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

NCT ID: NCT00958919

Last Updated: 2013-04-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 14 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-08-31
• Study Completion Date: 2010-10-31

Brief Summary

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.

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.

Conditions

Chronic Obstructive Pulmonary Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

naloxone

Group Type: EXPERIMENTAL

naloxone

Intervention Type: DRUG

10 mg naloxone in 25 ml total volume

normal saline

Group Type: PLACEBO_COMPARATOR

normal saline

Intervention Type: DRUG

25 ml

Interventions

naloxone

10 mg naloxone in 25 ml total volume

Intervention Type: DRUG

normal saline

25 ml

Intervention Type: DRUG

Other Intervention Names

endorphin receptor antagonist; salt water

Eligibility 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.

• Minimum Eligible Age: 50 Years
• Maximum Eligible Age: 90 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Dartmouth-Hitchcock Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Donald A Mahler, M.D.

Role: PRINCIPAL_INVESTIGATOR

Dartmouth-Hitchcock Medical Center

Locations

Dartmouth-Hitchcock Medical Center

Lebanon, New Hampshire, United States

Countries

United States

References

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.

Reference Type: RESULT

PMID: 21513438 (View on PubMed)

Other Identifiers

21721

Identifier Type: -

Identifier Source: org_study_id