Low-Dose Flumazenil Decreased Diazepam Use During Benzodiazepine Detoxification

Depressed black woman portrait suffering for addiction
A study was conducted to gather data on the safety and efficacy of low-dose subcutaneous flumazenil for reducing benzodiazepine use and withdrawal symptoms.

In patients taking 30 mg or more daily diazepam equivalents, low-dose flumazenil may aid in benzodiazepine (BZD) detoxification, according to results of a pilot study published in Drug and Alcohol Dependence.

This study was conducted at Currumbin Clinic and Fresh Start Recovery Programme in Australia. Participants (N=26) with a history of daily BZD use for more than 3 months at 10 mg or more diazepam equivalents who desired to cease use were randomly assigned to receive 2 4-mg flumazenil infusions per day for approximately 4 days followed by placebo infusion during the same schedule or placebo first followed by flumazenil. Participants could request 10-mg diazepam on an as-needed basis without a daily maximum when they scored 2 or more on the Clinical Institute Withdrawal Assessment Scale-BZDs (CIWA-B). The primary outcomes were daily diazepam use, withdrawal symptoms, and craving scores.

Stratified by baseline use, patients using a low daily dose (<30 mg diazepam equivalents) and high daily dose (≥30 mg diazepam equivalents) were randomly assigned to receive flumazenil first (n=5; n=8) or second (n=6; n=7), respectively. The study participants were 60% to 71% women, aged mean 45.6 to 62.5 years, and they were taking 14.2 to 72.3 mg BZD equivalents per day.

Among the low-dose group, the change in diazepam use (U, 10.00; P =.429), withdrawal symptoms (U, 7.50; P =.556), and craving scores (U, 8.00; P =.476) did not differ significantly between the flumazenil or placebo first cohorts.

Among the high-dose group, flumazenil first associated with greater reduction in diazepam use (t[8.10], -2.76; P =.024) but no difference in withdrawal symptoms (U, 19.00; P =.836) or craving scores (U, 27.00; P =.908).

A total of 12 adverse events were reported. Three events were related to flumazenil (nausea or vomiting [n=2] and itching [n=1]) and 2 were attributed to the procedure (injection site pain [n=1] and infusion site bleeding after strenuous activity [n=1]).

The major limitation of this study was the small sample size; however, this was a pilot study designed to inform a larger, randomized-controlled trial.

“The data suggests that low-dose flumazenil reduces diazepam use in participants aiming to cease BZDs taking doses at and above the therapeutic range (≥30mg diazepam equivalent) prior to treatment for at least 3 months,” the study authors wrote. “While there was no evidence of flumazenil’s efficacy in participants taking low dose BZDs (<30mg diazepam), this was a pilot study that was underpowered; therefore, findings should be interpreted with caution.”


Jones JD, Campbell AN, Brandt L, et al. A randomized clinical trial of the effects of brief versus extended opioid overdose education on naloxone utilization outcomes by individuals with opioid use disorder. Drug Alcohol Depend. Published online May 23, 2022. doi:10.1016/j.drugalcdep.2022.109505