Antiglutamatergic startegies for ethanol detoxification
Context. 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 N-methyl-D-aspartate (NMDA) glutamate receptor upregulation contribute to ethanol dependence and withdrawal. Objective. To compare three antiglutamatergic strategies for ethanol detoxification to placebo and to the benzodiazepine, diazepam: the glutamate release inhibitor, lamotrigine; the NMDA glutamate receptor antagonist, memantine; and the AMPA/kainite receptor inhibitor, topiramate. Design. This placebo-controlled randomized blinded psychopharmacology trial studied male alcohol dependent inpatients (n=127) with clinically significant alcohol withdrawal symptoms. Subjects were assigned to one 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 within the symptom triggered protocol 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 to placebo. The active medications did not differ from diazepam. There was preliminary evidence of greater lamotrigine efficacy relative to memantine or topiramate at the doses studied. 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 establish their effectiveness in treating alcohol withdrawal.