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

Abstract 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 C 50  = 10.5 ± 4.8 ng/ml (95% ci 4.37–21.2 ng/ml) and t ½ 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.