Magnus P Ekström, Anna Bornefalk-Hermansson, Amy P Abernethy, David C Currow
Safety of Benzodiazepines and Opioids in Very Severe Respiratory Disease: National Prospective Study
IntroductionBreathlessness is a major cause of impaired activity and quality of life, affecting as many as a fifth of people aged over 65. [1,2] Chronic obstructive pulmonary disease (COPD) is a major cause of breathlessness, morbidity, and mortality. Worldwide, more than 300 million people have COPD, many of whom have breathlessness that affects their daily life for many years. [2,3] Breathlessness predicts mortality in COPD, to a stronger degree than impairment of lung function.  The burden of breathlessness increases with increasing age and severity of the respiratory disease; 98% of patients with end stage respiratory disease experience breathlessness, which persists at rest or on minimal exertion, despite optimal treatment of the underlying disease (chronic refractory breathlessness). Patients with severe COPD are more breathless than patients with advanced lung cancer and are breathless for longer periods of time. 
Randomised trials have shown that oral sustained release morphine can relieve chronic refractory breathlessness. [7,8] Whether benzodiazepines reduce breathlessness is not clear, and their safety in this setting is unknown.  Benzodiazepines are also used to treat anxiety and opioids to treat pain, conditions that are highly prevalent in patients with severe COPD. 
A concern among clinicians is that benzodiazepines and opioids alone or in combination could cause adverse events, including respiratory depression, confusion, falls, and even premature death in patients with respiratory compromise. Risks might be higher in frail patients, especially if they have not previously been treated with either or both drugs, and in people with severe COPD and hypercapnia. These concerns are cited by clinicians as an obstacle to prescribing these drugs and might contribute to less than optimal management of breathlessness. [11,12]
Safety data for benzodiazepines and opioids in patients with severe COPD are limited. A pooled analysis of prospective trials including 178 patients with refractory breathlessness, 49% of whom had COPD, found no serious adverse events or admissions to hospital associated with treatment with low doses of opioid.
 Studies of lower dose benzodiazepines and lower dose opioids in patients with COPD found not a single case of respiratory depression. [9,14,15] These studies, however, were mostly small short term trials that included a limited number of selected patients with close follow-up.
[9,14] Safety data from clinical practice are lacking. [13,14] Estimates implying a minimal increase in risk with low dose treatments would be informative in a presumed high risk population.
Conclusions and Clinical ImplicationsThe evidence generated indicates that there is a cohort of patients with severe COPD who seem to tolerate regular lower dose opioids in a way that is likely to deliver a net symptomatic benefit. The level of follow-up and healthcare given to patients might influence the outcomes, and our findings should be interpreted in the context of current levels of clinical contact.
For clinicians, this study further supports the safety of regular low dose systemic opioids to reduce breathlessness in severely ill patients with respiratory compromise and hypercapnia—patients who have an immense need for relief of symptoms.
[1,5,10] The need for higher opioid doses for symptomatic control should be balanced against the possible increased risk of adverse events. Our study supports the suggestion that benzodiazepines should not be the first line treatment for breathlessness in those with respiratory failure, given the unclear evidence of net clinical benefit.
 Benzodiazepines and opioids can be safely combined in lower doses. All treatments assume adequate follow-up of the patient’s clinical condition and symptoms, including proper prophylaxis and treatment for expected effects such as opioid related constipation. [8,14] The approach for chronic breathlessness is no different from that of opioid treatment for pain. 
Sustained release morphine should be considered as a first line treatment and should be initiated at a low dose regularly and titrated upward over days and weeks, balancing beneficial and adverse effects. [14,34] Titration up to 30 mg morphine daily might safely improve breathlessness in over 60% of patients, with a mean decrease of 35% in the intensity of breathlessness from the person’s own baseline. 
In conclusion, benzodiazepines and higher dose opioids were associated with increased adjusted mortality, whereas lower dose opioids were not associated with increased risk of hospital admission or death in patients with respiratory failure associated with COPD.