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Study Authors: Cornelia A. Verberkt, Marieke H.J. van den Beuken-van Everdingen, et al.; Eric W. Widera

Target Audience and Goal Statement: Pulmonologists, pain management specialists, primary care physicians, public health and policy experts

The goal of this study was to evaluate the effects of low-dose, oral sustained-release morphine on disease-specific health status, respiratory outcomes, and breathlessness in patients with advanced chronic obstructive pulmonary disease (COPD).

Question Addressed:

Does low-dose, oral sustained-release morphine improve disease-specific health status or cause respiratory adverse effects in patients with moderate to very severe chronic breathlessness due to advanced COPD?

Study Synopsis and Perspective:

Of patients with severe to very severe COPD, 46% to 91% live with chronic and disabling breathlessness at rest and on minimal exertion, despite optimal treatment with bronchodilators, corticosteroids, and/or phosphodiesterase inhibitors.

Breathlessness and exercise intolerance are independently associated with increased morbidity for these patients, marked by restrictions in activities of daily living and increased use of emergency health services, as well as mortality.

Despite its significant impact, chronic breathlessness is under-reported by patients and often under-recognized by clinicians, perhaps in part because people affected tend to adjust their lifestyle to minimize the frequency and duration of more intense breathlessness.

Management of breathlessness is an important goal of treatment in advanced COPD. Previous small, short-term studies of low-dose opioids in the palliative care of patients with advanced disease have generally suggested that this treatment may produce a small, but clinically important, improvement in dyspnea, without increasing risk of respiratory depression or carbon dioxide retention.

In the first study powered to detect a change in respiratory outcomes of morphine treatment, researchers found that short-term treatment with a low dose of the opioid was associated with significantly improved health status in patients with advanced COPD and chronic breathlessness refractory to optimal pharmaceutical and non-pharmaceutical treatment.

In this randomized trial of over 100 patients, twice-daily treatment for 4 weeks with oral sustained-release morphine (10 mg) was associated with a significantly lower COPD Assessment Test (CAT) score compared with placebo (-2.18 points, 95% CI -4.14 to -0.22, P=0.03), with no significant change in respiratory outcomes observed in either treatment group, reported Daisy Janssen, MD, PhD, of Maastricht University in the Netherlands, and colleagues in JAMA Internal Medicine.

“Low-dose morphine treatment, therefore, seems to be safe even in this group of patients with moderate-to-severe COPD,” Janssen and team wrote.

The MORDYC trial originally included 124 COPD patients with moderate to very severe breathlessness (modified Medical Research Council [mMRC] breathlessness grades 2-4) recruited from 2016 to 2019, with data on 111 patients included in the final analysis. Mean age was 65.4 years, 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 publication of a 2017 study that redefined MCID as between 2.0 to 3.0.

Janssen and team acknowledged several study limitations, including the large number of patients who were unwilling to participate, contributing to insufficient inclusion of the original target population. “Where we expected a response rate of 50%, only 27% of eligible patients gave informed consent. As a result, we had to expand the inclusion criteria to participants with mMRC grade 2,” they wrote. Additionally, although the study was one of the first with a trial duration of more than 1 week, the long-term effects of morphine and possible adverse effects remain unknown, they noted.

Source References: JAMA Internal Medicine 2020; DOI: 10.1001/jamainternmed.2020.3134

Editorial: JAMA Internal Medicine 2020; DOI: 10.1001/jamainternmed.2020.3133

Study Highlights and Explanation of Findings:

This randomized trial found that short-term treatment with low-dose, oral sustained-release morphine was associated with significantly improved health status in patients with advanced COPD and chronic breathlessness.

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

A study published earlier this year 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,” Janssen and team wrote, noting that while their own systematic review showed no evidence for this, most of the included studies were small and did not measure arterial blood gases.

Approaches to managing breathlessness in COPD may also vary by specialty. A small survey of specialists in respiratory and palliative medicine in Australia, New Zealand, and the U.K. found that respiratory physicians focused more on pulmonary rehabilitation, whereas those in palliative medicine recommended breathing techniques, anxiety management, and a handheld fan. Use of short-acting oral morphine for breathlessness was recommended by 75% of palliative medicine physicians compared with 41% of respiratory physicians (P<0.0001), who cited opioid concerns related to respiratory depression and lack of knowledge.

In addition to insufficient supporting scientific evidence, data suggest that physicians may not prescribe low-dose opioids for refractory COPD-related breathlessness due to an inability to predict which patients will respond to opioids.

One pooled analysis of four studies of dyspnea related mainly to COPD or chronic heart failure found that worse baseline breathlessness intensity was a strong predictor of response to an opioid (P<0.001), while disease group or functional status was not. The analysis also confirmed younger age (<75 years) predicted relative response (P=0.025), independently of functional status or exercise tolerance.

In an editorial published with the study, Eric Widera, MD, of the University of California San Francisco, said 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 of 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.

Janssen and team concluded that their results should be confirmed in a future multicenter randomized trial that includes a measure of daily physical activity, and enrolls only patients with severe to very severe chronic breathlessness despite optimized COPD treatment.

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