Role of Endorphins in Perception of Dyspnea With Resistive Loading in Chronic Obstructive Pulmonary Disease (COPD)
Condition: Chronic Obstructive Pulmonary Disease
MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Dyspnea
Study type: Interventional

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.
    

Intervention name(s): naloxone; normal saline
Intervention type(s): Drug; Drug
Intervention description(s): 10 mg naloxone in 25 ml total volume; 25 ml
Other intervention name(s): endorphin receptor antagonist; salt water
Intervention MeSH terms: Naloxone; Endorphins
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: breathlessness intensity; breathlessness unpleasantness; endorphins; resistive breathing loads