Background: Cebranopadol is a potent, first-in-class analgesic with a novel mechanistic approach combining nociceptin/orphanin FQ peptide (NOP) and opioid peptide receptor agonism.
Objective: We aim to evaluate, for the first time, the analgesic efficacy, safety, and tolerability of cebranopadol in patients suffering from moderate to severe acute pain following bunionectomy.
Study design: We conducted a phase IIa, randomized, multi-center, double-blind, double-dummy, placebo- and active-controlled, parallel group clinical trial.
Methods: A total of 258 patients who underwent a primary bunionectomy were randomly assigned to receive a single oral administration of cebranopadol 200 µg, 400 µg, or 600 µg, morphine controlled-release (CR) 60 mg, or placebo. The primary efficacy end-point was the sum of pain intensity (SPI) 2 to 10 hours (SPI2-10) after the first investigational medicinal product (IMP) intake time-point.
Results: Cebranopadol doses of 400 µg and 600 µg were more effective in reducing postoperative acute pain compared to placebo, from 2 hours until approximately 22 hours after the first IMP intake time-point. No difference was observed between cebranopadol 200 µg and placebo. Per the subject global impression of the IMP assessment, patients who received cebranopadol 400 µg and 600 µg were more satisfied with the ability of the medication to treat their pain compared to those who received morphine CR 60 mg. On the primary end-point, the effect of morphine CR 60 mg was smaller than that of cebranopadol 400 µg and 600 µg. However, the analgesic effect of morphine CR 60 mg emerged later relative to IMP intake, as shown by the fact that similar SPI results as seen for cebranopadol 400 µg and 600 µg were obtained for later time windows. Cebranopadol treatment was safe, and single-dose administrations of 400 µg were better tolerated than morphine CR 60 mg. The relative frequency of patients with at least one treatment-emergent adverse event (TEAE) increased with increasing cebranopadol doses and was highest in the morphine CR 60 mg group.
Limitation: Although a double-dummy design was used to ensure blinding, a limitation of this trial was that cebranopadol and morphine CR were administered at 2 different time-points post-surgery, given the anticipated difference in the time to reach the maximum plasma concentration between the 2 treatments.
Conclusion: Administration of single cebranopadol doses of 400 µg and 600 µg induced more effective analgesia following bunionectomy surgery compared to the traditional opioid morphine on the primary end-point (SPI2-10), while both cebranopadol doses and morphine ensured adequate 24-hour pain relief. Moreover, cebranopadol was better tolerated and received a better overall rating by the patients.
Key words: Opioids, morphine, µ-opioid receptor, nociceptin/orphanin FQ peptide receptor, analgesic, bunionectomy, surgery, post-operative pain, single hallux valgus repair.