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

重新利用氟马西尼用于院前肌肉注射治疗因娱乐性药物过量而导致的昏迷

• 批准号: MR/X030237/1
• 负责人: Michael Eddleston
• 金额: $ 310.65万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX030237%2F1
• 关键词: Repurposing; flumazenil; pre; hospital; intramuscular

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.

2021 年，英国有 4,390 人因吸毒过量而死亡。其中大多数死亡是由于使用吗啡和海洛因等阿片类药物造成的，这些药物通常与苯二氮卓类药物合用。最知名的苯二氮卓类药物是安眠药“地西泮”，自 20 世纪 60 年代以来就已出现。然而，过去 10 年来出现了新的、更强效、非法和危险的苯二氮卓类药物，例如依替唑仑和阿普唑仑。它们的出现恰逢死亡人数大幅增加，特别是在苏格兰。苯二氮卓类药物会导致昏迷和呼吸减慢，有时甚至停止，尤其是与阿片类药物一起服用时。有一种非常好的解毒剂，称为纳洛酮，可用于治疗阿片类药物中毒。现在，这种方法在患者到达医院之前使用，由救护车护理人员或吸毒者的朋友和亲戚注射到肌肉中，这些吸毒者发现吸毒过量后陷入困境。肌肉路线是最好的，因为它不需要专业技能。政府已将这种解毒剂引入社区广泛使用，从而挽救了许多生命。训练有素的旁观者向昏迷不醒的人注射解毒剂，挽救他们的呼吸并防止死亡。针对苯二氮卓类药物过量，还有一种类似的解毒剂，称为氟马西尼。不幸的是，这种药物并没有用于这种药物过量的情况，因为在 20 世纪 80 年代，服用多种药物的昏迷患者服用该药物后，会导致癫痫发作（癫痫发作）。临床医生担心会引起癫痫发作。然而，大多数患者服用了抗抑郁药（例如阿米替林）和苯二氮卓类药物。正是抗抑郁药引起了癫痫发作。幸运的是，这种药物现在已不太常用，尤其是 20 世纪 80 年代常见的高剂量药物。尽管面对死亡人数大幅增加，社区团体尝试让医生和护理人员使用氟马西尼，但人们担心癫痫发作仍然存在，氟马西尼很少使用。然而，不断上升的药物死亡人数表明，我们迫切需要查明氟马西尼是否真的危险，或者是否可以在社区安全使用，以试图阻止这些死亡。重要的是，我们在安全的环境中测试氟马西尼任何发生的癫痫发作都可以得到很好的治疗。因此，我们建议在 4 个熟悉护理病人和处理癫痫发作的急诊科进行初步研究。这项研究将测试通过肌肉注射给予氟马西尼是否可以唤醒患者以及引起癫痫发作的频率。第一阶段将通过肌肉注射（IM）途径为昏迷的患者（被认为受到过量苯二氮卓类药物的影响）增加氟马西尼的剂量，以达到治疗目的。看看这条路线是否有效。一旦确定了 2 种有效剂量，我们将（随机）给予类似患者不给予氟马西尼或两种有效剂量中的一种。这将使我们更好地了解肌内注射氟马西尼的效果如何。最后，我们将随机分配患者服用一剂氟马西尼或盐水，以观察肌内注射氟马西尼引起癫痫发作的频率。这三个阶段将总共对 635 名患者进行研究。我们预测氟马西尼会导致不到 3% 的患者癫痫发作，并且这将被患者和临床医生认为是可以接受的 - 希望氟马西尼能够挽救生命。如果成功的话，在我们下一阶段的工作中，我们将利用这些数据设计一项救护车研究，看看当护理人员第一次在社区遇到昏迷的病人时，是否能够安全地给予。政府的带回家纳洛酮政策拯救了许多生命；现在迫切需要探索在患者到达医院之前使用氟马西尼是否可以解决英国的药物死亡危机并挽救更多生命。