Skolnick Phil, Paavola Jordan, Heidbreder Christian
Indivior, Inc., N, Chesterfield, VA 23235, United States.
Drug Alcohol Depend Rep. 2024 Aug 13;12:100268. doi: 10.1016/j.dadr.2024.100268. eCollection 2024 Sep.
More than 90 % of opioid overdose deaths in North America are now caused by synthetic opioids, and while they are not as prevalent in the European illicit drug market, there are indications that they may become so in the near future. Multiple publications have argued that neither higher doses of naloxone nor more potent opioid receptor antagonists are needed to reverse a synthetic opioid overdose. However, the unique physicochemical properties of synthetic opioids result in a very rapid onset of respiratory depression compared to opium-based molecules, reducing the margin of opportunity to reverse an overdose. While intravenous administration rapidly delivers the high naloxone concentrations needed to reverse a synthetic opioid overdose, this option is often unavailable to first responders. A translational mechanistic model of opioid overdose developed by the FDA's Division of Applied Regulatory Science provides an unbiased approach to evaluate the effectiveness of overdose reversal strategies. Reports using this model demonstrated the naloxone tools (2 mg intramuscular and 4 mg intranasal) used by many first responders can result in an unacceptable loss of life following a synthetic opioid (fentanyl, carfentanil) overdose. Moreover, sequential (2.5 minutes between doses) administration of up to four doses of intranasal naloxone was no more effective at reducing the incidence of cardiac arrest (a surrogate endpoint for lethality) than a single dose, suggesting that attempts at titration may not provide the rapid absorption required to reverse a synthetic opioid overdose. This model was also used to compare the effectiveness of intranasal naloxone to intranasal nalmefene, a recently FDA-approved opioid receptor antagonist with a more rapid absorption and a higher affinity at mu-opioid receptors compared to intranasal naloxone. Intranasal nalmefene resulted in large and clinically meaningful reductions in the incidence of cardiac arrest compared to intranasal naloxone. Furthermore, simultaneous administration of four doses of intranasal naloxone was needed to reduce the incidence of cardiac arrest to levels approaching those produced by a single dose of intranasal nalmefene. These data are consistent with evidence that synthetics have indeed disrupted conventional wisdom in the treatment of opioid overdose.
目前，北美地区超过90%的阿片类药物过量致死案例是由合成阿片类药物导致的。虽然它们在欧洲非法毒品市场上并不那么普遍，但有迹象表明，在不久的将来它们可能会变得普遍起来。多篇出版物认为，逆转合成阿片类药物过量并不需要更高剂量的纳洛酮或更强效的阿片受体拮抗剂。然而，与基于鸦片的分子相比，合成阿片类药物独特的物理化学性质导致呼吸抑制起效非常迅速，减少了逆转过量用药的机会窗口。虽然静脉注射能迅速提供逆转合成阿片类药物过量所需的高浓度纳洛酮，但急救人员往往无法采用这种方式。美国食品药品监督管理局应用监管科学司开发的阿片类药物过量转化机制模型提供了一种无偏见的方法来评估过量用药逆转策略的有效性。使用该模型的报告表明，许多急救人员使用的纳洛酮工具（2毫克肌肉注射和4毫克鼻内给药）在合成阿片类药物（芬太尼、卡芬太尼）过量后可能会导致不可接受的生命损失。此外，连续（剂量间隔2.5分钟）给予多达四剂鼻内纳洛酮在降低心脏骤停（致死率的替代终点）发生率方面并不比单剂量更有效，这表明滴定给药可能无法提供逆转合成阿片类药物过量所需的快速吸收。该模型还用于比较鼻内纳洛酮与鼻内纳美芬的有效性，纳美芬是美国食品药品监督管理局最近批准的一种阿片受体拮抗剂，与鼻内纳洛酮相比，其吸收更快，对μ-阿片受体的亲和力更高。与鼻内纳洛酮相比，鼻内纳美芬使心脏骤停的发生率大幅降低，且具有临床意义。此外，需要同时给予四剂鼻内纳洛酮才能将心脏骤停的发生率降低到接近单剂量鼻内纳美芬所产生的水平。这些数据与以下证据一致，即合成阿片类药物确实打破了阿片类药物过量治疗的传统观念。
