Among patients with chronic obstructive pulmonary disease (COPD) and severe chronic breathlessness, short-term daily treatment with low doses of extended-release morphine did not significantly reduce the intensity of worst breathlessness, a randomized trial showed.
At 1 week, change in the intensity of worst breathlessness was not significantly different between patients who received 8 mg/day of morphine and those who received placebo (mean difference -0.3, 95% CI -0.9 to 0.4) or between those who received 16 mg/day of morphine and the placebo group (mean difference -0.3, 95% CI -1.0 to 0.4), reported Magnus Ekström, MD, PhD, of Blekinge Hospital in Karlskrona, Sweden, and colleagues.
“The lack of efficacy was consistent across severities of breathlessness (modified MRC [Medical Research Council] breathlessness scale score of 3 or 4),” they wrote in JAMA.
After 3 weeks, the secondary outcome of change in mean daily step count was not significantly different between any of the following morphine groups versus placebo:
- 8 mg: mean difference -1,453 (95% CI -3,310 to 405)
- 16 mg: mean difference -1,312 (95% CI -3,220 to 596)
- 24 mg: mean difference -692 (95% CI -2,553 to 1,170)
- 32 mg: mean difference -1,924 (95% CI -47,699 to 921)
That these physiological variables were not altered by the study intervention “indicat[es] that the fear of significant respiratory depression associated with use of opiates at these doses in patients with COPD is unwarranted,” noted Richard M. Schwartzstein, MD, of Harvard Medical School in Boston, in an accompanying editorial.
Among ambulatory COPD patients, chronic breathlessness is well known to lead to decreased physical activity and muscular and cardiovascular deconditioning, which may explain why “the symptom of dyspnea is a better predictor of mortality than forced expiratory volume in the first second of expiration, a measure of the severity of airway resistance on spirometry in patients with COPD,” he wrote.
He pointed out that “extended-release opiates are typically reserved for patients with dyspnea at rest, often in the setting of palliative care at the end of life,” but this study did not “specifically comment on dyspnea at rest.”
“The absence of dyspnea at rest would call into question the premise for use of daily long-acting opiates instead of rapid-onset, short-acting opiates as needed prior to planned exertion … [which] would minimize the adverse events associated with opiate use,” he added.
Schwartzstein noted that pulmonary rehabilitation improves exercise capacity and reduces dyspnea in patients with COPD, even though their lung function is not altered. The absence of any improvement in activity may be explained by habitual avoidance of activities that may provoke dyspnea, and reduced activity due to muscular fatigue as opposed to breathing capacity, “both of which may improve with pulmonary rehabilitation.”
Other benefits of pulmonary rehabilitation include breathing training to minimize dynamic hyperinflation and to provide a sense of control during activity, “which may reduce the fear and anxiety associated with the breathing discomfort” and help desensitize patients to dyspnea, he wrote.
This multicenter double-blind trial enrolled 156 people with COPD and chronic breathlessness from 20 centers in Australia between September 2016 to mid-November 2019. Median age was 72 years, and 48% were women.
Participants were randomized 1:1:1 to 8 mg or 16 mg of oral extended-release morphine or placebo during week 1. At the start of weeks 2 and 3, they were randomized 1:1 to 8 mg, which was added to the prior week’s dose, or placebo.
At follow-up through Dec. 26, 2019, 88% of patients completed treatment at week 1 (48 in the 8 mg group, 43 in the 16 mg group, and 47 in the placebo group).
The primary outcome of severe chronic breathlessness was defined as a modified MRC breathlessness scale score of 3 or 4 (score range 0-10), corresponding to patients’ reports of being “too breathless to leave the house,” or “breathless when dressing,” despite optimal treatment for underlying causes, Ekström and team noted.
Treatment-emergent adverse events (TEAEs), including constipation, fatigue, dizziness, nausea, and vomiting, occurred in 64% of the 8-mg group, 78% of the 16-mg group, and 48% of the placebo group during week 1, and “did not appear to be associated with study drug adherence,” the group wrote.
Serious TEAEs included increased breathlessness, infections, morphine-related adverse events, hospitalizations, and deaths, and occurred in 33% of those who received any dose of morphine compared with 12% of those taking placebo.
Ekström and colleagues acknowledged that only 42% of patients completed treatment at week 3, which was a limitation to the study. Other limitations included assessment of breathlessness in daily life and not during standardized exercise testing, and potential underdosing of long-acting morphine due to the 24-hour dosing interval.
“Further research is needed to determine if specific groups of people with COPD are more likely to experience a reduction in breathlessness with morphine, if some may benefit from higher doses of morphine, and to clarify the role of short-acting opioids for severe episodes of breathlessness,” Ekström and colleagues wrote.
This study was funded by a grant from the National Health and Medical Research Council of Australia and sponsored by Flinders University, Adelaide, Australia.
Ekström reported receiving a grant from the Swedish Research Council.
Co-authors reported multiple relationships with government entities and foundations, as well as pharmaceutical companies.
Schwartzstein reported serving as a medical education consultant to a law firm.