Poster Number-21 - Cebranopadol, a Novel Potent Analgesic: Pooled Analysis of Clinical Opiate Withdrawal Scales

Cebranopadol, a Novel Potent Analgesic: Pooled Analysis of Clinical Opiate Withdrawal Scales

Purpose:

Cebranopadol is a novel, highly potent, and centrally active opioid receptor agonist with high affinity for the μ-opioid receptors and nociceptin/orphanin FQ peptide (NOP) receptors and lesser affinity for κ-opioid receptors and δ-opioid receptors. Agonism of the NOP receptor has been associated with a reduction in adverse events related to the agonism of the µ-opioid receptor including respiratory depression, euphoria, sedation and physical dependence.  Animal studies with cebranopadol have demonstrated a limited potential for the development of physical dependence.

During clinical trials, patients were monitored for the development of physical dependence and withdrawal. This descriptive analysis explores the development of physical dependence by evaluating the evidence of withdrawal in patients following discontinuation of cebranopadol.

Methods: Nine phase 2/3 clinical trials were conducted with cebranopadol across multiple pain types. In 5 studies during which patients received at least 4 weeks of treatment, investigators also administered the clinical opiate withdrawal scale (COWS), measuring the signs and symptoms of withdrawal. An analysis of the adverse events reported as well as an analysis of the COWS from the safety populations across these studies was conducted.

Results: A total of 1,068 patients received treatment with cebranopadol with daily doses ranging from 25-800μg. Comparator agents included placebo (n=404), tapentadol prolonged release (PR) 200mg twice daily (BID) (n=126), pregabalin 300mg BID (N=65), or oxycodone controlled release (CR) 10-50mg BID (n=155), for a duration of 4 to 12 weeks. In contrast to standard clinical practice with opioids, all study drugs were discontinued abruptly at the end of each trial with the exception of pregabalin which was tapered over one week. The overall incidence of the treatment emergent adverse event (TEAE) drug withdrawal syndrome was similar between cebranopadol and placebo with higher rates observed in the oxycodone and tapentadol arms within the respective studies. Additionally, when evaluating COWS, incidences of mild withdrawal were similar for cebranopadol across studies and lower than oxycodone CR or tapentadol PR in the respective studies. The incidences of moderate withdrawal were lower in the cebranopadol group than in the oxycodone CR or tapentadol PR groups during the respective studies.

Conclusion: Cebranopadol has demonstrated limited physical dependence across a wide range of doses including the high dose of 800μg which is greater than double the highest therapeutic dose that is expected to be used for pain in phase 3 trials. Considering its safety across a wide range of doses, cebranopadol may serve as a much-needed treatment option for patients with moderate to severe pain.

References: • Toll L, Bruchas MR, Calo' G, Cox BM, Zaveri NT. Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems. Pharmacol Rev. 2016;68(2):419-457.
• Wesson DR, Ling W. The Clinical Opiate Withdrawal Scale (COWS). J Psychoactive Drugs. 2003;35(2):253-259.
• Data on file. Tris Pharma, Inc. IB12ed.