A reappraisal of the mechanisms of action of ketamine to treat complex regional pain syndrome in the light of cortical excitability changes.

OBJECTIVE: To evaluate the changes in glutamate/GABA balance of intracortical excitability produced by ketamine, delivered at subanaesthetic dose to treat patients with complex regional pain syndrome (CRPS). METHODS: In 19 patients with CRPS, we assessed the effect of a 5-day ketamine protocol on various clinical aspects, including pain and depression, and on cortical excitability parameters provided by transcranial magnetic stimulation testing. RESULTS: The rest motor threshold (RMT) and the amplitude of the motor evoked potentials at 120% of RMT were not modified after ketamine therapy. In contrast, ketamine reduced intracortical facilitation (ICF) in both hemispheres and increased short-interval intracortical inhibition (SICI), which was defective at baseline only in the hemisphere corresponding to the painful side. These changes positively correlated with pain relief. CONCLUSION: This study shows for the first time that the remarkable analgesic effects produced by ketamine in CRPS patients is associated with cortical excitability changes in favour of an enhanced GABAergic transmission in the hemisphere corresponding to the painful side and an overall reduction of excitability in the contralateral hemisphere. SIGNIFICANCE: Analgesic effects of ketamine cannot be resumed to its classical antigutamatergic action related to N-methyl-d-aspartate receptor blockade.

Three-phase Bone Scintigraphy Can Predict the Analgesic Efficacy of Ketamine Therapy in CRPS.

OBJECTIVES: The efficacy of ketamine in relieving complex regional pain syndrome (CRPS) lacks predictive factors. The value of three-phase bone scintigraphy (TPBS) was assessed for this purpose. MATERIALS AND METHODS: TPBS was performed in 105 patients with unilateral, focal CRPS of type 1 before 5 days of ketamine infusions. Tracer uptake was measured in the region of interest concerned by CRPS and the contralateral homologous region. For the 3 scintigraphic phases (vascular, tissular, and bone phases), an asymmetry ratio of fixation was calculated between the affected and the unaffected sides (vascular phase [VPr], tissular phase [TPr], and bone phase [BPr]). Ketamine efficacy was assessed on pain intensity scores. RESULTS: Ketamine-induced pain relief did not correlate with VPr, TPr, and BPr, but with the ratios of these ratios: BPr/TPr (r=0.32, P=0.009), BPr/VPr (r=0.34, P=0.005), and TPr/VPr (r=0.23, P=0.02). The optimum cut-off value for predicting the response to ketamine therapy was >1.125 for BPr/TPr, >1.075 for BPr/VPr, and >0.935 for TPr/VPr. The combination of increased values of BPr/TPr, BPr/VPr, and TPr/VPr was highly significantly associated with ketamine therapy outcome. CONCLUSIONS: The relative hyperfixation of the radioactive tracer in the limb region concerned by CRPS in phases 2 and 3 versus phase 1 of TPBS correlated positively to the analgesic efficacy of ketamine. This study shows for the first time the potential predictive value of TPBS regarding ketamine therapy outcome. In addition, these results suggest that the analgesic action of ketamine is not restricted to "central" mechanisms, but may also involve "peripheral" mechanisms related to tissue inflammation and bone remodeling.