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Methadone: A new old drug with promises and pitfalls

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Abstract

Although methadone is not a new medication, its use in pain management has increased rapidly over the past decade. This article reviews the unique pharmacologic properties of methadone, including its long-acting nature, highly variable clearance rate, and its antagonism of the N-methyl-d-aspartate receptor. We discuss potential benefits and risks of methadone over other opioid medications. Preclinical studies suggest methadone may reduce abuse potential, tolerance development, and sensitization of nociceptive pathways. Pharmacologic properties of methadone suggest potential greater risk of dangerous or fatal side effects from overdose, QT interval prolongation, and drug interactions. However, clinical studies have yet to confirm that methadone produces either better clinical outcomes or higher rates of adverse events than other opioid analgesics. Clinicians who understand the special properties of methadone and follow recommended precautionary prescribing and monitoring practices can safely and effectively use methadone for pain treatment.

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References and Recommended Reading

  1. Brown R, Kraus C, Fleming M, et al.: Methadone: applied pharmacology and use as adjunctive treatment in chronic pain. Postgrad Med J 2004, 80:654–659.

    Article  PubMed  CAS  Google Scholar 

  2. Leavitt SB, Shinderman M, Maxwell S, et al.: When “enough” is not enough: new perspectives on optimal methadone maintenance dose. Mt Sinai J Med 2000, 67:404–411.

    PubMed  CAS  Google Scholar 

  3. Crettol S, Deglon JJ, Besson J, et al.: ABCB1 and cytochrome P450 genotypes and phenotypes: influence on methadone plasma levels and response to treatment. Clin Pharmacol Ther 2006, 80:668–681.

    Article  PubMed  CAS  Google Scholar 

  4. Garrido MJ, Troconiz IF: Methadone: a review of its pharmacokinetic/pharmacodynamic properties. J Pharmacol Toxicol Methods 1999, 42:61–66.

    Article  PubMed  CAS  Google Scholar 

  5. Duché JC, Urien S, Simon N, et al.: Expression of the genetic variants of human alpha-1-acid glycoprotein in cancer. Clin Biochem 2000, 33:197–202.

    Article  PubMed  Google Scholar 

  6. Kristensen K, Christensen CB, Christrup LL: The mu1, mu2, delta, kappa opioid receptor binding profiles of methadone stereoisomers and morphine. Life Sci 1995, 56:45–50.

    Article  Google Scholar 

  7. Scott CC, Robbins EB, Chen KK: Pharmacological comparison of the optical isomers of methadone. J Pharmacol Exp Ther 1948, 93:282–286.

    PubMed  CAS  Google Scholar 

  8. Ingoglia NA, Dole VP: Localization of d- and l-methadone after intraventricular injection into rat brains. J Pharmacol Exp Ther 1970, 175:84–87.

    PubMed  CAS  Google Scholar 

  9. Gorman AL, Elliott KJ, Inturrisi CE: The d- and l-isomers of methadone bind to the non-competitive site on the Nmethyl-D-aspartate (NMDA) receptor in rat forebrain and spinal cord. Neurosci Lett 1997, 223:1–4.

    Article  Google Scholar 

  10. Davis WR, Johnson BD: Prescription opioid use, misuse, and diversion among street drug users in New York City. Drug Alcohol Depend 2008, 92:267–276.

    Article  PubMed  Google Scholar 

  11. Dunbar S, Yaksh TL: Concurrent spinal infusion of MK801 blocks spinal tolerance and dependence induced by chronic intrathecal morphine in the rat. Anesthesiology 1996, 84:1177–1188.

    Article  PubMed  CAS  Google Scholar 

  12. Jhamandas KH, Marsala M, Ibuki T, et al.: Spinal amino acid release and precipitated withdrawal in rats chronically infused with spinal morphine. J Neurosci 1996, 16:2758–2766.

    PubMed  CAS  Google Scholar 

  13. Inturrisi CE: The role of N-methyl-D-aspartate (NMDA) receptors in pain and morphine tolerance. Minerva Anestesiol 2005, 71:401–403.

    PubMed  CAS  Google Scholar 

  14. Mendez IA, Trujillo KA: NMDA receptor antagonists inhibit opiate antinociceptive tolerance and locomotor sensitization in rats. Psychopharmacology 2008, 196:497–509.

    Article  PubMed  CAS  Google Scholar 

  15. Ibuki T, Marsala M, Masuyama T, et al.: Spinal amino acid release and repeated withdrawal in spinal morphine tolerant rats. Br J Pharmacol 2003, 138:689–697.

    Article  PubMed  CAS  Google Scholar 

  16. Davis AM, Inturrisi CE: d-Methadone blocks morphine tolerance and N-methyl-D-aspartate-induced hyperalgesia. J Pharmacol Exp Ther 1999, 289:1048–1053.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  18. Galer BS, Lee D, Ma T, et al.: MorphiDex (morphine sulfate/dextromethorphan hydrobromide combination) in the treatment of chronic pain: three multicenter, randomized, double-blind, controlled clinical trials fail to demonstrate enhanced opioid analgesia or reduction in tolerance. Pain 2005, 115:284–295.

    PubMed  CAS  Google Scholar 

  19. Arttamangkul S, Quillinan N, Low M, et al.: Differential activation and trafficking of mu-opioid receptors in brain slices. Mol Pharmacol 2008, 74:972–979.

    Article  PubMed  CAS  Google Scholar 

  20. Martini L, Whistler JL: The role of mu-opioid receptor desensitization and endocytosis in morphine tolerance and dependence. Curr Opin Neurobiol 2007, 17:556–564.

    Article  PubMed  CAS  Google Scholar 

  21. Kim JA, Bartlett S, He L, et al.: Morphine-induced receptor endocytosis in a novel knockin mouse reduces tolerance and dependence. Curr Biol 2008, 18:129–135.

    Article  PubMed  CAS  Google Scholar 

  22. Eckholm E, Pierce O: Methadone rises as a painkiller with big risks. New York Times. August 16, 2008:A1.

  23. Paulozzi LJ, Xi Y: Recent changes in drug poisoning mortality in the United States by urban rural status and by drug type. Pharmacoepidemiol Drug Saf 2008, 17:997–1005.

    Article  PubMed  Google Scholar 

  24. Paulozzi LJ, Ryan GW: Opioid analgesics and rates of fatal drug poisoning in the United States. Am J Prev Med 2006, 31:506–511.

    Article  PubMed  Google Scholar 

  25. Gilson AM, Ryan KM, Joranson DE, et al.: A reassessment of trends in the medical use and abuse of opioid analgesics and implications for diversion control: 1997–2002. J Pain Symptom Manage 2004, 28:176–188.

    Article  PubMed  Google Scholar 

  26. Joranson DE, Ryan KM, Gilson AM, et al.: Trends in medical use and abuse of opioid analgesics. JAMA 2000, 283:1710–1714.

    Article  PubMed  CAS  Google Scholar 

  27. Wedman EF, Bigelow GE, Johnson RE, et al.: QT-interval effects of methadone, levomethadyl, and buprenorphine in a randomized trial. Arch Intern Med 2007, 167:2469–2475.

    Article  Google Scholar 

  28. Woosley RL, Pearson EC: QT prolongation and torsades de pointes among methadone users: reports to the FDA spontaneous reporting system. Pharmacoepidemiol Drug Saf 2005, 14:747–753.

    Article  PubMed  CAS  Google Scholar 

  29. Al-Khatib SM, LaPointe NM, Allen C, et al.: What clinicians should know about the QT interval. JAMA 2003, 286:2120–2127.

    Article  Google Scholar 

  30. Fredheim OMS, Moksnes K, Borchgrevink PC, et al.: Clinical pharmacology of methadone for pain. Acta Anaesthesiol Scand 2008, 52:879–889.

    Article  PubMed  CAS  Google Scholar 

  31. Saarto T, Wiffen PJ: Antidepressants for neuropathic pain. Cochrane Database Syst Rev 2007, 4:CD005454.

  32. McCance-Katz EF, Rainey PM, Friedland G, et al.: Effect of opioid dependence pharmacotherapies on zidovudine disposition. Am J Addict 2001, 10:296–307.

    PubMed  CAS  Google Scholar 

  33. Chan GM, Stajic M, Marker EK, et al.: Testing positive for methadone and either a tricyclic antidepressant or a benzodiazepine is associated with an accidental overdose death: analysis of medical examiner data. Acad Emerg Med 2006, 13:543–547.

    Article  PubMed  Google Scholar 

  34. Grass H, Behnsen S, Kimont HG, et al.: Methadone and its role in drug-related fatalities in Cologne 1989–2000. Forensic Sci Int 2000, 132:195–200.

    Article  CAS  Google Scholar 

  35. Cone EJ, Fant RV, Rohay JM, et al.: Oxycodone involvement in drug abuse deaths: a DAWN-based classification scheme applied to an oxycodone postmortem database containing over 1000 cases. J Anal Toxicol 2000, 27:57–67.

    Google Scholar 

  36. Sheedy DL, Garrick TM, Fortis AH, et al.: Changing trends in heroin-related deaths in Sydney, Australia: 1995 to 1999. Am J Addict 2003, 12:52–59.

    Article  PubMed  Google Scholar 

  37. Oliver P, Keen J: Concomitant drugs of misuse and drug using behaviours associated with fatal opiate-related poisonings in Sheffield, UK, 1997–2000. Addiction 2003, 98:191–197.

    Article  PubMed  Google Scholar 

  38. Mikolaenko I, Robinson CA Jr, Davis GG: A review of methadone deaths in Jefferson County, Alabama. Am J Forensic Med Pathol 2002, 23:299–304.

    Article  PubMed  Google Scholar 

  39. Shields LB, Hunsaker Iii JC, Corey TS, et al.: Methadone toxicity fatalities: a review of medical examiner cases in a large metropolitan area. J Forensic Sci 2007, 52:1389–1395.

    Article  PubMed  Google Scholar 

  40. Iguchi MY, Handelsman L, Bickel WK, Griffiths RR: Benzodiazepine and sedative use/abuse by methadone clients. Drug Alcohol Depend 1993, 32:257–266.

    Article  PubMed  CAS  Google Scholar 

  41. Bespalov AY, Zvartau EE, Beardsley PM: Opioid-NMDA receptor interactions may clarify conditioned (associative) components of opioid analgesic tolerance. Neurosci Biobehav Rev 2001, 25:343–353.

    Article  PubMed  CAS  Google Scholar 

  42. Mitchell JM, Basbaum AI, Fields HL: A locus and mechanism of action for associative morphine tolerance. Nat Neurosci 2000, 3:47–53.

    Article  PubMed  CAS  Google Scholar 

  43. Andersen G, Christrup L, Sjøgren P: Relationships among morphine metabolism, pain and side effects during long-term treatment: an update. J Pain Symptom Manage 2003, 25:74–91.

    Article  PubMed  CAS  Google Scholar 

  44. Weschules DJ, Bain KT: A systematic review of opioid conversion ratios used with methadone for the treatment of pain. Pain Med 2008, 9:595–612.

    Article  PubMed  Google Scholar 

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Correspondence to Jodie A. Trafton.

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Trafton, J.A., Ramani, A. Methadone: A new old drug with promises and pitfalls. Current Science Inc 13, 24–30 (2009). https://doi.org/10.1007/s11916-009-0006-0

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