Chaturbedi Anik, Mann John, Chakravartula Shilpa, Thrasher Bradlee, Arabidarrehdor Ghazal, Zirkle Joel, Meshkin Hamed, Nallani Srikanth C, Florian Jeffry, Li Zhihua
Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food & Drug Administration, Silver Spring, Maryland, USA.
Division of Neuropsychiatric Pharmacology, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food & Drug Administration, Silver Spring, Maryland, USA.
Clin Pharmacol Ther. 2025 Mar;117(3):836-845. doi: 10.1002/cpt.3527. Epub 2025 Jan 28.
In response to increased illicit use of synthetic opioids, various μ-receptor antagonist formulations, with varied pharmacological characteristics, have been and are being developed. To understand how pharmacologic characteristics such as absorption rate and clearance rate affect reversal in treating community opioid overdose, we used our previously published translational opioid model. We adapted this model with in vitro receptor binding data and clinical pharmacokinetic data of three intranasal nalmefene formulations along with an intranasal naloxone formulation to study the reversal of fentanyl and carfentanil-induced respiratory depression in chronic opioid users. Nalmefene has a longer plasma half-life and slower unbinding from the μ-receptor compared to naloxone. For a more rapid reversal of acute overdose-induced respiratory depression, a fast-absorbing antagonist formulation may be of greater utility than a slow-absorbing one containing the same dosage of the antagonist. For preventing renarcotization caused by a long opioid exposure, a slow-clearing antagonist with slow unbinding from the receptor may be of value. While a more potent antagonist with a longer half-life may have the potential to facilitate recovery from respiratory depression for overdose with synthetic opioids, such interventions may also lead to longer and more pronounced withdrawal. This emphasizes the need for a nuanced consideration of several facets while choosing a μ-receptor antagonist, dose, and formulation to treat community opioid overdose cases.
针对合成阿片类药物非法使用的增加，已经并正在开发各种具有不同药理学特性的μ受体拮抗剂制剂。为了了解诸如吸收率和清除率等药理学特性如何影响社区阿片类药物过量治疗中的逆转效果，我们使用了我们之前发表的转化性阿片类药物模型。我们将该模型与三种鼻内纳美芬制剂以及一种鼻内纳洛酮制剂的体外受体结合数据和临床药代动力学数据相结合，以研究慢性阿片类药物使用者中芬太尼和卡芬太尼引起的呼吸抑制的逆转情况。与纳洛酮相比，纳美芬具有更长的血浆半衰期和从μ受体解离更慢的特点。对于急性过量引起的呼吸抑制的更快逆转，快速吸收的拮抗剂制剂可能比含有相同剂量拮抗剂的缓慢吸收制剂更有用。对于预防因长期阿片类药物暴露引起的再麻醉，从受体缓慢解离的清除缓慢的拮抗剂可能有价值。虽然半衰期更长的更强效拮抗剂可能有促进合成阿片类药物过量导致的呼吸抑制恢复的潜力，但此类干预措施也可能导致更长时间和更明显的戒断反应。这强调了在选择μ受体拮抗剂、剂量和制剂来治疗社区阿片类药物过量病例时，需要对多个方面进行细致考虑。
