Flynn Shawn M, France Charles P
Department of Pharmacology (S.M.F., C.P.F.), Department of Psychiatry (C.P.F.), and Addiction Research, Treatment, and Training Center of Excellence (S.M.F., C.P.F.), University of Texas Health Science Center at San Antonio, San Antonio, Texas.
Department of Pharmacology (S.M.F., C.P.F.), Department of Psychiatry (C.P.F.), and Addiction Research, Treatment, and Training Center of Excellence (S.M.F., C.P.F.), University of Texas Health Science Center at San Antonio, San Antonio, Texas
J Pharmacol Exp Ther. 2022 Mar;380(3):171-179. doi: 10.1124/jpet.121.000912. Epub 2021 Dec 13.
Drug overdose deaths involving synthetic opioids, primarily fentanyl, have risen dramatically over the past decade and are currently the driving force of the opioid epidemic in the United States. Fentanyl analogs with greater potency than fentanyl (e.g., carfentanil) pose serious risk to public health. Although fentanyl analogs are primarily encountered by humans as constituents of a mixture of drugs, research has primarily evaluated the effects of these drugs alone. The present study characterized interactions between opioid receptor agonists in seven male Sprague-Dawley rats trained to discriminate 10 g/kg fentanyl from saline while responding under a fixed-ratio 10 schedule of food presentation. Dose-effect curves were determined for each drug alone and in binary mixtures (fentanyl:heroin, fentanyl:carfentanil, and heroin:carfentanil) at fixed-dose ratios of 3:1, 1:1, and 1:3 relative to the ED for each drug when given alone. Dose addition analyses were used to determine the nature of the drug-drug interaction for each mixture. Additive interactions were observed for all binary mixtures at each fixed dose ratio, except the 1:3 fentanyl:carfentanil mixture, which exhibited supra-additive effects at the 80% effect level. These results suggest a lack of a significant interaction between the discriminative stimulus effects of these opioid receptor agonists at the doses tested in this study. Future studies expanding these findings to the respiratory depressant effects of these drugs are of significant importance to rule out possible interactions directly relevant to opioid overdose that occur at doses much larger than those tested in this study. SIGNIFICANCE STATEMENT: In the United States, drug overdose deaths involving synthetic opioids, primarily fentanyls including superpotent fentanyl analogs (e.g., carfentanil), have increased 12-fold over the past decade. Although previous studies have evaluated the effects of carfentanil alone, fentanyl analogs are encountered by humans as a mixture with other drugs; this study determined the effects of mixtures of carfentanil and other opioids (fentanyl and heroin) to characterize interactions between these drugs that might contribute to their apparent increased lethality in humans.
在过去十年中，涉及合成阿片类药物（主要是芬太尼）的药物过量死亡人数急剧上升，目前是美国阿片类药物流行的驱动力。效力比芬太尼更强的芬太尼类似物（如卡芬太尼）对公众健康构成严重风险。尽管芬太尼类似物主要作为药物混合物的成分被人类接触到，但研究主要评估的是这些药物单独的作用效果。本研究对7只雄性斯普拉格-道利大鼠进行了特征描述，这些大鼠经过训练，在固定比例为10的食物呈现时间表下做出反应时，能够区分10毫克/千克的芬太尼和生理盐水。分别测定了每种药物单独以及以相对于每种药物单独给药时的半数有效剂量（ED）的固定剂量比3:1、1:1和1:3形成的二元混合物（芬太尼：海洛因、芬太尼：卡芬太尼以及海洛因：卡芬太尼）的剂量-效应曲线。采用剂量相加分析来确定每种混合物中药物-药物相互作用的性质。在每个固定剂量比下，所有二元混合物均观察到相加相互作用，但1:3的芬太尼：卡芬太尼混合物在80%效应水平时表现出超相加效应。这些结果表明，在本研究测试的剂量下，这些阿片受体激动剂的辨别刺激效应之间缺乏显著的相互作用。将这些发现扩展到这些药物的呼吸抑制作用的未来研究对于排除在比本研究测试剂量大得多的剂量下发生的、与阿片类药物过量直接相关的可能相互作用具有重要意义。重要声明：在美国，过去十年中，涉及合成阿片类药物（主要是包括超强效芬太尼类似物（如卡芬太尼）在内的芬太尼）的药物过量死亡人数增加了12倍。尽管先前的研究评估了卡芬太尼单独的作用效果，但人类接触到的芬太尼类似物是与其他药物的混合物；本研究确定了卡芬太尼与其他阿片类药物（芬太尼和海洛因）混合物的作用效果，以描述这些药物之间可能导致其在人类中明显更高致死率的相互作用。
