Background & Aims

The development of cebranopadol marks a significant shift in ongoing research dedicated at creating potent, novel pain medications with an enhanced safety profile, attenuating the risk of respiratory depression inherent to opioids. Cebranopadol, a first-in-class, dual nociceptin/orphanin FQ peptide (NOP) receptor and µ-opioid peptide (MOP) receptor agonist (dual NMR agonist), derives its effect from activation of the NOP and MOP receptors leading to substantial antinociceptive effects and reduced MOP-related side effects. Prior preclinical and clinical studies have demonstrated cebranopadol’s benefits including reduced abuse potential, dependence, and respiratory depression. Moreover, results of a prior clinical trial suggest a respiratory depression ceiling.1-4
This study was conducted to assess the effects of cebranopadol on ventilatory drive, central nervous system, and pain responses in comparison to oxycodone and placebo.

Methods

The study employed a randomized, double-blind, partial crossover design with four periods separated by a two-week minimum washout period. After ethics approval, informed consent and screening, 30 healthy volunteers were randomized to receive encapsulated formulations of 4 out of 6 available treatments: placebo, cebranopadol 600μg, 800μg, or 1000μg, and oxycodone 30mg or 60mg on four separate study days. During each study visit, the ventilatory response to hypercapnia (Ve55), electrical and pressure pain threshold, electrical pain tolerance, pupil diameter and pharmacokinetic (PK) samples were obtained for 12 consecutive pre-defined timepoints. These PK and pharmacodynamic (PD) results were used to develop a population PK/PD model in NONMEM.

Results

Although all doses of cebranopadol administered had a greater analgesic potency than either dose of oxycodone, the PK/PD results were able to establish a model to compare respiratory depression at equianalgesic doses. The PK/PD analysis highlighted cebranopadol’s advantages over oxycodone, showing approximately 25% less respiratory depression for equivalent analgesia, attributed to NOP activation. In addition, cebranopadol featured prolonged analgesic effects, with a gradual onset and offset, and a longer time to peak impact on respiratory and pain parameters compared to oxycodone.
Special consideration was given to safety parameters related to respiratory function (e.g., apnea/decreased saturation), which were significantly more frequent after oxycodone 60 mg than any other treatment, occurring approximately 2 to 3 times more often. Generally, non-respiratory AEs were comparable between cebranopadol 600 and 800µg versus oxycodone 30mg, and cebranopadol 1000µg versus oxycodone 60mg.

Conclusions

This study confirms that cebranopadol produces potent analgesia that will persist for longer and will be associated with less respiratory depression when compared to equianalgesic doses of oxycodone.
The delayed onset of respiratory effects is a noteworthy clinical benefit of cebranopadol, allowing for the gradual accumulation of arterial CO2, thereby mitigating the full manifestation of respiratory depression. This characteristic of cebranopadol both gives the body time to adjust its breathing and gives healthcare providers a more extended timeframe for appropriate interventions, strengthening its overall safety in clinical use. Taken together, the results of this and previous clinical studies, as well as results from preclinical models, provide evidence to support the likelihood a ceiling of respiratory depression exists in humans. However, these data lead us to conclude further studies are needed to fully characterize the ceiling of respiratory effects cebranopadol may exhibit.

References

1.Ding H, Trapella C, Kiguchi N, Hsu FC, Caló G, Ko MC. Functional Profile of Systemic and Intrathecal Cebranopadol in Nonhuman Primates. Anesthesiology. Sep 1 2021;135(3):482-493. doi:10.1097/aln.0000000000003848
2.Koch ED, Kapanadze S, Eerdekens MH, et al. Cebranopadol, a Novel First-in-Class Analgesic Drug Candidate: First Experience With Cancer-Related Pain for up to 26 Weeks. J Pain Symptom Manage. Sep 2019;58(3):390-399. doi:10.1016/j.jpainsymman.2019.05.012
3.Linz K, Schröder W, Frosch S, Christoph T. Opioid-type Respiratory Depressant Side Effects of Cebranopadol in Rats Are Limited by Its Nociceptin/Orphanin FQ Peptide Receptor Agonist Activity. Anesthesiology. 2017;126(4):708-715. doi:10.1097/ALN.0000000000001530
4.Dahan A, Boom M, Sarton E, et al. Respiratory Effects of the Nociceptin/Orphanin FQ Peptide and Opioid Receptor Agonist, Cebranopadol, in Healthy Human Volunteers. Anesthesiology. Apr 2017;126(4):697-707. doi:10.1097/ALN.0000000000001529
5.Hellinga M, Algera MH, van der Schrier R, et al. A biomarker of opioid-induced respiratory toxicity in experimental studies. iScience. Apr 21 2023;26(4):106520. doi:10.1016/j.isci.2023.106520

Presenting Author

Simone C. Jansen

Poster Authors

Simone Jansen

LUMC ( Leiden University Medical Center)

Lead Author

E-mail

Antonio Pardo

MD

Tris Pharma, Inc.

Lead Author

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Joseph Greico

PhD

Tris Pharma, Inc.

Lead Author

E-mail

James Hackworth

PhD

Tris Pharma, Inc.

Lead Author

E-mail

Albert Dahan

MD, PhD

LUMC ( Leiden University Medical Center)

Lead Author

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