S(+)-ketamine Effect on Experimental Pain and Cardiac Output: A Population Pharmacokinetic-Pharmacodynamic Modeling Study in Healthy Volunteers

• Published in: Anesthesiology (Philadelphia) Vol. 111; no. 4; pp. 892 - 903
• Main Authors: SIGTERMANS, Marnix, DAHAN, Albert, MOOREN, René, BAUER, Martin, KEST, Benjamin, SARTON, Elise, OLOFSEN, Erik
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01.10.2009
• Subjects: Adolescent; Adult; Algorithms; Anesthesia; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Anesthetics, Dissociative - adverse effects; Anesthetics, Dissociative - pharmacokinetics; Anesthetics, Dissociative - therapeutic use; Biological and medical sciences; Cardiac Output - drug effects; Dose-Response Relationship, Drug; Electric Stimulation; Endpoint Determination; Female; Hot Temperature; Humans; Hyperalgesia - drug therapy; Infusions, Intravenous; Ketamine - adverse effects; Ketamine - analogs & derivatives; Ketamine - blood; Ketamine - pharmacokinetics; Ketamine - therapeutic use; Male; Medical sciences; Models, Statistical; Pain - drug therapy; Pain Measurement - drug effects; Pain Threshold - drug effects; Sex Characteristics; Young Adult; Human; Pain; Ketamine; General anesthetic; Anesthesia; Glutamate receptor; Antagonist; Cardiac output; NMDA receptor; Pharmacokinetics; Modeling
• ISSN: 0003-3022; 1528-1175
• DOI: 10.1097/ALN.0b013e3181b437b1

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. 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. 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. 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.