Clinical concepts and commentary.

AS part of the effort to develop mechanisms-based approaches to pain therapy, renewed interest has focused on the use of ketamine for treatment of acute and chronic pain. In particular, the role of N-methyl-D-aspartate (NMDA) excitatory glutamate receptors in nociceptive transmission has been established in humans. NMDA receptors participate in the development and maintenance of what can be called “pathologic pain” after tissue injury: increased pain perception as a result of pain sensitization, in part from synaptic plasticity. Ketamine binds noncompetitively to the phencyclidine binding site of NMDA receptors but also modifies them via allosteric mechanisms. When studied at subanesthetic doses, its analgesic efficacy correlates well with its inhibiting action on NMDA receptor-mediated pain facilitation and a decrease in activity of brain structures that respond to noxious stimuli. Ketamine therefore represents a promising modality in several perioperative strategies to prevent pathologic pain. Another reason for the renewed interest in ketamine is the availability of S( ) ketamine. Ketamine has a chiral center at the carbon-2 atom of the cyclohexanone ring, and therefore exists as the optical stereoisomers S( ) and R(-) ketamine. Until recently, ketamine was marketed as a racemate, containing equimolar amounts of the enantiomers. S( ) ketamine has a fourfold greater affinity for NMDA receptors than does R(-) ketamine. This difference results in a clinical analgesic potency of S( ) ketamine approximately two times greater than that of racemic and four times greater than that of R(-) ketamine, whereas S( ) ketamine has a shorter duration of action. We discuss the perioperative use of ketamine as an adjunct to general and regional anesthesia and to postoperative pain therapy. Focus will be on the administration of the drug at subanesthetic concentrations; we will refer to this as “subanesthetic ketamine.” Anti-nociceptive Therapy with Ketamine during Anesthesia