A brief course of morphine provided some relief for patients with cough related to idiopathic pulmonary fibrosis (IPF) in a small, phase II double-blind crossover trial.

Two weeks of low-dose controlled-release morphine reduced objective awake cough frequency by 39.4% over a placebo treatment phase (95% CI -54.4 to -9.4), reported Philip Molyneaux, PhD, of Imperial College London’s National Heart and Lung Institute, and colleagues of the PACIFY COUGH study.

With morphine, the average daytime cough frequency was reduced from 21.6 coughs per hour at baseline to 12.8 per hour at 14 days; with placebo, cough frequency barely budged, going from 21.5 to 20.6 coughs per hour, according to findings published in Lancet Respiratory Medicine.

No treatment is approved for chronic cough, either in IPF patients or other groups. The FDA recently rejected oral gefapixant, an investigational elective P2X3 receptor antagonist, for unexplained or refractory chronic cough due to weak effectiveness data.

“There is a large unmet need for treatments that improve quality of life in individuals with IPF and address highly prevalent and frequently disabling symptoms like cough,” Molyneaux’s group wrote. “Insufficient clarity about the pathogenic mechanisms driving cough in IPF has limited the therapeutic options available to patients and clinicians.”

“Individuals with IPF have been shown to have a more sensitive cough reflex than healthy volunteers … Although much can be learned from studies on refractory chronic cough when considering the treatment of IPF-related cough, the biological mechanisms that contribute to cough probably differ in these conditions,” the group wrote.

In PACIFY COUGH, the most commonly reported morphine side-effects were nausea (14%) and constipation (21%). Adverse events were similar between the two treatment groups, with 43% of the morphine group experiencing an event versus 42% of placebo patients. One patient in the placebo group died, a result of their underlying IPF.

Longer-term safety data are needed given concerns about the potential for addiction and withdrawal stemming from opioid use as well, the investigators suggested.

“Questions remain about the pathophysiology of IPF cough and how it overlaps with refractory chronic cough,” added Dominic Sykes, MBBS, BSc, and Simon Hart, PhD, BSc, both of Hull York Medical School in Cottingham, England, in an accompanying comment. “Further work is required to phenotype cough in patients with IPF to identify personalized therapeutic targets.”

Additionally, it is unclear if opioids can help breathlessness in these patients the same way it has been shown in chronic obstructive pulmonary disease, Sykes and Hart pointed out. They cited the ongoing MABEL trial — testing low-dose morphine for 56 days in patients with cardiac or respiratory disease (including IPF) — as a potential source of answers regarding opioids and breathlessness.

The current study was unable to show that morphine improved patient breathlessness.

However, quality of life was reportedly improved based on questionnaire data. Sykes and Hart stressed the importance of including quality-of-life measures, stating that “arguably, patient-reported outcomes should be the primary outcome of choice in cough studies.”

A total of 44 patients had been randomized for the crossover PACIFY COUGH trial. Eligible participants were middle-age and elderly people diagnosed with IPF within 5 years before screening, reporting a cough lasting at least 8 weeks and a cough severity of 30 mm or higher on the visual analogue scale. Eligible patients were also required to have a forced vital capacity (FVC) of 45% of predicted or higher, an FEV₁ to FVC ratio of 0.7 or higher, and a diffusion capacity of carbon monoxide (DLCO) corrected for hemoglobin of 30% of predicted or higher. Current smokers and people with an acute IPF exacerbation in the prior 6 months were excluded.

The cohort had a mean age of 71 years and a 30% female population. Most patients were white (91%). Indicating moderately impaired lung function overall, the average FVC was 2.7 L, the predicted FVC was 82%, and predicted DLCO was 48%.

Patients were randomized to 2-week morphine and placebo treatment periods, in either order, with a 7-day washout in between. Treatment adherence was 98% in both the morphine and placebo groups.

Researchers noted that the trial excluded patients with severe fibrosis, those with either a requirement for long-term oxygen therapy or a life expectancy of less than 6 months, potentially limiting its results.

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