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QUESTION: In patients with alcohol dependence and a recent history of drinking to intoxication, is treatment with naltrexone for 3 or 12 months in addition to standardised psychosocial treatment more effective than placebo for reducing alcohol consumption?
Design
Randomised {allocation concealed*}†, blinded (participants and health care providers),* controlled trial with 52 weeks of follow up.
Setting
15 Veterans Affairs medical centres in the US.
Patients
627 outpatients (mean age 49 y, 98% men) who had a diagnosis of alcohol dependence according to the Diagnostic and Statistical Manual of Mental Disorders, 4th ed, criteria; who had not drunk for ≥ 5 days; and who had a recent history of drinking to intoxication (≥ 6 drinks for men and ≥ 4 drinks for women at least twice during a 1 wk period in the 30 d before screening). Exclusion criteria included previous use of naltrexone and other substance abuse or dependence. Follow up was 90% and 93% at 13 and 52 weeks, respectively.
Intervention
209 patients each were allocated to naltrexone, 50 mg once daily, for 3 months (short term group); naltrexone, 50 mg once daily, for 12 months (long term group); or placebo. All patients received individual 12 step facilitation counselling for 13 months and were encouraged to attend Alcoholics Anonymous meetings. Visits were weekly for 16 weeks, every 2 weeks during weeks 17 to 36, and monthly during weeks 37 to 56.
Main outcome measures
Time to relapse (d from randomisation to first d of heavy drinking) during the first 3 months, percentage of drinking days (PDD), and number of drinks per drinking day (NDPDD) for a 12 month period.
Main results
Analysis was by intention to treat. At 13 weeks, the combined short term and long term naltrexone groups did not differ from the placebo group for time to relapse (table). At 52 weeks, the short term and long term naltrexone groups did not differ from the placebo group for PDD or NDPDD (NDPDD evaluated for the 66% of patients who consumed alcohol during follow up) (table).
Conclusion
In patients with alcohol dependence and a recent history of drinking to intoxication, treatment with naltrexone for 3 or 12 months in addition to standardised psychosocial treatment was no more effective than placebo for reducing alcohol consumption.
Commentary
2 meta-analyses have supported the effectiveness of naltrexone in treating alcohol dependence.1,2 2 further studies showing its efficacy have since been published.3,4 The negative study by Krystal et al and the 2 negative studies in the meta-analysis by Streeton and Whelan1 are the only truly multicentre studies in which naltrexone or placebo was offered in addition to standard abstinence oriented treatment programmes.
Although no large trial of naltrexone has used coping skills therapy (CST), naltrexone has shown efficacy when adjunctive CST has been used in small studies. Fuller and Gordis5 comment that CST differs from the 12 step facilitation therapy (used in this study) because a lapse to drinking is dedramatised in CST, with harm-free drinking being seen as an acceptable goal.
Standard end points for treatment trials of patients with alcoholism, including PDD and NDPDD, were used in this study. However, some investigators consider that naltrexone has an effect in reducing the number of days of heavy drinking (> 5 drinks). Under this assumption, NDPDD blurs the distinction between those who sometimes drink a little and sometimes drink a lot and those who drink equally frequently but who usually consume moderate amounts. The negative result of this study can be seen as an example of how results of treatment trials weaken when extrapolated outside specialised research centres; it can also be seen as support for further trials of opiate antagonist treatment with alternative types of adjunctive psychotherapy.
Naltrexone for 3 months (short term) or 12 months (long term) v placebo for alcohol dependence‡
QUESTION: In patients with alcohol dependence and a recent history of drinking to intoxication, is treatment with naltrexone for 3 or 12 months in addition to standardised psychosocial treatment more effective than placebo for reducing alcohol consumption?
Footnotes
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Sources of funding: Department of Veterans Affairs Office of Research and Development and Dupont Pharmaceuticals.
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For correspondence: Dr J H Krystal, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, USA.john.krystal{at}yale.edu.
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Abstract and commentary also appear in Evidence-Based Mental Health.
↵† Information provided by author.