The N-methyl-D-aspartate (NMDA) receptor and its activation is intimately involved in the pathological processes of wind-up, central sensitization, hyperalgesia, allodynea, and reduced opioid effectiveness (tolerance) (Dickenson 1994). Unfortunately, there are few NMDA receptor antagonists available to us clinically.
Recent advances in the understanding of postoperative pain have demonstrated its association with sensitization of the CNS which clinically elicits pain hypersensitivity. NMDA receptors play a major role in synaptic plasticity and are specifically implicated in CNS facilitation of pain processing. Therefore, NMDA receptor antagonists, and specifically ketamine, have been employed in clinical practice at subanesthetic (i.e., low) doses to exert a specific NMDA blockade and hence modulate central sensitization induced both by the incision and tissue damage and by perioperative analgesics such as opioids (Kock and Lavand'homme 2007).
Ketamine is probably the best known agent which is used primarily as an intravenous anesthetic. In subanesthetic doses it has been shown to inhibit or reverse acute opioid tolerance and can enhance opioid analgesia (Ellers et al. 2001). It has also been successfully used combined with morphine in PCA to decrease opioid requirements (Svedicic et al. 2003).
Dextromethorphan is an antitussive found in many cough medications. However it has been found to have antinociceptive effects and can attenuate acute pain sensation through antagonistic effects on the NMDA receptor (Weinbrown et al. 2000). It is available in oral form; however, at doses necessary to produce adequate pain relief (up to 100 mg qid) it can be too sedating and poorly tolerated by patients at that dose.
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