Raymond Anton, MD, et al presented a poster* at a recent meeting of the Research Society on Alcoholism describing a placebo controlled, randomized study of flumazenil/hydroxyzine/gabapentin for alcohol dependence. Available as the Prometa protocol, this off label use of off patent drugs has been touted as a treatment for alcoholism and addictions to methamphetamine and cocaine.
In this study the flumazenil, a benzodiazepine antagonist, was administered intravenously on two consecutive days. Hydroxyzine, an antihistamine, was administered before the flumazenil infusions and at bedtime as needed for six days. Participants, including some with "mild/moderate alcohol withdrawal," took increasing doses of gabapentin for 39 days and attended counseling. Whether the protocol in this study “cured” any of the subjects of alcoholism has apparently not yet been determined. That might presumably take many years and begs the question of whether this cure would simply consist of successful abstinence or actual ability to drink “normally.” Participants were reported to tolerate intravenous administration of flumazenil.
The other question that remains is whether the flumazenil (or the hydroxyzine) adds anything to the effectiveness of gabapentin alone. Gabapentin, an unscheduled anticonvulsant drug also used off label to treat anxiety, is an obvious candidate for treating alcohol withdrawal. Flumazenil on the other hand can precipitate seizures (at least in some patients who have recently used benzodiazepines or other sedative-hypnotics), something for which alcoholics in withdrawal are already at increased risk. We need a study comparing flumazenil/hydroxyzine/gabapentin to gabapentin alone as well as to placebo to settle that question. In the meantime, if you are thinking of trying this combination on your patients, be warned that the protocol is protected by a “use” patent (7,348,321) owned by Hythiam, Inc. If this corporation is looking after its licensees and their considerable financial investment in the license, Hythiam might sue you for patent infringement. But if the gabapentin works just as well by itself, Hythiam might not have much worth licensing.
*R.F. Anton, H. Myrick, P. Latham, A. Baros, T. Wright, S. Stewart, R. Malcolm, R. Wald, P. Randall “Double Blind Controlled Trial of Flumazenil and Gabapentin for the Treatment of Alcohol Dependence”