Abstract
The opioid class of drugs, a large group, is mainly used for the treatment of acute and chronic persistent pain. All are eliminated from the body via metabolism involving principally CYP3A4 and the highly polymorphic CYP2D6, which markedly affects the drug’s function, and by conjugation reactions mainly by UGT2B7. In many cases, the resultant metabolites have the same pharmacological activity as the parent opioid; however in many cases, plasma metabolite concentrations are too low to make a meaningful contribution to the overall clinical effects of the parent drug. These metabolites are invariably more water soluble and require renal clearance as an important overall elimination pathway. Such metabolites have the potential to accumulate in the elderly and in those with declining renal function with resultant accumulation to a much greater extent than the parent opioid. The best known example is the accumulation of morphine-6-glucuronide from morphine. Some opioids have active metabolites but at different target sites. These are norpethidine, a neurotoxic agent, and nordextropropoxyphene, a cardiotoxic agent. Clinicians need to be aware that many opioids have active metabolites that will become therapeutically important, for example in cases of altered pathology, drug interactions and genetic polymorphisms of drug-metabolizing enzymes. Thus, dose individualisation and the avoidance of adverse effects of opioids due to the accumulation of active metabolites or lack of formation of active metabolites are important considerations when opioids are used.
Similar content being viewed by others
References
Cowan A, Lewis JW, Macfarlane IR (1977) Agonist and antagonist properties of buprenorphine, a new antinociceptive agent. Brit J Pharmacol 60:537–545
Cowan A, Doxey JC, Harry EJ (1977) The animal pharmacology of buprenorphine, an oripavine analgesic agent. Br J Pharmacol 60:547–554
Dahan A, Yassen A, Bijl H et al (2005) Comparison of the respiratory effects of intravenous buprenorphine and fentanyl in humans and rats. Br J Anaesth 94:825–834
Dahan A, Yassen A, Romberg R et al (2006) Buprenorphine induces ceiling in respiratory depression but not in analgesia. Br J Anaesth 96:627–632
Codd EE, Shank RP, Schupsky JJ et al (1995) Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception. J Pharmacol Exp Ther 274:1263–1270
Katchman AN, McGroary KA, Kilborn MJ et al (2002) Influence of opioid agonists on cardiac human ether-a-go-go-related gene K(+) currents. J Pharmacol Exp Ther 303:688–694
Huang P, Kehner GB, Cowan A et al (2001) Comparison of pharmacological activities of buprenorphine and norbuprenorphine: norbuprenorphine is a potent opioid agonist. J Pharmacol Exp Ther 297:688–695
Leander JD (1987) Buprenorphine has potent kappa opioid receptor antagonist activity. Neuropharmacol 26:1445–1447
Jensen ML, Foster D, Upton R et al (2007) Comparison of cerebral pharmacokinetics of buprenorphine and norbuprenorphine in an in vivo sheep model. Xenobiotica 37:441–457
Budd K, Collett BJ (2003) Old dog - new (ma)trix. Br J Anaesth 90:722–724
Vachharajani NN, Shyu WC, Greene DS et al (1997) The pharmacokinetics of butorphanol and its metabolites at steady state following nasal administration in humans. Biopharm Drug Dispos 18:191–202
Pachter IJ, Evens RP (1985) Butorphanol. Drug Alcohol Depend 14:325–338
Gaver RC, Vasiljev M, Wong H et al (1980) Disposition of parenteral butorphanol in man. Drug Metab Dispos 8:230–235
Ameer B, Salter FJ (1979) Drug therapy reviews: evaluation of butorphanol tartrate. Am J Hosp Pharm 36:1683–1691
Chen ZR, Somogyi AA, Reynolds G et al (1991) Disposition and metabolism of codeine after single and chronic doses in one poor and seven extensive metabolisers. Br J Clin Pharmacol 31:381–390
Yue QY, Hasselstrom J, Svensson JO et al (1991) Pharmacokinetics of codeine and its metabolites in Caucasian healthy volunteers: comparisons between extensive and poor hydroxylators of debrisoquine. Br J Clin Pharmacol 31:635–642
Vree TB, Verwey-van Wissen CP (1992) Pharmacokinetics and metabolism of codeine in humans. Biopharm Drug Dispos 13:445–460
Chen ZR, Somogyi AA, Bochner F (1988) Polymorphic O-demethylation of codeine. Lancet 2:914–915
Sindrup S, Brøsen K (1995) The pharmacogenetics of codeine hypoalgesia. Pharmacogenetics 5:335–346
Poulsen L, Riishede L, Brosen K et al (1998) Codeine in post-operative pain: study of the influence of sparteine phenotype and serum concentrations of morphine and morphine-6-glucuronide. Eur J Clin Pharmacol 54:451–454
Sindrup SH, Poulsen L, Brosen K et al (1993) Are poor metabolisers of sparteine/debrisoquine less pain tolerant than extensive metabolisers? Pain 53:335–339
Somogyi AA, Barratt DT, Coller JK (2007) Pharmacogenetics of opioids. Clin Pharmacol Ther 81:429–444
Caraco Y, Sheller J, Wood AJ (1996) Pharmacogenetic determination of the effects of codeine and prediction of drug interactions. J Pharmacol Exp Ther 278:1165–1174
Eckhardt K, Li S, Ammon S et al (1998) Same incidence of adverse drug events after codeine administration irrespective of the genetically determined differences in morphine formation. Pain 76:27–33
Quiding H, Lundqvist G, Boreus LO et al (1993) Analgesic effect and plasma concentrations of codeine and morphine after two dose levels of codeine following oral surgery. Eur J Clin Pharmacol 44:319–323
Srinivasan V, Wielbo D, Simpkins J et al (1996) Analgesic and immunomodulatory effects of codeine and codeine 6-glucuronide. Pharm Res 13:296–300
Lötsch J, Skarke C, Schmidt H et al (2006) Evidence for morphine-independent central nervous opioid effects after administration of codeine: contribution of other codeine metabolites. Clin Pharmacol Ther 79:35–48
Kirchheiner J, Schmidt H, Tzvetkov M et al (2007) Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication. Pharmacogenomics J 7:257–265
Dalén P, Frengell C, Dahl M-L et al (1997) Quick onset of severe abdominal pain after codeine in an ultrarapid metabolizer of debrisoquine. Ther Drug Monit 19:543–544
Gasche Y, Daali Y, Fathi M et al (2004) Codeine intoxication associated with ultrarapid CYP2D6 metabolism. N Engl J Med 351:2827–2831
Koren G, Cairns J, Chitayat D et al (2006) Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother. Lancet 368:704
Leysen JE, Gommeren W, Niemegeers CJ (1983) [3H]Sufentanil, a superior ligand for mu-opiate receptors: binding properties and regional distribution in rat brain and spinal cord. Eur J Pharmacol 87:209–225
Neil A (1984) Affinities of some common opioid analgesics towards four binding sites in mouse brain. Naunyn-Schmiedeberg’s Arch Pharmacol 328:24–29
Somogyi AA, Menelaou A, Fullston SV (2004) CYP3A4 mediates dextropropoxyphene N-demethylation to nordextropropoxyphene: human in vitro and in vivo studies and lack of CYP2D6 involvement. Xenobiotica 34:875–887
Flanagan RJ, Johnston A, White AS et al (1989) Pharmacokinetics of dextropropoxyphene and nordextropropoxyphene in young and elderly volunteers after single and multiple dextropropoxyphene dosage. Br J Clin Pharmacol 28:463–469
Ebert B, Andersen S, Hjeds H et al (1998) Dextropropoxyphene acts as a noncompetitive N-methyl-D-aspartate antagonist. J Pain Symptom Manage 15:269–274
Ulens C, Daenens P, Tytgat J (1999) Norpropoxyphene-induced cardiotoxicity is associated with changes in ion-selectivity and gating of HERG currents. Cardiovasc Res 44:568–578
Schmidt H, Vormfelde SV, Klinder K et al (2002) Affinities of dihydrocodeine and its metabolites to opioid receptors. Pharmacol Toxicol 91:57–63
Fromm MF, Hofmann U, Griese E-U et al (1995) Dihydrocodeine: a new opioid substrate for the polymorphic CYP2D6 in humans. Clin Pharmacol Ther 58:374–382
Mignat C, Wille U, Ziegler A (1995) Affinity profiles of morphine, codeine, dihydrocodeine and their glucuronides at opioid receptor subtypes. Life Sci 56:793–799
Thompson CM, Wojno H, Greiner E et al (2004) Activation of G-proteins by morphine and codeine congeners: insights to the relevance of O- and N-demethylated metabolites at mu- and delta-opioid receptors. J Pharmacol Exp Ther 308:547–554
Kirkwood LC, Nation RL, Somogyi AA (1997) Characterization of the human cytochrome P450 enzymes involved in the metabolism of dihydrocodeine. Br J Clin Pharmacol 44:549–555
Webb JA, Rostami-Hodjegan A, Abdul-Manap R et al (2001) Contribution of dihydrocodeine and dihydromorphine to analgesia following dihydrocodeine administration in man: a PK-PD modelling analysis. Br J Clin Pharmacol 52:35–43
Platten HP, Scheweizer E, Dilger K et al (1998) Pharmacokinetics and the pharmacodynamic action of midazolam in young and elderly patients undergoing tooth extraction. Clin Pharmacol Ther 63:552–560
Wilder-Smith CH, Hufschmid E, Thormann W (1998) The visceral and somatic antinociceptive effects of dihydrocodeine and its metabolite, dihydromorphine. A cross-over study with extensive and quinidine-induced poor metabolizers. Br J Clin Pharmacol 45:575–581
Magnan J, Paterson SJ, Tavani A et al (1982) The binding spectrum of nacrotic analgesic drugs with different agonist and antagonist properties. Naunyn-Schmiedeberg’s Arch Pharmacol 319:197–205
Kalvass JC, Olson ER, Cassidy MP et al (2007) Pharmacokinetics and pharmacodynamics of seven opioids in P-glycoprotein-competent mice: assessment of unbound brain EC50,u and correlation of in vitro, preclinical, and clinical data. J Pharmacol Exp Ther 323:346–355
Battershill AJ, Keating GM (2006) Remifentanil: a review of its analgesic and sedative use in the intensive care unit. Drugs 66:365–385
Hoke JF, Cunningham F, James MK et al (1997) Comparative pharmacokinetics and pharmacodynamics of remifentanil, its principle metabolite (GR90291) and alfentanil in dogs. J Pharmacol Exp Ther 281:226–232
Cox EH, Langemeijer MW, Gubbens-Stibbe JM et al (1999) The comparative pharmacodynamics of remifentanil and its metabolite, GR90291, in a rat electroencephalographic model. Anesthesiology 90:535–544
James MK, Feldman PL, Schuster SV et al (1991) Opioid receptor activity of GI 87084B, a novel ultra-short acting analgesic, in isolated tissues. J Pharmacol Exp Ther 259:712–718
Guitton J, Buronfosse T, Desage M et al (1997) Possible involvement of multiple cytochrome P450S in fentanyl and sufentanil metabolism as opposed to alfentanil. Biochem Pharmacol 53:1613–1619
Williams FM (1985) Clinical significance of esterases in man. Clin Pharmacokinet 10:392–403
Lockridge O, Mottershaw-Jackson N, Eckerson HW et al (1980) Hydrolysis of diacetylmorphine (heroin) by human serum cholinesterase. J Pharmacol Exp Ther 215:1–8
Yeh SY, McQuinn RL, Gorodetzky CW (1977) Identification of diacetylmorphine metabolites in humans. J Pharm Sci 66:201–204
Rentsch KM, Kullak-Ublick GA, Reichel C et al (2001) Arterial and venous pharmacokinetics of intravenous heroin in subjects who are addicted to narcotics. Clin Pharmacol Ther 70:237–246
Girardin F, Rentsch KM, Schwab MA et al (2003) Pharmacokinetics of high doses of intramuscular and oral heroin in narcotic addicts. Clin Pharmacol Ther 74:341–352
Selley DE, Cao CC, Sexton T et al (2001) mu Opioid receptor-mediated G-protein activation by heroin metabolites: evidence for greater efficacy of 6-monoacetylmorphine compared with morphine. Biochem Pharmacol 62:447–455
Rady JJ, Roerig SC, Fujimoto JM (1991) Heroin acts on different opioid receptors than morphine in Swiss Webster and ICR mice to produce antinociception. J Pharmacol Exp Ther 256:448–457
Rady JJ, Aksu F, Fujimoto JM (1994) The heroin metabolite, 6-monoacetylmorphine, activates delta opioid receptors to produce antinociception in Swiss-Webster mice. J Pharmacol Exp Ther 268:1222–1231
Rady JJ, Takemori AE, Portoghese PS et al (1994) Supraspinal delta receptor subtype activity of heroin and 6-monoacetylmorphine in Swiss Webster mice. Life Sci 55:603–609
Cone EJ, Darwin WD, Gorodetzky CW et al (1978) Comparative metabolism of hydrocodone in man, rat, guinea pig, rabbit, and dog. Drug Metab Dispos 6:488–493
Hutchinson MR, Menelaou A, Foster DJR et al (2003) CYP2D6 and CYP3A4 involvement in the primary oxidative metabolism of hydrocodone by human liver microsomes. Br J Clin Pharmacol 57:287–297
Otton SV, Schadel M, Cheung SW et al (1993) CYP2D6 phenotype determines the metabolic conversion of hydrocodone to hydromorphone. Clin Pharmacol Ther 54:463–472
Susce MT, Murray-Carmichael E, de Leon J (2006) Response to hydrocodone, codeine and oxycodone in a CYP2D6 poor metabolizer. Prog Neuro-Psychopharmacol Biol Psych 30:1356–1358
Foster A, Mobley E, Wang Z (2007) Complicated pain management in a CYP450 2D6 poor metabolizer. Pain Pract 7:352–356
Zheng M, McErlane KM, Ong MC (2002) Hydromorphone metabolites: isolation and identification from pooled urine samples of a cancer patient. Xenobiotica 32:427–439
Baldacci A, Thormann W (2006) Capillary electrophoresis contributions to the hydromorphone metabolism in man. Electrophoresis 27:2444–2457
Wright AW, Mather LE, Smith MT (2001) Hydromorphone-3-glucuronide: a more potent neuro-excitant than its structural analogue, morphine-3-glucuronide. Life Sci 69:409–420
Smith MT (2000) Neuroexcitatory effects of morphine and hydromorphone: evidence implicating the 3-glucuronide metabolites. Clin Exp Pharmacol Physiol 27:524–528
Sundstrom I, Hedeland M, Bondesson U et al (2002) Identification of glucuronide conjugates of ketobemidone and its phase I metabolites in human urine utilizing accurate mass and tandem time-of-flight mass spectrometry. J Mass Spectrom 37:414–420
Yasar U, Annas A, Svensson JO et al (2005) Ketobemidone is a substrate for cytochrome P4502C9 and 3A4, but not for P-glycoprotein. Xenobiotica 35:785–796
Al-Shurbaji A, Sawe J (2002) The pharmacokinetics of ketobemidone are not affected by CYP2D6 or CYP2C19 phenotype. Eur J Clin Pharmacol 57:877–881
Kharasch ED, Whittington D, Hoffer C et al (2005) Paradoxical role of cytochrome P450 3A in the bioactivation and clinical effects of levo-alpha-acetylmethadol: importance of clinical investigations to validate in vitro drug metabolism studies. Clin Pharmacokinet 44:731–751
Newcombe DA, Bochner F, White JM et al (2004) Evaluation of levo-alpha-acetylmethadol (LAAM) as an alternative treatment for methadone maintenance patients who regularly experience withdrawal: a pharmacokinetic and pharmacodynamic analysis. Drug Alcohol Depend 76:63–72
Stringer M, Makin MK, Miles J et al (2000) d-Morphine, but not l-morphine has low micromolar affinity for the non-competitive N-methyl-D-aspartate site in rat forebrain. Possible clinical implications for the management of neuropathic pain. Neurosci Lett 295:21–24
Dixon R, Crews T, Inturrisi C et al (1983) Levorphanol: pharmacokinetics and steady-state plasma concentrations in patients with pain. Res Commun Chem Pathol Pharmacol 41:3–17
Coffman BL, Rios GR, King CD et al (1997) Human UGT2B7 catalyzes morphine glucuronidation. Drug Metab Dispos 25:1–4
DeHaven-Hudkins DL, Burgos LC, Cassel JA et al (1999) Loperamide (ADL 2–1294), an opioid antihyperalgesic agent with peripheral selectivity. J Pharmacol Exp Ther 289:494–502
Kim KA, Chung J, Jung DH et al (2004) Identification of cytochrome P450 isoforms involved in the metabolism of loperamide in human liver microsomes. Eur J Clin Pharmacol 60:575–581
Dollery C (1991) Therapeutic drugs. Churchill Livingstone, Edinburgh
Lötsch J, Skarke C, Wieting J et al (2006) Modulation of the central nervous effects of levomethadone by genetic polymorphisms potentially affecting its metabolism, distribution, and drug action. Clin Pharmacol Ther 79:72–89
de Vos JW, Geerlings PJ, van den Brink W et al (1995) Pharmacokinetics of methadone and its primary metabolite in 20 opiate addicts. Eur J Clin Pharmacol 48:361–366
Foster DJR (2001) An examination of the metabolism and pharmacokinetics of methadone with respect to stereoselectivity. PhD Thesis, University of Adelaide, Adelaide
Lötsch J, Stockmann A, Kobal G et al (1996) Pharmacokinetics of morphine and its glucuronides after intravenous infusion of morphine and morphine-6-glucuronide in healthy volunteers. Clin Pharmacol Ther 60:316–325
Osborne R, Joel S, Trew D et al (1990) Morphine and metabolite behavior after different routes of morphine administration: demonstration of the importance of the active metabolite morphine-6-glucuronide. Clin Pharmacol Ther 47:12–19
Miller JW, Anderson HH (1954) The effect of N-demethylation on certain pharmacologic actions of morphine, codeine, and meperidine in the mouse. J Pharmacol Exp Ther 112:191–196
Loser SV, Meyer J, Freudenthaler S et al (1996) Morphine-6-O-beta-D-glucuronide but not morphine-3-O-beta-D-glucuronide binds to mu-, delta- and kappa- specific opioid binding sites in cerebral membranes. Naunyn-Schmiedeberg’s Arch Pharmacol 354:192–197
Ulens C, Baker L, Ratka A et al (2001) Morphine-6beta-glucuronide and morphine-3-glucuronide, opioid receptor agonists with different potencies. Biochem Pharmacol 62:1273–1282
Gong QL, Hedner J, Bjorkman R et al (1992) Morphine-3-glucuronide may functionally antagonize morphine-6-glucuronide induced antinociception and ventilatory depression in the rat. Pain 48:249–255
Bartlett SE, Cramond T, Smith MT (1994) The excitatory effects of morphine-3-glucuronide are attenuated by LY274614, a competitive NMDA receptor antagonist, and by midazolam, an agonist at the benzodiazepine site on the GABAA receptor complex. Life Sci 54:687–694
Halliday AJ, Bartlett SE, Colditz P et al (1999) Brain region-specific studies of the excitatory behavioral effects of morphine-3-glucuronide. Life Sci 65:225–236
Faura CC, Olaso MJ, Garcia Cabanes C et al (1996) Lack of morphine-6-glucuronide antinociception after morphine treatment. Is morphine-3-glucuronide involved? Pain 65:25–30
Gardmark M, Karlsson MO, Jonsson F et al (1998) Morphine-3-glucuronide has a minor effect on morphine antinociception. Pharmacodynamic modeling. J Pharm Sci 87:813–820
Ouellet DM, Pollack GM (1997) Effect of prior morphine-3-glucuronide exposure on morphine disposition and antinociception. Biochem Pharmacol 53:1451–1457
Penson RT, Joel SP, Bakhshi K et al (2000) Randomized placebo-controlled trial of the activity of the morphine glucuronides. Clin Pharmacol Ther 68:667–676
Penson RT, Joel SP, Clark S et al (2001) Limited phase I study of morphine-3-glucuronide. J Pharm Sci 90:1810–1816
Osborne R, Joel S, Grebenik K et al (1993) The pharmacokinetics of morphine and morphine glucuronides in kidney failure. Clin Pharmacol Ther 54:158–167
Ashby M, Fleming B, Wood M et al (1997) Plasma morphine and glucuronide (M3G and M6G) concentrations in hospice inpatients. J Pain Symptom Manage 14:157–167
Frances B, Gout R, Campistron G et al (1990) Morphine-6-glucuronide is more mu-selective and potent in analgesic tests than morphine. Prog Clin Biol Res 328:477–480
Frances B, Gout R, Monsarrat B et al (1992) Further evidence that morphine-6 beta-glucuronide is a more potent opioid agonist than morphine. J Pharmacol Exp Ther 262:25–31
Oguri K, Yamada-Mori I, Shigezane J et al (1987) Enhanced binding of morphine and nalorphine to opioid delta receptor by glucuronate and sulfate conjugations at the 6-position. Life Sci 41:1457–1464
Christensen CB, Reiff L (1991) Morphine-6-glucuronide: receptor binding profile in bovine caudate nucleus. Pharmacol Toxicol 68:151–153
Christensen CB, Jorgensen LN (1987) Morphine-6-glucuronide has high affinity for the opioid receptor. Pharmacol Toxicol 60:75–76
Pasternak GW, Bodnar RJ, Clark JA et al (1987) Morphine-6-glucuronide, a potent mu agonist. Life Sci 41:2845–2849
Hucks D, Thompson PI, McLoughlin L et al (1992) Explanation at the opioid receptor level for differing toxicity of morphine and morphine 6-glucuronide. Br J Cancer 65:122–126
Chen ZR, Irvine RJ, Somogyi AA et al (1991) Mu receptor binding of some commonly used opioids and their metabolites. Life Sci 48:2165–2171
Paul D, Standifer KM, Inturrisi CE et al (1989) Pharmacological characterization of morphine-6 beta-glucuronide, a very potent morphine metabolite. J Pharmacol Exp Ther 251:477–483
Shimomura K, Kamata O, Ueki S et al (1971) Analgesic effect of morphine glucuronides. Tohoku J Exp Med 105:45–52
Abbott FV, Palmour RM (1988) Morphine-6-glucuronide: analgesic effects and receptor binding profile in rats. Life Sci 43:1685–1695
Hasselstrom J, Alexander N, Bringel C et al (1991) Single-dose and steady-state kinetics of morphine and its metabolites in cancer patients–a comparison of two oral formulations. Eur J Clin Pharmacol 40:585–591
Skarke C, Darimont J, Schmidt H et al (2003) Analgesic effects of morphine and morphine-6-glucuronide in a transcutaneous electrical pain model in healthy volunteers. Clin Pharmacol Ther 73:107–121
Romberg R, Olofsen E, Sarton E et al (2004) Pharmacokinetic-pharmacodynamic modeling of morphine-6-glucuronide-induced analgesia in healthy volunteers. Anesthesiology 100:120–133
Thompson PI, Joel SP, John L et al (1995) Respiratory depression following morphine and morphine-6-glucuronide in normal subjects. Br J Clin Pharmacol 40:145–152
Buetler TM, Wilder-Smith OH, Wilder-Smith CH et al (2000) Analgesic action of i.v. morphine-6-glucuronide in healthy volunteers. Br J Anaesth 84:97–99
Lötsch J, Kobal G, Stockmann A et al (1997) Lack of analgesic activity of morphine-6-glucuronide after short-term intravenous administration in healthy volunteers. Anesthesiology 87:1348–1358
Motamed C, Mazoit X, Ghanouchi K et al (2000) Preemptive intravenous morphine-6-glucuronide is ineffective for postoperative pain relief. Anesthesiology 92:355–360
Tegeder I, Meier S, Burian M et al (2003) Peripheral opioid analgesia in experimental human pain models. Brain 126:1092–1102
Osborne R, Thompson P, Joel S et al (1992) The analgesic activity of morphine-6-glucuronide. Br J Clin Pharmacol 34:130–138
Hanna MH, Peat SJ, Woodham M et al (1990) Analgesic efficacy and CSF pharmacokinetics of intrathecal morphine-6-glucuronide: comparison with morphine. Br J Anaesth 64:547–550
Grace D, Fee JP (1996) A comparison of intrathecal morphine-6-glucuronide and intrathecal morphine sulfate as analgesics for total hip replacement. Anesth Analg 83:1055–1059
Romberg R, van Dorp E, Hollander J et al (2007) A randomized, double-blind, placebo-controlled pilot study of IV morphine-6-glucuronide for postoperative pain relief after knee replacement surgery. Clin J Pain 23:197–203
Cann C, Curran J, Milner T et al (2002) Unwanted effects of morphine-6-glucoronide and morphine. Anaesthesia 57:1200–1203
Peat SJ, Hanna MH, Woodham M et al (1991) Morphine-6-glucuronide: effects on ventilation in normal volunteers. Pain 45:101–104
Romberg R, Olofsen E, Sarton E et al (2003) Pharmacodynamic effect of morphine-6-glucuronide versus morphine on hypoxic and hypercapnic breathing in healthy volunteers. Anesthesiology 99:788–798
Fromm MF, Eckhardt K, Li S et al (1997) Loss of analgesic effect of morphine due to coadministration of rifampin. Pain 72:261–267
Koopman-Kimenai PM, Vree TB, Booij LH et al (1993) Pharmacokinetics of intravenously administered nicomorphine and its metabolites in man. Eur J Anaesthesiol 10:125–132
Lobbezoo MW, Van Rooy HH, Van Wijngaarden I et al (1982) Opiate receptor binding of nicomorphine and its hydrolysis products in rat brain. Eur J Pharmacol 82:207–211
Rasmussen I (2000) Identification of cytochrome P450 isoforms involved in the metabolism of oxycodone. Master of Science Thesis, University of Adelaide, Adelaide
Lalovic B, Phillips B, Risler L et al (2004) Quantitative contribution of CYP2D6 and CYP3A to oxycodone metabolism in human liver and intestinal microsomes. Drug Metab Dispos 32:447–454
Ishida T, Oguri K, Yoshimura H (1979) Isolation and identification of urinary metabolites of oxycodone in rabbits. Drug Metab Dispos 7:162–165
Lalovic B, Kharasch E, Hoffer C et al (2006) Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy human subjects: role of circulating active metabolites. Clin Pharmacol Ther 79:461–479
Beaver WT, Wallenstein SL, Rogers A et al (1978) Analgesic studies of codeine and oxycodone in patients with cancer. II. Comparisons of intramuscular oxycodone with intramuscular morphine and codeine. J Pharmacol Exp Ther 207:101–108
Leow KP, Smith MT (1994) The antinociceptive potencies of oxycodone, noroxycodone and morphine after intracerebroventricular administration to rats. Life Sci 54:1229–1236
Nielsen CK, Ross FB, Lotfipour S et al (2007) Oxycodone and morphine have distinctly different pharmacological profiles: radioligand binding and behavioural studies in two rat models of neuropathic pain. Pain 132:289–300
Ross FB, Smith MT (1997) The intrinsic antinociceptive effects of oxycodone appear to be kappa-opioid receptor mediated. Pain 73:151–157
Poyhia R, Olkkola KT, Seppala T et al (1991) The pharmacokinetics of oxycodone after intravenous injection in adults. Br J Clin Pharmacol 32:516–518
Poyhia R, Seppala T, Olkkola KT et al (1992) The pharmacokinetics and metabolism of oxycodone after intramuscular and oral administration to healthy subjects. Br J Clin Pharmacol 33:617–621
Twistler ST, Enggaard TP, Noehr-Jensen L et al (2008) The hypoalgesic effect of oxycodone in human experimental pain models in relation to the CYP2D6 oxidation polymorphism. In: Scandinavian Association for the Study of Pain, 31st annual meeting
Beaver WT, Wallenstein SL, Houde RW et al (1977) Comparisons of the analgesic effects of oral and intramuscular oxymorphone and of intramuscular oxymorphone and morphine in patients with cancer. J Clin Pharmacol 17:186–198
Prommer E (2006) Oxymorphone: a review. Support Care Cancer 14:109–115
Goldstein G (1985) Pentazocine. Drug Alcohol Depend 14:313–324
Berkowitz B (1973) Pharmacokinetics and neurochemical effects of pentazocine and its optical isomers. Adv Biochem Psychopharmacol 8:495–501
MacDonald AD, Woolfe G, Bergel F et al (1946) Analgesic action of pethidine derivatives and related compounds. Brit J Pharmacol 1:4–14
Ramirez J, Innocenti F, Schuetz EG et al (2004) CYP2B6, CYP3A4, and CYP2C19 are responsible for the in vitro N-demethylation of meperidine in human liver microsomes. Drug Metab Dispos 32:930–936
Latta KS, Ginsberg B, Barkin RL (2002) Meperidine: a critical review. Am J Ther 9:53–68
Thierry C, Boeynaems J-M, Paolo M (2005) Actions of tilidine and nortilidine on cloned opioid receptors. Eur J Pharmacol 506:205–208
Vollmer KO, Thomann P, Hengy H (1989) Pharmacokinetics of tilidine and metabolites in man. Arzneimittelforschung 39:1283–1288
Hadja JP, Jahncen E, Ole S et al (2002) Sequential first-pass metabolism of nortilidine: the active metabolite of the synthetic opioid drug tilidine. J Clin Pharmacol 42:1257–1261
Seiler KU, Jahncen E, Trenk D et al (2001) Pharmacokinetics of tilidine in terminal renal failure. J Clin Pharmacol 41:79–84
Brennscheidt U, Brunnmuller U, Proppe D et al (2007) Pharmacokinetics of tilidine and naloxone in patients with severe hepatic impairment. Arzneimittelforschung 57:106–111
Gillen C, Haurand M, Kobelt DJ et al (2000) Affinity, potency and efficacy of tramadol and its metabolites at the cloned human mu-opioid receptor. Naunyn-Schmiedeberg’s Arch Pharmacol 362:116–121
Poulsen L, Arendt-Nielsen L, Brøsen K et al (1996) The hypoalgesic effect of tramadol in relation to CYP2D6. Clin Pharmacol Ther 60:636–644
Borlak J, Hermann R, Erb K et al (2003) A rapid and simple CYP2D6 genotyping assay - case study with analgetic tramadol. Metabolism 52:1439–1443
Fliegert F, Kurth B, Gohler K (2005) The effects of tramadol on static and dynamic pupillometry in healthy subjects-the relationship between pharmacodynamics, pharmacokinetics and CYP2D6 metaboliser status. Eur J Pharmacol 61:257–266
Slanar O, Nobilis M, Kvetina J et al (2006) CYP2D6 polymorphism, tramadol pharmacokinetics and pupillary response. Eur J Clin Pharmacol 62:75–76
Slanar O, Nobilis M, Kvetina J et al (2007) Miotic action of tramadol is determined by CYP2D6 genotype. Physiol Res 56:129–136
Levo A, Koski A, Ojanpera I et al (2003) Post-mortem SNP analysis of CYP2D6 gene reveals correlation between genotype and opioid drug (tramadol) metabolite ratios in blood. Forensic Sci Int 135:9–15
Pedersen RS, Damkier P, Brøsen K (2005) Tramadol as a new probe for cytochrome P450 2D6 phenotyping: a population study. Clin Pharmacol Ther 77:458–467
Enggaard TP, Poulsen L, Arendt-Nielsen L et al (2006) The analgesic effect of tramadol after intravenous injection in healthy volunteers in relation to CYP2D6. Anesth Analg 102:146–150
Stamer UM, Musshoff F, Kobilay M et al (2007) Concentrations of tramadol and O-desmethyltramadol enantiomers in different CYP2D6 genotypes. Clin Pharmacol Ther 82:41–47
Coffman BL, King CD, Rios GR et al (1998) The glucuronidation of opioids, other xenobiotics, and androgens by human UGT2B7Y(268) and UGT2B7H(268). Drug Metab Dispos 26:73–77
Moffat AC, Osselton MD, Widdop B (eds) (2004) Clarke’s analysis of drugs and poisons, 3rd ed., vol. 2. Pharmaceutical Press, London
Oguri K, Yamada-Mori I, Shigezane J et al (1984) Potentiation of physical dependence by conjugation at the 6-position of nalorphine. Eur J Pharmacol 102:229–235
Konno F, Kobayashi C, Morimoto R et al (1986) Pharmacological effects of nalorphine and nalorphine-7,8-oxide (nalorphine-epoxide): interaction of the intrinsic activity, affinity and pharmacological responses. Arch Int Pharmacodyn Ther 282:219–232
Wang D, Raehal KM, Bilsky EJ et al (2001) Inverse agonists and neutral antagonists at mu opioid receptor (MOR): possible role of basal receptor signaling in narcotic dependence. J Neurochem 77:1590–1600
Sadee W, Wang D, Bilsky EJ (2005) Basal opioid receptor activity, neutral antagonists, and therapeutic opportunities. Life Sci 76:1427–1437
Weinstein SH, Pfeffer M, Schor JM (1973) Metabolism and pharmacokinetics of naloxone. Adv Biochem Psychopharmacol 8:525–535
Wahlstrom A, Winblad B, Bixo M et al (1988) Human brain metabolism of morphine and naloxone. Pain 35:121–127
Reber P, Brenneisen R, Flogerzi B et al (2007) Effect of naloxone-3-glucuronide and N-methylnaloxone on the motility of the isolated rat colon after morphine. Dig Dis Sci 52:502–507
Yamano S, Ichinose F, Todaka T et al (1999) Purification and characterization of two major forms of naloxone reductase from rabbit liver cytosol, new members of aldo-keto reductase superfamily. Biol Pharm Bull 22:1038–1046
Olsen LD, Klein P, Nelson WL et al (1990) Conjugate addition ligands of opioid antagonists. Methacrylate esters and ethers of 6 alpha- and 6 beta-naltrexol. J Med Chem 33:737–741
Porter SJ, Somogyi AA, White JM (2002) In vivo and in vitro potency studies of 6beta-naltrexol, the major human metabolite of naltrexone. Addict Biol 7:219–225
Raehal KM, Lowery JJ, Bhamidipati CM et al (2005) In vivo characterization of 6beta-naltrexol, an opioid ligand with less inverse agonist activity compared with naltrexone and naloxone in opioid-dependent mice. J Pharmacol Exp Ther 313:1150–1162
Ferrari A, Bertolotti M, Dell’Utri A et al (1998) Serum time course of naltrexone and 6 beta-naltrexol levels during long-term treatment in drug addicts. Drug Alcohol Depend 52:211–220
Acknowledgements
Supported by the National Health and Medical Research Council of Australia. J.C. is a FTT Fricker Research Fellow at the University of Adelaide.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Coller, J.K., Christrup, L.L. & Somogyi, A.A. Role of active metabolites in the use of opioids. Eur J Clin Pharmacol 65, 121–139 (2009). https://doi.org/10.1007/s00228-008-0570-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00228-008-0570-y