Antiglutamatergic Strategies for Ethanol Detoxification: Comparison With Placebo and Diazepam

Authors

  • Evgeny M. Krupitsky,

    1. St. Petersburg Regional Center of Addictions and Psychopharmacology, Pavlov State Medical University, St. Petersburg, Russia
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  • Anatoly A. Rudenko,

    1. St. Petersburg Regional Center of Addictions and Psychopharmacology, Pavlov State Medical University, St. Petersburg, Russia
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  • Andrey M. Burakov,

    1. St. Petersburg Regional Center of Addictions and Psychopharmacology, Pavlov State Medical University, St. Petersburg, Russia
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  • Tatyana Y. Slavina,

    1. St. Petersburg Regional Center of Addictions and Psychopharmacology, Pavlov State Medical University, St. Petersburg, Russia
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  • Alexander A. Grinenko,

    1. St. Petersburg Regional Center of Addictions and Psychopharmacology, Pavlov State Medical University, St. Petersburg, Russia
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  • Brian Pittman,

    1. Department of Psychiatry, NIAAA Center for the Translational Neuroscience of Alcoholism, Yale University School of Medicine, New Haven, Connecticut
    2. Alcohol Research Center, VA Connecticut Healthcare System, West Haven, Connecticut
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  • Ralitza Gueorguieva,

    1. Department of Psychiatry, NIAAA Center for the Translational Neuroscience of Alcoholism, Yale University School of Medicine, New Haven, Connecticut
    2. Alcohol Research Center, VA Connecticut Healthcare System, West Haven, Connecticut
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  • Ismene L. Petrakis,

    1. Department of Psychiatry, NIAAA Center for the Translational Neuroscience of Alcoholism, Yale University School of Medicine, New Haven, Connecticut
    2. Alcohol Research Center, VA Connecticut Healthcare System, West Haven, Connecticut
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  • Edwin E. Zvartau,

    1. St. Petersburg Regional Center of Addictions and Psychopharmacology, Pavlov State Medical University, St. Petersburg, Russia
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  • John H. Krystal

    1. Department of Psychiatry, NIAAA Center for the Translational Neuroscience of Alcoholism, Yale University School of Medicine, New Haven, Connecticut
    2. Alcohol Research Center, VA Connecticut Healthcare System, West Haven, Connecticut
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  • The authors acknowledge support from the Civilian Research Development Fund (CRDF), the National Institute on Alcohol Abuse and Alcoholism (R21-AA014543-01A1, KO5 AA 14906-01, I-P50 AA-12870-04), and the U.S. Department of Veterans Affairs via their Merit Review Program and Alcohol Research Center for their support of this study.

Reprint requests: John H. Krystal, MD, Alcohol Research Center (116-A), VA Connecticut Healthcare System, 950 Campbell Ave., West Haven, CT 06516; Fax: +203-937-3468; E-mail: john.krystal@yale.edu

Abstract

Background: Benzodiazepines are the standard pharmacotherapies for ethanol detoxification, but concerns about their abuse potential and negative effects upon the transition to alcohol abstinence drive the search for new treatments. Glutamatergic activation and glutamate receptor up-regulation contribute to ethanol dependence and withdrawal. This study compared 3 antiglutamatergic strategies for ethanol detoxification with placebo and to the benzodiazepine, diazepam: the glutamate release inhibitor, lamotrigine; the N-methyl-d-aspartate glutamate receptor antagonist, memantine; and the AMPA/kainite receptor inhibitor, topiramate.

Methods: This placebo-controlled randomized single-blinded psychopharmacology trial studied male alcohol-dependent inpatients (n=127) with clinically significant alcohol withdrawal symptoms. Subjects were assigned to 1 of 5 treatments for 7 days: placebo, diazepam 10 mg TID, lamotrigine 25 mg QID, memantine 10 mg TID, or topiramate 25 mg QID. Additional diazepam was administered when the assigned medication failed to suppress withdrawal symptoms adequately.

Results: All active medications significantly reduced observer-rated and self-rated withdrawal severity, dysphoric mood, and supplementary diazepam administration compared with placebo. The active medications did not differ from diazepam.

Conclusions: This study provides the first systematic clinical evidence supporting the efficacy of a number of antiglutamatergic approaches for treating alcohol withdrawal symptoms. These data support the hypothesis that glutamatergic activation contributes to human alcohol withdrawal. Definitive studies of each of these medications are now needed to further evaluate their effectiveness in treating alcohol withdrawal.

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