Ketamine Psychedelic and Antinociceptive Effects Are Connected
Erik Olofsen, Jasper Kamp, Thomas K. Henthorn, Monique van Velzen, Marieke Niesters, Elise Sarton, Albert Dahan
Anesthesiology February 21, 2022 Peer reviewed DOI: 10.1097/aln.0000000000004176 via OpenAlex
Summary
The pharmacodynamics of S-ketamine for pain relief and psychedelic effects are similar, with a potency parameter of 0.51 nmol/ml and a blood-effect site equilibration half-life of 8.3 minutes. In a study with 17 healthy male volunteers receiving different doses of ketamine, R-ketamine did not influence these effects, while S-norketamine showed a minor antagonistic effect. The findings suggest a potential connection between ketamine's analgesic and dissociative properties, warranting further investigation.
Study at a glance
| Design | post hoc analysis |
|---|---|
| Sample size | 17 |
| Population | healthy male volunteers |
| Key finding | The pharmacodynamics of S-ketamine did not differ for antinociception and external perception. |
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.