Pharmacokinetic and pharmacodynamic considerations for NMDA receptor antagonists in the treatment of chronic neuropathic pain.

INTRODUCTION: Chronic neuropathic pain is a debilitating disease caused by a lesion of the somatosensory nervous system. The N-methyl-D-aspartate receptor (NMDAR) plays an important role in the development of this pain state. Proof of efficacy of NMDAR inhibitors in treating neuropathic pain is limited, with the non-selective NMDAR antagonist ketamine being most effective. AREAS COVERED: This review discusses the efficacy of subanesthetic doses of ketamine in alleviating chronic neuropathic pain, and highlights its pharmacokinetics and dynamics. The reader will understand under which treatment conditions ketamine is most effective, and through which mechanisms ketamine acts to induce long-term pain relief. The reader will gain an understanding of ketamine's complex metabolism and the role of its metabolite norketamine. Possible future alternatives for ketamine are discussed aimed at blockade of the subunit of the NMDAR involved in spinal and supraspinal pain pathways (NR2B). EXPERT OPINION: More proof from good-quality randomized clinical trials on the efficacy of NMDAR inhibitors is required. A major advantage of ketamine therapy is the ability of the molecule to induce rapid and potent antidepressant effects. This is relevant taken the fact that chronic pain and depression are closely linked and are often present in the same patient.