OPIOID ANALGESICS AS NONCOMPETITIVE N-METHYL-D-ASPARTATE (NMDA) ANTAGONISTS

Much evidence points to the involvement of N-methyl-D-aspartate (NMDA) receptors in the development and maintainance of neuropathic pain. In neuropathic pain, there is generally involved a presumed opioid-insen sitive component, which apparently can be blocked by NMDA receptor ant agonists. However, in order to obtain complete analgesia, a combinatio n of an NMDA receptor antagonist and an opioid receptor agonist is nee ded. Recent in vitro data have demonstrated that methadone, ketobemido ne, and dextropropoxyphene, in addition to being opioid receptor agoni sts, also are weak noncompetitive NMDA receptor antagonists. Clinical anecdotes suggest that the NMDA receptor antagonism of these opioids m ay play a significant role in the pharmacological action of these comp ounds; however, no clinical studies have been conducted to support thi s issue. In the present commentary, we discuss evidence for the NMDA r eceptor antagonism of these compounds and its relevance for clinical p ain treatment; an overview of structure-activity relationships for the relevant opioids as noncompetitive NMDA receptor antagonists also is given. It is concluded that although the finding that some opioids are weak noncompetitive NMDA receptor antagonists in vitro has created mu ch attention among clinicians, no clinical studies have been conducted to evaluate the applicability of these compounds in the treatment of neuropathic pain conditions. (C) 1998 Elsevier Science Inc.