Alcohol withdrawal is a major public health problem in that it perpetuates further drinking, can cause medical emergencies such as seizures and delirium tremens, and may contribute to alcohol dementia. Recently it has been suggested that alcohol withdrawal may be caused by the increased release of an inverse agonist of benzodiazepine receptors, - such compounds having actions opposite to those of the conventional benzodiazepines, being anxiogenic and preconvulsant. If this hypothesis is correct then the actions of the conventional benzodiazepines such as diazepam in treating withdrawal could be due to competition at the receptor. Recently a potent and specific benzodiazepine receptor antagonist flumazenil has been released for clinical use. Flumazenil blocks the actions of inverse agonists as well as agonists and so should block the action of any inverse agonist present in alcohol withdrawal. Thus flumazenil could be an alternative treatment to agonist benzodiazepines for this disorder. The present study will test whether an endogenous inverse agonist contributes to withdrawal by administering flumazenil to 20 alcoholics in withdrawal in a double-blind placebo controlled fashion. A dose of 2 mg/subject will be used which is known to occupy the majority of brain benzodiazepine receptors and fully reverse the actions of inverse agonists. An age and sex matched control population will be tested under the same conditions to determine if there is any evidence of abnormal responses to flumazenil in alcoholics. If flumazenil is shown to be active against any of the feature of alcohol withdrawal it could provide an alternative treatment to benzodiazepine agonists. In relation to these latter compounds flumazenil has the advantage of being free from the risks of sedation, dependence and abuse.
|Potokar, J; Coupland, N; Glue, P et al. (1997) Flumazenil in alcohol withdrawal: a double-blind placebo-controlled study. Alcohol Alcohol 32:605-11|