The NMDA receptor in opioid-induced hyperalgesia: From neuroplasticity to perioperative prevention- Narrative review

Abstract

Importance. Opioid-induced hyperalgesia (OIH) is a paradoxical increase in nociceptive sensitivity attributable to opioid exposure. In the perioperative period, recognition is difficult because pain from surgical injury, inadequate analgesia, pharmacological tolerance, and acute withdrawal produce overlapping phenotypes. Remifentanil is the most extensively investigated clinical model because it combines high potency, rapid titratability, and abrupt offset after infusion cessation. Objective. To examine the N-methyl-D-aspartate (NMDA) receptor as a point of convergence between opioid signalling, glutamatergic transmission, and pronociceptive neuroplasticity, and to critically appraise perioperative strategies intended to modulate this pathway. Observations. NMDA receptor activation requires the coincident binding of glutamate and glycine or D-serine, postsynaptic depolarisation, and relief of voltage-dependent Mg²⁺ block. The resulting Ca²⁺ influx activates protein kinase C, Ca²⁺/calmodulin-dependent protein kinase II, and transcriptional pathways that promote receptor phosphorylation and trafficking, long-term potentiation, descending facilitation, and central sensitisation. Glial activation, cytokines, and the NLRP3 inflammasome may further amplify this network. Ketamine and magnesium have the most direct mechanistic relationship with the NMDA receptor; methadone, dexmedetomidine, amantadine, buprenorphine, and regional analgesia offer complementary mechanisms. However, reductions in postoperative pain or opioid consumption do not, in isolation, demonstrate prevention of OIH. Clinical evidence remains limited by inconsistent definitions, heterogeneous comparators, small samples, and infrequent use of quantitative sensory testing (QST). Conclusions and Relevance. Prevention should be individualised and multimodal: avoid unnecessarily high opioid exposure, establish an analgesic bridge before discontinuing remifentanil, reduce nociceptive input, and reserve NMDA-modulating interventions for settings in which the anticipated benefit outweighs the risk. The NMDA receptor is a biologically coherent therapeutic target, but it is neither a diagnostic marker nor an exclusive explanation for OIH.