These authors contributed equally to this work.
Population pharmacokinetic—pharmacodynamic modeling of ketamine-induced pain relief of chronic pain
Article first published online: 13 JAN 2012
2011 European Federation of Chapters of the International Association for the Study of Pain
European Journal of Pain
Volume 15, Issue 3, pages 258–267, March 2011
How to Cite
Dahanl, A., Olofsenl, E., Sigtermans, M., Noppers, I., Niesters, M., Aarts, L., Bauer, M. and Sarton, E. (2011), Population pharmacokinetic—pharmacodynamic modeling of ketamine-induced pain relief of chronic pain. European Journal of Pain, 15: 258–267. doi: 10.1016/j.ejpain.2010.06.016
- Issue published online: 13 JAN 2012
- Article first published online: 13 JAN 2012
- Received 4 March 2010; received in revised from 2 June 2010; accepted 17 June 2010
- NMDA receptor antagonist;
- Chronic pain;
- PK—PD modeling;
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.