Addressing opioid tolerance and opioid-induced hypersensitivity: Recent developments and future therapeutic strategies.

Faris Khan,Aman Mehan

doi:10.1002/prp2.789

Abstract

Opioids are a commonly prescribed and efficacious medication for the treatment of chronic pain but major side effects such as addiction, respiratory depression, analgesic tolerance, and paradoxical pain hypersensitivity make them inadequate and unsafe for patients requiring long‐term pain management. This review summarizes recent advances in our understanding of the outcomes of chronic opioid administration to lay the foundation for the development of novel pharmacological strategies that attenuate opioid tolerance and hypersensitivity; the two main physiological mechanisms underlying the inadequacies of current therapeutic strategies. We also explore mechanistic similarities between the development of neuropathic pain states, opioid tolerance, and hypersensitivity which may explain opioids’ lack of efficacy in certain patients. The findings challenge the current direction of analgesic research in developing non‐opioid alternatives and we suggest that improving opioids, rather than replacing them, will be a fruitful avenue for future research.

Highlights

Pain is “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”[1]
Opioid use is associated with side effects that become more severe with increased use, for example, severe drowsiness and breathing difficulties
Decreasing analgesic efficacy is observed clinically with prolonged use of any strong opioid; this is a combination of tolerance to their analgesic effect and the development of opioid-induced hypersensitivity (OIH) within pain signaling pathways

Summary

| INTRODUCTION

Pain is “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”[1]. A range of experimental G- protein/βarr[2] biased MOR agonists has been developed and tested in mouse models, with the hope that there may be an optimum ratio of G-protein:B-arrestin signaling that would result in an “improved” opioid.[124] Bias is related to different conformational states of the receptor, triggered by structural variations of the ligand and the transducers present.[125] Agonists highly biased toward G-proteins with poor recruitment of B-arrestin[2] appear to have more favorable properties, including higher antinociceptive potential and attenuated development of tolerance One such MOR G-protein-biased ligand, TRV130, was shown to cause less GI dysfunction and respiratory depression than morphine at equianalgesic doses in rats.[121] Preclinical data of TRV130 suggested it may be a safer and less tolerant prone opioid for treating chronic pain. Peripherally restricted opioids do not appear to offer the same level of analgesic coverage for painful conditions as centrally acting

Role in analgesia

Suitable pharmacological target?

| CONCLUSION