Efficacy and safety of oliceridine versus remifentanil for analgesia in mechanically ventilated critically ill adults (CO-ROAM): a multicenter, assessor-blinded, non-inferiority randomized controlled trial

Remifentanil provides effective analgesia during invasive mechanical ventilation (IMV), but its utility is limited by opioid-related adverse events. Oliceridine, a G protein-biased μ-opioid receptor agonist, may decouple analgesia from these effects, but lacks evidence in critically ill patients. This multicentre, assessor- and patient-blinded, non-inferiority randomised controlled trial was conducted across 19 intensive care units (ICUs) in China. Adults receiving IMV were randomised 1:1 to oliceridine or remifentanil, titrated to a Critical-Care Pain Observation Tool score below 3. The primary endpoint was time in target analgesic range (TTR; non-inferiority margin −10%). Of 307 randomised patients, 304 comprised the modified intention-to-treat population (151 oliceridine, 153 remifentanil). Median TTR was 96.0% versus 92.3% (absolute difference 3.7%, 95% CI −0.3–5.7%). Oliceridine was associated with fewer mild-to-moderate adverse drug reactions (ADRs), occurring at 15.9 versus 22.2 events per 100 patient-days (IRR 0.72, 95% CI 0.52–1.00, P = 0.049), and a lower rate of respiratory depression during the study period (0% vs. 4.6%, P = 0.015). Post-extubation respiratory depression (0% vs. 7.9%, P = 0.005) and analgesic-sedation costs were both lower with oliceridine. IMV duration, ICU stay, and 28-day mortality did not differ. Subgroup analyses identified a nominal ADR benefit in patients with Acute Physiology and Chronic Health Evaluation II > 17 and a larger nominal TTR difference in those without acute respiratory distress syndrome. Oliceridine provides non-inferior analgesia to remifentanil with a more favourable respiratory safety profile and lower costs in critically ill adults. ClinicalTrials.gov NCT06454292 (registered June 11, 2024). In this multicentre randomised trial of 304 mechanically ventilated critically ill adults, oliceridine provided non-inferior analgesia to remifentanil with no post-extubation respiratory depression events (0% vs 7.9%) and numerically fewer mild-to-moderate adverse drug reactions and lower analgesic-sedation expenditure, supporting oliceridine as a promising analgesic alternative where respiratory safety during ventilator liberation is paramount.