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

The N-methyl-D-aspartate receptor (NMDAR) is linked to chronic postsurgical pain (CPSP), pain persisting beyond three months after surgery. Activation of NMDAR by painful stimuli and glutamate triggers calcium influx and signaling cascades leading to central sensitization and CPSP. The most studied perioperative NMDAR antagonists—ketamine, magnesium, and methadone—show improved acute postoperative analgesia, but evidence for preventing CPSP is weak. Few studies examine long-term outcomes, and those that do are often underpowered or exclude high-risk patients. Meta-analyses of ketamine for CPSP yield inconsistent findings; data on magnesium and methadone are even more limited. Future research should focus on high-risk patients and combinations of antagonists given for the longest feasible duration.

Study at a glance

Abstract

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.