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

Abstract

IntroductionMorphine 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.MethodsMultisite (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.ResultsAnalysed 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.ConclusionNo differences were observed between arms for breathlessness, but the intervention arm used less rescue immediate-release morphine.Trial registration numberACTRN12609000806268.

Dyspnea in COPD: New Mechanistic Insights and Management Implications

“…Dynamic hyperinflation results in a relatively rapid and shallow breathing pattern: the attendant increased velocity of shortening of the inspiratory muscles results in functional muscle weakness, decreases dynamic lung compliance, worsening pulmonary gas exchange (higher V D /V T ) and negative cardiopulmonary interactions (reduced venous return and reduced left ventricular ejection fraction) [53][54][55][56]. With increasing mechanical impairment and progressive resting lung hyperinflation as COPD progresses, these abnormal physiological events appear at progressively lower exercise intensities.…”

Opioids for breathlessness: a narrative review

“…20 Since this review, the largest to date phase III clinical trial of 7 days oral low dose sustained release morphine and placebo for chronic breathlessness due to various conditions has reported. 37 This study was larger than the population even in the most recent review. 18 There was no benefit for the primary outcome of breathlessness now over placebo but methodological issues 38 make interpretation difficult: i) due to slow recruitment, eligibility criteria were expanded to include people with less severe breathlessness.…”

Breathlessness and opioid prescribing in COPD in general practice: a cross-sectional, observational study

“…The pharmacological treatment with best evidence for the reduction of chronic breathlessness is regular, low-dose, sustained-release morphine [10,11]. The strongest evidence for its effectiveness is in people with severe breathlessness (modified Medical Research Council breathlessness scale 3 or 4 [12,13]) and chronic obstructive pulmonary disease (COPD) [14].…”