17 September 2024

Research Fellow, Dr Adejoke O. Oluyase, and Palliative Care Expert, Prof Irene J. Higginson, King’s College Hospital NHS Foundation Trust, share the findings from the international BETTER-B randomised trial. The aim of the project was to test the effectiveness of mirtazapine (a drug repurposed for severe breathlessness) in patients with advanced respiratory diseases. 

What is breathlessness? 

Breathlessness is the feeling of being out of breath as your lungs work harder to draw in more oxygen. It is a frightening symptom that leads to increased distress for patients, families and carers, and is a major cause of suffering. It is highly prevalent in respiratory diseases, affecting over two million people in the UK and 75 million people globally.  

Despite being highly prevalent, research shows it is often neglected and under-treated.  

Treatments not primarily based on medication (Non-pharmacological treatments) are the first-line treatment options for severe breathlessness. There are currently no licensed medicines for severe breathlessness, apart from regular, low-dose, sustained-release morphine in Australia - the usage of which is backed by limited evidence indicating small benefits. There is an urgent need to find other pharmacological treatment options. 

What is the international BETTER-B randomised trial? 

Mirtazapine, a widely used antidepressant, is a drug with a plausible biological mechanism for the treatment of severe breathlessness.  

The drug appears to modulate respiratory sensation - even in the absence of a mood disorder - by enhancing neurotransmitter (e.g serotonin) levels centrally. Smaller scale studies showed promise with mirtazapine. Furthermore, there is evidence that mirtazapine is sometimes prescribed for breathlessness in advanced respiratory diseases, without full trial evidence, because clinicians lack effective treatments. We therefore carried out the BETTER-B trial to find out mirtazapine’s effectiveness, compared to a placebo, in relieving severe breathlessness among people with Chronic Obstructive Pulmonary Disease (COPD) and Interstitial Lung Disease (ILD). The trial was carried out in 16 centres across the UK, Germany, Italy, Ireland, Poland, New Zealand, and Australia. Patients and carers were involved in the research processes from inception to the end of the trial. 

What were the results? 

We enrolled and randomly assigned 225 eligible adults with COPD or ILD and severe breathlessness across all our sites. 

There was no difference in severe breathlessness between those taking mirtazapine and those taking a placebo during the main period of the trial. 

Similar results were found for other measures. This included a person’s quality of life, broader symptoms, anxiety and depression, and frequency of breathlessness episodes. There were no differences found up to six months after the start of the trial. 

There was some evidence that people treated with mirtazapine experienced slightly more side effects and needed more care, from hospitals and from their family members, than those receiving the placebo during the first two months of treatment. 

We carried out in-depth interviews with people with severe breathlessness and their carers or family members to understand their experiences. Some people described their symptoms fluctuating without a clear pattern of improvement. Many did not notice any changes in their health, including sleep, appetite, mood, and drowsiness. Some experienced mild side effects such as dizziness, memory problems, or dry mouth. These interviews highlighted the persistent challenges of breathlessness faced day-to-day. These first-hand accounts highlight the importance of person-centred care for people living with lung diseases or receiving palliative care. 

What could this mean for people with severe breathlessness in respiratory diseases? 

Based on our findings, these are our recommendations: 

  • We do not recommend mirtazapine as a treatment for severe breathlessness in COPD or ILD. 
  • The evidence for any medicine offered off-label (i.e prescribing medicines for a use which it has not been licensed for) should be made clear. 
  • If a medicine is prescribed off-label, it is important to monitor whether it helps or not and be aware of any new symptoms. There might be side-effects of the medication. 
  • There is a need for a person-centred approach in managing breathlessness. 
  • People with severe breathlessness and COPD and ILD should be found early, and offered effective non-pharmacological treatments, such as those offered by pulmonary rehabilitation and breathlessness support services. These already have a good evidence, and are recommended in leading guidelines. Pulmonary rehabilitation and breathlessness support services should be utilised, to find approaches that are tailored to individual needs. They can offer information, tips on how to breathe better, and help to plan activities, however small, to give more personal control over breathlessness. 
  • Research into symptomatic treatments for severe breathlessness is urgently needed, with advocacy for such research. 

What are the next steps for the trial?  

Our BETTER-B trial findings have been published by the Lancet Respiratory Medicine. Summaries of our findings and recommendations are available on the BETTER-B website with brief summaries for patients and carers, policy makers and clinicians. We are disseminating our trial findings widely to key stakeholders including patient and carer groups, clinicians, policy makers, national and international organisations. 

How did working within KHP help progress the trial? 

KHP played a pivotal role in supporting the BETTER-B trial. Our co-sponsor representative in this trial was King’s Health Partners Clinical Trials Office. In addition, King’s College Hospital NHS FT was one of our recruiting sites and the Princess Royal University Hospital (PRUH) was a Participant Identification Centre. We thank all the patients and families who took part in the trial.  

Our gratitude also goes to the clinicians who supported this study including Dr Laura-Jane Smith, Dr Irem Patel, Dr Lynette Linkson, Dr Peter Cho, Dr Geoffrey Warwick, Dr Charlie Reilly, Professor Surinder Birring, Maria Koulopoulou amongst other. 

We thank members of the BETTER-B consortium including Dr Sabrina Bajwah, Professor Matthew Maddocks, Professor Charles Normand, Dr Peter May, Chloe Nast and Paramjote Kaler.  

For more information on managing breathlessness, please see: Managing breathlessness in advanced illness.