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Respiratory effects of biased ligand oliceridine in older volunteers: a pharmacokinetic-pharmacodynamic comparison with morphine
is associated with less respiratory depression than nonbiased opioids, such
as morphine. The authors quantified the respiratory effects of oliceridine and
morphine in elderly volunteers. The authors hypothesized that these opioids
differ in their pharmacodynamic behavior, measured as effect on ventilation at
an extrapolated end-tidal Pco2 at 55 mmHg, V̇E
55.
Methods: This four-arm double-blind, randomized, crossover study examined
the respiratory effects of intravenous 0.5 or 2 mg oliceridine and 2 or
8 mg morphine in 18 healthy male and female volunteers, aged 55 to 89 yr, on
four separate occasions. Participants’ CYP2D6 genotypes were determined,
hypercapnic ventilatory responses were obtained, and arterial blood samples
were collected before and for 6 h after treatment. A population pharmacokinetic–
pharmacodynamic analysis was performed on V̇
E55, the primary...Show moreBackground: Oliceridine is a G protein–biased μ-opioid, a drug class that
is associated with less respiratory depression than nonbiased opioids, such
as morphine. The authors quantified the respiratory effects of oliceridine and
morphine in elderly volunteers. The authors hypothesized that these opioids
differ in their pharmacodynamic behavior, measured as effect on ventilation at
an extrapolated end-tidal Pco2 at 55 mmHg, V̇E
55.
Methods: This four-arm double-blind, randomized, crossover study examined
the respiratory effects of intravenous 0.5 or 2 mg oliceridine and 2 or
8 mg morphine in 18 healthy male and female volunteers, aged 55 to 89 yr, on
four separate occasions. Participants’ CYP2D6 genotypes were determined,
hypercapnic ventilatory responses were obtained, and arterial blood samples
were collected before and for 6 h after treatment. A population pharmacokinetic–
pharmacodynamic analysis was performed on V̇
E55, 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 respiratory
depression with peak effects occurring at 0.5 to 1 h after opioid dosing.
After peak effect, compared with morphine, respiratory depression induced
by oliceridine returned faster to baseline. The effect-site concentrations
causing a 50% depression of V̇E
55 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
after both low- and high-dose oliceridine, compared with the other
participants.
Conclusions: Oliceridine and morphine differ in their respiratory pharmacodynamics
with a more rapid onset and offset of respiratory depression for
oliceridine and a smaller magnitude of respiratory depression over time.
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- All authors
- Simons, P.; Schrier, R. van der; Lemmen, M. van; Jansen, S.; Kuijpers, K.W.K.; Velzen, M. van; Sarton, E.; Nicklas, T.; Michalsky, C.; Demitrack, M.A.; Fossler, M.; Olofsen, E.; Niesters, M.; Dahan, A.
- Date
- 2023-03-01
- Journal
- Anesthesiology
- Volume
- 138
- Issue
- 3
- Pages
- 249 - 263