Respiratory and antinociceptive effects of Nociceptin Receptor–µ-Opioid Receptor agonist cebranopadol versus full opioid receptor agonist oxycodone: a comparison in healthy volunteers

BACKGROUND: The novel analgesic cebranopadol targets the nociceptin (NOP) and mu-opioid (MOP) receptor, acting as a novel full dual NOP-MOP-receptor agonist, with possible differences in respiratory effects compared to selective MOP-opioids like oxycodone.

METHODS: 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 1000 µg, n=20) or oxycodone (30 mg, n=20; or 60 mg, n=20) on 4 occasions in a partial-crossover design. On each occasion ventilation at an extrapolated isohypercapnic level of 55 mmHg (V̇ E 55) 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 was performed (primary endpoint) as well as an exploratory population pharmacokinetic/pharmacodynamic analyses on respiratory and analgesic endpoints.

RESULTS: Oxygen desaturations (to ∼80%) were observed in 65% of subjects after oxycodone 60 mg versus cebranopadol 1000 µg in 25% of subjects (all occurring in between respiratory or pain testing). 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 respiratory C 50 values (drug concentration causing 50% effect) was 0.20±0.54 for cebranopadol versus 36±6 ng/mL for oxycodone. Cebranopadol was more potent than oxycodone in producing analgesia.

CONCLUSIONS: 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.