Patients with IPF reported less severe, less frequent cough within 2 weeks of nalbuphine ER in CORAL, with gains sustained through week 6.
Nalbuphine extended-release (ER) produced early, sustained improvements in patient-reported cough severity and frequency among patients with
No therapy is approved in the US for chronic cough in IPF, and available treatments for the disease, including nintedanib, pirfenidone, and nerandomilast, target progression rather than symptom burden.1,2 Nalbuphine ER, a mixed kappa opioid receptor agonist and mu opioid receptor antagonist, acts both centrally and peripherally on the cough reflex arc. In the primary CORAL analysis published in JAMA, 24-hour objective cough frequency fell by 47.9%, 53.4%, and 60.2% in the 27-mg, 54-mg, and 108-mg groups at week 6 vs 16.9% with placebo.3
“Cough’s a real problem for patients with pulmonary fibrosis,” said investigator Phil Molyneaux, MD, PhD, of Royal Brompton Hospital, in an interview with HCPLive at CHEST 2026. “We’ll see it in up to 80% of our patients, and it’s there at the beginning as soon as they’re diagnosed, and it lives and it stays with them throughout the whole disease.”
Molyneaux said the burden extends past the cough itself, with patients and family members describing workplace disruption, social isolation, and chest and rib pain from coughing.
CORAL was a randomized, double-blind, placebo-controlled phase 2b trial enrolling 165 patients with IPF and chronic cough lasting at least 8 weeks.¹,3 Participants were randomly assigned 1:1:1:1 to nalbuphine ER 27 mg, 54 mg, or 108 mg twice daily or placebo for 6 weeks.1 Patient-reported outcomes included the Cough Severity Numerical Rating Scale (CS-NRS; range, 0 to 10), the Evaluating Respiratory Symptoms in IPF (E-RS:IPF) cough frequency subscale (range, 0 to 4), and the Patient Global Impression of Severity (PGI-S) for cough (range, 0 to 3).¹
Patient-reported cough severity improved vs placebo by week 1. Change from baseline in CS-NRS at week 1 was −2.02 with 27 mg (P =.0001), −2.11 with 54 mg (P =.0002), and −2.48 with 108 mg (P <.0001).¹ At week 2, relative change from baseline in the E-RS:IPF cough subscale reached −26.46% (P =.0091), −33.88% (P =.0007), and −30.38% (P =.0014) in the 27-mg, 54-mg, and 108-mg groups, respectively.¹
PGI-S cough improved by −0.8 in both the 27-mg (P =.0380) and 54-mg (P =.0057) groups at week 2, and the −0.6 change with 108 mg did not reach significance (P =.1683).¹ Improvements across all 3 measures persisted through week 6 in the 54-mg and 108-mg groups.
At week 6, the 54-mg group showed changes of −3.17 in CS-NRS (P =.0065), −43.07% in the E-RS:IPF cough subscale (P =.0041), and −1.0 in PGI-S cough (P =.0068).¹ Corresponding week 6 changes in the 108-mg group were −3.00 (P =.0144), −42.35% (P =.0047), and −0.9 (P =.0237).¹
“Patients began to see benefit right after a week on therapy,” said Molyneaux. “They felt their cough was less frequent… [and] less severe.”
Molyneaux noted objective cough counts and patient perception often diverge. Some patients reporting no cough register 20 to 30 coughs per hour on a 24-hour recorder, and others reporting severe cough register very few. He said objective counts confirm a treatment effect, and patient-reported outcomes show what the change means to the patient.
The 108-mg dose did not clearly outperform 54 mg on patient-reported outcomes. Molyneaux said the reason is not fully understood and may reflect a maximal dose effect. Both doses appeared effective, and investigators have carried 54 mg twice daily into the phase 3 program, which has begun recruiting.
In the primary CORAL analysis, titration-related adverse events such as nausea were common in the nalbuphine ER groups.3 Serious adverse events occurred in 1.6% of patients across the combined nalbuphine ER groups and in 10% of patients receiving placebo, with no fatal events.
On prescribing an opioid-class agent, Molyneaux said clinicians already use off-label options, including gabapentin and morphine, for cough in IPF without a substantial evidence base. He noted drug dependency studies of nalbuphine have been conducted. In his view, randomized data on efficacy and safety should support adoption if the agent is approved.
He acknowledged 6 weeks is a short window for a chronic disease. The phase 3 trials will use objective cough count at week 24 as the primary endpoint, with CS-NRS and patient-reported cough frequency as secondary measures. Patients will remain on treatment for 52 weeks to generate longer-term safety data.
“Looking at patients' perception of their cough severity…[and] cough frequency…for a year…will give us enough safety data to help reassure everybody that the drug is not only effective but also safe,” Molyneaux said.
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