A phase I study of d-methadone in patients with chronic pain

Natalie Moryl, MD; Cristina Tamasdan, MD; Dana Tarcatu, MD; Howard T. Thaler, PhD; Denise Correa, PhD; Richard Steingart, MD, FACC; Richard Payne, MD; Eugenie Obbens, MD, PhD

doi:10.5055/jom.2016.0311

Authors

Natalie Moryl, MD
Cristina Tamasdan, MD
Dana Tarcatu, MD
Howard T. Thaler, PhD
Denise Correa, PhD
Richard Steingart, MD, FACC
Richard Payne, MD
Eugenie Obbens, MD, PhD

DOI:

https://doi.org/10.5055/jom.2016.0311

Keywords:

D-methadone, pain, NMDA, N-methyl-D-aspartate antagonist

Abstract

D-Methadone is the d optical isomer of racemic mixture (DL-methadone) used clinically to treat pain and addiction in the United States. D-Methadone is practically devoid of opioid activity but maintains N-methyl-D-aspartate (NMDA) receptor antagonism. Evidence from extensive preclinical studies suggests that NMDA receptor antagonists attenuate neuronal plasticity, reverse opioid analgesic tolerance, and alleviate chronic pain states. The authors conducted a phase I open label study of D-methadone administered for the first time to patients with chronic pain to determine the safety and tolerability of D-methadone. In addition to their long-term regimen of opioids, the patients received 40 mg of d-methadone twice daily for 12 days. Analgesia and toxicity were recorded by the patients in a daily diary and assessed in clinic on days 1, 8, and 12. Eight patients of the 10 enrolled completed the study. Pain scores on Edmonton Symptom Assessment System (ESAS) did not change between days 1 and 12, but five of eight patients (62.5 percent) characterized D-methadone as moderately or very effective in relieving pain on the Global Assessment for pain. Five of the eight patients (62.5 percent) who completed the study requested to start treatment with commercially available methadone (DL-racemic methadone) after completing the study. D-Methadone at the dose of 40 mg PO Q 12 hours was well tolerated.

Perspective: This is the first clinical study of D-methadone in patients suffering from chronic pain. Additional phase I and phase II studies are needed to confirm its safety and analgesic effects. If D-methadone is well tolerated, it is likely to become a useful adjuvant to the treatment of a wide spectrum of pain syndromes.

Author Biographies

Natalie Moryl, MD

Pain and Palliative Care Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York; Weil Cornell Medical College, New York, New York.

Cristina Tamasdan, MD

Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York.

Dana Tarcatu, MD

Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York.

Howard T. Thaler, PhD

Epidemiology and Biostatistics Department, Memorial Sloan Kettering Cancer Center, New York, New York

Denise Correa, PhD

Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York.

Richard Steingart, MD, FACC

Cardiology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York

Richard Payne, MD

Pain and Palliative Care Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York

Eugenie Obbens, MD, PhD

Pain and Palliative Care Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York; Weil Cornell Medical College, New York, New York.

References

Dickenson AH, Sullivan AF: Differential effects of excitatory amino acid antagonists on dorsal horn nociceptive neurones in the rat. Brain Res. 1990; 506: 31-39.

Inturrisi CE: Preclinical evidence for a role of glutamatergic systems in opioid tolerance and dependence. Semin Neurosci. 1997; 9: 110-119.

Scott CC, Robbins EB, Chen KK: Pharmacologic comparison of the optical isomers of methadone. J Pharm Exp Ther. 1948; 93: 282-286.

Shimoyama N, Shimoyama M, Elliott KJ, et al.: d-Methadone is antinociceptive in the rat formalin test. J Pharm Exp Ther. 1997; 283: 648-652.

Ventafridda V, Ripamonti C, Bianchi M, et al.: A randomized study on oral administration of morphine and methadone in the treatment of cancer pain. J Pain Symptom Manage. 1986; 1: 203-207.

Max MB, Byas-Smith MG, Gracely RH, et al.: Intravenous infusion of the NMDA antagonist, ketamine, in chronic posttraumatic pain with allodynia: A double-blind comparison to alfentanil and placebo. Clin Neuropharmacol. 1995; 18: 360-368.

Elliott KJ, Hynansky A, Inturrisi CE: Dextromethorphan attenuates and reverses morphine tolerance. Pain. 1994; 59: 361-368.

McQuay HJ, Carroll D, Jadad AR, et al.: Dextromethorphan for the treatment of neuropathic pain: A double-blind randomized controlled crossover trial with integral n-of-1 design. Pain. 1994; 59: 127-133.

Bell R, Eccleston C, Kalso E: Ketamine as an adjuvant to opioids for cancer pain. Cochrane Database Syst Rev. 2003; 1: CD003351.

Mercadante S, Arcuri E, Tirelli W, et al.: Analgesic effect of intravenous ketamine in cancer patients on morphine therapy: A randomized, controlled, double-blind, crossover, double-dose study. J Pain Symptom Manage. 2000; 4: 2-251.

Yang CY, Wong CS, Chang JY, et al.: Intrathecal ketamine reduces morphine requirements in patients with terminal cancer pain. Can J Anaesth. 1996; 43: 379-383.

Benítez-Rosario MA, Salinas-Martín A, Aguirre-Jaime A, et al.: Morphine-methadone opioid rotation in cancer patients: Analysis of dose ratio predicting factors. J Pain Symptom Manage. 2009; 37: 1061-1068.

Crews JC, Sweeney NJ, Denson DD: Clinical efficacy of methadone in patients refractory to other mu opioid receptor analgesics for the management of terminal cancer pain. Cancer. 1993; 72: 2266-2272.

Fainsinger R, Schoeller T, Bruera E: Methadone in the management of cancer pain: A review. Pain. 1992; 49: 87-91.

Foley KM, Houde R: Methadone in cancer pain management: Individualize dose and titrate to effect. J Clin Oncol. 1998; 16: 3213-3215.

Galer BS, Coyle N, Pasternak GW, et al.: Individual variability in the response to different opioids: report of five cases. Pain. 1986; 25: 297-312.

Gorman ES, Warfield CA: The use of opioids in the management of pain. Hosp Pract. 1986; 12: 48A-48H.

Manfredi PL, Borsook D, Chandler SW, et al.: Intravenous methadone for cancer pain unrelieved by morphine and hydromorphone: Clinical observations. Pain. 1997; 70: 99-101.

Meracadante S, Ferrera P, Villari P, et al.: Switching from oxycodone to methadone in advanced cancer patients. Support Care Cancer. 2011; 20: 191-194.

Morley JS, Watt JW, Wells JC, et al.: Methadone in pain uncontrolled by morphine. Lancet. 1993; 342: 1243.

Parsons HA, de la Cruz M, El Osta B, et al.: Methadone initiation and rotation in the outpatient setting for patients with cancer pain. Cancer. 2010; 116: 520-528.

Ripamonti C, Groff L, Brunelli C, et al.: Switching from morphine to oral methadone in treating cancer pain: What is the equianalgesic dose ratio? J Clin Oncol. 1998; 16: 3216-3221.

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

Inturrisi CE: Pharmacology of methadone and its isomers. Minerva Anestesiol. 2005; 71: 436-437.

Holtman JR Jr, Wala EP: Characterization of the antinociceptive and pronociceptive effects of methadone in rats. Anesthesiology. 2007; 106: 563-571.

Tiseo PJ, Inturrisi CE: Attenuation and reversal of morphine tolerance by the competitive N-methyl-d-aspartate receptor antagonist, LY274614. J Pharmacol Exp Ther. 1993; 264: 1090-1096.

Morgan RW, Nicholson KL: Characterization of the antinociceptive effects of the individual isomers of methadone after acute and chronic administrations. Behav Pharmacol. 2011; 22: 548-557.

Mercadante S, Casuccio A, Agnello A, et al: Morphine versus methadone in the pain treatment of advanced-cancer patients followed up at home. J Clin Oncol. 1998; 16:3656-1961.

Davis AM, Inturrisi CE: d-Methadone blocks morphine tolerance and N-methyl-d-aspartate (NMDA)-induced hyperalgesia. J Pharmacol Exp Ther. 1998; 289: 1048-1053.

Gorman AL, Elliott KJ, Inturrisi CE: The D- and L-isomers of methadone bind to the non-competitive sit on the N-methylD-aspartate (NMDA) receptor in rat forebrain and spinal cord. Nerurosci Lett. 1997; 223: 5-8.

Isbell H, Eisenman AJ: The addiction liability of some drugs of the methadone series. J Pharmacol Exp Ther. 1948; 93: 305-313.

Fraser HF, Isbell H: Human pharmacology and addictiveness of certain dextroisomers of synthetic analgesics: I. D-3-Hydroxy-N-phenethylmorphinan, II. D-3-Methoxy-N-phenethylmorphinan, III. D-Methadone. Bull. Narcot. 1962; 14: 25-35.

Chang A, Emmel DW, Rossi GC, et al.: Methadone analgesia in morphine-insensitive CXBK mice. Eur J Pharm. 1998; 351: 189-191.

de Vos JW, Ufkes JG, Kaplan CD, et al.: l-Methadone and D,L-methadone in methadone maintenance treatment: A comparison of therapeutic effectiveness and plasma concentrations. Eur Addict Res. 1998; 4: 134-141.

Hiltunen AJ, Beck O, Hjemdahl P, et al.: Rated well-being in relation to plasma concentrations of L- and D-methadone in satisfied and dissatisfied patients on methadone maintenance treatment. Psychopharmacology. 1999; 143: 385-393.

Moody DE, Lin SN, Chang Y, et al.: An enantiomer-selective liquid chromatography-tandem mass spectrometry method for methadone and DDP validated for use in human plasma, urine, and liver microsomes. J Anal Toxicol. 2008; 32: 208-219.

Olsen GD, Wendel HA, Livermore JD, et al.: Clinical effects and pharmacokinetics of racemic methadone and its optical isomers. Clin Pharm Ther. 1997; 21: 147-157.

Nilsson MI, Anggard E, Holmstrand J, et al.: Pharmacokinetics of methadone during maintenance treatment: Adaptive changes during the induction phase. Eur J Clin Pharmacol. 1982; 22: 343-349.

Foster DJR., Somogyi AA, Dyer KR, et al.: Steady-state pharmacokinetics of (R)- and (S)-methadone in methadone maintenance patients. Br J Clin Pharmacol. 2000; 50: 427-440.

Foster DJR, Somogyi AA, White JM, et al.: Population pharmacokinetics of (R)-, (S)- and rac-methadone in methadone maintenance patients. Br J Clin Pharmacol. 2004; 57: 742-755.

FDA Information for Healthcare Professionals: Methadone Hydrochloride. Available at http://www.fda.gov/downloads/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm142839.pdf. Accessed January 13, 2016.

Mitchell TB, Dyer KR, Newcombe D, et al.: Subjective and physiological responses among racemic-methadone maintenance patients in relation to relative (S)- vs. (R)-methadone exposure. Br J Clin Pharmacol. 2004; 58: 609-617.

Rostami-Hodjegan A, Wolff K, Hay AW, et al.: Population pharmacokinetics of methadone in opiate users: Characterization of time-dependent changes. Br J Clin Pharmacol. 1999; 48: 43-45.

Cretol S, Deglon JJ, Besson J, et al.: Methadone enantiomer plasma levels, CYP2B6, CYP2C19, and CYP2C9 genotypes, and response to treatment. Clin Pharmacol Ther. 2005; 78: 593-604.

Verebely K, Volavka J, Mulé S, et al.: Methadone in man: pharmacokinetic and excretion studies in acute and chronic treatment. Clin Pharmacol Ther. 1975; 18: 180-190.