Morphine analgesia in cancer pain: Role of the glucuronides

Authors

  • Richard T. Penson, MRCP, MD
  • Simon P. Joel, PhD
  • Anna Gloyne, BSc
  • Simon Clark, BSc
  • Maurice L. Slevin, FRCP, MD

DOI:

https://doi.org/10.5055/jom.2005.0021

Keywords:

morphine, cancer pain, glucuronides, analgesia

Abstract

Preclinical data and limited studies in humans have suggested that morphine-6-glucuronide (M6G) has analgesic activity and morphine-3-glucuronide (M3G), contributes adversely to the therapeutic effect of morphine. This open point-prevalence study in 103 patients on oral morphine for cancer-related pain investigated the correlations between morphine doses, metabolites, and the degree of pain relief or toxicity. Morphine, M6G, and M3G were assayed by high-performance liquid chromatography on a single blood sample taken between two and four hours after dose. Pain, analgesia, and toxicity were recorded on numerical and visual analog scales. Patients received a median dose of 60 (range, 10 to 620) mg per day morphine, for a median of 4.1 weeks (range, 0.2 to 46.0 weeks). M3G:M6G ratios fell within a narrow range, with a median value of 4.39 (interquartile range, 3.78 to 6.96; range, 2.18 to 14.95). There were no significant correlations between M3G:M6G and morphine dose, or any measure of analgesia. The correlation between plasma concentration and pain score (i.e., better analgesia) was stronger for M6G (r = 0.308, p < 0.01) than morphine (r = 0.197, p = 0.05). These data suggest that M6G contributes significantly to the analgesic potency of oral morphine. No evidence was found for differences in M3G:M6G ratios contributing to analgesia or toxicity.

Author Biographies

Richard T. Penson, MRCP, MD

Division of Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts.

Simon P. Joel, PhD

Department of Medical Oncology, St. Bartholomew’s Hospital, West Smithfield, London, England.

Anna Gloyne, BSc

Department of Medical Oncology, St. Bartholomew’s Hospital, West Smithfield, London, England.

Simon Clark, BSc

Department of Medical Oncology, St. Bartholomew’s Hospital, West Smithfield, London, England.

Maurice L. Slevin, FRCP, MD

Department of Medical Oncology, St. Bartholomew’s Hospital, West Smithfield, London, England.

References

Ventafridda V, Tamburine M, Caraceni A, et al.: A validation study of WHO method for cancer pain relief. Cancer. 1987; 5: 850-856.

Faura CC, Moore AR, Horga JF, et al.: Morphine and morphine-6-glucuronide plasma concentrations and effect in cancer pain. J Pain Symptom Manage. 1996a; 11: 95-102.

Osborne RJ, Joel SJ, Trew D, et al.: Morphine and metabolite behaviour after different routes of morphine administration: Demonstration of the importance of the active metabolite morphine 6-glucuronide. Clin Pharmacol Ther. 1990; 47: 12-19.

Shimomura K, Katama O, Ueki S, et al.: Analgesic effects of morphine glucuronides. Tohoku J Exp Med. 1971; 105: 45-52.

Pasternak GW, Bodnar RJ, Clark JA, et al.: Morphine-6-glucuronide, a potent mu agonist. Life Sci. 1987; 41: 2845-2849.

Boerner U, Abbott S and Roe RL. The metabolism of morphine and heroin in man. Drug Metab Rev. 1975; 4: 39-73.

Svensson JO, Rane A, Sawe J, et al.: Determination of morphine, morphine-3-glucuronide and (tentatively) morphine-6-glucuronide in plasma and urine using ion-pair high-performance liquid chromatography. J Chromatogr. 1982; 230: 427-432.

Osborne R, Joel S, Slevin M: Morphine intoxication in renal failure: The role of morphine-6-glucuronide. Br Med J (Clin Res Ed). 1986; 292: 1548-1549.

Hanna MH, Peat SJ, Woodham M, et al.: Analgesic efficacy and CSF pharmacokinetics of intrathecal morphine-6-glucuronide: Comparison with morphine. Br J Anaesth. 1990; 64: 547-550.

Peat SJ, Hanna MH, Woodham M, et al.: Morphine-6-glucuronide: Effects on ventilation in normal volunteers. Pain. 1991; 45: 101-104.

Osborne RJ, Thompson PI, Joel SJ, et al.: The analgesic effects of morphine 6-glucuronide. Br J Clin Pharmacol. 1992; 34: 130-138.

Thompson PI, Joel SP, John L, et al.: Respiratory depression following morphine and morphine-6-glucuronide in normal subjects. Br J Clin Pharmacol. 1995; 40: 145-152.

Buetler TM, Wilder-Smith OH, Wilder-Smith CH, et al.: Analgesic action of i.v. morphine-6-glucuronide in healthy volunteers. Br J Anaesth. 2000; 84: 97-99.

Loh HH, Liu HC, Cavalli A, et al.: mu Opioid receptor knockout in mice: Effects on ligand-induced analgesia and morphine lethality. Brain Res Mol Brain Res. 1998; 54: 321-326.

Hand CW, Blunnie WP, Claffey LP, et al.: Potential analgesic contribution from morphine-6-glucuronide in CSF. Lancet. 1987; 2(8569): 1207-1208.

Portenoy RK, Thaler HT, Inturrisi CE, et al.: The metabolite morphine-6-glucuronide contributes to the analgesia produced by morphine infusion in patients with pain and normal renal function. Clin Pharmacol Ther. 1992; 51: 422-431.

Lotsch J, Kobal G, Geisslinger G: No contribution of morphine-6-glucuronide to clinical morphine effects after shortterm administration. Clin Neuropharmacol. 1998; 21: 351-354.

Lotsch J, Weiss M, Ahne G, et al.: Pharmacokinetic modeling of M6G formation after oral administration of morphine in healthy volunteers. Anesthesiology. 1999; 90: 1026-1038.

Smith MT, Watt JA, Cramond T: Morphine-3-glucuronide: A potent antagonist of morphine analgesia. Life Sci. 1990; 47: 579-585.

Gong QL, Hedner J, Bjorkman R, et al.: Morphine-3-glucuronide may functionally antagonize morphine-6-glucuronide induced antinociception and ventilatory depression in the rat. Pain. 1991; 48: 249-255.

Bowsher D. Paradoxical pain. Br Med J. 1993; 306: 473-474.

Smith GD, Smith MT: 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.

Suzuki N, Kalso E, Rosenberg PH: Intrathecal morphine-3-glucuronide does not antagonize spinal antinociception by morphine or morphine-6-glucuronide in rats. Eur J Pharmacol. 1993; 24: 247-250.

Hewett K, Dickenson AH, McQuay HJ: Lack of effect of morphine-3-glucuronide on the spinal antinociceptive actions of morphine in the rat: An electrophysiological study. Pain 1993; 53: 59-63.

Kaiko RF, Foley KM, Grabinski PY, et al.: Central nervous system excitatory effects of meperidine in cancer patients. Ann Neurol. 1983; 13: 180-185.

Sjogren P, Dragsted L, Christensen CB: Myoclonic spasms during treatment with high doses of intravenous morphine in renal failure. Acta Anaesthesiol Scand. 1993; 37: 780-782.

Joel SP, Osborne RJ, Slevin ML: An improved method for the simultaneous determination of morphine and its principal glucuronide metabolites. J Chromatogr. 1988; 430: 394-399.

Littman GS, Walker BR, Schneider BE: Reassessment of verbal and visual analogue ratings in analgesic studies. Clin Pharmacol Ther. 1985; 38: 16-23.

Cockcroft D, Gault M: Prediction of creatinine clearance from serun creatinine. Nephron 1976; 16: 31.

Hasselstrom J, Sawe J: Morphine pharmacokinetics and metabolism in humans. Enterohepatic cycling and relative contribution of metabolites to active opioid concentrations. Clin Pharmacokinet 1993; 24: 344-354.

Sawe J: High dose morphine and methadone in cancer patients. Clinical pharmacokinetic considerations in oral treatment. Clin Pharmacokinet. 1986; 11: 87-106.

Venn RF, Michalkiewicz A, Hardy P, et al.: Concentrations of morphine, morphine metabolites, and peptides in human CSF and plasma. Pain. 1990; Suppl 5: S188.

McQuay HJ, Carroll D, Faura C, et al.: Oral morphine in cancer pain: influences on morphine and metabolite concentration. Clin Pharmacol Ther. 1990; 48: 236-244.

Wolff T, Samuelsson H, Hedner T: Morphine and morphine metabolite concentrations in cerebrospinal fluid and plasma in cancer pain patients after slow-release oral morphine administration. Pain. 1995; 62: 147-154.

Faura CC, Olaso MJ, Cabanes CG, et al.: Lack of morphine-6-glucuronide antinociception after morphine treatment. Is morphine-3-glucuronide involved? Pain. 1996b; 65: 25-30.

Morley JS, Miles JB, Wells PE, et al.: Paradoxical pain. 7th World Congress on Pain. Paris: IASP, 1993: A40.

Samuelsson H, Hedner T, Venn R, et al.: CSF and plasma concentrations of morphine and morphine glucuronides in cancer patients receiving epidural morphine. Pain. 1993; 52: 179-185.

Goucke CR, Hackett LP, Ilett KF: Concentrations of morphine, morphine-6-glucuronide and morphine-3-glucuronide in serum and cerebrospinal fluid following morphine administration to patients with morphine-resistant pain. Pain. 1994; 56: 145-149.

Van Dongen RT, Crul BJ, Koopman-Kimenai PM, et al.: Morphine and morphine-glucuronide concentrations in plasma and CSF during long-term administration of oral morphine. Br J Clin Pharmacol. 1994; 38: 271-273.

Coughtrie MW, Ask B, Rane A, et al.: The enantioselective glucuronidation of morphine in rats and humans: Evidence for the involvement of more than one UDP-glucuronosyltransferase isoenzyme. Biochem Pharmacol. 1989; 38: 3273-3280.

Lear L, Nation RL, Stupans I: Influence of morphine concentration on detergent activation of rat liver morphine-UDP-glucuronosyltransferase. Biochem Pharmacol. 1991; 42: S55-S60.

Lawrence AJ, Michalkiewicz A, Morley JS: Differential inhibition of hepatic morphine UDP-glucuronosyltransferases by metal ions. Biochem Pharmacol. 1992; 43: 2335-2340.

Wahlstrom A, Lenhammar L, Ask B, et al.: Tricyclic antidepressants inhibit opioid receptor binding in human brain and hepatic morphine glucuronidation. Pharmacol Toxicol. 1994; 75: 23-27.

Coffman BL, Rios GR, King CD, et al.: Human UGT2B7 catalyzes morphine glucuronidation. Drug Metab Dispos. 1997; 25: 1-4.

Coffman BL, King CD, Rios GR, et al.: The glucuronidation of opioids, other xenobiotics, and androgens by human UGT2B7Y(268) and UGT2B7H(268). Drug Metab Dispos. 1998; 26: 73-77.

Hartley R, Quinn M, Green M, et al: Morphine glucuronidation in premature neonates. Bri J Clin Pharmacol. 1993b; 35: 314-317.

Tiseo PJ, Thaler HT, Lapin J, et al.: Morphine-6-glucuronide concentrations and opioid-related side effects: A survey in cancer patients. Pain. 1995; 61: 47-54.

Ashby M, Fleming B, Wood M, et al.: Plasma morphine and glucuronide (M3G and M6G) concentrations in hospice inpatients. J Pain Symptom Manage. 1997; 14: 157-67.

Klepstad P, Kaasa S, Borchgrevink PC: Start of oral morphine to cancer patients: Effective serum morphine concentrations and contribution from morphine-6-glucuronide to the analgesia produced by morphine. Eur J Clin Pharmacol. 2000; 55: 713-719.

Penson RT, Joel SP, Bakhshi K, et al.: Randomized placebocontrolled trial of the activity of the morphine glucuronides. Clin Pharmacol Ther. 2000; 68: 667-676.

Downloads

Published

05/01/2005

How to Cite

Penson, MRCP, MD, R. T., S. P. Joel, PhD, A. Gloyne, BSc, S. Clark, BSc, and M. L. Slevin, FRCP, MD. “Morphine Analgesia in Cancer Pain: Role of the Glucuronides”. Journal of Opioid Management, vol. 1, no. 2, May 2005, pp. 83-90, doi:10.5055/jom.2005.0021.

Issue

Section

Articles