Poster Number-22 - Cebranopadol, a Novel Potent Analgesic: Limitations in Physical Dependence Using Short- and Long-term Rodent Studies

Cebranopadol, a Novel Potent Analgesic: Limitations in Physical Dependence Using Short- and Long-term Rodent Studies

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. These studies evaluate the development of physical dependence in response to use of cebranopadol in mice and rats.

Methods:

In a short-term study in mice, cebranopadol was administered in seven escalating doses over two days. The first three administrations were given in an escalating dose scheme. The remaining doses were maintained at the level of the third dose. There were 5 dosing groups (1.0-100μg/kg) with 12 mice each. Withdrawal was precipitated by administration of naloxone 2 hours after the last administration of cebranopadol. The mice were placed in glass jars immediately after administration of naloxone and the number of jumps (all 4 paws off the bottom surface) were recorded over 15 minutes. Withdrawal was quantified from the number of jumps occurring 0-10 min after administration of naloxone. The number of animals with a jumping frequency of more than 10 jumps/10 min were rated as withdrawal positive.
During the long-term study in rats, cebranopadol was administered twice daily at three different doses: 16μg/kg/day, 160μg/kg/day and 400μg/kg/day. A placebo group served as negative control. One group with morphine administered via the drinking fluid (targeted dose of 80 mg/kg/day) served as positive control with a respective placebo group (water as drinking fluid) served as a negative control. The study drug was administered over a period of 4 weeks, followed by a week of spontaneous withdrawal and observation, followed by another week of drug administration, followed by forced withdrawal with naloxone. Endpoints measured include body weight, food and fluid intake, locomotor activity (H-maze test).  Changes in body weight and withdrawal signs and symptoms were monitored to determine withdrawal.

Results:

In the short-term study, across the 5 dosing groups that were evaluated, 4 mice demonstrated withdrawal symptoms in the two highest doses:  1 in the 46.4μg/kg group and 3 in the 100μg/kg group demonstrating a dose-dependent increase. In the dosages 1.0, 4.64 and 10.0μg/kg no withdrawal was detectable.

During the long-term study in rats, both cebranopadol and morphine led to reduced body weight. Cebranopadol generally reduced food and fluid intake compared to placebo, whereas the effects of morphine on food and fluid intake were transient. Cebranopadol reduced locomotor activity compared to the respective placebo group; morphine had no significant effect on this parameter.

Following spontaneous withdrawal, rats in the morphine and cebranopadol groups experienced weight loss. The maximal body weight loss was 1.2% to 2.0% in the cebranopadol groups and 11.3% in the morphine group. Limited signs of withdrawal were observed in the 16μg/kg/day cebranopadol group with no symptoms observed at the higher doses, but significant signs of withdrawal following cessation of morphine were observed.
Naloxone-induced withdrawal led to more pronounced weight loss in the cebranopadol group with the maximal weight loss being 4.4% to 5.3%. No other significant withdrawal symptoms were observed. Alternatively in the morphine group the maximal weight loss following naloxone induced drug withdrawal was 11.6% with significant withdrawal symptoms observed.

Conclusion: Cebranopadol is a highly potent analgesic with efficacy demonstrated across a variety of pain types and animal models at effective doses (ED₅₀) ranging from 0.5-5.6 μg/kg. Spontaneous and precipitated withdrawal following cebranopadol administration was limited demonstrating a low potential for cebranopadol to lead to physical dependence in rodents despite supratherapeutic doses. Clinical studies have demonstrated consistent results in humans. Further studies to understand the application of these findings in humans are ongoing.

References: • Linz K, Christoph T, Tzschentke TM, et al. Cebranopadol: a novel potent analgesic nociceptin/orphanin FQ peptide and opioid receptor agonist. J Pharmacol Exp Ther. 2014;349(3):535-548.
• 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.
• Tzschentke TM, Kögel BY, Frosch S, Linz K. Limited potential of cebranopadol to produce opioid-type physical dependence in rodents. Addict Biol. 2018;23(5):1010-1019.
• Data on file. Tris Pharma, Inc. PH665.
• Data on file. Tris Pharma, Inc. PH704.