Chronic pain can be maintained by a state of sensitization within the central nervous system that is mediated in part by the excitatory amino acids glutamate and aspartate binding to the N-methyl-D-aspartate (NMDA) receptor. A number of antagonists to the NMDA receptor are antinociceptive in animal models but are associated with significant dose-limiting side effects. Commercially available NMDA-receptor antagonists include ketamine, dextromethorphan, memantine, and amantadine. The opioids methadone, dextropropoxyphene, and ketobemidone are also antagonists at the NMDA receptor. The NMDA-receptor antagonists have a significant impact on the development of tolerance to opioid analgesics. Consequently, NMDA-receptor antagonists may represent a new class of analgesics and may have potential as coanalgesics when used in combination with opioids.