A single arm, open label pilot study of low dose regular opioids with low dose regular benzodiazepines for the relief of refractory breathlessness.

Breathlessness at rest or on minimal exertion (speaking, bathing, dressing) continues to be a major clinical problem for many people with advanced progressive illnesses such as cancer, end-stage cardiac failure or chronic obstructive pulmonary disease even when they are receiving the best treatment for that underlying disease. Although there are some interventions that may offer benefit (oxygen therapy (when oxygen levels in the blood are low), sustained release low dose morphine) for this refractory breathlessness, other therapeutic options need to be explored. Benzodiazepines are widely used as sedatives to help with sleep, to reduce anxiety and to decrease the risk of seizures in people who have, or are at risk of epilepsy. These medications are also widely used around the world to treat breathlessness, however there have been no adequately powered studies that have explored net symptomatic benefit (symptom relief, side effects, maintenance of any benefit) for refractory breathlessness. Each benzodiazepine has slightly different properties in the level of sedation, ability to reduce anxiety and duration of effect. Two key questions need to be answered in order to establish the place of benzodiazepines in the management of refractory background dyspnoea: is there a net symptomatic benefit from benzodiazepines and, if so, is that benefit maintained over time? The latter question is important given the rapid tolerance to benzodiazepines when used as sedatives. Given the ability to dose once daily, the well defined pharmacokinetic and pharmacodynamics (including in children) and the range of formulations/routes of administration available, clonazepam has been chosen for this study. The proposed dose is unlikely to cause significant sedation and is at the lower end of the dosing range for its major long term clinical use in epilepsy. Aim: The primary aim of this pilot study is to refine protocol design including recruitment and retention to the study, establish levels of symptomatic response and variance in that response for power calculations for a definitive trial, and establish whether that benefit is maintained at two weeks.