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Clinical Trial
. 2025 Jun;69(6):581-588.e2.
doi: 10.1016/j.jpainsymman.2025.02.020. Epub 2025 Feb 25.

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

Magnus Ekström  1 , Fatima Alameri  2 , Sungwon Chang  3 , Diana Ferreira  3 , Miriam J Johnson  4 , David C Currow  3
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Free article
Clinical Trial

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

Magnus Ekström et al. J Pain Symptom Manage. 2025 Jun.
Free article

Abstract

Context: Morphine to treat severe chronic breathlessness might increase adverse events (AEs).

Objectives: 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).

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: COPD; Opioids; adverse events; breathlessness; placebo controlled trial; randomized controlled trial.

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Conflict of interest statement

Disclosure and Acknowledgments The authors thank all participants who made this research possible at a very difficult time of their life, and to the families and friends who supported them. Thanks go to the staff at each site also for their enduring efforts in working with participants to complete the study. This study was funded by the National Health and Medical Research Council, Australia (Grant Number APP1065571) and sponsored by Flinders University, Adelaide, Australia. The trial medications (Kapanol and placebo capsules) were provided by Mayne Pharma. ME was supported by an unrestricted grant from the Swedish Research Council (Dnr: 2019-02081). The funding sources had no role in the planning, conduct or reporting of this study. FA, DF, SC and ME report no conflicts of interest relevant for this work. DCC has received an unresticted research grant from Mundipharma, is an unpaid member of an advisory board for Helsinn Pharmaceuticals and has consulted for and received intellectual property payments from Mayne Pharma. MJJ has received consulting payments from Mayne Pharma.

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