DECEMBER 19, 2023
LAS VEGAS—A novel, first-in-class analgesic candidate in development for relief of acute pain could present less risk for abuse and addiction than current opioid-based agents, if promising results from a human addiction potential (HAP) trial,1 presented at the 2023 PAINWeek conference, are confirmed in evaluations that subject it to multiple potential modes of misuse.
“Based on all of our preclinical and human studies, we believe snorting or injecting cebranopadol would not make it
LAS VEGAS—A novel, first-in-class analgesic candidate in development for relief of acute pain could present less risk for abuse and addiction than current opioid-based agents, if promising results from a human addiction potential (HAP) trial,1 presented at the 2023 PAINWeek conference, are confirmed in evaluations that subject it to multiple potential modes of misuse.
“Based on all of our preclinical and human studies, we believe snorting or injecting cebranopadol would not make it more abusable,” James Hackworth, PhD, the president of the Brand Division at Tris Pharma, told Pain Medicine News. “However, because we know the medical community will have concerns about such abuse based on what has happened with other drugs, we will conduct human abuse potential trials where subjects will assess cebranopadol’s abuse potential via snorting and injection.”
Cebranopadol, an agonist at both the nociceptin/orphanin FQ peptide (NOP) and mu-opioid peptide (MOP) receptors, has been assessed in phase 2 studies for acute (postoperative) pain2 and chronic low back pain.3 Hackworth expects results from a phase 3 trial in acute pain to be available in 2025.
In the current randomized, double-blind HAP trial, a single oral dose of placebo, cebranopadol 600 mcg, cebranopadol 1,000 mcg, tramadol immediate-release (IR) 600 mg and oxycodone IR 40 mg were each given to 45 participants, characterized as nondependent recreational opioid users, in a five-way crossover design, to ascertain the relative “liking” or “good drug effect,” which could reinforce inappropriate consumption.
“Many drugs have theoretical abuse potential, as cebranopadol seemingly does at very high doses,” Hackworth said. “We know from the data generated in our HAP study that cebranopadol is ‘liked’ significantly less than the C-IV [Schedule IV] analgesic tramadol and the C-II (analgesic) oxycodone … by recreational opioid users.”
“The importance of this is that cebranopadol has the potential to safely replace drugs that have significantly higher abuse potential in the treatment of moderate to severe pain and at doses in the therapeutic range, data show that cebranopadol produces no euphoria whatsoever, so using it to treat pain should not result in people wanting to abuse the drug. This is very different than what we see with currently approved products, where research has shown that a large fraction of people who misuse opioids were initially prescribed the medications to legitimately manage pain and enjoyed the feeling of the drug. This does not appear to be a risk with cebranopadol,” Hackworth noted.
Hackworth acknowledged that the potential for abuse and addiction can emerge from development of dependence and aversion to withdrawal, in addition to drug “liking,” and so elaborated on why he is confident that cebranopadol will not be a preferred drug of abuse.
“We have extensive preclinical and human data showing that physical dependence is not a concern with cebranopadol. In all of our human trials—ranging from a single dose to six months of continuous treatment—the drug has been discontinued abruptly without taper at the end of therapy, and we have seen no signal for withdrawal,” Hackworth said.
Advantage of Co-Activating NOP and MOP Receptors
In a recent review of the therapeutic potential of co-activating NOP and MOP receptors for pain conditions, Kiguchi Norikazu, PhD, a researcher in the Department of Pharmacology at Wakayama Medical University in Wakayama, Japan, and colleagues describe a synergy from NOP receptor activation inhibiting dopaminergic transmission while enhancing MOP receptor–mediated analgesia.4
“These newly developed ligands … potently induce antinociception without MOP receptor agonist–associated side effects such as abuse potential, respiratory depression, itching sensation and physical dependence,” Norikazu and colleagues reported.
“In addition, in both rodent and NHP (nonhuman primate) models, bifunctional NOP/MOP receptor agonists can attenuate reward processing and/or the reinforcing effects of opioids and other abused drugs,” they noted.
In the phase 2 study of cebranopadol for postoperative acute pain, a single dose of 200, 400 or 600 mcg was compared with morphine controlled release (CR) 60 mg or placebo in randomized, double-blind assignment to 258 patients who had undergone a primary bunionectomy. The primary end point was the sum of pain intensity two to 10 hours after dosing, with cebranopadol and morphine CR administered at different time points based on pharmacokinetic differences to reach maximum plasma concentration.
The investigators reported that cebranopadol doses of 400 and 600 mcg, but not 200 mcg, were more effective in reducing postoperative acute pain compared with placebo from two to approximately 22 hours after dosing. Although not superior to morphine in reducing pain, the investigators related global impression measures indicating that patients were “more satisfied” with the effect of cebranopadol 400 or 600 mcg on their pain than those receiving morphine CR (albeit acknowledging the slower onset of the CR morphine dose).
“Cebranopadol has the potential to safely replace drugs that have significantly higher abuse potential in the treatment of moderate to severe pain,” Hackworth said. “At doses in the therapeutic range, data show that cebranopadol produces no euphoria whatsoever, so using it to treat pain should not result in people wanting to abuse the drug.”
That assessment of and expectations for cebranopadol are shared by Joseph Pergolizzi Jr., MD, MBA, the chief operating officer of NEMA Research, in Naples, Fla.
“The (HAP) data were encouraging because the current data aligned with previously publicly reported data that cebranopadol demonstrated significantly lower abuse potential compared to both Schedule II oxycodone and Schedule IV tramadol opioids, thereby furthering the understanding of the abuse potential of cebranopadol,” said Pergolizzi, a Pain Medicine News editorial advisory board member. “Cebranopadol is the first drug being developed in this class and has the potential to serve as a much-needed novel treatment option for patients with moderate to severe pain.”
—Kenneth Bender
References
Pergolizzi chaired the PAINWeek conference poster and abstract committee, and includes Tris Pharma among the companies for which he consults, but notes that he has no relationship with the HAP trial or the investigators.
