Esketamine as Adjunct Analgesia: Dose-Finding RCT in Chinese Lumbar Surgery

Esketamine Reduces Opioid Use After Lumbar Surgery: Key Findings

A 2026 randomized controlled trial (RCT) conducted in China and registered under ChiCTR2500095890 demonstrates that adjunctive esketamine can reduce opioid consumption and improve postoperative pain control following lumbar decompression surgery. In this study, 120 patients were randomized into four groups: a control group receiving standard sufentanil-based patient-controlled intravenous analgesia (PCIA), and three experimental groups receiving lower-dose sufentanil combined with esketamine at 0.25, 0.5, or 1.0 mg/kg. All esketamine regimens resulted in significantly lower pain scores and opioid use compared to control, with the lowest dose (0.25 mg/kg) offering similar analgesic benefits and fewer adverse effects than higher doses.

Mechanism and Clinical Context: Esketamine in Multimodal Analgesia

Esketamine, the S-enantiomer of ketamine, is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist with established dissociative anesthetic and analgesic properties. Its opioid-sparing effect is particularly relevant in the perioperative setting, where minimizing opioid exposure is a clinical priority due to risks of dependence, respiratory depression, and other adverse effects. In this RCT, esketamine adjunct therapy not only reduced sufentanil requirements but also improved oxidative stress markers, suggesting potential benefits beyond analgesia. Notably, the lowest tested dose (0.25 mg/kg) achieved comparable pain control to higher doses, indicating a ceiling effect for analgesia within the studied range.

Policy and Research Implications: Toward Safer Analgesic Protocols

The results of this trial support the integration of low-dose esketamine into multimodal analgesia protocols for lumbar surgery, with potential applicability to other surgical contexts. Given the ongoing opioid crisis and increasing regulatory scrutiny of perioperative opioid prescribing, evidence for effective opioid-sparing strategies is highly relevant to policymakers, hospital formulary committees, and guideline developers. The trial's dose-finding design provides actionable data for protocol development, emphasizing that higher esketamine doses do not confer additional analgesic benefit but do increase sedation and psychomimetic risks. An underappreciated insight is that esketamine's reduction of oxidative stress markers (such as lower malondialdehyde and cortisol) may have implications for postoperative recovery quality, a factor not routinely captured in analgesia trials and worth further investigation.

Risks, Limitations, and Unknowns

While esketamine was generally well tolerated at all tested doses, higher doses (0.5 and 1.0 mg/kg) were associated with increased sedation, hypotension, and dissociative symptoms. The lowest dose (0.25 mg/kg) offered a favorable efficacy-safety balance, but even at this dose, monitoring for psychomimetic effects remains prudent. The study population was limited to adults undergoing lumbar decompression surgery in a single Chinese center, which may limit generalizability to other surgical populations or healthcare systems. Additionally, the trial did not assess long-term outcomes such as persistent pain, opioid use beyond 48 hours, or potential neuropsychiatric sequelae. Regulatory frameworks for perioperative esketamine use vary by jurisdiction, and off-label use remains a consideration outside formal protocols.

Outlook: Next Steps for Clinical Practice and Research

This trial positions low-dose esketamine as a promising adjunct in perioperative pain management, with immediate implications for protocol optimization and opioid stewardship. Future research should address long-term outcomes, comparative effectiveness with other non-opioid adjuncts, and implementation in diverse surgical and demographic populations. For institutions and regulators, the findings justify pilot adoption of low-dose esketamine in multimodal protocols, provided that patient selection and monitoring are rigorous. As the field moves forward, the integration of biochemical recovery markers into analgesia research may offer new insights into optimizing perioperative care.

By Dr. Wenjie Liu, MD, PhD (Anesthesiology, Peking Union Medical College Hospital). How we research: This article was reviewed by Dr. Liu on June 17, 2026, referencing the original trial registry and publication.