Introduction In-hospital use of opioids is associated with multiple adverse events, prolonged length of stay and opioid-related readmissions.1,2,3,4 Particularly respiratory depression from potent opioids is associated with not only respiratory depression but also cardiorespiratory collapse and death.5 Despite these adverse effects, opioids remain the cornerstone of pharmacotherapy for moderate-to-severe acute pain because of their efficacy.6 One strategy to mitigate opioid-induced adverse events is the development of safer opioids, e.g. opioids that produce less respiratory depression and lead to less addiction or abuse. One example of this strategy is the development of oliceridine that was recently approved by regulatory authorities in the United States for the treatment of postoperative pain.7 It differs from other opioids in that it is assumed that after activation of the µ-opioid receptor, oliceridine is biased toward the G-protein intracellular pathway which is predominantly associated with analgesia, and shows limited recruitment of the β-arrestin pathway, which is associated with opioidrelated adverse events (e.g.7,8,9,10,11 respiratory depression and tolerance).8,9,12 Theoretically, this would suggest that oliceridine has a lower probability of respiratory depression than, for example, morphine a full µ-opioid receptor agonist without biased toward the G-protein pathway. This was indeed observed in a study that examined the antinociceptive and respiratory effects of oliceridine versus morphine and showed a higher probability of antinociception versus respiratory depression for oliceridine while the reverse was true for morphine.13 In that study, healthy young volunteers were studied. In the current study, we tested older and somewhat obese individuals (age range 55- to 90 years, body mass index up to 34 kg/m2) because such individuals are an increasing part of our clinical caseload and opioids in these older individuals possibly may have a higher potency for respiratory depression than in younger individuals. In the current sample of such older individuals, we performed a population pharmacokinetic-pharmacodynamic modeling study on the effect intravenous oliceridine versus morphine on ventilation at an extrapolated end-tidal carbon dioxide concentration of 55 mmHg ( ˙VE55), the main endpoint of the study. We hypothesized that oliceridine and morphine differ in their pharmacodynamic behavior, measured as effect on ventilation at an extrapolated end-tidal PCO2 of 55 mmHg. 66
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