Effect of regular low-dose extended-release morphine on chronic breathlessness in chronic obstructive pulmonary disease: the BEAMS randomized clinical trial

ABSTRACTImportance: Chronic breathlessness is common in people with chronic obstructive pulmonary disease (COPD). Regular, low-dose, extended-release (ER) morphine may relieve breathlessness, but evidence about its efficacy and dosing is needed.Objective: To determine the effect of different doses of ER morphine on chronic breathlessness in patients with COPD after 1 week of treatment.Design, Setting and Participants: Multicenter, randomized double-blind, placebo-controlled, clinical trial at 20 centers in Australia. 160 patients with COPD and chronic breathlessness (defined as a modified Medical Research Council score of 3 to 4) were enrolled between September 1, 2016 and November 20, 2019 and followed up through December 26, 2019. Interventions: Patients were randomized (1:1:1) to daily, oral ER morphine 8 mg, 16 mg or placebo during week 1. At the start of weeks 2 and 3, patients were randomized (1:1) to daily ERmorphine 8 mg or placebo, which was added to the prior week’s dose.Main Outcomes and Measures: The primary outcome was change of worst breathlessness on a numerical rating scale (0 to 10) from mean baseline (days -3 to -1) to mean at days 5 to 7 with morphine 8 mg, 16 mg and placebo. The co-primary outcome was change in daily steps(actigraphy) from baseline (day -1) to mean at days 19 to 21.73 Results: Among 156 patients randomized (median age, 72 years; 48% women), 138 (88%) patients completed week 1 with ER morphine 8 mg (n=55), 16 mg (n=51), placebo (n=50); week3: morphine 8 mg (n=39), 16 mg (n=52), 24 mg (n=40), 32 mg (n=12), placebo (n=13). Change in worst breathlessness at 1 week was not significantly different between placebo and morphine77 8 mg (mean difference (MD), -0.3; 95% CI, -0.9–0.4) and 16 mg (MD, -0.3; 95%, CI -1.0–0.4).Change in mean daily steps at 3 weeks was not significantly different for morphine 8 mg (MD, - 1453; 95% CI -3310–405), 16 mg (MD, -1312; 95% CI -3220–596), 24 mg (MD, -692; 95% CI -2553–1170) or 32 mg (MD, -1924; 95% CI -47699–921) vs placebo.Conclusions and Relevance: Among patients with COPD and severe chronic breathlessness, daily low-dose, ER morphine did not improve worst breathlessness at 1 week of treatment. Thesefindings do not support the use of these doses of ER morphine to relieve breathlessness.Trial registration: ClinicalTrials.gov NCT02720822 https://clinicaltrials.gov/ct2/show/NCT0272082