Effect of Regular, Low-Dose, Extended-release Morphine on Chronic Breathlessness in Chronic Obstructive Pulmonary Disease
Magnus Ekström, Diana Ferreira, Sungwon Chang, Sandra Louw, Miriam J. Johnson, Danny J. Eckert, Belinda Fazekas, Katherine J. Clark, Meera Agar, David C. Currow, Christine F. McDonald, John O. Miners, Carl M. J. Kirkpatrick, Andrew A. Somogyi, Linda Denehy, Nikki McCaffrey, Lawrence Lam, Aine Greene, Brian Le, Katherine Clark, Kwun M. Fong, Meera Agar, Rohit Joshi, Sharon L. Kilbreath, Diana Ferreira, Angela Clow, Nina Smith, Richella Ryan, Sara Booth, Peter Martin, Suharsha Kanathigoda, Caitlin Sheehan, Jessica Lee, Peter Allcroft, Erica Cameron-Taylor, Philip Good, Louise Welch, Richard Chye, Jennifer Phillip, John R. Wheatley, Anu krishnan, Michael Epton, Rajesh Aggarwal, Philip McCloud, Jessie S. M. Chan, Douglas Bellamy, Frances Bellemore, Priyanka Bhatarai, Helen Biggins, Mary-Rose Birch, Lesley Burke, Tracey Burns, Naomi Byfieldt, D. Charlesworth, G. Edward Collins, Helen Cooper, Urska Cosic, D. Mark Courtney, Georgie Cupples, Anna Dowd, Ruth Dunleavey, Terence S. Edgar, Amanda Fischer, Lisa Fuhrmeister, Jan Gesling, Rosetta Hart, Kim Hopkinson, Michelle Kaczurowski, Sally Kidd, Ngaire Kingi, Vera Margitanovic, Gillian McCarthy, Robin O'Reilly, Mary Perry, Bronwyn Raymond, Di Saward, Aaron Shanon-Honson, Karyn M. Sullivan, Michelle L. Tonkin, Zac Vandersman, Penny West, Julie Wilcock, Malina Storer, Sarah Nestor, Safrina Thristiawati, Manraaj Sidhu
Abstract
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.