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Population pharmacokinetic—pharmacodynamic modeling of ketamine-induced pain relief of chronic pain


Department of Anesthesiology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. Tel.: +31 71 526 2301


Aims: Pharmacological treatment of chronic (neuropathic) pain is often disappointing. In order to enhance our insight in the complex interaction between analgesic drug and chronic pain relief, we performed a pharmacokinetic—pharmacodynamic (PK—PD) modeling study on the effect of S(+)-ketamine on pain scores in Complex Regional Pain Syndrome type 1 (CRPS-1) patients.

Methods: Sixty CRPS-1 patients were randomly allocated to received a 100-h infusion of S(+)-ketamine or placebo. The drug infusion rate was slowly increased from 5 mg/h (per 70 kg) to 20 mg/h based upon the effect/side effect profile. Pain scores and drug blood samples were obtained during the treatment phase and pain scores were further obtained weekly for another 11 weeks. A population PK—PD model was developed to analyze the S(+)-ketamine-pain data.

Results: Plasma concentrations of S(+)-ketamine and its metabolite decreased rapidly upon the termination of S(+)-ketamine infusion. The chance for an analgesic effect from ketamine and placebo treatment was 67±10% and 23±9% (population value±SE), respectively. The pain data were well described by the PK—PD model with parameters C50=10.5±4.8 ng/ml (95% ci 4.37–21.2 ng/ml) and t½ for onset/offset=10.9±4.0 days (5.3–20.5 days).

Discussion: 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.