• Sabry Ayad, Mark A Demitrack, David A Burt, Cathy Michalsky, Linda Wase, Michael J Fossler, and Ashish K Khanna.
• Department of Anesthesiology, Cleveland Clinic, Outcomes Research, Anesthesiology Institute, Fairview Hospital, 18101 Lorain Avenue, Cleveland, OH, 44111, USA. Saayad@ccf.org.
• Clin Drug Investig. 2020 Aug 1; 40 (8): 755-764.

Background And ObjectiveOpioid-induced respiratory depression (OIRD) is a potentially fatal complication associated with conventional opioids. Currently, there is a paucity of validated endpoints available to measure respiratory safety. Oliceridine, an investigational intravenous (IV) opioid, is a G-protein selective μ-agonist with limited activity on β-arrestin2, a signaling pathway associated with adverse events including OIRD. In controlled phase III trials, oliceridine 0.35 mg and 0.5 mg demand doses demonstrated comparable analgesia to morphine 1 mg with favorable improvements in respiratory safety. In this exploratory analysis, we report dosing interruption (DI) and average cumulative duration of DI (CDDI) for both oliceridine and morphine.MethodsPatients requiring analgesia after bunionectomy or abdominoplasty were randomized to IV demand doses of placebo, oliceridine (0.1 mg, 0.35 mg, or 0.5 mg), or morphine (1 mg), administered via patient-controlled analgesia (PCA), following a loading dose (oliceridine 1.5 mg, morphine 4 mg, volume-matched placebo) with a 6-min lockout interval. Certified nurse anesthetists monitored each patient and withheld study medication according to the patient's respiratory status. For each patient, the duration of all DIs was summed and reported as CDDI. A zero-inflated gamma mixture model was used to compute the mean CDDI for each treatment.ResultsProportion of patients with DI was lower with oliceridine (0.1 mg: 3.2%, 0.35 mg: 13.9%, 0.5 mg: 15.1%) versus morphine (22%). The CDDI was also lower across all demand doses of oliceridine versus morphine.ConclusionUsing DI as a surrogate for OIRD indicates improved respiratory safety with oliceridine versus morphine that merits further investigation.

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