Sublingual Flumazenil for the Residual Effects of Hypnotics: Zolpidem and Brotizolam

Residual morning drowsiness is a frequent side effect of hypnotics. This study examined the safety and efficacy of sublingual Flumazenil in reversing the residual hypnotic effect. A double-blind, placebo-controlled, randomized crossover study with 20 healthy subjects who slept for 1.5 hours following sleep induction was conducted. Upon awakening, they underwent neurocognitive tests including immediate word recall test (iWRT), Digit Symbol Substitution Test (DSST), and mood/performance questionnaires. They were then treated by Flumazenil or placebo and were reevaluated after 20 and 60 minutes. A week later, the same procedures were performed (placebo/Flumazenil accordingly). All 20 volunteers completed the study. Flumazenil was superior to placebo by 59% to 93% (P < .05-.001) in improving performance in the various neurocognitive tasks. Subjects reported a significant improvement in vigilance with Flumazenil, both at 20 minutes and 60 minutes. iWRT improved with Flumazenil vs placebo at 20 minutes (4.2 ± 0.8 vs 1.3 ± 0.9 words, P < .005) and 60 minutes (5.4 ± 1.1 vs 1.2 ± 1.2 words, P < .02). Sublingual administration of Flumazenil is safe and effective in reversing the hypnotic effects of Zolpidem and Brotizolam. This may offer a comprehensive and safer treatment for insomniac patients.