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.

Study Overview

• Status: Completed
• Conditions: Chronic Obstructive Pulmonary Disease
• Intervention / Treatment: Drug: Fentanyl Citrate; Drug: Combivent

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 4

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Kingston, Ontario, Canada, K7L 2V7
      • Respiratory Investigation Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 36 years to 86 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Fentanyl Citrate; 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; 100 mcg fentanyl citrate will be inhaled via nebulizer; Other Names: Inhaled fentanyl
Active Comparator: Combivent Bronchodilator; 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; 0.5 mg ipratropium bromide + 2.5 mg salbutamol will be inhaled via nebulizer; Other Names: Bronchodilator

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Dr. Denis O'Donnell
• Collaborators: Queen's University; Ontario Lung Association
• Investigators: Principal Investigator: Denis E O'Donnell, MD, FRCPC, Queen's University

Study record dates

Study Major Dates

• Study Start (Actual): September 20, 2017
• Primary Completion (Actual): March 21, 2022
• Study Completion (Actual): March 31, 2023

Study Registration Dates

• First Submitted: January 12, 2018
• First Submitted That Met QC Criteria: January 12, 2018
• First Posted (Actual): January 19, 2018

Study Record Updates

• Last Update Posted (Actual): April 3, 2024
• Last Update Submitted That Met QC Criteria: April 1, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Disease Attributes; Signs and Symptoms, Respiratory; Chronic Disease; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Dyspnea; Physiological Effects of Drugs; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Analgesics, Opioid; Narcotics; Adjuvants, Anesthesia; Anti-Asthmatic Agents; Respiratory System Agents; Fentanyl; Bronchodilator Agents
• Other Study ID Numbers: DMED-1926-16

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No