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.

药物过量的药物在2021年在英国造成4,390人死亡。这些死亡中的大多数遵循了吗啡和海洛因等阿片类药物，通常与一组称为苯二氮卓类药物结合使用。最著名的苯并二氮卓是自1960年代以来就已经存在的安眠药“地西ep”。然而，在过去的十年中，新的，更强大的，更强大，非法和危险的苯二氮卓类药物出现了，例如埃蒂佐拉姆和阿普唑仑。它们的外表与死亡人数大幅增长相吻合，尤其是在苏格兰。苯二氮卓类药物会导致昏迷和呼吸减速，有时会停止，尤其是在服用阿片类药物时。一个非常好的解毒剂，称为纳洛酮，可用于阿片类药物中毒。现在，通过救护车医护人员或朋友和亲属使用毒品的人的亲戚将患者注入肌肉之前，现在可以在患者上医院前使用这种情况。肌肉路线最好，因为它不需要专业技能。政府已将这种解毒剂引入了广泛的社区使用中，从而挽救了许多生命。受过训练的旁观者将解毒剂注射到发现失去知觉的人中，救出呼吸并预防死亡。存在类似的解毒剂，用于苯二氮卓类药物过量，称为氟马兹尼尔。不幸的是，这种药物不适用于这种过量药物，因为在1980年代，它与服用多种药物的失去知觉患者后，它与癫痫发作（癫痫病）有关。临床医生担心引起癫痫发作。但是，大多数患者服用了抗抑郁药（例如一种称为阿米替林）和苯二氮卓类药物。引起癫痫发作的是抗抑郁药。幸运的是，这种类型的药物现在被少了很多常见，尤其是在1980年常见的高剂量。但是，数量增加的毒品死亡表明，我们迫切需要找出氟马兹尼菌是否实际上是危险的，或者是否可以在社区中安全地使用它，以阻止这些死亡。重要的是，我们在安全的环境中测试flumazenil，在安全的环境中进行任何癫痫发作的癫痫发作都可以得到很好的处理。因此，我们建议在4个急诊医学部门进行一项初步研究，这些研究熟悉照顾生病的患者并处理癫痫发作。这项研究将测试通过注射肌肉给予患者的flumazenil是否会唤醒患者以及它的常见癫痫发作。第一阶段将使昏迷的患者（被认为受苯二氮卓类药物过多影响），会增加肌肉内（IM）路线是否有效的剂量的flumazenil剂量。一旦确定了2种有效剂量，我们将不flumazenil或两种有效剂量之一给予类似的患者（随机）。这将使我们更好地了解Im flumazenil的工作状况。在本文中，我们将随机分配患者或盐水盐水，以查看flumazenil引起癫痫发作的频率。总共将在三个阶段研究635名患者。我们预测，氟马兹尼尔将在不到3％的患者中引起癫痫发作，这将被患者和临床医生认为可以接受 - 希望flumazenil挽救生命。如果成功的话，在我们的下一阶段，我们将使用数据与救护车设计一项研究，以查看当护理人员首先遇到社区中的昏迷患者时是否可以安全地给予它。政府的纳洛酮政策挽救了许多生命；现在，迫切需要探索在患者到达医院之前是否使用flumazenil是否可以解决英国的毒品死亡危机并挽救更多生命。