Morphine yields antitussive effect in IPF

Morphine appears to effectively palliate cough in patients with idiopathic pulmonary fibrosis (IPF), findings from the phase II PACIFY COUGH crossover trial suggest.

“To our knowledge, this study is the first to report a benefit of morphine in IPF-related cough … This multicentre study shows that low-dose controlled-release (CR) morphine is effective in reducing awake cough frequency and improving quality of life (QoL) in participants with significant IPF-related cough,” said the researchers.

In the intention-to-treat analysis, morphine cut objective awake cough frequency by 39.4 percent as opposed to placebo by day 14 (p=0.0005). A similar effect was seen in the per-protocol analysis (40.3 percent; p=0.0009). [Lancet Respir Med 2024:doi:10.1016/S2213-2600(23)00432-0]

Moreover, mean daytime cough frequency dropped from 21.6 coughs/hour at baseline to 12.8 coughs/hour on day 14 (change, –40.8 percent; p<0.0001). With placebo, the frequencies for the two timepoints were similar (21.5 and 20.6 coughs/hour; change, –4.3 percent; p=0.66).

PROs, safety

Cough-related patient-reported outcomes (PROs) were also better with morphine than placebo, as reflected by the drops in cough Visual Analogue Scale (–16.1 mm; p<0.0001), L-IPF* impacts score (–5.2 points; p=0.033), L-IPF overall symptom score (–5.2 points; p=0.0078), and L-IPF cough domain score (–10.8 points; p=0.0004), as well as the increase in the Leicester Cough Questionnaire score (1.8 points; p=0.0002).

“These effects remained significant when adjusting for placebo,” the researchers noted. “With respect to global impression of change, morphine treatment led to an improvement in cough in over half of participants (56 percent) and overall QoL in a third (32 percent).”

Forty percent of morphine recipients reported adverse events (AEs) as opposed to only 14 percent in the placebo arm. The most frequent AE with morphine was constipation (21 percent), but it did not warrant laxative use.

The use of opioids in individuals with chronic respiratory illness is usually curtailed by AEs and the potential for abuse and addiction, the researchers noted. In one study, extended-release nalbuphine halved awake cough frequency in IPF patients, but AEs drove nearly a quarter of recipients to stop treatment. [NEJM Evid 2023;doi.org/10.1056/EVIDoa2300083]

In the current trial, only one patient stopped morphine, with fewer participants reporting side effects compared with those in the nalbuphine trial. “Safety assessments conducted during study visits were reassuring,” they said.

Limited treatment alternatives

There is insufficient evidence to support treatment options for IPF-related cough. [ERJ Open Res 2017;3:00084-2017; Respirology 2011;16:969-975] “Morphine is thought to depress the cough reflex, acting directly on the neural pathways in the brain. Antitussive effects might occur with doses lower than those usually required for analgesia,” the researchers said.

Forty-four patients (mean age 71 years, 70 percent men) were randomized 1:1 to oral CR morphine 5 mg or placebo BID for 14 days, followed by crossover after a 7-day washout period. Overall treatment adherence was 98 percent in both arms.

“Given the negative effects of cough in individuals with IPF, these findings merit [the] short-term use [of morphine] in clinical practice … The corroborative findings of improvements in cough-related PROs and reduction in objective cough counts support the role of low-dose CR morphine as an antitussive in IPF,” said the researchers.

“[Moreover, with] no direct evidence to guide cough treatment in IPF, [the results] are important for almost 85 percent of IPF patients who have cough and the clinicians involved in their treatment,” they added.

The researchers called for longer term studies to ascertain the durability of the antitussive effects of morphine and the impact of cough improvement on disease outcomes. Future trials should also explore the possibility of dose escalation or titration among those who did not respond to treatment.