TARGET Study: Intravenous Dexamethasone Palmitate for Postoperative Pain Prevention: Protocol for a Multicenter, Randomised Controlled Study.

Introduction: Inadequate postoperative pain control still hinders recovery, fuels opioid dependence, and promotes chronic pain. Although perioperative systemic dexamethasone offers anti-inflammatory and opioid-sparing benefits, its clinical success is unpredictable, and concerns over systemic adverse events persist. To address these limitations, dexamethasone palmitate-a novel lipophilic prodrug engineered as a nanoparticle emulsion-utilizes enhanced permeability and retention (EPR) effects to concentrate selectively at inflammatory sites, promising superior local anti-inflammatory and analgesic properties with minimized systemic toxicity. Consequently, this clinical trial is designed to investigate the safety and efficacy of preoperatively administering intravenous dexamethasone palmitate for the prevention of acute postoperative pain. Methods and Analysis: This is a multicenter, randomised, open-label, positive-controlled trial. We plan to enrol 446 patients aged 18-65 years who are scheduled for various surgeries under general anaesthesia, including minimally invasive and open procedures. Patients will be randomised to receive either 8 mg dexamethasone palmitate or 8 mg dexamethasone intravenously after anaesthesia induction. The primary outcome will be the proportion of patients who experience moderate to severe pain (visual analogue scale score >30 mm) at 24 hours post-operatively. The secondary outcomes will include cumulative opioid consumption (morphine milligram equivalents), total consumption of supplemental oxycodone/paracetamol tablets, pain scores at multiple time points, time to first patient-controlled analgesia bolus, patient satisfaction, incidence of postoperative nausea and vomiting, quality of recovery (QoR-15), and length of hospital stay. Statistical analyses will include a log-binomial regression model for the primary outcome and appropriate parametric or nonparametric tests for secondary outcomes, with a two-sided p value <0.05 considered significant. Ethics and Dissemination: Ethical approval was obtained from the Institutional Review Board (IRB) of Beijing Tiantan Hospital Affiliated with Capital Medical University (KY 2025-041-02-04). The results will be disseminated in open-access publications and plain-language summaries. Trial Registration: Clinicaltrials.gov (NCT07341854) Registered on 09 January 2026.