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

The Role of Endorphins in the Perception of Dyspnea With Resistive Loading in Patients With 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 Overview

• Status: Completed
• Conditions: Chronic Obstructive Pulmonary Disease
• Intervention / Treatment: Drug: naloxone; Drug: normal saline

Detailed Description

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.

1. normal saline (25 ml volume) intravenous infusion given 5 minutes before resistive breathing
2. 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.

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756-0001
      • Dartmouth-Hitchcock Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: normal saline	Drug: normal saline; 25 ml; Other Names: salt water
Experimental: naloxone	Drug: naloxone; 10 mg naloxone in 25 ml total volume; Other Names: endorphin receptor antagonist

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intensity of Breathlessness	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)
Unpleasantness of Breathlessness	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)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Endurance Time	Length of time that subjects were able to continue Resistive Load Breathing	Period 1 (Day 3 or 4) and Period 2 (Day 5, 6 or 7)
Change in Level of B-endorphin Immunoreactivity During Naloxone Intervention	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 Level of B-endorphin Immunoreactivity During Saline Intervention	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

Collaborators and Investigators

• Sponsor: Dartmouth-Hitchcock Medical Center
• Investigators: Principal Investigator: Donald A Mahler, M.D., Dartmouth-Hitchcock Medical Center

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: August 1, 2009
• Primary Completion (Actual): August 1, 2010
• Study Completion (Actual): October 1, 2010

Study Registration Dates

• First Submitted: August 13, 2009
• First Submitted That Met QC Criteria: August 13, 2009
• First Posted (Estimate): August 14, 2009

Study Record Updates

• Last Update Posted (Estimate): April 11, 2013
• Last Update Submitted That Met QC Criteria: March 1, 2013
• Last Verified: March 1, 2013

More Information

Terms related to this study

• Keywords: endorphins; breathlessness intensity; breathlessness unpleasantness; resistive breathing loads
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Signs and Symptoms, Respiratory; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Dyspnea; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Sensory System Agents; Narcotic Antagonists; Naloxone; Endorphins
• Other Study ID Numbers: 21721