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

Document Type

Journal Article

Publication Title

Drug and Alcohol Dependence

Volume

236

PubMed ID

35644071

Publisher

Elsevier

School

School of Medical and Health Sciences

RAS ID

51753

Comments

MacDonald, T., Gallo, A. T., Basso-Hulse, G. M., Bennett, K. S., & Hulse, G. K. (2022). A double-blind randomised crossover trial of low-dose flumazenil for benzodiazepine withdrawal: A proof of concept. Drug and alcohol dependence, 236, 109501. https://doi.org/10.1016/j.drugalcdep.2022.109501

Abstract

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.

DOI

10.1016/j.drugalcdep.2022.109501

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