Breathlessness is the sensation of struggling to breathe as the lungs work harder to draw in more oxygen. It is a frightening and distressing symptom that causes significant anxiety and suffering for patients, families, and carers.
With my illness, breathlessness is the main and most problematic symptom for me. My mother also had suffered from breathlessness – she had terminal cancer. And my 90-year-old uncle currently suffers from it – he has asbestos on the lungs. It is such a debilitating symptom and has a huge impact on quality of life. Anything to reduce the impact of this symptom would have been a great help to me and my family
Breathlessness is very common in respiratory diseases, affecting an estimated two million people in the UK and 75 million globally. It results in high health, social and informal care costs. Despite its prevalence, research indicates that breathlessness is often neglected or under-treated. Treatments not primarily based on medication (non-pharmacological treatments) are considered the first-line approach for managing severe breathlessness. However, when these methods fail, there are no globally approved medications for its treatment, except in Australia, where low-dose, sustained-release morphine is used with limited supporting evidence for small benefits. Consequently, there is an urgent need to develop alternative pharmacological treatment options.
The international BETTER-B randomised trial investigated the potential of mirtazapine, a widely used antidepressant, as a treatment for severe breathlessness. Mirtazapine has a plausible biological mechanism for this purpose, as it appears to modulate respiratory sensation by enhancing central neurotransmitter levels, such as serotonin, even in the absence of a mood disorder. Smaller scale studies suggested promising results with mirtazapine. Additionally, evidence indicates that it is sometimes prescribed in advanced respiratory diseases for breathlessness, without full trial evidence, due to the lack of effective alternatives.
We therefore conducted the BETTER-B trial to evaluate the effectiveness of mirtazapine compared to a placebo in alleviating severe breathlessness in patients with Chronic Obstructive Pulmonary Disease (COPD) and Interstitial Lung Disease (ILD). The study was carried out across 16 centres in the UK, Germany, Italy, Ireland, Poland, New Zealand, and Australia. Patients and caregivers were actively involved in shaping the research processes from inception to the end of the trial.
In the BETTER-B trial, we enrolled 225 adults with COPD or ILD experiencing severe breathlessness across multiple international sites. Participants were randomly assigned to receive either mirtazapine or a placebo. Over the main 56-day trial period, there was no difference in severe breathlessness between the two groups. Similar findings were observed for other outcomes, including a person’s quality of life, broader symptoms, anxiety and depression levels, and the frequency of breathlessness episodes, with no differences persisting up to six months after the trial began.
Participants treated with mirtazapine reported slightly more side effects and required more care from hospitals and family members during the first two months of treatment compared to those on the placebo. Side effects reported included dizziness, memory problems and dry mouth.
In-depth interviews with participants and their carers provided further insights. Some people described their symptoms as fluctuating unpredictably, with no clear signs of improvement. Many did not notice any changes in their health, including sleep, appetite, mood, or drowsiness. The interviews underscored the ongoing daily challenges of living with severe breathlessness and highlighted the importance of person-centred care for people living with lung diseases or receiving palliative care.
Based on our findings, these are our recommendations:
Our BETTER-B survey revealed that 19% of respiratory medicine physicians and 11% of palliative care physicians frequently recommend antidepressants for severe breathlessness in COPD, indicating that these medications are already being used off-label. However, this new trial concludes that mirtazapine is not recommended for treating breathlessness. It emphasizes the need for caution when using unlicensed medications and underscores the importance of conducting rigorous trials of medicines used in palliative care
We need more research into potential treatments for severe breathlessness. For now, we advise clinicians to focus on early identification and prioritise non-pharmacological approaches, such as those offered by breathlessness support services, to manage this symptom
The BETTER-B trial findings have helped to understand that mirtazapine does not work for breathlessness. There is a need to search for new and effective treatments for severe breathlessness.