RCT Abstract - Morphine for chronic breathlessness (MABEL): a multi-site, parallel group, dose titration, double-blind, randomised, placebo-controlled trial.

Background: The effectiveness of opioids for breathlessness seen in laboratory-based studies has not been replicated in clinical trials. We aimed to assess the effectiveness of oral morphine for breathlessness in long-term conditions.

Methods: This 11-centre, phase-3, parallel-group, double-blind, placebo-controlled trial randomised (1:1, stratification: site, causal disease) consenting adults with modified Medical Research Council breathlessness ≥3 due to cardio-respiratory conditions to 5-10mg twice-daily oral long-acting morphine/placebo (blinded laxative; 56 days). Primary outcome; Day-28 worst breathlessness/24 hours numeric rating scale (NRS). Secondary outcomes included: physical activity levels; worst cough NRS; quality of life; morphine-related toxicities. Primary analysis: repeated measures analysis of covariance adjusted for baseline worst breathlessness and stratification variables.

Findings: Between 18th March 2021 and 26th October 2023, we randomised 143 participants (75 morphine, 68 placebo); 140 formed the modified intention-to-treat population (90% power; males 93/140 (66%); mean age 70.5 [SD 9.4]). By Day-28, 60/73 (82%) morphine versus 56/67 (84%) placebo participants had ≥90% adherence. We found no evidence of a Day-28 primary outcome difference (morphine 6·19 [5·57, 6·81], placebo 6·10 [5·44, 6·76]; adjusted mean difference [AMD]; 0·09 [95% CI -0·57, 0·75], p=0·78), or any secondary measure except increased moderate/vigorous physical activity (AMD; 9·51 mins/day (0·54, 18·48); not significant after multiple measures correction). Evidence of improved cough was seen at Day-56 (AMD; -1·41 [-2·18, -0·64]). The morphine group had more adverse events (251 versus 162); serious adverse events (15 versus 3; 3 and 0 related respectively), and more study drug withdrawals (13 versus 2). There were no treatment-related deaths.

Interpretation: We found no evidence that morphine improves worst breathlessness intensity. Further research is needed to understand if there is any role of morphine in chronic breathlessness, but our findings do not support its use in this setting.