Mechanisms of Remifentanil-Induced Postoperative Hyperalgesia: A Comprehensive Review

Abstract

Remifentanil, a widely used ultra-short-acting μ-opioid receptor agonist in clinical anesthesia, is strongly associated with postoperative hyperalgesia (remifentanil-induced hyperalgesia, RIH), posing significant challenges to postoperative pain management. RIH is characterized by an abnormally heightened pain perception following opioid withdrawal, and its underlying mechanisms are complex and multifactorial. Current research highlights the roles of central sensitization, peripheral sensitization, and multiple interacting molecular pathways. These include NMDA receptor activation, glial cell activation, neuroinflammation, disinhibition of inhibitory neurotransmission, and dysfunction of the descending pain modulation system. Additionally, alterations in ion channel expression, synaptic plasticity enhancement, and peripheral responses to inflammatory mediators contribute critically to RIH development. Individual factors such as age, sex, genetic polymorphisms, and surgical type significantly influence the risk of RIH. Although substantial progress has been made in elucidating the molecular mechanisms of RIH, a unified theoretical framework and effective clinical strategies remain lacking. Future studies should emphasize multi-omics approaches and clinically relevant experimental models to uncover key regulatory targets and provide a theoretical basis for individualized analgesic interventions.