Opioid Analgesics

(rINN)
Synonyms: Analgésicos opioides u opiáceos; Analgésiques Opioïdes; Opioid-analgetika.
Cyrillic synonym: Опиоидные Аналгетики.

💊 Dependence and Withdrawal

Repeated use of opioids is associated with the development of psychological and physical dependence. Although this is less of a problem with legitimate therapeutic use, dependence may develop rapidly when opioids are regularly abused for their euphoriant effects. Drug dependence of the opioid type is characterised by an overwhelming need to keep taking the drug (or one with similar properties), by a physical requirement for the drug in order to avoid withdrawal symptoms, and by a tendency to increase the dose owing to the development of tolerance. Abrupt withdrawal of opioids from persons physically dependent on them precipitates a withdrawal syndrome, the severity of which depends on the individual, the drug used, the size and frequency of the dose, and the duration of drug use. Withdrawal symptoms may also follow the use of an opioid antagonist such as naloxone or a mixed agonist and antagonist such as pentazocine in opioid-dependent persons. Neonatal abstinence syndrome may occur in the offspring of opioid-dependent mothers and these infants can suffer withdrawal symptoms at birth. Opioid analgesics can be classified according to the receptors at which they act (see Uses and Administration, below) and withdrawal syndromes are characteristic for a receptor type. Cross-tolerance and crossdependence can be expected between opioids acting at the same receptors. Dependence associated with morphine and closely related μ-agonists appears to result in more severe withdrawal symptoms than those associated with κ-receptor agonists. Onset and duration of withdrawal symptoms also vary according to the duration of action of the specific drug. With morphine and diamorphine withdrawal symptoms usually begin within a few hours, reach a peak within 36 to 72 hours, and then gradually subside; they develop more slowly with methadone. Withdrawal symptoms include yawning, mydriasis, lachrymation, rhinorrhoea, sneezing, muscle tremor, weakness, sweating, anxiety, irritability, disturbed sleep or insomnia, restlessness, anorexia, nausea, vomiting, loss of weight, diarrhoea, dehydration, leucocytosis, bone pain, abdominal and muscle cramps, gooseflesh, vasomotor disturbances, and increases in heart rate, respiratory rate, blood pressure, and temperature. Some physiological values may not return to normal for several months after the acute withdrawal syndrome. Withdrawal symptoms may be terminated by a suitable dose of the original or a related opioid. Tolerance diminishes rapidly after withdrawal so that a previously tolerated dose may prove fatal. For a discussion of the treatment of opioid dependence and neonatal abstinence syndrome, see below.
1. Van Ree JM, et al. Opioids, reward and addiction: an encounter of biology, psychology, and medicine. Pharmacol Rev 1999; 51: 341–96.

Diagnosis.

Naloxone and other opioid antagonists have been used to diagnose opioid dependence.

Treatment of opioid dependence.

The treatment of opioid dependence has been the subject of a number of reviews and discussions.1-10 Planned withdrawal (detoxification) may be effected slowly or rapidly. The usual method in many countries is to replace the drug of dependence with methadone (an opioid agonist) given as a liquid oral preparation, and then gradually withdraw the methadone if possible. Methadone is suitable for withdrawal therapy because it can be given orally and its long half-life allows once daily use. Oral diamorphine has been used similarly to methadone; reefers containing diamorphine have also been used in some centres. Dihydrocodeine tablets have been used successfully. The partial opioid agonist buprenorphine, given sublingually, is another alternative to methadone in the treatment of opioid dependence, and withdrawal symptoms may possibly resolve more quickly than with methadone.11 However, it should only be given to patients with moderate dependence; those dependent on high doses of opioids may experience withdrawal symptoms when given buprenorphine. The methadone derivative levacetylmethadol was a more recent introduction but its proarrhythmic effects have led to its use being suspended. Iatrogenic opioid dependence may occur in patients receiving μagonists such as morphine, fentanyl, or pethidine for the management of acute pain or in an intensive care setting for more than 5 to 10 days. Methadone has been used successfully to manage opioid withdrawal in adult intensive care patients.12 However, some13 avoid using methadone to manage withdrawal in children because of the stigma of its associations with managing withdrawal in drug addicts. In physically dependent but non-addicted patients, gradual weaning using the same opioid that was used therapeutically is preferred where possible, although in some cases, it may be necessary to change to a different opioid because of ease of use, duration of action, and ability to taper the dose; virtually any opioid can be used.13 Other drugs used in the management of opioid withdrawal include alpha2-adrenoceptor agonists such as clonidine and opioid antagonists such as naltrexone and naloxone. Clonidine may help to suppress symptoms of opioid withdrawal, such as anxiety, insomnia, and muscle aches. It appears to be more effective when used in the control of symptoms after abrupt withdrawal than when used during gradual withdrawal of methadone. Hypotension may limit its usefulness in some patients. The clonidine analogue lofexidine may produce similar results to those obtained with clonidine and appears to be less sedating and hypotensive.14 Naltrexone and naloxone block the euphoriant effects of opioids although their use as monotherapy in detoxification is limited by unacceptable opioid withdrawal effects. Naltrexone may be used with alpha2-adrenoceptor agonists such as clonidine or lofexidine to ameliorate symptoms but there are insufficient data to determine whether such combinations reduce the duration of withdrawal treatment or increase the rate of transfer to maintenance therapy with an opioid antagonist.15 Naloxone and naltrexone are also being used in the relatively new technique of rapid or ultra rapid opioid detoxification,16-18 which is achieved while the patient is heavily sedated or under general anaesthesia and hence unaware of any unpleasant withdrawal symptoms. However, although detoxification may be achieved within 24 hours and has a high initial success rate, the technique itself is not without risks and it does not obviate the need for maintenance treatment (see below). Concomitant counselling and other psychosocial services have been shown to be important in the outcome of withdrawal therapy.19,20 Detoxification alone does not ensure long-term abstinence. A number of other drugs may be of use as adjuncts in the management of withdrawal symptoms. Diphenoxylate with atropine or loperamide may be used for the control of diarrhoea. Promethazine has been used for its antiemetic and sedative actions. Beta blockers such as propranolol may be of use for patients with pronounced somatic anxiety symptoms. Benzodiazepines or clomethiazole can be given to relieve anxiety and associated insomnia but only short courses should be used in order to minimise the risk of dependence and abuse. Long-term maintenance treatment (stabilisation treatment) with an opioid is sometimes used, in conjunction with psychosocial support, to enable the patient to acquire some form of social stability. Methadone is most commonly used; the use of diamorphine although feasible21,22 is controversial23 and is advocated by only a few individual centres. Buprenorphine is another possibility.24 The use of methadone for maintenance has been reviewed.25-27 Naltrexone can be effective in maintaining abstinence in opioid addicts after detoxification, especially after rapid or ultra rapid detoxification. It is considered that naltrexone would probably be of most use in highly motivated addicts with good sociological and psychological support to discourage impulsive use of opioids.1,28,29 The problems associated with the management of the pregnant patient with opioid dependence have been discussed.30 The aim should be to stabilise the patient first using methadone since acute withdrawal can result in fetal death. Drug withdrawal is best done slowly during the second trimester. It has been suggest ed that if patients present during the final trimester and cannot be detoxified, maintenance with diamorphine might be preferable to the use of methadone as it might produce less severe withdrawal symptoms in the neonate.31 The management of neonatal abstinence syndrome is discussed below.
1. Herridge P, Gold MS. Pharmacological adjuncts in the treatment of opioid and cocaine addicts. J Psychoactive Drugs 1988; 20: 233–42
2. Guthrie SK. Pharmacologic interventions for the treatment of opioid dependence and withdrawal. DICP Ann Pharmacother 1990; 24: 721–34
3. Wodak A. Managing illicit drug use: a practical guide. Drugs 1994; 47: 446–57
4. Mattick RP, Hall W. Are detoxification programmes effective? Lancet 1996; 347: 97–100
5. Seivewright NA, Greenwood J. What is important in drug misuse treatment? Lancet 1996; 347: 373–6
6. National Concensus Development Panel on Effective Medical Treatment of Opiate Addiction. Effective medical treatment of opiate addition. JAMA 1998; 280: 1936–43
7. DOH. Drug misuse and dependence: guidelines on clinical management. London: The Stationery Office, 1999. Also available at: http://www.dh.gov.uk/prod_consum_dh/groups/ dh_digitalassets/04.00dh/04.00en/documents/digitalasset/ dh_4078198.pdf (accessed 28/08/08
8. O’Connor PG, Fiellin DA. Pharmacological treatment of heroindependent patients. Ann Intern Med 2000; 133: 40–54
9. Gonzalez G, et al. Treatment of heroin (diamorphine) addiction: current approaches and future prospects. Drugs 2002; 62: 1331–43
10. Raisch DW, et al. Opioid dependence treatment, including buprenorphine/naloxone. Ann Pharmacother 2002; 36: 312–21
11. Gowing L, et al. Buprenorphine for the management of opioid withdrawal. Available in The Cochrane Database of Systematic Reviews; Issu
2. Chichester: John Wiley; 2006 (accessed 26/06/08)
12. Böhrer H, et al. Methadone treatment of opioid withdrawal in intensive care patients. Lancet 1993; 341: 636–7
13. Yaster M, et al. The management of opioid and benzodiazepine dependence in infants, children, and adolescents. Pediatrics 1996; 98: 135–40
14. Gowing L, et al. Alpha2 adrenergic agonists for the management of opioid withdrawal. Available in The Cochrane Database of Systematic Reviews; Issu
4. Chichester: John Wiley; 2004 (accessed 26/06/08)
15. Gowing L, et al. Opioid antagonists with minimal sedation for opioid withdrawal. Available in The Cochrane Database of Systematic Reviews; Issu
1. Chichester: John Wiley; 2006 (accessed 26/06/08)
16. Justins D. Rapid opioid detoxification under anaesthesia. Hosp Med 1998; 59: 180
17. Cook TM, Collins PD. Rapid opioid detoxification under anaesthesia. Hosp Med 1998; 59: 245–7
18. Gowing L, et al. Opioid antagonists under heavy sedation or anaesthesia for opioid withdrawal. Available in The Cochrane Database of Systematic Reviews; Issu
2. Chichester: John Wiley; 2006 (accessed 26/06/08)
19. McLellan AT, et al. The effects of psychosocial services in substance abuse treatment. JAMA 1993; 269: 1953–9
20. Amato L, et al. Psychosocial and pharmacological treatments versus pharmacological treatments for opioid detoxification. Available in The Cochrane Database of Systematic Reviews; Issu
3. Chichester: John Wiley; 2008 (accessed 26/06/08)
21. Perneger TV, et al. Randomised trial of heroin maintenance programme for addicts who fail in conventional drug treatments. BMJ 1998; 317: 13–18
22. Rehm J, et al. Feasibility, safety, and efficacy of injectable heroin prescription for refractory opioid addicts: a follow-up study. Lancet 2001; 358: 1417–20
23. Farrell M, Hall W. The Swiss heroin trials: testing alternative approaches. BMJ 1998; 316: 639
24. Kakko J, et al. 1-year retention and social function after buprenorphine-assisted relapse prevention treatment for heroin dependence in Sweden: a randomised, placebo-controlled trial. Lancet 2003; 361: 662–8
25. Farrell M, et al. Methadone maintenance treatment in opiate dependence: a review. BMJ 1994; 309: 997–1001
26. Ward J, et al. Role of maintenance treatment in opioid dependence. Lancet 1999; 353: 221–6
27. Bell J, Zador D. A risk-benefit analysis of methadone maintenance treatment. Drug Safety 2000; 22: 179–90
28. Ginzburg HM, MacDonald MG. The role of naltrexone in the management of drug abuse. Med Toxicol 1987; 2: 83–92
29. Gonzalez JP, Brogden RN. Naltrexone: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the management of opioid dependence. Drugs 1988; 35: 192–213
30. Gerada C, et al. Management of the pregnant opiate user. Br J Hosp Med 1990; 43: 138–41
31. Thomas CS, Osborn M. Inhaling heroin during pregnancy. BMJ 1988; 296: 1672.
NEONATAL ABSTINENCE SYNDROME. Infants born to opioid-dependent mothers may suffer withdrawal, with signs including CNS hyperirritability, gastrointestinal dysfunction, respiratory distress, yawning, sneezing, mottling, and fever. Onset of symptoms is partly dependent on the drug and varies from shortly after birth to 2 weeks of age, although most symptoms appear within 72 hours. Some symptoms may persist for 3 months or more. The American Academy of Pediatrics (AAP)1 recommended that treatment of the neonate with abstinence syndrome should be primarily supportive and considered that many infants with signs of drug withdrawal could be managed in this way. They advised adoption of abstinence scoring methods to judge the need for drug therapy, although such systems do not appear to have been validated. Drugs that have been used for opioid withdrawal include paregoric (a USP 31 preparation containing opium), diluted tincture of opium, morphine, methadone, diazepam, chlorpromazine, phenobarbital, and clonidine. Naloxone should not routinely be given to infants of opioid-dependent mothers because of the risk of seizures with abrupt opioid withdrawal. The AAP1 made no definite recommendations but considered that, when appropriate, specific drug therapy should be used for treatment of withdrawal symptoms. Thus for opioid withdrawal, tincture of opium was the preferred drug. Others favour treatment with oral morphine solution.2 The BNFC notes that although morphine is widely used and the dose can be easily adjusted, methadone may provide smoother control of symptoms. Practice varies widely and evidence for the efficacy of particular drugs in the management of neonatal abstinence syndrome is scanty and difficult to compare.3,4 It has been suggested that diazepam may be less useful than phenobarbital or paregoric but the use of paregoric (which contains both camphor and alcohol) has been questioned. In the UK, chlorpromazine has also been widely used5 although a systematic review6 found insufficient evidence to support such use. The authors6 also found that phenobarbital may reduce the severity of withdrawal symptoms in those receiving an opioid; there was insufficient evidence to support the use of clonidine.
1. American Academy of Pediatrics, Committee on Drugs. Neonatal drug withdrawal. Pediatrics 1998; 101: 1079–88. Correction. ibid.; 102: 660 [dosage error]
2. Gregg JEM, et al. Maternal narcotic abuse and the newborn. Arch Dis Child 1988; 63: 684
3. Theis JGW, et al. Current management of the neonatal abstinence syndrome: a critical analysis of the evidence. Biol Neonate 1997; 71: 345–56
4. Johnson K, et al. Treatment of neonatal abstinence syndrome. Arch Dis Child Fetal Neonatal Ed 2003; 88: F2–F5
5. Morrison CL, Siney C. A survey of the management of neonatal opiate withdrawal in England and Wales. Eur J Pediatr 1996; 155: 323–6
6. Osborn DA, et al. Sedatives for opiate withdrawal in newborn infants. Available in The Cochrane Database of Systematic Reviews; Issu
3. Chichester: John Wiley; 2005 (accessed 26/06/08).

💊 Adverse Effects

In usual doses the commonest adverse effects of opioid analgesics are nausea, vomiting, constipation, drowsiness, and confusion; tolerance to these (except constipation) generally develops with long-term use. Micturition may be difficult and there may be ureteric or biliary spasm; the latter may be associated with alterations in liver enzyme values. There is also an antidiuretic effect. Dry mouth, dizziness, sweating, facial flushing, headache, vertigo, bradycardia, tachycardia, palpitations, orthostatic hypotension, hypothermia, restlessness, changes of mood, decreased libido or potency, hallucinations, and miosis also occur. These effects tend to occur more commonly in ambulant patients than in those at rest in bed and in those without severe pain. Raised intracranial pressure occurs in some patients. Muscle rigidity has been reported after high doses. The euphoric activity of opioids has led to their abuse. For a discussion of opioid dependence, see above. Larger doses of opioids produce respiratory depression and hypotension, with circulatory failure and deepening coma. Convulsions may occur, especially in infants and children. Rhabdomyolysis progressing to renal failure has been reported in overdosage. Death may occur from respiratory failure. Toxic doses of specific opioids vary considerably with the individual and regular users may tolerate large doses. The triad of coma, pinpoint pupils, and respiratory depression is considered indicative of opioid overdosage; dilatation of the pupils occurs as hypoxia develops. Pulmonary oedema after overdosage is a common cause of fatalities among opioid addicts. Morphine and some other opioids have a dose-related histamine-releasing effect which may be responsible in part for reactions such as urticaria and pruritus as well as hypotension and flushing. Contact dermatitis has been reported and pain and irritation may occur on injection. Anaphylactic reactions after intravenous injection have been reported rarely.
Some adverse effects of pure opioid agonists, such as the respiratory depressant effect of morphine, are dose related, whereas agonist-antagonists such as buprenorphine, butorphanol, and nalbuphine exhibit a ‘ceiling effect’ as the dose increases. The type and extent of adverse effects experienced in practice may depend on whether or not opioid-sensitive pain is present, whether the opioid analgesic is being given for the control of chronic severe pain or acute pain, and the route used. In a review3of the use of opioids in chronic pain it was noted that, despite worries to the contrary, respiratory depression and dependence liability are not generally a problem when appropriate doses are used to treat opioid-sensitive pain. In fact the presence of opioidsensitive pain appears to protect against the respiratory depressant effect, although it may occur if the source of opioid-sensitive pain is removed (e.g. by surgery) without adequate reduction in opioid dosage. The adverse effects of opioid analgesics when used in advanced cancer have also been discussed.4 Constipation was considered to be the most troublesome adverse effect; significant respiratory depression was rarely seen with recommended regimens, since pain antagonises the central depressant effects of morphine. In the context of acute postoperative pain opioid-induced respiratory depression is of concern but short-term postoperative use is unlikely to cause dependence (although see Treatment of Opioid Dependence, above for references to iatrogenic physical dependence).5 It was hoped that giving opioids by the spinal route would result in fewer adverse effects, especially respiratory depression. In postoperative pain relief with spinal opioids, the incidence of adverse effects is said to be low when patients are properly monitored.6 However, some7 have reported pruritus, nausea and vomiting, and urinary retention to be common and respiratory depression to occur; more seriously the appearance of respiratory depression could be considerably delayed. These effects were more common with morphine, but all opioid analgesics had the propensity to produce respiratory depression when given spinally.7 Delayed respiratory depression has been attributed to the poor lipid solubility of morphine, but does occur after other opioids. Some have considered that despite earlier worries, potentially fatal late respiratory depression was as rare with the spinal route as postoperative respiratory depression with the conventional route.8,9 Disputes regarding the frequency of respiratory depression associated with even conventional use of opioid analgesics might be due to the methods used for measuring respiratory effects.10 The incidence of ventilatory depression has been reported to be higher after intrathecal than epidural use of morphine.11
1. Duthie DJR, Nimmo WS. Adverse effects of opioid analgesic drugs. Br J Anaesth 1987; 59: 61–77
2. Schug SA, et al. Adverse effects of systemic opioid analgesics. Drug Safety 1992; 7: 200–13
3. McQuay HJ. Opioids in chronic pain. Br J Anaesth 1989; 63: 213–26
4. Twycross RG, Lack SA. Oral morphine in advanced cancer. 2nd ed. Beaconsfield: Beaconsfield Publishers, 1989
5. Mitchell RWD, Smith G. The control of acute postoperative pain. Br J Anaesth 1989; 63: 147–58
6. Lutz LJ, Lamer TJ. Management of postoperative pain: review of current techniques and methods. Mayo Clin Proc 1990; 65: 584–96
7. Morgan M. The rational use of intrathecal and extradural opioids. Br J Anaesth 1989; 63: 165–88
8. Anonymous. Spinal opiates revisited. Lancet 1986; i: 655–6
9. McQuay HJ. Spinal opiates. Br J Hosp Med 1987; 37: 354–5
10. Wheatley RG, et al. Postoperative hypoxaemia: comparison of extradural, i.m. and patient-controlled opioid analgesia. Br J Anaesth 1990; 64: 267–75
11. Gustafsson LL, et al. Adverse effects of extradural and intrathecal opiates: report of a nationwide survey in Sweden. Br J Anaesth 1982; 54: 479–85.

Effects on the cardiovascular system.

For reference to histamine release and cardiovascular effects following the intravenous administration of some opioids see under Pethidine.

Effects on the endocrine system.

Endogenous opioid peptides may have a role in the regulation of endocrine function. Like endorphin and enkephalins, morphine has been found to stimulate prolactin release1 and synthetic analogues of morphine are reported to have similar properties; long-term intrathecal opioids (morphine or hydromorphone) have been reported to produce hypogonadotrophic hypogonadism, adrenal insufficiency, and growth hormone deficiency, although tolerance to the effects on prolactin develops with long-term use.2 Opioids such as morphine are also part of a large group of drugs implicated in causing hyperglycaemia.3
1. Hell K, Wernze H. Drug-induced changes in prolactin secretion: clinical implications. Med Toxicol 1988; 3: 463–98
2. Abs R, et al. Endocrine consequences of long-term intrathecal administration of opioids. J Clin Endocrinol Metab 2000; 85: 2215–22
3. O’Byrne S, Feely J. Effects of drugs on glucose tolerance in noninsulin-dependent diabetics (part II). Drugs 1990; 40: 203–19.

💊 Treatment of Adverse Effects

Activated charcoal may be given orally in conscious patients if a substantial overdose has been ingested within 1 hour provided that the airway can be protected (see below); it should be considered in all patients if a substantial amount of a modified-release preparation has been ingested. Intensive supportive therapy may be required to correct respiratory failure and shock. In addition, the specific antagonist naloxone is used for rapid reversal of the severe respiratory depression and coma produced by excessive doses of opioid analgesics. Since naloxone has a shorter duration of action than many opioids patients who have already responded should be kept under close observation for signs of relapse and repeated injections given according to the respiratory rate and depth of coma. Alternatively, in situations where repeated administration is required, such as where a longer acting opioid is known or suspected to be the cause of symptoms, a continuous intravenous infusion of naloxone, adjusted according to response, may be used. All patients should be observed for at least 6 hours after the last dose of naloxone. The use of opioid antagonists such as naloxone in persons physically dependent on opioids may induce withdrawal symptoms.

Activated charcoal.

The National Poisons Information Service in the UK considers the benefit of gastric decontamination in the management of overdosage with opioid analgesics to be uncertain. However, it is suggested that oral activated charcoal may be considered if given within 1 hour of ingestion and the quantity of opioid analgesic is substantial or, for these specific drugs, exceeds the following amount:
buprenorphine: 100 micrograms/kg (adult); 100 micrograms/kg (child)
codeine: 350 mg (adult); 5 mg/kg (child)
dihydrocodeine: 420 mg (adult); 3 mg/kg (child)
methadone: any amount in an opioid-naive patient or more than the prescribed daily dose if on methadone therapeutically
tramadol: 500 mg (adult); 10 mg/kg (child) See also under individual monographs.

Constipation.

For reference to the use of opioid antagonists, particularly naloxone, to relieve opioid-induced constipation without compromising analgesic control in patients receiving long-term therapy with opioids, see Reversal of Opioid Effects under Uses and Administration of Naloxone.
1. Kurz A, Sessler DI. Opioid-induced bowel dysfunction: pathophysiology and potential new therapies. Drugs 2003; 63: 649–71.

💊 Precautions

Opioid analgesics are generally contra-indicated in acute respiratory depression and obstructive airways disease, although opioids such as morphine are used in some forms of dyspnoea (see below). They are also contra-indicated or should be used with great caution in acute alcoholism, convulsive disorders, head injuries, and conditions in which intracranial pressure is raised. They should not be given to comatose patients. Opioid analgesics should be given with caution or in reduced doses to patients with hypothyroidism, adrenocortical insufficiency, asthma or decreased respiratory reserve, renal or hepatic impairment, prostatic hyperplasia, hypotension, shock, inflammatory or obstructive bowel disorders, or myasthenia gravis. Dosage should be reduced in elderly or debilitated patients. Opioid analgesics should be given with great care to infants, especially neonates. Their use during labour may cause respiratory depression in the neonate. Babies born to opioid-dependent mothers may suffer withdrawal symptoms (see Neonatal Abstinence Syndrome, above). Therapy with opioid analgesics should be stopped gradually in patients who may have developed physical dependence, to avoid precipitating withdrawal symptoms (see Dependence, above). Opioid analgesics with some antagonist activity, such as buprenorphine, butorphanol, nalbuphine, or pentazocine, may precipitate withdrawal symptoms in physically dependent patients who have recently used pure agonists such as morphine. Drowsiness may affect the ability to perform skilled tasks; those so affected should not drive or operate machinery.

Asthma.

Opioids appear to be safe and may be used with caution in controlled asthma; however, they should be avoided during acute exacerbations.1
1. Barnes PJ, Chung KF. Difficult asthma. BMJ 1989; 299: 1031–2.

Biliary-tract disorders.

It is usually recommended that opioids such as morphine should either be avoided in patients with biliary disorders or that they should be given with an antispasmodic. Morphine can cause an increase in intrabiliary pressure as a result of effects on the sphincter of Oddi1 and may therefore be expected to exacerbate rather than relieve pain in patients with biliary colic or other biliary-tract disorders. Biliary-type pain after cholecystectomy has also been associated with codeine2 and morphine.3 Morphine caused a more marked delay in gallbladder emptying than pethidine, pentazocine, or butorphanol in a study4 in healthy subjects; this was considered confirmation that morphine should be avoided in biliary disorders. In another study5 fentanyl and sufentanil did not constrict the common bile duct like morphine; they may be suitable for perioperative pain control in patients in whom spasm of the common bile duct is undesirable. The suggestion that pethidine should be preferred to morphine in patients with acute pancreatitis, because of its lesser effect on the bile duct, has been questioned.6
1. Helm JF, et al. Effects of morphine on the human sphincter of Oddi. Gut 1988; 29: 1402–7
2. Druart-Blazy A, et al. The underestimated role of opiates in patients with suspected sphincter of Oddi dysfunction after cholecystectomy. Gastroenterol Clin Biol 2005; 29: 1220–3
3. Roberts-Thomson IC, et al. Sympathetic activation: a mechanism for morphine induced pain and rises in liver enzymes after cholecystectomy? Gut 1990; 31: 217–21
4. Hahn M, et al. The effect of four narcotics on cholecystokinin octapeptide stimulated gall bladder contraction. Aliment Pharmacol Ther 1988; 2: 129–34
5. Vieira ZEG, et al. Evaluation of fentanyl and sufentanil on the diameter of the common bile duct by ultrasonography in man: a double blind, placebo controlled study. Int J Clin Pharmacol Ther 1994; 32: 274–7
6. Thompson DR. Narcotic analgesic effects on the sphincter of Oddi: a review of the data and therapeutic implications in treating pancreatitis. Am J Gastroenterol 2001; 96: 1266–72.

Children.

Children under 6 months of age may be more sensitive to opioids; neonates in particular may be more sensitive to respiratory depression with morphine than adults. Pharmacokinetic differences may contribute to this increased sensitivity. Nonetheless, neonates can be treated with opioids such as morphine if receiving respiratory support. Older infants and children can be treated effectively with morphine or other opioid analgesics and from the age of 5 or 6 months morphine metabolism follows the course seen in adults. For a discussion of the choice of analgesic in children. References.
1. Choonara IA. Pain relief. Arch Dis Child 1989; 64: 1101–2
2. Lloyd-Thomas AR. Pain management in paediatric patients. Br J Anaesth 1990; 64: 85–104
3. Bhatt-Mehta V. Current guidelines for the treatment of acute pain in children. Drugs 1996; 51: 760–76
4. Marsh DF, et al. Opioid systems and the newborn. Br J Anaesth 1997; 79: 787–95.

The elderly.

Ageing can affect the pharmacokinetics and pharmacodynamics of opioids although the net effects of these changes on opioid analgesia in the elderly remain unclear.1 Practical recommendations include careful review of indication for opioid use both initially and at regular intervals thereafter, starting opioids cautiously at lower doses and with longer dosing intervals, and regular consideration given to dose reduction and drug substitution or discontinuation. If possible, further drugs should not be prescribed to manage the adverse effects of opioids.
1. Wilder-Smith OHG. Opioid use in the elderly. Eur J Pain 2005; 9: 137–40.

Hepatic impairment.

The pharmacokinetics of opioids may be altered in patients with hepatic dysfunction. A review1 of opioid use in this patient group considered that opioids such as morphine and hydromorphone that are metabolised by glucuronidation were relatively safe when compared with those metabolised by cytochrome P450 isoenzymes; the half-lives of glucuronidated opioids were found to be maintained until late disease whereas the prolonged half-lives seen with opioids metabolised by P450 isoenzymes were not accurately predicted by disease severity. It was also recommended that oral immediate-release or parenteral, short-acting opioids were preferable to long-acting preparations such as transdermal or modified-release formulations.
1. Davis M. Cholestasis and endogenous opioids: liver disease and exogenous opioid pharmacokinetics. Clin Pharmacokinet 2007; 46: 825–50.

Phaeochromocytoma.

Morphine and some other opioids can induce the release of endogenous histamine and thereby stimulate catecholamine release. Both diamorphine1 and pethidine2have been reported to cause hypertension when given to patients with phaeochromocytoma and histamine-releasing opioids should be avoided in such patients. Alfentanil, like fentanyl, does not release histamine and may be the opioid of choice in the anaesthetic management of patients with phaeochromocytoma.3
1. Chaturvedi NC, et al. Diamorphine-induced attack of paroxysmal hypertension in phaeochromocytoma. BMJ 1974; 2: 538
2. Lawrence CA. Pethidine-induced hypertension in phaeochromocytoma. BMJ 1978; 1: 149–50
3. Hull CJ. Phaeochromocytoma: diagnosis, preoperative preparation and anaesthetic management. Br J Anaesth 1986; 58: 1453–68.

Renal impairment.

A literature review1 concluded that codeine and morphine are best avoided in patients with renal failure and/or on dialysis; hydromorphone may be used with caution and monitoring, and use of fentanyl and methadone appeared to be safe. Similar recommendations have been made for patients with end-stage renal disease who are not undergoing dialysis.2See also under the individual monographs.
1. Dean M. Opioids in renal failure and dialysis patients. J Pain Symptom Manage 2004; 28: 497–504
2. Murtagh FE, et al. The use of opioid analgesia in end-stage renal disease patients managed without dialysis: recommendations for practice. J Pain Palliat Care Pharmacother 2007; 21: 5–16.

💊 Interactions

As serious and sometimes fatal reactions have followed use of pethidine in patients receiving MAOIs (including moclobemide), pethidine and related drugs are contra-indicated in patients taking MAOIs or within 14 days of stopping such treatment; other opioid analgesics should be avoided or given with extreme caution. Life-threatening reactions have also been reported when selegiline, a selective inhibitor of monoamine oxidase type B, has been given with pethidine. The depressant effects of opioid analgesics are enhanced by other CNS depressants such as alcohol, anaesthetics, anxiolytics, hypnotics, tricyclic antidepressants, and antipsychotics. Cyclizine may counteract the haemodynamic benefits of opioids. Cimetidine inhibits the metabolism of some opioids, especially pethidine. The actions of opioids may in turn affect the activities of other drugs. For instance, their gastrointestinal effects may delay absorption as with mexiletine or may be counteractive as with cisapride, metoclopramide, or domperidone. Opioid premedicants such as papaveretum have been reported to reduce serum concentrations of ciprofloxacin.

Alcohol.

Rapid release or dose-dumping of hydromorphone from a modified-release preparation (Palladone; Purdue Frederick, USA) has been associated with the ingestion of alcohol. Health Canada1 has warned that this interaction may occur with all modified-release formulations of opioid analgesics. Licensed product information for some modified-release preparations of morphine sulfate also warns against such use.
1. Health Canada. Potentially fatal interaction between slow-release opioid painkillers and alcohol (issued 3rd August, 2005). Available at: http://www.hc-sc.gc.ca/ahc-asc/media/ advisories-avis/_2005/2005_84-eng.php (accessed 26/06/08)

Antivirals.

Interactions between opioid analgesics and HIVprotease inhibitors or reverse transcriptase inhibitors are complex, and the results of the limited number of studies and reports in vivo have not always borne out predictions about the nature of potential interactions.
Substantial decreases in the area under the plasma concentration-time curve (AUC) and in the plasma concentration have been reported for pethidine when given with ritonavir; however, plasma concentrations of the toxic metabolite norpethidine are greatly increased, and licensed product information for ritonavir counsels against such combined use. Ritonavir is predicted to reduce plasma concentrations of morphine. Plasma concentrations of methadone may be reduced if given with HIV-protease inhibitors although the effect may not be clinically significant. The NNRTIs nevirapine and efavirenz have also been reported to reduce plasma-methadone levels and withdrawal symptoms have occurred when given to patients receiving methadone. In addition, efavirenz has been reported to decrease the AUC of buprenorphine.
In contrast, an increase in AUC and in elimination half-life of fentanyl has been reported in subjects also receiving ritonavir. Licensed product information for ritonavir also considers that increased plasma concentrations of buprenorphine, dextropropoxyphene, and tramadol, with an increased likelihood of opioid toxicity, may occur if these drugs are given during ritonavir treatment. Licensed information for meptazinol also states that increased plasma concentrations of meptazinol have been noted when given with ritonavir. The NNRTI delavirdine has been reported to increase the plasma concentrations of buprenorphine and methadone.

Histamine H2-antagonists.Histamine H

2-antagonists may enhance the effects of some opioid analgesics. Cimetidine was reported to alter the clearance and volume of distribution of pethidine1 whereas ranitidine did not.2 Morphine has been considered less likely to interact with cimetidine than pethidine because of differences in metabolism. In a study3 cimetidine did not affect the disposition of morphine in healthy subjects. A later study4 in patients undergoing major surgery suggested that preor postoperative intravenous cimetidine did not significantly affect outcomes such as morphine consumption and incidence of adverse effects when compared with placebo. Nevertheless, there have been isolated reports of possible interactions between morphine and H2-antagonists; apnoea, confusion, and muscle twitching have been associated with cimetidine plus morphine,5and confusion associated with ranitidine plus morphine.6 There has also been a report7 of a patient receiving regular analgesia with oral methadone and subcutaneous morphine who became unresponsive 6 days after starting cimetidine for prophylaxis of peptic ulcer; treatment with naloxone was required.
1. Guay DRP, et al. Cimetidine alters pethidine disposition in man. Br J Clin Pharmacol 1984; 18: 907–14
2. Guay DRP, et al. Ranitidine does not alter pethidine disposition in man. Br J Clin Pharmacol 1985; 20: 55–9
3. Mojaverian P, et al. Cimetidine does not alter morphine disposition in man. Br J Clin Pharmacol 1982; 14: 809–13
4. Chia Y-Y, et al. Randomized, double-blind study comparing postoperative effects of treatment timing with histamine H -receptor antagonist cimetidine. Acta Anaesthesiol Scand 2005; 49: 865–9
5. Fine A, Churchill DN. Potentially lethal interaction of cimetidine and morphine. Can Med Assoc J 1981; 124: 1434, 1436
6. Martinez-Abad M, et al. Ranitidine-induced confusion with concomitant morphine. Drug Intell Clin Pharm 1988; 22: 914–15
7. Sorkin EM, Ogawa GS. Cimetidine potentiation of narcotic action. Drug Intell Clin Pharm 1983; 17: 60–1.

💊 Uses and Administration

Opioid analgesics possess some of the properties of naturally occurring or endogenous opioid peptides. Endogenous opioid peptides are widely distributed in the CNS and are also found in other parts of the body. They appear to function as neurotransmitters, modulators of neurotransmission, or neurohormones. Their presence in the hypothalamus suggests a role in the regulation of endocrine function. Opioids have been shown to stimulate the release of some pituitary hormones, including prolactin and growth hormone, and to inhibit the release of others, including corticotropin. Endogenous peptides include the enkephalins, endorphins, and dynorphins; their polypeptide precursors may also be precursors for non-opioid peptides. Proenkephalin is the precursor of met- and leu-enkephalin; pro-opiomelanocortin is the precursor of beta-endorphin, beta-lipotrophin, melanocyte-stimulating hormone, and corticotropin; and prodynorphin is the precursor of dynorphins and neoendorphins. Pharmacologically the opioid analgesics are broadly similar; qualitative and quantitative differences may be dependent on their interaction with opioid receptors. There are several types of opioid receptor and they are distributed in distinct patterns through the central and peripheral nervous systems. The three main types in the CNS were originally designated μ (mu), κ (kappa), and δ (delta) although they have been reclassified as OP 3 , OP 2 , and OP 1 , respectively. Activities attributed to the stimulation of these receptors have been as follows:
μ—analgesia (mainly at supraspinal sites), respiratory depression, miosis, reduced gastrointestinal motility, and euphoria;
Published February 06, 2019.