Harms of Morphine for Chronic Breathlessness in Relation to Dose, Duration and Titration Phase.

Abstract

Morphine to treat severe chronic breathlessness might increase adverse events (AEs). We aimed to evaluate the risk of AEs in relation to dose, duration and titration phase of regular, low-dose sustained-release (SR) oral morphine for chronic breathlessness in people with chronic obstructive pulmonary disease (COPD). Secondary analysis of a double-blind, randomized, trial of SR morphine titrated to 0-32 mg/day over three weeks in people with COPD and chronic breathlessness. Risk of AEs by morphine or placebo dose, duration and titration phase (initiation, stable dose or up-titration) was analyzed using multivariable generalized estimating equation (GEE) models. We included 156 people (49% female) of whom 100 (64%) experienced any AE during week 1: 64% of those on 8 mg/morphine/day; 78% on 16 mg/morphine/day; and 48% on placebo. In multivariable analysis, the AE risk was highest the first week of morphine treatment and decreased in week two (adjusted rate ratio [aRR] 0.71; 95% confidence interval (CI) 0.54, 0.94) and week three (aRR 0.49; 95% CI 0.37, 0.67). Over the three weeks, the AE risk was similar between titration phases, and there was no statistically significant trend with higher morphine doses (P-values>0.10). Most AEs did not require treatment discontinuation or dose reduction and resolved by the end of titration. In people with COPD and severe chronic breathlessness, the risk of AEs was highest during the first week of treatment in a dose-related fashion but did not differ by titration phase or by dose of once-daily SR morphine between 8 and 32 mg/day. Trial registration NCT02720822.