Regular extended release morphine for chronic breathlessness: a multi-centre double-blind RCT

Abstract

Introduction: Chronic breathlessness causes significant suffering with no medication registered for symptomatic reduction. This study measured efficacy and safety of regular, low dose, extended release (ER) morphine orally on chronic breathlessness intensity. Methods: A national, multi-site, parallel arm, fixed dose (20mg ER morphine daily; docusate with sennosides), double-blind, randomised, placebo-controlled study ran in 14 inpatient and outpatient respiratory, cardiology and palliative care services. Both arms were allowed up to six 2.5mg doses of ‘rescue’ immediate release morphine per day. The primary intention-to-treat endpoint was change from baseline at one week between groups in breathlessness intensity ‘now’ (100mm visual analogue scale [VAS]; twice daily diary). Secondary endpoints included ‘worst’, ‘best’ and ‘average’ breathlessness scores, function, quality of life and adverse events. An a priori regression model explored baseline clinical predictors of response. Results: Opioid-naive adults (n=284) with modified Medical Research Council (mMRC) Scale breathlessness scores 2-4 were randomised: morphine (n=145); placebo (n=139). Outcomes between arms were similar. The placebo arm used more ‘rescue’ morphine (9.0 doses versus 5.8 doses; p=0.003). People with COPD and mMRC 3 or 4 had statistically and clinically significant reductions in worst breathlessness, −10.1mm (95% CI, −19.0 to −1.2). The morphine group had more constipation and nausea/vomiting but no excess serious adverse events. Conclusions: There was no overall affect in people with more severe breathlessness, especially in people with COPD. There was a clinically significant reduction in worst breathlessness.