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

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.