Could Flumazenil Be Used Pre-hospital by Intramuscular Injection for Coma due to Mixed Drug Overdose Not Responding to Naloxone?: A Systematic Review of the Evidence

Abstract

Background/Rationale: Benzodiazepine-involved overdose deaths are increasing. Flumazenil is rarely used due to fear of seizures; however, the risk benefit may favour its use. Flumazenil is licensed for intravenous (IV) use, but intramuscular (IM) treatment would be required pre-hospital. Objective: To identify and synthesise pre-clinical and clinical data on the parenteral IM flumazenil safety and efficacy. Methods: PubMed, Google Scholar, Cochrane and Scopus searches without any language restriction. Adverse effect studies were limited to systematic reviews and large cohort studies (n > 100), IM administration efficacy to studies in large animal (mammalian, excluding reptiles and birds) and humans. Results: Two systematic reviews reported adverse effects from IV or IM flumazenil in clinical use and combined retrospective/prospective patient cohort. Seizures were uncommon (< 2%) including mixed overdoses. Seven studies (four animal, three human) reported on IM flumazenil. Animal studies indicated IM flumazenil efficacy. In a canine cross-over study, IM flumazenil reversed midazolam sedation moderately slower than IV. Two clinical observational studies reported sedation reversal with IM flumazenil, whereas a cross-over study found no IM flumazenil response at 15 min. Conclusion: IM flumazenil data are sparse, but it may be effective and safe. Clinical research is urgently needed to determine whether pre-hospital IM flumazenil can prevent benzodiazepine-involved overdose deaths.