A Randomized, Open-label Trial Comparing Methadone and Levo-Alpha-Acetylmethadol (LAAM) in Maintenance Treatment of Opioid Addiction

Abstract

Introduction: Levo-Alpha-Acetylmethadol (LAAM) is a synthetic opioid analgesic with μ-agonistic activity and a long duration of action. There are several, almost exclusively US American studies showing the efficacy of LAAM as a maintenance drug which has the advantage that it needs to be administered only three times a week. LAAM is currently not marketed in EU countries due to cardiac complications. We report on the first European multi-center, parallel group, flexible dose, open-label, randomized clinical trial comparing LAAM and methadone in patients with opioid dependence.

Methods: Eighty-four opioid addicts in ongoing maintenance treatment with stable methadone doses were treated with methadone under study conditions for 5 weeks (run-in phase), then randomly assigned to a methadone (n=41) or a LAAM (n=43) group. Study duration was 24 weeks after randomization. Objective measures (drug urine screenings, retention rate), subjective measures (symptoms of withdrawal and craving, report of substance use), and safety data were collected weekly. The main outcome criterion was the number of opiate-free urine samples per number of weeks of study participation.

Results: Non-inferiority was shown for LAAM compared to methadone. Both substances were well tolerated. There were no clinical cardiac complications in either group.

Discussion: Our study confirmed the results of previous investigations with LAAM as being efficacious and well tolerated in opioid dependence. A discussion to reconsider the availability of LAAM is recommended.

References

• 1 American Psychiatric Association . Position statement on methadone maintenance treatment.  Am J Psychiatry. 1994;  151 792-794
• 2 Anglin MD, Conner BT, Annon J. et al . Levo-alpha-acetylmethadol (LAAM) versus methadone maintenance: 1-year treatment retention, outcomes and status.  Addiction. 2007;  102 1432-1442
• 3 Bauer P, Kieser M. A unifying approach for confidence intervals and testing of equivalence and difference.  Biometrika. 1996;  83 934-937
• 4 Binchy JM, Molyneux EM, Manning J. Accidental ingestion of methadone by children in Merseyside.  BMJ. 1994;  308 1335-1336
• 5 Blaschke D, Parwani AS, Huemer M. et al . Torsade de pointes during combined treatment with risperidone and citalopram.  Pharmacopsychiatry. 2007;  40 294-295
• 6 Clark N, Lintzeris N, Gijsbers A. et al .LAAM maintenance vs. methadone maintenance for heroin dependence. (Cochrane Review). In: The Cochrane Library, Issue 2. Oxford: Update Software 2003
• 7 Clinical Global Impressions. In: Internationale Skalen für Psychiatrie (Collegium Internationale Psychiatriae Scalarum). Beltz Verlag, Göttingen 1996
• 8 Derogatis CR. SCL-90. Administration, Scoring & Procedures. Manual-I for the (revised) version and other instruments of the Psychopathology Rating Scale Series. Johns Hopkins University School of Medicine 1977
• 9 Dyer KR, White JM. Patterns of symptom complaints in methadone maintenance patients.  Addiction. 1997;  92 1445-1455
• 10 Dyer KR, Foster DJ, White JM. et al . Steady-state pharmacokinetics and pharmacodynamics in methadone maintenance patients: comparison of those who do and do not experience withdrawal and concentration-effect relationships.  Clin Pharmacol Ther. 1999;  65 685-694
• 11 Eissenberg T, Stitzer ML, Bigelow GE. et al . Relative potency of levo-alpha-acetylmethadol and methadone in humans under acute dosing conditions.  J Pharmacol Exp Ther. 1999;  289 936-945
• 12 Finn P, Wilcock K. Levo-alpha acetyl methadol (LAAM). Its advantages and drawbacks.  J Subst Abuse Treat. 1997;  14 559-564
• 13 Franke GH. Self-Report Symptom Inventory 90 Items Revised. Deutsche Bearbeitung. Göttingen, Bern: Beltz Verlag 1995
• 14 Freedman RR, Czertko G. A comparison of thrice weekly LAAM and daily methadone in employed heroin addicts.  Drug Alcohol Depend. 1981;  8 215-222
• 15 Garbe E, Röhmel J, Gundert-Remy U. Clinical and statistical issues in therapeutic equivalence trials.  Eur J Clin Pharmacol. 1993;  45 1-7
• 16 Glanz M, Klawansky S, MacAullife W. et al . Methadone vs. L-alpha-acetylmethadol (LAAM) in the treatment of opiate addiction. A meta-analysis of the randomized, controlled trials.  Am J Addict. 1997;  6 339-349
• 17 Gourevitch MN, Hartel D, Tenore P. et al . Three oral formulations of methadone. A clinical and pharmacodynamic comparison.  J Subst Abuse Treat. 1999;  17 237-241
• 18 Grevert P, Masover B, Goldstein A. Failure of methadone and levomethadyl acetate (levo-alpha-acetylmethadol, LAAM) maintenance to affect memory.  Arch Gen Psychiatry. 1977;  34 849-853
• 19 Gsellhofer B, Fahrner EN, Platt J. European Addiction Severity Index (EuropASI). München: Institut für Therapieforschung 1993
• 20 Irwin S, Blachly PH, Marks J. et al . The behavioral, cognitive and physiologic effects of long-term methadone and methadyl treatment. 1973 [proceedings].  NIDA Res Monogr. 1976;  8 66-67
• 21 Jaffe JH, Senay EC. Methadone and l-methadyl acetate. Use in management of narcotics addicts.  JAMA. 1971;  216 1303-1305
• 22 Jaffe JH, Senay EC, Schuster CR. et al . Methadyl acetate vs. methadone. A double-blind study in heroin users.  JAMA. 1972;  222 437-442
• 23 Jaffe JH. Can LAAM, like Lazarus, come back from the dead?.  Addiction. 2007;  102 1342-1343
• 24 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 1290-1297
• 25 Jones B, Jarvis P, Lewis JA. et al . Trials to assess equivalence: the importance of rigorous methods.  BMJ. 1996;  313 36-39
• 26 Jones HE, Fitzgerald H, Johnson RE. Males and females differ in response to opioid agonist medications.  Am J Addict. 2005;  14 223-233
• 27 Kleber HD. Pharmacologic treatments for heroin and cocaine dependence.  Am J Addict. 2003;  12 ((Suppl)) S5-S18
• 28 Karp-Gelernter E, Savage C, MacCabe OL. Evaluation of clinic attendance schedules for LAAM and methadone: a controlled study.  Int J Addict. 1982;  17 805-813
• 29 Kuo I, Brady J, Butler C. et al . Feasibility of referring drug users from a needle exchange program into an addiction treatment program: experience with a mobile treatment van and LAAM maintenance.  J Subst Abuse Treat. 2003;  24 67-74
• 30 Lehmacher W. Äquivalenznachweise bei Multicenter-Studien. In: Michaelis J, Hommel G, Wellek S, eds. Europäische Perspektiven der Medizinischen Informatik, Biometrie und Epidemiologie. München: MMV Medizin Verlag 1993: 152-154
• 31 Ling W, Charuvastra C, Kaim SC. et al . Methadyl acetate and methadone as maintenance treatments for heroin addicts. A veterans administration cooperative study.  Arch Gen Psychiatry. 1976;  33 709-720
• 32 Ling W, Klett CJ, Gillis RD. A cooperative clinical study of methadyl acetate. I. Three-times-a-week regimen.  Arch Gen Psychiatry. 1978;  35 345-353
• 33 Ling W, Shoptaw S, Wesson D. et al . Treatment effectiveness score as an outcome measure in clinical trials.  NIDA Res Monogr. 1997;  175 208-220
• 34 Ling W, Rawson RA, Compton M. Clinical treatment of opioid addiction and dependence.  Methods Mol Med. 2003;  84 285-295
• 35 Longshore D, Annon J, Anglin MD. et al . Levo-alpha-acetylmethadol (LAAM) versus methadone: treatment retention and opiate use.  Addiction. 2005;  100 1131-1139
• 36 Marcovici M, O'Brien CP, MacLellan AT. et al . A clinical, controlled study of l-alpha-acetylmethadol in the treatment of narcotic addiction.  Am J Psychiatry. 1981;  138 234-236
• 37 MacCaul ME, Bigelow GE, Stitzer ML. et al . Short-term effects of oral methadone in methadone maintenance subjects.  Clin Pharmacol Ther. 1982;  31 753-761
• 38 MacLellan AT, Luborsky L, Woody GE. et al . An improved diagnostic evaluation instrument for substance abuse patients. The Addiction Severity Index.  J Nerv Ment Dis. 1980;  168 26-33
• 39 National Institute of Mental Health 028 CGI .Clinical Global Impressions. In: Goy W, Bonato RR, eds. Manual for the EDCEU assessment battery, 2. rev. ed. Chevy Chase, Maryland 1976
• 40 Panell J, Charuvastra VC, Ouren J. Methadyl acetate versus methadone: the experience of one hospital.  Med J Aust. 1977;  2 150-152
• 41 Rawson RA, Hasson AL, Huber AM. et al . A 3-year progress report on the implementation of LAAM in the United States.  Addiction. 1998;  93 533-540
• 42 Rawson RA, MacCann MJ, Hasson AJ. et al . Addiction pharmacotherapy 2000: new options, new challenges.  J Psychoactive Drugs. 2000;  32 371-378
• 43 Reilly JG, Ayis SA, Ferrier IN. et al . QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients.  Lancet. 2000;  355 1048-1052
• 44 Ritter AJ, Lintzeris N, Clark N. et al . A randomized trial comparing levo-alpha acetylmethadol with methadone maintenance for patients in primary care settings in Australia.  Addiction. 2003;  98 1605-1613
• 45 Röhmel J. Therapeutic equivalence investigations: statistical considerations.  Stat Med. 1998;  17 1703-1714
• 46 Savage C, Karp EG, Curran SF. et al . Methadone/LAAM maintenance: a comparison study.  Compr Psychiatry. 1976;  17 415-424
• 47 Senay EC, Dorus W, Renault PF. Methadyl acetate and methadone. An open comparison.  JAMA. 1977;  237 138-142
• 48 Stimmel B. Maintenance therapy for opioid addiction with methadone, LAAM and buprenorphine: The emperor's new clothes phenomenon.  J Addict Dis. 2001;  20 7-14
• 49 Tennant FS, Rawson RA, Pumphrey E. et al . Clinical experiences with 959 opioid dependent patients treated with l-alpha acetymethadol (LAAM).  J Subst Abuse Treat. 1986;  3 195-202
• 50 Ulrich S, Hiemke C, Laux G. et al . Value and actuality of the prescription information for therapeutic drug monitoring of psychopharmaceuticals: a comparison with the medico-scientific evidence.  Pharmacopsychiatry. 2007;  40 121-127
• 51 Walsh SL, Johnson RE, Cone EJ. et al . Intravenous and oral l-alpha-acetylmethadol: pharmacodynamics and pharmacokinetics in humans.  J Pharmacol Exp Ther. 1998;  285 71-82
• 52 Zaks A, Fink M, Freedman AM. Levomethadyl in maintenance treatment of opiate dependence.  JAMA. 1972;  220 811-813

Correspondence