Ketamine produces potent analgesia combined with psychedelic effects. It has been suggested that these two effects are associated and possibly that analgesia is generated by ketamine-induced dissociation. The authors performed a post hoc analysis of previously published data to quantify the pharmacodynamic properties of ketamine-induced antinociception and psychedelic symptoms. The hypothesis was that ketamine pharmacodynamics (i.e., concentration–effect relationship as well as effect onset and offset times) are not different for these two endpoints.

Seventeen healthy male volunteers received escalating doses of S– and racemic ketamine on separate occasions. Before, during, and after ketamine infusion, changes in external perception were measured together with pain pressure threshold. A population pharmacokinetic–pharmacodynamic analysis was performed that took S– and R-ketamine and S– and R-norketamine plasma concentrations into account.


The pharmacodynamics of S-ketamine did not differ for antinociception and external perception with potency parameter (median [95% CI]) C50, 0.51 (0.38 to 0.66) nmol/ml; blood-effect site equilibration half-life, 8.3 [5.1 to 13.0] min), irrespective of administration form (racemic ketamine or S-ketamine). R-ketamine did not contribute to either endpoint. For both endpoints, S-norketamine had a small antagonistic effect.


The authors conclude that their data support an association or connectivity between ketamine analgesia and dissociation. Given the intricacies of the study related to the pain model, measurement of dissociation, and complex modeling of the combination of ketamine and norketamine, it is the opinion of the authors that further studies are needed to detect functional connectivity between brain areas that produce the different ketamine effects.

Editor’s Perspective
What We Already Know about This Topic
  • Ketamine produces potent analgesia and psychedelic effects related to its dissociative properties at subanesthetic doses
  • It has been suggested that ketamine analgesia may be generated by its dissociative effects, although there is evidence that suggests the two endpoints are independent and not connected
What This Article Tells Us That Is New
  • In a planned secondary analysis, a population pharmacokinetic–pharmacodynamic model of ketamine and its metabolite norketamine was developed to describe the relationship between effect site concentrations of S– and R-ketamine and their metabolites and pressure pain threshold and the change in external perception as a measure of ketamine psychotropic effect
  • The pharmacodynamics of S-ketamine did not differ for antinociception and external perception, which had the same potency parameter (C50) and plasma-effect site equilibration half-time whether administered as racemic ketamine or S-ketamine
  • R-ketamine did not contribute to either endpoint, while S-norketamine had a small antagonistic effect for both endpoints