Neurocognitive Effect of Biased µ-Opioid Receptor Agonist Oliceridine, a Utility Function Analysis and Comparison with Morphine.

BACKGROUND

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.