Because benzodiazepines are currently so common in UK drug deaths, there is a need to determine whether flumazenil can be given effectively and safely to patients with reduced consciousness following suspected benzodiazepine overdose. This study will address safety and efficacy in three stages: (1) a placebo-controlled, dose-finding study (n=72, maximum of 6 cohorts of 12 participants) to find a safe and effective intramuscular flumazenil dose; (2) a larger 3-arm randomised trial (n=189) to more precisely estimate efficacy of 2 doses identified in stage 1; and then (3) a 2-arm randomised safety study (n=374), comparing fixed-dose intramuscular flumazenil vs no flumazenil, to assess incidence of seizures and improvement in consciousness in hospital.
If a safe and effective dose of intramuscular flumazenil is identified, we will work with the ambulance service to design a pragmatic cluster RCT to test routine intramuscular flumazenil administration (vs placebo) in patients with reduced consciousness from presumed drug overdose by ambulance paramedics at first contact. If that study indicates that flumazenil is effective at reversing coma and respiratory depression, a second cluster RCT of ‘take-home flumazenil’ will determine whether use alongside naloxone at the earliest opportunity saves lives.
The need for these studies is clear. Almost 1,500 people die in the UK each year from combined opioid and benzodiazepine overdose; no-one has yet done the work to find out whether flumazenil can be given safely to these patients or determined whether flumazenil can prevent some of the deaths.
‘Take-home naloxone’ has been successfully introduced by the UK government; a similar approach to benzodiazepine overdose needs urgent and careful investigation. This study initiates the work program with hospital-based studies to address these issues with the intention to repurpose flumazenil for pre-hospital use.