Background: Oliceridine is a G protein–biased μ-opioid, a drug class thatis associated with less respiratory depression than nonbiased opioids, suchas morphine. The authors quantified the... Show moreBackground: Oliceridine is a G protein–biased μ-opioid, a drug class thatis associated with less respiratory depression than nonbiased opioids, suchas morphine. The authors quantified the respiratory effects of oliceridine andmorphine in elderly volunteers. The authors hypothesized that these opioidsdiffer in their pharmacodynamic behavior, measured as effect on ventilation atan extrapolated end-tidal Pco2 at 55 mmHg, V̇E55.Methods: This four-arm double-blind, randomized, crossover study examinedthe respiratory effects of intravenous 0.5 or 2 mg oliceridine and 2 or8 mg morphine in 18 healthy male and female volunteers, aged 55 to 89 yr, onfour separate occasions. Participants’ CYP2D6 genotypes were determined,hypercapnic ventilatory responses were obtained, and arterial blood sampleswere collected before and for 6 h after treatment. A population pharmacokinetic–pharmacodynamic analysis was performed on V̇E55, the primary endpoint;values reported are median ± standard error of the estimate.Results: Oliceridine at low dose was devoid of significant respiratory effects.High-dose oliceridine and both morphine doses caused a rapid onset of respiratorydepression with peak effects occurring at 0.5 to 1 h after opioid dosing.After peak effect, compared with morphine, respiratory depression inducedby oliceridine returned faster to baseline. The effect-site concentrationscausing a 50% depression of V̇E55 were 29.9 ± 3.5 ng/ml (oliceridine) and21.5 ± 4.6 ng/ml (morphine), the blood effect-site equilibration half-lives differedby a factor of 5: oliceridine 44.3 ± 6.1 min and morphine 214 ± 27 min.Three poor CYP2D6 oliceridine metabolizers exhibited a significant differencein oliceridine clearance by about 50%, causing higher oliceridine plasma concentrationsafter both low- and high-dose oliceridine, compared with the otherparticipants.Conclusions: Oliceridine and morphine differ in their respiratory pharmacodynamicswith a more rapid onset and offset of respiratory depression foroliceridine and a smaller magnitude of respiratory depression over time. Show less