Skip to main content
Postgraduate Medical Journal logoLink to Postgraduate Medical Journal
. 2004 Nov;80(949):654–659. doi: 10.1136/pgmj.2004.022988

Methadone: applied pharmacology and use as adjunctive treatment in chronic pain

R Brown 1, C Kraus 1, M Fleming 1, S Reddy 1
PMCID: PMC1743125  PMID: 15537850

Abstract

This article reviews the unique pharmacological properties of methadone and outlines its appropriate clinical application, with focus upon its use in the treatment of chronic pain. Although methadone is most widely known for its use in the treatment of opioid dependence, methadone also provides effective analgesia. Patients who experience inadequate pain relief or intolerable side effects with other opioids or who suffer from neuropathic pain may benefit from a transition to methadone as their analgesic agent. Adverse effects, particularly respiratory depression and death, make a fundamental knowledge of methadone's pharmacological properties essential to the provider considering methadone as analgesic therapy for a patient with chronic pain.

Full Text

The Full Text of this article is available as a PDF (77.3 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alderman C. P., Frith P. A. Fluvoxamine-methadone interaction. Aust N Z J Psychiatry. 1999 Feb;33(1):99–101. doi: 10.1046/j.1440-1614.1999.00522.x. [DOI] [PubMed] [Google Scholar]
  2. Altice F. L., Friedland G. H., Cooney E. L. Nevirapine induced opiate withdrawal among injection drug users with HIV infection receiving methadone. AIDS. 1999 May 28;13(8):957–962. doi: 10.1097/00002030-199905280-00012. [DOI] [PubMed] [Google Scholar]
  3. Ayonrinde O. T., Bridge D. T. The rediscovery of methadone for cancer pain management. Med J Aust. 2000 Nov 20;173(10):536–540. [PubMed] [Google Scholar]
  4. Barnett P. G., Hui S. S. The cost-effectiveness of methadone maintenance. Mt Sinai J Med. 2000 Oct-Nov;67(5-6):365–374. [PubMed] [Google Scholar]
  5. Bart P. A., Rizzardi P. G., Gallant S., Golay K. P., Baumann P., Pantaleo G., Eap C. B. Methadone blood concentrations are decreased by the administration of abacavir plus amprenavir. Ther Drug Monit. 2001 Oct;23(5):553–555. doi: 10.1097/00007691-200110000-00010. [DOI] [PubMed] [Google Scholar]
  6. Begré Stefan, von Bardeleben Ulrich, Ladewig Dieter, Jaquet-Rochat Sylvie, Cosendai-Savary Line, Golay Kerry Powell, Kosel Markus, Baumann Pierre, Eap Chin B. Paroxetine increases steady-state concentrations of (R)-methadone in CYP2D6 extensive but not poor metabolizers. J Clin Psychopharmacol. 2002 Apr;22(2):211–215. doi: 10.1097/00004714-200204000-00017. [DOI] [PubMed] [Google Scholar]
  7. Bertschy G., Eap C. B., Powell K., Baumann P. Fluoxetine addition to methadone in addicts: pharmacokinetic aspects. Ther Drug Monit. 1996 Oct;18(5):570–572. doi: 10.1097/00007691-199610000-00008. [DOI] [PubMed] [Google Scholar]
  8. Bruera E., MacMillan K., Hanson J., MacDonald R. N. Palliative care in a cancer center: results in 1984 versus 1987. J Pain Symptom Manage. 1990 Feb;5(1):1–5. doi: 10.1016/s0885-3924(05)80002-8. [DOI] [PubMed] [Google Scholar]
  9. Bruera E., Pereira J., Watanabe S., Belzile M., Kuehn N., Hanson J. Opioid rotation in patients with cancer pain. A retrospective comparison of dose ratios between methadone, hydromorphone, and morphine. Cancer. 1996 Aug 15;78(4):852–857. doi: 10.1002/(SICI)1097-0142(19960815)78:4<852::AID-CNCR23>3.0.CO;2-T. [DOI] [PubMed] [Google Scholar]
  10. Cicero T. J., Bell R. D., Wiest W. G., Allison J. H., Polakoski K., Robins E. Function of the male sex organs in heroin and methadone users. N Engl J Med. 1975 Apr 24;292(17):882–887. doi: 10.1056/NEJM197504242921703. [DOI] [PubMed] [Google Scholar]
  11. Clarke S. M., Mulcahy F. M., Tjia J., Reynolds H. E., Gibbons S. E., Barry M. G., Back D. J. Pharmacokinetic interactions of nevirapine and methadone and guidelines for use of nevirapine to treat injection drug users. Clin Infect Dis. 2001 Sep 24;33(9):1595–1597. doi: 10.1086/322519. [DOI] [PubMed] [Google Scholar]
  12. Clarke S. M., Mulcahy F. M., Tjia J., Reynolds H. E., Gibbons S. E., Barry M. G., Back D. J. The pharmacokinetics of methadone in HIV-positive patients receiving the non-nucleoside reverse transcriptase inhibitor efavirenz. Br J Clin Pharmacol. 2001 Mar;51(3):213–217. doi: 10.1046/j.1365-2125.2001.00342.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Cobb M. N., Desai J., Brown L. S., Jr, Zannikos P. N., Rainey P. M. The effect of fluconazole on the clinical pharmacokinetics of methadone. Clin Pharmacol Ther. 1998 Jun;63(6):655–662. doi: 10.1016/S0009-9236(98)90089-3. [DOI] [PubMed] [Google Scholar]
  14. Crews J. C., Sweeney N. J., Denson D. D. Clinical efficacy of methadone in patients refractory to other mu-opioid receptor agonist analgesics for management of terminal cancer pain. Case presentations and discussion of incomplete cross-tolerance among opioid agonist analgesics. Cancer. 1993 Oct 1;72(7):2266–2272. doi: 10.1002/1097-0142(19931001)72:7<2266::aid-cncr2820720734>3.0.co;2-p. [DOI] [PubMed] [Google Scholar]
  15. Daeninck P. J., Bruera E. Reduction in constipation and laxative requirements following opioid rotation to methadone: a report of four cases. J Pain Symptom Manage. 1999 Oct;18(4):303–309. doi: 10.1016/s0885-3924(99)00086-x. [DOI] [PubMed] [Google Scholar]
  16. De Conno F., Groff L., Brunelli C., Zecca E., Ventafridda V., Ripamonti C. Clinical experience with oral methadone administration in the treatment of pain in 196 advanced cancer patients. J Clin Oncol. 1996 Oct;14(10):2836–2842. doi: 10.1200/JCO.1996.14.10.2836. [DOI] [PubMed] [Google Scholar]
  17. DeMaria P. A., Jr, Serota R. D. A therapeutic use of the methadone fluvoxamine drug interaction. J Addict Dis. 1999;18(4):5–12. doi: 10.1300/J069v18n04_02. [DOI] [PubMed] [Google Scholar]
  18. Dyer K. R., White J. M. Patterns of symptom complaints in methadone maintenance patients. Addiction. 1997 Nov;92(11):1445–1455. [PubMed] [Google Scholar]
  19. Eap Chin B., Buclin Thierry, Baumann Pierre. Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence. Clin Pharmacokinet. 2002;41(14):1153–1193. doi: 10.2165/00003088-200241140-00003. [DOI] [PubMed] [Google Scholar]
  20. Gardner-Nix J. S. Oral methadone for managing chronic nonmalignant pain. J Pain Symptom Manage. 1996 May;11(5):321–328. doi: 10.1016/0885-3924(95)00191-3. [DOI] [PubMed] [Google Scholar]
  21. Gerber J. G., Rosenkranz S., Segal Y., Aberg J., D'Amico R., Mildvan D., Gulick R., Hughes V., Flexner C., Aweeka F. Effect of ritonavir/saquinavir on stereoselective pharmacokinetics of methadone: results of AIDS Clinical Trials Group (ACTG) 401. J Acquir Immune Defic Syndr. 2001 Jun 1;27(2):153–160. doi: 10.1097/00126334-200106010-00010. [DOI] [PubMed] [Google Scholar]
  22. Gunne L. M., Grönbladh L. The Swedish methadone maintenance program: a controlled study. Drug Alcohol Depend. 1981 Jun;7(3):249–256. doi: 10.1016/0376-8716(81)90096-x. [DOI] [PubMed] [Google Scholar]
  23. Hamilton S. P., Nunes E. V., Janal M., Weber L. The effect of sertraline on methadone plasma levels in methadone-maintenance patients. Am J Addict. 2000 Winter;9(1):63–69. doi: 10.1080/10550490050172236. [DOI] [PubMed] [Google Scholar]
  24. Hauri-Bionda R., Bär W., Friedrich-Koch A. Beitrag zur Frage der Fahrfähigkeit/Fahreignung Methadonsubstituierter. Schweiz Med Wochenschr. 1998 Oct 10;128(41):1538–1547. [PubMed] [Google Scholar]
  25. Herrlin K., Segerdahl M., Gustafsson L. L., Kalso E. Methadone, ciprofloxacin, and adverse drug reactions. Lancet. 2000 Dec 16;356(9247):2069–2070. doi: 10.1016/S0140-6736(00)03409-7. [DOI] [PubMed] [Google Scholar]
  26. Inturrisi Charles E. Clinical pharmacology of opioids for pain. Clin J Pain. 2002 Jul-Aug;18(4 Suppl):S3–13. doi: 10.1097/00002508-200207001-00002. [DOI] [PubMed] [Google Scholar]
  27. Iribarne C., Berthou F., Carlhant D., Dreano Y., Picart D., Lohezic F., Riche C. Inhibition of methadone and buprenorphine N-dealkylations by three HIV-1 protease inhibitors. Drug Metab Dispos. 1998 Mar;26(3):257–260. [PubMed] [Google Scholar]
  28. Leng G., Finnegan M. J. Successful use of methadone in nociceptive cancer pain unresponsive to morphine. Palliat Med. 1994;8(2):153–155. doi: 10.1177/026921639400800209. [DOI] [PubMed] [Google Scholar]
  29. Ling W., Charuvastra C., Kaim S. C., Klett C. J. Methadyl acetate and methadone as maintenance treatments for heroin addicts. A veterans administration cooperative study. Arch Gen Psychiatry. 1976 Jun;33(6):709–720. doi: 10.1001/archpsyc.1976.01770060043007. [DOI] [PubMed] [Google Scholar]
  30. Longwell B., Betz T., Horton H., Witte C. L., Witte M. H. Weight gain and edema on methadone maintenance therapy. Int J Addict. 1979 Apr;14(3):329–335. doi: 10.3109/10826087909054585. [DOI] [PubMed] [Google Scholar]
  31. Lotsch Jorn, Skarke Carsten, Tegeder Irmgard, Geisslinger Gerd. Drug interactions with patient-controlled analgesia. Clin Pharmacokinet. 2002;41(1):31–57. doi: 10.2165/00003088-200241010-00004. [DOI] [PubMed] [Google Scholar]
  32. McCance-Katz E. F., Farber S., Selwyn P. A., O'Connor A. Decrease in methodone levels with nelfinavir mesylate. Am J Psychiatry. 2000 Mar;157(3):481–481. doi: 10.1176/appi.ajp.157.3.481. [DOI] [PubMed] [Google Scholar]
  33. Mendelson J. H., Mello N. K. Plasma testosterone levels during chronic heroin use and protracted abstinence: study of Hong Kong addicts. NIDA Res Monogr. 1978;(19):142–148. [PubMed] [Google Scholar]
  34. Mendelson J. H., Mendelson J. E., Patch V. D. Plasma testosterone levels in heroin addiction and during methadone maintenance. J Pharmacol Exp Ther. 1975 Jan;192(1):211–217. [PubMed] [Google Scholar]
  35. Mendelson J. H., Meyer R. E., Ellingboe J., Mirin S. M., McDougle M. Effects of heroin and methadone on plasma cortisol and testosterone. J Pharmacol Exp Ther. 1975 Nov;195(2):296–302. [PubMed] [Google Scholar]
  36. Mercadante S., Casuccio A., Fulfaro F., Groff L., Boffi R., Villari P., Gebbia V., Ripamonti C. Switching from morphine to methadone to improve analgesia and tolerability in cancer patients: a prospective study. J Clin Oncol. 2001 Jun 1;19(11):2898–2904. doi: 10.1200/JCO.2001.19.11.2898. [DOI] [PubMed] [Google Scholar]
  37. Moolchan E. T., Umbricht A., Epstein D. Therapeutic drug monitoring in methadone maintenance: choosing a matrix. J Addict Dis. 2001;20(2):55–73. doi: 10.1300/J069v20n02_05. [DOI] [PubMed] [Google Scholar]
  38. Newman R. G., Whitehill W. B. Double-blind comparison of methadone and placebo maintenance treatments of narcotic addicts in Hong Kong. Lancet. 1979 Sep 8;2(8141):485–488. doi: 10.1016/s0140-6736(79)91550-2. [DOI] [PubMed] [Google Scholar]
  39. Ottomanelli G. Methadone patients and alcohol abuse. J Subst Abuse Treat. 1999 Mar;16(2):113–121. doi: 10.1016/s0740-5472(98)00030-0. [DOI] [PubMed] [Google Scholar]
  40. Ragni G., De Lauretis L., Bestetti O., Sghedoni D., Gambaro V. Gonadal function in male heroin and methadone addicts. Int J Androl. 1988 Apr;11(2):93–100. doi: 10.1111/j.1365-2605.1988.tb00984.x. [DOI] [PubMed] [Google Scholar]
  41. Ragni G., De Lauretis L., Gambaro V., Di Pietro R., Bestetti O., Recalcati F., Papetti C. Semen evaluation in heroin and methadone addicts. Acta Eur Fertil. 1985 Jul-Aug;16(4):245–249. [PubMed] [Google Scholar]
  42. Rainey Petrie M. HIV drug interactions: the good, the bad, and the other. Ther Drug Monit. 2002 Feb;24(1):26–31. doi: 10.1097/00007691-200202000-00005. [DOI] [PubMed] [Google Scholar]
  43. Raistrick D., Hay A., Wolff K. Methadone maintenance and tuberculosis treatment. BMJ. 1996 Oct 12;313(7062):925–926. doi: 10.1136/bmj.313.7062.925. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Reilly P. M., Sees K. L., Shopshire M. S., Hall S. M., Delucchi K. L., Tusel D. J., Banys P., Clark H. W., Piotrowski N. A. Self-efficacy and illicit opioid use in a 180-day methadone detoxification treatment. J Consult Clin Psychol. 1995 Feb;63(1):158–162. doi: 10.1037//0022-006x.63.1.158. [DOI] [PubMed] [Google Scholar]
  45. Reimann G., Barthel B., Rockstroh J. K., Spatz D., Brockmeyer N. H. Effect of fusidic acid on the hepatic cytochrome P450 enzyme system. Int J Clin Pharmacol Ther. 1999 Nov;37(11):562–566. [PubMed] [Google Scholar]
  46. Ripamonti C., Groff L., Brunelli C., Polastri D., Stavrakis A., De Conno F. Switching from morphine to oral methadone in treating cancer pain: what is the equianalgesic dose ratio? J Clin Oncol. 1998 Oct;16(10):3216–3221. doi: 10.1200/JCO.1998.16.10.3216. [DOI] [PubMed] [Google Scholar]
  47. Ripamonti Carla, Bianchi Mauro. The use of methadone for cancer pain. Hematol Oncol Clin North Am. 2002 Jun;16(3):543–555. doi: 10.1016/s0889-8588(02)00017-5. [DOI] [PubMed] [Google Scholar]
  48. Specka M., Finkbeiner T., Lodemann E., Leifert K., Kluwig J., Gastpar M. Cognitive-motor performance of methadone-maintained patients. Eur Addict Res. 2000 Mar;6(1):8–19. doi: 10.1159/000019004. [DOI] [PubMed] [Google Scholar]
  49. Spring W. D., Jr, Willenbring M. L., Maddux T. L. Sexual dysfunction and psychological distress in methadone maintenance. Int J Addict. 1992 Nov;27(11):1325–1334. doi: 10.3109/10826089209047354. [DOI] [PubMed] [Google Scholar]
  50. Stenbacka M., Leifman A., Romelsjö A. The impact of methadone on consumption of inpatient care and mortality, with special reference to HIV status. Subst Use Misuse. 1998 Dec;33(14):2819–2834. doi: 10.3109/10826089809059353. [DOI] [PubMed] [Google Scholar]
  51. Strain E. C., Stitzer M. L., Liebson I. A., Bigelow G. E. Dose-response effects of methadone in the treatment of opioid dependence. Ann Intern Med. 1993 Jul 1;119(1):23–27. doi: 10.7326/0003-4819-119-1-199307010-00004. [DOI] [PubMed] [Google Scholar]
  52. Ward J., Hall W., Mattick R. P. Role of maintenance treatment in opioid dependence. Lancet. 1999 Jan 16;353(9148):221–226. doi: 10.1016/S0140-6736(98)05356-2. [DOI] [PubMed] [Google Scholar]
  53. White J. M., Irvine R. J. Mechanisms of fatal opioid overdose. Addiction. 1999 Jul;94(7):961–972. [PubMed] [Google Scholar]
  54. Yuan C. S., Foss J. F., O'Connor M., Moss J., Roizen M. F. Gut motility and transit changes in patients receiving long-term methadone maintenance. J Clin Pharmacol. 1998 Oct;38(10):931–935. doi: 10.1002/j.1552-4604.1998.tb04389.x. [DOI] [PubMed] [Google Scholar]

Articles from Postgraduate Medical Journal are provided here courtesy of BMJ Publishing Group

RESOURCES