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

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:

Each subject will participate in 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.