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

• Sponsor: Dartmouth-Hitchcock Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00958919
• Collaborator: (none)
• Enrollment: 14
• Location: 1
• Arms: 2
• Duration (Months): 14
• Patients Per Site Per Month: 1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Chronic Obstructive Pulmonary Disease	Drug: naloxone; Drug: normal saline	N/A

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 Design

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: The Role of Endorphins in the Perception of Dyspnea With Resistive Loading in Patients With COPD
• Study Start Date: Aug 1, 2009
• Actual Primary Completion Date: Aug 1, 2010
• Actual Study Completion Date: Oct 1, 2010

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Intensity of Breathlessness [At 1 minute intervals during Resistive Load Breathing at Period 1 (Day 3 or 4) and Period 2 (Day 5, 6 or 7)]

   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".

2. Unpleasantness of Breathlessness [At 1 minute intervals during Resistive Load Breathing at Period 1 (Day 3 or 4) and Period 2 (Day 5, 6 or 7)]

   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

1. Endurance Time [Period 1 (Day 3 or 4) and Period 2 (Day 5, 6 or 7)]

   Length of time that subjects were able to continue Resistive Load Breathing

2. Change in Level of B-endorphin Immunoreactivity During Naloxone Intervention [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 serum levels of beta-endorphin immunoreactivity measured in pmol/L in subjects receiving Naloxone

3. Change in Level of B-endorphin Immunoreactivity During Saline Intervention [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 serum levels of beta-endorphin immunoreactivity measured in pmol/L in subjects receiving Saline

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years to 90 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1	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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Dartmouth-Hitchcock Medical Center
• ClinicalTrials.gov Identifier: NCT00958919
• Other Study ID Numbers: 21721
• First Posted: Aug 14, 2009
• Last Update Posted: Apr 11, 2013
• Last Verified: Mar 1, 2013

• 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; Dyspnea; Naloxone; Endorphins

Study Results

Participant Flow

Recruitment Details	March 2009 - June 2010; medical center
Pre-assignment Detail	17 subjects recruited; 3 subjects excluded (2 did not meet inclusion criteria; 1 refused participation after signing consent).

Arm/Group Title	Normal Saline First, Then Naloxone	Naloxone First, Then Normal Saline
Arm/Group Description	Intravenous saline (25 ml) in first intervention period and intravenous Naloxone (10mg/25 ml) in second intervention period.	Intravenous Naloxone (10mg/25 ml)in first intervention period and intravenous saline (25 ml) in second intervention period.
Period Title: First Intervention
STARTED	7	7
COMPLETED	7	7
NOT COMPLETED	0	0
Period Title: First Intervention
STARTED	7	7
COMPLETED	7	7
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Entire Study Population
Arm/Group Description	Includes groups randomized to receive saline first and Naxolone first.
Overall Participants	14
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64 (9)
Sex: Female, Male (Count of Participants)
Female	8 57.1%
Male	6 42.9%
Region of Enrollment (participants) [Number]
United States	14 100%

Outcome Measures

1. Primary Outcome

Title	Intensity of Breathlessness
Description	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".
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)

Outcome Measure Data

Analysis Population Description

Total number of subjects completing both periods of the study.

Arm/Group Title	Normal Saline	Naloxone
Arm/Group Description	Intravenous saline (25 ml)	Intravenous Naloxone (10mg/25ml)
Measure Participants	14	14
Mean (Standard Deviation) [units on a scale]	77 (21)	83 (18)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Normal Saline, Naloxone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.0004
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	5
	Confidence Interval	(2-Sided) 95%; 2.69 to 9.38
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Unpleasantness of Breathlessness
Description	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".
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)

Outcome Measure Data

Analysis Population Description

Total number of subjects completing both periods of the study.

Arm/Group Title	Normal Saline	Naloxone
Arm/Group Description	Intravenous saline (25 ml)	Intravension Naloxone (10mg/25ml)
Measure Participants	14	14
Mean (Standard Deviation) [units on a scale]	77 (19)	81 (20)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Normal Saline, Naloxone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.024
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	4
	Confidence Interval	(2-Sided) 95%; 0.49 to 6.85
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Endurance Time
Description	Length of time that subjects were able to continue Resistive Load Breathing
Time Frame	Period 1 (Day 3 or 4) and Period 2 (Day 5, 6 or 7)

Outcome Measure Data

Analysis Population Description

Total number of subjects completing both periods of the study.

Arm/Group Title	Normal Saline	Naloxone
Arm/Group Description	Intravenous saline (25 ml) given prior to start of Resistive Load Breathing	Intravenous Naloxone (10mg/25ml)given prior to start of Resistive Load Breathing
Measure Participants	14	14
Mean (Standard Deviation) [minutes]	13.9 (4.7)	12.5 (5.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Normal Saline, Naloxone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.45
	Comments
	Method	t-test, 2 sided
	Comments

4. Secondary Outcome

Title	Change in Level of B-endorphin Immunoreactivity During Naloxone Intervention
Description	Change in serum levels of beta-endorphin immunoreactivity measured in pmol/L in subjects receiving Naloxone
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

Outcome Measure Data

Analysis Population Description

Total number of subjects completing period with Naloxone intervention.

Arm/Group Title	Baseline	End of Resistance Load Breathing
Arm/Group Description	Pre-infusion of Naloxone (10 mg/25 ml)	End of Resistance Load Breathing post-infusion of Naloxone (10 mg/25 ml)
Measure Participants	14	14
Mean (Standard Deviation) [pmol/L]	6.0 (1.5)	18.5 (3.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Normal Saline, Naloxone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	t-test, 2 sided
	Comments

5. Secondary Outcome

Title	Change in Level of B-endorphin Immunoreactivity During Saline Intervention
Description	Change in serum levels of beta-endorphin immunoreactivity measured in pmol/L in subjects receiving Saline
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

Outcome Measure Data

Analysis Population Description

Total number of subjects completing period with saline intervention.

Arm/Group Title	Baseline	End of Resistance Load Breathing
Arm/Group Description	Pre-infusion of Normal Saline (25 ml)	End of Resistance Load Breathing post-infusion of Normal Saline (25 ml)
Measure Participants	14	14
Mean (Standard Deviation) [pmol/L]	6.7 (1.4)	13.4 (2.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Normal Saline, Naloxone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	t-test, 2 sided
	Comments

Adverse Events

Arm/Group Title	Normal Saline		Naloxone
Arm/Group Description	25 ml Intravenous		10mg/25ml Intravenous
All Cause Mortality
	Normal Saline		Naloxone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Normal Saline		Naloxone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/14 (0%)
Other (Not Including Serious) Adverse Events
	Normal Saline		Naloxone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/14 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.