Clinical Outcomes of a 3-day Benzodiazepine Detoxification Protocol With Continuous Subcutaneous Flumazenil Infusion: An Open-label Pilot Study

OBJECTIVES: Abstinence rates of benzodiazepine tapering in individuals with sedative, hypnotic, or anxiolytic use disorder (SHA‑UD) are approximately 50%. Continuous subcutaneous flumazenil infusion during tapering may increase success rates and shorten tapering regimens; however, data on safety and effectiveness remain limited. We therefore aimed to assess the safety, withdrawal symptoms, and abstinence rates associated with flumazenil‑assisted 3-day benzodiazepine tapering in individuals with SHA‑UD. METHODS: This exploratory, single‑arm, open‑label pilot study included adult participants with SHA‑UD (n=31) who had experienced at least one previous unsuccessful professionally guided tapering attempt. Participants received a 6‑day continuous subcutaneous flumazenil infusion (4 mg/24 h), while benzodiazepines were fully tapered during the first 3 days. Outcomes included adverse events, interictal epileptiform discharges (IEDs) on EEG, withdrawal severity, anxiety, and abstinence rates at 3‑month follow‑up. RESULTS: After a withdrawal seizure occurred in one of the first 4 participants, valproate prophylaxis was introduced; no further seizures were observed thereafter. IEDs were detected in 6 participants during or after flumazenil infusion. Supportive medication (eg, propranolol, promethazine) was required in 87% of participants to manage withdrawal symptoms. Withdrawal severity and anxiety increased during detoxification, peaking during the final days of flumazenil infusion (P=0.023). Sixteen participants (52%) were confirmed abstinent at 3-month follow-up by self-report and urinalysis. CONCLUSIONS: These findings warrant further investigation of flumazenil-assisted benzodiazepine detoxification in individuals with SHA-UD. Controlled studies are needed to further establish its safety profile and comparative effectiveness.