Repurposing flumazenil for pre-hospital intramuscular treatment of coma due to recreational drug overdose
Lead Research Organisation:
University of Edinburgh
Department Name: Centre for Cardiovascular Science
Abstract
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.
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.
Technical Summary
Unintentional drug overdoses killed 4,390 people in the UK in 2021. There has been a recent major increase in the number of deaths associated with benzodiazepines (BZDs), particularly in Scotland (918/1330 [69.0%] of deaths) and particularly with potent illegal BZDs such as etizolam and alprazolam. BZDs cause respiratory depression; synergistic effects with opioids may be causing many deaths. A BZD antidote (flumazenil) is available - akin to naloxone, which has been introduced as a 'take-home' opioid antidote for use in the community by first-responders and trained bystanders and shown to save lives. In contrast, flumazenil is only licensed for the intravenous route in hospital and there are concerns about seizures (although incidence is <1.0% in systematic reviews). There is an urgent need to determine whether it can be used safely by the intramuscular (IM) route before hospital by paramedics or bystanders for presumed drug overdose. We here propose 3 emergency department (ED) studies to identify an effective IM flumazenil dose and then determine the seizure incidence (the safety concern of interest) as precursor to community studies. We will first identify an IM dose that improves conscious level in patients with presumed drug overdose in a dose-escalation study (10:2 flumazenil:placebo ratio, 6 doses, n=72) in one ED. When two potentially effective doses are identified, the study will be expanded to four study sites and a randomised placebo-controlled, parallel group design (n=189) used to estimate efficacy more precisely. Finally, 374 patients will be randomised (1:1) to IM flumazenil/matched placebo; primary outcome will be seizure incidence. If found to be effective and safe, cluster randomised clinical trials (RCTS) will be designed with ambulance services and communities. The government's take-home naloxone policy has saved many lives; there is now a need to explore whether similar pre-hospital use of flumazenil can help address the UK's drug death crisis.
