Chapter 34
Opioid Analgesics and Antagonists
Algesia (pain) is an ill-defined, unpleasant sensation, usually evoked by an external or internal noxious stimulus.
even be unbearable and incapacitating. It is the most important symptom that brings the patient to the physician. Excessive pain may produce other effects—sinking sensation, apprehension, sweating, nausea, palpitation, rise or fall in BP, tachypnoea. Analgesics relieve pain as a symptom, without affecting its cause. They are used when the noxious stimulus (evoking the pain) cannot be removed or as adjuvants to more etiological approach to pain. Analgesics are divided into two groups, viz.
A. Opioid/narcotic/morphine-like analgesics.
OPIOID ANALGESICS
Opium A dark brown, resinous material obtained from poppy (Papaver somniferous) capsule. It contains two types of alkaloids.
Phenanthrene derivatives Morphine (10% in opium) Codeine (0.5% in opium) Thebaine (0.2% in opium), (Nonanalgesic).
MORPHINE
Morphine is the principal alkaloid in opium and still widely used. Therefore, it is described as prototype.
PHARMACOLOGICAL ACTIONS
(a) Analgesia Morphine is a strong analgesic. Though dull, poorly localized visceral pain is relieved better than sharply defined somatic pain; higher doses can mitigate even severe pain—degree of analgesia increasing with dose. Nociceptive pain arising from stimulation of peripheral pain receptors is relieved better than neurotic pain (such as trigeminal neuralgia) due to inflammation of or damage to neural structures. The associated reactions to intense pain (apprehension, fear, autonomic effects) are also dampened. Suppression of pain perception is selective, without affecting other sensations or producing proportionate generalized CNS depression (contrast general anesthetics).
Perception of pain and its emotional or suffering component are both altered so that pain is no longer as unpleasant or distressing, i.e. the patient tolerates pain better. The analgesic action of morphine has spinal and supraspinal components. Intrathecal injection has been shown to cause segmental analgesia without affecting other modalities. It acts in the substantia gelatinase of dorsal horn to inhibit release of excitatory transmitters from primary afferents carrying pain impulses. The action appears to be exerted through interneurons which are involved in the ‘gating’ of pain impulses. Release of glutamate from primary pain afferents in the spinal cord and its postsynaptic action on dorsal horn neurons is inhibited by morphine. Action at supraspinal sites in medulla, midbrain, limbic and cortical areas may alter processing and interpretation of pain impulses as well as send inhibitory impulses through descending pathways to the spinal cord. Several aminergic and other neuronal systems appear to be involved in the action of morphine. Simultaneous action at spinal and supraspinal sites greatly amplifies the analgesia.
(b) Sedation which is different from that produced by hypnotics is seen. Drowsiness and indifference to surroundings as well as to own body occurs without motor incoordination, ataxia or apparent excitement (contrast alcohol). Higher doses progressively induce sleep and coma. Morphine has no anticonvulsant action, rather, fits may be precipitated.
(c) Mood and subjective effects These are prominent. Morphine has a calming effect; there is loss of apprehension, feeling of detachment, lack of initiative, limbs feel heavy and body warm, mental clouding and inability to concentrate occurs. In the absence of pain or apprehension, these are generally appreciated as unpleasant by normal people. However, patients in pain or anxiety, and especially addicts, perceive it as pleasurable floating sensation: refer it as ‘high’. Rapid i.v. injection by addicts gives them a ‘kick’ or ‘rush’ which is intensely pleasurable—akin to orgasm. Thus, one has to learn to perceive the euphoric effect of morphine.
The pleasurable and reinforcing effects of μ opioid agonists (morphine-like) appear to involve a separate set of neuronal mechanisms than those involved in analgesia and sedation. The euphoric effects are most likely mediated by DA release in nucleus accumbency, whereas κ agonists (nalorphine like) inhibit DA release and produce aversion. Inhibition of NA release in locus coeruleus by opioids is implicated in their action to allay apprehension and fear.
(d) Respiratory Centre Morphine depresses respiratory Centre in a dose dependent manner; rate and tidal volume are both decreased: death in poisoning is due to respiratory failure. Neurogenic, hypercapnic and later hypoxic drives to the respiratory Centre are suppressed in succession. In addition, there is indifference to breathing: apneic patient may breathe if commanded.
(e) Cough canter It is depressed, more sensitive to morphine than respiratory canter.
(f) Temperature regulating Centre It is depressed; hypothermia occurs in cold surroundings.
(g) Vasomotor Centre It is depressed at higher doses and contributes to the fall in BP.
Morphine stimulates:
(a) CTZ Nausea and vomiting occur as side effects, especially if stomach is full and the patient stands or moves about. Thus, morphine appears to sensitize the CTZ to vestibular and other impulses. Larger doses depress vomiting canter directly: emetics should not be tried in morphine poisoning.
(b) Edinger Westphal nucleus of III nerve is stimulated producing miosis. This is a central action; no miosis occurs on topical application of morphine to the eye. Mydriasis occurs in some species like cats. Other ocular effect is a decrease in intraocular tension.
(c) Vagal Centre It is stimulated→ bradycardia is the usual response.
(d) Certain cortical areas and hippocampal cells are stimulated. Excitation is seen in an occasional individual. Muscular rigidity and immobility is consistently manifested at high doses (especially on i.v. injection): resembles catalepsy seen in rats and mice. Convulsions may occur in morphine poisoning. The proconvulsant action has been ascribed to inhibition of GABA release by hippocampal interneurons. Species like cat, lion, horse, sheep and cow are uniformly excited and show hyperthermia.
2. Neuro-endocrine Hypothalamic activation by afferent collaterals is dampened. Hypothalamic influence on pituitary is reduced. As a result FSH, LH, ACTH levels are lowered, while prolactin and GH levels are raised (these are under predominant inhibitory control). The sex hormone and corticosteroid levels are lowered in the short term, but tolerance develops in the long term. Only few chronic abusers suffer from infertility; hypocorisms' is not a problem in them. Morphine can release ADH and reduce urine volume.
3. CVS Morphine causes vasodilatation due to: (a) histamine release. (b) depression of vasomotor canter. (c) direct action decreasing tone of blood vessels. There is a shift of blood from pulmonary to systemic circuit due to greater vasodilatation in the latter. Therapeutic doses cause little change in the BP of recumbent normovolaemic patient. Postural hypotension and fainting do occur due to impairment of vascular reflexes. Morphine has little direct effect on heart; rate generally decreases due to stimulation of vagal canter but may increase reflex Lý if the BP falls. Cardiac work is consistently reduced due to decrease in peripheral resistance. Intracranial tension tends to rise as a consequence of CO2 retention leading to cerebral vasodilatation.
4. GIT Constipation is a prominent feature of morphine action. Several factors contribute: (a) Action directly on intestines and in CNS increases tone and segmentation but decreases propulsive movements. Tone of duodenum and colon may be increased to the level of spasm. (b) Spasm of pyloric, ileocaecal and anal sphincters. (c) Decrease in all gastrointestinal secretions: reduction in transfer of water and electrolytes from mucosa to the lumen. Absorption of fluid is increased due to stasis. (d) Central action causing inattention to defecation reflex. No tolerance develops to this action: addicts remain chronically constipated.
5. Other smooth muscles (a) Biliary tract Morphine causes spasm of sphincter of Oddi → intraciliary pressure is increased → may cause biliary colic. This action is only partly counteracted by atropine but more completely by opioid antagonist naloxone and direct smooth muscle relaxants like nitrates. (b) Urinary bladder Tone of both detrusor and sphincter is increased → urinary urgency and difficulty in micturition. Contractions of ureter are also increased. (c) Uterus The action is clinically insignificant, may slightly prolong Laboure. (d) Bronchi Morphine releases histamine which can cause bronchoconstriction. This is of no consequence in normal individuals but can be dangerous in asthmatics.
6. ANS Morphine causes mild hyper glycaemia due to central sympathetic stimulation. It has weak anticholinesterase action.
PHARMACOKINETICS
ADVERSE EFFECTS
2. Idiosyncrasy and allergy Allergy is uncommon and anaphylactoid reaction is rare. Urticaria, itch, swelling of lips are the manifestations. A local reaction at injection site may occur due to histamine release.
3. Apnoea This may occur in the newborn when morphine is given to the mother during labour. The blood-brain barrier of foetus is undeveloped, morphine attains higher concentration in foetal brain than in that of mother. Naloxone 10 μg/kg injected in the umbilical cord is the treatment of choice.
4. Acute morphine poisoning It is accidental, suicidal or seen in drug abusers. In the nontolerant adult, 50 mg of morphine i.m. produces serious toxicity. The human lethal dose is estimated to be about 250 mg. Manifestations are extensions of the pharmacological action. Stupor or coma, flaccidity, shallow and occasional breathing, cyanosis, pinpoint pupil, fall in BP and shock; convulsions may be seen in few, pulmonary edema occurs at terminal stages, death is due to respiratory failure.
Treatment: consists of respiratory support (positive pressure respiration also decreases pulmonary edema formation) and maintenance of BP (i.v. fluids, vasoconstrictors). Gastric lavage should be done with pot. permanganate to remove unabsorbed drug. Lavage is indicated even when morphine has been injected; being a basic drug it is partitioned to the acid gastric juice, ionizes there and does not diffuse back into blood.
Specific antidote: Naloxone 0.4–0.8 mg i.v. repeated every 2–3 min till respiration picks up, is the preferred specific antagonist because it does not have any agonistic action and does not per se depress respiration. It has a short duration of action. Injection should be repeated every 1–4 hours later on, according to the response. Nalorphine is no longer used.
5. Tolerance and dependence High degree of tolerance can be developed to morphine and related opioids if the drug is used repeatedly. It is partly pharmacokinetic (enhanced rate of metabolism), but mainly pharmacodynamic (cellular tolerance). Tolerance is exhibited to most actions, but not to constipating and miotic actions. Addicts tolerate morphine in grams: lethal dose is markedly increased. Patients in intense pain are relatively tolerant to depressant effects. Cross tolerance among opioids is of high degree. Morphine tolerant subjects are partially cross tolerant to other CNS depressants as well.
Morphine produces pronounced psychological and physical dependence, its abuse liability is rated high. Recently the NMDA antagonists and nitric oxide synthase inhibitors have been found to block morphine tolerance and dependence in animals. Thus, analgesic action of morphine can be dissociated from tolerance and dependence which contribute to its abuse. Concern about abuse has been a major limitation in the use of morphine, but appropriate medical use of morphine seldom progresses to dependence and abuse. Morphine abuse is higher among medical and paramedical personnel. Earlier, morphine addicts tended to be from the middle age group, but now younger individuals are also opting for it. Opium eating has been prevalent among natives in the orient.
Withdrawal of morphine is associated with marked drug-seeking behavior. Physical manifestations are—lacrimation, sweating, yawning, anxiety, fear, restlessness, gooseflesh, mydriasis, tremor, insomnia, abdominal colic, diarrhoea, dehydration, rise in BP, palpitation and rapid weight loss. Delirium and convulsions are not a characteristic feature (contrast barbiturates) and are seen only occasionally. Cardiovascular collapse and fatality are rare if supportive measures are instituted.
Opioid antagonists (nnaloxone, nalorphine) precipitate acute withdrawal syndrome in the dependent subject. In the more severely dependent, even 0.2 mg of naloxone can precipitate marked withdrawal.
Treatment: consists of withdrawal of morphine and substitution with oral methadone (long-acting, orally effective) followed by gradual withdrawal of methadone. However, relapse rate among post addicts is high. Long-term methadone maintenance and other techniques using agonist-antagonistic drugs are also employed.
PRECAUTIONS AND CONTRAINDICATIONS
1. Infants and the elderly are more susceptible to the respiratory depressant action of morphine.
2. It is dangerous in patients with respiratory insufficiency (emphysema, pulmonary fibrosis, cor pulmonale), sudden deaths have occurred.
3. Bronchial asthma: Morphine can precipitate an attack by its histamine releasing action.
(a) By retaining CO2, it increases intracranial tension which will add to that caused by head injury itself.
(c) Vomiting, miosis and altered mentation produced by morphine interfere with assessment of progress in head injury cases.
6. Undiagnosed acute abdominal pain: morphine can aggravate certain conditions, e.g. diverticulitis, biliary colic, pancreatitis. Inflamed appendix may rupture. Morphine can be given after the diagnosis is established. Pentazocine, buprenorphine are less likely to aggravate biliary spasm.
7. Elderly male: chances of urinary retention are high.
8. Hypothyroidism, liver and kidney disease patients are more sensitive to morphine.
9. Unstable personalities: are liable to continue with its use and become addicted.
Interactions
Phenothiazines, tricyclic antidepressants, MAO inhibitors, amphetamine and neostigmine potentiate morphine and other opioids, either by retarding its metabolism or by a pharmacodynamic interaction at the level of central neurotransmitters. Morphine retards absorption of many orally administered drugs by delaying gastric emptying. Dose: 10–50 mg oral, 10–15 mg i.m. or s.c. or 2–6 mg i.v.; 2–3 mg epidural/intrathecal; children 0.1–0.2 mg/kg.
MORPHINE SULPHATE 10 mg/ml inj; MORCONTIN 10, 30, 60, 100 mg continuous release tabs; 30–100 mg BD; RILIMORF 10, 20 mg tabs, 60 mg SR tab.
CLASSIFICATION OF OPIOIDS
1. Natural opium alkaloids: Morphine, Codeine.1. Codeine It is methyl-morphine, occurs naturally in opium, and is partly converted in the body to morphine. It is less potent than morphine (1/10th as analgesic), also less efficacious; is a partial agonist at μ opioid receptor with a low ceiling effect. The degree of analgesia is comparable to aspirin (60 mg codeine ~ 600 mg aspirin); can relieve mild to moderate pain only.
However, it is more selective cough suppressant (only 1/3rd as potent as morphine); subanalgesic doses (10–30 mg) suppress cough (see p. 214). Codeine has very low affinity for opioid receptors. The analgesic action has been ascribed to morphine generated by its demethylation by CYP2D6; codeine fails to produce analgesia in subjects with polymorphic CYP2D6. However, receptors involved in antitussive action appear to be distinct, because they bind codeine as well as morphine. Codeine has good activity by the oral route (oral: parenteral ratio 1:2). A single oral dose acts for 4–6 hours. Constipation is a prominent side effect when it is used as analgesic. Codeine has been used to control diarrhoea (see Ch. 48). Other side effects are milder. The abuse liability is low. Though codeine phosphate is water soluble and can be injected, parenteral preparation is not available.
3. Heroin (Diamorphine, Diacetylmorphine) It is about 3 times more potent than morphine; more lipid soluble: enters brain more rapidly but duration of action is similar. It is considered to be more euphorient (especially on i.v. injection) and highly addicting. Because of its high potency, it has been favoured in illicit drug trafficking. The sedative, emetic and hypotensive actions are said to be less prominent. However, it has no outstanding therapeutic advantage over morphine and has been banned in most countries except U.K.
4. Pethidine (Meperidine) Pethidine was synthesized as an atropine substitute in 1939, and has some actions like it. Though chemically unrelated to morphine, it interacts with opioid receptors and its actions are blocked by naloxone. Important differences in comparison to morphine are:
1. Dose to dose 1/10th in analgesic potency; however, analgesic efficacy approaches near to morphine and is greater than codeine.
2. After i.m. injection, the onset of action is more rapid but duration is shorter (2–3 hours).
3. It does not effectively suppress cough.
4. Spasmodic action on smooth muscles is less marked—miosis, constipation and urinary retention are less prominent.
Pethidine is believed to induce less biliary spasm than morphine; traditionally preferred in cholecystitis/biliary colic. However, there is no objective evidence to supportthis belief. One study* in patients undergoing cholecystectomy found pethidine to raise common bile duct pressure 14% more than equianalgesic dose of morphine.
5. It is equally sedative and euphoriant, has similar abuse potential. The degree of respiratory depression seen at equianalgesic doses is equivalent to morphine.
6. Tachycardia (due to antimuscarinic action) occurs instead of bradycardia.
7. It causes less histamine release and is safer in asthmatics.
8. It has local anaesthetic action: corneal anaesthesia is seen after systemic doses.
9. It is well absorbed, oral: parenteral activity ratio is high (1/3 to 1/2). Pethidine is nearly completely metabolized in liver. The plasma t½ of pethidine is 2–3 hours. Acidification of urine increases excretion of unchanged pethidine.
Side effects These are similar to morphine except those mentioned above. Some atropinic effects (dry mouth, blurred vision, tachycardia) may be noted in addition.
Overdose of pethidine produces many excitatory effects—tremors, mydriasis, hyperreflexia, delirium, myoclonus and convulsions. This is due to accumulation of norpethidine which has excitant effects. Renal failure patients given repeated doses of pethidine may also experience similar effects.
Nonselective MAO inhibitors interfere with hydrolysis but not with demethylation of pethidine—norpethidine is produced in excess and excitement occurs.
Tolerance and physical dependence develop slowly with pethidine. Probably due to its shorter duration of action, body functions get time to recover. For the same reason withdrawal syndrome develops more rapidly. Autonomic disturbances are less marked during pethidine withdrawal, than after morphine withdrawal.
Use Pethidine is primarily used as an analgesic (substitute of morphine) and in preanaesthetic medication, but not for cough or diarrhoea. It has also been used to control shivering during recovery from anaesthesia or that attending i.v. infusions. Potential adverse effects due to accumulation of norpethidine limit its utility in patients who require repeated dosing. It is the preferred opioid analgesic during labour—at equianalgesic doses neonatal respiratory depression is less marked, but still significant. Dose: 50–100 mg i.m., s.c. (may cause irritation, local fibrosis on repeated injection), occasionally given orally or i.v.
PETHIDINE HCL 100 mg/2 ml inj; 50, 100 mg tab.
5. Fentanyl A pethidine congener, 80–100 times more potent than morphine, both in analgesia and respiratory depression. In analgesic doses it produces few cardiovascular effects; has little propensity to release histamine. Because of high lipid solubility, it enters brain rapidly and produces peak analgesia in 5 min after i.v. injection. The duration of action is short: starts wearing off after 30–40 min due to redistribution, while elimination t½ is ~4 hr. In the injectable form it is almost exclusively used in anaesthesia (see p. 376). Transdermal fentanyl has become available for use in cancer or other types of chronic pain for patients requiring opioid analgesia.
DUROGESIC transdermal patch delivering 25 μg/hr, 50 μg/hr or 75 μg per hour; the patch is changed every 2–3 days.
6. Methadone A synthetic opioid, chemically dissimilar but pharmacologically very similar to morphine—has analgesic, respiratory depressant, emetic, antitussive, constipating and biliary actions similar to morphine.
The most important feature of methadone is high oral: parenteral activity ratio (1 : 2) and its firm binding to tissue proteins. In single doses it is only slightly more potent than morphine and has comparable duration of action (4–6 hours on i.m. injection), but it cumulates in tissues on repeated administration—duration of action is progressively lengthened due to gradual release from these sites; plasma t½ on chronic use is 24– 36 hours. Plasma protein binding is 90% and it is metabolized in liver, primarily by demethylation and cyclization—metabolites are excreted in urine. Rifampin and phenytoin can cause withdrawal symptoms to appear in methadone dependent subjects by inducing its metabolism.
Because of slow and persistent nature of action, sedative and subjective effects are less intense. It is probably incapable of giving a ‘kick’. The abuse potential is rated lower than morphine. Tolerance develops more slowly, probably due to progressive filling of tissue stores. Withdrawal syndrome is of gradual onset, taking 1–2 days after discontinuation, is prolonged and less severe.
Methadone has been used primarily as substitution therapy of opioid dependence: 1 mg of oral methadone can be substituted for 4 mg of morphine, 2 mg of heroin and 20 mg of pethidine. Another technique is methadone maintenance therapy in opioid addicts—sufficient dose of methadone is given orally to produce high degree of tolerance so that pleasurable effects of i.v. doses of morphine or heroin are not perceived and the subject gives up the habit.
It can also be used as an analgesic for the same conditions as morphine; dose 2.5–10 mg oral or i.m. but not s.c. It is occasionally employed as antitussive.
PHYSEPTONE 10 mg inj, 2 mg/5 ml linctus.
7. Dextropropoxyphene It is chemically related to methadone but is quite similar in analgesic action and in side effects to codeine, except that it is a poor antitussive and probably less constipating. It is nearly ½ as potent as codeine and has a lower oral: parenteral activity ratio. It is metabolized in liver; t½ is variable (4–12 hours). Delirium and convulsions have occurred in overdose. The demethylated metabolite of propoxyphene is cardiotoxic. The abuse liability is similar to or lower than codeine.
Dextropropoxyphene (60–120 mg) is used as a mild oral analgesic. It is marketed only in combination with paracetamol ± other drugs; but the contribution of dextropropoxyphene to the analgesic effect of the combination is questionable. The cardiac toxicity of its demethylated metabolite and seizures are dangerous in overdose; only partly antagonized by naloxone. Because of reported fatalities and no clear advantage of the combinations over paracetamol alone, such preparations have been withdrawn in the UK, but are quite popular in India, USA, etc, probably due to the perceived addictive potential of codeine.
PARVODEX 60 mg cap: PARVON, PROXYVON, WALAGESIC: dextropropoxyphene 65 mg + paracetamol 400 mg cap; WYGESIC, SUDHINOL 65 mg + paracetamol 650 mg cap.
8. Tramadol This centrally acting analgesic relieves pain by opioid as well as additional mechanisms. Its affinity for μ opioid receptor is low, while that for κ and δ is very low. Unlike other opioids, it inhibits reuptake of NA and 5-HT, and thus activates monoaminergic spinal inhibition of pain. Its analgesic action is only partially reversed by the opioid antagonist naloxone.
Injected i.v. 100 mg tramadol is equianalgesic to 10 mg i.m. morphine; oral bioavailability is good (oral: parenteral dose ratio is 1.4). The t½ is 5 hours and effects last for 4–6 hrs. Tramadol causes less respiratory depression, sedation, constipation, urinary retention and rise in intrabiliary pressure than morphine. It is well tolerated; side effects are dizziness, nausea, sleepiness, dry mouth, sweating and lowering of seizure threshold. Haemodynamic effects are minimal.
Tramadol is indicated for mild-to-moderate short-lasting pain due to diagnostic procedures, injury, surgery, etc, as well as for chronic pain including cancer pain, but is not effective in severe pain. Little tendency to dose escalation is seen and abuse potential is low. Dose: 50–100 mg oral/i.m./slow i.v. infusion (children 1–2 mg/kg) 4–6 hourly.
CONTRAMAL, DOMADOL, TRAMAZAC 50 mg cap, 100 mg SR tab; 50 mg/ml inj in 1 and 2 ml amps.
1. As analgesic Opioid analgesics are indicated in severe pain of any type. However, they only provide symptomatic relief without affecting the cause. Pain may be valuable for diagnosis: should not be relieved by analgesic unless proper assessment of the patient has been done. Indiscriminate use of opioids can be hazardous. On the other hand, inadequate dose or reluctance to use these drugs in a patient in distress is equally deplorable .
Morphine or one of its parenteral congeners is indicated especially in traumatic, visceral, ischaemic (myocardial infarction), postoperative, burn, cancer pain and the like. It should be given promptly in myocardial infarction to allay apprehension and reflex sympathetic stimulation. Opioids, especially pethidine, have been extensively used for obstetric analgesia, but one must be prepared to deal with the foetal and maternal complications.
d in an emergency. It may prevent neurogenic shock and other autonomic effects of excruciating pain. Opioids should not be restricted in case of pain of terminal illness (cancer pain), but for other chronic conditions, due consideration must be given to their addicting liabilities. Neuropathic pain responds less predictably to opioid analgesics.
Epidural (2–3 mg) or intrathecal (0.2 mg) injection of morphine produces segmental analgesia lasting ~12 hour without affecting other sensory, motor or autonomic modalities. It is being used for surgical analgesia in abdominal, lower limb and pelvic operations as well as for labour, postoperative, cancer and other intractable pain. Respiratory depression occurs after a delay due to ascent of the opioid through the subarachnoid space to the respiratory centre. Use of fentanyl in place of morphine produces faster analgesia and reduces the risk of respiratory depression because of greater uptake by nerves at the site of injection.
Patient controlled analgesia (PCA) is an attractive technique of postoperative pain control in which the patient himself regulates the rate of i.v. fentanyl infusion according to intensity of pain felt.
Transdermal fentanyl is a suitable option for chronic cancer and other terminal illness pain. The patch produces analgesia after ~12 hr, but then blood levels of fentanyl and intensity of analgesia remain fairly uniform if the patch is changed every 2–3 days.
For milder pain, e.g. toothache, headache, neuralgias, etc., aspirin-like analgesics are preferred. When they are not effective—codeine/ dextropropoxyphene may be used orally, either alone or in combination with aspirin-like drug. The combination enhances the ceiling analgesia. For majority of painful conditions, especially more severe and longerlasting pain, a NSAID should be combined with the opioid; helps to enance analgesia while keeping the opioid dose low.
2. Preanaesthetic medication Morphine and pethidine are used in few selected patients (see p. 378).
3. Balanced anaesthesia and surgical analgesia Fentanyl, morphine, pethidine, alfentanil or sufentanil are an important component of anaesthetic techniques (see p. 376-77)
4. Relief of anxiety and apprehension Especially in myocardial infarction, internal bleeding (haematemesis, threatened abortion, etc.) morphine or pethidine have been employed. However, they should not be used as anxiolytics or to induce sleep.
5. Acute left ventricular failure (cardiac asthma) Morphine (i.v.) affords dramatic relief by—
(a) Reducing preload on heart due to vasodilatation and peripheral pooling of blood.
(b) Tending to shift blood from pulmonary to systemic circuit; relieves pulmonary congestion and edema.
(c) Allays air hunger by depressing respiratory centre.
(d) Cuts down sympathetic stimulation by calming the patient, reduces cardiac work.
It is also indicated to relieve pulmonary edema due to infarction of lung and other causes, but not due to irritant gases. It is contraindicated in bronchial asthma.
6. Cough Codeine or its substitutes are widely used for suppressing dry, irritating cough (see Ch. 16).
7. Diarrhoea The constipating action of codeine has been used to check diarrhoea and to increase the consistency of stools in colostomy. Synthetic opioids exclusively used as antidiarrhoeals are diphenoxylate and loperamide. The risk and benefits of their use are detailed in Ch. 48
OPIOID RECEPTORS
Opioid ligands can interact with different opioid receptors as agonists, partial agonists or competitive antagonists. The overall pattern of effect of a particular agent depends not only on the nature of its interaction with different opioid receptors, but also on its relative affinity for these, e.g. morphine is an agonist on μ, κ and δ receptors, but its affinity for μ receptors is much higher than that for the other two. The effects, therefore, are primarily the result of μ receptor activation.
The nature and intensity of action of complex action opioids and antagonists are summarized in Table 34.2.
µ receptor The μ receptor is characterized by its high affinity for morphine. It is the major receptor mediating actions of morphine and its congeners. Endogenous ligands for μ receptor— peptides called Endomorphins 1 and 2—have only recently been found in mammalian brain—produce biological effects ascribed to this receptor. Other opioid peptides viz. β-endorphin, enkephalins and dynorphins bind to μ receptor with lower affinity. β-funaltrexamine is a relatively selective but irreversible μ antagonist. High density of μ receptors has been detected in periaqueductal gray, thalamus, nucleus tractus solitarious, nucleus ambiguus and area postrema.
Two subtypes of μ receptor have been proposed: μ1: Has higher affinity for morphine, mediates supraspinal analgesia and is selectively blocked by naloxonazine. μ2: Has lower affinity for morphine, mediates spinal analgesia, respiratory depression and constipating action.
κ receptor This receptor is defined by its high affinity for ketocyclazocine and dynorphin A; the latter is considered to be its endogenous ligand. Norbinaltorphimine is a selective κ antagonist. Two subtypes of κ receptor κ1 and κ3 are functionally important. Analgesia caused by κ agonists is primarily spinal (through κ1 receptor). However, κ3 receptors mediate lower ceiling supraspinal analgesia. Other κ actions are listed in Table 34.1.
δ receptor This receptor has high affinity for leu/met enkephalins which are its endogenous ligands. The δ mediated analgesia is again mainly spinal (δ receptors are present in dorsal horn of spinal cord), but the affective component of supraspinal analgesia appears to involve δ receptors because these receptors are present in limbic areas—also responsible for dependence and reinforcing actions. The proconvulsant action is more prominent in δ agonists. Myenteric plexus neurones express high density of δ receptors—mediate reduced g.i. motility. Naltrindole is a selective δ antagonist.
It thus appears that μ and δ receptor responses are quite similar, but those exerted through κ receptor are distinct. In certain areas κ actions are antagonistic to μ actions.
The σ (sigma) receptor is no longer considered an opioid receptor, because it is neither activated by morphine nor blocked by naloxone. However, certain opioids, e.g. pentazocine, butorphanol and many unrelated compounds (including some hallucinogens) bind to σ receptors. Certain naloxone insensitive effects of pentazocine like drugs, e.g. dysphoria, psychotomimetic action, tachycardia, mydriasis are believed to be mediated by σ receptors.
Opioid receptor transducer mechanisms All 3 types of opioid receptors (μ, κ, δ) have been cloned; all are G-protein coupled receptors located mostly on prejunctional neurones. They generally exercise inhibitory modulation by decreasing release of the junctional transmitter (Fig. 34.1). As such, various monoaminergic (NA, DA, 5-HT), GABA, glutamate (NMDA/ AMPA) pathways are intricately involved in opioid actions.
Opioid receptor activation reduces intracellular cAMP formation and opens K+ channels (mainly through μ and δ receptors) or suppresses voltage gated N type Ca2+ channels (mainly κ receptor). These actions result in neuronal hyperpolarization and reduced availability of intracellular Ca2+ → decreased neurotransmitter release by CNS and myenteric neurones (e.g. glutamate from primary nociceptive afferents).
However, other mechanisms and second messengers may also be involved, particularly in the long-term.
COMPLEX ACTION OPIOIDS AND OPIOID ANTAGONISTS
Naloxone, Naltrexone, Nalmefene Clinically, the agonist-antagonist (agonist at one opioid receptor, antagonist at another) and partial/weak agonist (low intrinsic activity) opioids are analgesics of comparable efficacy to low doses of morphine, but with a limited dose range. They cause low ceiling respiratory depression and have lower abuse potential. However, in only few situations they have proven to be advantageous over the full μ receptor agonists.
1. Nalorphine It is N-allyl-normorphine; was the first opioid antagonist introduced in 1951 which could reverse morphine action. Later it was found to have agonistic actions as well. Nalorphine is a κ agonist and μ antagonist; has analgesic action with a lower ceiling, but is not used clinically because of dysphoric and psychotomimetic effects. Naloxone has replaced it as a morphine antidote.
2. Pentazocine It is the first agonist-antagonist to be used as an analgesic. It has weak μ antagonistic and more marked κ agonistic actions. The profile of action is similar to morphine; important differences are: (a) Analgesia caused by pentazocine is primarily spinal (κ1) and has a different character than that caused by morphine. Parenterally 30 mg pentazocine = 10 mg morphine; but ceiling effect is lower, i.e. at higher doses proportionate increase in analgesia does not occur. (b) Sedation and respiratory depression is 1/3 to 1/2 of morphine at lower doses, and has a lower ceiling, does not increase much beyond 60 mg dose.
FORTWIN 25 mg tab., 30 mg/ml inj., PENTAWIN, SUSEVIN 30 mg/ml inj
Pentazocine is indicated for postoperative and moderately severe pain in burns, trauma, fracture, cancer, etc. Though abuse liability is low, frequent side effects and potential for dysphoric/psychotomimetic effect limits its utility in chronic (cancer) pain.
3. Butorphanol It is a κ analgesic, similar to but more potent than pentazocine (butorphanol 2 mg = pentazocine 30 mg). Likewise, analgesia and respiratory depression have a lower ceiling than morphine. Sedation, nausea, cardiac stimulation and other side effects are similar to pentazocine, but subjective effects are less dysphoric. Psychotomimetic effects are less marked (it is a weaker σ agonist at higher doses). BP is not increased.
Postaddicts recognize it as a barbiturate rather than opiate and mostly dislike it. However, it produces physical dependence; withdrawal can be precipitated by high dose of naloxone, but the syndrome is mild. The abuse potential of butorphanol is low. The most outstanding feature is that butorphanol can neither substitute for nor antagonize morphine. This shows its very weak interaction with μ receptors.
It has been used in a dose of 1–4 mg i.m. or i.v. for postoperative and other short-lasting (e.g. renal colic) painful conditions, but should be avoided in patients with cardiac ischaemia. The duration of action is similar to morphine.
BUTRUM 1 mg/ml, 2 mg/ml inj.
4. Buprenorphine It is a synthetic thebaine congener, highly lipid-soluble μ analgesic that is 25 times more potent than morphine. It has a slower onset and longer duration of action. After a single dose, analgesia lasts for 6–8 hours; but with repeated use, duration of action increases to ~24 hours. Certain other effects last still longer. Sedation, vomiting, miosis, subjective and cardiovascular effects are similar to morphine, but constipation is less marked. Postural hypotension is prominent. Respiratory depression (and analgesia) exhibit ceiling effect. It substitutes for morphine at low levels of dependence but precipitates withdrawal in highly dependent subjects, reflecting its partial agonistic action at μ receptors. Antagonistic action on κ receptor has also been described.
Lower degree of tolerance and physical as well as psychological dependence develops with buprenorphine on chronic use. Its withdrawal syndrome resembles that of morphine, but is delayed for several days, is milder and longer. Lasting. ‘Drug seeking’ is present. Abuse liability is rated lower than morphine.
Even naloxone (at high dose) only partially reverses buprenorphine effects and does not precipitate its withdrawal; probably because of more tight binding of buprenorphine to opioid receptors.
Buprenorphine has good efficacy by sublingual route, is highly plasma protein bound and remains in tissues for several days; t½ is 40 hours. It is mostly excreted unchanged in bile and finds its way out of the body in faeces. Dose: 0.3–0.6 mg i.m., s.c. or slow i.v., also sublingual 0.2–0.4 mg 6–8 hourly.
NORPHIN, TIDIGESIC 0.3 mg/ml inj. 1 and 2 ml amps. 0.2 mg sublingual tab; BUPRIGESIC, PENTOREL 0.3 mg/ml inj in 1, 2 ml amp
Use: Buprenorphine is indicated for longlasting painful conditions requiring an opioid analgesic, e.g. cancer pain. It has also been recommended for premedication, postoperative pain, in myocardial infarction and in the treatment of morphine dependence. Buprenorphine is not suitable for use during labour, because if respiratory depression occurs in the neonate, it cannot be effectively reversed by naloxone. Nalbuphine, Meptazinol and Dezocine are other agonistantagonist opioids introduced in some countries.
PURE OPIOID ANTAGONISTS
Naloxone also blocks the actions of endogenous opioid peptides (see below). These peptides have been implicated in a variety of physiological functions; it is surprizing that naloxone does not produce hyperalgesia or other effects in normal individuals. However, it has been found to render those individuals more susceptible to pain who normally have high tolerance. It blocks placebo, acupuncture and stress induced analgesia: showing involvement of endogenous opioid peptides in these. Naloxone partly antagonizes respiratory depression produced by certain nonopioids also, e.g. N2O, diazepam.
Naloxone is inactive orally because of high first pass metabolism in liver. Injected i.v. it acts in 2–3 min. The primary pathway of metabolism is glucuronidation. Plasma t½ is 1 hour in adults and 3 hours in newborns. Adverse effects of naloxone are uncommon; may include rise in BP and pulmonary edema.
NARCOTAN 0.4 mg in 1 ml (adult) and 0.04 mg in 2 ml (infant) amps; NALOX, NEX 0.4
mg inj.
Use Naloxone is the drug of choice for morphine poisoning (0.4–0.8 mg i.v. every 2–3 min: max 10 mg) and for reversing neonatal asphyxia due to opioid use during Laboure (10 μg/kg in the cord). It is also used to treat overdose with other opioids and agonist antagonists (except buprenorphine). Other possible clinical applications of naloxone are:
To reverse respiratory depression due to intraoperative use of opioids: 0.1–0.2 mg i.v. (this dose usually preserves analgesia in the postoperative period).
It has also been tried as an adjunct to intraspinal opioid analgesia: reverses respiratory depression without abolishing pain relief.
Diagnosis of opioid dependence—precipitates withdrawal in dependent subjects.
It also partially reverses alcohol intoxication.
Naloxone has been found to elevate BP in endotoxic or hypovolaemic shock, stroke and spinal injury. In these conditions injection of morphine worsens cardiovascular status and opioid peptides are believed to be involved in the pathogenesis. However, the value of naloxone compared to conventional therapy is uncertain.
2. Naltrexone It is chemically related to naloxone and is another pure opioid antagonist, that is devoid of subjective and other agonistic effects, but very high doses have caused unpleasant feelings in some individuals. It is more potent than naloxone. Naltrexone differs from naloxone in being orally active and having a long duration of action (1–2 days) which makes it suitable for ‘opioid blockade’ therapy of postaddicts: 50 mg/ day is given orally so that if the subject takes his/ her usual shot of the opioid, no subjective effects are produced and the craving subsides. Alcohol craving is also reduced by naltrexone; it is being used to prevent relapse of heavy drinking (see p. 385). Side effects are nausea and headache; high doses can cause hepatotoxicity.
NALTIMA 50 mg tab.
3. Nalmefene This pure opioid antagonist lacks hepatotoxicity of naltrexone, has higher oral bioavailability and is longer acting.
ENDOGENOUS OPIOID PEPTIDES
1. Endorphins β-endorphin (β-END) having 31 amino acids is the most important of the endorphins. It is derived from Pro-opiomelanocortin (POMC) which also gives rise to γ-MSH, ACTH and two lipotropins. β-END is primarily μ agonist, but also has δ action.
2. Enkephalins Methionine-enkephalin (metENK) and leucine-enkephalin (leu-ENK) are the most important. Both are pentapeptides. The large precursor peptide proenkephalin has 4 metENK and 1 leu-ENK residues. The two ENKs have a slightly different spectrum of activity; while met-ENK has equal affinity for μ and δ sites, leu-ENK prefers δ receptors.
3. Dynorphins Dynorphin A and B (DYN-A, DYN-B) are 8–17 amino acid peptides derived from prodynorphin which contains 3 leu-ENK residues also. DYNs are more potent on κ receptors, but also activate μ and δ receptors.
Distribution of the 3 families of peptides is summarized below
1. POMC – Arcuate nucleus which sends pro- (limited jections to limbic areas and distribution) medulla. – Anterior pituitary (modulates hormone release). – Pancreatic islets (modulates insulin, glucagon release).
2. Proenkephalin – Pain areas in spinal cord, trigeminal (wide nucleus, periaqueductal grey distribution) matter. – Affective areas in limbic system, locus coeruleus and cortex. – Medulla (autonomic functions). – Median eminence of hypothalamus (neuro-endocrine control). – Adrenal medulla, gastric and intestinal glands.
3. Prodynorphin – Wide distribution roughly parallel to proenkephalin, but in distinct neurons of the same area.
The opioid peptides constitute an endogenous opioid system which normally modulates pain perception, mood, hedonic (pleasure related) and motor behaviour, emesis, pituitary hormone release and g.i.t. motility, etc.
β-END injected directly into the brain is 20– 40 times more potent analgesic than morphine. Its primary localization in hypothalamus and pituitary and its long t½ ascribes it a neurohormone function which modulates the release of other hormones. It decreases LH, FSH release and increases GH and prolactin release. Naloxone has opposite effects on the levels of these hormones—suggesting that the system is constitutively active.
The wide distribution of ENKs and DYNs and their short t½ suggests function as neuromodulator or neurotransmitter. They appear to regulate pain responsiveness at spinal and supraspinal levels. Naloxone blocks placebo, acupuncture and stress-induced analgesias, suggesting the involvement of opioid peptides in these responses. Opioid peptides also appear to participate in regulation of affective behaviour and autonomic function.
Recently a novel opioid peptide Nociceptin/orphanin FQ (N/OFQ) has been isolated from mammalian brain. It is localized in cortex, hippocampus, spinal cord and certain sensory sites; is believed to play a role in stress response, reward and reinforcing actions, learning and memory. The N/OFQ receptor, also labelled ‘Opioidreceptor-like-1’ (ORL-1) receptor, is thus the 4th opioid receptor to be identified. At certain sites, N/OFQ can act as an ‘antiopioid’ through the ORL-1 receptor. In the pain control mechanisms, N/OFQ appears to play both opioid-like as well as antagonistic roles, depending on the site and the basal state of pain.
Morphine and other opioids act as exogenous agonists on some of the receptors for these peptides. This has given an explanation for the existence of specific receptors in the body for exogenous substances like morphine. Morphine itself has now been detected in mammalian brain.
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