Two pharmacological agents have repeatedly been shown to be efficacious for relapse prevention in alcohol dependence: The putative glutamate-antagonist acamprosate and the opioid-antagonist naltrexone. Clinical evidence for both drugs is based on various outcome criteria. Whereas for acamprosate primarily abstinence maintenance has been demonstrated, studies with naltrexone have mostly emphasised the prevention of heavy drinking. The remaining effects of both drugs are not always reported; accordingly the corresponding database is fragmentary. Thus, the primary objective of the present meta-analysis was to complete the efficacy profiles for acamprosate and naltrexone and to compare them with each other. Unreported results, requested from the study investigators and the drug manufacturers, were integrated in the computation of effect sizes. For the meta-analysis, emphasis was placed on the conceptual distinction between having a first drink and returning to heavy drinking. Naltrexone was found to have a significant effect on the maintenance of abstinence as well as the prevention of heavy drinking. Acamprosate was shown only to support abstinence; it did not influence alcohol consumption after the first drink. When the efficacy profiles of the two drugs were compared, acamprosate was found to be more effective in preventing a lapse, whereas naltrexone was better in preventing a lapse from becoming a relapse. The superiority of either one drug or over the other one cannot be determined as a general rule, it rather depends on the therapeutic target. Benefits in the treatment of alcohol dependence might be optimized by matching the efficacy profiles of specific antidipsotropics with the motivational status of alcohol-dependent patients.
American Psychiatric Association (1987) Diagnostic and Statistical Manual of Mental Disorders, 3rd edition. American Psychiatric Association , Wahington DC
2.
American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders, 4th edition. American Psychiatric Association , Wahington DC
3.
Anton R.F., Moak D.H., Waid L.R., Latham P.K., Malcolm R.J., Dias J.K. (1999) Naltrexone and cognitive behavioral therapy for the treatment of outpatient alcoholics: results of a placebo-controlled trial . Am J Psychiatry156: 1758—1764
4.
Anton R.F., O'Malley S.S., Ciraulo D.A., Cisler R.A., Couper D., Donovan D.M., Gastfriend D.R., Hosking J.D., Johnson B.A., LoCastro J.S., Longabaugh R., Mason B.J., Mattson M.E., Miller W.R., Pettinati H.M., Randall C.L., Swift R., Weiss R.D., Williams L.D., Zweben A. (2006) Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial. JAMA295: 2003—2017
5.
Auriacombe M., Robinson M., Grabot D., Tignol J. (2000). Naltrexone is ineffective to prevent relapse to alcohol in a realistic outpatient setting. A double blind one-year controlled study. Abstract CPDD
6.
Balldin J., Berglund M., Borg S., Mansson M., Bendtsen P., Franck J., Gustafsson L., Halldin J., Nilsson L.H., Stolt G., Willander A. (1999) A 6-month controlled naltrexone study: combined effect with cognitive behavioural therapy in outpatient treatment of alcohol dependence. Alcohol Clin Exp Res27: 1142—1149
7.
Baltieri D.A., de Andrade A.G. (2003) Efficacy of acamprosate in the treatment of alcohol-dependent outpatients. Rev Bras Psyiquaiatr25: 156—159
Begg C.B. (1988) Publication bias: a problem in interpreting medical data. J R Soc Aust151: 445—463
10.
Berglund M., Andreasson S., Franck J., Fridell M., Hakanson I., Johansson B.A. (2003) Treatment of alcohol and drug abuse - an evidence-based review. Swedish Council on Technology Assessment in Health Care (SBU) Volume: Report No. 156
11.
Besson J., Aeby F., Kasas A., Lehert P., Potgieter A. (1998) Combined efficacy of acamprosate and disulfiram in the treatment of alcoholism: a controlled study. Alcohol Clin Exp Res22: 573—579
12.
Borg S. ( 2003) Randomised controlled trial of acamprosate versus placebo in Swedish alcoholics. Unpublished study
13.
Bouza C., Magro A., Muñoz A., Amate J.M. (2004) Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: a systematic review. Addiction99: 811—828
14.
Chan A.W., Altman D.G. (2005) Identifying outcome reporting bias in randomised trials on PubMed: review of publications and survey of authors. Br Med J330: Epub 2005 Jan 28
15.
Chick J., Howlett H., Morgan M.Y., Ritson B. (2000a) United Kingdom multicentre acamprosate study (UKMAS): a 6-month prospective study of acamprosate versus placebo in preventing relapse after withdrawal from alcohol. Alcohol Alcohol35: 176—187
16.
Chick J., Anton R., Checinski K., Croop R., Drummond D.C., Farmer R., Labriola D., Marshall J., Moncrieff J., Morgan M.Y., Peters T., Ritson B. (2000b) A multicentre, randomized, double-blind, placebo-controlled trial of naltrexone in the treatment of alcohol dependence or abuse. Alcohol Alcohol35: 587—593
17.
Chick J., Lehert P., Landron F. (2003) Does acamprosate improve reduction of drinking as well as aiding abstinence?J Psychopharmacol17: 397—402
18.
DerSimonian R., Laird N.M. (1986) Meta-analysis in clinical trials. Control Clin Trials7: 177—188
19.
Gastpar M., Bonnet U., Boning J., Mann K., Schmidt L.G., Soyka M., Wetterling T., Kielstein V., Labriola D., Croop R. (2002) Lack of efficacy of naltrexone in the prevention of alcohol relapse: results from a german multicenter study. J Clin Psychopharmacol22: 592—598
20.
Geerlings P.J., Ansoms C., van den Brink W. (1997) Acamprosate and prevention of relapse in alcoholics. Results of a randomized, placebo-controlled, double-blind study in out-patient alcoholics in The Netherlands, Belgium and Luxembourg. Eur Addict Res3: 129—137
21.
Gual A., Lehert P. (2001) Acamprosate during and after acute alcohol withdrawal: a double-blind placebo-controlled study in Spain. Alcohol Alcohol36: 413—418
22.
Guardia J., Caso C., Arias F., Gual A., Sanahuja J., Ramirez M., Mengual I., Gonzalvo B., Segura L., Trujols J., Casas M. (2002) A double-blind, placebo controlled study of naltrexone in the treatment of alcohol dependence disorder: results from a multicenter clinical trial. Alcohol Clin Exp Res26: 1381—1387
23.
Hedges L.V., Olkin I. (1985) Statistical methods for meta-analysis. Academic Press, Orlando, FL
24.
Heinälä P., Alho H., Kiianmaa K., Lonnqvist J., Kuoppasalmi K., Sinclair J.D. (2001) Targeted use of naltrexone without prior detoxification in the treatment of alcohol dependence: a factorial double-blind, placebo-controlled trial. J Clin Psychopharmacol21: 287—292
25.
Hersh D., Van Kirk J.R., Kranzler H.R. (1998) Naltrexone treatment of comorbid alcohol and cocaine use disorders. Psychopharmacology (Berl ) 139: 44—52
26.
Higgins J.P., Thompson S.G. (2002) Quantifying heterogeneity in a meta-analysis. Stat Med21: 539—1558
27.
Hopkins J.S., Garbutt J.C., Poole C.L., West S.L., Carey T.S. (2002) Naltrexone and acamprosate: meta-analysis of two medical treatments for alcoholism. Alcohol Clin Exp Res26 (Suppl)
28.
Kadden R., Carroll, K.M., Donovan D., Cooney N., Monti P., Abrams D., Litt M., Hester R. (1999). Cognitive-behavioral coping skills therapy manual: a clinical research guide for therapists treating individuals with alcohol abuse and dependence. NIAAA Project MATCH Monograph Series Vol. 3. NIH Pub. No. 94-3724. National Institute on Alcohol Abuse and Alcoholism , Rockville, Maryland
29.
Keller M. (1972) On the loss-of-control phenomenon in alcoholism . Br J Addict67: 153—166
30.
Kiefer F., Jahn H., Tarnaske T., Helwig H., Briken P., Holzbach R., Kämpf P., Stracke R., Baehr M., Naber D., Wiedemann K. (2003) Comparing and combining naltrexone and acamprosate in relapse prevention of alcoholism: a double-blind, placebo-controlled study . Arch Gen Psychiatry60: 92—99
31.
Killeen T.K., Brady K.T., Gold P.B., Simpson K.N., Faldowski R.A., Tyson C., Anton R.F. (2004) Effectiveness of naltrexone in a community treatment program. Alcohol Clin Exp Res28: 1710—1717
32.
Kranzler H.R., Modesto-Lowe V., Van Kirk J.R. (2000). Naltrexone vs. nefazodone for treatment of alcohol dependence. A placebo-controlled trial. Neuropsychopharmacology22: 493—503
33.
Kranzler H.R., Van Kirk J.R. (2001) Efficacy of naltrexone and acamprosate for alcoholism treatment: a meta-analysis. Alcohol Clin Exp Res25: 1335—1341
34.
Krystal J.H., Joyce A., Cramer B.S., William F., Krol P.D., Gail F., Kirk M.S., Robert A., Rosenheck M.D. (2001) Naltrexone in the treatment of alcohol dependence . The New England Journal of Medicine345: 1734—1739
35.
Ladewig D., Knecht T., Leher P., Fendl A. (1993) Acamprosate — a stabilizing factor in long-term withdrawal of alcoholic patients. Ther Umsch50: 182—188
36.
Latt N.C., Jurd S., Houseman J., Wutzke S.E. (2002) Naltrexone in alcohol dependence: a randomised controlled trial of effectiveness in a standard clinical setting. Med J Aust176: 530—534
37.
Lee A., Tan S., Lim D., Winslow R.M., Wong K.E., Allen J., Hall W., Parker G. (2001) Naltrexone in the treatment of alcoholism — an effectiveness study in singapore. Drug Alcohol Rev20: 193—199
38.
Lhuintre J., Daoust M., Moore N.D., Chretien P., Saligaut C., Tran G., Boismare F., Hillemand B. (1985) Ability of calcium bis acetyl homotaurine, a GABA agonist, to prevent relapse in weaned alcoholics. Lancet1: 1014—1016
39.
Lhuintre J.P., Moore N., Tran G., Steru L., Langrenon S., Daoust M., Parot P., Ladure P., Libert C., Boismare F., Hillemand B. (1990) Acamprosate appears to decrease alcohol intake in weaned alcoholics. Alcohol Alcohol25: 613—622
40.
Light R.J., Pillemer D.B. (1984) Summing up: the science of reviewing research. Harvard University Press, Cambridge
41.
Lipha Pharmaceuticals I (2002) Clinical background materials for psychopharmacologic drugs advisory committee meeting. NDA 21-431. Acamprosate for maintenance of abstinence
42.
Littleton J., Zieglgansberger W. (2003) Pharmacological mechanisms of naltrexone and acamprosate in the prevention of relapse in alcohol dependence. Am J Addict12 (Suppl): 3—11
43.
Mann K., Lehert P., Morgan M.Y. (2004) Pharmacotherapy of alcohol dependence: a review of the clinical data. CNS Drugs18: 485—504Mantel N., Haenszel W. (1959) Statistical aspects of the analysis of data from retrospective disease. J Natl Cancer Inst22: 719—748
44.
Marlatt G.A., Gordon J.R. (1985) Relapse prevention: maintenance strategies in the treatment of addictive behaviours. Guilforld Press, New York
45.
Mason B.J. (2001) Results of the multicenter study of acamprosate in the treatment of alcoholism. Biol Psychiatry48: (Suppl 8) 77S (abstract)
46.
Mason B.J. (2006) Effect of oral acamprosate on abstinence in patients with alcohol dependence in a double-blind, placebo-controlled trial: the role of patient motivation. Results of the multicenter study of acamprosate in the treatment of alcoholism. J Psyciatr Res40: 383—393
47.
Monti P.M., Rohsenow D.J., Swift R.M., Gulliver S.B., Colby S.M., Mueller T.I., Brown R.A., Gordon A., Abrams D.B., Niaura R.S., Asher M.K. (2001) Naltrexone and cue exposure with coping and communication skills training for alcoholics: treatment process and 1-year outcomes. Alcohol Clin Exp Res25: 1634—1647
48.
Morley K.C., Teesson M., Reid S.C., Sannibale C., Thomson C., Phung N., Weltman M., Bell J.R., Richardson K., Haber P.S. (2006) Naltrexone versus acamprosate in the treatment of alcohol dependence: a multi-centre, randomized, double-blind, placebo-controlled trial. Addiction101: 1451—1462
49.
Morris P.L., Hopwood M., Whelan G., Gardiner J., Drummond E. (2001) Naltrexone for alcohol dependence. Addiction96: 1565—1573
50.
Namkoong K., Lee B.O., Lee P.G., Choi M.J., Lee E., Investigators K A C T (2003) Acamprosate in Korean alcohol-dependent patients: a multicentre, randomized, double-blind, placebo-controlled study. Alcohol Alcohol38: 135—141
51.
Niederhofer H., Staffen W. (2003) Acamprosate and its efficacy in treating alcohol dependent adolescents. Eur Child Adolesc Psychiatry12: 144—148
52.
O'Malley S.S., Jaffe A.J., Chang G., Schottenfeld R. (1992) Naltrexone and coping skills therapy for alcohol dependence. Arch Gen Psychiatry49: 876—880
53.
O'Malley S.S., Froehlich J.C. (2003) Advances in the use of naltrexone: an integration of preclinical and clinical findings. Recent Dev Alcohol16: 217—243
54.
O'Malley S.S., Rounsaville B.J., Farren C., Namkoong K., Wu R., Robinson J., O'Connor P.G. (2003) Initial and maintenance naltrexone treatment for alcohol dependence using primary care vs specialty care: a nested sequence of 3 randomized trials. Arch Intern Med163: 1695—1704
55.
Oslin D., Liberto J.G., O'Brien J., Krois S., Norbeck J. (1997) Naltrexone as an adjunctive treatment for older patients with alcohol dependence. Am J Geriatr Psychiatry5: 324—332
56.
Paille F.M., Guelfi J.D., Perkins A.C., Royer R.J., Steru L., Parot P. (1995) Double-blind randomized multicentre trial of acamprosate in maintaining abstinence from alcohol. Alcohol Alcohol30: 239—247
57.
Pelc I., Le Bon O., Lehert P., Verbanck P. (1992) Acamprosate in the treatment of alcohol dependence: a six month postdetoxification study. In Soyka M (ed.), Acamprosate in Relapse Prevention of Alcoholism . Springer, Berlin
58.
Pelc I., Verbanck P., Le Bon O., Gavrilovic M., Lion K., Lehert P. (1997) Efficacy and safety of acamprosate in the treatment of detoxified alcohol-dependent patients. A 90-day placebo-controlled dose-finding study. Br J Psychiatry171: 73—77
59.
Poldrugo F. (1997) Acamprosate treatment in a long-term community-based alcohol rehabilitation programme. Addiction92: 1537—1546
60.
Rousseaux J.P., Hers D., Ferauge M. (1996) Does acamprosate influence alcohol consumption of weaned alcoholics?J Pharm Belg51: 65—68
61.
Rybakowski J.K., Zilkowski M., Volpicelli J.R.A study of lithium, carbamazepine and male patients with alcohol dependence — results from four month of treatment. Abstract ESBRA1997
62.
Sass H., Soyka M., Mann K., Zieglgänsberger W. (1996) Relapse prevention by acamprosate. Results from a placebo-controlled study on alcohol dependence. Arch Gen Psychiatry53: 673—680
63.
Schöechlin C., Engel R.R. (2000) Meta-analysis of pharmacotherapeutic trials. In Zernig G, Saria A, Kurz M, O'Malley S (eds), Handbook of alcoholism. InnsbruckUniversity Press, Innsbruck
64.
Sinclair J.D. (2001) Evidence about the use of naltrexone and for different ways of using it in the treatment of alcoholism. Alcohol Alcohol36: 2—10
65.
Slattery J., Chick J., Cochrane M., Craig J., Godfrey C., Kohli H., MacPherson K., Parrot S., Quinn S., Tochel C., Watson H. (2003) Prevention of relapse in alcohol dependence. Health Technology Assesment Report 3
66.
Spanagel R., Pendyala G., Abarca C., Zghoul T., Sanchis-Segura C., Magnone M.C., Lascorz J., Depner M., Holzberg D., Soyka M., Schreiber S., Matsuda F., Lathrop M., Schumann G., Albrecht U. (2005) The clock gene Per2 influences the glutamatergic system and modulates alcohol consumption. Nat Med, 11: 23—24
67.
Srisurapanont M., Jarusuraisin N. (2001) Opioid antagonists for alcohol dependence. Cochrane Database Syst Rev2. CD001867
68.
Srisurapanont M., Jarusuraisin N. (2005) Naltrexone for the treatment of alcoholism: a meta-analysis of randomized controlled trials. J Psychopharmacol8: 267—280
69.
Streeton C., Whelan G. (2001) Naltrexone, a relapse prevention maintenance treatment of alcohol dependence: a meta-analysis of randomized controlled trials. Alcohol Alcohol36: 544—552
70.
Supnick J.A., Colletti G. (1984) Relapse coping and problem solving training following treatment for smoking. Addict Behav9: 401—404
71.
Tempesta E., Janiri L., Bignamini A., Chabac S., Potgieter A. (2000) Acamprosate and relapse prevention in the treatment of alcohol dependence: a placebo-controlled study. Alcohol Alcohol35: 202—209
72.
Volpicelli J.R., Alterman A.I., Hayashida M., O'Brien C.P., O'Brien C. (1992) Naltrexone in the treatment of alcohol dependence . Arch Gen Psychiatry49: 876—880
73.
Volpicelli J.R., Watson N.T., King A.C., Sherman C.E., O'Brien C.P. (1995) Effect of naltrexone on alcohol `high' in alcoholics . Am J Psychiatry152: 613—615
74.
Volpicelli J.R., Rhines J.S., Rhines K.C., Volpicelli L.A., Alterman A.I., O'Brien C.P. (1997) Naltrexone and alcohol dependence: role of subject compliance. Arch Gen Psychiatry54: 737—742
75.
Wasserman D.A., Weinstein M.G., Havassy B.E., Hall S.M. (1998). Factors associated with lapses to heroin use during methadone maintenance. Drug Alcohol Depend52: 183—192
76.
Whitworth A.B., Fischer F., Lesch O.M., Nimmerrichter A., Oberbauer H., Platz T., Potgieter A., Walter H., Fleischhacker W.W. (1996) Comparison of acamprosate and placebo in long-term treatment of alcohol dependence. Lancet25: 1438—1442
77.
Williamson P.R., Gamble C. (2005) Identification and impact of outcome selection bias in meta-analysis. Stat Med24: 1547—1561
