Authors: Jansen S et al.
Anesthesiology. December 2025. DOI: 10.1097/ALN.0000000000005894
Summary
This randomized, double-blind, placebo-controlled study compared the respiratory and antinociceptive effects of the dual nociceptin–mu opioid receptor (NOP–MOP) agonist cebranopadol with the full mu-opioid receptor agonist oxycodone in healthy volunteers. The rationale for the study stems from preclinical and early clinical data suggesting that NOP receptor activity may mitigate opioid-induced respiratory depression while preserving analgesia.
Thirty healthy volunteers participated in a partial crossover design, receiving placebo, multiple oral doses of cebranopadol (600, 800, and 1000 µg), and oxycodone (30 mg and 60 mg) across four study sessions. Ventilatory control was assessed using hypercapnic ventilatory response testing, with ventilation extrapolated to an isohypercapnic level of 55 mmHg (V̇E55) as the primary respiratory endpoint. Analgesic effects were measured using electrical pain tolerance testing over a 24-hour period following drug administration. Mixed-effects modeling and exploratory population pharmacokinetic/pharmacodynamic (PK/PD) analyses were performed.
Oxycodone, particularly at the 60 mg dose, produced substantially more respiratory compromise than cebranopadol. Oxygen desaturations to approximately 80% occurred in 65% of subjects after oxycodone 60 mg, compared with 25% of subjects after cebranopadol 1000 µg. All active drug conditions differed significantly from placebo with respect to respiratory effects, but cebranopadol 600 µg caused significantly less respiratory depression than oxycodone 30 mg despite providing comparable analgesia. PK/PD modeling demonstrated a clear separation between the two agents, with cebranopadol exhibiting a markedly lower respiratory depressant effect at equianalgesic concentrations. Notably, cebranopadol showed greater analgesic potency than oxycodone while maintaining a wider apparent safety margin for respiratory depression.
Overall, the study provides human experimental evidence that dual NOP–MOP receptor agonism may offer clinically meaningful advantages over traditional opioids by decoupling analgesia from respiratory depression, a key limitation of current opioid therapy.
Key Points
Cebranopadol produced significantly less respiratory depression than oxycodone at equianalgesic doses.
Severe oxygen desaturation was more frequent with oxycodone, particularly at higher doses.
Pharmacokinetic/pharmacodynamic modeling demonstrated a clear separation between analgesic and respiratory effects for cebranopadol.
Cebranopadol was more potent than oxycodone in producing analgesia in healthy volunteers.
Dual NOP–MOP agonism represents a promising strategy to improve opioid safety profiles.
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