Background 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. Methods 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. 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. 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. Conclusions 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.

Opioids are effective analgesics, but they can have harmful adverse effects, such as addiction and potentially fatal respiratory depression. Naloxone is currently the only available treatment for reversing the negative effects of opioids, including respiratory depression. However, the effectiveness of naloxone, particularly after an opioid overdose, varies depending on the pharmacokinetics and the pharmacodynamics of the opioid that was overdosed. Long-acting opioids, and those with a high affinity at the µ-opioid receptor and/or slow receptor dissociation kinetics, are particularly resistant to the effects of naloxone. In this review, we will examine the pharmacology of naloxone and its safety and limitations in reversing opioid-induced respiratory depression under different circumstances, including its ability to prevent cardiac arrest.

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Ketamine is administered predominantly via the intravenous route for the various indications, including anesthesia, pain relief and treatment of depression. Here we report on the pharmacokinetics of sublingual and buccal fast-dissolving oral-thin-films that contain 50 mg of S-ketamine in a population of healthy male and female volunteers. Twenty volunteers received one or two oral thin films on separate occasions in a randomized crossover design. The oral thin films were placed sublingually (n = 15) or buccally (n = 5) and left to dissolve for 10 min in the mouth during which the subjects were not allowed to swallow. For 6 subsequent hours, pharmacokinetic blood samples were obtained after which 20 mg S-ketamine was infused intravenously and blood sampling continued for another 2-hours. A population pharmacokinetic analysis was performed in NONMEM pharmacokinetic model of S-ketamine and its metabolites S-norketamine and S-hydroxynorketamine; p < 0.01 were considered significant. S-ketamine bioavailability was 26 ± 1% (estimate ± standard error of the estimate) with a 20% lower bioavailability of the 100 mg oral thin film relative to the 50 mg film, although this difference did not reach the level of significance. Due to the large first pass-effect, 80% of S-ketamine was metabolized into S-norketamine leading to high plasma levels of S-norketamine following the oral thin film application with 56% of S-ketamine finally metabolized into S-hydroxynorketamine. No differences in pharmacokinetics were observed for the sublingual and buccal administration routes. The S-ketamine oral thin film is a safe and practical alternative to intravenous S-ketamine administration that results in relatively high plasma levels of S-ketamine and its two metabolites.

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Ketamine is a versatile drug used for many indications and is administered via various routes. Here, we report on the pharmacodynamics of sublingual and buccal fast-dissolving oral-thin-films that contain 50 mg of S-ketamine in a population of healthy male and female volunteers. Twenty volunteers received one or two 50 mg S-ketamine oral thin films in a crossover design, placed for 10 min sublingually (n = 15) or buccally (n = 5). The following measurements were made for 6 h following the film placement: antinociception using three distinct pain assay; electrical, pressure, and heat pain, and drug high on an 11-point visual analog scale. Blood samples were obtained for the measurement of plasma S-ketamine, S-norketamine, and S-hydroxynorketamine concentrations. A population pharmacodynamic analysis was performed in NONMEM to construct a pharmacodynamic model of S-ketamine and its metabolites. P-values < 0.01 were considered significant. The sublingual and buccal 50 and 100 mg S-ketamine oral thin films were antinociceptive and produced drug high with effects lasting 2–6 h, although a clear dose-response relationship for antinociception could not be established. The effects were solely related to the parent compound with no contribution from S-norketamine or S-hydroxynorketamine. S-ketamine potency was lower for antinociception (C50 ranging from 1.2 to 1.7 nmol/mL) than for drug high (C50 0.3 nmol/ml). The onset/offset of effect as defined by the blood-effect-site equilibration half-life did not differ among endpoints and ranged from 0 to 5 min. In conclusion, the 50-mg S-ketamine oral thin film was safe and produced long-term antinociception in all three nociceptive assays with side effects inherent to the use of ketamine. The study was registered at the trial register of the Dutch Cochrane Center (www.trialregister.nl) under identifier NL9267 and the European Union Drug Regulating Authorities Clinical Trials (EudraCT) database under number 2020-005185-33.