Designing safer analgesics: a focus on μ-opioid receptor pathways

Introduction: The recent dramatic increase in intentional and unintentional deaths attributed to opioids has refocused attention on the therapeutic ratio (risk-benefit ratio) of opioid analgesics. Almost all traditional opioid analgesics produce their effects (therapeutic and adverse) via the activation of mu-opioid receptor (MOR) pathways. It is therefore important to examine the question of whether this natural endogenous pathway can still be activated, but with greater safety. Areas covered: Other comprehensive reviews have focused on pharmacokinetic (e.g. peripheral restriction) and pharmacodynamic (e.g. functional selectivity, biased ligand) approaches. Herein, the authors focus on a different approach, specifically, multi-mechanistic 'atypical opioids' that synergistically combines MOR activation plus one or more non-opioid mechanism of analgesic action. Expert opinion: Four 'atypical opioid' analgesics on the market act as mu-opioid receptor pathway agonists but have a non-opioid mechanism of action that significantly contributes to the analgesic effect. The multi-mechanistic action of these products confers particular clinical utility in that they provide effective analgesia with relatively lower opioid load, and they are generally associated with fewer or less severe opioid-related adverse effects and less abuse compared to traditional opioid analgesics.