The scarcity and limited risk/benefit ratio of painkillers available on the market, in addition to the opioid crisis, warrant reflection on new innovation strategies. The pharmacopoeia of analgesics is based on products that are often old and derived from clinical empiricism, with limited efficacy or spectrum of action, or resulting in an unsatisfactory tolerability profile. Although they are reference analgesics for nociceptive pain, opioids are subject to the same criticism. The use of opium as an analgesic is historical. Morphine was synthesized at the beginning of the 19th century. The efficacy of opioids is limited in certain painful contexts and these drugs can induce potentially serious and fatal adverse effects. The current North American opioid crisis, with an ever-rising number of deaths by opioid overdose, is a tragic illustration of this. It is therefore legitimate to develop research into molecules likely to maintain or increase opioid efficacy while improving their tolerability. Several avenues are being explored including targeting of the mu opioid receptor (MOR) splice variants, developing biased agonists or targeting of other receptors such as heteromers with MOR. Ion channels acting as MOR effectors, are also targeted in order to offer compounds without MOR-dependent adverse effects. Another route is to develop opioid analgesics with peripheral action or limited central nervous system (CNS) access. Finally, endogenous opioids used as drugs or compounds that modify the metabolism of endogenous opioids (Dual ENKephalinase Inhibitors) are being developed. The aim of the present review is to present these various targets/strategies with reference to current indications for opioids, concerns about their widespread use, particularly in chronic non-cancer pains, and ways of limiting the risk of opioid abuse and misuse.

中文翻译：

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专注于MOR相关策略的当前类阿片药物的替代。

除阿片类药物危机外，市场上止痛药的稀缺性和有限的风险/收益比，值得反思新的创新策略。止痛药的药典基于的产品通常是陈旧的，并且来源于临床经验，疗效或作用范围有限，或者导致耐受性不理想。尽管阿片类药物是镇痛的参考镇痛药，但它们也受到同样的批评。使用鸦片作为止痛药是历史悠久的。吗啡是在19世纪初合成的。在某些痛苦的情况下，阿片类药物的疗效有限，这些药物可能会引起潜在的严重和致命的不良反应。当前的北美阿片类药物危机，过量服用阿片类药物导致死亡人数不断上升，是对此的悲惨例证。因此，有可能对可能维持或增加阿片样物质功效同时改善其耐受性的分子进行研究。正在探索几种途径，包括靶向阿片类阿片受体（MOR）剪接变体，发展有偏向的激动剂或靶向其他受体（例如与MOR杂合的异构体）。还以充当MOR效应子的离子通道为目标，以提供没有MOR依赖性副作用的化合物。另一种途径是开发具有外周作用或中枢神经系统（CNS）通路受限的阿片类镇痛药。最后，正在开发用作药物或修饰内源性阿片类药物代谢的内源性阿片类药物（双重ENKephalinase抑制剂）。