Perioperative opioid analgesia-when is enough too much? A review of opioid-induced tolerance and hyperalgesia

Opioids are a mainstay of acute pain management but can have many adverse effects, contributing to problematic long-term use. Opioid tolerance (increased dose needed for analgesia) and opioid-induced hyperalgesia (paradoxical increase in pain with opioid administration) can contribute to both poorly controlled pain and dose escalation. Hyperalgesia is particularly problematic as further opioid prescribing is largely futile. The mechanisms of opioid tolerance and hyperalgesia are complex, involving mu opioid receptor signalling pathways that offer opportunities for novel analgesic alternatives. The intracellular scaffold protein beta-arrestin-2 is implicated in tolerance, hyperalgesia, and other opioid side-effects. Development of agonists biased against recruitment of beta-arrestin-2 could provide analgesic efficacy with fewer side-effects. Alternative approaches include inhibition of peripheral mu opioid receptors and blockade of downstream signalling mechanisms, such as the non-receptor tyrosine kinase Src or N-methyl-D-aspartate receptors. Furthermore, it is prudent to use multimodal analgesic regimens to reduce reliance on opioids during the perioperative period. In the third paper in this Series we focus on clinical and mechanism-based understanding of tolerance and opioid-induced hyperalgesia, and discuss current and future strategies for pain management.