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.

Effect of Prophylactic Fentanyl Buccal Tablet on Episodic Exertional Dyspnea: A Pilot Double-Blind Randomized Controlled Trial

“…(8, 9) Several case series of oral transmucosal fentanyl citrate and intranasal fentanyl reported some benefits. (10-12) However, subsequent randomized controlled trials of subcutaneous fentanyl,(13) nebulized fentanyl (14, 15) and fentanyl pectin nasal spray (FPNS)(16) yielded mixed results compared to placebo.…”

Impact of Prophylactic Fentanyl Pectin Nasal Spray on Exercise-Induced Episodic Dyspnea in Cancer Patients: A Double-Blind, Randomized Controlled Trial

“…(13) Moreover, nebulized fentanyl was found to be associated with a decrease in exertional dyspnea in patients with chronic obstructive pulmonary disease but not in healthy men. (14, 15) A recent systematic review on the effect of fentanyl for refractory breathlessness included 13 studies and only 2 randomized controlled trials. (16) The investigators concluded that fentanyl showed some promise but adequately powered randomized trials are needed.…”

Effect of Inhaled Nebulized Furosemide (40 and 120 mg) on Breathlessness during Exercise in the Presence of External Thoracic Restriction in Healthy Men

“…As reviewed in the introduction, relief of breathlessness following inhalation of nebulized furosemide has been mechanistically linked to altered pulmonary vagal afferent activity from PSRs (most likely SARs), presumably mimicking greater V T expansion (Nishino et al, 2000 ; Sudo et al, 2000 ; Nehashi et al, 2001 ; Moosavi et al, 2007 ; Nishino, 2009 ). On this basis, we reasoned that the potential dose-response effect of nebulized furosemide on breathlessness might be uniquely revealed during constant-load CPET in the presence of an external thoracic restriction when V T expansion (and presumably also activation of SARs) is reduced and breathlessness is (i) severely intense and unpleasant, (ii) described as a heightened sense of “unsatisfied inspiration” and (iii) identified as a main exercise-limiting symptom (Harty et al, 1999 ; O'Donnell et al, 2000 ; Mendonca et al, 2014 ; Kotrach et al, 2015 ). By studying healthy men as opposed to symptomatic adults with advanced disease, we also minimized the potentially confounding influences of psycho-physiological comorbidities, skeletal muscle deconditioning/dysfunction, hypoxemia, hypercapnia, concomitant medication use, etc.…”

“…Visit 1 included: screening for eligibility criteria; routine clinical assessment of heart rate and rhythm by 12-lead electrocardiography (GE Marquette's CardioSoft® 12-lead ECG system; CareFusion, Yorba Linda, CA), blood pressure by automated sphygmomanometer (Carescape™ V100 Dynamap® monitor; GE Healthcare, Freidburg, Germany) and oxyhemoglobin saturation by finger pulse oximeter (Carescape™ V100 Dynamap® monitor); collection of arterialized capillary blood samples from a warmed earlobe (Finalgon® Cream, Boehringer Ingelheim GmbH) into a pre-heparinized capillary tube (safeCLINITUBES, D957P-70-125; Radiometer Copenhangen, Denmark) for measurement of [K + ], [Na + ], [Cl − ], and [ ]—and subsequent calculation of the anion gap [i.e., ([Na + ] + [K + ])–([Cl − ] + [ ])]—using an OPTI TM CCA-TS2 analyzer (OPTI Medical Systems Inc., Roswell, GA, USA); pulmonary function testing, including spirometry and slow vital capacity (SVC) maneuvers; external thoracic restriction by chest wall strapping (CWS) to reduce SVC by ~20% of its baseline (unrestricted) value at rest (Mendonca et al, 2014 ; Kotrach et al, 2015 ); spirometry and SVC maneuvers after ~5-min of acclimatization to the CWS; and a symptom-limited incremental cardiopulmonary cycle exercise test (CPET) in the presence of CWS to determine peak power output (PPO) as well as to familiarize participants to CPET with CWS.…”

“…An inelastic strap (Nike Structured Strength Training Belt; Beaverton, OR, USA) was fitted just beneath the axillae and around the chest to envelope the rib cage (Mendonca et al, 2014 ; Kotrach et al, 2015 ). The desired degree of lung volume restriction was achieved by tightening a Velcro strap at the back of the CWS while participants expired to residual volume, followed shortly thereafter by a series of SVC maneuvers.…”