Dissociative and Analgesic Properties of Ketamine Are Independent

Abstract

Background: Ketamine is a dissociative anesthetic with analgesic properties. Ketamine's analgesic properties have been suggested to result from its dissociative properties. To the authors' knowledge, this postulate is unsubstantiated. The authors hypothesize that the dissociative and analgesic properties of ketamine are independent.

Methods: The authors conducted a single-site, open-label study of ketamine anesthesia (2 mg/kg) in 15 healthy subjects. Midazolam was administered at a prespecified time point to attenuate dissociation. The authors longitudinally assessed precalibrated cuff pain intensity and quality using Patient-Reported Outcomes Measurement Information System questionnaires, and dissociation, using the Clinician Administered Dissociative States Scale. Mixed effects models were used to assess whether dissociation accounted for the effect of ketamine on pain intensity and quality.

Results: The dissociation model demonstrated an inverted U-shaped quadratic relationship between time and dissociation scores. Additive to this effect, midazolam reduced the dissociation adjusted means by 10.3 points (95% CI, 3.4 to 17.1; P = 0.005). The pain intensity model also demonstrated a U-shaped quadratic relationship between time and pain intensity. When the pain intensity model was reanalyzed with dissociation scores as an additional covariate, the dissociation term was not retained in the model, and the other effects were preserved in direction and strength. This result was conserved for nociceptive and neuropathic pain quality.

Conclusions: Ketamine's analgesic properties are not exclusively caused by dissociation. Thus, ketamine may be used as a probe to advance our knowledge of dissociation independent neural circuits that encode pain.

Fig. 1.

Schematic of the study protocol. We acquired data using an open-label and single-site study design in (n=15) healthy subjects. Subjects were induced to lose responsiveness with 2mg/kg of intravenous ketamine. We also administered a 2mg of intravenous midazolam to attenuate ketamine-induced dissociation. We assessed pain intensity and quality using Patient-Reported Outcomes Measurement Information System questionnaires and dissociative symptoms using the Clinician Administered Dissociative States Scale.

Fig. 2.

Raw and predicted data for ketamine induced dissociation and pain measures. Each dashed line connects conditional predicted values from the model for the same subject (arbitrary colors are a visual aid to differentiate subjects). Raw values are depicted with markers and aligned with the same color scheme above. Markers shapes are grouped to represent the different assessment periods. (A) Illustration of predicted inverted “U” shaped quadratic relationship between Clinician Administered Dissociative States Scale and time after ketamine administration. Also apparent in the figure is an attenuating effect of midazolam noticeable after the point of its administration for each subject. The final backward elimination models demonstrated a “U” shaped quadratic relation between time and (B) pain intensity, (C) nociceptive pain, and (D) neuropathic pain. The two distinct clusters of trajectories in (D) illustrate a main effect of sex (higher cluster corresponds to males; lower females).