Long-term opioid use for chronic pain can lead to tolerance, misuse, and hyperalgesia, making dose reduction difficult, especially when opioid-use disorder is present. Ketamine, an NMDA receptor antagonist with antihyperalgesic effects, may help. In a historical cohort of 59 chronic pain patients with opioid-use disorder who had failed outpatient tapering, a 5-day hospital stay with low-dose ketamine infusion reduced the average daily opioid dose from 207 mg morphine milligram equivalent to 92 mg at discharge and 103 mg at 12 months. Over half of patients achieved more than 50% tapering immediately, and seven stopped entirely. Ketamine was well tolerated with no significant withdrawal symptoms. Controlled studies are needed to confirm these results.
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.