title: S(+)-ketamine effect on experimental pain and cardiac output: a population pharmacokinetic-pharmacodynamic modeling study in healthy volunteers.
abstract: 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.
authors.affiliation: Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Marnix
authors.initials: M
authors.lastname: Sigtermans
authors.forename: Albert
authors.initials: A
authors.lastname: Dahan
authors.forename: René
authors.initials: R
authors.lastname: Mooren
authors.forename: Martin
authors.initials: M
authors.lastname: Bauer
authors.forename: Benjamin
authors.initials: B
authors.lastname: Kest
authors.forename: Elise
authors.initials: E
authors.lastname: Sarton
authors.forename: Erik
authors.initials: E
authors.lastname: Olofsen
mesh_terms: D000293:Adolescent; D000328:Adult; D000465:Algorithms; D000778:Anesthetics, Dissociative / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002302:Cardiac Output / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D023381:Endpoint Determination; D005260:Female; D006358:Hot Temperature; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy; D007262:Infusions, Intravenous; D007649:Ketamine / Q000009:adverse effects* / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D015233:Models, Statistical; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects; D012727:Sex Characteristics; D055815:Young Adult
chemical_list: D000778:Anesthetics, Dissociative; D007649:Ketamine; C033419:norketamine