Oral Nalbuphine Significantly Reduces Chronic Cough in IPF

An oral dosage of nalbuphine was found to reduce the frequency of cough in patients with idiopathic pulmonary fibrosis (IPF), according to a new study published in JAMA.¹

IPF-associated cough affects up to 80% of patients with IPF, substantially impairing their quality of life; consequently, there is a pressing need for more effective treatments like nalbuphine, an oral extended-release (ER) opioid κ receptor agonist and μ receptor antagonist.

How Oral Nalbuphine ER Addresses Chronic Cough in IPF

Nalbuphine targets the opioid receptors involved in cough. Unlike other μ-opioid agonists, such as codeine and morphine, nalbuphine ER is nonaddictive and doesn’t cause respiratory depression or euphoria, ranking its safety profile higher than that of its alternatives.¹

Prior research confirms nalbuphine’s efficacy and safety at a specific dosage of 162 mg twice daily.² However, this phase 2b, double-blind, parallel-group, placebo-controlled trial, CORAL (NCT05964335), investigates the safety and efficacy of nalbuphine in 3 different dosages.¹

Patients were randomized 1:1:1:1 to receive a twice-daily dosage of nalbuphine ER at 27 mg, 54 mg, or 108 mg or the placebo. Patients who received the higher doses underwent a titration period of 2 weeks, which increased daily until the final assigned dose was achieved. All participants were treated with their target dose for 4 weeks, followed by a 2-week safety follow-up visit. The primary outcome, objective cough, was measured at baseline, week 2, week 4, and week 6 over 24 hours with a digital cough monitor. The secondary outcome was the relative change in cough severity, which the researchers measured with the Evaluating Respiratory Symptoms: IPF (E-RS:IPF) tool.

The trial was conducted between February 2024 and February 2025. Of the 223 patients screened at various sites, only 162 were enrolled in the trial. The median age was 71 years, and 71.5% of patients were male.

Efficacy Results: Significant Reduction in Cough Frequency and Severity

The mean duration of cough was 3.0 years for patients on nalbuphine ER 27 mg, 4.1 years for nalbuphine ER 54 mg, 5.4 years for nalbuphine ER 108 mg, and 4.4 years for placebo.

In the nalbuphine ER groups, the mean (SD) relative decrease in the cough count and the absolute decrease in coughs/h were 47.9% (38.5%), from 24.6 to 11.9 coughs/h (P = .008) for 27 mg; 53.4% (54.0%), from 28.0 to 14.9 coughs/h (P < .001) for 54 mg; and 60.2% (36.7%), from 31.5 to 11.9 coughs/h (P < .001) for 108 mg, when compared with placebo (16.9% [47.9%]; from 29.4 to 28.1 coughs/h).

For the key secondary outcome of patient-reported cough frequency at week 6, the relative changes were −31.4% (P = .14), −40.6% (P = .004), and −40.2% (P < .005) in the 27 mg, 54 mg, and 108 mg groups, respectively, compared with −21.9% for placebo.

The absolute E-RS:IPF cough frequency scores for those who received nalbuphine decreased by more points compared with the placebo. Patients in the nalbuphine groups also had a higher percentage reduction in cough count compared with placebo, and it increased in tandem with the dosage. Serious adverse events (AEs) were only reported in 1.6% of patients in the 3 nalbuphine groups compared with 10% reported in the placebo group.

Safety Profile and Common Adverse Events of Nalbuphine ER

The most commonly reported AEs leading to discontinuation for the 3 nalbuphine groups were each reported in 2.4% of patients and included headaches, nausea, and vomiting. Overall, the most common AEs reported in 10% of patients in the nalbuphine groups included headaches, nausea, vomiting, constipation, fatigue, dizziness, dry mouth, and somnolence.

This trial was limited by a treatment duration of 6 weeks, in addition to it being a phase 2b trial; the results will need to be confirmed in phase 3.

“For patients with IPF-associated chronic cough, all 3 doses of nalbuphine ER (27 mg, 54 mg, and 108 mg twice daily) reduced objectively measured cough frequency, and the 2 higher doses improved patient-reported cough frequency and severity,” the study authors concluded.

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