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Thorax. 2019 Sep 26. pii: thoraxjnl-2019-213681. doi: 10.1136/thoraxjnl-2019-213681. [Epub ahead of print]

Regular, sustained-release morphine for chronic breathlessness: a multicentre, double-blind, randomised, placebo-controlled trial.

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IMPACCT, Faculty of Heath, University of Technology Sydney, Sydney, New South Wales, Australia
College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia.
McCloud Consulting Group, Sydney, New South Wales, Australia.
IMPACCT, Faculty of Heath, University of Technology Sydney, Sydney, New South Wales, Australia.
Respiratory and Sleep Medicine, Austin Health, Heidelberg, Victoria, Australia.
University of Melbourne, Melbourne, Victoria, Australia.
Northern Sydney Local Health District, Saint Leonards, New South Wales, Australia.
Northern Clinical School, University of Sydney, Sydney, New South Wales, Australia.
Deakin Health Economics, Deakin University Faculty of Health, Burwood, Victoria, Australia.
Department of Clinical Sciences, Division of Respiratory Medicine & Allergology, Lund University, Lund, Sweden.



Morphine may decrease the intensity of chronic breathlessness but data from a large randomised controlled trial (RCT) are lacking. This first, large, parallel-group trial aimed to test the efficacy and safety of regular, low-dose, sustained-release (SR) morphine compared with placebo for chronic breathlessness.


Multisite (14 inpatient and outpatient cardiorespiratory and palliative care services in Australia), parallel-arm, double-blind RCT. Adults with chronic breathlessness (modified Medical Research Council≥2) were randomised to 20 mg daily oral SR morphine and laxative (intervention) or placebo and placebo laxative (control) for 7 days. Both groups could take ≤6 doses of 2.5 mg, 'as needed', immediate-release morphine (≤15 mg/24 hours) as required by the ethics review board. The primary endpoint was change from baseline in intensity of breathlessness now (0-100 mm visual analogue scale; two times per day diary) between groups. Secondary endpoints included: worst, best and average breathlessness; unpleasantness of breathlessness now, fatigue; quality of life; function; and harms.


Analysed by intention-to-treat, 284 participants were randomised to morphine (n=145) or placebo (n=139). There was no difference between arms for the primary endpoint (mean difference -0.15 mm (95% CI -4.59 to 4.29; p=0.95)), nor secondary endpoints. The placebo group used more doses of oral morphine solution during the treatment period (mean 8.7 vs 5.8 doses; p=0.001). The morphine group had more constipation and nausea/vomiting. There were no cases of respiratory depression nor obtundation.


No differences were observed between arms for breathlessness, but the intervention arm used less rescue immediate-release morphine.




chronic breathlessness; placebo study; randomised controlled trial; sustained release morphine; symptom relief

Conflict of interest statement

Competing interests: DCC has unrestricted research grant from Mundipharma, is an unpaid member of an advisory board for Helsinn Pharmaceuticals, and has consulted to Specialist Therapeutics and Mayne Pharma, and received intellectual property payments from Mayne Pharma. All other authors declare no competing interests.

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