A UK randomised study shows no improvement in dyspnoea with low-dose morphine and a higher burden of adverse events, challenging its role in clinical practice.
A major new clinical trial published in The Lancet Respiratory Medicine has reignited debate about the role of morphine in treating chronic breathlessness.
The UK-based MABEL study assessed the use of low-dose morphine in patients with persistent dyspnoea despite optimal disease management.
While the findings suggest that clinically significant respiratory depression was rare under the trial’s carefully controlled conditions, experts caution that the results may not be directly transferable to real-world practice.
The study was run between March 2021 and October 2023, with 143 participants randomly assigned to receive either morphine (73 participants) or placebo (67 participants). Three participants did not receive the allocated treatment.
Participants had a mean age of 70.5 years and were mostly male (93 [66%]). All participants were assessed by the site physician as having an mMRC (Modified Medical Research Council Dyspnea Scale) breathlessness score of 3 or more at enrolment, and 134 (97%) participants self-reported an mMRC breathlessness score of 3 or more at baseline. All bar four participants had at least one comorbidity, and breathlessness was mainly due to chronic lung disease.
By day 28, 64 (88%) participants in the morphine group versus 66 (99%) in the placebo group had 90% or greater adherence to their allocated treatment.
The researchers found no evidence of difference in worst breathlessness at day 28 (morphine 6.19 [95% CI 5.57 to 6.81] vs placebo 6.10 [5.44 to 6.76]; adjusted mean difference 0.09 [95% CI –0.57 to 0.75], p=0.78) or any secondary measure, except for improved cough seen at day 56 (adjusted mean difference –1.41 [–2.18 to –0.64]).
Increased moderate to vigorous physical activity was seen at day 28 (adjusted mean difference 9.51 min/day [0.54–18.48]) but this was not significant after multiple-measures correction.
The morphine group had more adverse events (251 vs 162), serious adverse events (15 vs three, of which three in the morphine group and zero in the placebo group were deemed to be related to the study), and study drug withdrawals (13 vs two). There were no treatment-related deaths.
“We found no evidence that morphine improves worst breathlessness intensity,” the authors wrote.
“Further research is needed to understand whether there is any role for morphine in chronic breathlessness, but our findings do not support its use in this setting.”
Chronic breathlessness is a common and debilitating symptom in advanced respiratory and cardiac conditions, substantially affecting quality of life for patients and families.
When disease-modifying therapies are unable to provide adequate relief, clinicians often turn to supportive interventions. For decades, opioids have been considered as a possible option, yet concerns about safety, particularly respiratory suppression, have prevented widespread adoption.
In an accompanying editorial in The Lancet Respiratory Medicine, Dr Marlies van Dijka and Professor Huib A M Kerstjens of the University of Groningen in the Netherlands, said the MABEL trial findings contributed considerably to the evidence base against opioids for breathlessness.
“Combined with the lack of support for other medications such as mirtazapine and benzodiazepines, we should probably focus much more on non-pharmacological treatments such as breathing and relaxation techniques, elements of cognitive behavioural therapy, a hand-held fan or a crisis action plan,” they wrote.
“Although the MABEL trial gave some indication for increased physical activity and decreased coughing, with the current status of the evidence, we suggest that the time has come to stop considering long-acting morphine for chronic breathlessness.”
They said opioids for chronic breathlessness have been tested since the 1980s, noting that a 2015 meta-analysis of 16 randomised controlled trials (RCTs; 271 patients) showed a positive effect of opioids on breathlessness, “and for a while it appeared that the biggest challenge was to convince health-care providers and patients to prescribe them for this indication”.
“However, in recent years, the paradigm has shifted with the publication of several larger placebo-controlled RCTs investigating opioids for breathlessness, which did not show this same positive effect,” they wrote.
“In a 2024 meta-analysis, Smallwood and colleagues made a distinction between daily life and laboratory exercise studies investigating opioids for breathlessness.
“They found that there was no effect of long-acting opioids on breathlessness in a daily life setting (10 RCTs, 788 patients), but did find a positive effect on breathlessness for trials investigating mainly single-dose, short-acting opioids during exercise testing (6 RCTs, 70 patients).”
Dr van Dijka and Professor Kerstjens said the latest MABEL study was an important advance knowledge because it was adequately powered, well-designed, and had some interesting additional endpoints such as coughing and physical activity.
They also noted two positive findings from the study – including the potential effects of increased physical activity.
“However, before further research on opioids for physical activity is performed, it would be wise to consider whether patients will be motivated to use opioids for this indication because treatment with opioids is not something patients take lightly [due to concerns about addiction, side-effects, and association of opioids with end-of-life care],” they wrote.
The second positive finding related to a significant improvement in day 56 cough score of –1.41 points (95% CI –2.18 to –0.64) in favour of the morphine arm.
“This finding is not new. In fact, slow-release morphine is suggested because treatment in the British Thoracic Society’s clinical statement on chronic cough,” the authors wrote.
“Nevertheless, the finding is interesting as refractory chronic cough is common in cardiorespiratory conditions, known to decrease quality of life, and often lacks adequate treatment.
“We do believe that these results should be interpreted with caution, especially since the patients included in the MABEL trial were not selected for coughing, and we do not know the effects of coughing on their quality of life.”
The Lancet Respiratory Medicine, September 2025
The Lancet Respiratory Medicine, September 2025
