Effect of Regular, Low-Dose, Extended-release Morphine on Chronic Breathlessness in Chronic Obstructive Pulmonary Disease

Importance Chronic breathlessness is common in people with chronic obstructive pulmonary disease (COPD). Regular, low-dose, extended-release morphine may relieve breathlessness, but evidence about its efficacy and dosing is needed. Objective To determine the effect of different doses of extended-release morphine on worst breathlessness in people with COPD after 1 week of treatment. Design, Setting, and Participants Multicenter, double-blind, placebo-controlled randomized clinical trial including people with COPD and chronic breathlessness (defined as a modified Medical Research Council score of 3 to 4) conducted at 20 centers in Australia. People were enrolled between September 1, 2016, and November 20, 2019, and followed up through December 26, 2019. Interventions People were randomized 1:1:1 to 8 mg/d or 16 mg/d of oral extended-release morphine or placebo during week 1. At the start of weeks 2 and 3, people were randomized 1:1 to 8 mg/d of extended-release morphine, which was added to the prior week’s dose, or placebo. Main Outcomes and Measures The primary outcome was change in the intensity of worst breathlessness on a numerical rating scale (score range, 0 [none] to 10 [being worst or most intense]) using the mean score at baseline (from days −3 to −1) to the mean score after week 1 of treatment (from days 5 to 7) in the 8 mg/d and 16 mg/d of extended-release morphine groups vs the placebo group. Secondary outcomes included change in daily step count measured using an actigraphy device from baseline (day −1) to the mean step count from week 3 (from days 19 to 21). Results Among the 160 people randomized, 156 were included in the primary analyses (median age, 72 years [IQR, 67 to 78 years]; 48% were women) and 138 (88%) completed treatment at week 1 (48 in the 8 mg/d of morphine group, 43 in the 16 mg/d of morphine group, and 47 in the placebo group). The change in the intensity of worst breathlessness at week 1 was not significantly different between the 8 mg/d of morphine group and the placebo group (mean difference, −0.3 [95% CI, −0.9 to 0.4]) or between the 16 mg/d of morphine group and the placebo group (mean difference, −0.3 [95%, CI, −1.0 to 0.4]). At week 3, the secondary outcome of change in mean daily step count was not significantly different between the 8 mg/d of morphine group and the placebo group (mean difference, −1453 [95% CI, −3310 to 405]), between the 16 mg/d of morphine group and the placebo group (mean difference, −1312 [95% CI, −3220 to 596]), between the 24 mg/d of morphine group and the placebo group (mean difference, −692 [95% CI, −2553 to 1170]), or between the 32 mg/d of morphine group and the placebo group (mean difference, −1924 [95% CI, −47 699 to 921]). Conclusions and Relevance Among people with COPD and severe chronic breathlessness, daily low-dose, extended-release morphine did not significantly reduce the intensity of worst breathlessness after 1 week of treatment. These findings do not support the use of these doses of extended-release morphine to relieve breathlessness. Trial Registration ClinicalTrials.gov Identifier: NCT02720822