A risk-benefit assessment of flumazenil in the management of benzodiazepine overdose

The worldwide expansion in the use of benzodiazepines has led to their frequent, and often inappropriate, use and to an increase in their involvement in self-induced poisoning and iatrogenic overdosing. Flumazenil is a specific and competitive antagonist at the central benzodiazepine receptor, reversing all effects of benzodiazepine agonists without tranquillising or anticonvulsant actions. Incremental intravenous bolus injections of flumazenil 0.1 to 0.3 mg are the most effective and well tolerated in the diagnosis and treatment of pure benzodiazepine overdose; additional boluses or an infusion (0.3 to 0.5 mg/h) can be given to prevent patients from relapsing into coma. Intravenous flumazenil 10 to 20 μg/kg is effective in neonates and small children. Intramuscular, oral (20 to 25 mg 3 times daily or as required) and rectal administration may be used as alternatives in long term regimens. Patients with mixed-drug overdose require higher doses (up to 2 mg bolus, ≃ 1 mg/h infusion) to regain consciousness. Children and the elderly, chronically ill patients, and pregnant women and their fetuses all respond satisfactorily to flumazenil, but the usefulness of the drug in patients with hepatic encephalopathy and alcohol overdose is debatable. The use of flumazenil results in complete awakening with restoration of upper airway protective reflexes, thus enabling gastric lavage to be performed and transfer of the patient from the emergency room to another hospital department. Resumption of effective spontaneous respiration allows for expeditious extubation, weaning off mechanical ventilation or the avoidance of endotracheal intubation. While flumazenil is not associated with haemodynamic adverse effects, caution should be exercised when using this agent in patients who have co-ingested chloral hydrate or carbamazepine or whose ECG shows abnormalities typical of those seen after overdose with tricyclic antidepressants (TCAs); the use of flumazenil in the presence of these drugs can sometimes induce treatable cardiac dysrrhythmia. Flumazenil per se does not induce adverse effects. Coma reversal by flumazenil may cause mild, short-lived reactions caused by sudden awakening. Withdrawal symptoms in long term benzodiazepine users and seizures in patients who have taken an overdose of TCA or carbamazepine and a benzodiazepine can occur with flumazenil; these symptoms are avoidable by utilising slow flumazenil dose titration.