Sabry Ayad1,2, Mark A Demitrack3, David A Burt4, Cathy Michalsky4, Linda Wase3, Michael J Fossler4, Ashish K Khanna5,6. 1. Department of Anesthesiology, Cleveland Clinic, Outcomes Research, Anesthesiology Institute, Fairview Hospital, 18101 Lorain Avenue, Cleveland, OH, 44111, USA. Saayad@ccf.org. 2. Department of Anesthesiology, Wake Forest School of Medicine, Winston-Salem, NC, USA. Saayad@ccf.org. 3. Clinical Operations and Medical Affairs, Trevena Inc., Chesterbrook, PA, USA. 4. Clinical Development and Quantitative Sciences, Trevena Inc., Chesterbrook, PA, 19087, USA. 5. Department of Anesthesiology, Wake Forest School of Medicine, Winston-Salem, NC, USA. 6. Outcomes Research Consortium, Cleveland, OH, USA.
Abstract
BACKGROUND AND OBJECTIVE: Opioid-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. METHODS:Patients 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. RESULTS: Proportion 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. CONCLUSION: Using DI as a surrogate for OIRD indicates improved respiratory safety with oliceridine versus morphine that merits further investigation.
RCT Entities:
BACKGROUND AND OBJECTIVE: Opioid-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. METHODS:Patients 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. RESULTS: Proportion 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. CONCLUSION: Using DI as a surrogate for OIRD indicates improved respiratory safety with oliceridine versus morphine that merits further investigation.
Authors: E Andrew Townsend; Bruce E Blough; David H Epstein; S Stevens Negus; Yavin Shaham; Matthew L Banks Journal: Neuropsychopharmacology Date: 2022-07-29 Impact factor: 8.294