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

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.

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.

Eligibility Criteria:
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 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.