Extended-release nalbuphine quells IPF-related cough

The investigational extended-release (ER) nalbuphine helps alleviate chronic cough associated with idiopathic pulmonary fibrosis (IPF), as shown in the phase IIb CORAL study.

The primary outcome of 24-h cough frequency, measured using a digital cough monitor, decreased by a greater magnitude after 6 weeks of treatment with nalbuphine ER vs placebo. Cough count dropped by 47.9 percent with the 27-mg dose of nalbuphine ER (from 24.6 to 11.9 coughs/h; p=0.008), by 53.4 percent with the 54-mg dose (from 28 to 14.9 coughs/h; p<0.001), and by 60.2 percent with the 108-mg dose (from 31.5 to 11.9 coughs/h; p<0.001) as opposed to only 16.9 percent with placebo (from 29.4 to 28.1 coughs/h). [JAMA 2026;doi:10.1001/jama.2025.26179]

For the patient-reported cough frequency, as measured using the cough subscale of the Evaluating Respiratory Symptoms in IPF (E-RS: IPF) tool (score range 0–4), significant reductions were observed at only the two higher doses of nalbuphine ER vs placebo. At week 6, E-RS: IPF cough frequency scores decreased by 40.2 percent with the 108-mg dose (from 2.4 to 1.4; p<0.005), by 40.6 percent with the 54-mg dose (from 2.6 to 1.4; p=0.004), and by 31.4 percent with the 24-mg dose (from 2.3 to 1.5; p=0.14) as compared with only 21.9 percent with placebo (from 2.6 to 1.9).

The analysis included 165 IPF patients (median age 71 years, 71.5 percent male, 77 percent were on antifibrotic medication) with cough for at least 8 weeks and a Cough Severity Numerical Rating Scale score of at least 4. These patients were randomly assigned to receive nalbuphine ER at 27 (n=42), 54 (n=43), or 108 mg (n=40) or placebo (n=40), administered orally twice daily for 6 weeks.

“Nalbuphine ER is an opioid kappa receptor agonist and mu receptor antagonist. [It] acts on the cough reflex arc centrally and peripherally by targeting opioid receptors involved in cough,” according to the investigators.

They noted that the reductions observed in objectively measured and patient-reported cough frequency with nalbuphine ER may have important implications, given that cough, which affects up to 80 percent of patients with IPF, “substantially impairs quality of life (QoL).” [J Thorac Dis 2024;16:8338-8349; Ann Am Thorac Soc 2023;20:1267-1273; Am J Respir Crit Care Med. 2024;209:1165-1167; Respir Res 2024;25:325]

Indeed, in CORAL, the reductions in cough frequency occurred with improvements in QoL. The Leicester Cough Questionnaire (LCQ) total score, which measured the effect of cough on QoL, increased by 1.63 with 27-mg nalbuphine ER, by 3.21 with the 54-mg dose, and by 2.86 with the 108-mg dose relative to placebo at week 6. The odds of meeting the criteria for an LCQ response (≥1.3-point increase in LCQ score) were greater with nalbuphine ER 54 mg (odds ratio [OR], 5.4, 95 percent confidence interval [CI], 1.7–17.1) and 108 mg (OR, 7.6, 95 percent CI, 2.2–26.3) than with placebo.

Furthermore, as an opioid mu receptor antagonist, nalbuphine ER may have a better safety profile compared with “mu receptor agonists such as codeine and morphine, which can cause respiratory depression, euphoria, and addiction,” the investigators said.

“Titration-related adverse events (AEs), such as nausea, were common in the combined nalbuphine ER groups in CORAL. However, these AEs were grade 1 or 2 in severity and were manageable, reflected by the low and comparable rates of discontinuations due to AEs in the combined nalbuphine ER groups (5.6 percent) and the placebo group (5 percent),” they added.

Serious AEs occurred in 1.6 percent of patients in the combined nalbuphine ER groups and in 10 percent of patients in the placebo group, with no fatal events.