Inhaled Δ9-tetrahydrocannabinol does not enhance oxycodone-induced respiratory depression: randomised controlled trial in healthy volunteers.

BACKGROUND: In 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. METHODS: In 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. RESULTS: In 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. CONCLUSIONS: In humans, THC has no effect on ventilatory control after placebo or oxycodone pretreatment. CLINICAL TRIAL REGISTRATION: 2021-000083-29 (EU Clinical Trials Register.).

Respiratory Effects of Biased Ligand Oliceridine in Older Volunteers: A Pharmacokinetic-Pharmacodynamic Comparison with Morphine.

BACKGROUND: 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, V̇E55. 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 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. After peak effect, compared with 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 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.

S-Ketamine oral thin film-Part 2: Population pharmacodynamics of S-ketamine, S-norketamine and S-hydroxynorketamine.

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.

S-Ketamine Oral Thin Film-Part 1: Population Pharmacokinetics of S-Ketamine, S-Norketamine and S-Hydroxynorketamine.

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.

[Metamizol: current status in Dutch practice]. / Pijnbestrijding met metamizol in de Nederlandse praktijk.

Metamizole is a non-selective NSAID with a strong analgesic and spasmolytic effect. In the late 1970s, metamizole has been withdrawn from the market in many industrialized countries because of an allegedly unacceptable high risk of agranulocytosis. The absolute risk of metamizole-related agranulocytosis is estimated to be less than 1 per million daily doses. The incidence of agranulocytosis may be reduced by short-term use and careful consideration when prescribing to specific patient categories. Metamizole has a relatively favorable safety profile with respect to morbidity and mortality compared to other NSAIDs. In the Netherlands the official registration of metamizole has been limited for years to intravenous and postoperative use. In March 2021, the Dutch Medicine Assessment Board certified one oral formulation of metamizol under strict conditions. The debate about the wider application of (oral) metamizole in the Netherlands should be re-opened.

Buprenorphine: a treatment and cause of opioid-induced respiratory depression.

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 serious respiratory depression, particularly when combined with sedatives such as benzodiazepines.

Assessment of respiratory effort during sleep: Esophageal pressure versus noninvasive monitoring techniques.

Monitoring of respiratory effort is paramount in the clinical diagnostic recording of sleep. Increased respiratory effort is a sign of obstructive sleep-disordered breathing and is associated with arousals from sleep. Respiration is the result of muscle activity that induces negative intrathoracic pressure and expansion of the thoracic and abdominal cavities. Therefore respiratory effort may be recorded from mechanical, electrical and electromechanical signals. Several techniques are available for the recording of respiratory effort. Monitoring of esophageal pressure is still the method of choice, as the pressure signal directly reflects the respiratory muscle force. However, esophageal pressure monitoring is cumbersome and may be replaced with noninvasive techniques. In order to be reliable, these techniques must be validated against the esophageal pressure standard. The present review presents a concise description of the technical principles and, if available, a comparison with esophageal pressure data, based on a systematic literature search. Most data are available on respiratory inductance plethysmography, and confirm that this technique is suitable for routine diagnostic investigation of respiratory effort during sleep. Pulse transit time, diaphragmatic electromyography, snoring loudness, suprasternal pressure monitoring, midsagittal jaw movement and forehead venous pressure monitoring are promising alternative techniques although only limited validation is available.