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The clinical role of NMDA receptor antagonists for the treatment of postoperative pain

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Recent advances in the understanding of postoperative pain have demonstrated its association with sensitization of the central nervous system (CNS) which clinically elicits pain hypersensitivity. N-methyl-d-aspartate (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 commonly used in clinical practice, have been implicated in perioperative pain management. At subanesthetic (i.e. low) doses, ketamine exerts a specific NMDA blockade and hence modulates central sensitization induced both by the incision and tissue damage and by perioperative analgesics such as opioids. However, the mechanisms underlying ketamine anti-hyperalgesic effect are not totally understood, and neither is the relationship between central sensitization and the risk of developing residual pain after surgery. This chapter examines the role of low doses of ketamine as an adjuvant drug in current perioperative pain management and questions the anti-hyperalgesic mechanisms involved.

Section snippets

N-methyl-d-aspartate (NMDA) receptor, Ketamine and pain processing

Until recently, the interest in ketamine for pain management has been minimal3, 4, particularly because in postoperative patients ketamine used as the sole analgesic by systemic or spinal route affords only weak pain relief5 while inducing bothersome dysphoric side-effects. Nevertheless, progress in the understanding of pain physiopathology, and specifically postoperative pain, has led to a reconsideration of the interactions between ketamine and pain processing.6, 7

As previously mentioned,

NMDA receptors and postoperative hyperalgesia

What does ‘postoperative hyperalgesia’ mean? Postoperative pain is not, as usually thought, a simple symptom which spontaneously disappears with the completion of the healing process. Postoperative pain is a complex perception, elaborated and modulated at peripheral, spinal and supra-spinal levels, caused by specific physiopathologic mechanisms.22 Postoperative pain involves several neurotransmitter systems that will either facilitate or inhibit nociceptive inputs of somatic, neuropathic,

Ketamine for balanced postoperative analgesia – relationship with opioids

The mechanism of action of NMDA receptor antagonists differs from that of classic analgesics such as opioids. Indeed, NMDA antagonists demonstrate an anti-hyperalgesic effect because they reduce central hyperexcitability (i.e. facilitated response to sensory inputs) without affecting basal nociceptive threshold.15 Therefore, their association with classical analgesics seems particularly useful to improve the management of perioperative pain.

Other NMDA receptors antagonists – clinical alternatives to ketamine

Although ketamine is the most used drug in clinical practice, several other drugs possess NMDA antagonist properties. Among them, dextromethorphan, the D-isomer of the codeine analog levorphanol which is widely prescribed for its central antitussive action, possesses only weak affinity to μ-opioid receptors and has no analgesic effect. In contrast, as a non-competitive NMDA antagonist, the modulatory effect of the drug has been assessed under different experimental conditions involving the

Summary

Postoperative pain is not limited to the processing of nociceptive inputs but is associated with CNS sensitization which clinically elicits pain hypersensitivity and increases pain perception. From current research, it is now evident that sensitization not only results from tissue lesions but can also occur as a consequence of perioperative treatments, i.e. opioid use. Because N-methyl-d-aspartate (NMDA) receptors play a major role in synaptic plasticity and are specifically implicated in CNS

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