CMAJ Practice Five things to know about … Flumazenil in benzodiazepine overdose Howard An MD MSc, Jesse Godwin MD Isolated benzodiazepine overdoses are rarely fatal Flumazenil antagonizes benzodiazepine activity A population-based retrospective study Benzodiazepines promote the binding of γ-aminobutyric acid (GABA) to its reported a rate of 3.0–7.9 deaths per receptor. The “Z” drugs (zopiclone, zaleplon and zolpidem) act in a similar man- 1 3 million benzodiazepine prescriptions. ner. Flumazenil is a benzodiazepine analogue with minimal intrinsic activity. It Sedation is common, but severe respi- binds to the extracellular surface of GABAA receptors and competitively dis- ratory depression and hemodynamic places benzodiazepine molecules, preventing further benzo diazepine binding.3 instability are rare.2 Supportive care is generally sufficient for the manage- 2 ment of benzodiazepine overdose. 1 Flumazenil has a short half-life Select patients may benefit from the Evidence regarding optimal dosing is Flumazenil should not be used administration of flumazenil limited. The manufacturer recom- routinely mends an initial dose of 0.2 mg given Flumazenil can reverse respiratory over 15 seconds.5 A suggested, more Flumazenil is contraindicated in pa- depression in the rare patient with cautious approach would be to ad- tients with unknown or mixed over- severe, isolated benzodiazepine or “Z” minister flumazenil in 0.1-mg doses dose, benzodiazepine tolerance, sei- drug toxicity who does not have con- (or 0.01 mg/kg) each over one min- zure disorders or a prolonged QRS traindications to its use. It is most ute, to a maximum of 1 mg, or until interval.3 In a recent meta-analysis, often considered in accidental pediat- an effect is achieved or toxicity devel- serious adverse events were signifi- ric ingestions or reversal of iatrogenic ops.2 The half-life of flumazenil is cantly more common among pa- oversedation. Case reports have shown about 50 minutes, which is shorter tients with suspected benzodiaz- successful flumazenil reversal of para- than that of5 most benzodiazepines. epine overdose treated with doxic reactions (agitation) associated Therefore, sedation often recurs. Car- 4 4 flumazenil than among those in the with benzodiazepines. Flumazenil diorespiratory monitoring is neces- placebo group (risk ratio 3.81, 95% does not reverse sedation due to barbi- sary, and repeat dosing or infusion confidence interval 1.28–11.39; turates, ethanol or opioids. may be required.5 number needed to harm = 50).2 Sei- zures and ventricular dysrhythmias can develop, especially if with- drawal is precipitated in benzodiaz- References Competing interests: None declared. epine-tolerant individuals or if flu- 1. Buckley NA, McManus PR. Changes in fatalities 3 due to overdose of anxiolytic and sedative drugs in mazenil reverses the protective the UK (1983–1999). Drug Saf 2004;27:135-41. This article has been peer reviewed. effect of benzodiazepines in pa- 2. Penninga EI, Graudal N, Ladekarl MB, et al. Affiliations: Divisions of Emergency Medicine Adverse events associated with flumazenil treatment tients with unknown or mixed over- for the management of suspected benzodiazepine (Godwin) and Clinical Pharmacology and Toxi- dose.3 Seizures may become more intoxication: a systematic review with meta-analyses cology (An, Godwin), Department of Medicine, of randomised trials. Basic Clin Pharmacol Toxicol University of Toronto; Ontario Poison Centre difficult to manage and may require 2016;118:37-44. (An, Godwin), Division of Clinical Pharmacol- the use of propofol or barbiturates. 3. Sivilotti MLA. Flumazenil, naloxone and the ‘coma ogy and Toxicology, Hospital for Sick Children, cocktail.’ Br J Clin Pharmacol 2016;81:428-36. Toronto, Ont. A poison centre should be consulted 4. Jackson BF, Beck LA, Losek JD. Successful if the use of flumazenil is being flumazenil reversal of paradoxical reaction to Correspondence to: Howard An, howard.an@ midazolam in a child. J Emerg Med 2015;48:e67-72. gmail.com considered. 5. Anexate [package insert]. Basel (Switzerland): Hoffman–La Roche; 2008. CMAJ 2016. DOI:10.1503/cmaj.160357 © 2016 Joule Inc. or its licensors CMAJ, December 6, 2016, 188(17–18) E537.