Xerostomia Clinical Aspects and Treatment

Original Articles

Xerostomia: Clinical Aspects and Treatment Sandra F. Cassolato and Robert S. Turnbull Faculty of Dentistry, University of Toronto, 124 Edward Street, Toronto, Canada M5G 1G6

Abstract Xerostomia or dry mouth is a condition that is frequently encountered in dental practice. The most common cause is the use of certain systemic medications, which make the elderly at greater risk because they are usually more medicated. Other causes include high doses of radiation and certain diseases such as Sjögren’s syndrome. Xerostomia is associated with difficulties in chewing, swallowing, tasting or speaking. This results in poor diet, malnutrition and decreased social interaction. Xerostomia can cause oral discomfort, especially for denture wearers. Patients are at increased risk of developing dental caries. A thorough intraoral and extra-oral clinical examination is important for diagnosis. Treatment may include the use of salivary substitutes (Biotene), salivary stimulants such as pilocarpine, ongoing dental care, caries prevention, a review of the current prescription drug regimen and possible elimination of drugs having anticholinergic effects. Because of the ageing population, and the concomitant increase in medicated individuals, dentists can expect to be presented with xerostomia in an increasing number of patients in the coming years and therefore should be familiar with its diagnosis and treatment. Therefore, the purpose of this review is to outline for clinicians the common aetiologies, clinical identification, and routine therapeutic modalities available for individuals with xerostomia.

Keywords: xerostomia, saliva, pilocarpine, saliva substitutes, salivary stimulants

Introduction Xerostomia is a condition associated with both a decrease in the amount of saliva produced and an alteration in its chemical composition, therefore causing dry mouth. This can have a deleterious effect on many aspects of oral function and general well being. It can cause a significant decline in quality of life by decreasing taste sensation and impairing chewing ability. Furthermore, it may alter regular eating patterns, reducing the pleasure of eating due to impaired or diminished taste sensation. Patients with xerostomia often report an avoidance of some foods, such as dry foods (bread) and sticky foods (peanut butter), due to the inability to chew or swallow effectively. Also, xerostomia may impair a patient’s ability to speak, cause cracks and fissures in the oral mucosa and halitosis. It can cause denture wearing to be very

uncomfortable, exacerbating chewing difficulties. This is mainly due to a reduced surface tension between the dry mucosa and the denture. This all can lead to poor diet. Indeed, xerostomia has been shown to be a contributing factor to the high prevalence of geriatric malnutrition in the United States1. Moreover, it can pose problems for patients socially by impairing their ability or willingness to talk, Xerostomia can affect numerous aspects of oral function, contributing to pain, caries and oral infections. It also may deter a patient from air travel because of decreased humidity in airplanes2. Saliva Ninety percent of saliva is produced by the major salivary glands: the parotid, submandibular and sublingual glands. The remaining 10% is produced by minor salivary glands, which are important as

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they lie beneath all of the oral mucosa with the exception of the gingiva and the dorsum of the tongue. These minor glands can be grouped into lingual, labial, buccal, palatine and glossopalatine3. Each of the above mentioned glands produces its own secretion which varies in composition. Saliva is composed of mainly water; the other components are divided into inorganic and organic factors4. These components all act to influence bacteria in the oral environment. Saliva has two major secretions. The first is a serous fluid produced mainly by the parotid (2025% of total) and submandibular glands (70-75% of total)5. This fluid is a protein-rich secretion containing bactericidal substances such as proteolytic enzymes and antibodies. Histologically, serous cells are basophilic and contain many dense secretory granules. The second salivary secretion is mucous which is produced predominantly by the submandibular and sublingual glands. The secretions of the minor salivary glands are also purely mucous. Mucous cells, which produce secretions rich in glycoconjugates, contain water and mucin, making them significant in lubrication and preventing epithelial dehydration. Histologically, mucous cells are lightly stained, and their granules tend to fuse into a single mass. Saliva serves a number of functions. Firstly, it acts as the first defence against mechanical, chemical and infectious attacks by protecting against numerous oral bacteria and fungus. By providing local antimicrobial activity through enzymes such as immunoglobulin A, lysozyme, lactoperoxidase and histatins, saliva aids in reducing oral infections. Furthermore, it acts as a vehicle for nutrients and digestive enzymes and assists in the preparation of the food bolus. It also functions to maintain tooth integrity from dental decay by supporting ongoing remineralization of teeth. It does so by providing a reservoir of calcium and phosphate ions and forming the glycoprotein pellicle. It also physically protects teeth from harmful substances by coating them with glycoproteins and mucoids. This also assists in oral lubrication. In addition, saliva functions in maintaining a neutral oral pH through bicarbonate and phosphate buffer systems. Chewing, swallowing and speech are all facilitated by saliva5,6. Reduced saliva, either qualitatively or quantitatively, may negatively impact on oral health. Research indicates that there is a loss of salivary parenchymal acinar cells which occurs in ageing7. These effects are often unrecognised as the parotid gland is capable of maintaining function

without obvious changes in amount, composition or variability8. Saliva is thought to be secreted by a two-stage mechanism9. Acinar cells produce an osmotic gradient that is mediated by a co-transporter loop in the basolateral membrane 10. This osmotic gradient results in the production of salivary fluid. The saliva of patients with xerostomia becomes more viscous and foamy, losing its lubricating ability and adhering to teeth and mucous membranes. This thick saliva causes food and bacteria to adhere to the teeth, resulting in a buildup of plaque, which may ultimately contribute to periodontal disease. It is the decline in production of mucin that results in xerostomia. Epidemiology Xerostomia is frequently described as a symptom of middle-aged and elderly individuals; however, it may develop in any person of any age. If ignored, it can result in serious oral consequences. A study by Nederfors et al11 interviewed 3,313 randomly selected individuals aged 20 to 80 years in Sweden and found that the prevalence of perceived xerostomia was 21.3% for men and 27.3% for women. This difference in gender was found to be statistically significant. In addition, this study reported that individuals who are taking any medication report a higher prevalence of xerostomia (32.5% for males and 28.4% for females) than individuals who are not medicated (18.8% for males and 14.6% for females). Also, they found that the prevalence of xerostomia increases with age, continuation of medication, and the number of medications taken. In a study conducted in Rochester, New York, from a convenience sample of 710 American adults ranging in age from 19 to 88 years, using a standardized oral health questionnaire and oral examination, Billings et al12 observed that 24% of females and 18% of males suffered from xerostomia. They found that xerostomia was associated with the use of medications with hyposalivatory side-effects, difficulty consuming dry foods, cracked lips, dry eyes, difficulty swallowing, and in males, cigarette smoking. A Maryland study by Hochberg et al13 asked 2,520 non-institutionalized community dwelling persons aged 65-84 years if they suffer from dry mouth and 17% answered positive. They found that the prevalence of dry mouth symptoms increased with age, was more common in women than men and was greater in whites than blacks. A study in Florida by Gilbert et al14 of 600

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community-dwelling elderly people, with a mean age of 78 years, found that 39% reported having dryness of their mouth. Of these, 79% had at least one medical condition, 57% were taking at least one prescribed or over-the-counter medication and 33% were taking at least one potentially xerogenic medication. Along with xerogenic medications, age, diabetes, arthritis, perceived medical health, and dependence in physical functioning were significantly associated with the condition. Individuals with xerostomia were also more likely to have reported signs and symptoms of dental disease, sensory changes, and other oral symptoms. Ikebe et al 15 investigated the prevalence of perceived dry mouth among a group of independently living elderly people in Japan. They found that 37.8% reported oral dryness on waking, yet only 9.1% of them noticed a subjective feeling of dry mouth during eating. A total of 41% of subjects had at least one of these symptoms. An interview of 368 elderly individuals in Helsinki, Finland by Narhi16 showed that 46% had subjective symptoms of xerostomia and 12% reported continuous oral dryness. Xerostomia was found to be associated with the female gender, mouth breathing and the use of systemic medications. In a study by Locker 17, almost 20% of a population of older adults reported xerostomia and it was found to be the single most common of 22 symptoms and complaints listed. A logistic regression analysis found that income, taking prescribed medications and experiencing a stressful life change within the previous six months all had a significant effect. A study by Pajukoski et al18 of home-living elderly patients (mean age 82 years), hospitalized because of sudden worsening of their general health, revealed the prevalence of complaints of dry mouth to be 63% in hospitalized patients and 57% in out-patients. Loesche et al19 analysed the relationship between complaints of xerostomia and food avoidance in geriatric patients in a veteran affairs clinic and retirement home. Among 529 subjects older than 56 years, 72% reported that they experience xerostomia sometime during the day and 55% of these said they use one or more medications for it. The authors found that subjects with xerostomia had difficulty chewing and in starting to swallow. Sheiham et al 20 reported that patients with xerostomia were significantly more likely to avoid crunchy foods like vegetables, dry foods like bread, and sticky foods such as peanut butter. Furthermore, they found associations with

statistical significance between xerostomia and food avoidance and the following medications: the inhalants ipratropium and triamcinolone and the systemic agents oxybutynin and triazolam. Another study of 284 highly medicated (mean 3.6 drugs per individual) institutionalized elderly by Thomson et al21 asked subjects, “how often does your mouth feel dry?” Only patients taking anticholinergic medication reported a higher prevalence of xerostomia. In a Scottish study by Samaranayake et al22, the oral problems of 147 elderly patients in five longterm care hospital wards were investigated and 35% complained of dry mouth. Moore et al23 showed that subjects with Type 1 diabetes reported symptoms of dry mouth more frequently than a control group. Salivary flow rates were also impaired in Type 1 diabetics. Sreebny et al24 examined the prevalence of xerostomia in a group of 40 ambulatory diabetic patients not taking medications causing xerostomia. They found that 43% complained of dry mouth, 82% of which were women. In this population, xerostomia was not related to age or the type and duration of diabetes. These patients suffered more symptoms of water loss and oropharyngeal, ocular and vaginal dryness than an age and gender-matched healthy nondiabetic control. Also, the salivary flow rates of the diabetic subjects were consistently lower than the controls. Amongst a group of patients with rheumatoid arthritis, Russell et al25 found that 42% showed symptoms of xerostomia. The literature also suggests that xerostomia is more commonly associated with HIV+ patients26. Xerostomia is found in 30% of patients dying from cancer, increasing in severity with advanced disease27. A controlled study of healthy persons across all ages found no statistically significant difference in an individual’s ability to make parotid saliva, either stimulated or unstimulated28. Recent literature suggests that symptoms of xerostomia start when there is a decrease of 45% in normal salivary flow29. In summary, most studies show that salivary gland hypofunction is not a normal part of ageing. Cross-sectional and longitudinal studies report that parotid salivary gland function in healthy individuals is predominantly age-independent30,31. Salivary flow changes are associated with medical conditions and medications that tend to be more common in middle-aged and older individuals. Xerostomia in the geriatric population is generally due to medications, systemic diseases and head and neck radiotherapy. Not only is there a relationship between number of drugs and subjective dryness of the mouth, there is also an important relationship

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between subjective dryness and number of identified diseases in an individual. Overall, the prevalence of xerostomia increases with age and accounts for approximately 30% of the population aged 65 and older32. Aetiology The aetiology of xerostomia can be either temporary or chronic. Temporary hyposalivation affects only resting salivary secretion and patients maintain their ability to react to both gustatory and olfactory stimulation. In patients with chronic hyposalivation, both resting and stimulated secretion rates are reduced, but more importantly, dental and oral mucosal disease are more prevalent33. This contributes to a reduced response to treatment. The most pronounced salivary dysfunction occurs in patients who have received therapeutic irradiation for head and neck malignancies and those with Sjögren’s syndrome34,35. Medications The most common aetiology of xerostomia amongst patients in a dental practice is use of certain systemic medications11,36. These drugs, used individually, or in combination can affect salivary function. Complaints of dry mouth in a geriatric population are usually related to their increased use of medications causing xerostomia and not due to changes in the function of the major salivary glands 37 . Nederfors et al 11 found a strong association of xerostomia with increasing age and continuing pharmacotherapy. Furthermore, in healthy persons, salivary function is well preserved throughout life. Medication usage is the most common cause of

reduced salivary output and alteration of salivary composition36. Over 500 medications exist that may cause xerostomia 4. The most common medications are presented in Table 1. The main mechanism of these drugs is by inhibiting signalling pathways within salivary tissue and reducing fluid output of the gland. Most of these have a less pronounced effect, affecting a small proportion of patients depending on the number of prescription drugs they are taking36,38,39. A patient’s drug regimen should be regularly reviewed to identify drugs that may contribute to the patient’s xerogenic symptoms. Discussing the causal drugs with the prescriber may identify an alternative drug that may have less effect on salivary flow. Radiation Xerostomia is one of the major side effects of radical radiation therapy for head and neck malignancies. It may be related to the disease, or as a result of the irradiation volume to the salivary glands40. As radiation treatment progresses, the destruction of the parenchyma of the salivary glands and their vascular supply produces xerostomia 37 . The degree of destruction of glandular tissue depends largely on the dose of radiation administered and is most often permanent. The level of radiation necessary to destroy malignant cells ranges from 40-70 Gy. The salivary tissue is extremely sensitive to radiation and dosages greater than 30 Gy are sufficient to change salivary function permanently41. Unless the whole gland has undergone high doses of radiation, partial recovery of the gland is likely to occur, taking 6-12 months. Xerostomia may be prevented by shielding the

Table 1. Category of xerogenic medications and examples. Drug Category

Example

Anorexiant Anti-anxiety Anticholinergics Anticonvulsant Antidepressants Tricyclic Selective serotonin reuptake inhibitors Anti-emetics Antihistamines Antihypertensives Antiparkinsonian Antipsychotic Bronchodilator Decongestant Diuretic Muscle relaxant Narcotic analgesic Sedative

phentermine, phendimetrazine hydroxyzine, lorazepam, prazepam, diazepam dicyclomine, mepenzolate felbamate, gabapentin amitriptyline, imipramine, doxepin sertraline, paroxetine, fluoxetine meclizine, bucilzine fexofenadine, azelastine, loratadine clonidine, methyldopa, prazosin biperiden, selegiline clozapine, chlorpromazine ipratopium, albuterol, metaproterenol pseudoephedrine spirnolactone, chlorothiazide, furosemide cyclobenzaprine, baclofen meperidine, morphine flurazapam, triazolam, temazepam

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salivary glands during radiotherapy or modulation of the intensity of radiation when possible34. Particular chemotherapeutic agents may also alter salivary buffering capacity38. In addition, drugs used to treat cancer can cause a thickening of saliva inducing a dry feeling and contributing to impairment of salivary functions. Sjögren’s syndrome Nutritional deficiencies and various diseases are sometimes accompanied by a reduced salivary flow rate. It should be emphasized that the relationship between these two factors and dry mouth is poorly documented in the literature, except for Sjögren’s syndrome. Sjögren’s syndrome is an autoimmune disorder primarily affecting the salivary and lachrymal glands where clusters of infiltrating lymphocytes replace the parenchyma of the glands and there is a subsequent loss of secretory epithelial cells42. As a consequence, major changes occur in both the salivary flow rate and composition. Sjögren’s syndrome is reported to have a female to male ratio of 9:1. The disease typically affects middle-aged and elderly white women but may occur in persons of all ages and ethnic backgrounds. Primary Sjögren’s syndrome occurs when xerostomia and keratoconjunctivitis sicca develop as isolated clinical entities, whereas secondary Sjögren’s syndrome is when there is a complication of pre-existing connective tissue disease 42. Approximately 25% of patients with rheumatoid arthritis manifest evidence of secondary Sjögren’s syndrome. Other common causes of secondary Sjögren’s syndrome include systemic lupus erythematosus, scleroderma and other connective tissue diseases43. Sjögren’s syndrome can be detected by a reduced sublingual salivary pool, unexplained dental caries, complaints of dry mouth, keratoconjunctivitis sicca, vaginal dryness, joint pain and fatigue43,44. More diverse presentations include unexplained diarrhoea, renal tubular acidosis, severe muscle weakness and unusual haematologic changes. A dentist should refer the patient to his or her family physician for further investigation and perhaps a subsequent referral to a rheumatologist. Several tests to objectively evaluate the oral component of Sjögren’s syndrome are available. One of the most common tests is a labial salivary gland biopsy, which is typically a biopsy taken from the minor salivary glands, unless a malignancy is suspected 45. The specimen is examined histologically by a pathologist for infiltration of periductular inflammatory cells, and a depletion in the number of the secretory units,

namely acini and ducts, which are both important evidence of Sjögren’s syndrome46. Eighty percent of the inflammatory infiltrate is composed of Tlymphocytes. The remaining cells are Blymphocytes and plasma cells. Histopathologic results are graded on a scale depending on the number of inflammatory foci per 4 mm2 with a single focus being equal to a cluster of 50 or more lymphocytes. The diagnosis of Sjögren’s syndrome is made when at least one focus per 4 mm2 is found, provided other diagnostic criteria are satisfied47. Serologic studies are important to definitively diagnose suspected cases of Sjögren’s syndrome48. The presence of non-specific markers of autoimmunity such as antinuclear antibodies, rheumatoid factor, increased serum immunoglobulin and total protein levels and an increase in erythrocyte sedimentation rate are obtained. Specific autoantibodies, such as anti Ro/SSA or anti-La/SSB, are also significant49. No single serologic marker however, is characteristically found in all cases of Sjögren’s syndrome48. A number of other diagnostic tests can be used for objective evaluation of the oral component of Sjögren’s syndrome. These diagnostic tests include sialometry, contrast sialography, sequential salivary gland scintigraphy and ultrasonography42. The evidence for the involvement of specific viruses in Sjögren’s syndrome is conflicting and presently remains unknown. Some of the viruses that have been implicated in the development of Sjögren’s syndrome are cytomegalovirus, EpsteinBarr virus, hepatitis C virus, retroviruses (human T cell leukaemia/lymphoma virus-1 (HTLV) and human immunodeficiency virus type I (HIV-I), human retrovirus 5)42,50. No direct correlation however, has been established between these viruses and Sjögren’s syndrome. The occurrence of salivary gland non-Hodgkin’s lymphoma is a major complication of Sjögren’s syndrome51. Most of the lymphomas that occur in patients with Sjögren’s syndrome are low-grade marginal zone B cell lymphomas which encompass both mucosa-associated lymphoid tissue (MALT) lymphomas and their nodal counterpart which are monocytoid B cell lymphomas (MBCL)52. There is a strong epidemiological association between Sjögren’s syndrome and Hepatitis C virus (HCV) infection. Even though only 10% of HCVinfected patients will have symptomatic xerostomia, 77% of patients will have evidence of Sjögren’s syndrome after diagnostic testing53. Sarcoidosis is another chronic inflammatory disease that alters salivary gland function causing

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xerostomia. In this disease, non-caseating granulomas are formed, contributing to the destruction of the glands54. Miscellaneous A study by Moore et al23 reported that dry-mouth was associated with the use of cigarettes, dysgeusia and more frequent snacking behaviour. In this study, medications causing xerostomia and elevated fasting blood glucose concentrations were significantly associated with decreased salivary flow. Other factors that may contribute to xerostomia include poorly controlled diabetes42, chronic graft versus host disease55, thyroid disorders56, hepatitis C infection 42, Milkulicz’s disease 4, surgical removal of the salivary glands, dehydration and psychogenic conditions such as fear, anxiety, depression, mouth breathing and nasal obstruction. Also, patients that have had an injury to the head and neck can damage the nerves that innervate the salivary glands and thus produce xerostomia57. Oral candidiasis can be associated with xerostomia and antifungal drugs may be necessary. Patients that wear dentures should be advised to remove them before using topical antifungal agents. Dentures must also be disinfected by soaking them in a fungicidal substance overnight and then rinsing them before insertion. Diagnosis Assessing the entire oral cavity is critical in the diagnosis of xerostomia. This involves careful evaluation of signs and symptoms. Clinical techniques of assessment that can be used include extra-oral and intra-oral examinations, proper investigation of salivary gland function by calculating resting and stimulated flow rates, and a biopsy of salivary glands54. In addition to a clinical investigation, a detailed inquiry about medications and systemic conditions is critical. During the intra-oral examination, the practitioner should first visually examine the opening of the duct in the parotid and submandibular glands. Following this, gentle extraoral pressure should be applied to each gland to observe the viscosity of saliva. Normal parotid and submandibular glands are not palpable because they are softer than their surrounding tissues. If there is pathology and the glands are palpable, when palpating the parotid gland, the practitioner must distinguish the masseter muscle from its superficial location over the mandibular ramus. When palpating the submandibular glands, the practitioner should place an index finger in the floor of the distal aspect of the mouth and another finger should be placed on the skin extra-orally medial

to the mandibular angle36. Clinically, the dentist may have increased difficulty in stimulating saliva from the ducts of the major salivary glands as the patient’s tongue is often fissured and lobulated on its dorsal side. Upon clinical examination, depending on the cause of dry mouth, a variety of signs and complications are visible that can vary in severity. It is important to first determine a differential diagnosis and to ensure that other conditions are not present simultaneously. It is possible for example, that a patient suffering from burning mouth syndrome may have no obvious aetiology accompanying the dry mouth and hence this may mask the true diagnosis 41 . An intra-oral examination should identify the lubricity of the mucosa and the presence and location of dental decay. Measuring salivary flow under resting or stimulated secretions is a critical step in evaluating dry mouth and helping to make an accurate diagnosis. Navazesh et al 58 reported that unstimulated whole salivary flow rate below 0.12 to 0.16 ml/min shows a higher incidence of abnormalities of the soft and hard tissues. In order to ensure reproducibility, and give a quantitative assessment of salivary production, techniques used in salivary flow measurement must be standardized54. According to Daniels et al36, because measuring salivary flow rates is not a common practice in most dental surgeries due to its time consuming nature, it may be difficult to standardize. Four clinical formulae to assist in predicting the presence or absence of salivary hypofunction were identified by Navazesh et al58. They used the following four methods as their clinical measures: dryness of the buccal mucosa, absence of saliva expressible from the ducts, the total number of decayed, missing and filled teeth, and dryness of the lips. Clinical manifestations The xerogenic patient characteristically has mucosa that is dry and sticky, and saliva with a stringy or foamy consistency. The normally moist, glistening appearance of the oral cavity is often replaced with a thin, pale, cracked appearance that is more susceptible to gingivitis and bleeding. Saliva that is normally found on the floor of the mouth is usually absent54. Patients often complain of a sticky, dry sensation in the mouth. They encounter increased problems with chewing, swallowing, tasting or speaking. There is often difficulty with normal eating habits due to changes in taste and difficulty eating spicy

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or acidic food. Due to the lack of saliva, patients may develop cracked lips, a dry irritated tongue, numerous mouth sores and periodontal disease. Halitosis is a common problem and the dryness of the mouth and lips can cause discomfort ranging from mild irritation to a severe burning sensation59. Patients with significantly decreased salivary output due to prolonged xerostomia have an increased risk of developing dental caries60. This is a result of the decrease in pH of saliva and the proliferation of cariogenic bacteria, namely Streptococcus mutans and Lactobacillus species. The decay is most often recurrent or primary and located at sites generally not usually susceptible to caries such as the cervical margins, incisal margins or the tips of teeth54. Furthermore, since the normal balance of oral flora is altered and bacteria and fungus can flourish, patients are more prone to oral and oesophageal infections2. Patients with xerostomia may have oral mucosa that appears erythematous. This discolouration is most commonly on the dorsal surface of the tongue, the hard or soft palate, the commissures of the mouth and under removable prostheses5,54. It is identified clinically by erythematous and atrophied filiform papillae on the dorsal tongue, appearing smooth and cobblestone-like, or fissured. Pseudomembranous candidiasis may occasionally occur, presenting as a removable white plaque that can be found on any mucosal surface. Angular cheilitis may be another complication, usually occurring in the presence of intraoral candidiasis, presenting as cracking or fissuring of the commissures. It is frequently associated with Candida albicans, but may be caused by Staphylococcus aureus. Some patients are susceptible to mucositis and ulceration because the dry mucosa is more vulnerable to trauma61. Patients with post-irradiation xerostomia may produce little or no saliva and frequently experience oral discomfort and pain as well as the other classic symptoms of xerostomia previously discussed. Taste perception is significantly altered often resulting in nutritional problems 62 . In addition, they have an increased incidence of dental caries and oral infections. This is due to the loss of bactericidal components and of the self-cleansing actions of saliva that leads to the accumulation of dental plaque that ultimately changes the normal oral microflora. Patients with systemic diseases, such as Sjögren’s syndrome and HIV infection, may develop enlarged parotid glands and submandibular glands. In a study by Daniels et al36, between one-third and one-half of patients with

Sjögren’s syndrome develop enlargement of major salivary glands. In Sjögren’s and HIV patients, the enlarged glands are most often bilateral, firm and non-tender, usually affecting most or the entire gland. It is important however, in the presence of persistent and significantly enlarged salivary glands and neck lymph nodes, to rule out malignancies such as lymphoma32. Computerized tomography and needle aspiration to determine cytologic and flow cytometric analyses, can be beneficial in the diagnosis. Patients with xerostomia often experience sleep disturbances due to the need to wake up and quench their dry mouth. Long-time denture-wearers with xerostomia frequently experience tissue friability due to lack of lubrication and often require frequent sips of water40. In addition to these oral symptoms, patients with dry mouth develop other symptoms that include dry throat, nose, skin, scalp, dry or burning eyes, decreased ability to smell, heartburn, constipation, vaginal itching 42 and fungal infections24. Treatment Caries prevention and comprehensive dental care With the diminished salivary output xenogenic patients are more prone to caries, and therefore diligent oral hygiene and regular dental care are essential. It is also important to instruct patients on the role of dietary sugars in the development of caries and the need to avoid cariogenic snacks. Antibacterial mouthwashes such as 0.12% chlorhexidine are useful to inhibit the development of dental plaque and gingivitis since patients with xerostomia tend to have a greater susceptibility. The use of topical fluorides should be based on the severity of the patient’s condition as well as individual caries risk33. Fluoride is known as the single most important intervention of radiationinduced damage. For low risk patients, the recommended regimen is regularly applied topical fluorides plus a daily rinse with 0.05% sodium fluoride36. For more severely affected patients, high concentration fluoride solutions in a tray such as 1.23% acidulated phosphate fluoride gel for four minutes is recommended four times per year. Fluoride varnish is also beneficial and should be considered as a possibility.Denture wearing can be very uncomfortable for patients with xerostomia due to reduced oral lubrication, often making chewing difficult and painful. Relining dentures may improve the fit and significantly affect patient comfort, general appearance and self-esteem. Biotene Denture Grip is a moisturizing adhesive that may be recommended to patients.

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Saliva substitutes Moistening the oral mucosa with artificial saliva substitutes has been shown to give relief63. Since saliva is a complex secretion with a variety of functions, it is difficult to mimic through artificial methods. One of the most frequently used saliva substitutes is water. Patients should understand that dry mouth is rarely associated with systemic dehydration and that consuming large quantities of water does not overcome xerostomia; however, frequent intake of water will assist in reducing symptoms. Milk also contains many chemical and physical properties suitable as a saliva substitute. It acts by moisturizing and lubricating dehydrated tissues, buffering oral acids, decreasing the risk of enamel demineralisation, and it also contributes to remineralization due to its calcium and phosphate content64. The most commonly prescribed saliva substitutes are the artificial salivas. Unfortunately they are usually not effective for more than a few hours. These products are commonly used by patients at their bedside, when they awake during the night, or when talking. They can be categorized based on their contents: glycerine and lemon or carboxymethylcellulose and mucin. They include remineralising contents such as calcium, phosphate, fluoride and sugar alcohols (e.g. sorbitol), which have a low cariogenic potential65. They are important lubrication for the mucosa and throat and help to clean teeth from bacteria and debris. The lemon-based saliva substitutes however, if used frequently, are potentially erosive to enamel63. Saliva substitutes provide a critical means of maintaining some physiological function in patients with impaired salivary flow and can help to reduce the incidence of dental decay and dental erosion63. However, they need to be used frequently and over a long period of time. Saliva substitutes are available as lozenges, rinses, sprays, swab sticks and as reservoirs in dentures66. It is important to select a product with low erosive potential to prevent the demineralisation of enamel and subsequent dental decay. The entire oral mucosa should be covered and a small pool left under the patient’s tongue. Patients should be advised not to rinse their mouth following administration. Salivary substitutes may provide an allergic potential in patients who are sensitive to some of the preservatives present in the artificial saliva products41. Biotene and Oralbalance Biotene® is available as a sugar-free chewing gum, an alcohol-free mouthwash and a toothpaste, while

Oralbalance® is available as a moisturizing gel. Biotene and Oralbalance (Laclede Professional Products, Rancho Dominguez, CA US) contain three primary enzymes: lactoperoxidase, lysozyme, glucose oxidase and one protein that is naturally found in human saliva called lactoferrin. This enzyme system acts to penetrate the cell wall of plaque-forming bacteria, helping to maintain a healthy balance of oral flora40. The goal of the various enzymes is to replace the missing salivary enzyme activity absent or decreased in patients with xerostomia, reducing harmful organisms, while not harming beneficial ones 67 Candida species are sensitive to this enzyme system68. Lactoferrin acts to deprive bacteria of iron. Biotene is naturally sweetened with xylitol. Oral Balance helps moisturize the oral mucosa, soothing and relieving oral dryness. Multiple co-factors such as hydrogen peroxide and halides, enable the efficiency of the anti-microbial activity. As outlined on the product package, Biotene mouthwash is indicated for individuals experiencing dry mouth or having oral irritations. Directions for use of Biotene mouthwash are to use approximately one tablespoon whenever desired. Patients are to swish thoroughly for 30 seconds and expectorate. For the best results, it is recommended to use Biotene mouthwash in conjunction with Biotene toothpaste, especially at bedtime. Biotene toothpaste is a non-foaming, mild toothpaste claiming not to irritate sore tissues. It is recommended in place of regular toothpastes, after each meal or as directed by a dentist or physician. Patients with normal salivary gland function do not benefit from Biotene toothpaste, however, studies have shown that in xerostomic patients, a lactoperoxidase-system containing toothpaste such as Biotene can improve gingival health compared to a control toothpaste 69 . In patients with xerostomia, by combining the use of Biotene toothpaste with a lactoperoxidase-containing gel, such as Oralbalance, research shows that gingival inflammation is significantly improved70. Oralbalance should be applied onto the tongue or directly to the affected areas and spread thoroughly. The manufacturer claims that this product quickly relieves dry mouth, protects against irritations and burning sensations for several hours and promotes healing of inflammation. It is also recommended for use under dentures. There have been two clinical studies published in the literature that examine the efficacy of Biotene. A 1999 study by Epstein68 compared the

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use of Oralbalance gel and Biotene toothpaste against a control of carboxymethylcellulose gel and a commercial toothpaste. This study examined 19 patients receiving head and neck radiation treatment for advanced cancer. Patients using Oralbalance and Biotene reported these two products to be more effective than the controls (p=0.04). These patients also reported less dry mouth upon waking (p=0.05). A study by Warde40 involved 28 patients with post-irradiation xerostomia due to treatment for head and neck cancer. These patients were given a two-month supply of Biotene toothpaste, mouthwash, chewing gum and Oralbalance gel. They were given full instructions on how to use these products. They were told to brush with Biotene toothpaste in the morning, after eating, and at bedtime. The Biotene chewing gum, mouthwash and Oralbalance gel were to be used as desired to relieve symptoms of xerostomia. After two months of treatment, 54% of patients reported an improvement in intraoral dryness, 36% of which experienced a major improvement. Also, 46% said there was an improvement in their ability to eat normally and 61% said there was an improvement in oral discomfort; however, only 10 patients said they would continue using the products. Furthermore, this study did not evaluate the placebo effect, but did state that further research is needed to examine placebo influences. From these preliminary studies, it appears that Biotene helps patients with xerostomia, however, as Warde et al40 state, “a randomized phase III study is needed”. They also say that although pilocarpine, Biotene and Oralbalance work by different mechanisms, using them in combination may be more effective. Salivary stimulants The secretion of saliva is largely controlled by the parasympathetic nervous system. Therefore, salivary flow can be stimulated by a variety of factors such as stimulating the receptors within the salivary glands in the oral cavity (afferent pathways) or, alternatively, to act directly on parasympathetic nerves (efferent pathways). One of the most productive ways to combat xerostomia is to stimulate oral receptors by physiological or pharmacological means and hence stimulate salivary function. Atkinson et al5 reported that reduced mastication would exacerbate atrophy of the salivary glands. For this reason, research indicates the importance of physiologically stimulating these glands by masticatory or gustatory stimuli such as chewing xylitol gum71 or sucking sugar-free hard candies36. Consumption of

foods that require active chewing will assist in stimulating salivation and will decrease the incidence of taste abnormalities. Also, patients should be informed that dry and spicy foods should be avoided as they tend to irritate mucosal tissues33,59,71. Additionally, organic acids such as ascorbic acid, malic acid and citric acid increase salivation. However, due to their acidity, these substances also have a tendency to demineralise and erode enamel resulting in dental caries, thus, they are not recommended for long-term relief of xerostomia. Some of the marketed salivary stimulants such as Salix® saliva stimulating lozenge, contain sorbitol (Scandinavian Formulas, Perkasie, PA US). The manufacturer claims that Salix® increases salivation of a reduced salivary gland function through physiological stimulation of the taste buds. There are side effects of salivary stimulants containing sorbitol. Sorbitol is an osmotic laxative agent which can induce gastrointestinal symptoms such as diarrhoea, due to its osmotic potential72. Numerous studies have shown that gum chewing stimulates salivary flow in patients with xerostomia73. This is mainly because the act of chewing is, in itself, associated with enhanced salivation through effects on oral baroreceptors. In addition, stimulation of taste receptors may also contribute to the enhanced salivary response. Pilocarpine HCl (Salagen, Pharmacia Canada Inc.) In patients suffering from severe xerostomia, systemic cholinergic stimulants such as pilocarpine may be prescribed if no contraindications exist. The salivary-stimulative effects of orally ingested pilocarpine hydrochloride have been reported since the late 1960s74. The mechanisms responsible for the effects of pilocarpine on salivary flow stimulation are both local and direct cellular stimulation. The parasympathetic action of pilocarpine induces water and electrolyte flow in saliva. Research also has shown that pilocarpine stimulates the production of mucin and of several other salivary constituents75. The usual dosage in adults is one or two 5.0 mg tablets three or four times daily33, not to exceed 30 mg per day41. Patients should be treated for a minimum of 90 days for optimum results. The lowest dose that is tolerated and effective should be used for maintenance. Several weeks must elapse before the symptomatic improvement becomes apparent because the reversal of the atrophic and desiccated changes induced by salivary deprivation does not occur immediately after using pilocarpine. The time required to

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increase salivation once pilocarpine has been taken orally is 15 minutes, peaking at 60 minutes and has a duration of two or three hours76. The most frequent side effect of patients taking 5.0 mg three times a day of pilocarpine is perspiration. Additional dose-dependent adverse effects experienced by patients include nausea, rhinitis, chills, frequent urination, dizziness, headache, facial blushing, increased lacrimation, and pharyngitis41,62. Pilocarpine is considered to be a cholinergic parasympathomimetic drug that exhibits potent muscarinic-stimulating properties77. Because pilocarpine is a parasympathomimetic drug, there is some risk of cardiovascular and pulmonary side-effects and thus, it is only available by prescription36. In 1966, Dawes74 showed that pilocarpine stimulation fails to reproduce the normal combined sympathetic and parasympathetic balance, thus leading to changes in salivary composition. Pilocarpine is only approved for use as a sialogogue in patients undergoing radiation therapy 78 , in patients who have Sjögren’s syndrome79 and for drug-induced xerostomia80. In such patients, products such as oral rinses, saliva substitutes, salivary stimulants and sipping water frequently usually are not adequate62. Pilocarpine tablets should be administered with caution and under close medical supervision to patients with significant cardiovascular disease (hypotension, hypertension, bradycardia, and tachycardia) and pulmonary disease (e.g. controlled asthma, chronic bronchitis, or chronic obstructive pulmonary disease). Contraindications for pilocarpine include patients with narrow-angle glaucoma, patients with uncontrolled asthma41, and patients with gastric ulcers77. Evidence regarding its efficacy following radiation is not definite; various reports indicate that approximately 50% of patients may benefit from its use81. In 1993, Johnson et al78 examined 207 patients undergoing head and neck radiation therapy and taking pilocarpine for symptoms of xerostomia. Their research showed that 44% of patients reported improved salivation while on a dose of 5.0 mg three times a day. They concluded that pilocarpine could improve many symptoms associated with post-irradiation xerostomia such as oral dryness, discomfort and speaking difficulty. The success rate of pilocarpine is often variable and hence patients may also require additional care such as fluoride supplements and salivary substitutes to prevent radiation-induced caries. When a dentist is considering using pilocarpine, it is suggested to also consult with the patient’s

physician41. Close monitoring of the patient is recommended because of the possible significant cholinergic side effects. The interaction of pilocarpine with other medications such as betaadrenergic antagonists, and drugs with parasympathomimetic effects, may preclude its use in many patients with medication induced salivary dysfunction. There have been no formal drug interaction studies performed for pilocarpine. It is advised that when a patient is on sialogogue medication, they ingest approximately 1,900 ml of water daily82. Other systemic sialogogues are also available such as anetholtrithion (Sialor®, Paladin Labs Inc) and cevimeline hydrochloride (Evoxac, Daiichi Pharmaceutical Corporation). Fife et al83 studied the efficacy of cevimeline HCl in treating xerostomia in 75 patients with Sjögren’s syndrome in a double-blind, randomized, placebo-controlled trial. Their study reported that treatment with cevimeline HCl, 30 mg three times daily, was well tolerated and provided significant relief of xerostomia for up to six weeks. They found that although 60 mg three times daily provided similar symptomatic improvement, there was an increase in the occurrence of adverse effects, especially gastrointestinal tract disorders. Further work to determine the long-term efficacy and safety of cevimeline HCl was suggested. Other treatments In the absence of a known cause of Sjögren’s syndrome, a suggested preventive treatment of lymphoproliferations is to decrease the hyperactivation of autoreactive B cells when present. Immunosuppressive drugs such as methotrexate or tumour necrosis factor alpha antagonists have been investigated52. Research indicates that highly active antiretroviral therapy (HAART) has been associated with a reduction in morbidity and mortality in HIV-infected patients 84 . The frequencies of HIV-associated periodontal disease, Kaposi’s sarcoma, and other oral lesions, such as xerostomia were found to be reduced following HAART85. A Phase II double-blind study comparing four doses of oral interferon alpha (IFN) revealed that 150 units of IFN lozenges three times a day for twelve weeks in subjects with primary Sjögren’s syndrome resulted in salivary flow improvement and reduced symptoms of xerostomia86. Conclusions Xerostomia is a condition that can be very debilitating for patients. With the ageing population it is likely to be increasingly encountered in a dental

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office and dental practitioners should be cognizant of its diagnosis and treatment.

References 1. Rhodus N L, Brown J. The association of xerostomia and inadequate intake in older adults. J Am Diet Assoc 1990; 90: 1688-1692. 2. Iwamoto R R. A nursing perspective on radiation-induced xerostomia. Oncology 1996; 10 (suppl): 12-15. 3. Provenza D V, Oral Histology. Philadelphia: Lippincott , 1964. 4. Carranza F A, Newman M G, Takei T T. Carranza’s Clinical Periodontology. Philadelphia: W.B. Saunders Company, 2002. 5. Atkinson J L, Wu A J. Salivary gland dysfunction: causes, symptoms and treatment. J Am Dent Assoc 1994; 125: 409-416. 6. Locker D. Xerostomia in older adults: a longitudinal study. Gerodontology 1995; 12: 18-25. 7. Drummond J R, Newton J P, Abel R W. Tomographic measurements of age changes in the human parotid gland. Gerodontology 1995; 12: 2630. 8. Wu A J, Atkinson J C, Fox P C, et al. Crosssectional and longitudinal analyses of stimulated parotid salivary constituents in healthy different aged subjects. J Gerontol Med Sci 1993; 48: M219-224. 9. Thaysen J H, Thorn N A, Schwartz I L. Excretion of sodium, potassium, chloride and carbon dioxide in human parotid saliva. Am J Physiol 1954; 178: 155-159. 10. Turner R J. Mechanisms of fluid secretion by salivary glands. Ann NY Acad Sci 1993; 694: 24-35. 11. Nederfors T, Isaksson R, Morestad H, et al. Prevalence of perceived symptoms of dry mouth in an adult Swedish population: relation to age, sex and pharmacotherapy. Community Dent Oral Epidemiol 1997; 25: 211-216. 12. Billings R J, Proskin H M, Moss M E. Xerostomia and associated factors in a communitydwelling adult population. Community Dent Oral Epidemiol 1996; 24: 312-316. 13. Hochberg M C, Tielsch J, Munoz B, et al. Prevalence of symptoms of dry mouth and their relationship to saliva production in community dwelling elderly: the SEE project. Salisbury Eye Evaluation. J Rheumatol 1998; 25: 486-491.

14. Gilbert G H. Heft M W, Duncan R P. Mouth dryness as reported by older Floridians. Community Dent Oral Epidemiol 1993; 21: 390-397. 15. Ikebe K, Nokubi T, Sajima H, et al. Perception of dry mouth in a sample of community-dwelling older adults in Japan. Spec Care Dent 2001; 21: 5259. 16. Narhi T O. Prevalence of subjective feelings of dry mouth in the elderly. J Dent Res 1994; 73: 2025. 17. Locker D. Subjective reports of oral dryness in an older adult population. Community Dent Oral Epidemiol 1993; 21: 165-168. 18. Pajukoski H, Meurman J H, Halonen P, et al. Prevalence of subjective dry mouth and burning mouth in hospitalized elderly patients and outpatients in relation to saliva, medication, and systemic diseases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001; 92: 641-649. 19. Loesche W J, Bromberg J, Terpenning M S, et al. Xerostomia, xerogenic medications and food avoidances in selected geriatric groups. J Am Geriatr Soc 1995; 43: 401-407. 20. Sheiham A, Steele J G, Marcenes W, et al. The impact of oral health on stated ability to eat certain foods; findings from the National Diet and Nutrition Survey of Older People in Great Britain. Gerodontology 1999; 16: 11-20. 21. Thomson W M, Brown R H, Williams S M. Medication and perception of dry mouth in a population of institutionalized elderly people. NZ Med J 1993; 106: 219-21. 22. Samaranayake L P, Wilkieson C A, Lamey P J, et al. Oral disease in the elderly in long-term hospital care. Oral Dis 1995; 1: 147-151. 23. Moore P A, Guggenheimer J, Etzel K R, et al. Type 1 diabetes mellitus, xerostomia, and salivary flow rates. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001; 92: 281-291. 24. Sreebny L M, Yu A, Green A, et al. Xerostomia in diabetes mellitus. Diabetes Care 1992; 15: 900904. 25. Russell S, Reisine S. Investigation of xerostomia in patients with rheumatoid arthritis. J Am Dent Assoc 1998; 129: 733-739. 26. Schiodt M. Less common oral lesions associated with HIV infection: prevalence and classification. Oral Dis 1997; 3(Suppl 1): 208-13. 27. Addington-Hall J, McCarthy M. Dying from cancer: results of a national population-based investigation. Palliat Med 1995; 9: 295-305.

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28. Heft M W, Baum B J. Unstimulated and stimulated parotid salivary flow rate in individuals of different ages. J Dent Res 1984; 63: 1182-1185. 29. Ghezzi E M, Lange L A, Ship J A. Determination of variation of stimulated salivary flow rates. J Dent Res 2000; 79: 1874-1878. 30. Baum B J. Evaluation of stimulated parotid saliva flow rate in different age groups. J Dent Res 1981; 60: 1292-1296. 31. Ship J A, Nolan N, Puckett S. Longitudinal analysis of parotid and submandibular salivary flow rates in healthy, different aged adults. J Gerontol Med Sci 1995; 50A: M285-289.

44. Fox R I, Konttinen Y, Fisher A. Short analytical review – use of muscarinic agonists in the treatment of Sjögren’s syndrome. Clin Immunol 2001; 101: 249-263. 45. Fox R I, Stern M, Michelson P. Update in Sjögren’s syndrome. Curr Opin Rheumatol 2000; 12: 391-398. 46. Edgar W M, O’Mullane D M. Saliva and dental health. London: British Dental Association, 1990. 47. Vivino F B, Katz W A. Sjögren’s syndrome: clinical picture and diagnostic tests. J Musculoskel Med 1995; 12: 40-52.

32. Ship J A, Pillemer S R, Baum B J. Xerostomia and the geriatric patient. J Am Geriatr Soc 2003; 50: 535-543.

48. Fox P C, Brennan, Pillemer S, et al. Sjögren’s syndrome: a model for dental care in the 21st century. J Am Dent Assoc 1998; 129: 719-728.

33. Fox P C. Management of dry mouth. Dent Clin North Am 1997; 41: 863-875.

49. Ben-Chetrit E, Fox R I, Tan E M. Dissociation of immune responses to the SS-A (Ro) 52-kd and 60kd polypeptides in systemic lupus erythematosus and Sjögren’s syndrome. Arthritis Rheumatol 1990; 33: 349-355.

34. Atkinson J C, Baum B J. Salivary Enhancement: Current Status and Future Therapies. J Dent Educ 2001; 65: 1096-1101. 35. Longman L P, Higham S M, Rai K, et al. Salivary gland hypofunction in elderly patients attending a xerostomia clinic. Gerodontology 1995; 12: 67-72. 36. Daniels T E, Wu A J. Xerostomia - clinical evaluation and treatment in general practice. J Can Dent Assoc 2000; 28: 933-941. 37. Baum BJ . Salivary gland fluid secretion during ageing. J Am Geriatr Soc 1989; 37: 453.

50. Venables P J, Rigby SP . Viruses in the etiopathogenesis of Sjögren’s syndrome. J Rheumatol 1997; 24(suppl. 50): 3-5. 51. Royer B, Cazals-Hatem D, Sibilia J, et al. Lymphomas in patients with Sjögren’s syndrome and marginal zone B-cell neoplasms, arise in diverse extranodal and nodal sites, and are not associated with viruses. Blood 1997; 90: 766-775.

38. McDonald E, Marion C. Dry mouth: Diagnosing and treating its multiple causes. Geriatrics 1992; 46: 61-63.

52. Mariette X. Lymphomas complicating Sjögren’s syndrome and hepatitis C virus infection may share a common pathogenesis: chronic stimulation of rheumatoid factor B cells. Ann Rheum Dis, 2001; 60: 1007-1010.

39. Sreebny L M, Schwartz S S. A reference guide to drugs and dry mouth - 2nd edition. Gerodontology 1997; 14: 33-47.

53. Mayo M , Kaplan N M. Extrahepatic manifestations of hepatitis C infection. Am J Med Sci 2003; 325: 135-148.

40. Warde P, Kroll B, O’Sullivan B, et al. A phase II study of Biotene in the treatment of postradiation xerostomia in patients with head and neck cancer. Support Care Cancer 2000; 8: 203-208.

54. Greenspan B. Xerostomia: Diagnosis and Management. Oncology 1996; 10 (Suppl): 7-11.

41. Wynn R L, Meiller T F. Artificial saliva products and drugs to treat xerostomia. Gen Dent 2000; 48: 630-636. 42. Al-Hashimi I. The management of Sjögren’s syndrome in dental practice. J Am Dent Assoc 2001; 132: 1409-1417. 43. Rostron J, Rogers S, Longman L, et al. Health-related quality of life in patients with primary Sjögren’s syndrome and xerostomia: a comparative study. Gerodontology 2002; 19: 53-59.

55. Nagler R, Marmary Y, Krausz Y, et al. Major salivary gland dysfunction in human acute and chronic graft-versus-host disease (GVHD). Bone Marrow Transplant 1996; 17: 219-224. 56. Tenovuo, J O. Human Saliva: Clinical Chemistry and Microbiology vol 1. Florida: CRC Press Inc., 1989. 57. Navazesh M, Brightman V J, Pogoda J M. Relationship of medical status, medications, and salivary flow rates in adults of different ages. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996; 81: 172-176.

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58. Navazesh M, Christensen C, Brightman V. Clinical criteria for the diagnosis of salivary gland hypofunction. J Dent Res 1992; 71: 1363-1369. 59. Garg A K, Malo M. Manifestations and treatment of xerostomia and associated oral effects secondary to head and neck radiation therapy. J Am Dent Assoc 1997; 128: 1128-1133. 60. Mersel A. Oral health status and dental needs in a geriatric institutionalized population in Paris. Gerodontology 1989; 8: 47-51.

73. Davies A N. A comparison of artificial saliva and chewing gum in the management of xerostomia in patients with advanced cancer. Palliat Med 2000; 14: 197-203. 74. Dawes C. The composition of human saliva secreted in response to a gustatory stimulus and to pilocarpine. J Physiol 1966; 183: 360-368.

61. Atkinson J C, Fox P C. Salivary gland dysfunction. Clin Geriatr Med 1992; 8: 499-511.

75. Zimmerman R P, Mark R J, Tran L M, et al. Concomitant pilocarpine during head and neck irradiation is associated with decreased post-treatment xerostomia. Int J Radiat Oncol Biol Phys 1997; 37: 571-575.

62. Jacobs C, Van der Pas M. A multicenter maintenance study of oral pilocarpine tablets for radiation-induced xerostomia. Oncology 1996; 10 (Suppl): 16-20.

76. Fox P C, Atkinson J C, Macynski A A, et al. Pilocarpine treatment of salivary gland hypofunction and dry mouth (xerostomia). Arch Intern Med 1991; 151: 1479-1152.

63. Smith G, Smith A J, Shaw L, et al. Artificial saliva substitutes and mineral dissolution. J Oral Rehabil 2001; 28: 728-731.

77. Bernardi R, Perin C, Becker F L, et al. Effect of pilocarpine mouthwash on salivary flow. Braz J Med Biol Res 2002; 35: 105-110.

64. Herod G I. The use of milk as a saliva substitute. J Public Health Dent 1994; 54: 184-189. 65. Kielbassa A M, Parichereh Shohadai A, Schulte-Monting J. Effect of saliva substitutes on mineral content of demineralized and sound dental enamel. Support Care Cancer 2000; 9: 40-47.

78. Johnson J T, Ferretti G A, Nethery W J, et al. Oral pilocarpine for post-irradiation xerostomia in patients with head and neck cancer. New Eng J Med 1993; 329: 390-395.

66. Sinclair C F, Frost P M, Walter J D. New design for an artificial saliva reservoir for the mandibular complete denture. J Pros Dent 1996; 75: 276-280.

79. Vivino F B, Al-Hashimi I, Khan Z. Pilocarpine tablets for the treatment of dry mouth and dry eye symptoms in patients with Sjögren’s syndrome: a randomized, placebo-controlled, fixed dose, multicenter trial. Arch Intern Med 1999; 159: 174181.

67. Epstein J B, Scully C. The role of saliva in oral health and causes and effects of xerostomia. J Can Dent Assoc 1992; 58: 217-221.

80. Compendium of Pharmaceuticals and Specialities (CPS). 36th ed. Toronto (ON): Webcom Limited; 2001. P1203.

68. Epstein J B, Emerton S, Stevenson-Moore P. A double-blind crossover trial of Oral Balance gel and Biotene toothpaste versus placebo in patients with xerostomia following radiation therapy. Oral Oncol 1999; 35: 132-137. 69. Van Steenberghe D, Van den Eynde E, Jacobs R, et al. Effect of a lactoperoxidase containing toothpaste in radiation-induced xerostomia. Int Dent J 1994; 44: 133-138. 70. Banoczy J B, Dombi C, Czegledly A, et al. A clinical study with lactoperoxidase-containing gel and toothpaste in patients with dry mouth syndrome. J Clin Dent 1994; 5: 65-69. 71. Odusola F. Chewing gum as an aid in treatment of hyposalivation. NY State Dent J 1991; 57: 28-31. 72. Ratnaike R N. Mechanisms of drug-induced diarrhoea in the elderly. Drugs & Ageing 1998; 13: 245-253.

81. Rieke J W, Hafermann M D, Johnson J J, et al. Oral pilocarpine for radiation-induced xerostomia: integrated efficacy and safety results from two prospective randomized clinical trials. Int J Radiat Oncol Biol Phys 1995; 31: 661-669. 82. Zunt S L. Lecture entitled: Diagnosis and management of dry mouth/xerostomia/salivary gland hypofunction. Presented at Faculty of Dentistry, University of Toronto, Nov. 2002. 83. Fife R S, Chase W F, Dore R K, et al. Cevimeline for the treatment of xerostomia in patients with Sjögren syndrome: a randomized trial. Arch Intern Med 2002; 162: 1293-1300. 84. Brodt H R, Kamps B S, Gute P, et al. Changing incidence of AIDS-defining illnesses in the era of antiretroviral combination therapy. AIDS 1997; 11: 1731-1738.

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85. Ramirez-Amador V, Esquivel-Pedraza L, Sierra-Madero J, et al. The changing clinical spectrum of human immunodeficiency virus (HIV)related oral lesions in 1, 000 consecutive patients: a 12-year study in a referral center in Mexico. Medicine 2003; 82: 39-50. 86. Ship J A, Fox P C, Michalek J E, et al. Treatment of primary Sjögren’s syndrome with lowdose natural human interferon-alpha administered by the oral mucosal route: a phase II clinical trial. IFN Protocol Study Group. J Interferon Cytokine Res 1999; 19: 943-951.

Address of correspondence: Professor Robert S. Turnbull Discipline of Periodontics Faculty of Dentistry, University of Toronto 124 Edward Street Toronto, Ontario Canada M5G 1G6 Tel: 416-979-4928 Fax: 416-979-4936 e-mail: [email protected]

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