The studies described in this thesis investigate the effects of different pharmacotherapieson antinociception and ventilatory control. Additionally, inherent variabilities in patient phenotypes... Show moreThe studies described in this thesis investigate the effects of different pharmacotherapieson antinociception and ventilatory control. Additionally, inherent variabilities in patient phenotypes within the population were assessed to gain a deeper understanding of the individual effects of analgesics and the ventilatory effects of disease, particularly type 2 diabetes mellitus (T2DM). Show less
Dam, C.J. van; Schrier, R. van der; Velzen, M. van; Lemmen, M. van; Simons, P.; Kuijpers, K.W.K.; ... ; Niesters, M. 2023
BackgroundIn humans, the effect of cannabis on ventilatory control is poorly studied, and consequently, the effect of Δ9-tetrahydrocannabinol (THC) remains unknown, particularly when THC is... Show moreBackgroundIn humans, the effect of cannabis on ventilatory control is poorly studied, and consequently, the effect of Δ9-tetrahydrocannabinol (THC) remains unknown, particularly when THC is combined with an opioid. We studied the effect of THC on breathing without and with oxycodone pretreatment. We hypothesised that THC causes respiratory depression, which is amplified when THC and oxycodone are combined.MethodsIn this randomised controlled crossover trial, healthy volunteers were administered inhaled Bedrocan® 100 mg (Bedrocan International B.V., Veendam, The Netherlands), a pharmaceutical-grade high-THC cannabis variant (21.8% THC; 0.1% cannabidiol), after placebo or oral oxycodone 20 mg pretreatment; THC was inhaled 1.5 and 4.5 h after placebo or oxycodone intake. The primary endpoint was isohypercapnic ventilation at an end-tidal Pco2 of 55 mm Hg or 7.3 kPa (VE55), measured at 1-h intervals for 7 h after placebo/oxycodone intake.ResultsIn 18 volunteers (age 22 yr [3]; 9 [50%] female), oxycodone produced a 30% decrease in VE55, whereas placebo was without effect on VE55. The first cannabis inhalation resulted in VE55 changing from 20.3 (3.1) to 23.8 (2.4) L min−1 (P=0.06) after placebo, and from 11.8 (2.8) to 13.0 (3.9) L min−1 (P=0.83) after oxycodone. The second cannabis inhalation also had no effect on VE55, but slightly increased sedation.ConclusionsIn humans, THC has no effect on ventilatory control after placebo or oxycodone pretreatment. Show less
Simons, P.; Schrier, R. van der; Lemmen, M. van; Jansen, S.; Kuijpers, K.W.K.; Velzen, M. van; ... ; Dahan, A. 2023
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
Simons, P.; Olofsen, E.; Velzen, M. van; Lemmen, M. van; Dasselaar, T. van; Mohr, P.; ... ; Dahan, A. 2022
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... Show moreKetamine 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. Show less
Simons, P.; Olofsen, E.; Velzen, M. van; Lemmen, M. van; Mooren, R.; Dasselaar, T. van; ... ; Dahan, A. 2022
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... Show moreKetamine 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. Show less
Dahan, A.; Lemmen, M. van; Jansen, S.; Simons, P.; Schrier, R. van der 2022
Buprenorphine is a partial agonist at the mu opioid receptor. Due to its relatively low maximum effect on respiratory depression it is considered by some to be a safe opioid. But it can produce... Show moreBuprenorphine is a partial agonist at the mu opioid receptor. Due to its relatively low maximum effect on respiratory depression it is considered by some to be a safe opioid. But it can produce serious respiratory depression, particularly when combined with sedatives such as benzodiazepines. Show less
