Role of Endorphins in Perception of Dyspnea With Resistive Loading in Chronic Obstructive Pulmonary Disease (COPD)

Role of Endorphins in Perception of Dyspnea With Resistive Loading in Chronic Obstructive Pulmonary Disease (COPD)

Endorphins are released in response to breathing difficulty and can modify the perception of breathlessness. In this randomized placebo-controlled trial, resistive breathing loads are used to provoke breathlessness in patients with chronic obstructive pulmonary disease. The hypothesis of the study is that intravenous (IV) administration of naloxone, a medication which blocks endorphin activity, will increase the perception of breathlessness experienced by patients while breathing through a resistance device, compared with IV administration of normal saline.

Study Design: The study is a randomized, double-blind, placebo-controlled investigation comparing the intravenous administration of: normal saline, considered a placebo, is expected to have no effect on patient ratings of dyspnea. naloxone, an opioid receptor antagonist with penetration into the central nervous system and blocks the effect of beta-endorphins, is expected to increase ratings of dyspnea in patients with COPD. Dyspnea will be induced by resistive load breathing for a minimum of 10 minutes. Subjects: Twenty subjects with COPD will be recruited from the outpatient clinic at the Dartmouth-Hitchcock Medical Center. Procedures: There are three visits each 2 - 3 days apart. Visit 1 The purposes of Visit 1 are: to ensure that patients meet inclusion and exclusion criteria to collect baseline data to familiarize each patient with the study protocol to practice breathing through the resistive load system Visit 2 (2 - 3 days after Visit 1) Patients will perform pulmonary function tests and then inhale 2 puffs (180 mcg) of albuterol metered-dose inhaler (MDI) in order to provide standardized bronchodilatation prior to resistance breathing. Thirty minutes later, pulmonary function tests will be repeated to measure the response. Next, patients will be randomized to one of two blinded study medications. normal saline (25 ml volume) intravenous infusion given 5 minutes before resistive breathing naloxone (10mg in 25 ml total volume) intravenous push given 5 minutes prior to resistive breathing An 18-20 gauge catheter will be inserted into an arm vein to be used for drawing blood and for administration of either normal saline or naloxone. In a seated position, the patient will breathe quietly through the mouth piece without any resistance. After 5 minutes, 10 ml of venous blood will be removed for measurement of baseline plasma beta-endorphin immunoreactivity. Then, the physician will give the normal saline or naloxone solution intravenously through tubing connected to the catheter. Five minutes after the infusion has been given, the resistance load (obtained at Visit 1) will be added to the inspiratory side of a two-way valve. The patient will be instructed to continue breathing through the resistance "for as long as possible." At one minute intervals, the patient will be asked to place a mark on a vertical visual analog scale (VAS) in order to rate separately the intensity and the unpleasantness of dyspnea. When the patient is no longer able to breathe through the resistance system, the patient will be asked to make final ratings of the intensity and the unpleasantness of dyspnea. Thereafter, resistance breathing will be stopped, and the mouthpiece will be removed from the patient. Next, 10ml of venous blood will be removed for measurement of the plasma beta-endorphin immunoreactivity. A third 10 ml aliquot of venous blood will be taken at 30 minutes after completion of the resistive breathing session. During the 5 minutes of breathing normally at rest and during the resistance breathing, the following non-invasive measurements will be made: inspiratory mouth pressure (Pm); expired gas will be analyzed breath-by-breath for minute ventilation (VE), oxygen consumption (VO2), and carbon dioxide production (VCO2) using a metabolic measurement system (MedGraphics); oxygen saturation will be recorded using a pulse oximeter; and end-tidal partial pressure of CO2. Visit 3 At Visit 3, the same procedures will be used as described for Visit 2, except that the patient will be randomized to the alternative blinded study medication that he/she did not receive at Visit 2.

The average of all ratings for the intensity of breathlessness at equivalent times for each subject during Resistive Load Breathing (RLB). For example, if 1 subject provided 6 ratings during 6 minutes of RLB with naloxone and 10 ratings during 10 minutes of RLB with normal saline, then ratings for intensity through 6 minutes were used for analysis for that patient. This approach was used for all subjects to yield a total of 154 ratings for naloxone and for normal saline. Subject rating of intensity of breathlessness was obtained at 1 minute intervals during RLB on a 100 mm Visual Analog Scale anchored at the bottom by "No Intensity" and at the top by "Greatest Intensity".

At 1 minute intervals during Resistive Load Breathing at Period 1 (Day 3 or 4) and Period 2 (Day 5, 6 or 7)

The average of all ratings for the unpleasantness of breathlessness at equivalent times for each subject during Resistive Load Breathing (RLB). For example, if 1 subject provided 6 ratings during 6 minutes of RLB with naloxone and 10 ratings during 10 minutes of RLB with normal saline, then ratings for intensity through 6 minutes were used for analysis for that patient. This approach was used for all subjects to yield a total of 154 ratings for naloxone and for normal saline. Subject rating of intensity of unpleasantness was obtained during RLB on a 100 mm Visual Analog Scale anchored at the bottom by "No Unpleasantness" and at the top by "Greatest Unpleasantness".

At 1 minute intervals during Resistive Load Breathing at Period 1 (Day 3 or 4) and Period 2 (Day 5, 6 or 7)

Change in serum levels of beta-endorphin immunoreactivity measured in pmol/L in subjects receiving Naloxone

Baseline and at the end of Resistance Load Breathing during either Period 1 (Day 3 or 4) or Period 2 (Day 5, 6 or 7) depending on randomization

Change in serum levels of beta-endorphin immunoreactivity measured in pmol/L in subjects receiving Saline

Baseline and at the end of Resistance Load Breathing during either Period 1 (Day 3 or 4) or Period 2 (Day 5, 6 or 7) depending on randomization

Inclusion Criteria: Male or female patient 50 years of age or older; A diagnosis of COPD defined by American Thoracic Society-European Respiratory Society criteria Current or former smoker with a smoking history of greater than or equal to 10 pack-years; A post-bronchodilator forced expiratory volume in one second (FEV1) greater than or equal to 30% predicted and less than or equal to 80% predicted; AND A post-bronchodilator FEV1/forced vital capacity ratio less than 70%; and clinically stable COPD. Exclusion Criteria: Any patient who has a concomitant disease that might interfere with study procedures or evaluation; Inability to perform resistive breathing maneuvers; OR Any current use of a narcotic medication.

Gifford AH, Mahler DA, Waterman LA, Ward J, Kraemer WJ, Kupchak BR, Baird JC. Neuromodulatory effect of endogenous opioids on the intensity and unpleasantness of breathlessness during resistive load breathing in COPD. COPD. 2011 Jun;8(3):160-6. doi: 10.3109/15412555.2011.560132. Epub 2011 Apr 22.