BETTER B: BETter TreatmEnts for Refractory Breathlessness

Project Description

Breathlessness is a common, distressing, symptom in advanced disease, causing considerable disability for patients,1, 2 and anxiety and social isolation for them and their family and carers.3-5 Breathlessness (also called dyspnea or dyspnoea) is usually described as: "a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity. The experience derives from interaction among multiple physiological, psychological, social, and environmental factors and may induce secondary physiological and behavioural responses".1 Continuing breathlessness, despite optimal management of the underlying causes, is termed ‘intractable' or ‘refractory'. Over 2 million people experience breathlessness each year in the UK. This includes more than 90% of the over 1 million people in the UK diagnosed with moderate to severe chronic lung disease6, over 50% of the 200,000+ with incurable cancer and 50% of the 2 million with chronic heart failure, (many of whom will suffer refractory breathlessness).7-9 In addition, breathlessness is found in people severely affected by renal and liver failure, neurological conditions, HIV/AIDS and many autoimmune diseases.7, 10-12 Breathlessness increases as the disease progresses13, is associated with shortened life expectancy,14-16 is very frightening for patients and families4, 5, 8, 9, 17 and often results in hospitalisation18. There are few effective treatments for refractory breathlessness. Morphine has a role,19-25 but there are no other proven pharmacological treatments. Animal studies, case reports, observational series and a phase II trial suggest that serotonergic modulation is beneficial, but rigorous evaluation has not been conducted. We wish to test mirtazapine, a widely used noradrenergic and specific serotonergic antidepressant (NaSSA). Mirtazapine is an increasingly preferred antidepressant which appears to have a quicker onset of action and fewer drug interactions than other antidepressants, has a good safety record and may be better tolerated than other antidepressants in this population.26-31 It also has the added advantage of reducing anxiety,26-28, 32 which is a common consequence of severe episodes of breathlessness.33, 34 The side effect of weight gain may also be an advantage for some patients who have weight loss in advanced disease.32 To assess the efficacy of mirtazapine in patients with refractory breathlessness, it is expected that a randomised placebo-controlled double-blind phase III trial of approximately 250 patients will be required. However, it is important to determine whether such a large-scale trial in this population of poor prognosis patients is feasible, due to issues surrounding acceptability of randomisation, ability to recruit, and the use of a placebo control.35-37 We therefore propose a feasibility study of a randomised placebo-controlled double-blind trial, of 60 patients to address these issues.