Does nebulized fentanyl relieve dyspnea during exercise in healthy man?

Abstract

Few therapies exist for the relief of dyspnea in restrictive lung disorders. Accumulating evidence suggests that nebulized opioids selective for the mu-receptor subtype may relieve dyspnea by modulating intrapulmonary opioid receptor activity. Our respective primary and secondary objectives were to test the hypothesis that nebulized fentanyl (a mu-opioid receptor agonist) relieves dyspnea during exercise in the presence of abnormal restrictive ventilatory constraints and to identify the physiological mechanisms of this improvement. In a randomized, double-blind, placebo-controlled crossover study, we examined the effect of 250 μg nebulized fentanyl, chest wall strapping (CWS), and their interaction on detailed physiological and perceptual responses to constant work rate cycle exercise (85% of maximum incremental work rate) in 14 healthy, fit young men. By design, CWS decreased vital capacity by ∼20% and mimicked the negative consequences of a mild restrictive lung disorder on exercise endurance time and on dyspnea, breathing pattern, dynamic operating lung volumes, and diaphragmatic electromyographic and respiratory muscle function during exercise. Compared with placebo under both unrestricted control and CWS conditions, nebulized fentanyl had no effect on exercise endurance time, integrated physiological response to exercise, sensory intensity, unpleasantness ratings of exertional dyspnea. Our results do not support a role for intrapulmonary opioids in the neuromodulation of exertional dyspnea in health nor do they provide a physiological rationale for the use of nebulized fentanyl in the management of dyspnea due to mild restrictive lung disorders, specifically those arising from abnormalities of the chest wall and not affiliated with airway inflammation.

Trial registration: ClinicalTrials.gov NCT01853449.

Keywords: chest wall strapping; dyspnea; exercise; fentanyl; opioid.

Copyright © 2015 the American Physiological Society.

Figures

Fig. 1.

Flow diagram: enrollment, randomization, and analysis of study participants.

Fig. 2.

Effects of chest wall strapping (CWS), nebulized fentanyl (250 μg), and their interaction on ventilatory, breathing pattern, and dynamic operating lung volume responses to constant work rate cycle exercise performed at 85% of maximal incremental work rate, equivalent to 204 ± 10 W. Data points are means ± SE at rest, standard submaximal exercise time points including isotime (6.4 ± 0.7 min) and at peak exercise. CTRLFC, unrestricted control + nebulized fentanyl; CTRLPLA, unrestricted control + nebulized placebo; CWSFC, CWS + nebulized fentanyl; CWSPLA, CWS + nebulized placebo; TLC, total lung capacity; VT, tidal volume; SVC, slow vital capacity. *P < 0.05 CWSPLA vs. CTRLPLA. †P < 0.05 CWSFC vs. CTRLFC.

Fig. 3.

Effects of CWS, nebulized fentanyl (250 μg), and their interaction on neural respiratory drive and respiratory pressures during constant work rate cycle exercise performed at 85% of maximal incremental work rate, equivalent to 204 ± 10 W. Data points are means ± SE at rest, standard submaximal exercise time points including isotime (6.4 ± 0.7 min), and at peak exercise. A: root mean square of the diaphragm electromyogram (EMGdi,rms); B: esophageal pressure (Pes); C: transdiaphragmatic pressure (Pdi); D: gastric pressure (Pga). *P < 0.05 CWSPLA vs. CTRLPLA. †P < 0.05 CWSFC vs. CTRLFC.

Fig. 4.

Effects of CWS, nebulized fentanyl (250 μg), and their interaction on Borg 0–10 scale intensity and unpleasantness ratings of dyspnea during constant work rate cycle exercise performed at 85% of maximal incremental work rate, equivalent to 204 ± 10 W. Data points are means ± SE at rest, standard submaximal exercise time points including isotime (6.4 ± 0.7 min), and at peak exercise. *P < 0.05 CWSPLA vs. CTRLPLA. †P < 0.05 CWSFC vs. CTRLFC.