Oliceridine (Olinvyk) is a μ-opioid receptor agonist that in contrast to conventional opioids preferentially engages the G-protein–coupled signaling pathway. This study was designed to determine the utility function of oliceridine versus morphine based on neurocognitive tests and cold pressor test.


The study had a randomized, double-blind, placebo-controlled, partial block three-way crossover design. Experiments were performed in 20 male and female volunteers. The subjects received intravenous oliceridine (1 or 3 mg; cohorts of 10 subjects/dose), morphine (5 or 10 mg; cohorts of 10 subjects/dose), or placebo on three separate occasions. Before and after dosing, neurocognitive tests, cold pressor test, and plasma drug concentrations were obtained at regular intervals. Population pharmacokinetic–pharmacodynamic analyses served as the basis for construction of a utility function, which is an objective function of probability of benefit minus probability of harm. Antinociception served as the measure of benefit, and slowing of saccadic peak velocity and increased body sway as the measures of neurocognitive harm.


The oliceridine and morphine C50 values, i.e., the effect-site concentrations causing 50% effect, were as follows: antinociception, 13 ± 2 and 23 ± 7 ng/ml; saccadic peak velocity, 90 ± 14 and 54 ± 15 ng/ml; and body sway, 10 ± 2 and 5.6 ± 0.8 ng/ml, respectively. The ratio oliceridine/morphine of the therapeutic indices, C50(benefit)/C50(harm), were 0.34 (95% CI, 0.17 to 0.7; P < 0.01) for saccadic peak velocity and 0.33 (0.16 to 0.50; P < 0.01) for body sway. The oliceridine utility was positive across the effect-site concentration 5 to 77 ng/ml, indicative of a greater probability of benefit than harm. The morphine utility was not significantly different from 0 from 0 to 100 ng/ml. Over the concentration range 15 to 50 ng/ml, the oliceridine utility was superior to that of morphine (P < 0.01). Similar observations were made for body sway.


These data indicate that over the clinical concentration range, oliceridine is an analgesic with a favorable safety profile over morphine when considering analgesia and neurocognitive function.

Editor’s Perspective
What We Already Know about This Topic
  • Oliceridine is a μ-opioid receptor agonist that, unlike conventional opioids, preferentially engages the G-protein–coupled signaling pathway, which is associated with analgesia, and has reduced engagement of the β-arrestin pathway, which is associated with adverse effects
  • Over clinically relevant concentration ranges, oliceridine has a higher probability of providing analgesia than producing respiratory depression, and morphine has a higher probability of producing respiratory depression than providing analgesia
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 a randomized, double-blind, placebo-controlled, dose-ranging, partial block three-way crossover study of 20 healthy volunteers
  • The utility function was the probability of providing analgesia, an increase in hand withdrawal latency of 50% or more, minus the probability of producing a change of at least 25% in neurocognitive function, measured as saccadic peak velocity and body sway
  • Over clinically relevant concentration ranges, oliceridine had positive utility functions for both saccadic peak velocity (a biomarker of sedation) and body sway, and the morphine utility functions were not different from zero