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Background Mechanically ventilated patients in the intensive care unit (ICU) experience both nociception and pain-related distress, while simultaneously being at risk of ventilator-induced lung injury (VILI). Implementing individualized analgesic regimens is crucial to facilitate lung-protective ventilation strategies. Although preclinical studies suggest that oxycodone may attenuate VILI, clinical evidence supporting its use in critically ill patients remains limited, particularly in the ICU setting. Objective To evaluate the effects of intravenous oxycodone on respiratory mechanics and clinical outcomes in mechanically ventilated ICU patients, with a specific focus on those who have undergone abdominal surgery, thereby providing a novel theoretical basis and practical guidance for optimizing analgesic management and mitigating VILI risk. Methods A prospective randomized controlled trial was conducted. A total of 94 adult patients (aged≥18 years) requiring analgesic intervention, with a mechanical ventilation duration exceeding 24 hours and an Critical-care Pain Observation Tool (CPOT) score ≥3, were enrolled from the ICU of Zhoushan Hospital between August 2023 and March 2025. Participants were randomly assigned to either the sufentanil group or the oxycodone group, with 47 patients in each group. Both groups received standard treatment for underlying conditions and were managed with mechanical ventilation according to a conventional lung-protective ventilation strategy. The sufentanil group received a continuous intravenous infusion of sufentanil via micropump (loading dose: 0.5-1.0 μg/kg; maintenance dose: 0.02-0.15 μg·kg-1·h-1), while the oxycodone group received a continuous intravenous infusion of oxycodone injection (diluted to 1 mg/mL with 0.9% saline or 5% glucose solution; loading dose: 0.03 mg/kg; initial maintenance dose: 2 mg/h). Dosages were adjusted based on CPOT scores to maintain pain control with a target CPOT score below 3. Both groups received propofol for sedation as clinically indicated. Routine assessments included pain evaluation, respiratory mechanics monitoring, and arterial blood gas analysis. Outcome measures included demographic characteristics, airway peak pressure (Ppeak), airway plateau pressure (Pplat), driving pressure (ΔP), dynamic compliance (Cdyn), mechanical power MP), oxygenation index (P/F), and ventilation ratio (VR), recorded at baseline (0 h) and at 4 h, 12 h, and 24 h after initiation of analgesia. Additionally, cumulative analgesic consumption over 24 hours (converted to morphine equivalent), total propofol dose over 24 hours, duration of MV, and length of ICU stay (ICU-LOS) were documented. The study compared the effects of the two analgesic regimens on respiratory mechanics and clinical efficacy. A prespecified subgroup analysis was performed among 37 patients who underwent abdominal surgery (sufentanil subgroup: n=17; oxycodone subgroup: n=20). Results There was no significant interaction effect between group and time on respiratory mechanics and oxygenation/ventilation parameters (P>0.05). The main effect of group on these parameters was not statistically significant (P>0.05), whereas the main effect of time was significant for Ppeak, MP, and VR (P<0.05). Subsequent intergroup comparisons were conducted for total morphine equivalent dose (24-hour analgesic requirement), total propofol dose (24-hour sedative requirement), duration of mechanical ventilation, and ICU length of stay (LOS), with no statistically significant differences observed (P>0.05). However, a subgroup analysis restricted to patients who underwent abdominal surgery demonstrated a statistically significant difference in propofol dosage between the oxycodone and sufentanil groups (P<0.05). Conclusion Both oxycodone injection and sufentanil injection can effectively improve respiratory mechanics parameters and oxygenation-ventilation indices in mechanically ventilated ICU patients, thereby facilitating the implementation of lung-protective ventilation strategies and reducing the risk of VILI. In post-abdominal surgery patients requiring mechanical ventilation, oxycodone injection demonstrates superior efficacy in pain relief, allows for reduced use of sedative agents, mitigates clinical risks associated with high-dose sedation, and exhibits a more favorable safety profile.