Oliceridine is a G protein-biased µ-opioid, a drug class that is associated with less respiratory depression than non-biased opioids, such as morphine. We quantified the respiratory effects of oliceridine and morphine in elderly volunteers. We hypothesized that these opioids differ in their pharmacodynamic behavior, measured as effect on ventilation at an extrapolated end-tidal PCO2 at 55 mmHg, V̇E55.


This four-arm double-blind, randomized, crossover study examined the respiratory effects of intravenous oliceridine 0.5 or 2 mg and morphine 2 or 8 ;mg in 18 healthy male and female volunteers, aged 55-89 years, on four separate occasions. Participants’ CYP2D6 genotypes were determined, hypercapnic ventilatory responses were obtained and arterial blood samples collected before and for 6-h following treatment. A population pharmacokinetic-pharmacodynamic analysis was performed on V̇E55, the primary endpoint; values reported are median ± standard error of the estimate.


Oliceridine at low-dose was devoid of significant respiratory effects. High-dose oliceridine and both morphine doses caused a rapid onset of respiratory depression with peak effects occurring at 0.5 to 1-h after opioid dosing. Following peak effect, compared to morphine, respiratory depression induced by oliceridine returned faster to baseline. The effect-site concentrations causing a 50% depression of V̇E55 were 29.9 ;± ;3.5 ;ng/mL (oliceridine) and 21.5 ;± ;4.6 ;ng/mL (morphine), the blood effect-site equilibration half-lives differed by a factor of 5: oliceridine 44.3 ;± ;6.1 ;min and morphine 214 ;± ;27 ;min. Three poor CYP2D6 oliceridine metabolizers exhibited a significant difference in oliceridine clearance by about 50%, causing higher oliceridine plasma concentrations following both low- and high-dose oliceridine, compared to the other participants.


Oliceridine and morphine differ in their respiratory pharmacodynamics with a more rapid onset and offset of respiratory depression for oliceridine and smaller magnitude of respiratory depression over time.