Replacement of current opioid drugs focusing on MOR-related strategies.

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.

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Declaration of Competing Interest The authors declare that there are no conflicts of interest. We affirm that the manuscript has not been published and is not under consideration for publication elsewhere.