Summary
The prevalence of pain is high in multimorbid patients and they can experience a multitude of painful conditions. The changes in physiology and homeostasis associated with multimorbidity and increasing age and the immature metabolism of neonates all increase the risk of toxicity from analgesics. Altered pharmacokinetics and metabolism influence drug pharmacodynamics and therapeutic windows. Imbalances in local homeostatic mechanisms increase local toxicity. The gastrointestinal organs and the kidney have a major role in the absorption, metabolism and excretion of analgesics and changes in their function predispose individuals to adverse effects. Knowledge of such compromise should influence the choice of analgesic, the administration regimen and the mode of application.
The mainstay of chronic pain treatment are 3 classes of drugs: nonsteroidal anti-inflammatory drugs (NSAIDs), opioids and a host of so-called adjuvant drugs, which are used to enhance the analgesic action of the classic analgesics. In each class a wide range of drugs are available, that differ in pharmacokinetic and pharmacodynamic characteristics. These differences can be exploited to either increase analgesic efficacy and reduce toxicity, or to minimise the interference of pain therapy with daily life.
Clinically important differences in analgesic and toxic effects between drugs in each analgesic class will be discussed in this article from the perspective of reducing adverse effects. New knowledge concerning the mechanism of action of analgesics and their metabolites is making the specific selection of NSAIDs and opioids to reduce adverse effects in multimorbid, chronic pain patients possible.
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References
Cleeland CS, Gonin R, Hatfield AK, et al. Pain and its treatment in outpatients with metastatic cancer. N Engl J Med 1994; 330: 592–6
Cherny NI, Thaler HAT, Friedlander-Klar H, et al. Opioid responsiveness of cancer pain syndromes caused by neuropathic or nociceptive mechanisms: a combined analysis of controlled, single-dose studies. Neurology 1994; 44: 857–61
Hanks GW, Forbes K. Opioid responsiveness. Acta Anaesthesiol Scand 1997; 41: 154–8
Twycross RG, Lack SA. Analgesics. In: Symptom control in far advanced cancer: pain relief. London: Pitman Publishing, 1984
Inturrisi CE. Effects of other drugs and pathologic states on opioid disposition and response. In: Benedetti C, Chapman CR, Giron G, editors. Advances in pain research and therapy. Vol 14. New York: Raven Press, 1990: 171–80
Kaiko RF, Wallenstein SL, Rogers AG, et al. Clinical analgesic studies and sources of variation in analgesic responses to morphine. In: Foley KM, Inturrisi CE, editors. Advances in pain research and therapy. Vol 8. New York: Raven Press, 1986: 13–24
Moore RA, Sear JW, Bullingham RES, et al. Morphine kinetics in renal failure. In: Foley KM, Inturrisi CE, editors. Advances in pain research and therapy. Vol 8. New York: Raven Press, 1986: 65–72
Mather LE. Do the pharmacodynamics of the nonsteroidal anti-inflammatory drugs suggest a role in the management of postoperative pain? Drugs 1992; 44 Suppl. 5: 1–13
Yue QY, Säwe J. Interindividual and interethnic differences in codeine metabolism. In: Kalow W, editor. Pharmacogenetics of drug metabolism. New York: Pergamon Press, 1992: 721–7
Dandona P, Jeremy JY. Nonsteroidal anti-inflammatory drug therapy and gastric side-effects: does nabumetone provide a solution? Drugs 1990; 40 Suppl. 5: 16–24
O’Malley K. Clinical pharmacology and drug treatment in the elderly. Oxford: Churchill Livingstone, 1984: 71–98
Bodenham A, Shelley MP, Park GR. The altered pharmacokinetics and pharmacodynamics of drugs commonly used in critically ill patients. Clin Pharmacokinet 1988; 14: 347–73
Olkkola KT, Hamunen K, Maunuksela EL. Clinical pharmacokinetics and pharmacodynamics of opioid analgesics in infants and children. Clin Pharmacokinet 1995; 28: 385–404
Gaukroger PB. Paediatric analgesia: which drug? Which dose? Drugs 1991; 41: 52–9
Blaho K, Winbery S, Merigan K. Pharmacological considerations for the pediatric patient. Optom Clin 1996; 5: 61–90
McGuire DB. Comprehensive and multidimensional assessment and measurement of pain. J Pain Symptom Manage 1992; 7: 312–9
Hayes R. Pain assessment in the elderly. Br J Nurs 1995; 4: 1199–204
Simons W, Malabar R. Assessing pain in elderly patients who cannot respond verbally. J Adv Nurs 1995; 22: 663–9
Bieri D, Reeve RA, Champion GD, et al. The Faces pain scale for the self-assessment of the severity of pain experienced by children: development, initial validation, and preliminary investigation for ratio scale properties. Pain 1990; 41: 139–50
Guinsburg R, Berenguel RC, de Cassia Xavier R, et al. Are behavioural scales suitable for preterm and term neonatal pain assessment? Proceedings of the 8th World Congress on Pain. In: Jensen TS, Turner JA, Wiesenfeld-Hallin Z, editors. Progress in pain research development and management. Vol 8. Seattle: IASP Press, 1997: 893–901
Porter FL, Malhotra KM, Wolf CM, et al. Dementia and response to pain in the elderly. Pain 1996; 68: 413–21
Cummings EA, Reid GJ, Finlay GA, et al. Prevalence and source of pain in paediatric inpatients. Pain 1996; 68: 25–31
Desbiens NA, Mueller-Rizner N, Connors AF, et al. Pain in the oldest-old during hospitalisation and up to one yeat later. J Am Geriatr Soc 1997; 45: 1167–72
Puntillo KA, Miaskowski C, Kehrle K, et al. Relationship between behavioural and physiological indicators of pain, critical care patients’ self-report of pain, and opioid administration. Crit Care Med 1997; 25: 1159–66
McGrath PA, Speechley KN, Seifert CE, et al. A survey of children’s pain experience and knowledge — Phase 1. Proceedings of the 8th World Congress on Pain. In: Jensen TS, Turner JA, Wiesenfeld-Hallin Z, editors. Progress in pain research development and management. Vol 8. Seattle: IASP Press, 1997: 903–16
Fries JF, Miller SR, Spitz PW, et al. Towards an epidemiology of gastropathy associated with nonsteroidal anti-inflammatory drug use. Gastroenterology 1989; 96: 646–55
Baum C, Kennedy DL, Forbes MB. Utilization of nonsteroidal anti-inflammatory drugs. Arthritis Rheum 1985; 28: 686–92
Committee on Safety of Medicines. CME update: nonsteroidal anti-inflammatory drugs and serious gastrointestinal adverse reactions-2. BMJ 1986; 292: 1190–1
Johnson AG. NSAIDs and blood pressure: clinical importance for older patients. Drugs Aging 1998; 12: 17–27
Armstrong CP, Blower AL. Nonsteroidal anti-inflammatory drugs and life threatening complications of peptic ulceration. Gut 1987; 28: 527–32
Roth SH, Bennett RE. Nonsteroidal anti-inflammatory drug gastropathy. Arch Intern Med 1987; 147: 2093–100
Fries JF, Williams CA, Bloch DA, et al. Nonsteroidal anti-inflammatory drug-associated gastropathy: incidence and risk factor models. Am J Med 1991; 91: 213–22
Bjarnason I, Hayllar J, MacPherson AJ, et al. Side-effects of non-steroidal anti-inflammatory drugs on the small and large intestine in humans. Gastroenterology 1993; 104: 1832–47
Sugawa C, Takekuma Y, Lucas CE, et al. Bleeding esophageal ulcers caused by NSAIDs. Surg Endosc 1997; 11: 143–6
Lanza FL. Gastrointestinal toxicity of newer NSAIDs. Am J Gastroenterol 1993; 88: 1318–23
Carson JL, Willett LR. Toxicity of non-steroidal anti-inflammatory drugs. Drugs 1993; 46 Suppl. 1: 243–8
Gabriel SE, Jaakkimainen L, Bombardier C. Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs: a meta-analysis. Ann Intern Med 1991; 115: 787–96
Llewellyn JH, Prichard MH. Influence of age and disease state in nonsteroidal anti-inflammatory drug-associated gastric bleeding. J Rheumatol 1988; 15: 691–4
Garcia Rodriguez LA. Nonsteroidal antiinflammatory drugs, ulcers and risk: a collaborative meta-analysis. Semin Arthritis Rheum 1997; 26: 16–29
McMahon AD, Evans JM, White G, et al. A cohort study to measure the association between new NS AID prescribing and upper gastrointestinal haemorrhage and perforation. J Clin Epidemiol 1997; 50: 351–6
Wilcox CM, Alexander LN, Cotsonis GA, et al. Nonsteroidal antiinflammatory drugs associated with both upper and lower gastrointestinal bleeding. Dig Dis Sci 1997; 42: 990–7
Solomon DH, Gurwitz JH. Toxicity of nonsteroidal anti-inflammatory drugs in the elderly: is advanced age a risk factor? Am J Med 1997; 102: 208–15
Kemppainen H, Raiha I, Sourander L. Clinical presentation of peptic ulcer in the elderly. Gerontology 1997; 43: 283–8
Fries JF, Williams CA, Bloch DA. The relative toxicity of nonsteroidal anti-inflammatory drugs. Arthritis Rheum 1991; 34: 1353–60
Rossi AC, Hsu JP, Faich GA. Ulcerogenicity of piroxicam: an analysis of spontaneously reported data. BMJ 1987; 294: 147–50
Griffin MR, Piper JM, Daugherty JR, et al. Nonsteroidal anti-inflammatory drug use and increased risk for peptic ulcer disease in elderly persons. Ann Intern Med 1991; 114: 257–63
Laporte JR, Carne X, Vidal X, et al. Upper gastrointestinal bleeding in relation to previous use of analgesics and non-steroidal anti-inflammatory drugs. Lancet 1991; 337: 85–9
The International Agranulocytosis and Aplastic Anemia Study. Risks of agranulocytosis and aplastic anemia. JAMA 1986; 256: 1749–57
Strom BL, Berlin JA, Kinman JL, et al. Parenteral ketorolac and risk of gastrointestinal and operative site bleeding. JAMA 1996; 275: 376–82
Traversa G, Walker AM, Ippolito FM, et al. Gastroduodenal toxicity of different anti-inflammatory drugs. Epidemiology 1995; 6: 49–54
Vane JR, Botting RM. Mechanism of action of aspirin-like drugs. Semin Arthritis Rheum 1997; 26 Suppl. 1: 2–10
Wallace JL. Non-steroidal anti-inflammatory drugs and gastroenteropathy: the second hundred years. Gastroenterology 1997; 112: 1000–16
Fenner H. Differentiating among nonsteroidal anti-inflammatory drugs by pharmacokinetic and pharmacodynamic profiles. Semin Arthritis Rheum 1997; 26 Suppl. 1: 28–33
Bernhard GC. Worldwide safety experience with nabumetone. J Rheumatol 1992; 19 Suppl. 36: 48–57
Schattenkirchner M. An updated safety profile of etodolac in several thousand patients. Eur J Rheumatol Inflamm 1990; 10: 56–65
Marini U, Spotti D. Gastric tolerability of nimesulide. Drugs 1993; 46 Suppl. 1: 249–52
Davies R, Brogden RN. Nimesulide: an update of its pharmacodynamic and pharmacokinetic properties, and its therapeutic efficacy. Drugs 1994; 48: 431–54
Todd A, Brogden RN. Oxaprozin: a preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy. Drugs 1986; 32: 291–312
Elliott SN, McKnight W, Cirino G, et al. A nitric oxide-releasing nonsteroidal anti-inflammatory drug accelerates gastric ulcer healing in rats. Gastroenterology 1995; 109: 524–30
Davies NM, Roseth AG, Appleyard CB, et al. NO-naproxen vs naproxen: ulcerogenic, analgesic and anti-inflammatory effects. Aliment Pharmacol Ther 1997; 11: 69–79
Stern AI, Ward F, Siewert W. Lack of gastric mucosal protection by sucralfate during long-term aspirin ingestion in humans. Am J Med 1989; 86 Suppl. 6A: 66–9
Robinson MG, Griffin JW, Bowers J, et al. Effect of ranitidine on gastroduodenal mucosal damage induced by nonsteroidal anti-inflammatory drugs. Dig Dis Sci 1989; 34: 424–8
Hawkey CJ, Swannell AJ, Yeomans ND, et al. Site specific ulcer relapse in non-steroidal anti-inflammatory drug user: improved prognosis with H. pylori and with omeprazole compared to misoprostol [abstract]. Gut 1996; 39 Suppl. 1: W5
Curtis WD, Griffin JW. NS AID-induced gastroduodenal injury: therapeutic recommendations. Aliment Pharamcol Ther 1991; 5 Suppl. 1: 99–109
Yeomans ND, Tulassay Z, Juhasz L, et al. A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal antiinflammatory drugs. N Engl Med J 1998; 338: 719–26
Hawkey CJ, Karrasch JA, Szczepanski L, et al. Omeprazole compared with misoprostol for ulcers associated with nonsteroidal antiinflammatory drugs. N Engl Med J 1998; 338: 727–34
Ekstrom P, Carling L, Wetterhus S, et al. Prevention of peptic ulcer and dyspeptic symptoms with omeprazole in patients receiving continuous nonsteroidal antiinflammatory drug therapy. Scand J Gastroenterol 1996; 31: 753–8
Graham DY, Agrawal NM, Roth SH. Prevention of NS AID-induced gastric ulcer with misoprostol: a multicentre, double-blind, placebo-controlled trial. Lancet 1988; II: 1277–80
Lanza FL, Fakouhi D, Rubin A. A double-blind, placebo-controlled comparison of the efficacy and safety of 50, 100 and 200 micrograms of misoprostol QID in the prevention of ibuprofen-induced gastric and duodenal mucosal lesions and symptoms. Am J Gastroenterol 1989; 84: 633–6
Wright V. Arthrotec: a review of a new concept in NS AID therapy. J Orthopaed Rheumatol 1993; 6: 129–33
Melo Gomes JA, Roth SH, Zeeh J, et al. Double-blind comparison of efficacy and gastroduodenal safety of diclofenac/misoprostol, piroxicam, and naproxen in the treatment of osteoarthritis. Ann Rheum Dis 1993; 52: 881–5
Kim JG, Graham DY. Helicobacter pylori infection and development of gastric or duodenal ulcer in arthritic patients receiving chronic NSAID therapy. Am J Gastroenterol 1994; 89: 203–7
Wilcox CM. Relationship between nonsteroidal antiinflammatory drug use, Helicobacter pylori infection and gastroduodenal mucosal injury. Gastroenterology 1997; 113 Suppl. 6: S85–9
Pilotto A, Franceschi M, Leandro G, et al. The effect of Helicobacter pylori infection on NSAID-related gastroduodenal damage in the elderly. Eur J Gastroenterol Hepatol 1997; 9; 951–6
Schubert TT, Bologna SD, Nensey Y, et al. Ulcer risk factors: interactions between H. pylori infection, nonsteroidal use and age. Am J Med 1993; 94: 413–8
Chan FK, Sung JJ, Chung SC, et al. Randomised trial of eradication of Helicobacter pylori before non-steroidal anti-inflammatory drug therapy to prevent ulcers. Lancet 1997; 350: 975–9
Graham DY, Hepps KS, Ramirez FC, et al. Treatment of H. pylori reduces the rate of rebleeding in peptic ulcer disease. Scand J Gastroenterol 1993; 28: 939–42
Rokkas TH, Karameris A, Mavrogeorgis A, et al. Eradication of H. pylori reduces the possibility of rebleeding in peptic ulcer disease. Gastrointest Endosc 1995; 41: 1–4
Hopkins RJ. Current FDA-approved treatments for Helicobacter pylori and the FDA approval process. Gastroenterology 1997; 113 Suppl. 6: S126–30
Hollingworth P. The use of NSAIDs in paediatric rheumatic diseases. Br J Rheumatol 1993; 32: 73–7
Murray MD, Brater DC. Renal toxicity of the non-steroidal anti-inflammatory drugs. Annu Rev Pharmacol Toxicol 1993; 32: 435–65
Kenny GNC. Potential renal, haematological and allergic adverse effects associated with nonsteroidal anti-inflammatory drugs. Drugs 1992; 44 Suppl. 5: 31–7
Johnson AG. NSAIDs and increased blood pressure: what is the clinical significance. Drug Saf 1997; 17: 277–289
Clive DM, Stoff JS. Renal syndromes associated with non-steroidal anti-inflammatory drugs. N Engl J Med 1984; 310: 568–72
Murray MD, Brater DC. Effects of NSAIDs on the kidney. Prog Drug Res 1007; 49: 155–71
Lindsley CB, Warady BA. Nonsteroidal anti-inflammatory drugs. Renal toxicity. Review of pediatric issues. Clin Pediatr 1990; 29: 10–3
Brass EP. Hepatic toxicity of antirheumatic drugs. Cleve Clin J Med 1993; 60: 466–72
Rivera-Penera T, Gugig R, Davies J, et al. Outcome of acetaminophen overdose in pediatric patients and factors contributing to hepatotoxicity. J Pediatr 1997; 130: 300–4
Heubi JE, Barbacci MB, Zimmerman HJ. Therapeutic misadventures with acetaminophen: hepatotoxicity after multiple doses in children. J Pediatr 1998; 132: 22–7
de Almeida MA, Gaspar AP, Carvalho FS, et al. Adverse reactions to acetaminophen, ASA and NSAIDs in children: what alternatives? Allergy Asthma Proc 1997; 18: 313–8
Holder EP, Moore PT, Browne BA. Nonsteroidal anti-inflammatory drugs and necrotising fasciitis: an update. Drug Saf 1997; 17: 369–73
Willer JC, DeBroucker T, Bussel B, et al. Central analgesic effects of ketoprofen in humans: electrophysiological evidence for a supraspinal mechanism in a double-blind and cross-over study. Pain 1989; 38: 1–7
Malmberg AB, Yaksh TL. Hyperalgesia mediated by spinal glutamate or substance P receptor blocked by spinal cyclo-oxygenase inhibition. Science 1992; 257: 1277–80
McCormack K. Nonsteroidal anti-inflammatory drugs and spinal nociceptive processing. Pain 1994; 59: 9–44
Eisenberg E, Berkey C, Carr DB, et al. NSAIDs for cancer pain: meta-analysis of efficacy. In: Gebhart GF, Hammond DL, Jensen TS, editors. Proceedings of the 7th World Congress on Pain. Progress in pain research and management. Vol 2. Seattle: IASP Press, 1994: 697–707
Portenoy RK. The management of cancer pain. Compr Ther 1990; 16: 53–65
McCormack K, Brune K. Dissociation between the antinociceptive and anti-inflammatory effects of the nonsteroidal anti-inflammatory drugs. Drugs 1991; 41: 533–47
Brune K, Menzel-Soglowek S, Zeilhofer HU. Differential analgesic effects of aspirin-like drugs. Drugs 1992; 44 Suppl. 5: 52–9
Lötsch J, Geisslinger G, Mohammadian P, et al. Effects of flurbiprofen enantiomers on pain-related chemo-somatosensory evoked potentials in human subjects. Br J Clin Pharmacol 1995; 40: 339–46
Bonica JJ. Cancer pain: current status and future needs. In: Bonica JJ, editor. The management of pain. 2nd ed. Philadelphia: Lea & Febiger, 1990: 400–45
World Health Organization. Cancer pain relief. 2nd ed. Geneva: World Health Organization Press, 1996
Portenoy RK. Opioid therapy for chronic nonmalignant pain: current status. In: Fields HL, Liebeskind JC, editors. Pharmacological approaches to the treatment of chronic pain: new concepts and critical issues. Progress in pain research and management. Vol 1. Seattle: IASP Press, 1994: 247–287
Reisine T, Pasternak G. Opioid analgesics and antagonists. In: Hardman JG, Limbird LE, editors. Goodman & Gilman’s the pharmacological basis of therapeutics. 9th ed. New York: McGraw Hill, 1996: 521–55
Riviere PJM, Pascaud X, Chevalier E, et al. Fedotozine reverses ileus induced by surgery or peritonitis: action at peripheral kappa-opioid receptors. Gastroenterology 1993; 104: 724–31
Knapp RJ, Hawkins KN, Lui GK, et al. Multiple opioid receptors and novel ligands. In: Benedetti C, Chapman CR, Giron G, editors. Advances in pain research and therapy. Vol.14. New York: Raven Press, 1990: 45–85
Fraitag B, Homerin M, Hecketsweiler P. Double-blind dose-response multicenter comparison of fedotozine and placebo in the treatment of nonulcer dyspepsia. Dig Dis Sci 1994; 39: 1072–7
Huang LM. The excitatory effects of opioids. Neurochem Int 1992; 20: 463–8
Osborne R, Joel S, Trew D, et al. Morphine and metabolite behavior and different routes of morphine administration: demonstration of the active metabolite morphine-6-glucuronide. Clin Pharmacol Ther 1990; 47: 12–9
Lotsch J, Kobal G, Stockman A, et al. Lack of analgesic activity of morphine-6-glucuronide after short-term administration in healthy volunteers. Anesthesiology 1997; 87: 1348–58
Smith MT, Watt JA, Cramond T. Morphine-3-glucuronide: a potent antagonist of morphine analgesia. Life Sci 1992; 47: 579–85
Gong QL, Hedner J, Bjørkman R, et al. Morphine-3-glucuronide may functionally antagonize morphine-6-glucuronide induced antinociception and ventilatory depression in the rat. Pain 1992; 48: 249–55
Lee CR, McTavish D, Sorkin EM. Tramadol: a preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in acute and chronic pain states. Drugs 1993; 46: 313–40
Flacke JW, Flacke WE, Bloor BC. Histamine release by four narcotics: a double-blind study in humans. Anesth Analg 1987; 66: 723–30
Yaksh TL, Harty GJ, Onofrio BM. High doses of spinal morphine produce a nonopiate receptor-mediated hyperesthesia: clinical and theoretical implications. Anesthesiology 1986; 64: 590–7
Thune A, Baker RA, Saccone GT, et al. Differing effects of pethidine and morphine on human sphincter of Oddi motility. Br J Surg 1990; 77: 992–5
Raffa RB, Friedrichs E, Reimann W, et al. Opioid and non-opioid components independently contribute to the mechanism of action of tramadol, an ‘atypical’ opioid analgesic. J Pharmacol Exp Ther 1992; 260: 275–85
Wilder-Smith CH, Schimke J, Osterwalder B, et al. Oral tramadol, a mu-opioid agonist and monoamine reuptake-blocker, and morphine for strong cancer-related pain. Ann Oncol 1994; 5: 141–6
Wilder-Smith CH, Bettiga A. Tramadol has minimal interaction with gastrointestinal motor function. Br J Clin Pharmacol 1997; 43: 71–5
Wilder-Smith CH, Osler W, Bornman P. Characteristics and effective treatment of severe pain from chronic pancreatitis [abstract]. Gastroenterology 1997; 112: A495
Cuschieri R, Morran C, McArdle C. Comparison of morphine and sublingual buprenorphine following abdominal surgery. Br J Anaesth 1984; 56: 855–9
Lewis JW. Pharmacological profile of buprenorphine and its clinical use in cancer pain. In: Foley KM, Inturrisi CE, editors. Advances in pain research and therapy. Vol 8. New York: Raven Press, 1986: 267–70
Kaiko RF. Age and morphine analgesia in cancer patients with postoperative pain. Clin Pharmacol Ther 1980; 28: 823–6
Formain WB. Opioid analgesic drugs in the elderly. Clin Geriatr Med 1996; 12: 489–500
Milne RW, Nation RL, Somogyi AA, et al. The influence of renal function on the renal clearance of morphine and its glucuronide metabolites in intensive-care patients. Br J Clin Pharmacol 1992; 34: 53–9
Säwe J, Svensson JO, Odar-Cederlof I. Kinetics of morphine in patients with renal failure. Lancet 1985; II: 211
Osborne RJ, Joel SP, Slevin ML. Morphine intoxification in renal failure. BMJ 1986; 292: 1548–9
Barnes JN, Williams AJ, Tomson MJF, et al. Dihydrocodeine in renal failure. BMJ 1985; 290: 740–2
Szeto HH, Inturrisi CE, Houde R, et al. Accumulation of normeperidine, an active metabolite of meperidine, in patients with renal failure of cancer. Ann Int Med 1977; 86: 738–41
Davies G, Kingswood C, Street M. Pharmacokinetics of opioids in renal dysfunction. Clin Pharmacokinet 1996: 31: 410–22
Hickey PR. Opioids and outcome in pediatric surgery. In: Estafanous FG, editor. Opioids in anesthesia II. Boston: Butterworth-Heinemann, 1991: 134–46
Houck CS, Troshynski T, Berde C. Treatment of pain in children. In: Wall PD, Melzack R, editors. Textbook of pain. Edinburgh: Churchill Livingston, 1994: 1419–34
Klotz U, McHorse TS, Wilkinson GR, et al. The effect of cirrhosis on the disposition and elimination of meperidine in man. Clin Pharmacol Ther 1974; 16: 667–75
Neal EA, Meffin PJ, Gregory PB, et al. Enhanced bioavailability and decreased clearance of analgesics in patients with cirrhosis. Gastroenterology 1979; 77: 96–102
Säwe J, Kager L, Svensson JO, et al. Oral morphine in cancer patients: in. vivo kinetics and in vivo hepatic glucuronidation. Br J Clin Pharmacol 1985; 19: 495–501
Patwardhan RV, Johnson RF, Hoyumpa A. Normal metabolism of morphine in cirrhosis. Gastroenterology 1981; 81: 1006–11
McQuay HJ, Moore RA. Metabolism of narcotics. BMJ 1984; 288: 237–40
Hasselström J, Eriksson S, Persson A, et al. The metabolism and bioavailability of morphine in patients with severe liver cirrhosis. Br J Clin Pharmacol 1990; 29: 289–97
Novick DM, Kreek MJ, Fanizza AM, et al. Methadone disposition in patients with chronic liver disease. Clin Pharmacol Ther 1981; 30: 353–62
Alvan G, Bechtel P, Iselius L, et al. Hydroxylation polymorphisms of debrisquine and mephenytoin in European populations. Eur J Clin Pharmacol 1990; 39: 533–7
Sindrup SH, Brøsen K, Bjerring P, et al. Codeine increases pain thresholds to copper vapour laser stimuli in extensive but not in poor metabolizers of sparteine. Clin Pharmacol Ther 1990; 48: 686–93
Yue QY, Hasselström J, Svensson JO, et al. Pharmacokinetics of codeine and its metabolites in Caucasian healthy volunteers: comparisons between extensive and poor hydroxylators of debrisoquine. Br J Clin Pharmacol 1991; 31: 635–42
Desmeules J, Gascon MP, Dayer P, et al. Impact of environmental and genetic factors on codeine analgesia. Eur J Clin Pharmacol 1991; 41: 23–6
Wilder-Smith CH, Hufschmid E, Thormann W. The visceral and somatic antinociceptive effects of dihydrocodeine and its metabolite, dihydromorphine. Across-over study with extensive and quinidine-induced poor metabolisers. Br J Clin Pharmacol. In press
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Wilder-Smith, C.H. Pain Treatment in Multimorbid Patients, the Older Population and Other High-Risk Groups. Drug-Safety 18, 457–472 (1998). https://doi.org/10.2165/00002018-199818060-00006
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DOI: https://doi.org/10.2165/00002018-199818060-00006