The AAPS Journal

, Volume 8, Issue 2, pp E348–E352 | Cite as

Role of morphine's metabolites in analgesia: Concepts and controversies

  • Erica Wittwer
  • Steven E. Kern


The metabolites of morphine, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G), have been extensively studied for their contribution to clinical effects following administration of morphine. Those contributions to both the desired effect (ie, analgesia) and the undesired effects (eg, nausea, respiratory depression) are the subject of clinical controversy. Much attention and effort have been directed at investigating the properties of M6G because of interest in this substance as a possible substitute for morphine. It exhibits increased potency and the possibility of a better side effect profile compared with morphine, although the reported relative benefits vary widely. M3G is not analgesic, but its role in producing side effects, including the development of clinical tolerance, has been proposed. This review is focused on M6G and the factors that contribute to its clinical utility. The formation and distribution of M6G are presented, as are the analgesic effect and the onset of this effect. The impact of genetics, age, and gender on M6G and its effects is also reviewed.


Morphine morphine-6-glucuronide clinical pharmacology clinical covariates 


  1. 1.
    Coffman B, King C, Rios G, Tephly T. The glucuronidation of opioids, other xenobiotics, and androgens by human UGT2B7Y(268) and UGT2B7H(268).Drug Metab Dispos. 1998;26:73–77.PubMedGoogle Scholar
  2. 2.
    Ratka A, Wittwer E, Baker L, Kern S. Pharmacokinetics of morphine, morphine-3-glucuronide, and morphine-6-glucuronide in healthy older men and women.Am J Pain Manage. 2004;14:45–55.Google Scholar
  3. 3.
    Stone A, Mackenzie P, Galetin A, Houston J, Miners J. Isoform selectivity and kinetics of morphine 3- and 6-glucuronidation by human UDP-glucuronosyltransferases: evidence for atypical glucuronidation kinetics by UGT2B7.Drug Metab Dispos. 2003;31:1086–1089.CrossRefPubMedGoogle Scholar
  4. 4.
    Aasmundstad T, Storset P. Influence of ranitidine on the morphine-3-glucuronide to morphine-6-glucuronide ratio after oral administration of morphine in humans.Hum Exp Toxicol. 1998;17:347–352.CrossRefPubMedGoogle Scholar
  5. 5.
    Faura C, Collins S, Moore R, McQuay H. Systematic review of factors affecting the ratio of morphine and its major metabolites.Pain. 1998;74:43–53.CrossRefPubMedGoogle Scholar
  6. 6.
    Antonilli L, Suriano C, Paolone G, Badiani A, Nencini P. Repeated exposures to heroin and/or cadmium alter the rate of formation of morphine glucuronides in the rat.J Pharmacol Exp Ther. 2003;307:651–660.CrossRefPubMedGoogle Scholar
  7. 7.
    Antonilli L, Semeraro F, Suriano C, Signore L, Nencini P. High levels of morphine-6-glucuronide in street heroin addicts.Psychopharmacology (Berl). 2003;170:200–204.CrossRefGoogle Scholar
  8. 8.
    Lotsch J, Geisslinger G. Morphine-6-glucuronide: an analgesic of the future?Clin Pharmacokinet. 2001:40:485–499.CrossRefPubMedGoogle Scholar
  9. 9.
    Smith G, Smith M. Morphine-3-glucuronide: evidence to support its putative role in the development of tolerance to the antinociceptive effects of morphine in the rat.Pain. 1995;62:51–60.CrossRefPubMedGoogle Scholar
  10. 10.
    Vaughan CW, Connor M. In search of a role for the morphine metabolite morphine-3-glucuronide.Anesth Analg. 2003;97:311–312.CrossRefPubMedGoogle Scholar
  11. 11.
    Andersen G, Christrup L, Sjogren P. Relationships among morphine metabolism, pain and side effects during long-term treatment: an update.J Pain Symptom Manage. 2003;25:74–91.CrossRefPubMedGoogle Scholar
  12. 12.
    Ashby M, Fleming B, Wood M, Somogyi A. Plasma morphine and glucuronide (M3G and M6G) concentrations in hospice inpatients.J Pain Symptom Manage. 1997;14:157–167.CrossRefPubMedGoogle Scholar
  13. 13.
    Baker L, Hyrien O, Ratka A. Contributions of morphine-3-glucuronide and morphine-6-glucuronide to differences in morphine analgesia in humans.Am J Pain Manage. 2003;13:16–28.Google Scholar
  14. 14.
    Hemstapat K, Monteith G, Smith D, Smith M. Morphine-3-glucuronide's neuro-excitatory effects are mediated by indirect activation of NMDA receptors: mechanistic studies in embryonic cultured hippocampal neurones.Anesth Analg. 2003;97:494–505.CrossRefPubMedGoogle Scholar
  15. 15.
    Okura T, Saito M, Nakanishi M, et al. Different distribution of morphine and morphine-6β-glucuronide after intracerebroventricular injection in rats.Br J Pharmacol. 2003;140:211–217.CrossRefPubMedGoogle Scholar
  16. 16.
    Mantione KJ, Goumon Y, Esch T, Stefano Gb Morphine 6B glucuronide: fortuitous morphine metabolite or preferred peripheral regulatory opiate?Med Sci Monit. 2005;11:MS43-MS46.PubMedGoogle Scholar
  17. 17.
    Lotsch J, Skarke C, Darimont J, Schmidt H, Geisslinger G. The transfer half-life of morphine-6-glucuronide from plasma to effect site assessed by pupil size measurement in healthy volunteers.Anesthesiology 2001;95:1329–1338.CrossRefPubMedGoogle Scholar
  18. 18.
    Tunblad K, Hammarlund-Udenaes M, Jonsson EN. Influence of probenecid on the delivery of morphine-6-glucuronide to the brain.Eur J Pharm Sci. 2005;24:49–57.CrossRefPubMedGoogle Scholar
  19. 19.
    Bouw MRXR, Tunblad K, Hammarlund-Udenaes M, Blood-brain barrier transport and brain distribution of morphine-6-glucuronide in relation to the antinociceptive effect in rats—pharmacokinetic/pharmacodynamic modelling.Br J Pharmacol. 2001;134:1796–1804.CrossRefPubMedGoogle Scholar
  20. 20.
    Bourasset F, Cisternino S, Temsamani J, Scherrmann JM. Evidence for an active transport of morphine-6-β-D-glucuronide but not P-glycoprotein-mediated at the blood-brain barrier.J Neurochem. 2003;86:1564–1567.CrossRefPubMedGoogle Scholar
  21. 21.
    Lotsch J, Skarke C, Liefhold J, Geisslinger G. Genetic predictors of the clinical response to opioid analgesics.Clin Pharmacokinet. 2004;43:983–1013.CrossRefPubMedGoogle Scholar
  22. 22.
    Buetler TMW, Wilder-Smith OH, Wilder-Smith CH, Aebi S, Cerny T, Brenneisen R. Analgesic action of i.v. morphine-6-glucuronide in healthy volunteers.Br J Anaesth. 2000;84:97–99.PubMedGoogle Scholar
  23. 23.
    Hanna MHEK, Fung M. Randomized, double-blind study of the analgesic efficacy of morphine-6-glucuronide versus morphine sulfate for postoperative pain in major surgery.Anesthesiology. 2005;102:815–821.CrossRefPubMedGoogle Scholar
  24. 24.
    Motamed C, Mazoit X, Ghanouchi K, et al. Preemptive intravenous morphine-6-glucuronide is ineffective for postoperative pain relief.Anesthesiology 2000;92:355–360.CrossRefPubMedGoogle Scholar
  25. 25.
    Langlade A, Carr DB, Serrie A, Silbert BS, Szyfelbein SK, Lipkowski AW. Enhanced potency of intravenous, but not intrathecal, morphine and morphine-6-glucuronide after burn trauma.Life Sci. 1994;54:1699–1709.CrossRefPubMedGoogle Scholar
  26. 26.
    Grace D, Fee J. A comparison of intrathecal morphine-6-glucuronide and intrathecal morphine sulfate as analgesics for total hip replacement.Anesth Analg. 1996;83:1055–1059.CrossRefPubMedGoogle Scholar
  27. 27.
    Yamada H, Ishii K, Ishii Y, et al. Formation of highly analgesic morphine-6-glucuronide following physiologic concentration of morphine in human brain.J Toxicol Sci. 2003;28:395–401.CrossRefPubMedGoogle Scholar
  28. 28.
    Cann C, Curran J, Milner T, Ho B. Unwanted effects of morphine-6-glucuronide and morphine.Anaesthesia. 2002;57:1200–1203.CrossRefPubMedGoogle Scholar
  29. 29.
    Romberg R, Olofsen E, Sarton E, Teppema L, Dahan A. Pharmacodynamic effect of morphine-6-glucuronide versus morphine on hypoxic and hypercapnic breathing in healthy volunteers.Anesthesiology. 2003;99:788–798.CrossRefPubMedGoogle Scholar
  30. 30.
    Kilpatrick G, Smith T. Morphine-6-glucuronide: actions and mechanisms.Med Res Rev. 2005;25:521–544.CrossRefPubMedGoogle Scholar
  31. 31.
    Pasternak G. Incomplete cross tolerance and multiple mu opioid peptide receptors.Trends Pharmacol Sci. 2001;22:67–70.CrossRefPubMedGoogle Scholar
  32. 32.
    Rossi GC, Pan YX, Brown GP, Pasternak GW. Antisense mapping the MOR-1 opioid receptor: evidence for alternative splicing and a novel morphine-6-beta-glucuronide receptor.FEBS Lett. 1995;369:192–196.CrossRefPubMedGoogle Scholar
  33. 33.
    Rossi GC, Leventhal L, Pan YX, et al. Antisense mapping of MOR-1 in rats: distinguishing between morphine and morphine-6-beta-glucuronide antinociception.J Pharmacol Exp Ther. 1997;281:109–114.PubMedGoogle Scholar
  34. 34.
    Zelcer N, Wetering K, Hillebrand M, et al. Mice lacking multidrug resistance protein 3 show altered morphine pharmacokinetics and morphine-6-glucuronide antinociception.Proc Natl Acad Sci USA. 2005;102:7274–7279.CrossRefPubMedGoogle Scholar
  35. 35.
    Lotsch J, Zimmermann M, Darimont J, et al. Does the A118G polymorphism at the μ-opioid receptor gene protect against morphine-6-glucuronide toxicity?Anesthesiology. 2002;97;814–819.CrossRefPubMedGoogle Scholar
  36. 36.
    Lotsch J, Skarke C, Grosch S, Darimont J, Schmidt H, Geisslinger G. The polymorphism A118G of the human mu-opioid receptor gene decreased the pupil constrictory effect of morphine-6-glucuronide but not that of morphine.Pharmacogenetics. 2002;12:3–9.CrossRefPubMedGoogle Scholar
  37. 37.
    Romberg R, Olofsen E, Bijl H, et al. Polymorphims of mu-opioid receptor gene (OPRM1:c.118A>G) does not protect against opioid-induced respiratory depression despite reduced analgesic response.Anesthesiology. 2005;102:522–530.CrossRefPubMedGoogle Scholar
  38. 38.
    Mogil JSSS, Strasburg K, Kaplan L, et al. Melanocortin-1 receptor gene variants affect pain and μ-opioid analgesia in mice and humans.J Med Genet. 2005;42:583–587.CrossRefPubMedGoogle Scholar
  39. 39.
    Wittwer E, Ratka A, Kern S. The impact of endogeneous steroidal hormones on the pharmacokinetics of oral morphine: a population analysis. Proceedings of the 79th IARS Clinical and Scientific. Conference. 79th IARS Clinical and Scientific Conference; March 20–22, 2005; Honolulu, HI. Philadelphia, PA: LWW Publishers, 2004: PR04-R58.Google Scholar
  40. 40.
    Murthy BR, Pollack GM, Brouwer KL. Contribution of morphine-6-glucuronide to antinociception following intravenous administration of morphine to healthy volunteers.J Clin Pharmacol. 2002;42:569–576.CrossRefPubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2006

Authors and Affiliations

  • Erica Wittwer
    • 1
  • Steven E. Kern
    • 1
    • 2
  1. 1.Department of Pharmaceutics and Pharmaceutical Chemistry, College of PharmacyUniversity of UtahSalt Lake City
  2. 2.Department of Anesthesiology, School of MedicineUniversity of UtahSalt Lake City

Personalised recommendations