Canadian Journal of Anesthesia

, Volume 52, Issue 5, pp 513–523 | Cite as

Review article: Perioperative pain management of patients on methadone therapy

  • Philip W. H. PengEmail author
  • Paul S. Tumber
  • Douglas Gourlay
Regional anesthesia and pain



Methadone, an opioid traditionally associated with the management of opioid addictive disorders, has been prescribed increasingly as an analgesic for the management of various chronic pain conditions. Despite the increasing popularity of methadone, most anesthesiologists are not familiar with its complex pharmacology. The purpose of this article is to review the pharmacology of methadone and to suggest a management algorithm for the perioperative care of methadone patients.


A Medline search was performed to obtain the published literature on the pharmacology of methadone and its use perioperatively.

Principal findings

The complexity of methadone’s pharmacology is characterized by a high inter-individual variability, a potential for interaction with other medications, and a long elimination half-life. The postoperative management of methadone patients may be difficult as they are often ‘opioid-tolerant’ but may be ‘pain-intolerant’. For those patients who are taking part in methadone-maintenance programs, there is a potential for the problematic use of opioids or other substances. The management plan for patients taking methadone may differ depending on the type of surgery and the associated perioperative differences in fasting status and gastrointestinal function. In consideration of all the factors listed above, a management algorithm is outlined for the perioperative care of methadone patients.


Methadone is an opioid with complex properties, and a patient that is taking methadone can represent a unique challenge to the anesthesiologist. A good understanding of the pharmacology of methadone and of the type of patients on this medication will help to improve their perioperative care.


Morphine Cancer Pain Methadone Maintenance Treatment Methadone Maintenance Therapy Opioid Addiction 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Exposé de synthèse : Traitement de la douleur périopératoire chez les patients sous thérapie à la méthadone



La méthadone, opiacé habituellement associé au traitement des dépendances aux opiacés, est prescrite de plus en plus comme analgésique pour diverses douleurs chroniques. Malgré sa popularité croissante, la plupart des anesthésiologistes n’en connaissent pas la pharmacologie complexe. Nous avons revu la pharmacologie et recommander un algorithme de traitement périopératoire pour les patients traités avec la méthadone.


Une recherche dans Medline a été réalisée pour obtenir les publications sur la pharmacologie de la méthadone et son usage périopératoire.

Constatations principales

La complexité de la pharmacologie de la méthadone est caractérisée par une grande variabilité inter-individuelle, un potentiel d’interaction avec d’autres médicaments et une longue demi-vie d’élimination. Le traitement postopératoire des patients sous méthadone peut être difficile, car ils présentent souvent une «tolérance aux opiacés», mais ils peuvent être «intolérants à la douleur». Dans les cas de traitements d’entretien à la méthadone, il y a des problèmes possibles avec l’usage d’opiacés ou d’autres substances. Le plan de traitement des patients sous méthadone peut différer selon le type de chirurgie et les différences périopératoires associées de l’état de jeûne et de la fonction gastro-intestinale. En considérant tous ces facteurs, un algorithme de traitement est tracé pour les soins périopératoires des patients sous méthadone.


La méthadone est un opiacé aux propriétés complexes et l’anesthésie d’un patient sous méthadone peut représenter un grand défi. Une bonne connaissance de sa pharmacologie et du type de patients qui en consomment aidera à améliorer les soins périopératoires.


  1. 1.
    Health Canada. Best Practices. Methadone Maintenance Treatment. Ottawa: Minister of Public Works and Government Services, 2002. Available from URL; methadone_treatment_best_practices.pdf.Google Scholar
  2. 2.
    Fishman SM, Wilsey B, Mahajan G, Molina P. Methadone reincarnated: novel clinical applications with related concerns. Pain Med 2002; 3:339–48.PubMedCrossRefGoogle Scholar
  3. 3.
    Bruera E, Sweeney C. Methadone use in cancer patients with pain: a review. J Palliat Med 2002; 5:127–38.PubMedCrossRefGoogle Scholar
  4. 4.
    Moulin DE, Clark AJ, Speechley M, Morley-Forster PK. Chronic pain in Canada-prevalence, treatment, impact and the role of opioid analgesia. Pain Res Manage 2002; 7:179–84.Google Scholar
  5. 5.
    Davis MP, Walsh D. Methadone for relief of cancer pain: a review of pharmacokinetics, pharmacodynamics, drug interactions and protocols of administration. Support Care Cancer 2001; 9:73–83.PubMedCrossRefGoogle Scholar
  6. 6.
    Peng P, Castano E. Survey of chronic pain practice of anesthesiologists in Can J Anesth 2005; 52:383–9.PubMedGoogle Scholar
  7. 7.
    Kornick CA, Kilborn MJ, Santiago-Palma J, et al. QTc interval prolongation associated with intravenous methadone. Pain 2003; 105:499–506.PubMedCrossRefGoogle Scholar
  8. 8.
    Shir Y, Rosen G, Zeldin A, Davidson EM. Methadone is safe for treating hospitalized patients with severe pain. Can J Anesth 2001; 48:1109–13.PubMedGoogle Scholar
  9. 9.
    Prieto-Alvarez P, Tello-Galindo I, Cuenca-Pena J, Rull-Bartomeu M, Gomar-Sancho C. Continuous epidural infusion of racemic methadone results in effective postoperative analgesia and low plasma concentrations. Can J Anesth 2002; 49:25–31.PubMedGoogle Scholar
  10. 10.
    Jacobson L, Chabal C, Brody MC, Ward RJ, Ireton RC. Intrathecal methadone and morphine for postoperative analgesia: a comparison of the efficacy, duration, and side effects. Anesthesiology 1989; 70:742–6.PubMedCrossRefGoogle Scholar
  11. 11.
    Jacobson L, Chabal C, Brody MC, Ward RJ, Wasse L. Intrathecal methadone: a dose-response study and comparison with intrathecal morphine 0.5 mg. Pain 1990; 43:141–8.PubMedCrossRefGoogle Scholar
  12. 12.
    Sabatowski R, Kasper SM, Radbruch L. Patient-controlled analgesia with intravenous L-methadone in a child with cancer pain refractory to high-dose morphine (Letter). J Pain Symptom Manage 2002; 23:3–5.PubMedCrossRefGoogle Scholar
  13. 13.
    Inturrisi CE. Clinical pharmacology of opioids for pain. Clin J Pain 2002; 18:S3–13.PubMedCrossRefGoogle Scholar
  14. 14.
    Ebert B, Thorkildsen C, Andersen S, Christrup LL, Hjeds H. Opioid analgesics as noncompetitive N-methyl-Daspartate (NMDA) antagonists. Biochem Pharmacol 1998; 56:553–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Garrido MJ, Troconiz IF. Methadone: a review of its pharmacokinetic/pharmacodynamic properties. J Pharmacol Toxicol 1999; 42:61–6.CrossRefGoogle Scholar
  16. 16.
    Wolff K, Hay AW, Raistrick D, Calvert R. Steady-state pharmacokinetics of methadone in opioid addicts. Eur J Clin Pharmacol 1993; 44:189–94.PubMedCrossRefGoogle Scholar
  17. 17.
    Inturrisi CE, Colburn WA, Kaiko RF, Houde RW, Foley KM. Pharmacokinetics and pharmacodynamics of methadone in patients with chronic pain. Clin Pharmacol Ther 1987; 41:392–401.PubMedGoogle Scholar
  18. 18.
    Foster DJ, Somogyi AA, Bochner F. Methadone Ndemethylation in human liver microsomes: lack of stereoselectivity and involvement of CYP3A4. Br J Clin Pharmacol 1999; 47:403–12.PubMedCrossRefGoogle Scholar
  19. 19.
    Kharasch ED, Hoffer C, Whittington D, Sheffels P. Role of hepatic and intestinal cytochrome P450 3A and 2B6 in the metabolism, deposition, and miotic effects of methadone. Clin Pharmacol Ther 2004; 76:250–69.PubMedCrossRefGoogle Scholar
  20. 20.
    Sawe J. High-dose morphine and methadone in cancer patients. Clinical pharmacokinetic considerations of oral treatment. Clin Pharmacokinet 1986; 11:87–106.PubMedCrossRefGoogle Scholar
  21. 21.
    Richelson E. Pharmacokinetic drug interactions of new antidepressants: a review of the effects on the metabolism of other drugs. Mayo Clin Proc 1997; 72:835–47.PubMedGoogle Scholar
  22. 22.
    Ripamonti C, Groff L, Brunelli C, Polastri D, Starrakis A, De Conno F. Switching from morphine to oral methadone in treating cancer pain: what is the equianalgesic dose ratio? J Clin Oncol 1998; 16:3216–21.PubMedGoogle Scholar
  23. 23.
    Mercadante S, Casuccio A, Calderone L. Rapid switching from morphine to methadone in cancer patients with poor response to morphine. J Clin Oncol 1999; 17:3307–12.PubMedGoogle Scholar
  24. 24.
    Baumann P, Tinguely D, Schopf J. Increase of α1-acid glycoprotein after treatment with amitriptyline. Br J Clin Pharmacol 1982; 14:102–3.PubMedGoogle Scholar
  25. 25.
    White JM, Irvine RJ. Mechanism of fatal opioid overdose. Addiction 1999; 94:961–72.PubMedCrossRefGoogle Scholar
  26. 26.
    Gourlay DL, Heit HA. Treatment of polysubstance abuse in the active user (Letter). Pain Med 2004; 5:109–10.PubMedCrossRefGoogle Scholar
  27. 27.
    Drummer OH, Opeskin K, Syrjanen M, Cordner SM. Methadone toxicity causing death in ten subjects starting on a methadone maintenance program. Am J Forensic Med Pathol 1992; 13:346–50.PubMedCrossRefGoogle Scholar
  28. 28.
    Bates DW, Cullen DJ, Laird N, et al. Incidence of adverse drug events and potential adverse drug events. Implications for prevention. ADE Prevention Study Group. JAMA 1995; 274:29–34.PubMedCrossRefGoogle Scholar
  29. 29.
    May JA, White HC, Leonard-White A, Warltier DC, Pagel PS. The patient recovering from alcohol or drug addiction: special issues for the anesthesiologist. Anesth Analg 2001; 92:1601–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Compton P, Charuvastra VC, Kintaudi K, Ling W. Pain responses in methadone-maintained opioid abusers. J Pain Symptom Manage 2000; 20:237–45.PubMedCrossRefGoogle Scholar
  31. 31.
    Krantz MJ, Lewkowiez L, Hays H, Woodroffe MA, Robertson AD, Mehler PS. Torsade de pointes associated with very-high-dose methadone. Ann Intern Med 2002; 137:501–4.PubMedGoogle Scholar
  32. 32.
    The College of Physicians and Surgeons of Ontario. Methadone maintenance guidelines. Available from URL; Publications/methguide.htm.Google Scholar
  33. 33.
    Doverty M, White JM, Somogyi AA, Bochner F, Ali R, Ling W. Hyperalgesic response in methadone maintenance patients. Pain 2001; 90:91–6.PubMedCrossRefGoogle Scholar
  34. 34.
    Etches RC. Patient-controlled analgesia. Surg Clin North Am 1999; 79:297–312.PubMedCrossRefGoogle Scholar
  35. 35.
    Parker RK, Holtmann B, White PF. Patient-controlled analgesia. Does a concurrent opioid infusion improve pain management after surgery ? JAMA 1991; 266:1947–52.PubMedCrossRefGoogle Scholar
  36. 36.
    Parker RK, Holtmann B, White PF. Effects of a night- time opioid infusion with PCA therapy on patient comfort and analgesic requirements after abdominal hysterectomy. Anesthesiology 1992; 76:362–7.PubMedCrossRefGoogle Scholar
  37. 37.
    Etches RC. Respiratory depression associated with patient-controlled analgesia: a review of eight cases. Can J Anaesth 1994; 41:125–32.PubMedGoogle Scholar
  38. 38.
    Dunbar SA, Pulai IP. Repetitive opioid abstinence causes progressive hyperalgesia sensitive to N-methyl-D-aspartate receptor blockade in the rat. J Pharmacol Exp Ther 1998; 284:678–86.PubMedGoogle Scholar
  39. 39.
    Weinbroum AA. A single small dose of postoperative ketamine provides rapid and sustained improvement in morphine analgesia in the presence of morphine-resistant pain. Anesth Analg 2003 96:789–95.Google Scholar
  40. 40.
    Schmid RL, Sandler AN, Katz J. Use and efficacy of low-dose ketamine in the management of acute postoperative pain: a review of current techniques and outcomes. Pain 1999; 82:111–25.PubMedCrossRefGoogle Scholar
  41. 41.
    Fitzgibbon DR, Ready LB. Intravenous high-dose methadone administered by patient controlled analgesia and continuous infusion for the treatment of cancer pain refractory to high-dose morphine. Pain 1997; 73:259–61.PubMedCrossRefGoogle Scholar
  42. 42.
    Gourlay GK, Willis RJ, Lamberty J. A double-blind comparison of the efficacy of methadone and morphine in postoperative pain control. Anesthesiology 1986; 64:322–7.PubMedCrossRefGoogle Scholar
  43. 43.
    Richlin DM, Reuben SS. Postoperative pain control with methadone following lower abdominal surgery. J Clin Anesth 1991; 3:112–6.PubMedCrossRefGoogle Scholar
  44. 44.
    Chui PT, Gin T. A double-blind randomised trial comparing postoperative analgesia after perioperative loading doses of methadone or morphine. Anaesth Intensive Care 1992; 20:46–51.PubMedGoogle Scholar
  45. 45.
    Mitra S, Sinatra RS. Perioperative management of acute pain in the opioid-dependent patient. Anesthesiology 2004; 101:212–27.PubMedCrossRefGoogle Scholar
  46. 46.
    Bowdle TA, Even A, Shen DD, Swardstrom M. Methadone for the induction of anesthesia: plasma histamine concentration, arterial blood pressure, and heart rate. Anesth Analg 2004; 98:1692–7.PubMedCrossRefGoogle Scholar
  47. 47.
    Anderson R, Saiers JH, Abram S, Schlicht C. Accuracy in equianalgesic dosing: conversion dilemmas. J Pain Symptom Manage 2001; 21:397–406.PubMedCrossRefGoogle Scholar
  48. 48.
    Moryl N, Santiago-Palma J, Kornick C, et al. Pitfalls of opioid rotation: substituting another opioid for methadone in patients with cancer pain. Pain 2002; 96:325–8.PubMedCrossRefGoogle Scholar
  49. 49.
    Ballantyne JC, Mao J. Opioid therapy for chronic pain. N Engl J Med 2003; 349:1943–53.PubMedCrossRefGoogle Scholar
  50. 50.
    Foley KM. Opioids and chronic neuropathic pain (Editorial). N Engl J Med 2003; 348:1279–81.PubMedCrossRefGoogle Scholar
  51. 51.
    Manfredi PL, Borsook D, Chandler SW, Payne R. Intravenous methadone for cancer pain unrelieved by morphine and hydromorphone: clinical observations. Pain 1997; 70:99–101.PubMedCrossRefGoogle Scholar
  52. 52.
    Bruera E, Fainsinger R, Moore M, Thibault R, Spoldi E, Ventafridda V. Local toxicity with subcutaneous methadone. Experience of two centers. Pain 1991; 45:141–3.PubMedCrossRefGoogle Scholar

Copyright information

© Canadian Anesthesiologists 2005

Authors and Affiliations

  • Philip W. H. Peng
    • 1
    • 2
    Email author
  • Paul S. Tumber
    • 1
    • 2
  • Douglas Gourlay
    • 1
    • 2
    • 3
  1. 1.Wasser Pain Management Pain CenterMount Sinai HospitalCanada
  2. 2.Department of Anesthesia and Pain ManagementUniversity Health Network, University of TorontoCanada
  3. 3.Centre for Addiction and Mental HealthA WHO Centre of ExcellenceTorontoCanada

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