Purpose of Review

Although opioids are excellent analgesics, they are associated with severe short- and long-term side effects that are especially concerning for the treatment of chronic pain. Peripherally acting opioid receptor agonists promise to mitigate the more serious centrally mediated side effects of opioids, and the goal of this paper is to identify and elaborate on recent advances in these peripheral opioid receptor therapeutics.

Recent Findings

Peripheral opioid receptor agonists are effective analgesics that at the same time circumvent the problem of centrally mediated opioid side effects by (1) preferentially targeting peripheral opioid receptors that are often the source of the pain and (2) their markedly diminished permeability or activity across the blood-brain barrier. Recent novel bottom-up approaches have been notable for the design of therapeutics that are either active only at inflamed tissue, as in the case of fentanyl-derived pH-sensitive opioid ligands, or too bulky or hydrophilic to cross the blood-brain barrier, as in the case of morphine covalently bound to hyperbranched polyglycerols.

Summary

Recent innovations in peripheral opioid receptor therapeutics of pH-sensitive opioid ligands and limiting opioid permeability across the blood-brain barrier have had promising results in animal models. While this is grounds for optimism that some of these therapeutics will be efficacious in human subjects at a future date, each drug must undergo individualized testing for specific chronic pain syndromes to establish not only the nuances of each drug’s therapeutic effect but also a comprehensive safety profile.

中文翻译：

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外周阿片受体治疗的最新进展

审查目的

尽管阿片类药物是极好的镇痛剂，但它们与严重的短期和长期副作用有关，尤其是对于慢性疼痛的治疗。外周作用阿片受体激动剂有望减轻阿片类药物更严重的中枢介导的副作用，本文的目标是确定和详细阐述这些外周阿片受体疗法的最新进展。

最近的发现

外周阿片受体激动剂是有效的镇痛剂，同时通过 (1) 优先靶向通常是疼痛来源的外周阿片受体和 (2) 它们的渗透性或活性显着降低，从而避免了中枢介导的阿片副作用问题。血脑屏障。最近新的自下而上的方法以设计仅对发炎组织有效的疗法而著称，例如芬太尼衍生的 pH 敏感阿片类药物配体，或者体积太大或亲水性太大而无法穿过血脑屏障，如吗啡与超支化聚甘油共价结合。

概括

最近在 pH 敏感阿片类配体的外周阿片受体疗法和限制阿片类药物穿过血脑屏障的渗透性方面的创新在动物模型中取得了可喜的成果。虽然有理由乐观地认为，这些疗法中的一些将在未来的日期对人类受试者有效，但每种药物都必须针对特定的慢性疼痛综合征进行个体化测试，以不仅确定每种药物治疗效果的细微差别，而且还确定全面的安全性.