Commentaries Highlight Promise, Questions for Nalbuphine in IPF Cough

Results from the CORAL (NCT05964335) clinical trial assessing the efficacy of oral nalbuphine in idiopathic pulmonary fibrosis (IPF)-associated cough recently received multiple invited commentaries highlighting points of improvement and success in the phase 2b study.^1-3

All 3 invited commentaries, published in JAMA, acknowledged the importance of this preliminary drug, addressing an unmet need in IPF care. Current therapies for IPF have been shown to reduce vital forced capacity but do not address cough, which has been associated with worse outcomes and a decrease in health-related quality of life.

Why Treating IPF-Associated Cough Remains a Critical Unmet Need

Nalbuphine is an oral extended-release (ER) κ opioid receptor agonist and μ opioid receptor antagonist, targeting opioid receptors involved in cough.⁴ However, one of the invited commentaries stated that the study’s definition of nalbuphine may be an “oversimplification.” The commentary highlighted that nalbuphine is a mixed μ agonist/antagonist, raising concern about the study’s claim that the drug has low abuse potential.¹

Although the κ receptor agonist produces 80% of maximal stimulation in vitro, the μ receptor antagonist produces 47% of maximal stimulation and 74% inhibition. The comment underscores the potential clinical implications as this drug continues to be assessed, noting that the majority of adverse events (AE) reported are all associated with the μ receptor antagonist. These AEs were reported in 10% of patients in the nalbuphine group and included nausea, vomiting, dizziness, and constipation.^`

In response, the study’s author cited prior research observing nalbuphine acting as a μ antagonist as opposed to a partial agonist. Nalbuphine reverses respiratory depression caused by opioids and can trigger withdrawal in opioid-dependent patients, which aligns with antagonist behaviors, not partial agonists.⁵

Additionally, the author also noted that the AEs may not have only been caused by the μ antagonist but also by the κ receptor agonist. Nausea and vomiting, 2 of the most commonly reported AEs, can also be caused by μ antagonism, to which the author emphasized that the adverse effect profile of κ agonism cannot be ruled out.

The commentary also claimed that patients were naive to opioids; however, the author revealed that 33% of participants had a prior opioid use history, the most common drug being codeine.^1,5

Safety and Mechanism Questions Could Shape Future Nalbuphine Development

Another commentary, although it applauded the study design pairing 24-hour cough monitoring with patient-reported measures, pointed out a key limitation: the short 6-week follow-up. The commentary noted that the longer safety and durability of nalbuphine remain unclear. Additionally, it also points out the limitation in generalizability as it claims the trial “excluded clinically relevant subgroups commonly encountered in IPF clinical practice.”²

The 3rd commentary also commended the study author for addressing an unmet need in the IPF landscape. However, it highlighted the need for more data to inform clinical practice decision-making and future guidelines on directed therapies. Specifically, it asked for correlations between change in 24-hour cough frequency and ER symptoms, cough severity numerical rating scale, and the Leicester Cough Questionnaire.³

The author’s response to this specific commentary revealed new data not stated in the study’s abstract. The author wrote that in the 54 mg and 108 mg twice daily groups, 75% and 81% of patients met the published clinically meaningful threshold for better quality of life.⁵

Commentaries Offer a Roadmap for Future Phase 3 IPF Cough Trials

Overall, all 3 commentaries provide significant insight into how future study design or phase 3 trials should define patient outcomes and data. Although nalbuphine is still in its preliminary stage and far from being applied in clinical practice, commentaries such as these continue to urge clinical trials forward and influence further advancement in the space.

References
1. Morice AH, Sykes D, Hart SP. Nalbuphine for cough caused by idiopathic pulmonary fibrosis. JAMA. Published online May 28, 2026. doi:10.1001/jama.2026.5239
2. Liu C, Zhao X, Xie L. Nalbuphine for cough caused by idiopathic pulmonary fibrosis. JAMA. Published online May 28, 2026. doi:10.1001/jama.2026.5236
3. Liu Y, Chen J, Liu J. Nalbuphine for cough caused by idiopathic pulmonary fibrosis. JAMA. Published online May 28, 2026. doi:10.1001/jama.2026.5233

4. McCrear S. Oral nalbuphine significantly reduces chronic cough in IPF. AJMC^®. January 22, 2026. Accessed June 5, 2026. https://www.ajmc.com/view/oral-nalbuphine-significantly-reduces-chronic-cough-in-ipf

5. Mathur V, Molyneux PL, Cassella J. Nalbuphine for cough caused by idiopathic pulmonary fibrosis—reply. JAMA. Published online May 28, 2026. doi:10.1001/jama.2026.5242