A double-blind randomised crossover trial of low-dose flumazenil for benzodiazepine withdrawal: A proof of concept.

INTRODUCTION: Benzodiazepines (BZD) are a class of anxiolytics with varying uses, which primarily act on the GABAA receptor resulting in hyperpolarisation. BZDs are often a difficult drug class to cease once neuroadaptation has occurred; recommendations usually involve gradual dose reductions at variable rates. A growing body of evidence has suggested that low-dose flumazenil, a GABAA receptor antagonist, may be a useful agent to allow for rapid detoxification. AIM: To collect pilot data on the safety and efficacy of low-dose subcutaneous flumazenil to reduce BZD use, withdrawal symptoms, and craving in participants taking above and below the therapeutic maximum diazepam equivalent of 30 mg to inform on sample size for future trials. METHOD: In a randomised double-blinded crossover study design, participants received low-dose flumazenil first (4 mg/24 h for approximately eight days) or placebo first. Groups were divided into those taking < 30 mg diazepam equivalent and ≥ 30 mg diazepam equivalent at baseline. Main outcome measures were percentage reduction in daily diazepam use, withdrawal symptoms, and craving scores from baseline, difference in diazepam use across the placebo first group, and flumazenil related adverse events. RESULTS: Twenty-eight participants were recruited and randomised to flumazenil first (n = 14) and placebo first (n = 14). In participants taking ≥ 30 mg diazepam equivalent at baseline (n = 15), flumazenil significantly reduced diazepam use by 30.5% (p = 0.024) compared to placebo. CONCLUSION: Low-dose flumazenil may aid in BZD detoxification in participants taking daily diazepam equivalent doses greater than or equal to the therapeutic maximum (≥30 mg) by reducing the need for diazepam.

Outcomes of patients treated with low-dose flumazenil for benzodiazepine detoxification: A description of 26 participants.

INTRODUCTION: Benzodiazepines are commonly prescribed for a variety of indications and can be employed in the short- and long-term. While they are efficacious, issues arise from long-term use with the emergence of dependence and tolerance to doses within the therapeutic range and beyond. Discontinuation from benzodiazepines can be problematic for patients and may result in a withdrawal syndrome, which can be protracted and last months to years. METHODS: 26 participants received low-dose subcutaneous flumazenil infusions (4 mg/24 h for approximately eight days) as part of a randomised control crossover trial. Return to benzodiazepine use was assessed monthly for three months based on the benzodiazepine use in the previous week. Where data was not available, the treating psychiatrist examined patient files and clinical documents to determine benzodiazepine use. Withdrawal and craving scores were also measured. RESULTS: Abstinence rates from benzodiazepines at one-, two-, and three-month follow ups were 65.4 %, 50.0 %, and 46.2 % respectively. When considering patient files and clinical documents for those lost to follow-up, abstinence rates were higher at 73.1 %, 65.4 % and 61.5 % at the one-, two-, and three-month follow ups respectively. Withdrawal and craving scores were higher in those that had returned to any benzodiazepine use. CONCLUSION: Self-reported rates of abstinence from benzodiazepines at three months was between 46.2 % and 61.5 %. Flumazenil may yield greater success than benzodiazepine tapering from high dose benzodiazepine use (≥30 mg diazepam equivalent). Further research should compare abstinence rates after treatment with flumazenil compared to benzodiazepine tapering in high dose benzodiazepine users.