The N-methyl-D-aspartate (NMDA) receptor for glutamate has been implicated in the generation and maintenance of central (spinal) states of hypersensitivity. Thus antagonists at this receptor-channel complex have the potential not to totally abolish pain, but to prevent or block hyperalgesic states induced by tissue damage, inflammation, nerve damage and ischaemia. Information on amplification systems in the spinal cord such as the NMDA receptor is a step towards understanding why and how a painful stimulus is not always related to the response. There are now sufficient controlled clinical studies with agents such as ketamine to believe that, in humans, NMDA mediated events are critical in pathological and/or prolonged pain states. Consequently, use of antagonists may aid the treatment of difficult clinical pains when given alone or in combination with opioids. The combinations of opioids and NMDA antagonists may be especially helpful since some NMDA mediated events can be difficult to control with opioids alone (eg. neuropathic pain states). In addition, the ability of opioids to act presynaptically on C-fibre terminals to reduce transmitter release produces synergistic inhibitions with postsynaptically acting NMDA receptor antagonists. Consequently, low dose combinations may be possible with low side-effect liability. Finally, NMDA receptor activation would appear to be responsible for the generation of nitric oxide and prostanoids which further enhance pain transmission whereas adenosine release acts to control these NMDA mediated events. Thus, further targets for the indirect control of NMDA induced activity are possible.