Antiglutamatergic strategies for ethanol detoxification: comparison with placebo and diazepam.
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.
Krupitsky
Evgeny M
EM
St. Petersburg Regional Center of Addictions and Psychopharmacology, Pavlov State Medical University, St. Petersburg, Russia.
Rudenko
Anatoly A
AA
Burakov
Andrey M
AM
Slavina
Tatyana Y
TY
Grinenko
Alexander A
AA
Pittman
Brian
B
Gueorguieva
Ralitza
R
Petrakis
Ismene L
IL
Zvartau
Edwin E
EE
Krystal
John H
JH
D000328:Adult; D000437:Alcoholism / Q000188:drug therapy* / Q000523:psychology; D001143:Arousal; D001341:Autonomic Nervous System / Q000187:drug effects; D003863:Depression / Q000209:etiology / Q000523:psychology; D003975:Diazepam / Q000009:adverse effects / Q000627:therapeutic use*; D018691:Excitatory Amino Acid Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D005632:Fructose / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D018757:GABA Modulators / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D007297:Inpatients; D000077213:Lamotrigine; D008297:Male; D008559:Memantine / Q000009:adverse effects / Q000627:therapeutic use; D008875:Middle Aged; D019964:Mood Disorders / Q000209:etiology / Q000523:psychology; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology; D000077236:Topiramate; D014227:Triazines / Q000009:adverse effects / Q000627:therapeutic use
D018691:Excitatory Amino Acid Antagonists; D018757:GABA Modulators; D014227:Triazines; D000077236:Topiramate; D005632:Fructose; D003975:Diazepam; D000077213:Lamotrigine; D008559:Memantine