Nonopioid Therapy For Acute Pain Shows Positive Results in Phase 3 Trial
Cebranopadol met its primary endpoint of reduction in pain intensity as measured by the Pain Numeric Rating Scale (NRS) area under the curve from 2 through 48 hours.
Positive topline results have been announced from a phase 3 trial evaluating the efficacy and safety of cebranopadol for the treatment of moderate to severe acute pain in adult patients following bunionectomy surgery, Tris Pharma announced in a release.1 The company said the data, along with data from several other studies, will be submitted to the FDA as the basis for potential approval.
Nonopioid Therapy For Acute Pain Shows Positive Results in Phase 3 Trial / Dmitrijs - stock.adobe.com
Results from the ALLEVIATE-2 (NCT06423703) study showed that cebranopadol met the primary endpoint of reduction in pain intensity as measured by the Pain Numeric Rating Scale (NRS) area under the curve from 2 through 48 hours following dosing. The therapy was also generally well tolerated with a favorable safety profile and no serious adverse events.
READ MORE: Cebranopadol Shows Lower Abuse Potential Compared to Existing Pain Therapies
Cebranopadol is a first-in-class investigational therapy. It is a dual-NMR agonist, as it targets the nociceptin/orphanin FQ receptor and the µ-opioid receptor. Cebranopadol has the potential to treat multiple types of pain.
“We are in desperate need of effective medications that provide opioid-level analgesia while minimizing the risk of misuse and abuse,” Jeff Gudin, MD, anesthesiologist at the University of Miami, Miller School of Medicine, said in a release.1 “The strong analgesic effect, exceeding that observed with oxycodone in the bunionectomy study, coupled with low abuse potential, demonstrates the power of agonizing the NOP/MOP receptor system, which represents a breakthrough in our understanding of pain biology.”
ALLEVIATE-2 was a multicenter, randomized, double-blind, placebo-and active-controlled phase 3 study that evaluated the analgesic efficacy of cebranopadol compared with placebo for the management of moderate to severe acute pain following bunionectomy. The study cohort included 240 patients who were scheduled to undergo primary unilateral bunionectomy with first metatarsal osteotomy and internal fixation with no collateral procedures. Patients were excluded if they had a clinically significant disease, medical condition or current pain condition.
The study included 3 groups: cebranopadol 400 ug once daily for 3 days, oxycodone immediate release 4 times daily for 3 days, and placebo. The primary endpoint was pain intensity measured by the NRS area under the curve from 2 through 48 hours following surgery. Secondary outcomes included analgesic efficacy of cebranopadol through use of rescue medication, early discontinuation and patient’s overall assessment of the therapy.
The study found treatment with cebranopadol resulted in a statistically significant reduction in pain intensity on the NRS area under the curve through 48 hours. Although oxycodone showed more pain relief compared to placebo, its mean activity was lower compared to cebranopadol. Additionally, there was a higher proportion of patients in the cebranopadol group who did not require opioid rescue medication compared to placebo.
“These are extremely encouraging results that emphasize the important role dual-NMR drugs could play in treating moderate to severe acute pain with much lower risk of the misuse, physical dependence, addiction or overdose seen with opioids while still being able to provide a comparable level of analgesia,” Todd Bertoch, MD, lead investigator for the ALLEVIATE-2 study, said in a release.1 “The biggest challenge in the search for new drugs for pain has been finding something safe that can treat more severe pain that today requires use of an opioid. The level of analgesia seen across both ALLEVIATE-1 and ALLEVIATE-2 as well as the safety data that has been generated suggest that cebranopadol could fulfill this urgent need.”
In January 2025, Tris announced positive topline results from the ALLEVIATE-1 (NCT06545097) study, which evaluated the efficacy and safety of cebranopadol for the treatment of moderate to severe acute pain in adult patients following full abdominoplasty.2 The data showed that the therapy resulted in a statistically significant reduction in pain intensity compared to placebo. There were also no serious adverse events seen in the patients who received cebranopadol.
Tris also announced positive results shortly after from an intranasal human abuse potential study evaluating the intranasal pharmacokinetics and abuse potential of cebranopadol compared to oxycodone in adult nondependent recreational opioid users.3 The study showed a supratherapeutic dose of 1000 ug cebranopadol—which is 2.5 times higher than the therapeutic dose for the treatment of pain—was significantly less likeable compared to 40 mg oxycodone when crushed and taken intranasally.
READ MORE: Pain Management Resource Center
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