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

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.

• Fentanyl Citrate (Drug), also known as Inhaled fentanyl: 100 mcg fentanyl citrate will be inhaled via nebulizer
• Combivent (Drug), also known as Bronchodilator: 0.5 mg ipratropium bromide + 2.5 mg salbutamol will be inhaled via nebulizer

Primary outcomes

• Dyspnea intensity measured by the 10-point Borg Scale at a standardized time during cycle exercise test [10-minutes post-treatment]: 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.

Secondary outcomes

• Diaphragm electromyography (EMGdi) at a standardized time during cycle exercise test [10-minutes post-treatment]: 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.
• Ventilation at a standardized time during cycle exercise test [10-minutes post-treatment]: Exercise measurements of minute ventilation will be compared at a standardized time (4-minutes) during both post-treatment constant-load exercise tests.
• Breathing frequency at a standardized time during cycle exercise test [10-minutes post-treatment]: Exercise measurements of breathing frequency (respiratory rate) will be compared at a standardized time (4-minutes) during both post-treatment constant-load exercise tests.
• Tidal volume at a standardized time during cycle exercise test [10-minutes post-treatment]: Exercise measurements of tidal volume will be compared at a standardized time (4-minutes) during both post-treatment constant-load cycle exercise tests.
• Inspiratory capacity at a standardized time during cycle exercise test [10-minutes post-treatment]: Exercise measurements of inspiratory capacity will be compared at a standardized time (4-minutes) during both post-treatment constant-load cycle exercise tests.

Sex: All, ages: 40 Years to 90 Years

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.

• Study Protocol and Statistical Analysis Plan (PDF, 2017-08-23)

• Denis E O'Donnell, MD, FRCPC, Principal investigator, Queen's University