Dual agonists break the pain safety trade-off

The search for safer and more effective pain therapies remains one of medicine’s most pressing challenges. At the BIO International Convention 2026 in San Diego, the outlet interviewed James Hackworth, President of the Brand Division at Tris Pharma, about the science behind dual NOP/MOP agonists, its lead investigational therapy cebranopadol, and how a novel approach to pain treatment could reshape the future of both acute and chronic pain management.

The difficulty of finding safe relief

Pain is one of the most pervasive challenges in medicine, yet decades of research have failed to produce a significant breakthrough in safety. The difficulty arises from the subjective nature of pain, which makes measurement in lab settings unreliable. Researchers rely on animal models, observing behavior rather than communication, leading to ambiguity in translating preclinical findings.

Pharmacological disconnects exist between species. Certain adverse effects that limit dosing in humans, such as nausea and vomiting, do not appear in rodents. A rat can tolerate doses of an opioid that would be impossibly high in a person. This means a dose that looks therapeutically effective in an animal model may never be achievable in a patient.

The neurobiological aspect presents the most stubborn obstacle. Potent analgesia requires activity in the central nervous system, and the pathways that govern pain relief are closely intertwined with the pathways that govern reward and pleasure. Shared neurobiology is why many effective analgesics, including benzodiazepines and stimulants, carry abuse liability. Breaking that link is the central challenge of pain drug development.

How dual agonists differ from traditional opioids

Dual-NMR agonists stimulate the Nociception/Orphanin FQ Peptide (NOP) and MOP (Mu) receptors to work together. The aim is a combined pain-relieving effect greater than either pathway alone, while NOP attenuates the negative effects typically associated with MOP.

Traditional drugs like morphine and oxycodone function primarily through selective activation of MOP. While effective for pain, MOP stimulation drives the cascade of effects associated with the opioid crisis, including euphoria, respiratory depression, and addiction. NOP receptors serve a dual purpose, contributing to analgesia while simultaneously counteracting MOP-related adverse effects.

Research indicates that cebranopadol, a first-in-class dual NMR agonist, may have lower abuse potential and less respiratory depression than drugs like oxycodone. The mechanism aims to separate pain relief from the reward system, potentially offering a new safety profile.

The clinical path for cebranopadol

Tris Pharma intends to submit a New Drug Application (NDA) to the FDA this year. The president states that if accepted, the therapy could bring meaningful pain relief without the challenges patients have long faced. Approximately 80 million people per year in America experience acute pain. Many of these individuals require opioid-level pain relief for effective management.

The opioid addiction crisis has caused devastating loss of life. Fear of dependence and addiction forces patients to make an impossible choice: endure inadequate pain relief or accept risks that could lead to fatal overdose. With treatment, many patients experienced not only relief but euphoria, which opened a door to misuse that was difficult to close.

The future for chronic pain

Cebranopadol is currently evaluated in moderate-to-severe acute pain. Transitioning to chronic pain represents the next frontier. Patients living with chronic conditions often require sustained opioid therapy to function, and the risks associated with long-term opioid use can be even greater than with acute use, specifically, tolerance and the erosion of efficacy over time.

Tolerance remains a critical issue. Chronic opioid use often requires escalating doses to maintain the same level of pain control, which compounds safety concerns and addiction risk. Early animal studies indicate that dual NOP/MOP receptor agonists have a differentiated tolerance profile compared to existing treatments. If that signal holds in larger trials, it would be meaningful for millions of patients whose quality of life depends on finding a sustainable solution.

If the results translate to long-term care, prescribing habits could fundamentally alter. Currently, patients using opioids for chronic pain often face dose escalation to maintain relief, which directly increases the risk of dependence. A therapy offering sustained efficacy without this escalation could provide a stable alternative for lifelong pain management, potentially reducing the societal burden of the opioid crisis more effectively than short-term interventions.

Balancing efficacy and abuse deterrence

Dual NOP/MOP receptor agonists hold the potential to break the inverse relationship between efficacy and safety. The most effective analgesics often carry the highest abuse potential, while weaker drugs are safer but less effective. By using MOP to drive analgesia and NOP to blunt the reward signal, this new class of drugs aims to provide robust pain relief with a substantially reduced risk of abuse.

As the firm prepares for its regulatory submission, the medical community watches closely. If approved, cebranopadol could finally allow clinicians to address severe pain without forcing patients into the dangerous safety trade-off defining modern pain management for decades.