Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Pharmacotherapy for opioid use disorder

Eric Strain, MD
Section Editor
Andrew J Saxon, MD
Deputy Editor
Richard Hermann, MD


Opioids, used medically for pain relief, have analgesic and central nervous system depressant effects, as well as the potential to cause euphoria. Opioid use disorder can involve prescribed or nonprescribed use of pharmaceutical opioids or use of illicitly obtained heroin. Opioid use disorder is typically a chronic, relapsing illness, associated with significantly increased rates of morbidity and mortality.

In patients with opioid use disorder who have achieved abstinence through medically supervised withdrawal or other means, there are medication and nonmedication options for long-term maintenance treatment. Medication treatment is often much more effective in opioid use disorder compared with abstinence-based therapy, a nonmedication treatment [1,2].

Maintenance pharmacotherapy for opioid use disorder is reviewed here. The epidemiology, pharmacology, clinical manifestations, course, screening, assessment, diagnosis, and psychosocial treatment for opioid use disorder are discussed separately, as are topics on medically supervised opioid withdrawal, prescription drug misuse, substance use disorder in physicians, and treatment of acute pain in the patient chronically using opioids:

(See "Opioid use disorder: Epidemiology, pharmacology, clinical manifestations, course, screening, assessment, and diagnosis".)

(See "Medically supervised opioid withdrawal during treatment for addiction".)


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Sep 2016. | This topic last updated: Jul 29, 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
  1. Gunne LM, Grönbladh L. The Swedish methadone maintenance program: a controlled study. Drug Alcohol Depend 1981; 7:249.
  2. Kakko J, Svanborg KD, Kreek MJ, Heilig M. 1-year retention and social function after buprenorphine-assisted relapse prevention treatment for heroin dependence in Sweden: a randomised, placebo-controlled trial. Lancet 2003; 361:662.
  3. Hauri-Bionda R, Bär W, Friedrich-Koch A. [Driving fitness/driving capacity of patients treated with methadone]. Schweiz Med Wochenschr 1998; 128:1538.
  4. Strain EC, Stitzer ML, Liebson IA, Bigelow GE. Methadone dose and treatment outcome. Drug Alcohol Depend 1993; 33:105.
  5. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), American Psychiatric Association, Arlington, VA 2013.
  6. Mattick RP, Breen C, Kimber J, Davoli M. Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence. Cochrane Database Syst Rev 2009; :CD002209.
  7. Strain EC, Stitzer ML, Liebson IA, Bigelow GE. Dose-response effects of methadone in the treatment of opioid dependence. Ann Intern Med 1993; 119:23.
  8. Ball JC, Lange WR, Myers CP, Friedman SR. Reducing the risk of AIDS through methadone maintenance treatment. J Health Soc Behav 1988; 29:214.
  9. Novick DM, Joseph H, Croxson TS, et al. Absence of antibody to human immunodeficiency virus in long-term, socially rehabilitated methadone maintenance patients. Arch Intern Med 1990; 150:97.
  10. Gowing LR, Farrell M, Bornemann R, et al. Brief report: Methadone treatment of injecting opioid users for prevention of HIV infection. J Gen Intern Med 2006; 21:193.
  11. Nurco DN, Ball JC, Shaffer JW, Hanlon TE. The criminality of narcotic addicts. J Nerv Ment Dis 1985; 173:94.
  12. Gibson A, Degenhardt L, Mattick RP, et al. Exposure to opioid maintenance treatment reduces long-term mortality. Addiction 2008; 103:462.
  13. O'Conor LM, Woody G, Yeh HS, et al. Methadone and edema. J Subst Abuse Treat 1991; 8:153.
  14. Kleber HD. Treatment of narcotic addicts. Psychiatr Med 1985; 3:389.
  15. Brown R, Balousek S, Mundt M, Fleming M. Methadone maintenance and male sexual dysfunction. J Addict Dis 2005; 24:91.
  16. Quaglio G, Lugoboni F, Pattaro C, et al. Erectile dysfunction in male heroin users, receiving methadone and buprenorphine maintenance treatment. Drug Alcohol Depend 2008; 94:12.
  17. Ehret GB, Voide C, Gex-Fabry M, et al. Drug-induced long QT syndrome in injection drug users receiving methadone: high frequency in hospitalized patients and risk factors. Arch Intern Med 2006; 166:1280.
  18. Martell BA, Arnsten JH, Ray B, Gourevitch MN. The impact of methadone induction on cardiac conduction in opiate users. Ann Intern Med 2003; 139:154.
  19. Martell BA, Arnsten JH, Krantz MJ, Gourevitch MN. Impact of methadone treatment on cardiac repolarization and conduction in opioid users. Am J Cardiol 2005; 95:915.
  20. Peles E, Bodner G, Kreek MJ, et al. Corrected-QT intervals as related to methadone dose and serum level in methadone maintenance treatment (MMT) patients: a cross-sectional study. Addiction 2007; 102:289.
  21. Pearson EC, Woosley RL. QT prolongation and torsades de pointes among methadone users: reports to the FDA spontaneous reporting system. Pharmacoepidemiol Drug Saf 2005; 14:747.
  22. Byrne A. Concerns about consensus guidelines for QTc interval screening in methadone treatment. Ann Intern Med 2009; 151:216; author reply 218.
  23. Cohen SP, Mao J. Concerns about consensus guidelines for QTc interval screening in methadone treatment. Ann Intern Med 2009; 151:216.
  24. Pani PP, Trogu E, Maremmani I, Pacini M. QTc interval screening for cardiac risk in methadone treatment of opioid dependence. Cochrane Database Syst Rev 2013; :CD008939.
  25. Girgis G. Concerns about consensus guidelines for QTc interval screening in methadone treatment. Ann Intern Med 2009; 151:217.
  26. Bart G. Concerns about consensus guidelines for QTc interval screening in methadone treatment. Ann Intern Med 2009; 151:218; author reply 218.
  27. Ansermot N, Albayrak O, Schläpfer J, et al. Substitution of (R,S)-methadone by (R)-methadone: Impact on QTc interval. Arch Intern Med 2010; 170:529.
  28. McCance-Katz EF. (R)-methadone versus racemic methadone: what is best for patient care? Addiction 2011; 106:687.
  29. Pud D, Cohen D, Lawental E, Eisenberg E. Opioids and abnormal pain perception: New evidence from a study of chronic opioid addicts and healthy subjects. Drug Alcohol Depend 2006; 82:218.
  30. Chu LF, Clark DJ, Angst MS. Opioid tolerance and hyperalgesia in chronic pain patients after one month of oral morphine therapy: a preliminary prospective study. J Pain 2006; 7:43.
  31. Rosenblum A, Joseph H, Fong C, et al. Prevalence and characteristics of chronic pain among chemically dependent patients in methadone maintenance and residential treatment facilities. JAMA 2003; 289:2370.
  32. Compton P, Charuvastra VC, Ling W. Pain intolerance in opioid-maintained former opiate addicts: effect of long-acting maintenance agent. Drug Alcohol Depend 2001; 63:139.
  33. Caplehorn JR, Drummer OH. Mortality associated with New South Wales methadone programs in 1994: lives lost and saved. Med J Aust 1999; 170:104.
  34. Zador D, Sunjic S. Deaths in methadone maintenance treatment in New South Wales, Australia 1990-1995. Addiction 2000; 95:77.
  35. Caplehorn JR, Drummer OH. Fatal methadone toxicity: signs and circumstances, and the role of benzodiazepines. Aust N Z J Public Health 2002; 26:358.
  36. Strang J, McCambridge J, Best D, et al. Loss of tolerance and overdose mortality after inpatient opiate detoxification: follow up study. BMJ 2003; 326:959.
  37. Webster LR. Methadone-related deaths. J Opioid Manag 2005; 1:211.
  38. Williamson PA, Foreman KJ, White JM, Anderson G. Methadone-related overdose deaths in South Australia, 1984-1994. How safe is methadone prescribing? Med J Aust 1997; 166:302.
  39. Center for Substance Abuse Treatment (CSAT). Methadone-associated mortality: Report of a National Assessment. CSAT Pub. No. 28-03. Substance Abuse and Mental Health Services Administration, Rockville, MD 2004.
  40. Bell J, Zador D. A risk-benefit analysis of methadone maintenance treatment. Drug Saf 2000; 22:179.
  41. Desmond, DP, Maddux, JF. Deaths among heroin users in and out of methadone treatment. J Maint Addict 2000; 1:45.
  42. Clausen T, Anchersen K, Waal H. Mortality prior to, during and after opioid maintenance treatment (OMT): a national prospective cross-registry study. Drug Alcohol Depend 2008; 94:151.
  43. Federal Register: Methadone: Rules and regulations. The Federal Register 1989; 544:8954.
  44. http://www.dpt.samhsa.gov/pdf/FederalGuidelinesforOpioidTreatment5-6-2013revisiondraft_508.pdf (Accessed on September 22, 2015).
  45. Senay EC. Opioids: Methadone maintenance. In: Textbook of Substance Abuse Treatment, 2nd ed, Galanter M, Kleber HD (Eds), American Psychiatric Press, Inc., Washington DC 1999. p.271.
  46. Strain EC, Bigelow GE, Liebson IA, Stitzer ML. Moderate- vs high-dose methadone in the treatment of opioid dependence: a randomized trial. JAMA 1999; 281:1000.
  47. Johnson RE, Chutuape MA, Strain EC, et al. A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence. N Engl J Med 2000; 343:1290.
  48. Faggiano F, Vigna-Taglianti F, Versino E, Lemma P. Methadone maintenance at different dosages for opioid dependence. Cochrane Database Syst Rev 2003; :CD002208.
  49. Zador DA, Sunjic SD. Methadone-related deaths and mortality rate during induction into methadone maintenance, New South Wales, 1996. Drug Alcohol Rev 2002; 21:131.
  50. Center for Substance Abuse Treatment (CSAT). Pregnant, substance-abusing women (treatment improvement protocol 2). CSAT, Substance Abuse and Mental Health Services Administration, Rockville, MD 1993.
  51. Weaver M. Perinatal addiction. In: Principles of Addiction Medicine, 3rd ed, Graham AW, Shultz TK (Eds), American Society of Addiction Medicine, Inc., Chevy Chase 2003. p.1231.
  52. Wittmann BK, Segal S. A comparison of the effects of single- and split-dose methadone administration on the fetus: ultrasound evaluation. Int J Addict 1991; 26:213.
  53. Jarvis MA, Wu-Pong S, Kniseley JS, Schnoll SH. Alterations in methadone metabolism during late pregnancy. J Addict Dis 1999; 18:51.
  54. McCarthy JJ, Posey BL. Methadone levels in human milk. J Hum Lact 2000; 16:115.
  55. Geraghty B, Graham EA, Logan B, Weiss EL. Methadone levels in breast milk. J Hum Lact 1997; 13:227.
  56. Mattick RP, Breen C, Kimber J, Davoli M. Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database Syst Rev 2014; :CD002207.
  57. Buprenorphine: an alternative to methadone. Med Lett Drugs Ther 2003; 45:13.
  58. Buprenorphine and naloxone sublingual tablets US prescribing information (revised December, 2014) http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020733Orig1s014lbl.pdf.
  59. Soeffing JM, Martin LD, Fingerhood MI, et al. Buprenorphine maintenance treatment in a primary care setting: outcomes at 1 year. J Subst Abuse Treat 2009; 37:426.
  60. Fareed A, Vayalapalli S, Casarella J, Drexler K. Treatment outcome for flexible dosing buprenorphine maintenance treatment. Am J Drug Alcohol Abuse 2012; 38:155.
  61. Greenwald MK, Comer SD, Fiellin DA. Buprenorphine maintenance and mu-opioid receptor availability in the treatment of opioid use disorder: implications for clinical use and policy. Drug Alcohol Depend 2014; 144:1.
  62. Senay EC, Dorus W, Goldberg F, Thornton W. Withdrawal from methadone maintenance. Rate of withdrawal and expectation. Arch Gen Psychiatry 1977; 34:361.
  63. Strain EC, Preston KL, Liebson IA, Bigelow GE. Buprenorphine effects in methadone-maintained volunteers: effects at two hours after methadone. J Pharmacol Exp Ther 1995; 272:628.
  64. Walsh SL, Eissenberg T. The clinical pharmacology of buprenorphine: extrapolating from the laboratory to the clinic. Drug Alcohol Depend 2003; 70:S13.
  65. McNicholas L. Clinical guidelines for the use of buprenorphine in the treatment of opioid addiction. US Department of Health and Human Services, Rockville, MD 2004.
  66. Rosado J, Walsh SL, Bigelow GE, Strain EC. Sublingual buprenorphine/naloxone precipitated withdrawal in subjects maintained on 100mg of daily methadone. Drug Alcohol Depend 2007; 90:261.
  67. Fudala PJ, Bridge TP, Herbert S, et al. Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone. N Engl J Med 2003; 349:949.
  68. Liebschutz JM, Crooks D, Herman D, et al. Buprenorphine treatment for hospitalized, opioid-dependent patients: a randomized clinical trial. JAMA Intern Med 2014; 174:1369.
  69. Ling W, Casadonte P, Bigelow G, et al. Buprenorphine implants for treatment of opioid dependence: a randomized controlled trial. JAMA 2010; 304:1576.
  70. Rosenthal RN, Ling W, Casadonte P, et al. Buprenorphine implants for treatment of opioid dependence: randomized comparison to placebo and sublingual buprenorphine/naloxone. Addiction 2013; 108:2141.
  71. Rosenthal RN, Lofwall MR, Kim S, et al. Effect of Buprenorphine Implants on Illicit Opioid Use Among Abstinent Adults With Opioid Dependence Treated With Sublingual Buprenorphine: A Randomized Clinical Trial. JAMA 2016; 316:282.
  72. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm503719.htm (Accessed on May 31, 2016).
  73. Tracqui A, Kintz P, Ludes B. Buprenorphine-related deaths among drug addicts in France: a report on 20 fatalities. J Anal Toxicol 1998; 22:430.
  74. Byrne A. Reducing deaths among drug misusers. Standard of care in Britain was not addressed. BMJ 2001; 323:513.
  75. Gunderson EW, Wang XQ, Fiellin DA, et al. Unobserved versus observed office buprenorphine/naloxone induction: a pilot randomized clinical trial. Addict Behav 2010; 35:537.
  76. Fischer G. Treatment of opioid dependence in pregnant women. Addiction 2000; 95:1141.
  77. ACOG Committee on Health Care for Underserved Women, American Society of Addiction Medicine. ACOG Committee Opinion No. 524: Opioid abuse, dependence, and addiction in pregnancy. Obstet Gynecol 2012; 119:1070.
  78. Johnson RE, Jones HE, Fischer G. Use of buprenorphine in pregnancy: patient management and effects on the neonate. Drug Alcohol Depend 2003; 70:S87.
  79. Jones HE, Johnson RE, Jasinski DR, et al. Buprenorphine versus methadone in the treatment of pregnant opioid-dependent patients: effects on the neonatal abstinence syndrome. Drug Alcohol Depend 2005; 79:1.
  80. Kakko J, Heilig M, Sarman I. Buprenorphine and methadone treatment of opiate dependence during pregnancy: comparison of fetal growth and neonatal outcomes in two consecutive case series. Drug Alcohol Depend 2008; 96:69.
  81. Jones HE, Kaltenbach K, Heil SH, et al. Neonatal abstinence syndrome after methadone or buprenorphine exposure. N Engl J Med 2010; 363:2320.
  82. Wieneke H, Conrads H, Wolstein J, et al. Levo-alpha-acetylmethadol (LAAM) induced QTc-prolongation - results from a controlled clinical trial. Eur J Med Res 2009; 14:7.
  83. Rehm J, Gschwend P, Steffen T, et al. Feasibility, safety, and efficacy of injectable heroin prescription for refractory opioid addicts: a follow-up study. Lancet 2001; 358:1417.
  84. Nordt C, Stohler R. Incidence of heroin use in Zurich, Switzerland: a treatment case register analysis. Lancet 2006; 367:1830.
  85. van den Brink W, Hendriks VM, Blanken P, et al. Medical prescription of heroin to treatment resistant heroin addicts: two randomised controlled trials. BMJ 2003; 327:310.
  86. Oviedo-Joekes E, Brissette S, Marsh DC, et al. Diacetylmorphine versus methadone for the treatment of opioid addiction. N Engl J Med 2009; 361:777.
  87. Steffen T, Blättler R, Gutzwiller F, Zwahlen M. HIV and hepatitis virus infections among injecting drug users in a medically controlled heroin prescription programme. Eur J Public Health 2001; 11:425.
  88. Dijkgraaf MG, van der Zanden BP, de Borgie CA, et al. Cost utility analysis of co-prescribed heroin compared with methadone maintenance treatment in heroin addicts in two randomised trials. BMJ 2005; 330:1297.
  89. Berridge V. Heroin prescription and history. N Engl J Med 2009; 361:820.
  90. Minozzi S, Amato L, Vecchi S, et al. Oral naltrexone maintenance treatment for opioid dependence. Cochrane Database Syst Rev 2011; :CD001333.
  91. Comer SD, Sullivan MA, Yu E, et al. Injectable, sustained-release naltrexone for the treatment of opioid dependence: a randomized, placebo-controlled trial. Arch Gen Psychiatry 2006; 63:210.
  92. Krupitsky E, Nunes EV, Ling W, et al. Injectable extended-release naltrexone for opioid dependence: a double-blind, placebo-controlled, multicentre randomised trial. Lancet 2011; 377:1506.
  93. Tiihonen J, Krupitsky E, Verbitskaya E, et al. Naltrexone implant for the treatment of polydrug dependence: a randomized controlled trial. Am J Psychiatry 2012; 169:531.
  94. Lee JD, Friedmann PD, Kinlock TW, et al. Extended-Release Naltrexone to Prevent Opioid Relapse in Criminal Justice Offenders. N Engl J Med 2016; 374:1232.
  95. Fischer G, Gombas W, Eder H, et al. Buprenorphine versus methadone maintenance for the treatment of opioid dependence. Addiction 1999; 94:1337.
  96. Eder H, Fischer G, Gombas W, et al. Comparison of buprenorphine and methadone maintenance in opiate addicts. Eur Addict Res 1998; 4 Suppl 1:3.
  97. Luty J, O'Gara C, Sessay M. Is methadone too dangerous for opiate addiction? BMJ 2005; 331:1352.
  98. Bell JR, Butler B, Lawrance A, et al. Comparing overdose mortality associated with methadone and buprenorphine treatment. Drug Alcohol Depend 2009; 104:73.
  99. Kakko J, Grönbladh L, Svanborg KD, et al. A stepped care strategy using buprenorphine and methadone versus conventional methadone maintenance in heroin dependence: a randomized controlled trial. Am J Psychiatry 2007; 164:797.
  100. Hulse GK, Morris N, Arnold-Reed D, Tait RJ. Improving clinical outcomes in treating heroin dependence: randomized, controlled trial of oral or implant naltrexone. Arch Gen Psychiatry 2009; 66:1108.