Cebranopadol shows promise in phase 3 trials as a safer alternative to opioids for acute pain

A first-in-class investigational drug has been shown in two phase 3 trials to provide relief for moderate-to-severe acute pain in patients following abdominoplasty and bunionectomy surgery and is less subject to abuse than oxycodone and tramadol.

Tris Pharma presented data from its phase 3 ALLEVIATE-1 and ALLEVIATE-2 studies of cebranopadol at two recent meetings: the American Academy of Pain Medicine 2026 PainConnect annual meeting and the Annual Regional Anesthesiology and Acute Pain Medicine Meeting.

Approximately 80 million adults in the United States are treated for acute pain every year. Moderate-to-severe acute pain can often only be effectively treated with opioid analgesics, which, while effective, are associated with risks including respiratory depression, tolerance, dependence, misuse, and overdose.

Cebranopadol represents a new type of pain therapy: a dual nociceptin/orphanin FQ peptide (NOP) and μ-opioid peptide (MOP) receptor agonist. By activating both receptors, cebranopadol is designed to provide pain relief while potentially mitigating the risks associated with MOP agonists, such as morphine.

“As pain specialists, we often see how inadequately controlled acute pain can linger long after surgery or injury,” said Todd Bertoch, M.D., chief medical officer of CenExel Clinical Research and principal investigator on ALLEVIATE-2. “If we don’t get ahead of severe pain early, it can become chronic and much harder to treat. These phase 3 results underscore the potential of cebranopadol to redefine the standard of care for acute pain management.”

ALLEVIATE-1 enrolled 303 patients undergoing abdominoplasty surgery without liposuction or other collateral procedures. The study compared cebranopadol (400 µg on day 1 and 200 µg on day 2) with a placebo. ALLEVIATE-2 enrolled 242 patients undergoing unilateral bunionectomy with first metatarsal osteotomy. This study compared cebranopadol 400 µg with oxycodone immediate release 10 mg or a placebo.

The primary endpoints in both trials were met. Following abdominoplasty, a greater proportion of patients receiving cebranopadol 400 µg required no opioid rescue medication compared with those receiving a placebo. Following bunionectomy, a significantly higher proportion of patients receiving cebranopadol 400 µg required no opioid rescue medication compared with those receiving a placebo.

Cebranopadol was generally well tolerated and exhibited a favorable safety profile. Nausea was the most common adverse event across study groups, with the exception of the placebo group in the bunionectomy study. Other adverse events included vomiting, constipation, headache, dizziness, hypertension, and pruritus.

In the abdominoplasty study, 11 patients discontinued the study due to adverse events (3), loss to follow-up (2), withdrawal of consent (3), and other (3). In the bunionectomy study, one patient receiving oxycodone discontinued for hypersensitivity, which was considered a severe and serious adverse event.