Abstract

Ketamine is a mechanistically complex agent with clinical effects that span anesthesia, analgesia, and neuropsychiatric modulation. Although long associated with N-methyl-D-aspartate (NMDA) receptor antagonism, contemporary translational research emphasizes a broader pharmacologic profile that includes state-dependent circuit effects and metabolite-linked signaling. The recent approval of KETARx, a ketamine hydrochloride injection entering the U.S. market through the contemporary generic approval pathway, provides an opportunity to reassess ketamine within a framework that integrates modern pharmacokinetic and pharmacodynamic modeling, biomarker science, and updated regulatory standards. This review synthesizes mechanistic, pharmacologic, and regulatory evidence to construct a translational framework for KETARx in perioperative and chronic pain medicine. Advances in PK-PD modeling distinguish the contributions of parent ketamine and downstream metabolites, supporting infusion-forward strategies that preserve anti-hyperalgesic benefit while limiting psychotomimetic effects. Emerging biomarker and neuroimaging studies indicate that ketamine acts through network-level modulation rather than single-target receptor occupancy, although no clinically actionable predictors have been validated. Clinical evidence supports opioid-sparing effects in perioperative care and selective benefit in sensitization-linked pain trajectories, while longer-horizon safety considerations center on urological and hepatobiliary risks during repeated exposure. Special populations, including pediatric, geriatric, hepatically impaired, and peripartum patients, require protocol adaptation due to differences in metabolism, vulnerability, and tolerability. Overall, KETARx does not alter ketamine’s fundamental biology; however, it reinforces the need for precision in practice through PK-PD grounded dosing, phenotype-aligned outcome selection, and safety surveillance scaled to cumulative exposure.