Piercing the Ketamine Cloud.

Summary

Ketamine has many properties—analgesic, antidepressant, dissociative anesthetic, and others—making it hard to target for specific clinical uses. In a study of 15 healthy adults, Gitlin et al. tested whether ketamine's pain-relieving and dissociative effects are linked. Participants received a single anesthetic dose of ketamine (2 mg/kg) and rated dissociation and pain from a standardized pneumatic cuff stimulus. Using a statistical method called backward elimination, the authors found that dissociation scores did not predict pain scores, suggesting the two effects arise from independent mechanisms. The study also confirmed that midazolam reduced dissociation without affecting analgesia.

Study at a glance

Abstract

IF ketamine were an animal, it would have to be an octopus: unique, endlessly mutable, potentially dangerous, devilishly complicated to study, and seeming to extend its grasp into every corner of medicine. In the 50 years ketamine has been commercially available in the United States, practitioners and researchers have called it an analgesic, antidepressant, anti-inflammatory agent, dissociative anesthetic, drug of abuse, local anesthetic, neuroprotectant, neurotoxin, psychotomimetic, and therapeutic psychedelic. This (partial!) list makes clear the challenge in trying to harness ketamine for a specific, targeted use in a clinical setting. And yet as these various properties are investigated, we have the unique opportunity to deepen our understanding of how the nervous system works and to develop therapeutics that capitalize on these insights. In this issue of Anesthesiology, Gitlin et al. take a novel approach to untangling two of the most well-established properties of ketamine, analgesia and dissociation. For the anesthetic induction of a surgical patient, both effects are desirable. However, in an awake patient being treated for postsurgical or chronic pain, for example, the value of ketamine is in its powerful nonopioid analgesic properties, and dissociation may be a counterproductive side effect. So, are the analgesic and dissociative effects of ketamine separable? Can ketamine be mechanistically split apart, refined, and reconstructed into a more targeted therapy? Or are these two facets of ketamine inextricably linked? Even the first published description of ketamine links the two properties, describing how ketamine produces a “profound analgesia associated with a peculiar state of altered consciousness.” However, it is difficult to identify a study that directly compares the dissociative symptoms and analgesic effects using standardized measures and in a standardized experimental pain model. Gitlin et al. fill this gap in the literature by administering a single anesthetic dose of ketamine (2 mg/ kg) to a small (n = 15) cohort of healthy adult participants, and analyzed their ratings of both dissociation and pain in response to a standardized noxious stimulus (pneumatic cuff pressure). The authors hypothesized that if dissociation drives analgesia, then a participant’s rating of dissociation at various timepoints after ketamine should predict their rating of experimentally induced pain. Framing the question this way allowed the authors to apply a statistical approach related to stepwise multivariate regression, known as backward elimination. In essence, the authors constructed a statistical model to predict pain intensity scores, including factors such as sex, age, time after the ketamine dose, and dissociation score, and algorithmically eliminated each factor until only significantly predictive factors remained. The authors’ main finding was that a participant’s dissociation score had no predictive value for their pain score, implying that these two processes occur by independent mechanisms. One of the strengths of this study is their use of standardized, validated questionnaires for subjective measures, and a widely used experimental pain stimulus, which the authors note has both nociceptive and neuropathic qualities. The authors also nest an important experimental manipulation into their timeline, administering a dose of midazolam at 1 h after ketamine. It is common practice to give midazolam with ketamine to prevent a potentially unpleasant dissociative experience. Using a similar statistical approach to the one described above, the authors confirmed