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Short-term treatment with a low-dose opioid was associated with significantly improved health status in chronic obstructive pulmonary disease (COPD) patients with advanced disease and chronic breathlessness despite optimal pharmaceutical and non-pharmaceutical treatment.

In a randomized trial of over 100 patients, twice daily treatment for 4 weeks with an oral sustained-release morphine (10 mg) was associated with a significantly lower (CAT) score compared to placebo (-2.18 points, 95% CI -4.14 to -0.22, P=0.03), reported researcher Daisy Janssen, MD, PhD, of Maastricht University in The Netherlands, and colleagues.

No significant change in respiratory outcomes was observed in either treatment group, according to the findings in .

"Low-dose morphine treatment, therefore, seems to be safe even in this group of patients with moderate-to-severe COPD," Janssen and colleagues wrote. They added that fear of respiratory depression associated with opioid use in advanced COPD "might be unfounded."

Management of breathlessness is an important treatment goal in advanced COPD, the group explained, and previous studies have explored the use of low-dose opioids in the palliative care of patients with advanced disease.

Although low-dose opioids are recommended for end-of-life care or advanced disease in patients with refractory breathlessness in several treatment guidelines, including , the researchers noted that evidence for the recommendation remains limited.

in Thorax found 1-week treatment with low-dose, oral, sustained-release morphine to be associated with improvements in patients with severe, chronic breathlessness.

"Physicians remain reluctant to prescribe opioids for breathlessness in COPD for fear of respiratory depression," the researchers wrote, noting that while showed no evidence for this, most of the included studies were small and did not measure arterial blood gases.

"To our knowledge, (ours) is the first study powered to detect a change in respiratory outcomes of morphine treatment," they wrote.

The randomized MORDYC study originally included 124 COPD patients with moderate to very severe breathlessness (modified Medical Research Council [] breathlessness grades 2-4) recruited from 2016 to 2019, with data on 111 patients included in the final analysis. Mean [SD] age was 65.4 years [8.0], and 54% were men.

Difference in arterial partial pressure of carbon dioxide (PaCO₂) was numerically higher in the morphine group (1.19 mm Hg, 95% CI -2.70 to 5.07, P=0.55).

No significant or clinically relevant change in mean or worst breathlessness was observed between the morphine and placebo groups, although 48% and 35%, respectively, responded to the treatment (mean breathlessness improvement of 1.0 point on a 0-10 numeric rating scale). Morphine-treated patients with the worst breathlessness (mMRC grades 3 to 4) also showed an improvement of 1.33 points over the previous 24 hours (95% CI -2.50 to -0.16, P=0.03).

The researchers noted that while the 2.18-point improvement on CAT (which measures disease-specific health status) did not reach the trial's originally defined minimal clinically important difference (MCID) threshold of 3.18 points, the MCID was reassessed after the that redefined MCID as 2.0 to 3.0.

In an with the study, Eric Widera, MD, of the University of California San Francisco, wrote that while it is "reasonable to use the most current evidence to help interpret findings ... lowering the threshold that defines a clinically meaningful difference at the end of the study suggests that the role of opioids on health status is likely small for the population studied."

Widera wrote that the failure to show a clinically meaningful improvement in breathlessness may have been due to the inclusion of patients with severe dyspnea in the study.

Widera concluded that while opioids should never be prescribed as a first-line treatment for COPD patients with chronic breathlessness, the clinical evidence now confirms that they have a place in the treatment in a subset of patients with severe symptoms.

"For patients whose breathlessness remains refractory and severe (mMRC grade 3 or 4), most of the evidence over the last 4 decades has demonstrated that carefully prescribed low-dose opioids can yield a small yet clinically important improvement in breathlessness for individuals with advanced COPD," he wrote.

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