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

2021年，英国有4390人死于吸毒过量。这些死亡中的大多数是由于使用了阿片类药物，如吗啡和海洛因，通常与一组称为苯二氮卓类药物的药物联合使用。最著名的苯二氮卓类药物是安眠药安定，自20世纪60年代以来一直存在。然而，在过去的10年里，出现了新的、更有效、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。苯二氮类药物会导致昏迷和呼吸减慢，有时甚至停止，特别是与阿片类药物一起服用时。有一种非常好的解毒剂，名为纳洛酮，可用于阿片类药物中毒。现在，在患者到达医院之前，通过救护车护理人员或发现过量用药后陷入困境的吸毒者的朋友和亲属将其注射到肌肉中，这种方法已经被使用。肌肉路径是最好的，因为它不需要专业技能。政府已将这种解毒剂广泛应用于社区，结果拯救了许多人的生命。受过训练的旁观者将解毒剂注射到被发现昏迷的人体内，挽救他们的呼吸，防止死亡。苯二氮卓类药物过量的类似解毒剂也存在，称为氟马西尼。不幸的是，这种药物不能用于这种过量用药，因为在20世纪80年代，给服用了多种药物的昏迷患者服用这种药物后，它与癫痫发作(癫痫发作)有关。临床医生担心会导致癫痫发作。然而，这些患者中的大多数都服用了抗抑郁药(例如一种名为阿米替林的药物)和苯二氮卓类药物。正是这些抗抑郁药导致了癫痫发作。幸运的是，这种药物现在很少使用，特别是在20世纪80年代常见的高剂量下。尽管社区团体试图让医生和护理人员使用氟马西尼，但面对死亡人数的大幅增加，对癫痫的担忧仍然存在，氟马西尼很少使用。然而，药物死亡人数的上升表明，我们迫切需要查明氟马西尼是否确实危险，或者它是否可以在社区中安全使用，以试图阻止这些死亡事件。重要的是，我们应该在安全的环境中测试氟马西尼，在那里，任何癫痫发作都可以得到很好的治疗。因此，我们建议在4个熟悉照顾病人和处理癫痫发作的急诊内科开展初步研究。这项研究将测试肌肉注射氟马西尼是否可以唤醒患者，以及它导致癫痫发作的频率。第一阶段将通过肌肉注射(IM)途径给昏迷的患者(被认为受到过量的苯二氮卓类药物影响)增加剂量的氟马西尼，看看这条路线是否有效。一旦确定了两个有效剂量，我们将(随机)给类似的患者不给氟马西尼或给两个有效剂量中的一个。这将使我们更好地了解肌注氟马西尼的效果。最后，我们将随机分配患者服用一剂氟马西尼或盐水，以观察肌注氟马西尼导致癫痫发作的频率。共有635名患者将在这3个阶段进行研究。我们预测，氟马西尼将导致不到3%的患者癫痫发作，这将被患者和临床医生认为是可以接受的-希望氟马西尼拯救生命。如果成功，在我们下一阶段的工作中，我们将利用这些数据设计一项针对救护车的研究，看看当护理人员第一次在社区遇到昏迷的患者时，是否可以安全地给予这种药物。政府的带回家的纳洛酮政策拯救了许多人的生命；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，拯救更多的生命。

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.