Differential Mechanisms of Dyspnea Relief in Advanced COPD: Opiates vs. Bronchodilators

Study Overview
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Brief Summary
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Activity-related breathlessness (dyspnea) is the dominant symptom and persists despite optimal medical care in as many as 50% of patients with advanced chronic obstructive pulmonary disease (COPD). The objective of this project is to determine the underlying mechanisms of the activity-related breathlessness in patients with advanced COPD. To study the different pathways involved in causing breathlessness, we will compare the effects of two treatments, opiates with oxygen versus bronchodilators, which relieve breathlessness in different ways.

Detailed Description
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Dyspnea arises during exercise in COPD patients when there is a mismatch between the ventilatory demand (largely dictated by chemical stimuli) and the capacity to respond to that demand (dictated by mechanical/muscular factors). Our preliminary studies have indicated that treatment with opioids in COPD patients can improve activity related dyspnea by reducing central respiratory neural drive and breathing frequency without a significant change in the respiratory mechanics. By contrast, a reduction in exertional dyspnea following inhaled bronchodilators in COPD was mainly related to an improved respiratory mechanics with increased inspiratory capacity, tidal volume, and inspiratory reserve volume etcetera. By comparing the physiological mechanisms of dyspnea relief during the opiate 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. As such, the primary objective of this study is to compare the effects of inhaled opiate with oxygen versus 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.

Official Title
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Differential Mechanisms of Dyspnea Relief in Advanced COPD: Opiates vs. Bronchodilators

Conditions
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Chronic Obstructive Pulmonary Disease

Intervention / Treatment
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* Drug: Fentanyl Citrate
* Drug: Combivent


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Post-bronchodilator forced expiratory volume in 1 sec (FEV1) 30-79% predicted and FEV1/forced vital capacity (FVC) <70% 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 Male or female ≥40 yrs of age Cigarette smoking history ≥20 pack-years 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) Ability to perform all study procedures and provide/sign informed consent. Exclusion Criteria: Women of childbearing age who are pregnant or trying to become pregnant Diffusing capacity of the lung for carbon monoxide (DLCO) value of <40 %predicted Active cardiopulmonary disease other than COPD that could contribute to dyspnea and exercise limitation History/clinical evidence of asthma, atopy and/or nasal polyps History of hypercapnic respiratory failure or a clinical diagnosis of sleep disordered breathing History of allergy or adverse response to fentanyl Important contraindications to clinical exercise testing, including inability to exercise because of neuromuscular or musculoskeletal disease(s) Use of daytime oxygen or exercise-induced O2 desaturation to < 80% on room air Body mass index (BMI) <18.5 or ≥35.0 kg/m2 Use of antidepressant drugs (i.e., monoamine oxidase inhibitors, serotonin reuptake inhibitors) in previous 2 weeks Use of opioid drugs (e.g., morphine, fentanyl, oxycodone, codeine, etc.) in the previous 4 weeks.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Fentanyl Citrate<br>Single dose, nebulized 100 mcg fentanyl citrate. This is a randomized, double-blind, two-treatment crossover study comparing the effects of a single dose of nebulized 100 mcg fentanyl citrate with a constant fraction of 30% inhaled oxygen to that of a nebulized bronchodilator (Combivent). Treatments will be in randomized order: patients in one study arm will receive fentanyl at the first treatment visit and combivent at the second treatment visit, patients in the other arm will receive Combivent first and fentanyl second. | Drug: Fentanyl Citrate<br>* 100 mcg fentanyl citrate will be inhaled via nebulizer<br>* Other names: Inhaled fentanyl;|
| Active Comparator: Combivent Bronchodilator<br>Single dose, nebulized Combivent bronchodilator (0.5 mg ipratropium bromide + 2.5 mg salbutamol). This is a randomized, double-blind, two-treatment crossover study comparing the effects of a single dose of nebulized 100 mcg fentanyl citrate with a constant fraction of 30% inhaled oxygen to that of a nebulized bronchodilator (Combivent). Treatments will be in randomized order: patients in one study arm will receive fentanyl at the first treatment visit and combivent at the second treatment visit, patients in the other arm will receive Combivent first and fentanyl second. | Drug: Combivent<br>* 0.5 mg ipratropium bromide + 2.5 mg salbutamol will be inhaled via nebulizer<br>* Other names: Bronchodilator;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dyspnea intensity measured by the 10-point Borg Scale at a standardized time during cycle exercise test | The 10-point Borg scale ranges from 0 nothing at all to 10 maximal/extremely strong and will be used to rate the intensity of dyspnea during exercise: a decrease in this rating signifies an improvement. Dyspnea intensity will be assessed at a standardized time (4-minutes) in both post-treatment constant-load cycle exercise tests. | 10-minutes post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Diaphragm electromyography (EMGdi) at a standardized time during cycle exercise test | EMGdi will be used as an index of inspiratory neural drive. Assessments will be compared at a standardized time (4-minutes) during both post-treatment constant-load cycle exercise tests. | 10-minutes post-treatment | 
| Ventilation at a standardized time during cycle exercise test | Exercise measurements of minute ventilation will be compared at a standardized time (4-minutes) during both post-treatment constant-load exercise tests. | 10-minutes post-treatment | 
| Breathing frequency at a standardized time during cycle exercise test | Exercise measurements of breathing frequency (respiratory rate) will be compared at a standardized time (4-minutes) during both post-treatment constant-load exercise tests. | 10-minutes post-treatment | 
| Tidal volume at a standardized time during cycle exercise test | Exercise measurements of tidal volume will be compared at a standardized time (4-minutes) during both post-treatment constant-load cycle exercise tests. | 10-minutes post-treatment | 
| Inspiratory capacity at a standardized time during cycle exercise test | Exercise measurements of inspiratory capacity will be compared at a standardized time (4-minutes) during both post-treatment constant-load cycle exercise tests. | 10-minutes post-treatment |