Reversal of Propofol-induced Depression of the Hypoxic Ventilatory Response by BK-channel Blocker ENA-001: A Randomized Controlled Trial.

BACKGROUND: The use of anesthetics may result in depression of the hypoxic ventilatory response. Since there are no receptor-specific antagonists for most anesthetics, there is the need for agnostic respiratory stimulants that increase respiratory drive irrespective of its cause. The authors tested whether ENA-001, an agnostic respiratory stimulant that blocks carotid body BK-channels, could restore the hypoxic ventilatory response during propofol infusion. They hypothesize that ENA-001 is able to fully restore the hypoxic ventilatory response. METHODS: In this randomized, double-blind crossover trial, 14 male and female healthy volunteers were randomized to receive placebo and low- and high-dose ENA-001 on three separate occasions. On each occasion, isohypercapnic hypoxic ventilatory responses were measured during a fixed sequence of placebo, followed by low- and high-dose propofol infusion. The authors conducted a population pharmacokinetic/pharmacodynamic analysis that included oxygen and carbon dioxide kinetics. RESULTS: Twelve subjects completed the three sessions; no serious adverse events occurred. The propofol concentrations were 0.6 and 2.0 µg/ml at low and high dose, respectively. The ENA-001 concentrations were 0.6 and 1.0 µg/ml at low and high dose, respectively. The propofol concentration that reduced the hypoxic ventilatory response by 50% was 1.47 ± 0.20 µg/ml. The steady state ENA-001 concentration to increase the depressed ventilatory response by 50% was 0.51 ± 0.04 µg/ml. A concentration of 1 µg/ml ENA-001 was required for full reversal of the propofol effect at the propofol concentration that reduced the hypoxic ventilatory response by 50%. CONCLUSIONS: In this pilot study, the authors demonstrated that ENA-001 restored the hypoxic ventilatory response impaired by propofol. This finding is not only of clinical importance but also provides mechanistic insights into the peripheral stimulation of breathing with ENA-001 overcoming central depression by propofol.

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.

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.).

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.

Opioid-free anesthesia: A systematic review and meta-analysis.

STUDY OBJECTIVE: To evaluate all available evidence thus far on opioid based versus opioid-free anesthesia and its effect on acute and chronic postoperative pain. DESIGN: Systematic review and meta-analysis of randomized clinical trials. SETTING: Operating room, postoperative recovery room and ward. PATIENTS: Patients undergoing general anesthesia. INTERVENTIONS: After consulting MEDLINE, EMBASE and Cochrane database, studies which compared opioid free anesthesia (OFA) with opioid based anesthesia (OBA) were included (last search April 15th 2022). MEASUREMENTS: Primary outcomes were acute and chronic pain scores in NRS or VAS. Secondary outcomes were quality of recovery and postoperative opioid consumption. Risk of bias was assessed using the RoB2 tool and a random effects model for the meta-analysis was conducted. MAIN RESULTS: We identified 1245 citations, of which 38 studies met our inclusion criteria. There is moderate quality evidence showing no clinically relevant difference of Numeric Rating Scale (NRS) scores or opioid consumption in the postoperative period (pooled mean difference of 0.39 points with a CI of 0.19-0.59 and 4.02 MME with a CI of 1.73-6.30). We found only one small-sized study reporting no effect of opioid-free anesthesia on chronic pain. The quality of recovery was superior in patients with opioid-free anesthesia (mean difference of 8.26 points), however, this pooled analysis was comprised of only two studies. Postoperative nausea and vomiting (PONV) occurred less in opioid-free anesthesia, but bradycardia was more frequent. CONCLUSIONS: We concluded that we cannot recommend one strategy over the other. Future studies could focus on quality of recovery as outcome measure and adequately powered studies on the effects of opioid-free anesthesia on chronic pain are eagerly awaited.