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 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.Perioperative Medicine: Efficacy, Safety and Outcome (Anesthesiology/Intensive Care

Benefit and risk evaluation of biased mu-receptor agonist oliceridine versus morphine

Background: To improve understanding of the respiratory behavior of oliceridine, a mu-opioid receptor agonist that selectively engages the G-protein-coupled signaling pathway with reduced activation of the beta-arrestin pathway, the authors compared its utility function with that of morphine. It was hypothesized that at equianalgesia, oliceridine will produce less respiratory depression than morphine and that this is reflected in a superior utility.Methods: Data from a previous trial that compared the respiratory and analgesic effects of oliceridine and morphine in healthy male volunteers ( n = 30) were reanalyzed. A population pharmacokinetic-pharmacodynamic analysis was performed and served as basis for construction of utility functions, which are objective functions of probability of analgesia, P(analgesia), and probability of respiratory depression, P(respiratory depression). The utility function = P(analgesia >= 0.5) - P(respiratory depression >= 0.25), where analgesia >= 0.5 is the increase in hand withdrawal latency in the cold pressor test by at least 50%, and respiratory depression >= 0.25 is the decrease of the hypercapnic ventilatory response by at least 25%. Values are median +/- standard error of the estimate.Results: The two drugs were equianalgesic with similar potency values (oliceridine: 27.9 +/- 4.9 ng/ml; morphine 34.3 +/- 9.7 ng/ml; potency ratio, 0.81; 95% CI, 0.39 to 1.56). A 50% reduction of the hypercapnic ventilatory response by morphine occurred at an effect-site concentration of 33.7 +/- 4.8 ng/ml, while a 25% reduction by oliceridine occurred at 27.4 +/- 3.5 ng/ml (potency ratio, 2.48; 95% CI, 1.65 to 3.72; P < 0.01). Over the clinically relevant concentration range of 0 to 35 ng/ml, the oliceridine utility function was positive, indicating that the probability of analgesia exceeds the probability of respiratory depression. In contrast, the morphine function was negative, indicative of a greater probability of respiratory depression than analgesia.Conclusions: These data indicate a favorable oliceridine safety profile over morphine when considering analgesia and respiratory depression over the clinical concentration range

Effects of a respiratory functional training program on pain and sleep quality in patients with fibromyalgia: A pilot study

Objective: To evaluate the effect of 8-week respiratory functional training program on pain tolerance, sleep, and urinary antioxidant and cortisol levels in 18 patients with fibromyalgia. Methods: Participants underwent a 12-week intervention: 4 weeks as control and 8 weeks of breathing exercises. Pain tolerance assay was done by using an algometer, whereas sleep quality was evaluated by actigraphy and by the Pittsburgh Sleep Quality Index. Cortisol and antioxidant levels were determined using commercial assay kits. Results: Increases in the pain tolerance threshold were detected in the occiput point after one month of intervention as well as in the low cervical and second rib points after one and two months. Actigraphy revealed a decrease in sleep latency, whereas sleep questionnaire showed improvements in sleep quality, sleep duration and sleep efficiency. No changes in cortisol and antioxidant levels were detected. Conclusion: The 8-week breathing exercise intervention reduced pain and improved sleep quality