral area is prepared and draped. Abduction of the legs and inversion of the feet (‘‘pigeon toe’’) facilitates entry into the sacral hiatus. The apex of a triangle encompassing the bilateral sacroiliac joints is visualized on an AP fluoroscopic image. The point of entry into the sacrococcygeal hiatus is at the apex. The entry point is infiltrated with local anesthetic, and a 16-gauge epidural needle in inserted into the sacral hiatus under a lateral fluoroscopic view (Fig. 87–1A). The needle is advanced to a point below the S3 foramen. After aspiration is negative for blood or cerebrospinal fluid, 10 ml of nonionic contrast is injected under fluoroscopy. The dye is injected into the caudal epidural space, revealing a Christmas-tree shape as the dye spreads into the perineural structures inside the bony canal and along the nerves as they exit the vertebral canal. Epidural adhesions prevent dye spread so that dye does not outline the involved nerve roots (see Fig. 87–1B and C). A lateral view likewise shows no dye outlining the scarred nerve roots. The ideal catheter is a stainless steel, fluoropolymer-coated, spiral-tipped Racz Tun-L-Kath-XL (Epimed International, Inc.). The bevel of the needle should face the venterolateral aspect of the caudal canal of the affected side because this facilitates passage of the catheter to the affected side. To facilitate steering of the catheter to the desired location, a 158 bend is placed at the distal end (see Fig. 87–1D). After final placement of the catheter and confirmation of negative aspiration, another 5 to 10 ml of contrast medium is injected through the catheter. This additional dye should spread into the areas of the previous filling defect and outline the targeted nerve root (see Fig. 87–1E and F). Then, 1500 units of hyaluronidase in 10 ml of preservative-free saline is injected. Afterward, the local anesthetic and steroid are injected. When the procedure is completed, the catheter should be secured to the skin with a suture and covered with a sterile dressing. The catheter is connected to an adapter and to a bacteriostatic filter that is not removed until three daily injections have been completed. The filter is capped and the catheter is taped to the patient’s flank. During hospitalization, the patient is given intravenous antibiotics in the form of cephalosporin 1 g/day to prevent bacterial colonization. Once the patient is taken to the recovery room and vital signs are checked, 9 ml of 10% hypertonic saline is infused over 20 to 30 minutes. Occasionally, the patient may complain of severe, burning pain during the infusion, usually due to the spread of hypertonic saline to the anesthetized area. Should this occur, the infusion must be stopped and another bolus of 3 to 5 ml of local anesthetic administered. After 5 minutes, the hypertonic saline infusion can be restarted without incident. After hypertonic saline infusion is completed, 1.5 ml of preservative-free normal saline is used to flush the catheter. Then, the cap is replaced on the filter. The catheter is left in place for 3 days. On the 2nd and 3rd days, it is injected once a day with 10 ml of 0.25% ropivacaine after negative aspiration from the catheter. Fifteen minutes later, 10 ml of 10% saline is infused over 20 minutes for patient comfort. At the

632 Chapter 87  EPIDUR AL ADHESIOLYSIS

C

A

B

D

Figure 87^1. Example of the Racz procedure (percutaneous epidural adhesiolysis).

A, Lateral view with needle in the caudal canal. B, Preadhesiolysis epidurogram with preferential dye spread to one side. C, Epidurogram demonstrates significant scar tissue. Scar tissue is demonstrated by the presence of filling defects on the epidurogram.This patient had a previous back surgery. D, Posteroanterior (PA) view of the Racz catheter directed to the left L5 nerve root.The epidurogram has been taken before introduction of the Racz catheter and shows clear presence of scar tissue on the nerve root, with dye spread stopping at the level of L4 ^5.

XIII INTERVENTIONAL APPROACHES TO PAIN MANAGEMENT 633

E

F

Figure 87^1. Cont’d. Example of the Racz procedure (percutaneous epidural adhesiolysis). E, Postadhesiolysis (Racz procedure)

epidurogram.The epidurogram after the adhesiolysis demonstrates how the dye has spread upward cranially. It also extends onto the nerve roots. F, Postadhesiolysis (Racz procedure) epidurogram on the lateral view. Note how the dye has spread to almost the L1level on the lateral view.

end of the infusion, the catheter is flushed with 1.5 ml of preservative-free normal saline. On the 3rd day, the catheter is removed 10 minutes after the last injection.

TheTransforaminal Approach (Hammer and Coworkers12) The general idea is to produce scar tissue adhesiolysis in the particular affected nerve root. The fluoroscope is directed in a 358 to 408 angle to visualize the opening of the intervertebral foramen. A 17-gauge Tuohy or blunt trocar is advanced coaxially under the pedicle. Once bone contact has been confirmed, the fluoroscopic view is changed to a posteroanterior view to demonstrate proximity of the needle trocar tip to the lateral foraminal zone. The fluoroscopic view is changed to a lateral view for final positioning. The needle is advanced from the posterior border of the neuroforamina to the retrovertebral space parallel to and ‘‘hugging’’ the inferior border of the pedicle. Paresthesias should not be elicited. After contact, a posteroanterior view should reveal the tip to be in the midforaminal or subarticular zone. With the needle bevel facing posteriorly, a Brevikath (Epimed International, Inc.) catheter is gently advanced under the exiting nerve root and into the ventral epidural space. The bevel may be rotated cephalad to steer the catheter appropriately if needed.

Complications The most common and worrisome complications of adhesiolysis in the lumbar spine are related to dural puncture, spinal cord compression, catheter shearing, infection, steroids, hypertonic saline, and hyaluronidase. Unintended subarachnoid and subdural puncture with injection of local anesthetic or hypertonic saline is one of the major complications of this procedure. Hypertonic saline injected into the subarachnoid space has been reported to cause

cardiac arrhythmias, myelopathy, paralysis, and loss of sphincter control. In fact, Aldrete and associates14 attributed incidences of arachnoiditis after epidural adhesiolysis with hypertonic saline to subarachnoid leakage of hypertonic saline. The second specific complication of percutaneous epidural adhesiolysis is related to catheter shearing and retention in the epidural space. This has been reported in at least five cases.16 Spinal cord compression after rapid injections into the epidural space, which may cause large increases in intraspinal pressure with a risk of cerebral hemorrhage, visual disturbance, headache, and compromise of spinal cord blood flow, has been mentioned. Epidural infection after the procedure is a distinct possibility. Occasional sensitivity (3%) to hyaluronidase has been reported in a series of 1520 epidural administrations of this agent.17

Synthesis of Current Evidence Clinical effectiveness of percutaneous adhesiolysis was evaluated in one systematic review and one health technology assessment. Trescot and colleagues18 concluded that there was strong evidence to indicate the effectiveness of percutaneous epidural adhesiolysis with administration of epidural steroids for short- and long-term use in chronic refractory low back and radicular pain. Moderate evidence supported the effectiveness of the addition of hypertonic saline. Evidence of the effectiveness of hyaluronidase was negative. In the technology assessment of epidural adhesiolysis for the treatment of back pain from Office of the Medical Director, Washington State Department of Labor and Industries, randomized, prospective, and retrospective studies were evaluated.19 This study concluded that the number of prospective studies on epidural adhesiolysis was small and adhesiolysis may provide benefit by eliminating scar tissue, thereby allowing application of drugs to the affected nerves. The recent guidelines published by the

634 Chapter 87  EPIDUR AL ADHESIOLYSIS American Society of Interventional Pain Physicians20 analyzed eight studies. The four randomized trials included in the evidence synthesis were positive for short-term and long-term pain relief. Other details of the trials included in the analysis are incorporated into Table 87–1. The cost-effectiveness for 1 year of improvement in quality of life varied from $2,028 to $5,564.

spinal canal: dura mater, blood vessels, connective tissue, nerves, fat, and pathologic structures, including adhesisons, inflammation, and stenotic change. The primary indications for endoscopic adhesiolysis include retrieval of the epidural space under direct visualization, direct decompression of the epidural space, selective drainage of inflammatory mediators, and selective adhesiolysis of target nerve roots and foramen (Box 87–4).

Endoscopic Adhesiolysis

Indications

Definition

Spinal endoscopy is best performed by a caudal approach. General indications for spinal endoscopy include

Spinal canal endoscopy (epiduroscopy) was defined as percutaneous, minimally invasive endoscopic investigation of the epidural space to enable color visualization of anatomic structures inside the

n Observation of pathology and anatomy. n Direct drug application.

Table 87^1. Randomized Trials of Percutaneous Adhesiolysis and Hypertonic Saline Neurolysis Study/Methods

Participants

Interventions

Outcomes

Veihelmann et al21 Prospective, randomized, double-blind

99 patients with chronic low back pain and sciatica.

Group 1 underwent physical therapy. Group 2 underwent percutaneous adhesiolysis.

Manchikanti et al22 Randomized, double-blind

Group 1 (N = 25): controls; catheterization but no adhesiolysis. Group 2 (N = 25): catheterization, adhesiolysis, followed by injection of local anesthetic, normal saline, and steroid. Group 3 (N = 25): adhesiolysis followed by injection of local anesthetic, hypertonic saline, and steroid. N = 59. All the patients failed conservative management along with fluoroscopically directed epidural steroid injections.

72% of patients in group 3 (hypertonic neurolysis), 60% in group 2 (adhesiolysis only) compared with 0% in group 1 (control) showed significant improvement at 12 mo follow-up

Positive short-term ( 6 mo) and long-term (> 6 mo) relief. Contrast showed intrathecal placement in 2 patients. One catheter ruptured on removal. Positive short- and long-term relief.

Heavner et al13 Randomized, double-blind

Manchikanti et al23 Randomized, controlled

N = 45

Gerdesmeyer et al24 Prospective, controlled pilot Gerdesmeyer et al25 Observational

25 patients with monosegmental radiculopathy.

Group 1: hypertonic saline plus hyaluronidase. Group 2: hypertonic saline. Group 3: isotonic saline Group 4: isotonic saline plus hyaluronidase Control group (N = 15): physical therapy exercise program and medication. Treatment group (N = 30): adhesiolysis, hypertonic saline neurolysis, and epidural steroid injection. All patients underwent adhesiolysis.

61 patients with lumbar radiculopathy.

All patients underwent adhesiolysis

Adhesiolysis, hypertonic saline neurolysis, and injection of steroid.

1-Day adhesiolysis in all patients.

60 post–lumbar laminectomy patients.

Adhesiolysis, hypertonic saline neurolysis, and injection of steroid

Manchikanti et al15 Retrospective, randomized Manchikanti et al26 Retrospective

83% initial relief tapered to 49% at 3 mo, 43% at 6 mo, and 49% at 1 yr. No complications noted.

Pain relief in 97% at 3 mo, 93% at 6 mo, and 47% at 1 yr. No complications noted.

All patients had improvement in 12 wk. No complications noted. Positive short-term (< 3 mo) as well as long-term (6 mo). 2 partial catheter shearing and 1 infection noted. Initial pain relief in 79%, 68% at 3 mo, 36% at 6 mo, and 13% at 12 mo with one injection. With multiple injections, initial relief was seen in 100% of patients; however, it declined to 90% at 3 mo, 72% at 6 mo, and 52% at 1 yr.

XIII INTERVENTIONAL APPROACHES TO PAIN MANAGEMENT 635

Box 87^4 GOALS OF ENDOSCOPIC ADHESIOLYSIS    

Retrieve epidural space under direct visualization by lysis of adhesions Direct decompression of the epidural space Selective drainage of inflammatory mediators Selective adhesiolysis of target nerve roots and foramen

n Direct lysis of adhesions (with medications, blunt dissection,

laser, and other instruments). n Placement of catheter and electrode systems (epidural,

subarachnoid). n As an adjunct to minimally invasive surgery.

Technique Highlights of the procedure are documented in Box 87–5. 1. The patient is prepared and draped in a sterile fashion and placed prone. The caudal area is identified under fluoroscopic view. Using a 25-gauge needle, local anesthetic is administered extending from the skin to the sacrococcygeal ligament. An 18gauge Tuohy needle is introduced to the epidural space via a caudal approach. 2. A lumbar epidurogram is carried out with contrast. Filling defects are identified in both AP and lateral views (Fig. 87–2). 3. A 0.8-mm x 70-cm guidewire is inserted through the needle. The guidewire is threaded cephalad. 4. The 12-Fr dilator and one 9-Fr introducer sheath are carefully inserted over the wire. An incision is made over the guidewire to facilitate passage of the introducer. 5. After the dilator and sheath are inserted, the dilator is removed, leaving the introducer sheath. Care is taken not to advance the dilator and sheath proximal to the S3 foramen because the thecal sac extends to the S2 foramen. 6. The video-guided catheter (VGC) is introduced through the introducer. The VGC has two ports with a steering handle. Using one of the ports, the flexible fiberoptic scope is placed through one of the two lumens in the steering handle. Normal saline for irrigation of the epidural space is attached to the other port. 7. The fiberoptic scope is connected to the light source, and the camera is attached to a standard arthroscopic tower. The picture is focused and white-balanced. 8. Preservative-free saline is collected in 10-ml syringes. This helps to keep a tab on the total amount of normal saline injected. Intermittent dilation of the epidural space is achieved by giving aliquots of 3 to 5 ml of normal saline at a time and visualizing the epidural space. An endoscopic view of the nerve root should be attempted (Fig. 87–3).

Figure 87^2. Spinal epiduroscopy view before adhesiolysis.

Note the presence of significant scar tissue showing up as filling defects.

Pedicle Clean foramen

Nerve root

Box 87^5 TECHNIQUE FOR SPINAL ENDOSCOPIC ADHESIOLYSIS  Caudal epidural placement of needle  Determine epidurographic findings by injecting contrast and noting filling patterns  Insert spinal endoscope at S3 level  Open epidural space with normal saline  Visualize to L3 level gently  Determine epidural scar condition  Release soft scar tissue thoroughly  Confirm epiduroplasty and foraminotomy  Inject a mixture of local anesthetic and depot steroid  Confirm adhesiolysis by noting contrast pattern in both AP (posterior epidural space) and lateral (ventral epidural space) views.

Figure 87^3. Postspinal epiduroscopy adhesiolysis on lateral view. Significant improvement in dye spread in the ventral epidural space.

636 Chapter 87  EPIDUR AL ADHESIOLYSIS

Pedicle

Entrapped nerve root Foramen

Chronic granulation tissue

Epidural fat

Nerve root

Engorged vessel

Figure 87^4. Example of a normal nerve root on spinal

endoscopy. The foramen along with the nerve root and pedicle is well visualized.

9. Lysis of epidural adhesions is carried out by mechanical and hydrodissection. Mechanical dissection is carried out by sweeping movements of the VGC (e.g., ‘‘windshield-washer’’ movement). Hydrodissection is carried out by infusing intermittently small amounts of normal saline ( 3–5 ml at a time). Scar may be present as ‘‘soft scar’’ (Fig. 87–4) or as chronic hard scar (Fig. 87–5). Scar tissue is generally avascular (i.e., whitish in color). Epidural fat is usually yellowish. In some instances, acute or chronic scarring may be evident (Fig. 87–6). 10. Under direct vision, the catheter can be directed to the area of the filling defect. In fact, the catheter can be utilized to free up

Figure 87^6. Example of chronic scarring. The epidural fat is yellow in color. Exuberant granulation tissue almost obliterates the epidural space. Inference can be made about the entrapped nerve root. Chronic scarring is evident from the color of the scar tissue (yellowish vs. red and inflamed).

the nerve root from the inside-out (i.e., from the epidural space to the nerve root sleeve). The dissection has to be gentle, and both fluoroscopic and endoscopic views must be checked constantly. This procedure has been referred to as epiduroplasty and foraminoplasty. An example of such a procedure is depicted in Figures 87–7 and 87–8. 11. A mixture of depot steroid and local anesthetic may be injected at the area of the scar. Some authors believe in not giving any local anesthetic at all because it may result in inadvertent spread to the intrathecal space and a spinal motor block.

Soft scar

Nerve root Nerve root Inflamed granulation tissue

Epidural fat Epidural space

Figure 87^5. Soft scar. Spinal endoscopic view of soft scar reveals soft scar along with epidural fat and nerve root. Nerve root is usually whitish in color, epidural fat is yellow, and scar tissue is white. Spinal endoscopy is usually very effective in removing soft scar, as shown.

Figure 87^7. Acute on chronic scarring. Endoscopic view

demonstrates inflamed granulation tissue, which is reddish and angry looking.The entrapped nerve root is actually well-visualized (whitish appearance).The epidural space is patent and shows significant granulation tissue.

XIII INTERVENTIONAL APPROACHES TO PAIN MANAGEMENT 637

Complications

Pedicle

Foramen

Figure 87^8. Spinal endoscopic view during adhesiolysis. The ragged edges of previous scarring are visualized.The nerve root is in the process of being freed up.

12. The VGC is removed. The final step is performing a postprocedure epidurogram by instilling contrast dye. The epidurogram is performed in both AP and lateral views. The epidurogram should demonstrate a better contrast spread (Fig. 87–9). 13. The incision can be closed by a single absorbable suture or with dermabond.

The most common and worrisome complications of spinal endoscopy with lysis of adhesions are related to instrumentation and administration of high volumes of fluid resulting in excessive epidural hydrostatic pressure, which may cause spinal cord compression, excessive intracranial and intraspinal pressures, epidural hematoma, bleeding, infection, increased intraocular pressures with resultant visual deficiencies and even blindness, and dural puncture. Potential complications include increased or continued pain, transient dysesthesias, paresis, paralysis, local surgical site bleeding, allergic reactions, and side effects related to the administration of steroids. The safety of steroids and preservatives in epidural therapeutic doses has been demonstrated in both clinical and experimental studies. The major theoretical complications of corticosteroid administration include arachnoiditis, suppression of the pituitary-adrenal axis, hypocorticism, Cushing’s syndrome, osteoporosis, avascular necrosis of bone, steroid myopathy, weight gain, fluid retention, and hyperglycemia. Other complications reported with steroid administration include epidural lipomatosis, retinal hemorrhage, subcapsular cataract formation, insomnia, mood swings, psychosis, facial flushing, headache, gastrointestinal disturbances, and menstrual disturbances. However, none of these reports have been implicated after spinal endoscopy and administration of steroids. Manchikanti and coworkers27 prospectively evaluated the effect of neuraxial steroids on weight and bone mass density. The results of serial determination of weight and bone mass density showed no significant change at any interval or at the end of 1 year. To summarize, unintended access of the subarachnoid or subdural space is possible. An example of such an unintended subarachnoid access is presented in Figure 87–10. If this is recognized early, injection of local anesthetic or hypertonic saline may be avoided.

Synthesis of Current Evidence Spinal endoscopic adhesiolysis and target delivery of steroids were evaluated in one systematic review and one health technology assessment. The systematic review by Trescot and colleagues18 concluded that there was strong evidence to indicate the effectiveness of

Dura

Intrathecal nerve with vasa vasorum

Figure 87^9. Spinal endoscopic view after adhesiolysis. The

clean nerve root can now be visualized.The foramen is now open, and significant adhesiolysis can be appreciated.

Figure 87^10. Spinal endoscopic view of an intrathecal nerve root. If the endoscope enters the intrathecal space, the view is suddenly improved tremendously.The nerve root can be seen clearly, with the vasa vasorum distinctly visible and the whitish-looking dura clearly visible.

638 Chapter 87  EPIDUR AL ADHESIOLYSIS

Table 87^2. Description of Randomized and Observational Studies of Spinal Endoscopy Study/Methods

Participants

Interventions

Outcomes

Manchikanti et al28 Prospective, randomized, double-blind

N = 83. Group 1 control (n = 33): endoscopy without adhesiolysis. Group 2 (n = 50): spinal endoscopic adhesiolysis followed by injection of local anesthetic and steroid. 58 patients with degenerative lumbar spinal stenosis divided into monosegmental (n = 34) and multisegmental (n = 24) groups.

Endoscopy with or without adhesiolysis and injection of local anesthetic and steroid.

Treatment group: 80% pain relief at 3 mo, 56% at 6 mo, and 48% at 12 mo. Control group: improvement was noted only at 1 mo.

Epiduroscopy including adhesiolysis by injection of saline and steroids and local anesthetics.

Amount of fatty tissue and degree of vascularity were greater in the monosegmental group. Relief of low back pain was observed up to 12 mo in both groups. Relief of leg pain was evident up to 12 mo in the monosegmental group and up to 3 mo in the multisegmental group. 19 of 20 patients showed adhesions by epiduroscopy. 55% of the patients experienced significant pain relief at 3 mo, 40% at 6 mo, and 35% at 12 mo. Epidural adhesions present in 100% of patients, with 41% having dense adhesions. Pain relief and decrease in disability persisted up to 12 mo.

Igarashi et al30 Observational

Guerts et al29 Prospective, observational

Richardson et al31 Prospective case series

20 chronic low back pain patients. The majority of them with post–lumbar laminectomy syndrome failed to respond to other modalities of treatment. 34 patients with chronic severe low back pain. 50% had failed back surgery syndrome.

Manchikanti et al26 Retrospective

60 patients with post–lumbar laminectomy syndrome.

Manchikanti et al32 Retrospective

85 consecutive patients who underwent 112 epidural endoscopic procedures.

Epiduroscopy with adhesiolysis and target delivery of 120 mg methylprednisolone acetate, 600 IU hyaluronidase, and 150 mcg clonidine. Epidural adhesiolysis and target delivery of steroid. Adhesiolysis followed by injection of bupivacaine, methylprednisolone acetate, and clonidine Spinal endoscopy with targeted delivery of steroid.

Spinal endoscopy with targeted delivery of steroid.

spinal endoscopic adhesiolysis and epidural steroid administration for short-term improvement and moderate evidence for long-term improvement in managing chronic refractory low back and lower extremity pain. The recent guidelines published by the American Society of Interventional Pain Physicians analyzed six studies.15 Among the three prospective, observational studies, one evaluated the effectiveness of spinal endoscopic adhesiolysis in lumbar spinal stenosis, showing good short- and long-term improvement in patients with low back pain; however, long-term improvement of leg pain was seen only in the monosegmental group. The other two prospective evaluations also showed positive results. Both of the retrospective evaluations showed positive short- and long-term relief. Table 87–2 summarizes the various studies. The costeffectiveness of spinal endoscopy in patients failing to respond to all conservative modalities of treatment, including percutaneous adhesiolysis with a spring-guided catheter, was shown to be $7,020 to $8,127.

100% of patients reported relief initially, which declined to 75% at 3 mo, 40% at 6 mo, and 22% at 12 mo. 100% of patients reported pain relief initially. Pain relief decreased to 94% at 1–2 mo, to 77% at 2–3 mo, 52% at 3–6 mo, 21% at 6–12 mo, and 7% after 12 mo.

CONCLUSIONS Percutaneous and endoscopic adhesiolysis has been employed in interventional pain management of chronic refractory low back and lower extremity pain. The purpose of percutaneous epidural lysis of adhesions is to eliminate scar tissue and ensure delivery of high concentrations of injected drugs to the target area. Epidural lysis of adhesions and direct deposition of corticosteroids in the spinal canal are also achieved with a three-dimensional view provided by epiduroscopy or spinal endoscopy.

REFERENCES 1. Enthoven P, Skargren E, Oberg B. Clinical course in patients seeking primary care for back or neck pain: a prospective 5-year follow-up of outcome and health care consumption with subgroup analysis. Spine 2004;29:2458–2465.

XIII INTERVENTIONAL APPROACHES TO PAIN MANAGEMENT 639 2. Ross JS, Robertson JT, Frederickson RC, et al. Association between peridural scar and recurrent radicular pain after lumbar discectomy: magnetic resonance evaluation. ADCON-L European Study Group. Neurosurgery 1996;38:855–861; discussion 61-63. 3. Manchikanti L, Bakhit CE, Pampati V. Role of epidurography in caudal neuroplasty. Pain Digest 1998;8:277–281. 4. LaRocca H, Macnab I. The laminectomy membrane. Studies in its evolution, characteristics, effects and prophylaxis in dogs. J Bone Joint Surg Br 1974;56B:545–550. 5. McCarron RF, Wimpee MW, Hudkins PG, Laros GS. The inflammatory effect of nucleus pulposus. A possible element in the pathogenesis of low-back pain. Spine 1987;12:760–764. 6. Parke WW, Watanabe R. Adhesions of the ventral lumbar dura. An adjunct source of discogenic pain? Spine 1990;15:300–303. 7. Berger E, Davis JMB. Chronic pain following lumbar spinal surgery in 1000 patients. Proceedings of 9th World Congress on Pain, August 1999; pp 181–182. 8. Mixter WJ, Ayers JB. Herniation or rupture of the intervertebral disc into the spinal canal. N Engl J Med 1935;213:385–395. 9. Kuslich SD, Ulstrom CL, Michael CJ. The tissue origin of low back pain and sciatica. A report of pain response to tissue stimulation during operations on the lumbar spine using local anesthesia. Orthop Clin North Am 1991;22:181–187. 10. Bogduk N, Christophidis N, Cherry D, et al. Epidural use of steroids in the management of back pain. Report of working party on epidural use of steroids in the management of back pain. National Health and Medical Research Council. Canberra, Commonwealth of Australia, 1994; pp 1–76. 11. Racz GB, Heavner JE, Raj PP. Percutaneous epidural neuroplasty. Prospective one-year follow-up. Pain Dig 1999;9:97–102. 12. Hammer M, Doleys D, Chung O. Transforaminal ventral epidural adhesiolysis. Pain Physician 2001;4:273–279. 13. Heavner JE, Racz GB, Raj P. Percutaneous epidural neuroplasty: prospective evaluation of 0.9% NaCl versus 10% NaCl with or without hyaluronidase. Reg Anesth Pain Med 1999;24:202–207. 14. Aldrete JA, Zapata JC, Ghaly R. Arachnoiditis following epidural adhesiolysis with hypertonic saline. Report of two cases. Pain Digest 1996;6:368–370. 15. Manchikanti L, Pakanati R, Bakhit CE, et al. Role of adhesiolysis and hypertonic saline neurolysis in management of low back pain. Evaluation of modification of the Racz protocol. Pain Digest 1999;9:91–96. 16. Lou L, Racz G, Heavner J. Percutaneous epidural neuroplasty. In Waldman SD (ed): Interventional Pain Management, 2nd ed. Philadelphia: W.B. Saunders, 2000; pp 434–445. 17. Moore DC. The use of hyaluronidase in local and nerve block analgesia other than spinal block. 1520 cases. Anesthesiology 1951;12:611–628. 18. Trescot AM, Chopra P, Abdi S, et al. Systematic review of effectiveness and complications of adhesiolysis in the management of chronic spinal pain: an update. Pain Physician 2007;10:129–146. 19. State of Washington: ‘‘WAC 296-20-03001 Treatment requiring authorization.’’ Washington Administrative Code. Effective October 1, 2001. Last accessed June 30, 2004.

20. Boswell MV, Trescot AM, Datta S, et al. lnterventional techniques: evidence based practice guidelines in the management of chronic spinal pain. Pain Physician 2007;10:7–111. 21. Veihelmann A, Devens C, Trouller H, et al. Epidural neuroplasty versus physiotherapy to relieve pain in patients with sciatica: a prospective randomized blinded clinical trial. J Orthop Science 2006;11:365–369. 22. Manchikanti L, Rivera J, Pampati V, et al. One day lumbar epidural adhesiolysis and hypertonic saline adhesiolysis in treatment of chronic low back pain: a randomized double blind trial. Pain Physician 2004;7:177–186. 23. Manchikanti L, Pampati V, Fellows B, et al. Role of one day epidural adhesiolysis in management of chronic low back pain: A randomized clinical trial. Pain Physician 2001;4:153–166. 24. Gerdesmeyer L, Rechl H, Wagenpfeil S, et al. Minimally invasive epidural neurolysis in chronic radiculopathy. A prospective controlled study to prove effectiveness. Der Orhopade 2003;32:869–876. 25. Gerdesmeyer L, Lampe R, Veihelmann A, et al. Chronic radiculopathy. Use of minimally invasive percutaneous epidural neurolysis according to Racz. Der Schmerz 2005;19:285–295. 26. Manchikanti L, Pampati V, Bakhit CE, Pakanati RR. Non-endoscopic and endoscopic adhesiolysis in post lumbar laminectomy syndrome. A one-year outcome study and cost effective analysis. Pain Physician 1999;2:52–58. 27. Manchikant L, Pampati V, Beyer CD, et al. The effect of neuraxial steroids on weight and bone mass density: A prospective evaluation. Pain Physician 2000;3:357–366. 28. Manchikanti L, Boswell MV, Rivera JJ, et al. A randomized controlled trial of spinal endoscopic adhesiolysis in chronic refractory low back and lower extremity pain. BMC Anesthesiol 2005;5:10. 29. Guerts JW, Kallewaard JW, Richardson J, et al. Targeted methylprednisolone acetate/hyaluronidase/clonidine injection after diagnostic epiduroscopy for chronic sciatica: a prospective, 1-year follow up study. Reg Anesth Pain Med 2002;27:343–352. 30. Igarshi T, Hirabayashi Y, Seo N, et al. Lysis of adhesions and epidural injection of steroid/local anesthetic during epiduroscopy potentially alleviate low back and leg pain in elderly patients with lumbar spine stenosis. Br J Anesth 2004;93:181–187. 31. Richardson J, McGurgon P, Cheema S, et al. Spinal endoscopy in chronic low back pain with radiculopathy. A prospective case series. Anaesthesia 2001;56:454–460. 32. Manchikanti L. The value and safety of epidural endoscopic adhesiolysis. Am J Anesthesiol 2000;275–278.

SELECTED READINGS Boswell MV, Shah RV, Everett CR, et al. Interventional techniques in the management of chronic spinal pain: evidence-based practice guidelines. Pain Physician 2005;8:1–47. Manchikanti L, Saini B, Singh V. Spinal endoscopy and lysis of epidural adhesions in the management of chronic low back pain. Pain Physician 2001;4:240–265.

640 Chapter 88  SPINAL ANALGESIA

Chapter 88

SPINAL ANALGESIA Anthony Dragovich and Steven P. Cohen

INTRODUCTION The spinal administration of medications dates back over 120 years, when Corning1 described injecting cocaine between the spinous processes, first in a dog who experienced sensory loss and motor weakness and then in a man suffering from ‘‘spinal weakness and seminal incontinence.’’ In 1899, Bier2 reported the first use of intrathecal (IT) local anesthetic to provide surgical anesthesia. Two French physicians, Sicard3 and Cathelin,4 working independently, published the first reports of neuraxial analgesics to treat chronic pain within 1 month of each other in 1901, injecting cocaine through the sacral hiatus in patients suffering from lumbago and sciatica. In 1979, several years after the discovery of endogenous opioid receptors, Wang and coworkers5 first injected IT morphine to treat cancer pain. IT drug infusion systems have been in place since the early 1980s and have undergone numerous revisions to make them more tolerable, easier to program, and longer lasting.

PATIENT SELECTION In the early 1970s, the discovery of opioid receptors in neural tissue6,7 provided the impetus for the treatment of pain by injecting medications directly into the spinal canal, first in experimental animals8 and then in chronic pain patients.5 The first report of IT opioids to treat chronic pain was in cancer patients back in 1989. Given the high incidence of moderate to severe pain in terminal cancer patients; the likelihood of developing significant, dose-limiting side effects when oral opioids are used to treat pain; and lesser concerns regarding issues of tolerance, dependence, and addiction, the treatment of cancer pain with IT opioids is an appealing alternative.9,10 Excellent outcomes have been demonstrated in previous reviews using IT analgesia in patients with malignancy. For financial reasons, some experts recommend tunneled epidural catheters in lieu of implantable infusion devices in patients with life expectancies under 3 months.11 The main controversy surrounding spinal analgesia is whether IT therapy is effective in the long term for chronic nonmalignant pain. The use of opioids for chronic noncancer pain has come full circle since earlier studies found chronic neuropathic pain to be relatively resistant to opioids.12–15 In the mid-1990s, clinical trials began to appear suggesting that long-term opioid therapy might be effective in some patients with chronic nonmalignant pain.16,17 These reports, coupled with case series reporting low rates of addiction in long-term opioid users, resulted in a strong push in social, medical, and even legal circles to aggressively treat chronic pain.18 But shortly thereafter, the tide began to turn the other way, driven by a conglomeration of factors that all seemed to coalesce around the new millennium. These factors included evidence that opioidinduced hyperalgesia accounts for a significant component of

narcotic tolerance; literature suggesting that whereas opioids indeed provide short-term pain relief, their long-term ability to attenuate pain, improve psychological functioning, and enhance activities of daily living is less convincing; higher estimates from better studies on the incidence of addiction and aberrant behavior in chronic pain patients; well-publicized accounts of narcotic diversion and the burgeoning market in prescription drug abuse by street addicts and teenagers; and a crackdown by the U.S. Drug Enforcement Agency on health care professionals, including physicians, who prescribe and dispense controlled substances irresponsibly.19–23 It is our opinion that implantable IT pumps have a place in the treatment of chronic nonmalignant pain, albeit with certain caveats (Box 88–1). First, before embarking on an IT trial, patients should be screened for signs of substance abuse, aberrant behavior, and psychological conditions that might predispose them to failure. The dependent relationship established by the implantation of an IT infusion device makes risk stratification just as essential before consideration of an IT trial, even though IT pumps are less prone to abuse than oral or systemic opioids and carry minimal risk of diversion.24,25 A report by Kittleberger and associates26 described a patient with failed back surgery syndrome (FBSS) who was found to be self-extracting hydromorphone from his IT pump. Second, the likelihood of treatment success should be considered. Less invasive treatment such as nerve blocks, neuropathic pain medications, and conservative treatment should be performed prior to consideration of an IT trial. IT therapy is more efficacious for certain medical conditions. IT baclofen is well documented to be an effective treatment for spasticity-related pain, with or without central pain. In a multicenter, randomized, controlled study, ziconotide was demonstrated to be effective in acquired immunodeficiency syndrome (AIDS).27 Some evidence supports opioid IT treatment in herpes zoster and FBSS, but no evidence supports their use in fibromyalgia or chronic pelvic pain. Table 88–1 details

Box 88^1 SELECTION CRITERIA FOR INTRATHECAL PUMP PLACEMENT IN CANCER-RELATED AND NONMALIGNANT PAIN  Stable medical condition amenable to surgery.  Clear organic pain generator, preferably nociceptive in nature.  No psychological contraindication such as severe depression or bipolar disorder, addiction, or secondary gain issues.  No familial contraindication such as severe codependent behavior.  Documented responsible behavior and stable social situation that will facilitate proper device management.  Good pain relief with oral or parenteral opioids.  Intolerable side effects from systemic opioid therapy.  Baseline neurologic examination and psychological evaluation.  Failure of more conservative therapy including trials with nonopioid medications and nerve blocks.  Constant or almost constant pain requiring around-the-clock opioid therapy.  High degree of tolerance to opioids may limit effectiveness of intrathecal therapy.  No tumor encroachment of the thecal sac in cancer patients.  Life expectancy > 3 mo.  No practical issues that might interfere with device placement, maintenance, or assessment (e.g., morbid obesity, severe cognitive impairment).  Positive response to an intrathecal trial.

XIII INTERVENTIONAL APPROACHES TO PAIN MANAGEMENT 641

For example, Aldrete and Couto da Silva28 found that 22% of patients who were treated with IT opioids for FBSS developed lower extremity edema necessitating discontinuation or significant reduction of therapy after 24 months. Upon detailed questioning, it was noted that all patients who developed leg edema had prior pedal edema and venous stasis prior to pump insertion. The authors concluded that preexisting pedal edema and venous stasis were relative contraindications to long-term IT therapy.

Table 88^1. Summary of Intrathecal Medications

Drug

Typical Dose Range (mg/day) Clinical Evidence for Efficacy

Morphine

1–20

Hydromorphone 0.5–10 Fentanyl 0.02–0.3 Bupivacaine 4–30

Midazolam

0.2–6

Clonidine

0.03–1

Ketamine

1–50

Baclofen

0.05–0.8 mg/d

Ziconotide

0.002-0.02

Strong evidence for cancer pain Moderate evidence for nonmalignant pain Same as morphine Same as morphine Strong evidence for cancer pain Moderate evidence for nonmalignant pain Weak evidence for chronic back pain Anecdotal evidence for neuropathic pain Weak evidence for cancer pain Moderate evidence for back pain Moderate evidence for neuropathic pain Weak evidence for cancer pain Anecdotal evidence for neuropathic pain Strong evidence for spasticity– related pain Moderate evidence for neuropathic pain Moderate evidence for cancer and nonmalignant pain

OPIOIDS

common IT medications, their dose ranges, and a summary of the evidence of efficacy. Finally, a trial with either IT or epidural medication is of paramount importance in patients with non-cancer pain who otherwise meet criteria for consideration of IT therapy. This holds true irrespective of whether the intended therapy is with opioids, ziconotide, baclofen, or combinations of various medications. Short-term trials do have their drawbacks. Whereas short-term trials may predict short- and intermediate-term pain relief, their ability to prognosticate long-term outcomes is less established. Other limitations of IT trials include the lack of standardization regarding the types (combinations) and doses of medications administered and the limited outcome measures (usually pain relief rather than improvement in function). The main factors limiting success for long-term therapy are the development of tolerance and side effects, neither of which can be accurately predicted with a trial lasting several hours or days.

Morphine is currently the ‘‘gold standard’’ for spinally administered drug therapy and is the only opioid approved by the U.S. Food and Drug Administration (FDA) for IT delivery to treat chronic pain. As implantable intrathecal drug delivery (ITDD) systems have become more common, different opioids have been used to take advantage of their unique pharmacologic profiles. Opioid analgesics are neuromodulators of target cell activity.29 Somatic or visceral pain causes depolarization in Ad- or C-fibers, which is then transmitted to the primary synapse in the dorsal horn of the spinal cord. This is the synapse targeted by IT opioids. Peripherally located opioid receptors have been identified, but the predominant analgesic sites for opioids are still generally believed to reside in the central nervous system. In the brain, these receptor sites include the brainstem, thalamus, forebrain, and mesencephalon. In the spinal cord, they include postsynaptic receptors located on cells originating in the dorsal horn, as well as presynaptic receptors found on spinal terminals of primary afferent fibers.30 Three subtypes (m, d, and k) of opioid receptors have been characterized,31 all of which are G-protein complexes.32 The analgesic and nonanalgesic effects of opioids are mediated pre- and postsynaptically. Opioid binding to presynaptic, primary afferent nerve terminals causes inhibition of substance P and calcitonin gene-related peptide (CGRP) release through suppression of voltage-gated calcium channels.33 Substance P and CGRP are neuropeptides believed to be responsible for transmitting nociceptive signals across synapses. Postsynaptically, opioid binding to receptors located on somata and dendrites of intrinsic dorsal horn cells cause G-protein–mediated inhibition of adenyl cyclase and activation of inwardly rectifying potassium currents resulting in hyperpolarization of postsynaptic neurons.34 The effects of opioids are determined by their affinity for endogenous receptors, their ability to reach those receptors, and their lipid solubility. Table 88–2 illustrates the relative potencies and water solubility of five commonly used opioids for different routes of administration. In general, the degree of water solubility correlates positively with both the spread of analgesia and the side effects. A greater degree of rostral spread is exhibited when highly water-soluble opioids like morphine are injected into the subarachnoid space. This may improve analgesia in conditions requiring higher spinal levels or more extensive coverage. Conversely, many of the most common (pruritus, nausea, and vomiting) and feared

Table 88^2. Conversion Ratios Between Commonly Used Opioid Agonists Equianalgesic Doses of Opioids (mg) Opioid Agonist

Oral

Parenteral

Morphine Hydromorphone Meperidine Fentanyl Sufentanil

300 60 3000 — —

200 20 1000 1 0.1

Epidural

10 2 100 0.1 0.01

Intrathecal

1 0.2 10 0.01 0.001

Hydrophilicity

High Intermediate Low Low Low

642 Chapter 88  SPINAL ANALGESIA (delayed respiratory depression) adverse effects of spinal opioids are due to interactions with opioid receptors in the brain. Thus, adverse effects are more frequently encountered with hydrophilic drugs such as morphine. Opioids, particularly morphine, are the most studied class of IT medications. Increasing evidence suggests that IT opioids are superior to conventional medical management in patients with severe pain due to malignancy, especially when opioid dosage is limited by adverse effects. Several studies have investigated the early use of epidural opioids in cancer pain and found no advantage. However, two large studies investigating IT opioids found a significant reduction in pain scores and toxicity and a trend toward prolonged survival. In a prospective, multicenter, randomized, clinical trial, Smith and colleagues35 investigated a continuous ITDD system versus comprehensive medical management in 200 cancer patients. The primary end-points were a reduction in pain or a decrease in toxicity. At the 4-week follow-up, visual analog scale (VAS) pain scores and toxicity scores decreased in both groups. The VAS score in the comprehensive medical management group fell from 7.81 to 4.76, a reduction of 39.1%. In the ITDD system group, the VAS score fell from 7.57 to 3.67, a decrease of 51.5%. However, the VAS difference was not statistically significant because the study was not powered appropriately. Toxicity scores in the comprehensive medical management group fell 17% from 6.36 to 5.27, versus a greater than 50% reduction in the ITDD group, which decreased from 7.22 to 3.59 (P = .04). Survival was initially measured in the study only to monitor treatment safety, but at the 6-month mark, the estimated cumulative survival rate was 53.9% in the IT group versus 37.2% in the medical management group (P = .6). In a multicenter, open-label, clinical study, Rauck and coworkers36 evaluated a patient-activated IT morphine delivery system in 199 cancer patients who had either refractory pain or uncontrollable side effects. Pain decreased from a mean score of 6.1 to 4.2 at 1 month (31% decrease) and remained decreased through 13 months (P < .05). There was also a statistically significant reduction in drug toxicity and oral opioid requirements. However at the final 16-month follow-up, the difference between baseline and current pain scores was no longer significant. These and other smaller studies demonstrate a significant decrease in side effects when IT opioids are used in lieu of oral or systemic routes of administration. Significant decreases have been found for multiple opioid-related adverse effects including fatigability, depressed consciousness and cognitive impairment, sleep disturbances, nausea, vomiting, and constipation. ITDD system complications occur with about a 30% incidence and tend to be related to either surgery (e.g., hematomas, infections, wound dehiscence) or mechanical dysfunction (pump or catheter failures). In most studies, the reoperation rate is between 20% and 30%. One compelling issue in patients with long life expectancies is the development of tolerance to IT opioids necessitating escalating doses. In a randomized trial comparing morphine alone to morphine and bupivacaine IT infusions, van Dongen and associates37 found that morphine and bupivacaine possessed synergistic analgesic effects. Thus, combining an opioid with a local anesthetic can theoretically improve the toxicity profile. The evidence supporting IT opioids in chronic nonmalignant pain is less robust than in cancer pain. To some extent, this may be due to the different mechanisms characterizing pain in the two conditions. In patients with cancer, between 75% and 90% of pain is either nociceptive or mixed nociceptive-neuropathic in origin.38,39 The etiology of the pain is more variable in chronic nonmalignant pain. In the chronic pain conditions that are most amenable to spinal analgesia such as complex regional pain syndrome (CRPS) and FBSS, neuropathic pain tends to play a significant role. Numerous preclinical40 and clinical13,41 studies have shown that neuropathic pain is less responsive to opioids than nociceptive pain.

Thimineur and colleagues42 performed a prospective study in 88 patients to investigate long-term outcomes of IT opioid therapy in chronic nonmalignant pain in an effort to improve selection criteria for pump recipients. Pump candidates were patients who had pain severe enough to adversely affect physical function and quality of life after exhausting conservative treatment options. Thirty-eight patients responded to the IT morphine trial and were subsequently implanted, whereas 31 failed the trial and were classified as the ‘‘nonresponder group.’’ Eleven patients (9 in the nonresponder group) were noncompliant with treatment and were dropped from the study. Six died (3 from each group) prior to study completion from unrelated causes. Forty-one newly referred patients who entered the study served as a comparative group. The most frequently administered drug combination was morphine with clonidine. IT medication selection was left to the discretion of the attending physician. At the 36-month follow-up, pump recipients experienced improved mood scores, less disability, and significantly improved pain scores. The nonrecipient group worsened in all these parameters. However, the comparison group of 41 newly referred patients improved to a greater degree in all areas than pump recipients. The authors concluded that, although patients with severe noncancer pain who receive IT infusion therapy are likely improve with therapy, the overall severity of their symptoms will likely remain high. Multiple prospective studies support the conclusion that IT narcotics can be a safe and effective therapy in the management of severe refractory pain in a carefully selected population,43–45 although this belief is not universal46 (Table 88–3). Consistent with animal studies, the use of opioids alone may not be as efficacious as multimodal therapy in patients with neuropathic pain. This may explain the large number of patients with nonmalignant pain who are refractory to opioids but improve with the addition of local anesthetics or clonidine.47 Sufentanil and fentanyl possess higher intrinsic activity than morphine or, stated differently, interact with a fewer number of receptors to produce an equianalgesic response.48 This could theoretically lead to less tolerance because receptor activation is a prerequisite for receptor down-regulation. In a 7-day continuous infusion study comparing morphine with sufentanil in a rat model, sufentanil produced a smaller rightward shift in the doseresponse curve, indicative of less tolerance than morphine.49 As might be expected, fentanyl and sufentanil have analgesic efficacy similar to that of morphine when injected intrathecally in animal models.50 In a retrospective study by Willis and Doleys,51 the authors treated 29 patients with nonmalignant pain with IT opioids, 8 of whom received fentanyl after failing morphine or hydromorphone therapy. At their mean 31-month follow-up, the fentanyltreated patients reported a 68% decrease in overall pain. Hassenbusch and coworkers52 compared the effects of long-term IT infusion of morphine or sufentanil for the treatment of neuropathic pain. All patients were initially started on sufentanil but were switched to morphine if sufentanil was ineffective or intolerable side effects occurred. Eighteen of 22 patients successfully completed the trial and were implanted. Ten responded well to sufentanil, whereas 8 were switched to morphine. Three of the 8 patients on morphine were switched back to sufentanil after developing mild leg edema, which was resistant to diuretics but did respond after conversion to sufentanil. The mechanism of leg edema induced by IT morphine is controversial, but it may involve partial sympathetic blockade, which exacerbates preexisting peripheral venous insufficiency.28 Overall 61% (11 of 18) of the patients reported adequate pain relief. The morphine and sufentanil doses ranged from 11 to 53 mg/day and 12 to 72 mcg/day, respectively, with follow-ups ranging between 0.8 and 4.7 years. Catheter-related complications (migration, coiling, obstruction, or breakage) ranging from 20% to 40% in the published literature are the most frequent problems necessitating reoperation. Mechanical complications related to pump function include

XIII INTERVENTIONAL APPROACHES TO PAIN MANAGEMENT 643

Table 88^3. Outcomes with Intrathecal Opioids for Noncancer Pain Follow-up (Mean) (in yr)

Relief of Pain*

Condition Studied{

Comments and Complications

Two pumps explanted for poor pain relief. Used MSO4 or hydromorphone. Bupivacaine added in 13/16 patients. 2 patients terminated therapy; 53% had excellent relief. Used MSO4 or sufentanil. 33% reoperation rate. Edema resolved in 3 patients after switch to sufentanil 92% satisfied; 81% had improved quality of life. Somatic pain improved more than other types. 21.6% mechanical complication rate. Performed 1.4 additional procedures per patient. 11 reoperations.

Study

StudyType (Implanted)

Plummer et al, 1991128 Krames et al, 199362

Retrospective (N = 12) Retrospective (N = 16)

0.5

83%

Not mentioned

2.3

81%

NO, NP, mixed (FBSS)

Kanoff, 1994129

Retrospective (N = 15) Prospective comparative (N = 18)

0.2–4

73%

NP, mixed (FBSS)

0.8–4.7

61%

NP

Retrospective (N = 120) Retrospective physician survey (N = 296) Retrospective (N = 18) Retrospective (N = 26) Prospective observational (N = 11) Prospective observational (N = 30) Retrospective study evaluating IT fentanyl after prior opioid failure (N = 8) Prospective observational (N = 16) Retrospective patient survey (N = 88) Retrospective study evaluating IT hydromorphone Prospective registry (N = 136)

0.5–6 (mean 3.4) 1.0

77%

DA, mixed (FBSS), NP Mixed (FBSS), NP, NO, DA

2

25%

Mixed (FBSS)

2

77%

Not mentioned

0.5–3 (mean 2.3)

73%

Mixed (FBSS), NP

Two pumps removed for urinary retention.

2

50% had  25% pain relief 68%

Mixed (FBSS), NO, DA, NP

20% reoperation rate. Used MSO4 or hydromorphone, with 5 needing bupivacaine. Patients failed IT MSO4 or hydromorphone.

NO 57%, FBSS 61%, DA 75% 82%

NO, mixed (FBSS), DA

Three pumps replaced or explanted. 12 successes.

Mixed (FBSS), NP, NO Mixed (FBSS), NP, NO, DA

1

10%. 6 of 16 had  25% pain relief. 62%

Case series (N = 7) Prospective observational with two comparative groups (N = 31) Retrospective (N = 19)

2–7

Angina#

3

27%

Angina status post CABG Not mentioned

40% of patients required reoperation. 88% satisfaction rate. All patients failed IT MSO4. Most patients had fewer side effects with hydromorphone. 21 reoperations to correct mechanical problems. 36 physicians participated. Angina improved with IT fentanyl or MSO4. Pain, disability, and depression improved in implanted patients whereas nonpump recipients worsened.

0.3–12 (mean 4.5)

NO 64%, FBSS 58%, NP 25%

Hassenbusch et al, 199552

Winkelmuller et al, 199616 Paice et al, 1996130 Yoshida et al, 199646 Tutak and Doleys, 1996131 Angel et al, 199845

Anderson and Burchiel, 199943 Willis and Doleys, 199951

Kumar et al, 200144 Roberts et al, 2001132 Anderson et al, 2001133 Deer et al, 2004134

Cherry et al, 2003135 Thimineur et al, 200442

Njee et al, 2004136

2.5

1–4 (mean 1.5) 3

0.8

95%

Not mentioned

Mixed (FBSS), NP, NO

Mixed (FBSS), NP, NO

10% infection and catheter dislodgment rate. 90% patient satisfaction. Continued

644 Chapter 88  SPINAL ANALGESIA

Table 88^3. Outcomes with Intrathecal Opioids for Noncancer Painçcont’d

Study

Du Pen et al, 2006137

StudyType (Implanted)

Retrospective review of IT hydromorphone (N = 24)

Follow-up (Mean) (in yr)

Relief of Pain*

Condition Studied{

Comments and Complications

1

25%# in VAS

Mixed (FBSS), NO, NP

Average dose increase was 600% in 1 yr. Only 7 patients had 1-yr follow-up data.

*Percentage of patients with either good or excellent relief or  50% reduction in pain score. { FBSS is listed in parenthesis after ‘‘mixed’’ if the most prevalent cause of mixed neuropathic and nociceptive pain was FBSS. CABG, coronary artery bypass graft; DA, deafferentation pain; FBSS, failed back surgery syndrome; IT, intrathecal; NO, nociceptive pain; NP, neuropathic pain; VAS, visual analog scale.

motor failure, failure to respond to telemetry, and improper pump placement in the pouch. Surgical complications occur despite the relative simplicity of the operation and include superficial infections, meningitis, hematomas, and seromas. IT granuloma formation is a serious complication that carries the potential to produce spinal cord compression and paralysis distal to the mass. Over 100 cases have been reported, the first of which was in 1991.53,54 The etiology has not been fully elucidated but may be related to a mitogen-activated protein kinase cascade causing increased lymphocyte activity and changes in mast cell activity.55,56 The phenomenon appears to be a function of concentration (>25 mg/ml), daily dose (>10 mg/day), and duration of therapy. However, 39% of cases occurred with morphine concentrations less than 25 mg/ml, and 30% received daily morphine doses less than 10 mg/day. Some were noted within 1 month of the initiation of therapy.55 Some recommendations about how best to prevent, diagnose, and treat granulomas are to maintain the concentration and dose as low as possible, document baseline neurologic function, consider mass lesions when analgesic efficacy is lost or new-onset neurogenic pain occurs, and keep the threshold for imaging studies low.56 Owing to the decreased IT dose, many opioid-related side effects are decreased with this route of administration. In fact, one of the primary indications for a trial of IT opioids is good analgesic effect associated with intractable side effects on oral medications. Nevertheless, the neuraxial administration is not devoid of adverse effects. The most frequent side effects of IT opioids are constipation, urinary retention, nausea/vomiting, sweating, and libido disturbances secondary to hypogonadotrophic hypogonadism57 (Table 88–4). With the exceptions of sweating, peripheral edema, and constipation, these adverse effects tend to diminish with time.16 In summary, based on existing data, opioids with and without adjuncts appear to be effective for patients with chronic refractory malignant pain. The data for the treatment of nonmalignant pain with IT opioids are less convincing. Patients should be carefully selected for treatment and appropriately counseled as to the risks and benefits.

LOCAL ANESTHETICS Local anesthetics are the most widely utilized spinal analgesics, being used to provide both surgical anesthesia and pain relief. Local anesthetics provide analgesia via the blockade of sodium channels, which is the pivotal event in the depolarization of neurons. Local anesthetics block the transmission of all nerve fibers, not just the Ad- and C-fibers responsible for pain. Good intermediate to long-term outcomes mixing local anesthetics with opioids and other IT analgesics have been documented in numerous studies. Two studies by Sjoberg and associates58,59

conducted in over 100 cancer patients found that the combination of IT morphine and bupivacaine treatment resulted in adequate pain relief in almost 100% of subjects with cancer pain. However, the mean follow-up period in these studies was under 1 month. In a retrospective study, van Dongen and colleagues60 found that the addition of IT bupivacaine to opioids resulted in adequate analgesia in 10 of 17 cancer patients who failed IT opioid therapy alone. The mean follow-up in this study was 112 days. In a later, double-blind, randomized trial comparing IT morphine alone to IT morphine and bupivacaine in 20 cancer patients, the same group found that the combination group developed less opioid tolerance than the morphine-only group.37 Five patients in the IT morphine group switched to the combination group secondary to inadequate analgesia; 3 of 15 patients who received morphine and bupivacaine experienced subjective weakness that did not interfere with walking. The authors concluded the combination of IT bupivacaine and morphine provided synergistic analgesic effects. This is consistent with preclinical findings demonstrating synergistic antinociceptive effects

Table 88^4. Incidence of Side Effects with Long-term Intrathecal Opioid Therapy Side Effect

Constipation Sweating Nausea Urinary retention Vomiting Insomnia/nightmares Impotence Confusion Pruritus Edema Disturbance of libido Fatigue Dry mouth Dizziness Loss of appetite Hypothyroidism Amenorrhea Convulsions Provocation of asthma Adapted from references 16, 43, 44.

Incidence (%)

57 47 42 37 33 28 21 15 14 7 6 6 4 4 3 2 2 1 1

XIII INTERVENTIONAL APPROACHES TO PAIN MANAGEMENT 645

between IT morphine and lidocaine in rats, which is more prominent in models of visceral than somatic pain.61 IT combinations of local anesthetics and opioids have led to similarly beneficial results in nonmalignant pain. Krames and coworkers62 found that the addition of bupivacaine to IT opioids either decreased opioid side effects or enhanced analgesia in 77% of 13 patients with nonmalignant pain treated with an IT infusion pump, with a mean follow-up of almost 1 year. In a large cohort study by Deer and associates63 conducted in 109 patients with FBSS (n = 84) and metastatic cancer of the spine (n = 25), the authors found that the combination of opioids and bupivacaine provided superior analgesia and greater patient satisfaction. Combination therapy was also associated with less oral opioid and adjuvant use than IT opioids alone. The average exposure to bupivacaine was 62 weeks. Excellent results were also reported in mixing IT bupivacaine with morphine and clonidine and with morphine, clonidine, and midazolam in 26 patients with chronic back pain and/or leg pain (mean follow-up 27 mo).64 Finally, Dahm and colleagues65 reported dramatic pain relief in three patients with vertebral compression fractures refractory to conventional management who were then treated with IT bupivacaine alone (n = 2) or in combination with buprenorphine (n = 1) via a temporary, tunneled IT catheter. The mean dose of bupivacaine was 25 mg (range 10–70 mg), and the duration of treatment averaged 9 months. In clinical practice, effective doses of bupivacaine generally range from 3 to 50 mg/day, although there are some reports of daily doses exceeding 100 mg/day.66 Common side effects of IT local anesthetics include numbness, paresthesias, weakness, and bowel and/or bladder dysfunction, all of which can be diminished with combination therapy. Neurotoxicity is a theoretical concern when high concentrations are used with low infusion rates, although this risk appears to be negligible with bupivacaine or ropivacaine.

CALCIUM CHANNEL BLOCKERS zVoltage-gated calcium channels play an integral role in the transmission of pain. T, L, N, P, Q, and R subtypes of voltage-sensitive calcium channels have been identified. These channels are characterized by their biophysical properties such as sensitivity to pharmacologic blocking agents, single-channel conductance kinetics, and voltage-dependence. For example, the L-type channel is sensitive to dihydropyridines, the T-type is responsive to ethosuximide, and the N-type and P/Q-type channels respond to conotoxins. Except for T-type channels, all are high-threshold activated. There is compelling evidence in animal models of acute pain to support a role for N-type calcium channels in nociception, moderate evidence for L-type channels, and limited or no evidence for other calcium channels. Under conditions of persistent nociception induced by chemical, inflammatory, or neuropathic stimuli, all types of calcium channels may play a role in the maintenance of pain.67–69 High concentrations of voltage-gated calcium channels are found in the dorsal horn of the spinal cord and dorsal root ganglia. There is very little literature on the neuraxial use of L-type calcium channel blockers in humans. Whereas animal studies have failed to show independent antinociceptive effects for neuraxial L-type channel blockers, preclinical studies have demonstrated potentiation of the antinociceptive effects of morphine by IT verapamil.70 In the only human study evaluating neuraxial verapamil, Choe and coworkers71 found that combining epidural verapamil with bupivacaine in patients undergoing abdominal surgery significantly reduced postoperative analgesic requirements 48 hours postoperatively compared with patients who received epidural bupivacaine alone. However, because there are no studies evaluating the safety or long-term efficacy of IT L-type calcium channel blockers in chronic pain conditions, research and clinical emphasis in this area has focused on N-type calcium channel blockers.

Ziconotide, approved by the FDA in December 2004 for IT use in patients with severe, chronic pain refractory to other treatments, is a synthetic form of the peptide o-conotoxin MVIIA isolated from venom produced by the marine snail Conus magus. In a multicenter, double-blind, placebo-controlled, cross-over study evaluating IT ziconotide for the treatment of refractory pain in 111 patients with cancer and AIDS, Staats and associates27 found that the treatment group obtained significantly better pain relief than control patients in all parameters. Patients in the ziconotide group averaged 53% pain relief versus 17.5% in those who received placebo. Half of the 68 ziconotide patients reported at least a 30% decrease in pain score compared with 18% in the placebo group. Opioid use decreased by 10% in the treatment group, which favorably compared with a 5% increase in the control patients. Thirty-one percent of the ziconotide patients experienced side effects, with the most common being confusion, somnolence, and urinary retention. The observation that there was no loss of efficacy for ziconotide during the 5-day maintenance phase (mean dose 21.8 mcg/day) is consistent with animal studies showing a lack of tolerance with calcium channel blockers. In an attempt to reduce side effects and increase tolerability, Rauck and colleagues72 conducted a double-blind, placebocontrolled study using a slower titration schedule and lower maximum dose than previous studies in 220 patients with chronic nonmalignant pain (mostly FBSS) refractory to conventional treatment. VAS pain scores improved by 15% in the ziconotide group versus 7% in the placebo group at the end of the 3-week treatment period. During the treatment period, 12% of the ziconotide patients reported adverse effects. Ziconotide is approved as a monotherapy in chronic pain patients who have failed conventional IT therapy. However, many physicians are now using the drug in combination with IT opioids and nonopioid analgesics.73 The major limitations for IT ziconotide are its prohibitive cost and the high incidence of side effects, which top 33% in some studies. These adverse effects include psychiatric symptoms (e.g., hallucinations, paranoia, and anxiety), neurologic symptoms (e.g., ataxia, nystagmus, and cognitive impairment), cardiovascular events (e.g., hypotension and chest pain), and myriad others (e.g., urinary retention, headaches, asthenia, and gastrointestinal complaints). Currently, IT ziconotide is considered a fourthline treatment for chronic pain patients.47

a2-AGONISTS a2-Adrenergic receptors play a key role in analgesic effects mediated at peripheral, spinal, and brainstem sites. The receptors are present on primary afferent terminals, in the superficial laminae of the spinal cord, and within several brainstem nuclei implicated in analgesia. Although some studies suggest that the a2A-receptor is primarily responsible for analgesia and sedation, several other subtypes of a2-receptors have been identified.74,75 The mechanism of action of neuraxial a2-agonists is similar to opioids. Presynaptically, they bind to a2-receptors on small primary afferent neurons, resulting in hyperpolarization and diminished release of neurotransmitters involved in relaying pain signals. a2-Agonists hyperpolarize the cell by increasing potassium conductance through Gi-coupled potassium channels on postsynaptic neurons.76 a-Adrenergic agonists also activate spinal cholinergic neurons, which may potentiate their analgesic effects. Clonidine has been shown to have synergistic analgesic effects when coadministered with neuraxial local anesthetics in perioperative settings. The evidence that clonidine in combination with an opioid is more effective than either agent alone in acute pain settings is weak and conflicting.77 In addition to their antinociceptive properties, a2-agonists produce dose-dependent sedation and anxiolysis. Clonidine is the most studied and only FDA-approved a2-agonist for IT use. Rainov and coworkers64 reported excellent

646 Chapter 88  SPINAL ANALGESIA or good results at 2-year follow-up visits in 73% of patients in a prospective, open-label study evaluating combination IT therapy in 26 adults with FBSS. Sixteen patients received clonidine as part of their IT therapy, half of which was in combination with morphine and bupivacaine. The mean dose was 0.06 mg/day. In a doubleblind, placebo-controlled study, Siddall and associates78 assessed the efficacy of IT morphine or clonidine, alone or combined, for up to 6 days in 15 patients with central pain secondary to spinal cord injury. The authors found that the combination of clonidine and morphine provided significantly better pain relief than saline (37% vs. 0% reduction) or either drug alone (20% reduction for morphine, 17% decrease for clonidine). No significant difference was noted in the incidence of side effects between treatment groups. There are over two dozen published cases in addition to prospective studies reporting good outcomes using clonidine in combination with opioids and other analgesics for chronic pain, whereby IT clonidine, usually in combination with morphine, provided substantial relief for cancer pain, chronic back pain, and even spasticity-related pain in concert with baclofen.79–81 In two retrospective chart reviews, the results are split. Raphael and colleagues82 reported good outcomes in 74% of patients using combination IT drug therapy in patients with chronic low back pain (clonidine was administered to 27 of 37 patients) with no significant increases in opioid requirements after 2 years of therapy (mean follow-up 4.4 yr). However, Ackerman and coworkers83 found that IT clonidine, with or without opioids, was of limited value in 15 patients with cancer and chronic nonmalignant pain. When substantial relief was obtained, it tended to be of limited duration (