NMDA-receptor antagonists in neuropathic pain: experimental methods to clinical trials

Recent clinical data suggest that chronic pain due to nerve or soft tissue injury may result in the sensitization of the central nervous system, mediated in part by the excitatory amino acids, glutamate and aspartate. Only a handful of N-methyl-D-aspartate antagonists are clinically available. These include ketamine, dextromethorphan, memantine, and amantadine, as well as three clinically used opioids (methadone, dextropropoxyphene, and ketobemidone). This review summarizes the single-dose efficacy of the first two compounds in the treatment of experimental and neuropathic pain. In all examples presented here, NMDA-receptor antagonists with affinity at the phencyclidine site have been shown to modulate pain and hyperalgesia but are limited by dose-limiting side effects. Thus, provided their therapeutic ratio is favorable, NMDA-receptor antagonists may be effective in the treatment of some types of chronic pain.