Low-dose Morphine Improves Health in COPD Patients With Shortness of Breath, Phase 4 Trial Suggests

Regular, low-dose oral morphine led to significant health improvements in adults with advanced chronic obstructive pulmonary disease (COPD) who regularly experienced shortness of breath, according to results of a Phase 4 clinical trial.

Treatment with morphine did not cause lung-related side effects, and no additional exacerbation or hospitalizations were reported. 

The study, “Effect of Sustained-Release Morphine for Refractory Breathlessness in Chronic Obstructive Pulmonary Disease on Health Status,” was published in the journal JAMA Internal Medicine. 

Chronic shortness of breath, or breathlessness (dyspnea), is a common symptom in patients with advanced COPD and it has a considerable effect on daily life activities.

Treatment with lose-dose opioids, such as morphine, for COPD patients who fail to respond to other therapies has been recommended. However, evidence supporting this approach is limited.

Physicians also are reluctant to prescribe opioids for breathlessness in COPD for fear of respiratory depression, characterized by slow and ineffective breathing.

“To our knowledge, no large randomized clinical trials adequately powered to measure the effect of opioids on respiratory outcomes have yet been conducted,” the researchers wrote. 

So, researchers based at the Maastricht University in the Netherlands designed the Morphine for Treatment of Dyspnea in Patients With COPD (MORDYC) Phase 4 study (NCT02429050). It investigated whether regular, low-dose, oral sustained-release morphine improved health in COPD patients with moderate-to-very-severe chronic breathlessness. 

The impact of morphine treatment on adverse respiratory effects also was assessed.

Participants included those with modified Medical Research Council (mMRC) breathlessness grades of 2, 3, or 4, in which a higher grade reflects more severe shortness of breath. All had failed to respond to other medical interventions. 

A total of 111 participants (60 men) with a mean age of 65.4, were assigned randomly to receive 10 mg of morphine or placebo twice daily for four weeks. Patients who failed to respond to this dose had the option of 10 mg three times daily after one or two weeks.

Health status was measured using the COPD Assessment Test (CAT), a questionnaire designed to measure COPD’s impact, in which higher scores represent worse health status. A change of 2.0 to 3.0 points represented a clinically meaningful outcome.

Results showed that the average CAT score in patients receiving morphine improved significantly compared to those taking a placebo, with a difference of 2.18 points lower in the morphine group.

The CAT item measuring walking up stairs or a hill improved significantly by a reduction of 0.43 points. An assessment of patients with an mMRC grade of 3 or 4, representing more severe breathlessness, found no differences between treatment groups.  

The partial arterial pressure of oxygen (PaO₂), a measure of lung function, was higher by 1.19 mmHg (millimeters of mercury) in patients receiving morphine. Still, the difference was not significant between treatment groups.

No difference in distance walked in six minutes (6MWT) was found, or in other tests assessing physical functioning. 

Overall, there was no significant or clinically relevant change in average breathlessness in the previous 24 hours as measured with a numeric rating scale between 0 and 10, in which a higher score reflected more breathlessness.

However, there was a significant improvement in the worse reported breathlessness in the previous 24 hours in those with mMRC grades 3 and 4 taking morphine compared to placebo — 1.33 points lower in the morphine group.

Regarding safety, the number of patients in the morphine group that experienced one or more adverse side effects (81%) — including nausea, vomiting, drowsiness, constipation, and sleeplessness — was not different from the one in the placebo group (70%).

Eighteen patients experienced moderate-to-severe COPD exacerbation (a worsening of symptoms), which included seven patients receiving morphine and 11 taking placebo. No morphine-related hospital admissions or deaths occurred.

“In conclusion, this study has shown that regular, low-dose, oral sustained-release morphine for four weeks may have a positive effect on disease-specific health status in patients with moderate to very severe breathlessness,” the researchers wrote, adding that the therapy “does not appear to lead to respiratory adverse effects.”

The team also emphasized that “the worst breathlessness improved in participants with mMRC grades 3 to 4,” and “a larger randomized clinical trial with longer follow-up in patients with mMRC grades 3 to 4 is warranted.”