Streicher John M, Bilsky Edward J
Department of Pharmacology, University of Arizona College of Medicine, Tucson, AZ, USA.
Pacific Northwest University of Health Sciences, Yakima, WA, USA.
J Pharm Pract. 2018 Dec;31(6):658-669. doi: 10.1177/0897190017732263. Epub 2017 Sep 25.
Opioid receptors are distributed throughout the central and peripheral nervous systems and on many nonneuronal cells. Therefore, opioid administration induces effects beyond analgesia. In the enteric nervous system (ENS), stimulation of µ-opioid receptors triggers several inhibitory responses that can culminate in opioid-induced bowel dysfunction (OBD) and its most common side effect, opioid-induced constipation (OIC). OIC negatively affects patients' quality of life (QOL), ability to work, and pain management. Although laxatives are a common first-line OIC therapy, most have limited efficacy and do not directly antagonize opioid effects on the ENS. Peripherally acting µ-opioid receptor antagonists (PAMORAs) with limited ability to cross the blood-brain barrier have been developed. The PAMORAs approved by the U S Food and Drug Administration for OIC are subcutaneous and oral methylnaltrexone, oral naloxegol, and oral naldemedine. Although questions of cost-effectiveness and relative efficacy versus laxatives remain, PAMORAs can mitigate OIC and improve patient QOL. PAMORAS may also have applications beyond OIC, including reducing the increased cardiac risk or potential tumorigenic effects of opioids. This review discusses the burden of OIC and OBD, reviews the mechanism of action of new OIC therapies, and highlights other potential opioid-related side effects mediated by peripheral opioid receptors in the context of new OIC therapies.
阿片受体分布于中枢和外周神经系统以及许多非神经元细胞上。因此，使用阿片类药物会产生镇痛以外的其他作用。在肠神经系统（ENS）中，μ-阿片受体的刺激会引发多种抑制反应，最终可能导致阿片类药物引起的肠功能障碍（OBD）及其最常见的副作用——阿片类药物引起的便秘（OIC）。OIC会对患者的生活质量（QOL）、工作能力和疼痛管理产生负面影响。尽管泻药是治疗OIC的常见一线药物，但大多数疗效有限，且不能直接拮抗阿片类药物对肠神经系统的作用。已开发出能够透过血脑屏障的能力有限的外周作用μ-阿片受体拮抗剂（PAMORAs）。美国食品药品监督管理局批准用于治疗OIC的PAMORAs有皮下注射和口服的甲基纳曲酮、口服的纳洛西醇和口服的纳地美定。尽管在成本效益以及与泻药相比的相对疗效方面仍存在问题，但PAMORAs可以减轻OIC并改善患者的生活质量。PAMORAs可能还有除OIC之外的其他应用，包括降低阿片类药物增加的心脏风险或潜在的致瘤作用。本综述讨论了OIC和OBD的负担，回顾了新型OIC治疗的作用机制，并在新型OIC治疗的背景下强调了由外周阿片受体介导的其他潜在阿片类药物相关副作用。
