title: Population pharmacokinetic-pharmacodynamic modeling of ketamine-induced pain relief of chronic pain.
abstract: OBJECTIVE
  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 t½ for onset/offset=10.9±4.0 days (5.3-20.5 days).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Anesthesiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands. a.dahan@lumc.nl
authors.forename: Albert
authors.initials: A
authors.lastname: Dahan
authors.forename: Erik
authors.initials: E
authors.lastname: Olofsen
authors.forename: Marnix
authors.initials: M
authors.lastname: Sigtermans
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Noppers
authors.forename: Marieke
authors.initials: M
authors.lastname: Niesters
authors.forename: Leon
authors.initials: L
authors.lastname: Aarts
authors.forename: Martin
authors.initials: M
authors.lastname: Bauer
authors.forename: Elise
authors.initials: E
authors.lastname: Sarton
mesh_terms: D000328:Adult; D000698:Analgesia; D000700:Analgesics / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D002908:Chronic Disease; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007649:Ketamine / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D008959:Models, Neurological; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects; D012019:Reflex Sympathetic Dystrophy / Q000188:drug therapy*
chemical_list: D000700:Analgesics; D007649:Ketamine