Repurposing flumazenil for pre-hospital intramuscular treatment of coma due to recreational drug overdose

Overdoses with drugs killed 4,390 people in the UK in 2021. Most of these deaths follow use of opioid drugs such as morphine and heroin, often in combination with a group of drugs called benzodiazepines. The best-known benzodiazepine is the sleeping pill 'diazepam', which has been around since the 1960s. However, new, more powerful, illegal and dangerous benzodiazepines have appeared over the last 10 years, for example etizolam and alprazolam. Their appearance has coincided with a massive increase in deaths, particularly in Scotland. Benzodiazepine drugs cause coma and breathing to slow down and sometimes stop, especially when taken with opioids. A really good antidote, called naloxone, is available for opioid poisoning. This is now used before patients get to hospital, by being injected into muscle by either ambulance paramedics or friends and relatives of people who use drugs who find people in trouble after an overdose. The muscle route is best since it does not require specialist skills. The government has introduced this antidote into widespread community use, resulting in many lives being saved. Trained bystanders inject the antidote into people found unconscious, rescuing their breathing and preventing death. A similar antidote exists for benzodiazepine overdoses, called flumazenil. Unfortunately, this medicine is not used for such overdoses because in the 1980s it was associated with seizures (epileptic fits) after being given to unconscious patients who had taken multiple medicines. Clinicians are concerned about causing seizures. However, the majority of those patients had taken antidepressants (such as one called amitriptyline) plus benzodiazepines. It was the antidepressants that caused seizures. Luckily, this type of medicine is now much less commonly used, especially at the high doses common in the 1980s. Despite attempts by community groups to get flumazenil used by doctors and paramedics in the face of the huge increase in deaths, a concern about seizures still exists and flumazenil is little used. However, the rising number of drug deaths indicate that we urgently need to find out whether flumazenil is actually dangerous or whether it can be used safely in the community in an attempt to stop these deaths. It is important that we test flumazenil in a safe environment where any seizures that do occur can be well treated. We therefore propose to carry out an initial study in 4 emergency medicine departments, which are familiar with caring for ill patients and to dealing with seizures. This study will test whether flumazenil given by injection into muscles can wake patients up and how commonly it causes seizures. The first stage will give unconscious patients (considered to be affected by excess benzodiazepines) increasing doses of flumazenil by the intramuscular (IM) route to see if this route works. Once 2 effective doses have been identified, we will give similar patients (at random) either no flumazenil or one of the two effective doses. This will give us a better idea of how well IM flumazenil works. Finally, we will randomly allocate patients to one dose of flumazenil or to salty water to see how often IM flumazenil causes seizures. A total of 635 patients will be studied across the 3 stages. We predict that flumazenil will cause seizures in less than 3% of patients and that this will be considered acceptable by patients and clinicians - in the hope that flumazenil saves lives. If successful, in the next stage of our work, we will use the data to design a study with ambulances to see whether it can be given safely when paramedics first come across unconscious patients in the community. The government's take-home naloxone policy has saved many lives; there is now an urgent need to explore whether the use of flumazenil before patients arrive in hospital can address the UK's drug death crisis and save more lives.