RUFUS – Repurposing flumazenil for intramuscular treatment of coma due to unintentional drug overdose – a dose-finding safety and efficacy phase II/III study.

Unintentional overdoses with drugs killed 4,390 people in the UK in 2021. Most deaths follow use of opioid drugs such as morphine and heroin, often in combination with a group of drugs called benzodiazepines (BZDs). The best-known BZD is the sleeping pill diazepam (or Valium). However, powerful, illegal (unlicensed) and dangerous BZDs have appeared over the last 10 years, e.g. etizolam and alprazolam. Their use has coincided with a major increase in deaths. BZDs cause coma (reduced consciousness) and breathing to slow down and sometimes stop, especially when taken with opioids.

An effective antidote, naloxone, is available for opioid poisoning. This is used before patients get to hospital, injected into their muscle (called the intramuscular [IM] route) by paramedics or bystanders who find people in trouble after an overdose. The IM route is best since it does not require specialist skills. IM naloxone has been introduced into widespread community use (‘take-home naloxone’), resulting in many lives being saved.

A similar antidote exists for BZD overdoses, called flumazenil. Unfortunately, this medicine is not used for BZD overdoses because in the 1980s it was associated with seizures (epileptic fits) after being given to patients with reduced consciousness who had taken multiple medicines. Doctors are worried about causing seizures. However, the majority of the patients had taken tricyclic antidepressants (e.g. amitriptyline) plus BZDs. It is likely that it was the anti-depressants that caused seizures. Fortunately, this type of medicine is now less commonly prescribed.

The rising number of drug deaths following BZD use indicate that we urgently need to find out whether flumazenil can be used safely to prevent deaths.

This study will be carried out in hospital emergency medicine departments (EDs), which are familiar with caring for ill patients and treating seizures. The study will test whether flumazenil given by IM injection to overdose patients causes seizures and whether it can wake patients effectively.