S(+)-ketamine Effect on Experimental Pain and Cardiac Output: A Population Pharmacokinetic-Pharmacodynamic Modeling Study in Healthy Volunteers.
Sigtermans, Marnix M.D. *; Dahan, Albert M.D., Ph.D. +; Mooren, Rene B.Sc. ++; Bauer, Martin M.D. [S]; Kest, Benjamin Ph.D. ||; Sarton, Elise M.D., Ph.D. [S]; Olofsen, Erik M.Sc. #
111(4):892-903, October 2009.
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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.
(C) 2009 American Society of Anesthesiologists, Inc.