A phase III, multi-site, randomised, double blind, placebo controlled parallel arm study of daily extended release (ER) morphine for chronic breathlessness.

Introduction Phase II studies and meta-analyses support using regular low-dose oral morphine to safely reduce chronic breathlessness when underlying causes are treated optimally. Aim To determine efficacy and safety of ER morphine for relieving chronic breathlessness and predictors of response. Methods Opioid-naïve participants with modified Medical Research Council scores (mMRC) 2-4 despite optimal treatment of the underlying cause(s) were randomised to double-blinded placebo or 20mg ER morphine daily for 7 days. The primary outcome was reduction in breathlessness intensity (0-100mm visual analogue scale; a clinically meaningful reduction is \u3e5.5mm.). Secondary endpoints were adverse events. Results 282 participants (mean age 73.7, SD 9.5; 162 (57%) with COPD) were randomised in 12 sites in Australia. There was no difference in average breathlessness over the previous 24 hours, but worst breathlessness in people with COPD and mMRC 3 or 4 was significantly reduced in the intervention arm (response rate 54% vs 33%; p=0.035). Using an adjusted mixed model with daily scores, worst breathlessness improved on morphine compared to placebo (4.57mm; 95% CI, 0.31 to 8.83; p=0.036); in patients with COPD (6.30 mm; 95% CI, 1.36 to 11.24; p=0.012); and COPD with mMRC 3,4 (11.47mm; 95%CI, 5.21 to 17.73; p \u3c0.001). Withdrawals were similar between arms (time to event, event rate). Constipation and drowsiness were more frequent on morphine. There were no treatment-emergent episodes of respiratory depression. Conclusion People with COPD and more severe chronic breathlessness gain symptomatic benefit safely from daily ER morphine