Inhaled Fentanyl for Treatment of Dyspnea

Chronic obstructive pulmonary disease (COPD) is characterized by airflow obstruction, exercise limitation, and dyspnea. Often on cardiopulmonary exercise testing, patients develop dyspnea which limits peak work capacity but do not demonstrate a ventilatory limitation to exercise. Activity limitation due to dyspnea is often the primary complaint of patients with COPD. Dyspnea can have a number of different causes including increased central respiratory drive, inhibition of opioid receptor input from the airways, and encroachment on inspiratory capacity from dynamic hyperinflation. It is often poorly correlated with lung function but can significantly affect activity levels, functional status, mood, and quality of life. Standard treatment of dyspnea in COPD includes inhaled b-agonists, anticholinergics, corticosteroids, and occasionally, oral methylxanthines. Opioids play a prominent role in symptoms relief in palliative care, both for pain management and relief of dyspnea. For patients with dyspnea as the primary complaint, the use of inhaled opioids seems to offer the benefit of relieving dyspnea while, at the same time, avoiding the systemic side effects of opioids. Studies of inhaled morphine, however, have produced disappointing results. Studies of inhaled fentanyl are few but have shown improvement in subjective reports of dyspnea in terminally ill patients. The present study was designed to show the effect of a single dose of inhaled fentanyl on both symptom relief and exercise capacity in stable patients with COPD who have persistent symptoms of dyspnea. The authors studied 12 patients with stable COPD with Global Initiative for Chronic Obstructive Lung Disease classification ranging from stage I to stage III. On 2 separate visits, patients inhaled either 50 mcg of fentanyl or an equivalent volume of 0.9% normal saline. Ten minutes after each inhalation, pulmonary function testing was performed and then immediately afterwards, patients exercised at 75% of maximal work capacity, previously determined on cardiopulmonary exercise testing. The time that they could sustain exercise at this work load was recorded both after inhalation of fentanyl and placebo. At rest, during fixed intervals during exercise, and at the end of exercise, patients rated both intensity and unpleasantness of dyspnea. They were also asked to rate the unpleasantness of leg discomfort separately from dyspnea. The degree and unpleasantness of dyspnea was unchanged during and at the end of exercise with fentanyl. However, the rate of rise of dyspnea scores was significantly less towards the end of exercise when patients were treated with fentanyl. Thus, the perception of dyspnea as high-level exercise continued was blunted. The duration of exercise performed at 75% of maximal work load was greater with fentanyl than placebo (7.34 vs. 6.04 min). There was no difference in spirometric or plethysmographic lung measurements with fentanyl, indicating that the improvement in exercise capacity was not related to a change in lung function. Most studies of inhaled fentanyl were performed in the palliative care setting. This study was in stable COPD patients and, in addition to evaluating dyspnea, the investigators demonstrated an increase in sustainable exercise. This occurred without change in lung function. They demonstrated that a single dose of inhaled fentanyl increased exercise capacity by delaying the onset of intolerable dyspnea. The authors postulate that this could be due to either a decrease in peripheral input from opioid receptors in the lung or airways, a change in central processing of these signals, or a combination of the 2. Although this is a very small study involving only 12 patients and only used a single dose of inhaled fentanyl, it suggests that targeting this pathway may have substantial clinical benefit for patients with exercise limitation due to dyspnea. More needs to be known about whether fentanyl or other agents affecting opioid receptors would have sustained clinical effect with repeat dosing and whether patients would experience side effects from continuous dosing. Most treatments for COPD focus on bronchodilation and reduction in dynamic hyperinflation. This focuses on altering the perception of dyspnea, the most disabling symptom of COPD. Reduction in dyspnea may produce improved functional status and may increase quality of life and might even reduce health care utilization. There is much to be learned about the use of inhaled fentanyl or other agents for dyspnea. Furthermore, dyspnea is not unique to COPD and other patient populations may benefit as well. This is a small study designed to assess the physiological effect of inhaled fentanyl. The results indicate that there is much more that we can learn and hopefully apply to help our patients.