Background

To improve understanding of the respiratory behavior of oliceridine, a μ-opioid receptor agonist that selectively engages the G-protein–coupled signaling pathway with reduced activation of the β-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.

Editor’s Perspective
What We Already Know about This Topic
  • Classical opioid analgesics engage two distinct transduction pathways after μ-opioid receptor activation, the G-protein–coupled signaling pathway and the β-arrestin pathway

  • The G-protein pathway is primarily involved in analgesia, reward, and liking, while the β-arrestin pathway is involved in adverse effects such as respiratory depression

  • Oliceridine is a μ-opioid receptor agonist that selectively engages the G-protein–coupled signaling pathway with reduced activation of the β-arrestin pathway

What This Article Tells Us That Is New
  • Utility functions were developed from population pharmacokinetic–pharmacodynamic analyses of oliceridine and morphine concentration–effect relationships in 29 healthy male volunteers

  • The utility function was defined as the probability of providing analgesia, an increase in hand withdrawal latency of 50% or more, minus the probability of producing respiratory depression, a decrease of the ventilatory response to hypercapnia of at least 25%

  • Over the clinically relevant concentration range, oliceridine had a higher probability of providing analgesia than producing respiratory depression, while morphine had a higher probability of producing respiratory depression than providing analgesia

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