Differential Mechanisms of Dyspnea Relief in Advanced COPD: Opiates vs. Bronchodilators
Phase: PHASE4
Conditions: Chronic Obstructive Pulmonary Disease
Sponsor: Dr. Denis O'Donnell

Dr. Denis O’Donnell (Principal Investigator) 
Respiratory Investigation Unit 
Queen’s University & Kingston General Hospital 
76 Stuart Street, Kingston, ON, Canada K7L 2V7 
 
Protocol version: 23-Aug-2017 
 
page 1 
Differential Mechanisms of Dyspnea Relief in Advanced COPD: Opiates vs. Bronchodilators 
BACKGROUND & RATIONALE 
Chronic obstructive pulmonary disease (COPD) is a common respiratory illness which afflicts almost 
10% of Canadians over 40 years of age (1,2).  COPD sufferers report poor perceived quality of life and 
often must endure progressive physiological impairment, increasing morbidity and reduced survival. 
Activity-related breathlessness (dyspnea) is the dominant symptom and persists despite optimal medical 
care in as many as 50% of patients with advanced COPD (3). Thus, for many patients, effective relief of 
dyspnea remains an elusive goal and is a major challenge for caregivers.  Meaningful palliation of this 
symptom awaits a better understanding of its neurophysiological origins - the main focus of the 
proposed application.   
The physiology of dyspnea: Dyspnea is defined as “a subjective experience of breathing discomfort 
that consists of qualitatively distinct sensations that vary in intensity” (4). Current constructs of the 
neurobiology of dyspnea have arisen from animal studies that have provided a plausible neuro-
anatomical substrate for respiratory sensation, and from human studies that have measured sensory 
responses to graded external mechanical and chemical loading in the laboratory setting (5-19). More 
recently, clinical studies have focused on physiological mechanisms of dyspnea provoked by 
standardized stimuli (e.g., exercise) in specific patient populations (20,21). A consistent observation has 
been that dyspnea arises during exercise in COPD when there is mismatch between ventilatory demand 
(largely dictated by chemical stimuli) and the capacity to respond to that demand (dictated by mechanical/ 
muscular factors) (21,22). In line with this observation, dyspnea ratings during exercise in health and 
COPD have been shown to correlate strongly with indices such as ventilation relative to maximal 
ventilatory capacity (VE/MVC) and contractile muscular effort (esophageal pressure relative to 
maximum (Pes/Pes,max)) (20-22). 
 
Broadly speaking, these consistent physiological associations support the notion that dyspnea 
rises as a function of the amplitude of motor command output (and central corollary discharge) from 
bulbo-pontine and cortical centers in the brain to the active respiratory muscles (23-26) [Appendix 1]. 
There is some evidence that efferent central inspiratory neural drive (relative to maximum) is more 
important than afferent inputs from peripheral respiratory (chest wall and muscle) mechanoreceptors in 
modulating perceived dyspnea (27,28). While these past studies provide insight into the origins of 
sensory intensity of respiratory discomfort they do not easily explain differences in the quality of 
dyspnea between healthy individuals and those with COPD.  
Mechanisms of increased dyspnea intensity: A major limitation in the study of dyspnea is our inability 
to directly measure central inspiratory neural drive. Surrogate indices such as ventilatory output 
(VE/MVC) and contractile effort are dampened by prevailing mechanical constraints and likely 
underestimate true inspiratory neural drive (29). Recently, diaphragmatic electromyography (EMGdi) 
has been proposed as an indirect method of measuring the fractional inspiratory neural drive to the crural 
diaphragm, i.e., inspiratory EMGdi as a fraction of its maximum (EMGdi/EMGdi,max) (30-32). Dyspnea 
intensity ratings during exercise in healthy individuals and those with COPD rise linearly with 
EMGdi/EMGdi,max (33-35) [Appendix 2]. The higher dyspnea ratings for a given VE during exercise in 
COPD compared with healthy subjects is explained by the relatively higher EMGdi/EMGdi,max. This 
in turn reflects the combined effects of increased pulmonary gas exchange abnormalities (high 
physiological deadspace) and greater intrinsic mechanical loading and functional weakness of the 
inspiratory muscles. Furthermore, we have shown that the relationship between dyspnea intensity and 
EMGdi/EMGdi,max is unaffected by differences in static mechanics, respiratory muscle strength and the 
activity pattern of various inspiratory and expiratory muscles supporting  ventilation during exercise 
(35,36)[Appendix 2]. Collectively, these studies support the long held contention that dyspnea intensity 

Dr. Denis O’Donnell (Principal Investigator) 
Respiratory Investigation Unit 
Queen’s University & Kingston General Hospital 
76 Stuart Street, Kingston, ON, Canada K7L 2V7 
 
Protocol version: 23-Aug-2017 
 
page 2 
during activity is closely linked to the magnitude of descending motor command output to the inspiratory 
muscles. Accordingly, several studies have postulated, based on indirect evidence (breathing pattern and 
VE), that reduced inspiratory neural drive is one potential mechanism by which a number of therapeutic 
interventions reduce dyspnea intensity in COPD (37-42). However, the interpretation of these studies 
remains conjectural as they have not formally examined relationships between multi-component dyspnea 
and the integrated neuromechanical responses of the respiratory system to exercise. Therefore, the 
current study will be the first to comprehensively study in a novel manner the interaction between the 
sensory and neuromechanical effects of one such treatment (i.e., opiate medication), which putatively 
diminishes inspiratory neural drive during exercise in COPD. 
Quality of dyspnea: It is postulated that the intensity (strength) and quality (how it feels) of respiratory 
discomfort have different neuro-physiological underpinnings (4). The quality of dyspnea at the limits of 
tolerance is different in patients with COPD and in health despite similar intensity ratings (22,35). Thus, 
healthy individuals commonly select work/effort descriptors (“breathing requires more effort or work”) 
as being most representative of their experience while patients with COPD additionally select descriptors 
alluding to inspiratory difficulty and unsatisfied inspiration (“cannot get enough air in”). This latter 
descriptor is perceived as unpleasant and is rarely selected in health, even at high exercise intensities. 
During exercise in COPD there is an evolution of respiratory sensations from dominant increased 
work/effort early in exercise to unsatisfied inspiration later in exercise when tidal volume (VT) reaches 
its plateau – a point corresponding to the attainment of a minimal inspiratory reserve volume (IRV) of 
~0.5L (43). In other words, the point where VT becomes positioned on the upper non-compliant reaches 
of the respiratory system’s sigmoidal pressure-volume relation where the inspiratory muscles are 
burdened with increased elastic work. The VT plateau marks the onset of a widening disparity between 
increasing inspiratory neural drive (and central corollary discharge) often amplified by metabolic 
acidosis and/or hypoxemia and the blunted, mechanically constrained VT response. This disparity has 
been called neuromechanical dissociation. There is an abundance of mechanoreceptors in the airways, 
lungs, chest wall and respiratory muscles that can convey precise afferent feedback information about 
the dynamic status of the breathing apparatus and the appropriateness of its response to descending 
inspiratory neural drive via central integration of efferent-afferent signals [Appendix 1]. Bronchodilator 
therapy, which increases resting inspiratory capacity (IC) by reducing lung hyperinflation, delays the 
onset of critical mechanical constraints (i.e., the minimal IRV) (44,45). We have speculated that the 
improved ratio of respired effort to VT (Pes/Pes,max:VT/VCpredicted) – a crude index of 
neuromechanical dissociation – may explain the reduced selection frequency of unsatisfied inspiration 
after a bronchodilator (44,45). The current study will extend the previous work using more 
sophisticated evaluative methods to determine the mechanisms of dyspnea relief following 
bronchodilator treatment. Specifically, we will examine the inter-relationships between dyspnea 
intensity and quality, inspiratory neural drive, dynamic respiratory mechanics and muscle function 
and how these are altered by bronchodilators.   
Comparing mechanisms of dyspnea relief during opiate (with oxygen) and bronchodilator therapy: 
We hope to gain new insights into the mechanisms of dyspnea in COPD by selectively manipulating 
inspiratory neural drive (nebulized opiates) and abnormal respiratory mechanics (nebulized 
bronchodilators) within the same individuals. In a preliminary study, we established that relief of 
exertional dyspnea in patients with COPD following inhaled fentanyl – a lipophilic, μ-receptor opioid 
antagonist – was associated with reduced VE (37). Thus, inhaled fentanyl did not change the slope of the 
dyspnea/VE relation: the reduction in dyspnea at a given work rate mainly reflects the reduction in VE 
and breathing frequency [Appendix 3]. This suggests that reduction in inspiratory neural drive is 
potentially the key mechanism, particularly since respiratory mechanics were essentially unaltered by 

Dr. Denis O’Donnell (Principal Investigator) 
Respiratory Investigation Unit 
Queen’s University & Kingston General Hospital 
76 Stuart Street, Kingston, ON, Canada K7L 2V7 
 
Protocol version: 23-Aug-2017 
 
page 3 
this treatment. By contrast, reduced exertional dyspnea following inhaled bronchodilators in COPD was 
mainly related to improved mechanics (i.e., increased IC, VT, and inspiratory reserve volume (IRV); 
reduced Pes/Pes,max:VT/VCpredicted) as VE was unchanged or increased (40,44-46). In other words, 
the dyspnea/VE slope was reduced after bronchodilator: improvement in dyspnea at a given VE mainly 
reflected the improved mechanics [Appendix 3].  
The contrasting physiological effects of these two interventions present us with a unique 
opportunity to probe the origins of dyspnea in COPD and for the first time, to determine the role of 
inspiratory neural drive. Based on our recent studies (35,36), we postulate that regardless of the 
intervention, the key relationship between EMGdi/EMGdi,max and dyspnea intensity will remain 
unaltered. It follows that with both interventions, dyspnea intensity ratings will be reduced in proportion 
to the reduced EMGdi/EMGdi,max, albeit through different mechanisms: with opiates, direct central 
inhibitory effects; with bronchodilators, improved respiratory mechanics/muscle function which 
necessitate lower inspiratory neural drive for a given VE. Peculiar to bronchodilators, the improved 
mechanics will mean an improved ratio of inspiratory neural drive to ventilation and associated reduced 
unsatisfied inspiration.   
Studies were done previously on dyspnea relieving interventions in COPD such as the use of 
bronchodilator therapy and oxygen, both singly and in combination. In a previous study utilizing 
combined bronchodilator and oxygen therapy, we established that there was reduced hyperinflation 
(using bronchodilators) and reduced ventilatory drive (using oxygen) in normoxic COPD patients (40). 
There is minimal information available on the effects of using inhaled fentanyl and oxygen interventions 
combination on dyspnea in COPD. This would be the first study to demonstrate the physiological effects 
of inhaled fentanyl combined with oxygen therapy on dyspnea in COPD. 
 
OBJECTIVE: To compare the effects of inhaled opiate (with added oxygen) and bronchodilator 
treatments on the intensity of dyspnea, electromyographic estimates of inspiratory neural drive and 
respiratory mechanics and their interactions during a standardized exercise test using a randomized, 
controlled, crossover design in patients with COPD. 
HYPOTHESIS: The mechanisms of dyspnea relief during opiate and bronchodilator treatments will be 
different. With both inhaled opiate and bronchodilator, inspiratory neural drive and dyspnea intensity 
will diminish in tandem. Additionally, and in contrast to the effect of opiates, improvement in respiratory 
mechanics with inhaled bronchodilators will reduce neuromechanical dissociation and the attendant 
perceived unsatisfied inspiration. 
METHODS 
Subjects: Subjects will include 17 clinically stable patients with moderate-to-severe COPD recruited 
from: a database of COPD volunteers at the Respiratory Investigation Unit; respirology outpatient clinics 
at Hotel Dieu Hospital; notices posted in community health care facilities; and advertisements. Inclusion 
Criteria: 1) post-bronchodilator forced expiratory volume in 1 sec (FEV1) 30-79% predicted and 
FEV1/forced vital capacity (FVC) <70%; 2) clinically stable as defined by no changes in medication 
dosage or frequency of administration with no exacerbations or hospital admissions in the preceding 6 
weeks; 3) male or female 40 yrs of age; 4) cigarette smoking history ≥20 pack-years; 5) moderate-to-
severe chronic activity-related dyspnea as defined by a modified MRC dyspnea scale ≥2, COPD 
Assessment Test score ≥10 or Baseline Dyspnea Index focal score 6 (47-49); 6) ability to perform all 
study procedures and provide/sign informed consent. Exclusion Criteria: 1) women of childbearing age 
who are pregnant or trying to become pregnant; 2) diffusing capacity of the lung for carbon monoxide 
(DLCO) value of <40 %predicted; 3) active cardiopulmonary disease other than COPD that could 
contribute to dyspnea and exercise limitation; 4) history/clinical evidence of asthma, atopy and/or nasal 

Dr. Denis O’Donnell (Principal Investigator) 
Respiratory Investigation Unit 
Queen’s University & Kingston General Hospital 
76 Stuart Street, Kingston, ON, Canada K7L 2V7 
 
Protocol version: 23-Aug-2017 
 
page 4 
polyps; 5) history of hypercapnic respiratory failure or a clinical diagnosis of sleep disordered breathing; 
6) history of allergy or adverse response to fentanyl; 7) important contraindications to clinical exercise 
testing, including inability to exercise because of neuromuscular or musculoskeletal disease(s); 8) use of 
daytime oxygen or exercise-induced O2 desaturation to < 80% on room air; 9) body mass index (BMI) 
<18.5 or ≥35.0 kg/m2; 10) use of antidepressant drugs (i.e., monoamine oxidase inhibitors, serotonin 
reuptake inhibitors) in previous 2 weeks; 11) use of opioid drugs (e.g., morphine, fentanyl, oxycodone, 
codeine, etc.) in the previous 4 weeks. 
Study design: This will be a single-centre, randomized, double-blind, 2-treatment crossover study 
evaluating the differential effects of nebulized fentanyl citrate (100g) and nebulized bronchodilator 
(0.5mg ipratropium bromide + 2.5mg salbutamol) on exertional dyspnea and physiological responses to 
a standardized exercise task. After giving written informed consent, participants will complete 5 visits, 
each conducted in the morning 2-7 days apart [Appendix 4]. Visit 1 (screening): medical history, 
symptom evaluation, complete pulmonary function testing, a symptom-limited incremental exercise test 
to determine maximal work rate (Wmax), and familiarization to a new standardized exercise task (4-min 
cycle exercise test). Visits 2 & 3 (run-in): repeatability of the 4-min cycle exercise test. Visits 4 and 5 
(treatment): pre-drug pulmonary function tests (spirometry, plethysmography) and a 4-min cycle 
exercise test while breathing a gas mixture with a constant fraction of 21% oxygen (room air = 21% 
FiO2); nebulized of either fentanyl or bronchodilator; 30-min post-drug, subjects will perform post-drug 
pulmonary function tests and a 4-min cycle exercise test while breathing a gas mixture with a constant 
fraction of 30% oxygen (30% FiO2) after fentanyl and 21% oxygen (21% FiO2) after bronchodilator. 
Exercise tests at Visits 4 and 5 will include detailed measurements of dyspnea (intensity, quality, 
affective dimensions), EMGdi and pressure-derived respiratory mechanical measurements. Vital signs 
and systemic side-effects will be monitored. Regularly used inhaled corticosteroids will be permitted as 
usual throughout the study. Subjects will adhere to the standard withdrawal of bronchodilators prior to 
each visit: short-acting 2-agonists, short-acting anticholinergics, long-acting 2-agonists and long-acting 
anticholinergics will be withdrawn 6, 12, 24 and 24 hours, respectively. Subjects will avoid caffeine, 
heavy meals, alcohol and major physical exertion prior to visits. Although inhalation of fentanyl citrate 
has not been associated with significant adverse symptoms or side-effects there is always a possibility 
that study participants could experience certain side-effects such as drowsiness, sedation and dizziness. 
As such, participants will be required to have someone accompany them home after their fourth and fifth 
study visit. If someone is not available to drive them on those days they will be required to take a taxi to 
and from the lab. 
Study medications, randomization & blinding: Treatment will consist of a single dose of a 5 ml 
solution containing either: 100μg of fentanyl citrate (20 μg/ml) or a bronchodilator (Combivent: 0.5 mg 
ipratropium bromide + 2.5 mg salbutamol) administered by means of a jet nebuliser (Parimaster 
compressor with Pari LC Jet+ nebuliser; PARI Respiratory Equipment Inc., Richmond, VA, USA) with 
subjects breathing spontaneously for 15-min via facemask. The order of treatment (fentanyl, 
bronchodilator) given at Visits 4 and 5 will be randomized. Randomization and dispensing of study drug 
will be performed by the Investigational Drug Service (IDS; Pharmacy Services, Kingston General 
Hospital), an unblinded third party not affiliated with patient recruitment or data collection/analysis. 
Study medication will be supplied by the IDS. Unblinding will be permitted in response to a serious 
adverse event. The 100g dose of inhaled fentanyl citrate was selected because: 1) in previous studies, 
25g and 50g doses had either no effect or improvements of small magnitude (37,50); 2) based on 
pharmacokinetic studies (51), this dose should not result in any significant absorption into the systemic 
circulation, which in turn should not produce any significant side-effects; 3) we reasoned that the 25g 
and 50g doses were too small to be effective in patients with significant ventilation-perfusion 

Dr. Denis O’Donnell (Principal Investigator) 
Respiratory Investigation Unit 
Queen’s University & Kingston General Hospital 
76 Stuart Street, Kingston, ON, Canada K7L 2V7 
 
Protocol version: 23-Aug-2017 
 
page 5 
abnormalities; 4) most randomized controlled trials of inhaled morphine in cancer patients have used 
5mg nebulized doses, equivalent to 50g of nebulized fentanyl citrate, with only small or inconsistent 
effects (52). Studies to date have shown inhaled fentanyl to be well tolerated and respiratory depression 
(CO2 retention) has not been described at expected plasma levels (2-3μg/kg) (53). Based on our 
preliminary study, we expect ventilation to fall by 2-4L/min with inhaled fentanyl (37).  
Procedures 
Pulmonary function testing: Spirometry, body plethysmography, diffusing capacity of the lung for 
carbon dioxide (DLCO), maximum inspiratory/expiratory mouth pressures and impulse oscillometry 
(IOS) will be performed according to recommended techniques using automated equipment (Vmax 229d, 
Autobox V62j and MasterScreen IOS; SensorMedics, Yorba Linda, CA) (54-59). Measurements will be 
expressed as % of predicted normal values (60-64). 
Cardiopulmonary exercise testing (CPET): Exercise tests will be conducted on an electronically-braked 
cycle ergometer (Ergometrics 800S; SensorMedics) using a SensorMedics Vmax229d system as 
previously described (34-36). Incremental CPET will consist of steady-state rest followed by 1 minute 
of warm-up of unloaded pedalling then 10 watt increases in work rate every minute to the point of 
symptom-limitation [Appendix 5]. Maximal work rate (Wmax) will be defined as the highest work rate 
the subject can maintain for at least 30 seconds. Constant-load tests will consist of steady-state rest, 1 
minute of warm-up of unloaded pedalling and then an immediate stepwise increase work rate to 75% 
which will be maintained for 4 minutes (see below). Measurements will include: standard 
cardiorespiratory and breathing pattern parameters collected on a breath-by-breath basis and compared 
with predicted values based on age and height (65); oxygen saturation by pulse oximetry; heart rate by 
12-lead ECG; blood pressure by auscultation; operating lung volumes derived from IC maneuvers 
(66,67); EMGdi-derived measures of inspiratory neural drive to the diaphragm; the intensity of perceived 
leg discomfort; and exertional dyspnea intensity, quality and unpleasantness. Three main time points will 
also be evaluated: rest will be defined as the steady-state period after at least 3 minutes of breathing on 
the mouthpiece before exercise starts (cardiopulmonary parameters will be averaged over the last 30-sec 
of this period and resting ICs will be collected while breathing on the same circuit immediately after 
completion of the quiet breathing period); isotime will be defined as the last 30-sec increment of each 
minute (i.e., 1-min, 2-min, 3-min) during the 4-min exercise tests, and; end-exercise will be defined as 
the last 30-sec of loaded pedaling (i.e., 4-min).   
 
Adjustment of work rate for 4-min cycle tests. The work rate during the constant-load test will be 
adjusted to the highest work rate that can be sustained for the entire 4 minutes; the objective is to induce 
a level of dyspnea (a modified Borg rating ≥3) that is sufficiently high to be amenable to therapy.  After 
completion of the incremental test and an adequate rest period at Visit 1, a 4-minute cycle test at 
75%Wmax will be conducted. If the subject can complete 4 minutes and reaches a dyspnea intensity ≥3 
Borg units, then these work rate settings will be used for all subsequent cycle tests. If the subject cannot 
complete 4-minutes, then a lower work-rate (60%) will be tested. If the subject completes the 4-minutes 
but does not reach a high enough dyspnea rating, then a higher work-rate (90%) will be tested. At run-in 
Visit 2, further refinement of work rate will be conducted if required. After final selection of work rate 
to use for 4-min tests, repeatability of tests conducted at Visits 2 and 3 using the final selection of work 
rate will be evaluated by comparing end-exercise dyspnea intensity ratings and standard cardiopulmonary 
measurements.  
Symptom evaluation. Dyspnea (respiratory discomfort) will be defined as the “sensation of 
breathing discomfort” and leg discomfort as “the sensation of leg discomfort experienced during 
pedalling.”  The intensity (strength) of sensations will be rated at rest and during exercise using the 
modified 10-point Borg scale (68). We have recently provided validation for the novel use of the same 

Dr. Denis O’Donnell (Principal Investigator) 
Respiratory Investigation Unit 
Queen’s University & Kingston General Hospital 
76 Stuart Street, Kingston, ON, Canada K7L 2V7 
 
Protocol version: 23-Aug-2017 
 
page 6 
scale for measuring the intensity of several descriptive phrases related to specific qualities of dyspnea 
(e.g., effort, unsatisfied inspiration) and the affective dimension (e.g., unpleasantness) of dyspnea 
(37,69,70). This will allow us to assess which component(s) of perceived dyspnea is modified by the 
active intervention. Upon exercise cessation, subjects will be asked to verbalize their main reason for 
stopping exercise, i.e., breathing discomfort, leg discomfort, their combination or some other reason. 
Qualitative descriptors of respiratory discomfort at end-exercise will be collected by questionnaire (19).  
Respiratory pressures and diaphragm electromyography (EMGdi). An esophageal electrode-
balloon catheter will be inserted nasally and positioned as previously described (30,71). EMGdi will be 
recorded continuously using an esophageal electrode catheter consisting of 5 electrode pairs at rest and 
during exercise and analyzed as previously described (34-36). The raw EMGdi signal will be sampled at 
2000 Hz (PowerLab, model ML880; ADInstruments, CastleHill, NSW, Australia), band-pass filtered 
between 20-1000 Hz (Bioamplifier model RA-8; Guanzhou Yinghui Medical Equipment Co. Ltd, 
Guangzhou, China) and converted to a root mean square (RMS) using computer software (Chart v5.4, 
ADInstruments). For each breath, the data from the electrode pair with the largest value from the five 
electrode pairs will be used for analysis. Maximal EMGdi (EMGdi,max) will be determined from IC 
maneuvers (72).  EMGdi/EMGdi,max will be used as an index of the inspiratory neural drive to the crural 
diaphragm (30-33). Esophageal (Pes) and gastric pressures (Pga) will be recorded continuously at a rate 
of 200 Hz (PowerLab); transdiaphragmatic pressure (Pdi) will be recorded as the difference between Pga 
and Pes signals. The continuous flow signal from the Vmax229d system will be input into the PowerLab 
system for offline analysis. Pre- and post-exercise inspiratory sniffs will be performed to obtain 
maximum Pes (Pes,sn) and Pdi (Pdi,sn). IC maneuvers at rest and throughout exercise will be used to 
obtain dynamic peak inspiratory Pes (Pes,IC) and Pdi (Pdi,IC). Pre- and post-exercise FVC maneuvers 
will also performed to obtain dynamic peak expiratory Pes (Pes,FVC). Respiratory mechanics will be 
analyzed as previously described (34-36).  
Statistical analysis: A sample size of 17 will provide at least 80% power to detect a clinically significant 
treatment difference of 1 Borg unit in dyspnea intensity at a standardized time during constant work-rate 
exercise (i.e., at the end of the 4-min exercise test). This sample size estimation is based on the following 
assumptions: a standard deviation of 1.35 Borg units for the difference between values in a two-treatment 
crossover study [Appendix 3] (37,40), α=0.05, ß=0.8, and a two-tailed test of significance.  A p0.05 
significance level will be used for all statistical analyses.  
Paired t-tests with appropriate Bonferroni adjustments for multiple comparisons will be used to 
compare treatment responses, i.e., post-dose responses to fentanyl citrate versus bronchodilator. 
Comparisons will be made for: 1) resting pulmonary function; 2) cardiorespiratory (e.g., VE, VT, 
breathing frequency, HR, etc.), respiratory mechanical (e.g., IC, inspiratory reserve volume (IRV)), 
metabolic and gas exchange (e.g., VO2, carbon dioxide output (VCO2), end-tidal CO2 (PETCO2), SpO2), 
and perceptual (e.g., intensity of dyspnea and leg discomfort) responses measured at rest, isotime and 
end-exercise; 3) Pes, Pga and Pdi-derived measurements of respiratory mechanics and muscle 
recruitment patterns; 4) EMGdi-derived indices of inspiratory neural drive (e.g., EMGdi/EMGdi,max). 
Descriptors of dyspnea at end-exercise and reasons for stopping exercise will be analyzed as frequency 
statistics and compared between-groups and between-treatments using Fisher’s exact test.  
To identify contributors to exertional dyspnea intensity (and its qualitative and affective 
dimensions), Pearson correlations will be used to establish associations between intra-subject treatment 
differences (i.e., post- minus pre-treatment) in isotime (4-min) measurements of exertional dyspnea 
intensity and relevant independent variables which will include: concurrent differences in 
cardiorespiratory and dynamic respiratory mechanical measurements at isotime during exercise; 
differences in resting lung function measurements, and; various baseline characteristics (possible 

Dr. Denis O’Donnell (Principal Investigator) 
Respiratory Investigation Unit 
Queen’s University & Kingston General Hospital 
76 Stuart Street, Kingston, ON, Canada K7L 2V7 
 
Protocol version: 23-Aug-2017 
 
page 7 
covariates). A multivariable linear regression model will be used to further evaluate the relationship 
between dyspnea intensity and any significant variables: treatment will be included as a categorical 
effect, an interaction term will be used to determine whether the relationship was similar across 
treatments (independent variable*treatment), and subjects will be treated as random effects to account 
for serial measurements (subject nested within treatment). 
ANTICIPATED RESULTS & SIGNIFICANCE OF THE STUDY: We anticipate that the results will 
show that opiates and bronchodilators ameliorate dyspnea in COPD through different mechanisms. By 
comparing the mechanisms of dyspnea relief during distinctly different interventions, we will greatly 
advance our understanding of the neurophysiology of dyspnea causation. Our results will provide a solid 
physiological rationale for combining dyspnea-relieving medications with different modes of action in 
order to achieve additive or synergistic effects. Uncovering the mechanisms of action of inhaled fentanyl 
will set the stage for subsequent clinical trials to determine its efficacy for the management of 
breakthrough or intermittent dyspnea in patients with chronic lung diseases. We do not expect any 
significant barriers; we have access to a large group of patient volunteers and have established expertise 
in conducting these sorts of detailed physiological studies. 
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Dr. Denis O’Donnell (Principal Investigator) 
Respiratory Investigation Unit 
Queen’s University & Kingston General Hospital 
76 Stuart Street, Kingston, ON, Canada K7L 2V7 
 
Protocol version: 23-Aug-2017 
 
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Common neurophysiological mechanisms of dyspnea in chronic interstitial and obstructive lung 

Dr. Denis O’Donnell (Principal Investigator) 
Respiratory Investigation Unit 
Queen’s University & Kingston General Hospital 
76 Stuart Street, Kingston, ON, Canada K7L 2V7 
 
Protocol version: 23-Aug-2017 
 
page 9 
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Dr. Denis O’Donnell (Principal Investigator) 
Respiratory Investigation Unit 
Queen’s University & Kingston General Hospital 
76 Stuart Street, Kingston, ON, Canada K7L 2V7 
 
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page 10 
54. Miller MR, Crapo R, Hankinson J, Brusasco V, Burgos F, Casaburi R, et al; on behalf of the 
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Dr. Denis O’Donnell (Principal Investigator) 
Respiratory Investigation Unit 
Queen’s University & Kingston General Hospital 
76 Stuart Street, Kingston, ON, Canada K7L 2V7 
 
Protocol version: 23-Aug-2017 
 
page 11 
APPENDIX 1 
 
A Neurobiological Model of Dyspnea 
 
 
medulla
airways
lungs
muscles
Altered afferent 
activity
Ventilatory drive
Respiratory mechanics
somatosensory 
cortex
Respiratory discomfort
(sensory intensity, quality)
limbic system
Respiratory distress
(affective)
Corollary 
discharge
motor cortex
central & peripheral  
chemoreceptors
Pulmonary ventilation 
& gas exchange
PaO2
PaCO2, [H+]
Neuromechanical
dissociation
Bronchodilators
Opiates
VCO2
VD
 
 
Neural inputs that reach the somatosensory cortex and contribute to dyspnea come from: 1) altered 
afferent information from receptors in the airways (pulmonary stretch receptors, C-fibers), lungs 
(pulmonary stretch receptors, C-fibers, J-receptors) and from periperal locomotor and respiratory 
muscles (muscle spindles, Golgi tendon organs, type III and IV afferents); 2) feedback from central and 
peripheral chemoreceptors regarding adequacy of pulmonary ventilation and gas exchange; and 3) 
increased central corollary discharge from brainstem and cortical motor centers. When the 
mechanical/muscular response of the respiratory system is constrained below the level dictated or pre-
programmed by central respiratory motor drive, then the intensity of “respiratory discomfort” (i.e., the 
sense of unsatisfied inspiration) increases in proportion to the widening disparity between drive and 
mechanics, i.e., neuromechanical dissociation. Increased activation of limbic structures as a result of 
neuromechanical dissociation likely contributes to “respiratory distress.” Bronchodilators and opiates 
have different sites of action in this model. Abbreviations: PaCO2 = partial pressure of arterial carbon 
dioxide; [H+] = hydrogen ion concentration; PaO2 = partial pressure of arterial oxygen; VCO2 = carbon 
dioxide output. [Adapted from: Mahler DA, O’Donnell DE. Chest 2015;147:232-241, and O’Donnell 
DE, et al. Respir Physiol Neurobiol 2009;167:116-32.] 
 
 

Dr. Denis O’Donnell (Principal Investigator) 
Respiratory Investigation Unit 
Queen’s University & Kingston General Hospital 
76 Stuart Street, Kingston, ON, Canada K7L 2V7 
 
Protocol version: 23-Aug-2017 
 
page 12 
 
APPENDIX 2 
 
Relationship between Exertional Dyspnea Intensity and Inspiratory Neural Drive 
 
 
The relationship between exertional dyspnea intensity and an index of inspiratory neural drive to the 
diaphragm (EMGdi/EMGdi,max) is shown during incremental cycle exercise in patients with interstitial 
lung disease (ILD), patients with COPD and age-matched healthy controls (n=16 per group). This 
relationship was similar across groups. Values are mean±SEM. Square symbols represent tidal volume-
ventilation inflection points. EMGdi/EMGdi,max= inspiratory diaphragm electromyography as a 
fraction of maximum. [Adapted from: Faisal A, et al. Am J Respir Crit Care Med published online 
September 25, 2015 as doi: 10.1164/rccm.201504-0841OC] 
 
 
 

Dr. Denis O’Donnell (Principal Investigator) 
Respiratory Investigation Unit 
Queen’s University & Kingston General Hospital 
76 Stuart Street, Kingston, ON, Canada K7L 2V7 
 
Protocol version: 23-Aug-2017 
 
page 13 
APPENDIX 3 
Exertional Dyspnea Intensity in Response to Bronchodilators and Opiates 
0
1
2
3
4
5
6
7
10
20
30
40
50
Dyspnea intensity (Borg)
Ventilation (L/min)
Bronchodilator
Placebo
0
1
2
3
4
5
6
0
10
20
30
40
50
60
Dyspnea intensity (Borg)
Ventilation (L/min)
Fentanyl
Placebo
 
Dyspnea-ventilation relationships during constant-work rate exercise in COPD are shown from two different 
randomized, placebo-controlled crossover studies performed at the Respiratory Investigation Unit. 
Bronchodilators (left): In response to nebulized bronchodilator (ipratropium 0.5mg + salbutamol 2.5mg), 
dyspnea fell significantly for a given ventilation in 16 patients with moderate-to-severe COPD [Peters M, et al. 
Thorax 2006;61:559-567]. Reductions in dyspnea intensity were attributed to improvements in respiratory 
mechanics (i.e., an increased inspiratory capacity allowed greater tidal volume expansion). Opiates (right): In 
response to nebulized fentanyl 50μg (right), dyspnea-ventilation relationships were unaltered in 12 patients with 
COPD [Jensen D, et al. J Pain Symptom Manage 2012;43:706-719]. Decreases in ventilation with inhaled fentanyl 
resulted from decreases in breathing frequency (prolongation of expiratory time), with little change in respiratory 
mechanical measurements.  
Hypotheses: The relationship between dyspnea intensity and inspiratory neural drive to the diaphragm 
(EMGdi/EMGdi,max) will remain constant across both interventions (compared with placebo or pre-treatment 
conditions). Therefore: 1) improved respiratory mechanical/muscle function after a bronchodilator will necessitate 
lower inspiratory neural drive for a given ventilation; and 2) a reduction in inspiratory neural drive after fentanyl 
will result in a proportional decrease in ventilation. A schematic illustration of these responses is shown below. 
0
1
2
3
4
5
6
0
10
20
30
40
50
60
70
80
Dyspnea intensity (Borg)
EMGdi/EMGdi,max (%)
Post-Fentanyl
Pre-Fentanyl
0
1
2
3
4
5
6
7
10
20
30
40
50
60
70
80
Dyspnea intensity (Borg)
EMGdi/EMGdi,max (%)
Pre-Bronchodilator
Post-Bronchodilator
0
10
20
30
40
50
60
0
10
20
30
40
50
60
70
80
Ventilation (L/min)
EMGdi/EMGdi,max (%)
10
20
30
40
50
10
20
30
40
50
60
70
80
Ventilation (L/min)
EMGdi/EMGdi,max (%)

Dr. Denis O’Donnell (Principal Investigator) 
Respiratory Investigation Unit 
Queen’s University & Kingston General Hospital 
76 Stuart Street, Kingston, ON, Canada K7L 2V7 
 
Protocol version: 23-Aug-2017 
 
page 14 
 
APPENDIX 4 
 
Study Design 
 
Two-treatment crossover study 
(Fentanyl, Bronchodilator)
Randomization
(2 treatment orders)
F      ------------------
B
B      ------------------
F
Visit 1
(screening)
Visits 2 & 3
(run-in for 
familiarization,
repeatability of 
testing)
Visit 4
(treatment 1)
Visit 5
(treatment 2)
crossover
 
Experimental visits
Pre-treatment:
Insertion of EMGdi-pressure catheter
PFTs (spirometry, body plethysmography)
Constant work rate exercise (4-min exercise test)
breathing 21% oxygen
Treatment:
15-min nebulization of either fentanyl or bronchodilator
30-min rest
Post-treatment:
PFTs (spirometry, body plethysmography)
Constant work rate exercise (4-min exercise test) 
breathing either 30% oxygen (Fentanyl) or 21% oxygen 
(bronchodilator)
Primary endpoint: 
∆Dyspnea at 4-min 
of exercise