Esketamine: Less Drowsiness, More Analgesia

Racemic ketamine is a 1:1 mixture of 2 enantiomers that turn light in opposite direction: Dextrorotatory esketamine is approximately 4 times more affine for the N-methyl-D-aspartate (NMDA) receptor than levorotatory arketamine, which may explain why esketamine is about twice as potent as an analgesic and anesthetic as the racemate. Esketamine has attracted renewed interest in view of the opioid crisis, racemic ketamine’s abuse, and esketamine’s approval for expanded use. We evaluated the anesthesia literature concerning mental, cardiovascular, cerebral, and antinociceptive effects of esketamine published in English between 1980 and 2022. The review shows that esketamine and racemic ketamine are not “the same” at clinically equivalent analgesic and anesthetic dose: Psychomimetic effects seem to be essentially related to NMDA receptor blockade and esketamine is not devoid of unwanted mental impact. However, it probably involves less cholinergic inhibition. Cognitive disturbances during arousal, awakening, and recovery from the drug are less, and less pronounced with esketamine. The drug allows for an approximately 50% dose reduction in anesthesia and analgesia which goes along with a higher clearance and shorter recovery time as compared to racemic ketamine. In comparison of esketamine with placebo, esketamine shows cardiocirculatory stabilizing and neuroprotective effects which can be seen in anesthesia induction, cardiac surgery, and analgesia and sedation in brain injury. Evidence of esketamine’s antinociceptive efficacy is inconsistent, although a recent meta-analysis reports improved pain relief after surgery in a study with short observation time. To better define esketamine’s place, direct head-to-head comparison with the racemate at equi-analgesic/anesthetic dose is warranted.