Correlation between myoclonus and the 3-glucuronide metabolites in patients treated with morphine or hydromorphone: A pilot study

Shawn McCann, MD; Tony L. Yaksh, PhD; Charles F. von Gunten, MD, PhD

doi:10.5055/jom.2010.0008

Authors

Shawn McCann, MD
Tony L. Yaksh, PhD
Charles F. von Gunten, MD, PhD

DOI:

https://doi.org/10.5055/jom.2010.0008

Keywords:

morphine-3-glucuronide, hydromorphone-3-glucuronide, opioid neurotoxicity, myoclonus, morphine, hydromorphone

Abstract

Background: The 3-glucuronide metabolites of morphine and hydromorphone have been implicated as a causative factor for patients exhibiting myoclonus.
Objective: The primary goal of this study was to determine plasma levels of morphine-3-glucuronide (M3G) or hydromorphone-3-glucuronide (H3G) in patients demonstrating myoclonus and identify any trends or associations between the two.
Setting: Patients were recruited from San Diego Hospice and the Institute for Palliative Medicine’s inpatient unit.
Design: A prospective convenience sample comprised of 17 subjects, 12 with myoclonus and 5 without myoclonus. Analysis included demographic, metabolic and clinical variables. Plasma was assayed via high performance liquid chromatography for morphine, M3G, and morphine-6-glucuronide or hydromorphone and hydromorphone-3-glucuronide.
Results: No trends or associations were identified between plasma levels of M3G or H3G and myoclonus. Ratio levels of 3-glucuronide metabolite to their corresponding parent opioid were dramatically lower than anticipated.
Conclusion: In this small pilot study, it appears that the serum levels of metabolites M3G and H3G do not correlate with myoclonus.

Author Biographies

Shawn McCann, MD

Research Fellow 2004-2005, The Institute for Palliative Medicine, San Diego Hospice, San Diego, California. E-mail: semsdh@hotmail.com.

Tony L. Yaksh, PhD

Professor of Anesthesiology and Pharmacology and Vice-Chairman for Research, Department of Anesthesiology, UCSD Co-director, Symptom Control Program, UCSD Moores Cancer Center, San Diego, California.

Charles F. von Gunten, MD, PhD

Provost, The Institute for Palliative Medicine, San Diego Hospice, San Diego, California; Medical Director, Doris A. Howell Service, UCSD Moores Cancer Center, San Diego, California.

References

Blindauer K: Myoclonus and its disorders. Neurol Clin. 2001; 19(3): 723-734, viii.

Board INC: Global Consumption of Morphine. USA: University of Wisconsin Pain & Policies Study Group/WHO Collaborating Center, 1997.

Gordon MF: Toxin and drug-induced myoclonus. Adv Neurol. 2002; 89: 49-76.

Cann HM, Verhulst HL: Convulsions as a manifestation of acute dextro propoxyphene intoxication. Am J Dis Child. 1960; 99: 380-382.

Gary NE, Maher JF, DeMyttenaere MH, et al.: Acute propoxyphene hydrochloride intoxication. Arch Intern Med. 1968; 121(5): 453-457.

Qureshi EH: Propoxyphene hydrochloride poisoning. JAMA. 1964; 188: 470-471.

Kaiko RF, Foley KM, Grabinski PY, et al.: Central nervous system excitatory effects of meperidine in cancer patients. Ann Neurol. 1983; 13(2): 180-185.

Lauterbach EC: Hiccup and apparent myoclonus after hydrocodone: Review of the opiate-related hiccup and myoclonus literature. Clin Neuropharmacol. 1999; 22(2): 87-92.

Nabeel SDM, Walsh D, Nouneh C: Methadone-induced myoclonus in advanced cancer. Am J Hospice Palliat Care. 2001; 18(1): 51-53.

Mercadante S: Dantrolene treatment of opioid-induced myoclonus. Anesth Analg. 1995; 81(6): 1307-1308.

Bruera E, Pereira J: Acute neuropsychiatric findings in a patient receiving fentanyl for cancer pain. Pain. 1997; 69(1-2): 199-201.

Volavka J, Zaks A, Roubicek J, et al.: Electrographic effects of diacetylmorphine (heroin) and naloxone in man*1. Neuropharmacology. 1970; 9(6): 587-593.

Cartwright PD, Hesse C, Jackson AO: Myoclonic spasms following intrathecal diamorphine. J Pain Symptom Manage. 1993; 8(7): 492-495.

Sjogren P, Dragsted L, Christensen CB: Myoclonic spasms during treatment with high doses of intravenous morphine in renal failure. Acta Anaesthesiol Scand. 1993; 37(8): 780-782.

Parkinson SK, Bailey SL, Little WL, et al.: Myoclonic seizure activity with chronic high-dose spinal opioid administration. Anesthesiology. 1990; 72(4): 743-745.

Smith MTP, Wright AWEM, Williams BEF, et al.: Cerebrospinal fluid and plasma concentrations of morphine, morphine-3-glucuronide, and morphine-6-glucuronide in patients before and after initiation of intracerebroventricular morphine for cancer pain management. [Miscellaneous Article]. Anesth Analg. 1999; 88(1): 109-116.

Sjogren P, Jonsson T, Jensen NH, et al.: Hyperalgesia and myoclonus in terminal cancer patients treated with continuous intravenous morphine. Pain. 1993; 55(1): 93-7.

Potter JM, Reid DB, Shaw RJ, et al.: Myoclonus associated with treatment with high doses of morphine: The role of supplemental drugs. BMJ. 1989; 299(6692): 150-153.

MacDonald N, Der L, Allan S, et al.: Opioid hyperexcitability: The application of alternate opioid therapy. Pain. 1993; 53(3): 353-355.

Wright AW, Mather LE, Smith MT: Hydromorphone-3-glucuronide: A more potent neuro-excitant than its structural analogue, morphine-3-glucuronide. Life Sci. 2001; 69(4): 409-420.

Gilbert PE, Martin WR: Antagonism of the convulsant effects of heroin, d-propoxyphene, meperidine, normeperidine and thebaine by naloxone in mice. J Pharmacol Exp Ther. 1975; 192(3): 538-541.

Smith MT: Neuroexcitatory effects of morphine and hydromorphone: Evidence implicating the 3-glucuronide metabolites. Clin Exp Pharmacol Physiol. 2000; 27(7): 524-528.

Cherny N, Ripamonti C, Pereira J, et al.: Strategies to manage the adverse effects of oral morphine: An evidence-based report. J Clin Oncol. 2001; 19(9): 2542-2554.

Chung KS, Carson S, Glassman D, et al.: Successful treatment of hydromorphone-induced neurotoxicity and hyperalgesia. Conn Med. 2004; 68(9): 547-549.

de Stoutz ND, Bruera E, Suarez-Almazor M: Opioid rotation for toxicity reduction in terminal cancer patients. J Pain Symptom Manage. 1995; 10(5): 378-384.

Milne RW, Nation RL, Reynolds GD, et al.: High-performance liquid chromatographic determination of morphine and its 3- and 6-glucuronide metabolites: Improvements to the method and application to stability studies. J Chromatogr. 1991; 565(1-2): 457-464.

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(3): 157-167.

Sjogren P, Thunedborg LP, Christrup L, et al.: Is development of hyperalgesia, allodynia and myoclonus related to morphine metabolism during long-term administration? Six case histories. Acta Anaesthesiol Scand. 1998; 42(9): 1070-1075.

Reidenberg MM, Goodman H, Erle H, et al.: Hydromorphone levels and pain control in patients with severe chronic pain. Clin Pharmacol Ther. 1988; 44(4): 376-382.

Klepstad P, Hilton P, Moen J, et al.: Day-to-day variations during clinical drug monitoring of morphine, morphine-3-glucuronide and morphine-6-glucuronide serum concentrations in cancer patients. A prospective observational study. BMC Clin Pharmacol. 2004; 4(1): 7.

Wolff T, Samuelsson H, Hedner T: Concentrations of morphine and morphine metabolites in CSF and plasma during continuous subcutaneous morphine administration in cancer pain patients. Pain. 1996; 68(2-3):209-216.

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(2): 145-149.

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(2): 147-154.

Mercadante S, Bianchi M, Villari P, et al.: Opioid plasma concentration during switching from morphine to methadone: Preliminary data. Support Care Cancer. 2003; 11(5): 326-331.

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(3): 271-273.

Faura CC, Collins SL, Moore RA, et al.: Systematic review of factors affecting the ratios of morphine and its major metabolites. Pain. 1998; 74(1): 43-53.

Wolff J, Bigler D, Christensen CB, et al.: Influence of renal function on the elimination of morphine and morphine glucuronides. Eur J Clin Pharmacol. 1988; 34(4): 353-357.

D’Honneur G, Gilton A, Sandouk P, et al.: Plasma and cerebrospinal fluid concentrations of morphine and morphine glucuronides after oral morphine. The influence of renal failure. Anesthesiology. 1994; 81(1): 87-93.

Hagen N, Thirlwell MP, Dhaliwal HS, et al.: Steady-state pharmacokinetics of hydromorphone and hydromorphone-3-glucuronide in cancer patients after immediate and controlled-release hydromorphone. J Clin Pharmacol. 1995; 35(1): 37-44.

Babul N, Darke AC, Hagen N: Hydromorphone metabolite accumulation in renal failure. J Pain Symptom Manage. 1995; 10(3): 184-186.

Sjogren P, Jensen NH, Jensen TS: Disappearance of morphine-induced hyperalgesia after discontinuing or substituting morphine with other opioid agonists. Pain. 1994; 59(2): 313-316.

Jacobsen LS, Olsen AK, Sjogren P, et al.: [Morphine-induced hyperalgesia, allodynia and myoclonus—new side-effects of morphine?]. Ugeskr Laeger. 1995; 157(23): 3307-3310.

Smith NT, Benthuysen JL, Bickford RG, et al.: Seizures during opioid anesthetic induction—Are they opioid-induced rigidity? Anesthesiology. 1989; 71(6): 852-862.

Frucht SJ, Leurgans SE, Hallett M, et al.: The Unified Myoclonus Rating Scale. Adv Neurol. 2002; 89: 361-376.

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(1): 47-54.