Respiratory and Antinociceptive Effects of Nociceptin Receptor-µ-Opioid Receptor Agonist Cebranopadol versus Full Opioid Receptor Agonist Oxycodone: A Comparison in Healthy Volunteers.

Abstract

The novel analgesic cebranopadol targets the nociceptin (NOP) and µ-opioid (MOP) receptors, acting as a novel full dual NOP-MOP receptor agonist, with possible differences in respiratory effects compared to selective MOP opioids like oxycodone. In this randomized, double-blind, placebo-controlled study, 30 healthy volunteers received oral placebo (n = 20), cebranopadol (600 µg, n = 20; 800 µg, n = 20; or 1,000 µg, n = 20), or oxycodone (30 mg, n = 20; or 60 mg, n = 20) on four occasions in a partial crossover design. On each occasion, measures of ventilation at an extrapolated isohypercapnic level of 55 mmHg derived from hypercapnic ventilatory responses and electrical pain tolerance tests were obtained at regular intervals before and for 24 h after drug intake. Mixed model analyses on respiratory endpoints were performed (primary endpoint) as well as an exploratory population pharmacokinetic/pharmacodynamic analysis on respiratory and analgesic endpoints. Oxygen desaturations (to approximately 80%) were observed in 65% of subjects after oxycodone 60 mg versus cebranopadol 1,000 µg in 25% of subjects (all occurring when experimental respiratory or pain testing was not performed). A significant main effect and a significant separation of all cebranopadol and oxycodone doses versus placebo (all P < 0.0001) was observed with cebranopadol 600 µg producing less respiratory depression than oxycodone 30 mg ( P = 0.022). Pharmacokinetic/pharmacodynamic analyses showed that the respiratory drug concentration causing 50% effect was 0.20 ± 0.54 ng/ml for cebranopadol versus 36 ± 6 ng/ml for oxycodone (values are median ± standard error of the estimate). Cebranopadol was more potent than oxycodone in producing analgesia. The primary endpoint showed separation between the respiratory effects of cebranopadol and oxycodone, with 25% less respiratory depression at equianalgesia, as observed in the pharmacokinetic/pharmacodynamic analysis.