Neuroscientific Basis of Ketamine as an Analgesic and Emerging Role in the Management of Depression.

PURPOSE OF REVIEW: Ketamine was originally developed as a dissociative anesthetic and has remained a valuable agent in anesthesia related to its ability to preserve airway reflexes and relative hemodynamic stability. Over time, its clinical applications have expanded beyond procedural sedation to include roles in pain management and psychiatry. In pain medicine, the therapeutic rationale is primarily grounded in its noncompetitive antagonism of the N-methyl-D-aspartate (NMDA) receptor and modulation of central sensitization, a key mechanism underlying refractory neuropathic and centralized pain states. RECENT FINDINGS: Evidence from preclinical studies and randomized clinical trials suggests that intravenous ketamine may provide short-term analgesic benefit in the treatment of resistant neuropathic pain, phantom limb pain, and complex regional pain syndrome. Low-dose perioperative administration has demonstrated opioid-sparing effects as part of multimodal analgesia strategies. However, heterogeneity in dosing protocols, variability in duration of response, and limited long-term data restrict definitive recommendations. In psychiatry, ketamine and its S-enantiomer, esketamine, have demonstrated rapid antidepressant effects in patients with major depressive disorder and treatment-resistant depression, further highlighting its evolving therapeutic scope. Despite these promising applications, the use of ketamine requires careful patient selection and monitoring related to dissociative effects, cardiovascular changes, and potential for misuse. This narrative review synthesizes current evidence regarding ketamine’s mechanistic basis and clinical utility across anesthesia, pain management, and psychiatry, with particular emphasis on its role in chronic and perioperative pain. Continued research is needed to clarify optimal dosing strategies, durability of response, and long-term safety across diverse patient populations.