Pharmacological uses of flumazenil in benzodiazepine use disorders: a systematic review of limited data

Background: The estimated annual prevalence of drug use disorders is as high as 3%, underpinning the need to continually develop more effective treatments. Central nervous system dysregulation, contributing to acute and post-withdrawal syndromes, has traditionally been managed with benzodiazepines; however, a small but growing body of data indicate that the GABA_A receptor antagonist, flumazenil, may offer some advantages over traditional management. Aim: To review the literature on the safety and efficacy of flumazenil in benzodiazepine use disorders and identify gaps in the literature. Method: A systematic method was used to identify randomised control trials. Where randomised control trials existed, non-randomised control trials were included to supplement findings. Results: Eleven flumazenil trials were included with varying doses, frequencies and routes of administration. The evidence for flumazenil alone showed generally a reduction in withdrawal symptoms with the exception of one study where withdrawal symptoms initially increased. Flumazenil plus benzodiazepine tapering was assessed in one randomised control trial and a series of non-randomised control trials. Randomised control trial results showed that flumazenil plus benzodiazepine tapering was superior at reducing withdrawal symptoms compared to benzodiazepine tapering alone and placebo. Flumazenil was associated with no serious adverse events; however there remains a risk of seizures. Conclusion: Although flumazenil shows promising efficacy in the management of benzodiazepine use disorders and withdrawal, more randomized control trials are required before a definitive recommendation can be made around its use.