Correspondence
Naltrexone for Alcohol Dependence
N Engl J Med 2002; 346:1329-1331April 25, 2002
- Article
To the Editor:
Krystal et al. (Dec. 13 issue)1 “found no evidence that naltrexone combined with psychosocial therapy was an effective treatment for alcohol dependence.” We are concerned that the characteristics of the study sample may have made it difficult to detect significant differences among the treatment groups. Only 19 percent of the veterans initially evaluated were enrolled. In this extremely selected study sample, the results with naltrexone were similar to those without naltrexone. We were surprised that no significant differences were found among the study groups in the median number of days to relapse (176 days in the group assigned to 12 months of naltrexone, 115 days in the group assigned to 3 months of naltrexone, and 104 days in the placebo group). We recently reported the results of a comparison of naltrexone and acamprosate for alcohol treatment in which, after a 12-month follow-up, the mean number of days to relapse was 63 with naltrexone and 42 with acamprosate.2
Krystal et al. report good results in all the groups, in contrast to others' findings.3-5 The conclusion that naltrexone was ineffective is not justified.
5 ReferencesGabriel Rubio, M.D., Ph.D.
Guillermo Ponce, M.D.
Jorge Manzanares, Ph.D.
Hospital Universitario 12 de Octubre, 28041 Madrid, Spain
jorgemanzanares@teleline.es 1
Krystal JH ,Cramer JA ,Krol WF ,Kirk GF ,Rosenheck RA . Naltrexone in the treatment of alcohol dependence. N Engl J Med 2001;345:1734-1739
Full Text | Web of Science | Medline2
Rubio G ,Jimenez-Arriero MA ,Ponce G ,Palomo T . Naltrexone versus acamprosate: one year follow-up of alcohol dependence. Alcohol Alcohol 2001;36:419-425
Web of Science | Medline3
Anton RF ,Moak DH ,Waid LR ,Latham PK ,Malcolm RJ ,Dias JK . Naltrexone and cognitive behavioral therapy for the treatment of outpatient alcoholics: results of a placebo-controlled trial. Am J Psychiatry 1999;156:1758-1764
Web of Science | Medline4
Chick J ,Anton R ,Checinski K , et al. A multicentre, randomized, double-blind, placebo-controlled trial of naltrexone in the treatment of alcohol dependence or abuse. Alcohol Alcohol 2000;35:587-593
Web of Science | Medline5
Heinala P ,Alho H ,Kiianmaa K ,Lonnqvist J ,Kuoppasalmi K ,Sinclair JD . Targeted use of naltrexone without prior detoxification in the treatment of alcohol dependence: a factorial double-blind, placebo-controlled trial. J Clin Psychopharmacol 2001;21:287-292
CrossRef | Web of Science | Medline
To the Editor:
The negative results with naltrexone reported by Krystal et al. are consistent with our findings1,2 but are not relevant to the question of whether naltrexone is effective. Naltrexone yields significant benefits but not in protocols such as theirs that support complete abstinence.1-4
In Finland, we conducted a 32-week, double-blind, randomized trial,1 in which we divided 121 alcohol-dependent outpatients into four groups. Two of the groups were instructed to abstain from alcohol, as in the study by Krystal et al. In these groups, naltrexone (50 mg) was no better than placebo. The other two groups had therapy aimed not at abstinence but at the prevention of binges; in these groups, naltrexone was significantly better than placebo and was significantly better than naltrexone given with instructions to abstain from alcohol. Similarly, we found that naltrexone was not effective in patients who were asked to abstain from alcohol but was effective in those who were not required to abstain.2 The same pattern was found in a Swedish study3 and in other trials.4 The primary benefits have consistently been seen in patients who drink alcohol while receiving naltrexone.4
The practical question is how to get this message across. Abstaining alcoholics cannot be advised to drink. The solution is to begin treatment with naltrexone before detoxification, when patients are still drinking. We found this approach to be both effective and safe.1 It is also considerably less expensive and more acceptable to patients than procedures involving prior detoxification.
4 ReferencesJohn David Sinclair, Ph.D.
Hannu Alho, M.D., Ph.D.
National Public Health Institute, Helsinki 00251, Finland
david.sinclair@ktl. fi Marc Shinderman, M.D.
Center for Addictive Problems, Chicago, IL 606101
Heinala P ,Alho H ,Kiianmaa K ,Lonnqvist J ,Kuoppasalmi K ,Sinclair JD . Targeted use of naltrexone without prior detoxification in the treatment of alcohol dependence: a factorial double-blind, placebo-controlled trial. J Clin Psychopharmacol 2001;21:287-292
CrossRef | Web of Science | Medline2
Maxwell S ,Shinderman MS . Use of naltrexone in the treatment of alcohol use disorders in patients with concomitant major mental illness. J Addict Dis 2000;19:61-69
CrossRef | Web of Science | Medline3
Mansson M ,Balldin J ,Berglund M ,Borg S . Six-month follow-up of interaction effect between naltrexone and coping skills therapy in outpatient alcoholism treatment. Alcohol Alcohol 1999;34:454-454 abstract.4
Sinclair JD . Evidence about the use of naltrexone and for different ways of using it in the treatment of alcoholism. Alcohol Alcohol 2001;36:2-10
Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Rubio and colleagues suggest that the time to a relapse of heavy drinking was longer in our study than in previous trials. They question whether the composition of the sample of patients might have contributed to this difference. Our criteria for enrollment were based on the advice of investigators who had conducted the principal U.S. studies of naltrexone with the objective of sampling a broadly representative group of alcohol-dependent patients treated at Department of Veterans Affairs institutions. Our results apply most directly to this population. The population we enrolled was similar to those in other studies, but the group that received placebo had better outcomes than placebo groups in other trials.
The recommendation to give naltrexone to patients who continue to drink is based on the hypothesis of Sinclair and colleagues that this method extinguishes the urge to drink alcohol by blocking the rewarding effects of alcohol. We attempted to determine whether our study provided indirect support for this hypothesis by conducting a post hoc analysis in which patients who sampled alcohol before a relapse were compared with those who did not sample alcohol before a relapse. Using our three end points of the time to relapse, the number of drinks per drinking day, and the percentage of drinking days, we found no significant differences between the patients who were taking naltrexone and those who were taking placebo. This result does not support the findings of Sinclair et al., but this comparison was not a direct test of their hypothesis because it was not part of our protocol design.
John H. Krystal, M.D.
Joyce A. Cramer, B.S.
Robert Rosenheck, M.D.
Veterans Affairs Connecticut Healthcare System, West Haven, CT 06516-2770
john.krystal@yale. edu - Citing Articles (3)
Citing Articles
1
Teresa Femenía, Jorge Manzanares. (2011) Increased ethanol intake in prodynorphin knockout mice is associated to changes in opioid receptor function and dopamine transmission. Addiction Biologyno-no
CrossRef2
Frank M. Orson, Berma M. Kinsey, Rana A.K. Singh, Yan Wu, Tracie Gardner, Thomas R. Kosten. (2008) Substance Abuse Vaccines. Annals of the New York Academy of Sciences 1141:1, 257-269
CrossRef3
Falk Kiefer, Miguel Angel Jiménez-Arriero, Oliver Klein, Alexander Diehl, Gabriel Rubio. (2008) Cloninger’s typology and treatment outcome in alcohol-dependent subjects during pharmacotherapy with naltrexone. Addiction Biology 13:1, 124-129
CrossRef
