Chronic cough remains one of the most debilitating and undertreated symptoms of idiopathic pulmonary fibrosis (IPF), affecting up to 80% of patients and substantially impairing quality of life. Despite advances in antifibrotic therapy, there are no approved treatments that specifically and reliably target IPF‑associated cough. New phase 2b data recently published in JAMA suggest that oral nalbuphine extended release (ER) may be a promising therapeutic option to address this challenging symptom.1
The CORAL study was a parallel‑group, dose‑ranging trial evaluating oral nalbuphine ER in adults with IPF‑associated chronic cough. The trial enrolled 165 patients, with 160 included in the primary analysis, across 52 sites in 10 countries. Participants had a confirmed diagnosis of IPF and a chronic cough lasting at least eight weeks. Key exclusions included recent respiratory infection, use of opioids or benzodiazepines, and continuous oxygen therapy for more than 16 hours per day.1
“The trial population closely mirrors the patients with IPF we see in routine clinical practice—predominantly male, an average age of around 70 years, and a significant cough burden,” said lead author Philip Molyneaux, MBBS, PhD, BSc, a consultant respiratory physician at the Royal Brompton and Harefield Hospitals in London. He said the exclusion criteria were selected to ensure patient safety, and the efficacy and safety profile observed with nalbuphine ER supports broader use and continued investigation in broader populations.
Patients were randomized in a 1:1:1:1 ratio to receive nalbuphine ER 27 mg, 54 mg, 108 mg, or placebo, administered orally twice daily for six weeks. Objective cough frequency was measured using 24‑hour digital cough monitoring, while patient‑reported outcomes (PROs) were assessed with validated symptom and quality‑of‑life instruments.1
Commenting on the trial design, Anna Gersten, MD, Assistant Professor of Medicine at Johns Hopkins University School of Medicine and Director, Breathlessness Clinic in Baltimore, Maryland, said the inclusion of objective monitoring strengthens the findings.
“What’s particularly interesting about this study is that it combines objective cough monitoring with [PROs],” she said. “That’s not something we consistently see in cough trials. And when you compare these results with prior studies, the magnitude of cough‑frequency reduction with the active drug looks very similar.”
At six weeks, all nalbuphine ER dose groups demonstrated statistically significant reductions from baseline in objective 24‑hour cough frequency, highlighting a consistent pharmacologic effect across the dose range, Dr. Molyneaux said.
The clinical relevance of the dose response became more pronounced at higher doses.
“The top two dose groups, 54 mg and 108 mg, demonstrated significant changes from baseline in patient‑reported outcome measures, including patient‑reported cough frequency, severity, and quality of life,” Dr. Molyneaux said. “This is significant because it shows that at the top two dose groups, patients are also recognizing a positive benefit on cough frequency, cough severity, and quality of life related to their cough.”
These findings suggest that while lower doses may suppress cough objectively, higher doses more consistently translate into benefits that patients perceive in their daily lives.
Patient‑reported cough frequency was assessed using the Evaluating Respiratory Symptoms in Idiopathic Pulmonary Fibrosis cough subscale, a daily diary measuring respiratory symptom severity. Cough severity was evaluated using the Cough Severity Numerical Rating Scale, while cough‑related quality of life was assessed using the Leicester Cough Questionnaire, which evaluates physical, psychological, and social domains. Dr. Molyneaux said additional PRO data were collected for secondary endpoint analyses, including the Patient Global Impression of Severity and Patient Global Impression of Change for cough.
“Patient‑reported improvement in cough frequency and cough severity corroborates the reduction in objective cough count and reflects the patient’s awareness of the drug’s benefit,” he said. “Improvement in quality of life is particularly significant because chronic cough imposes a substantial physical, emotional, and social burden on patients with IPF.”
Nalbuphine ER was generally well-tolerated over the six‑week treatment period. Common adverse events included nausea, vomiting, constipation, headache, dizziness, dry mouth, fatigue, and somnolence. Dr. Molyneaux said the adverse events observed were consistent with what is expected for this mixed agonist-antagonist opioid drug class, and most were mild to moderate, often occurring during dose initiation and resolving over time.1–2
Dr. Gersten said the short‑term safety findings were reassuring but urged caution when considering longer‑term use.
“The short‑term safety profile was not surprising and was generally consistent with what we see with other extended‑release opioid formulations,” she said. “The bigger unanswered question is long‑term use, because extended‑release opioids introduce additional complexity around tolerance, dependence, and discontinuation—particularly for patients being evaluated for lung transplantation.”
References
1. Molyneaux PL, Mogulkoc NM, Gunen H, et al. Oral nalbuphine in idiopathic pulmonary fibrosis-associated cough: the CORAL randomized clinical trial. JAMA. Published online January 22, 2026. doi:10.1001/jama.2025.26179
2. Maher TM, Avram C, Bortey E, et al. Nalbuphine tablets for cough in patients with idiopathic pulmonary fibrosis. NEJM Evid. 2023;2(8): EVIDoa2300083. doi:10.1056/EVIDoa2300083
