Complex Regional Pain Syndrome Type 1 (CRPS-1) responds poorly to standard pain treatment. We evaluated if the N-methyl-D-aspartate receptor antagonist S(+)-ketamine improves pain in CRPS-1 patients. Sixty CRPS-1 patients (48 females) with severe pain participated in a double-blind randomized placebo-controlled parallel-group trial. Patients were given a 4.2-day intravenous infusion of low-dose ketamine (n=30) or placebo (n=30) using an individualized stepwise tailoring of dosage based on effect (pain relief) and side effects (nausea/vomiting/psychomimetic effects). The primary outcome of the study was the pain score (numerical rating score: 0-10) during the 12-week study period. The median (range) disease duration of the patients was 7.4 (0.1-31.9) years. At the end of infusion, the ketamine dose was 22.2+/-2.0 mg/h/70 kg. Pain scores over the 12-week study period in patients receiving ketamine were significantly lower than those in patients receiving placebo (P<0.001). The lowest pain score was at the end of week 1: ketamine 2.68+/-0.51, placebo 5.45+/-0.48. In week 12, significance in pain relief between groups was lost (P=0.07). Treatment did not cause functional improvement. Patients receiving ketamine more often experienced mild to moderate psychomimetic side effects during drug infusion (76% versus 18%, P<0.001). In conclusion, in a population of mostly chronic CRPS-1 patients with severe pain at baseline, a multiple day ketamine infusion resulted in significant pain relief without functional improvement. Treatment with ketamine was safe with psychomimetic side effects that were acceptable to most patients.

Long-term S(+)-ketamine treatment is effective in causing pain relief in CRPS-1 patients with analgesia outlasting the treatment period by 50 days. These data suggest that ketamine initiated a cascade of events, including desensitization of excitatory receptor systems in the central nervous system, which persisted but slowly abated when ketamine molecules were no longer present.

Background: Low-dose ketamine behaves as an analgesic in the treatment of acute and chronic pain. To further understand ketamine's therapeutic profile, the authors performed a population pharmacokinetic-pharmacodynamic analysis of the S(؉)-ketamine analgesic and nonanalgesic effects in healthy volunteers. Methods: Ten men and ten women received a 2-h S(؉)ketamine infusion. The infusion was increased at 40 ng/ml per 15 min to reach a maximum of 320 ng/ml. The following measurements were made: arterial plasma S(؉)-ketamine and S(؉)norketamine concentrations, heat pain intensity, electrical pain tolerance, drug high, and cardiac output. The data were modeled by using sigmoid Emax models of S(؉)-ketamine concentration versus effect and S(؉)-ketamine ؉ S(؉)-norketamine concentrations versus effect. Results: Sex differences observed were restricted to pharmacokinetic model parameters, with a 20% greater elimination clearance of S(؉)-ketamine and S(؉)-norketamine in women resulting in higher drug plasma concentrations in men. S(؉)ketamine produced profound drug high and analgesia with six times greater potency in the heat pain than the electrical pain test. After ketamine-infusion, analgesia rapidly dissipated; in the heat pain test but not the electrical pain test, analgesia was followed by a period of hyperalgesia. Over the dose range tested, ketamine produced a 40-50% increase in cardiac output. A significant consistent contribution of S(؉)-norketamine to overall effect was detected for none of the outcome parameters. Conclusions: S(؉)-ketamine displays clinically relevant sex differences in its pharmacokinetics. It is a potent analgesic at already low plasma concentrations, but it is associated with intense side effects. KETAMINE is a phenylcyclidine derivative introduced in the early 1960s as an intravenous anesthetic agent. Ketamine acts as a noncompetitive antagonist of the ionotropic glutamate N-methyl-D-aspartate (NMDA) recep-* Doctoral Student,

Based on this systematic review, no conclusions can yet be made about the efficacy of NMDA receptor antagonists on neuropathic pain. Additional RCTs in homogenous groups of pain patients are needed to explore the therapeutic potential of NMDA receptor antagonists in neuropathic pain.

The data indicate that while ketamine's effect on acute experimental pain is driven by pharmacokinetics, its effect on CRPS pain persisted beyond the infusion period when drug concentrations were below the analgesia threshold for acute pain. This indicates a disease modulatory role for ketamine in CRPS-1 pain, possibly via desensitization of NMDAR in the spinal cord or restoration of inhibitory sensory control in the brain.