Esketamine-Based Opioid-Sparing Regimens in Chinese Perioperative Care

Esketamine Reduces Early Postoperative Anxiety in Hysterectomy Patients

A randomized, participant- and outcome-assessor-blinded controlled trial conducted in China (ChiCTR2300074484) found that an esketamine-based, opioid-sparing perioperative regimen significantly reduced anxiety and improved recovery metrics at 24 hours after total laparoscopic hysterectomy. Women aged 45–60 were randomized to receive either a conventional opioid-based regimen or one incorporating esketamine during anesthesia and patient-controlled intravenous analgesia (PCIA), with reduced opioid dosing. The primary outcome—Self-Rating Anxiety Scale (SAS) score at 24 hours—was lower in the esketamine group. Secondary measures, including pain, sleep quality, and quality of recovery (QoR-15), also favored esketamine at this early time point. However, by 72 hours post-surgery, after completion of PCIA, these benefits were no longer statistically significant.

Mechanism: NMDA Antagonism and Opioid-Sparing Effects

Esketamine, the S-enantiomer of ketamine, is a dissociative anesthetic and a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor. Its mechanism of action is distinct from both classic psychedelics (which act via serotonin 5-HT2A receptors) and standard opioids. By blocking NMDA receptors, esketamine can modulate pain perception, reduce central sensitization, and exert rapid-acting antidepressant and anxiolytic effects. In perioperative settings, these properties allow for reduced opioid requirements, potentially minimizing opioid-related adverse events and supporting faster recovery. Notably, the trial's design—incorporating esketamine throughout anesthesia and PCIA—reflects a growing trend in Chinese perioperative medicine to explore alternatives to high-dose opioids, especially for patients at risk of mood disturbances post-surgery.

Policy and Research Implications for Perioperative Protocols

The trial's findings may influence perioperative protocols in China and beyond by supporting short-term use of esketamine as an adjunct to reduce anxiety and opioid consumption after gynecological surgery. While esketamine is not classified as a classic psychedelic, its emerging role in perioperative mental health management aligns with broader efforts to address the psychological sequelae of surgery. The absence of increased neuropsychiatric adverse events—such as hallucinations or delirium—suggests that, when carefully titrated, esketamine can be integrated safely into standard care for select populations. Importantly, this trial highlights the value of patient- and outcome-assessor blinding in minimizing bias, a methodological strength sometimes lacking in earlier ketamine studies.

• Concrete regulatory context: The study was registered with the Chinese Clinical Trial Registry (ChiCTR2300074484), reflecting increasing regulatory scrutiny and transparency in perioperative research in China.
• Non-obvious implication: The rapid dissipation of benefit after PCIA cessation suggests that esketamine’s perioperative mental health effects may be highly time-dependent, raising questions about optimal dosing duration and the feasibility of extending benefits without increasing risk.

Risks, Limitations, and Unknowns

Although the esketamine-based regimen did not increase the incidence of neuropsychiatric adverse events in this study, the sample size (n=167) and short follow-up window limit the ability to detect rare or delayed complications. The trial excluded patients with pre-existing psychiatric disorders, substance use, or major medical comorbidities, so generalizability to broader surgical populations remains uncertain. Additionally, the lack of sustained benefit at 72 hours highlights a key limitation: esketamine’s anxiolytic and recovery-enhancing effects may be transient, necessitating further research into maintenance strategies or combination therapies. As with all NMDA antagonists, vigilance for dissociation, hemodynamic changes, and potential for misuse is warranted, especially if protocols are expanded beyond tightly controlled hospital settings.

Looking Forward: Integrating Dissociative Anesthetics in Perioperative Care

Future research should explore optimal dosing schedules, patient selection criteria, and the potential for combining esketamine with non-pharmacologic interventions to extend mental health benefits after surgery. Comparative effectiveness studies in diverse populations and surgical contexts will be essential to clarify the risk-benefit profile. As regulatory agencies in China and other jurisdictions evaluate these data, the trial sets a precedent for rigorous, blinded, and registered studies of dissociative anesthetics in perioperative mental health. For clinicians, the findings offer a cautiously optimistic signal that esketamine can be used safely to address early postoperative anxiety, but underscore the need for ongoing monitoring and individualized care planning.

By Dr. Lin Zhang, MD, PhD — Clinical Anesthesiologist and Researcher. Reviewed by Dr. Lin Zhang on 2026-11-13. Primary sources: OpenAlex trial summary, Chinese Clinical Trial Registry.