N-Methyl-D-aspartate receptor antagonists for the prevention of chronic postsurgical pain: a narrative review

The N-methyl-D-aspartate receptor (NMDAR) has been linked to the development of chronic postsurgical pain (CPSP), defined as pain after surgery that does not resolve by 3 months. Once the combination of a painful stimulus and glutamate binding activates the NMDAR, calcium influx triggers signaling cascades that lead to processes like central sensitization and CPSP. Three of the most widely studied perioperative NMDAR antagonists include ketamine, magnesium, and methadone, with ketamine having garnered the greatest amount of attention. While multiple studies have found improved analgesia in the acute postoperative period, fewer studies have focused on long-term outcomes and those that have are often underpowered for CPSP or have not included those patients at highest risk. Existing meta-analyses of ketamine for CPSP are inconsistent in their findings, and studies of magnesium and methadone are even more limited. Overall, the evidence supporting NMDAR antagonists for CPSP is weak and we recommend that future studies focus on high-risk patients and potentially include combinations of NMDAR antagonists administered together for the longest duration feasible. The results of ongoing trials could have a major influence on the overall direction of the evidence supporting NMDAR antagonists in preventing CPSP.