Triazolam Reversal by a Single Intraoral Fixed-Dose of Submucosal Flumazenil

Given the growing popularity among general dentists to use benzodiazepines to produce sedation, effective and easily administered pharmacologic rescue strategies are needed. Flumazenil (Romazicon®) is a commercially available antagonist selective for benzodiazepines and the intravenously (IV) titration of the drug has been repeatedly demonstrated capable of reversing the sedative effects of benzodiazepines. Objectives: This study evaluated whether a single, intraoral, submucosal administration of flumazenil (0.2 mg) is capable of attenuating the central nervous system (CNS) depression produced by incremental sublingual dosing of triazolam (total 0.75 mg). Methods: Fourteen healthy adults age 21-36 years, not receiving dental treatment, were first sedated with incrementally administered sublingual triazolam (0.75 mg total dose administered in 3 equal increments of 0.25 mg over 90 minutes). Thirty minutes after the last triazolam dose the subjects were randomly selected to receive a 2 ml intraoral submucosal injection of either 0.9% saline (placebo, n=7) or flumazenil (0.2 mg, n=7). Bispectral index monitoring (BIS) and the Observers Assessment of Alertness/Sedation (OAA/S) were used to measure hypnotic state and sedation level, respectively, every 30 minutes during the 6-hour study period. Results: The submucosal injection of the flumazenil and the placebo both resulted in a transient increase in the BIS scores of both groups (23% in the flumazenil group vs.14% in the placebo group). This increase in BIS scores was not sustained beyond 30 minutes in either group. In contrast, OAA/S scores increased in the group receiving flumazenil but not in the placebo (33% vs. 0%, respectively), also reaching a peak effect in 30 minutes before diminishing. Conclusion: These results suggest that further investigations are needed to determine the optimal intraoral submucosal dose of flumazenil needed to reverse complications that may arise from deeper sedation with elevated triazolam doses. Supported by NIDCR/NIH grant U54DE014254 and Aspect Medical Systems, Newton, MA.