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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Dartmouth-Hitchcock Medical Center
ClinicalTrials.gov Identifier:
NCT00958919
First received: August 13, 2009
Last updated: March 1, 2013
Last verified: March 2013
  Purpose

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.


Condition Intervention
Chronic Obstructive Pulmonary Disease
Drug: naloxone
Drug: normal saline

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: The Role of Endorphins in the Perception of Dyspnea With Resistive Loading in Patients With COPD

Resource links provided by NLM:


Further study details as provided by Dartmouth-Hitchcock Medical Center:

Primary Outcome Measures:
  • Intensity of Breathlessness [ Time Frame: At 1 minute intervals during Resistive Load Breathing at Period 1 (Day 3 or 4) and Period 2 (Day 5, 6 or 7) ] [ Designated as safety issue: No ]

    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".


  • Unpleasantness of Breathlessness [ Time Frame: At 1 minute intervals during Resistive Load Breathing at Period 1 (Day 3 or 4) and Period 2 (Day 5, 6 or 7) ] [ Designated as safety issue: No ]

    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".



Secondary Outcome Measures:
  • Endurance Time [ Time Frame: Period 1 (Day 3 or 4) and Period 2 (Day 5, 6 or 7) ] [ Designated as safety issue: No ]
    Length of time that subjects were able to continue Resistive Load Breathing

  • Change in Level of B-endorphin Immunoreactivity During Naloxone Intervention [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Change in serum levels of beta-endorphin immunoreactivity measured in pmol/L in subjects receiving Naloxone

  • Change in Level of B-endorphin Immunoreactivity During Saline Intervention [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Change in serum levels of beta-endorphin immunoreactivity measured in pmol/L in subjects receiving Saline


Enrollment: 14
Study Start Date: August 2009
Study Completion Date: October 2010
Primary Completion Date: August 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: naloxone Drug: naloxone
10 mg naloxone in 25 ml total volume
Other Name: endorphin receptor antagonist
Placebo Comparator: normal saline Drug: normal saline
25 ml
Other Name: salt water

  Hide Detailed Description

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.

  Eligibility

Ages Eligible for Study:   50 Years to 90 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00958919

Locations
United States, New Hampshire
Dartmouth-Hitchcock Medical Center
Lebanon, New Hampshire, United States, 03756-0001
Sponsors and Collaborators
Dartmouth-Hitchcock Medical Center
Investigators
Principal Investigator: Donald A Mahler, M.D. Dartmouth-Hitchcock Medical Center
  More Information

Publications:
Responsible Party: Dartmouth-Hitchcock Medical Center
ClinicalTrials.gov Identifier: NCT00958919     History of Changes
Other Study ID Numbers: 21721
Study First Received: August 13, 2009
Results First Received: November 5, 2012
Last Updated: March 1, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by Dartmouth-Hitchcock Medical Center:
breathlessness intensity
breathlessness unpleasantness
endorphins
resistive breathing loads

Additional relevant MeSH terms:
Lung Diseases
Lung Diseases, Obstructive
Pulmonary Disease, Chronic Obstructive
Respiratory Tract Diseases
Endorphins
Naloxone
Central Nervous System Agents
Molecular Mechanisms of Pharmacological Action
Narcotic Antagonists
Neurotransmitter Agents
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Sensory System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on October 21, 2014