OPIOID

Dr Pramod K Sharma

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Morphine, the prototype agonist is a natural alkaloid derived from P. somniferum Semisynthetic and synthetic agents are also available These drugs are used where strong analgesic action is required The term opioid refers broadly to all compounds related to opium Opiates are drugs derived from opium

Classification 

Strong agonists: morphine, heroin, pethidine (meperidine), methadone, fentanyl, sufentanil, remifentanil, alfentanil, oxymorphone, hydromorphone, levorphanol

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Moderate/low agonists: codeine, oxycodone, hydrocodone, propoxyphene, diphenoxylate, difenoxin, loperamide

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Mixed agonists agonists--antagonists: nalbuphine, buprenorphine, butorphanol, pentazocine

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Others: tramadol, tapentadol

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Antitussives: noscapine, dextromethorphan, codeine, levopropoxyphene

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Antagonists: naloxone, naltrexone, nalmefene, alvimopan, methylnaltrexone bromide

Endogenous opioid peptides Peptides with opioid like pharmacological properties  Three families have been described - endorphins - enkephalins (leu and metmet-enkephalin) - dynorphins  Endogenous peptides endomorphin endomorphin--1 & 2 also share properties of opioid peptides e.g. analgesia and high affinity to μ receptors 

Present at CNS sites involved in pain modulation  Released during pain or anticipation of pain 

Mechanism of action of opioids Act through activating opioid receptors  Opioid receptors are involved in transmission and modulation of pain  Some effects are mediated partly through action on peripheral receptors 

Opioid receptors Three major classes (μ (μ, δ, & κ)  Various subtypes also exist  All are G G--protein coupled receptors  Receptors are located in brain, spinal cord (dorsal horn) and peripheral tissues (primary afferents relaying pain sensation) 

Opioid Receptor Subtypes, their functions, and their endogenous peptide affinities

Receptor Subtype

Functions

Endogenous Opioid Peptide Affinity

(mu)

Supraspinal and spinal analgesia; sedation; inhibition of respiration; slowed gastrointestinal transit; modulation of hormone and neurotransmitter release

Endorphins > enkephalins > dynorphins

(delta)

Supraspinal and spinal analgesia; modulation Enkephalins > of hormone and neurotransmitter release endorphins and dynorphins

(kappa)

Supraspinal and spinal analgesia; psychotomimetic effects; slowed gastrointestinal transit

Dynorphins > > endorphins and enkephalins

Cellular action of opioid : Inhibition of cyclic adenosine monophosphate (cAMP) formation leads to opening of potassium channels and closing of calcium channels. Potassium efflux causes membrane hyperpolarization. The closing of calcium channels inhibits the release of neurotransmitters from nociceptive nerve terminals (glutamate, substance P, Ach, NE, serotonin etc.)

Opioids cause analgesia partly by activating inhibitory descending pathways, partly by inhibiting transmission in the dorsal horn, and partly by inhibiting excitation of sensory nerve terminals in the periphery  Repetitive CC-fibre activity facilitates transmission through the dorsal horn ('wind('wind-up') by mechanisms involving activation of NMDA and substance P receptors 

Summary of modulatory mechanisms in the nociceptive pathway. 5-HT, 5hydroxytryptamine; BK, bradykinin; CGRP, calcitonin gene-related peptide; NA, noradrenaline; NGF, nerve growth factor; NO, nitric oxide; NSAID, non-steroidal antiinflammatory drug; PG, prostaglandin; SP, substance P.

Supraspinal control system: Opioids excite neurons in the periaqueductal grey matter (PAG) and in the nucleus reticularis paragigantocellularis (NRPG), which in turn project to nucleus raphe magnus (NRM). From the NRM, 5-hydroxytryptamine (5-HT)- and enkephalin-containing neurons run to the substantia gelatinosa of the dorsal horn, and exert an inhibitory influence on transmission. Opioids also act directly on the dorsal horn, as well as on the peripheral terminals of nociceptive afferent neurons. The locus coeruleus (LC) sends noradrenergic neurons to the dorsal horn, which also inhibit transmission.

Schematic diagram of the gate control system. This system regulates the passage of impulses from the peripheral afferent fibres to the thalamus via transmission neurons originating in the dorsal horn. Neurons in the substantia gelatinosa (SG) of the dorsal horn act to inhibit the transmission pathway. Inhibitory interneurons are activated by descending inhibitory neurons or by non-nociceptive afferent input. They are inhibited by nociceptive C-fibre input, so the persistent C-fibre activity facilitates excitation of the transmission cells by either nociceptive or non-nociceptive inputs. This autofacilitation causes successive bursts of activity in the nociceptive afferents to become increasingly effective in activating transmission neurons.

Pharmacological effects: Morphine 

Analgesia: strong analgesic (spinal & supraspinal action); analgesia increases with dose; reduce both aspect of pain experience (sensory & affective); selectively suppress pain without affecting other sensations or producing proportionate generalized CNS depression; intrathecal injection cause regional analgesia

Analgesia is primarily through action on μ receptor; morphine does act at δ and κ receptor sites but to what extent this contributes to analgesic action is unclear Morphine action at μ receptor may evoke release of endogenous opioids that additionally act at δ and κ receptors

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Euphoria: IV morphine in patients & drug users produce pleasant floating sensation (↓anxiety and stress); Dysphoria (restlessness and malaise) may also occur; Euphoric effects are due to DA release in nucleus accumbance

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Sedation: drowsiness, clouding of mentation but little or no amnesia; induces sleep more frequently in elderly (easily arousable); disrupts both REM and NREM sleep combination with other CNS depressants may induce very deep sleep

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Respiratory depression: by inhibiting brainstem respiratory mechanism; rate and TV both reduced (↑ (↑ in alveolar Pco2); depression is dose related and is influenced by degree of sensory input occurring at that time Problematic in ↑ICT, asthma, COPD etc.

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Tolerance & physical dependence: mechanism is unclear, may be due to, - upregulation of cAMP system - receptor recycling - receptor uncoupling (dysfunction of structural interaction b/w μ receptors, G proteins, 2nd messenger and their target ion channels) - role of NMDA receptor ion channel complex

Cough suppression: cough reflex is depressed, more sensitive to depressant action of morphine than respiratory depression  Miosis: due to III cranial nerve stimulation; central action; valuable in diagnosis of overdose 

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Truncal rigidity: increase in tone of large truncal muscles usually apparent with high doses of highly lipid soluble agents (fentanyl, alfentanil etc.) if administered IV rapidly; It is due to supraspinal effect; May reduce thoracic compliance; may necessitate use of NMBs

Nausea & vomiting: through activation of CTZ (also vestibular component involved)  Temperature: Opioids alter the equilibrium point of the hypothalamic heat--regulatory mechanisms such that heat body temperature usually falls slightly; However, chronic high dosage may increase body temperature 

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CVS: bradycardia (pethidine cause tachycardia on i.v. inj); may cause hypotension (due to vasodilatation secondary to histamine release, VMC depression) if CVS is stressed Cerebral vasodilatation if Pco2 is increased → ↑ ICT There is a shift of blood from pulmonary to systemic circuit due to greater vasodilatation in the latter

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GIT: cause constipation through action in CNS and on ENS (increased tone and decreased propulsive movements), ↓ secretion, increased water absorption: no tolerance

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Biliary tract: contract biliary smooth muscles (colic), constrict sphincter of Oddi (elevated plasma amylase and lipase)

Uterus: slightly prolong labor due to reduce uterine tone (central & peripheral action)  Bronchi: constriction due to histamine release – dangerous in asthmatics  Neuroendocrine: stimulate release of ADH, GH, prolactin but inhibit release of LH 

Renal effects: function are depressed due to decrease renal plasma flow; ↑es ureteral and bladder tone; tone; ↑ tone of sphincter - Urinary retention  Pruritus: at therapeutic dose produce flushing, warming and itching of the skin (CNS effect plus histamine release) – More common with parenteral administration; spinal/epidural injection cause intense pruritus of lips and torso 

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Immune system: modulate immune response through action on lymphocytes proliferation, Antibody production and chemotaxis

Pharmacokinetics: opioids Oral dose of the opioid (eg, morphine) much higher than the parenteral dose (because of the first-pass effect)  Considerable interpatient variability exists: prediction of an effective oral dose difficult  Codeine and oxycodone are effective orally  All opioids bind to plasma proteins with varying affinity 

Distribute and localize in highest concentrations in tissues that are highly perfused (brain, lungs, liver, kidneys, and spleen)  Skeletal muscles serves as the reservoir  May accumulate in fatty tissue after frequent high-dose or continuous infusion of highly lipophilic opioids eg, fentanyl 

The opioids are converted in large part to polar metabolites (mostly glucuronides)  Morphine, is conjugated to M3G (neuroexcitatory) & M6G (only 10%)  Accumulation of these metabolites may occur in patients with renal failure  Hydromorphone 3 Glucuronide (H3G), also has CNS excitatory properties 

Esters (eg, heroin, remifentanil) are rapidly hydrolyzed by esterases  Hepatic oxidative metabolism is the primary route of degradation for meperidine, fentanyl, alfentanil, sufentanil 

Accumulation of a demethylated metabolite of meperidine (i.e. normeperidine) may occur in patients with decreased renal function or during overdose – causes excitement (seizures, tremors, hyperreflexia etc.)  Also nonnon-selective MAOIs interfere with hydrolysis but not with demethylation of pethidine: norpethidine excess – seizures 

Codeine, oxycodone, and hydrocodone undergo metabolism in the liver by P450 isozyme CYP2D6  Genetic polymorphism of CYP2D6 may cause variation in analgesic response to codeine  Polar metabolites, are excreted mainly in the urine with small amounts of unchanged drug sometimes 

Adverse Effects Sedation; restlessness, lethargy, hyperactivity ((dysphoric dysphoric reaction) reaction)  Respiratory depression – infants & elderly are more susceptible, may cause apnea in newborn if given to mother during labor; dangerous in patient with respiratory insufficiency - acute respiratory failure 

Nausea & vomiting  Constipation – does not diminish with continued use  Increased ICT  Postural hypotension – exaggerated response if person is hypovolemic  Urinary retention – elderly individuals are more susceptible 

Allergy – itching, urticaria more frequent with parenteral and spinal administration  Tolerance: begin with 1st dose; develops more readily if large doses given at short intervals; tolerance may be as great as 35 fold; develops to analgesic, sedating, respiratory depressant, antidiuretic, emetic & hypotensive effects but not to the miotic, constipating & convulsant actions 

Develops due to PK and PD factors Tolerance dissipates within days to months after discontinuation; Rate (appearance & disappearance) & degree depend on drug and individual; Tolerance also develops to mixed agonistagonistantagonist but to a lesser extent; No tolerance develops to antagonistic actions of mixed or pure antagonistic agents

Cross tolerance among μ agonists is often partial or incomplete - basis for “opioid rotation” (improved analgesia at a reduced overall equivalent dosage of a different opioid) NMDA antagonist (ketamine) & δ antagonist with μ receptor agonist action may prevent tolerance

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Physical dependence – withdrawal syndrome on discontinuation of drug s/s rhinorrhea, lacrimation, chills, diarrhea gooseflesh, hyperventilation, mydriasis, vomiting, anxiety, and hostility etc. Number and intensity of the s/s depend on the degree of physical dependence

The time of onset, intensity, and duration of abstinence syndrome vary based on the drug previously used Morphine / heroin, heroin, Onset – 6 to 10 hrs, Peak - 36 to 48 hrs, Duration - 5 days Meperidine - syndrome subsides in 24 h Methadone several days to reach the peak and it may last as long as 2 weeks

Antagonist precipitated withdrawal Within 3 minutes after injection of the antagonist, peaking in 10– 10–20 min and largely subsides after 1 hour In the case of agents with mixed effects, effects, syndrome appears to be somewhat different from that produced by morphine and other agonists

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Psychologic dependence – euphoria, indifference to stimuli, sedation & abdominal effects akin to orgasm on iv administration Abuse liability is high b’coz of these factors and it is further reinforced by development of physical dependence

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Patients with Addison’s disease and those with myxedema may have prolonged and exaggerated responses to opioids

Acute morphine poisoning In nonusers adults 50 mg i.m. may cause serious toxicity  Lethal dose is about about 250 mg  S/S: Stupor or coma, shallow and occasional breathing, cyanosis, pinpoint pupil (dilated in pethidine poisoning), fall in BP, convulsions, pulmonary edema, death is due to respiratory failure 

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Establish airway and ventilate the patient, maintain BP; gastric lavage with KMnO4; Naloxone: 0.4 0.4--0.8 mg i.v. repeat every 2-3 min till respiration picks up and subsequently every 11-4 hr based on response to therapy Care should be taken to avoid precipitating withdrawal in dependent patients (extremely sensitive to antagonists)

The safest approach is to dilute the standard naloxone dose (0.4 mg) and slowly administer it intravenously, monitoring arousal and respiratory function For reversing opioid poisoning in children, the initial dose of naloxone is 0.01 mg/kg

The DOA of the available antagonists is shorter than that of many opioids (patients can slip back into coma) e.g. methadone  In such cases, continuous infusion of naloxone should be considered  Toxicity owing to overdose of pentazocine and other opioids with mixed actions may require higher doses of naloxone 

Cautions during therapy     

Avoid combining full agonist with partial agonist (eg. Pentazocine with morphine) Don’t use in patient with head injuries In patients with impaired respiratory function may lead to acute respiratory failure Use in Patients with Impaired Hepatic or Renal Function - dosage should be reduced Patients with adrenal insufficiency and hypothyroidism may have prolonged and exaggerated responses to opioids

Drug interactions Depressant effects of some opioids may be exaggerated and prolonged by phenothiazines, MAOIs and TCAs - mechanisms not clear  Some phenothiazines reduce the opioid required to produce a given level of analgesia  Depending on the specific agent, the respiratoryrespiratory-depressant effects also seem to be enhanced, the degree of sedation is increased, and the hypotension accentuated 

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Some phenothiazine may be antianalgesic Amphetamine increase the analgesic and euphoriant effects and decrease sedation Some (e.g., hydroxyzine) enhance the analgesic effects of low doses of opioids TCAs may enhance morphinemorphine-induced analgesia Sedative Sedative--hypnotics increase CNS depression particularly respiratory depression MAOIs – high incidence of hyperpyrexic coma

Clinical uses 

Analgesia – used in cancer pain, postoperative pain, during labor, severe colics etc. Severe, constant pain is better controlled than sharp intermittent pain ROA: oral, rectal, parenteral, transdermal, buccal transmucosal, intranasal etc.

Acute pulmonary edema: i.v. morphine produces rapid relief from dyspnea in LVF - reduce anxiety (↓ (↓perception of shortness of breath, ↓ sympathetic stimulation) stimulation) - reduce cardiac pre & afterload - shift blood from pulmonary to systemic circuit * If respiratory depression is a problem, furosemide is a preferred option 

Diarrhea: may control diarrhea of any cause synthetic agents with more selective GI action and with few or no CNS effects are used. e.g. loperamide, diphenoxylate  Cough: lower than analgesic doses are required, synthetic agents with no analgesic and addictive action are preferred eg. Dextromethorphan, noscapine, codeine etc. 

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Anaesthesia: As preanaestheic medication As adjunct to other anaestheic agents In high doses (eg. Fentanyl) as primary component of anaesthetic regimen Commonly used in CV and other types of high risk surgery where primary aim is to minimize CV depression

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Shivering: all opioid reduce shivering (postanaesthetic or infusion related) but pethidine has most marked effect block shivering through action on a subtype of alpha 2 adrenoceptor

CODEINE Potency – 1/10th of the morphine  Approximately 60% as effective orally as parenterally as an analgesic and as a respiratory depressant  Low affinity for opioid receptors analgesic effect is due to its conversion to morphine (via CYP2D6)  Antitussive actions may involve distinct receptors that bind codeine itself 

TRAMADOL 

Weak μ agonist (affinity 1/6000 of morphine)

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Inhibits NE & 5HT uptake (analgesia partly)

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As effective as morphine in mildmild-to to--moderate pain (less effective in severe or chronic pain)

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As effective as meperidine in labor pain and may cause less neonatal respiratory depression

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An active metabolite (2(2-4 times as potent) may account for part of the analgesic effect

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Supplied as a racemic mixture RD < morphine; constipation < codeine Can cause seizures Analgesia is not entirely reversible by naloxone RD can be reversed (but naloxone increases the risk of seizure) Avoid in patients with a history of addiction Avoid with MAOIs/ drugs lowering seizure threshold Tapentadol: like tramadol in activity, efficacy & SEs

MEPERIDINE (PETHIDINE)       

A potent μ receptor agonist with LA property Constipation & urinary retention is less common Analgesic potency; 1/81/8-1/10 of morphine 1/3rd as effective when given orally No longer recommended for chronic pain Not to be used for >48 h; or in doses greater than 600 mg/day Produces less neonatal respiratory depression than morphine/methadone - used during labor

Can block neuronal uptake of 5HT  Should not be used with MAOIs (or at least for 14d after discontinuation of MAOIs) – can cause - serotonin syndrome (if patient is on MAOIs) - or features of acute pethidine overdose (if patient is on pethidine) 

FENTANYL Synthetic, MOR agonist  100 times more potent than morphine  Do not release histamine  Commonly used in anaesthesia (rapid peak analgesia and rapid termination of action after small bolus dosing; MAC sparing effect; minimal CVS depression)  Also in management of severe pain 

Agonist/antagonists Developed with the hope that they would have less addictive potential and less RD than morphine and related drugs  A "ceiling effect," limiting the amount of analgesia attainable, often is seen  Pentazocine and nalorphine, can produce severe psychotomimetic effects 

Nalbuphine & butorphanol – MOR antagonist but KOR agonist  Pentazocine – weak MOR antagonist or partial MOR agonist + KOR agonist  Buprenorphine – partial MOR agonist (dissociates very slowly) + KOR antagonist 

Pentazocine CNS effects similar to morphine (ceiling for RD effect)  Higher doses can produce dysphoric and psychotomimetic effects  At high doses - ↑ HR & BP due to activation of supraspinal receptors (reversed by naloxone) - avoid in IHD  Does Does’’nt reverse morphine induced RD but can ppt withdrawal in morphine addicts  Available as FDC with naloxone (tablet) 

Nalbuphine Similar to pentazocine but less likely to cause dysphoria and relatively safe in patients with stable IHD  Show ceiling effect for analgesia & RD  Can produce withdrawal in morphine dependent  Abuse potential in nonusers is similar to pentazocine 

Butorphanol Best suited for relief of acute pain  Cardiac effects are similar to pentazocine  Available also as nasal formulation – useful for acute pain relief including migraine pain  Can produce physical dependence 

Buprenorphine 20-50 times more potent than morphine 20but is a partial MOR agonist (limited IA)  Analgesia longer and RD is slower and last longer than morphine  May produce withdrawal in dependent  RD is not a problem (ceiling ??)  Prior naloxone administration prevent RD, but RD not reversed once it has developed 

Available as sublingual formulation also  Can produce physical dependence  Injectable preparations are used as analgesic  Oral formulation (alone or FDC with naloxone) – is used for treatment of opioid dependence but has limited role in t/t of addicts who require high maintenance dose of opioids (as it is a partial agonist) 

Antitussives Among the most effective drug for cough suppression  Act at doses below those required to produce analgesia  Different opioid receptors may be involved  MOA ??? both central & peripheral effects  e.g. dextromethorphan, noscapine, levopropoxyphene, codeine etc. 

Antidiarrheal Diphenoxylate: - A meperidine congener - At therapeutic doses - little or no morphine like effects - At high doses – typical opioid effects - Available only in combination with atropine sulfate - Difenoxin – a metabolite of diphenoxylate

Loperamide: - Slow motility by action on Sm muscles of GIT - May also reduce GI secretion - Poorly absorbed from GIT, poor penetration in CNS (efflux by PP-glycoprotein) - Verapamil, quinidine enhance its CNS effects - Even large doses do not produce pleasurable effects of opioids - Dose 2 2--8mg/d (max 16 mg in a day)

OPIOID ANTAGONOSTS       

Bind competitively to opioid receptors Little or no intrinsic activity Few effects in absence of agonist (exogenous) Visible effects in certain situations ie. Shock, endogenous opioid system activated No withdrawal syndrome on discontinuation No known abuse potential Opioid receptor upregulation in brain

Naloxone More selective for μ receptors  Not given orally – very high FPE in liver  Prevent/reverse effects of an agonist  Respiration improves in minutes, reverse sedation, improves BP if depressed  Reverse psychotomimetic & dysphoric effects of pentazocine (high dose needed)  May produce “overshoot phenomenon” 

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DOA depends on dose (1(1-4 h) Uses: opioid overdose; low dose (0.04 mg) to treat ADRs associated with iv/epidural opioids, prevent RD in neonates

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Naltrexone: active by oral route; longer acting (~24h); more potent than naloxone; may produce hepatotoxicity Uses: - treatment of alcohol dependence - prevention of relapse to opioid dependence, following opioid detoxification - available also as ER injectable suspension (i.m.) given every 4 weeks (380 mg)

Methylnaltrexone bromide: block peripheral μ receptors in gut, poor CNS penetration; Use: opioidopioid-induced constipation in patients with advanced illness, when response to laxative therapy inadequate Dose 8 8--12mg s.c every other day  May cause GI perforation 

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Alvimopan: accelerate the time to GI recovery following partial bowel resection surgery (for hospital use only) Peripherally acting μμ-opioid receptor antagonist

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Nalmefene: relatively pure MOR antagonist; more potent; longer acting; used i.v.