Highlight
– The MABEL phase 3 randomized, double‑blind, placebo‑controlled trial found no evidence that low‑dose oral long‑acting morphine (5–10 mg twice daily) reduces worst breathlessness at day 28 in patients with chronic breathlessness from cardiorespiratory disease.
– Secondary outcomes showed no benefit except some improvement in cough at day 56; modest increases in physical activity at day 28 were not robust after multiple‑measures correction.
– Morphine was associated with more adverse events, more serious adverse events (some judged related), and higher withdrawal rates; no treatment‑related deaths occurred.
Background and clinical context
Chronic breathlessness—persistent disabling dyspnoea despite optimal treatment of underlying cardiorespiratory disease—is common, distressing, and poorly controlled. It is prevalent across progressive conditions including chronic obstructive pulmonary disease (COPD), heart failure, interstitial lung disease, and advanced cancer. Management is multimodal, including optimization of disease‑directed therapy, pulmonary rehabilitation, psychosocial support, and symptomatic pharmacotherapy when indicated. Laboratory and smaller clinical studies suggested that opioids, particularly morphine, might reduce the subjective sensation of breathlessness by modulating central perception of respiratory drive and affective components of dyspnoea. However, evidence from robust clinical trials has been inconsistent, and safety concerns remain regarding opioid‑related adverse effects, especially in older people with cardiorespiratory comorbidity.
Study design and methods
The MABEL trial (Morphine for chronic breathlessness) was a phase 3, multicentre, parallel‑group, randomized, double‑blind, placebo‑controlled dose‑titration trial conducted at 11 UK centres. Adults with chronic breathlessness from cardiorespiratory causes and a modified Medical Research Council (mMRC) breathlessness score ≥3 were eligible. Participants were randomized 1:1 (stratified by site and causal disease) to receive oral long‑acting morphine (initially 5 mg twice daily with protocolized titration to 10 mg twice daily if needed) or matched placebo for 56 days. To reduce constipation‑related unblinding, all participants also received a blinded laxative.
The primary endpoint was worst breathlessness intensity in the past 24 hours at day 28, measured on a numerical rating scale (NRS; 0–10). Secondary outcomes included objective physical activity (minutes of moderate‑to‑vigorous activity per day), worst cough NRS, quality of life, morphine‑related toxicities, adherence, and safety metrics (adverse events, serious adverse events, withdrawals). Participants who received at least one dose of study medication were included in efficacy and safety analyses. The trial was registered with ISRCTN87329095 and EudraCT 2019‑002479‑33 and funded by the NIHR Health Technology Assessment programme (HTA Project 17/34/01).
Key results
Between March 18, 2021, and Oct 26, 2023, 143 participants were randomized; 73 were assigned to morphine and 67 to placebo (three participants did not receive allocated treatment and were excluded from treatment analyses). Baseline characteristics: mean age 70.5 years (SD 9.4), 66% male (93/143), and 94% White (132/143). Adherence to study medication was high: by day 28, 88% of morphine recipients versus 99% of placebo recipients had ≥90% adherence.
Primary outcome: At day 28, mean worst breathlessness (24 h recall NRS) was 6.19 (95% CI 5.57–6.81) in the morphine group and 6.10 (95% CI 5.44–6.76) in the placebo group. The adjusted mean difference was 0.09 (95% CI −0.57 to 0.75), p=0.78, indicating no evidence of benefit for morphine on the primary outcome.
Secondary outcomes: No consistent benefit was seen across secondary measures. Notable findings included an improvement in worst cough at day 56 favoring morphine (adjusted mean difference −1.41; 95% CI −2.18 to −0.64). The morphine arm showed an increase in moderate‑to‑vigorous physical activity at day 28 (adjusted mean difference 9.51 min/day; 95% CI 0.54–18.48), but this signal did not remain significant after correction for multiple measures.
Safety and tolerability: The morphine group experienced more adverse events (251 vs 162) and more serious adverse events (15 vs 3). Of the SAEs, three in the morphine group were judged to be related to study drug; none in the placebo group were judged related. Withdrawals attributable to study drug were higher with morphine (13 vs 2). There were no treatment‑related deaths reported.
Interpretation and clinical implications
In this rigorously conducted phase 3 trial, low‑dose oral long‑acting morphine did not reduce worst breathlessness at 28 days compared with placebo in people with chronic breathlessness from cardiorespiratory disease. The trial’s negative primary result contrasts with earlier laboratory and smaller clinical studies that suggested symptomatic benefit, highlighting the essential role of adequately powered, blinded randomized trials to evaluate symptomatic therapies.
The absence of a clinically meaningful reduction in worst breathlessness, combined with a higher burden of adverse events, serious events believed related to therapy, and more study withdrawals in the morphine arm, argues against routine use of low‑dose morphine for chronic breathlessness in similar populations. The isolated improvement in cough at day 56 and a transient objective increase in physical activity at day 28 raise the possibility of selective symptomatic effects or benefits in specific subgroups; these findings warrant cautious interpretation and further hypothesis‑driven investigation rather than immediate clinical adoption.
Why might earlier positive signals not translate into benefit in MABEL?
Several non‑mutually exclusive explanations can be considered. First, laboratory studies and small crossover trials often assess short‑term effects in highly selected participants under controlled conditions; these results may not generalize to the broader and more heterogeneous clinical populations enrolled in pragmatic phase 3 trials. Second, dosing and titration strategies matter: MABEL used a conservative low‑dose range (5–10 mg twice daily) intended to balance efficacy and safety; higher or individualized dosing might produce different effects but would likely carry greater safety risks. Third, the perception of breathlessness is influenced by psychological, behavioral, and contextual factors that may not respond to opioid therapy alone. Finally, unblinding due to opioid side effects can bias subjective outcomes in unblinded or inadequately blinded studies; MABEL’s use of blinded laxative and placebo control mitigates this risk and may reveal a true lack of pharmacologic effect beyond placebo.
Strengths and limitations of the trial
Strengths include the randomized double‑blind placebo‑controlled design, multicentre conduct, pragmatic eligibility reflecting real‑world patients with significant breathlessness, careful adherence monitoring, and comprehensive safety reporting. The use of blinded laxative is an important methodological step to reduce unblinding.
Limitations include a predominance of older White men which may limit generalizability to women and more ethnically diverse populations. The trial evaluated a specific low‑dose morphine regimen over 56 days; different opioids, dosing strategies, longer durations, or targeted patient selection (for example severe refractory breathlessness after specialist assessment) were not tested. As with any negative trial, subgroup heterogeneity could mask benefit in a small subset, but any true subgroup effects would need confirmatory evidence.
Practical recommendations for clinicians
– Based on MABEL, routine prescription of low‑dose long‑acting morphine for chronic breathlessness is not supported.
– Continue to prioritize disease‑directed therapies, optimization of comorbid conditions, nonpharmacologic interventions (pulmonary rehabilitation, breathlessness self‑management, psychosocial support), and individualized palliative approaches.
– Consider opioids for refractory breathlessness only after careful specialist assessment, when nonpharmacologic strategies and maximally tolerated disease‑specific treatments have been optimized, and with informed discussion of the limited evidence and known risks; if used, ensure close monitoring for adverse effects and reassessment of benefit.
Research implications and next steps
MABEL highlights the need for further research to define whether any subgroups derive net benefit from opioids for chronic breathlessness, whether alternative opioids or dosing regimens might be effective and safe, and how to combine pharmacologic therapy with behavioral and rehabilitative strategies. Mechanistic studies exploring predictors of opioid responsiveness (for example neurophysiologic or affective phenotypes) could enable precision approaches. Given the safety signals observed, future trials should carefully balance potential symptomatic gains against adverse events and include robust monitoring and predefined stopping rules.
Funding, registration, and citation
Funding: NIHR Health Technology Assessment programme (HTA Project 17/34/01).
Trial registration: ISRCTN87329095; EudraCT 2019‑002479‑33.
Primary citation: Johnson MJ, Williams B, Keerie C, Tuck S, Hart S, Bajwah S, Chaudhuri N, Pearson M, Cohen J, Evans RA, Currow DC, Higginson IJ, Hall P, Atter M, Norrie J, Fallon MT; MABEL collaborative. Morphine for chronic breathlessness (MABEL) in the UK: a multi‑site, parallel‑group, dose titration, double‑blind, randomised, placebo‑controlled trial. Lancet Respir Med. 2025 Nov;13(11):967‑977. doi: 10.1016/S2213‑2600(25)00205‑X. Epub 2025 Sep 28. PMID: 41033333.
Conclusion
The MABEL trial provides high‑quality evidence that low‑dose long‑acting morphine (5–10 mg twice daily) does not reduce worst breathlessness at 28 days compared with placebo in patients with chronic breathlessness from cardiorespiratory disease, and it is associated with greater adverse events and higher withdrawal rates. These results do not support routine use of morphine for chronic breathlessness and underline the need for continued research to identify safe, effective, and individualized treatments for this burdensome symptom.
Expert note
Clinicians should integrate these findings into shared decision‑making with patients, emphasizing proven strategies and reserving opioids for carefully selected, closely monitored cases where the potential benefit justifies the risk.
