Authors: Jansen S et al.
Journal: Anesthesiology, December 11, 2025. DOI: 10.1097/ALN.0000000000005894
Summary
This randomized, double-blind, placebo-controlled crossover study compared the respiratory and analgesic effects of cebranopadol—a dual nociceptin (NOP) and mu-opioid (MOP) receptor agonist—with those of the full MOP agonist oxycodone in healthy volunteers. Given ongoing concerns about opioid-induced respiratory depression, the investigators sought to determine whether dual NOP-MOP agonism confers a more favorable respiratory safety profile at equianalgesic doses.
Thirty healthy participants received placebo, multiple oral doses of cebranopadol (600–1000 µg), and oxycodone (30 or 60 mg) across four study visits. Ventilation was assessed using extrapolated isohypercapnic ventilation (V̇E55), alongside experimental pain tolerance testing, over a 24-hour period. Mixed-effects modeling and exploratory pharmacokinetic/pharmacodynamic analyses were used to compare respiratory depression and analgesic potency.
Both cebranopadol and oxycodone caused measurable respiratory depression compared with placebo. However, cebranopadol demonstrated significantly less respiratory depression than oxycodone at comparable analgesic effect. Clinically notable oxygen desaturations occurred more frequently with oxycodone 60 mg than with the highest dose of cebranopadol. Pharmacokinetic/pharmacodynamic modeling showed a clear separation between the agents, with cebranopadol producing approximately 25% less respiratory depression at equianalgesia while also showing greater analgesic potency.
These findings suggest that dual NOP-MOP agonism may partially decouple analgesia from respiratory depression, supporting cebranopadol as a potential analgesic option with an improved respiratory safety margin compared with traditional opioids.
Key Points
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Cebranopadol caused significantly less respiratory depression than oxycodone at equianalgesic doses.
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Oxygen desaturation events were more frequent with higher-dose oxycodone than with cebranopadol.
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Pharmacokinetic/pharmacodynamic analyses demonstrated approximately 25% less respiratory depression with cebranopadol at equianalgesia.
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Cebranopadol was more potent than oxycodone in producing analgesia.
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Dual NOP-MOP receptor agonism may improve the respiratory safety profile of opioid analgesics.
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