Undertreated Acute Pain Poses Long-Term Risks, But Prescription Opioids Still Do, Too ...

A new review accepted for publication in Frontiers in Pain Research underscores the ongoing challenges of managing moderate-to-severe acute pain in the US, particularly given the high risks associated with short-term opioid prescriptions. The peer-reviewed paper, commissioned by Tris Pharma, presents data showing that inadequately treated acute pain substantially increases the risk of chronic pain, while opioid use carries significant risks of misuse, dependence, and overdose.

“Physicians today face significant challenges when treating acute pain. Despite the availability of nonopioid options, opioids are often necessary for effective acute pain relief,” coauthor Charles Argoff, MD, Albany Medical College said in a statement. “Opioids carry inherent risks that are associated with prescribing precautions; however, completely avoiding them in the setting of severe acute pain may result in suboptimal pain reduction, increasing the likelihood of the acute pain becoming chronic." Argoff stressed that the paper further underscores the need for safer pain therapeutics "so that neither physicians nor patients have to choose between effective pain relief and risks detrimental to their quality of life, including addiction.”

Key findings from the review include:

• Roughly 25% of patients prescribed short-term opioids experience euphoria.
• An estimated 12% (8.3 million) of adult patients prescribed opioids misuse them, with higher risk in adolescents.
• More than 50% of patients addicted to heroin or fentanyl began as pain patients who experienced euphoria with prescription opioids.
• Approximately 80% of heroin and fentanyl users initially misused prescription opioids.
• There are roughly 80,000 opioid-related overdose deaths annually in the US, with hundreds of thousands of nonfatal overdoses leading to significant healthcare utilization and long-term complications.
• The total cost of acute and chronic pain in the US reached $923 billion in 2024.

Moderate-to-severe acute pain, a result of surgery, trauma, burns, or medical procedures, remains difficult to manage without opioids in many patients, particularly following orthopedic procedures and major surgeries.

Dual NOP/MOP Receptor Agonist

Tris Pharma is currently developing cebranopadol (TRN-228), a first-in-class dual nociceptin/orphanin FQ peptide (NOP) and µ-opioid peptide (MOP) receptor agonist for moderate-to-severe pain. The investigational analgesic was granted FDA Fast Track Designation for chronic low back pain.

Cebranopadol’s dual mechanism targets both NOP and MOP receptors, which play complementary and distinct roles in modulating pain pathways. Preclinical and clinical data suggest it may provide opioid-like efficacy with a potentially lower risk of misuse or physical dependence. Tris Pharma is further evaluating its potential in patients with substance use disorders, supported by a 5-year, up-to-$16.6 million grant from the National Institute on Drug Abuse. Cebranopadol has demonstrated efficacy in acute, chronic, and diabetic neuropathic pain, with a favorable safety profile, according to Tris Pharma.

The review, The burden of acute pain in the US in the wake of the opioid crisis reinforces the broader clinical challenge: physicians must balance the need for effective acute pain management with the risks of opioid therapy, highlighting the ongoing need for innovative therapies that provide robust analgesia while minimizing addiction potential.

Tris Pharma announces acceptance of new review article highlighting challenges to treating moderate-to-severe acute pain with currently available drugs. News release. Tris Pharma. October 16, 2025. Accessed October 17, 2025. https://www.trispharma.com/tris-pharma-frontiers-peer-reviewed-publication-announcement/

Tris Pharma's cebranopadol shows low potential for misuse in intranasal human abuse potential study. Patient Care. January 29, 2025. https://www.patientcareonline.com/view/cebranopadol-shows-low-potential-for-misuse-in-intranasal-human-abuse-potential-study

Jennings S. Topline data suggest novel pain therapy cebranopadol has significantly less potential for abuse compared to tramadol, oxycodone. Patient Care. December 19, 2022. https://www.patientcareonline.com/view/topline-data-suggests-novel-pain-therapy-cebranopadol-has-significantly-less-potential-for-abuse-compared-to-tramadol-oxycodone