Differentiating the Effects of Substance P and Beta-endorphin

Differentiating the Effects of Substance P and Beta-endorphin in the Perception of Breathlessness During Resistive Load Breathing in Patients With Chronic Obstructive Pulmonary Disease (COPD)

In previous studies we demonstrated that endogenous opioids (inhibitory neuropeptides) modulate the perception of breathing difficulty in patients with chronic obstructive pulmonary disease (COPD). Recently, we found that antagonism of substance P (an excitatory neuropeptide) with aprepitant did not affect the perception of breathing difficulty. However, after administration of aprepitant, blood levels of both substance P(+ 54 ± 39%) and beta-endorphin (+ 27 ± 17%) increased significantly. As these blood levels reflect cellular/tissue activity, we postulated that the concomitant release of excitatory (substance P) and inhibitory (beta-endorphin) neuropeptides had opposing effects (counterbalanced each other) on the perception of breathing difficulty.

The objective of the present study is to further examine the possible role of substance P on the perception of breathlessness. We propose to administer oral aprepitant and oral placebo in a randomized clinical trial in patients with COPD. However, four hours after patients take these medications, intravenous naloxone will be administered in order to block the effects of endogenous opioids (beta-endorphin) on opioid receptors. Five minutes later, patients will breathe thru a tube with fine wire mesh to provoke breathing difficulty, and then provide ratings of the intensity and unpleasantness of breathlessness every minute.

The two competing hypothesis of the study are:

1. if breathlessness ratings with aprepitant/naloxone = placebo/naloxone, then substance P has no effect on perception of breathing difficulty;
2. if breathlessness ratings with aprepitant/naloxone ≠ placebo/naloxone, then substance P has an effect on perception of breathing difficulty.

Study Overview

• Status: Completed
• Conditions: Chronic Obstructive Pulmonary Disease
• Intervention / Treatment: Drug: Placebo; Drug: Aprepitant

Detailed Description

This study is a randomized, controlled clinical trial comparing the acute effects of oral aprepitant (selective antagonist of substance P receptor) vs. placebo on ratings of breathlessness during resistive load breathing in patients with COPD. Four hours after randomization, all patients will receive intravenous naloxone (antagonist of opioid receptors) to block the effects of endogenous opioids on perception of breathlessness. The two competing hypothesis of the study are:

Breathing difficulty will be induced by the patient breathing thru a tube with fine wire mesh for approximately 10 - 20 minutes in the laboratory.

Approximately 20 patients with COPD will be recruited from the out-patient clinic at the Dartmouth-Hitchcock Medical Center. The population will consist of female or male adults at least 50 years of age, at least 10 pack-year history of smoking, and a diagnosis of COPD associated with chronic bronchitis based on standard criteria.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756-0001
      • Dartmouth-Hitchcock Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• male or female patient 50 years of age or older
• a diagnosis of COPD; former smoker with a history of greater than or equal to 10 pack-years
• a clinical diagnosis of chronic bronchitis (productive cough on most days for a minimum of three months per year for at least two successive 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
• a post-bronchodilator FEV1/forced vital capacity (FVC) ratio less than 70%; and clinically stable COPD.

Exclusion Criteria:

• current smoker
• pregnant women
• current or previous (within the past two weeks) use or of a narcotic medication
• any patient who has a concomitant disease that might interfere with study procedures or evaluation including lactose intolerance
• use of a drug that may cause possible drug interaction with aprepitant [including cilostazol, dofetilide, ergot alkaloids, oral or non-oral contraceptives, progestins, ranolazine, reboxetine, warfarin, ziprasidone, anxiolytic medications, anti-depressive medications, cholesterol lowering drugs (e.g., atorvastatin, simvastatin), theophylline, antifungal antibiotics, and macrolide antibiotics]
• use of a contraindicated medication including astemizole, cisapride, pimozide, and terfenadine;
• use of angiotensin converting enzyme inhibitor

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Aprepitant; Aprepitant 125 mg	Drug: Aprepitant; Other Names: aprepitant 125 mg capsule
Placebo Comparator: Placebo; Inert capsule	Drug: Placebo; Other Names: inert capsule

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Unpleasantness of Breathlessness	Unpleasantness of breathlessness was reported each minute by the patient on a visual analog scale. The scale range is 0-10 where 0 = No breathlessness and 10 = Severe breathlessness. The measures were collected up to 20 minutes per visit and combined for a final score. Total minimum score = 0, total maximum score 200. Data is collected during Resistive Load Breathing at Period 1 (Day 3 or 4) and Period 2 (Day 5, 6 or 7) during which either Placebo or Aprepitant was administered. A high unpleasantness indicates that breathing difficulty feels very bad or terrifying regardless of whether the intensity is high or low	Visit 2 (Approximately Day 3 where either Placebo or Aprepitant was administered).and Visit 3 (approximately Day 6 where either Placebo or Aprepitant was administered)
Intensity of Breathlessness	Intensity of Breathlessness was recorded on a visual analog scale. The scale range is 0-10 where 0 = minimum and 10 = maximal intensity. At each visit, participants were asked to report unpleasantness at 1 minute intervals. The measures were collected up to 20 minutes per visit and combined for a final score. Total minimum score = 0, total maximum score 200. Data is collected during Resistive Load Breathing at Period 1 (Day 3 or 4) and Period 2 (Day 5, 6 or 7) during which either Placebo or Aprepitant was administered.	Visit 2 (Approximately Day 3 where either Placebo or Aprepitant was administered).and Visit 3 (approximately Day 6 where either Placebo or Aprepitant was administered)

Collaborators and Investigators

• Sponsor: Dartmouth-Hitchcock Medical Center
• Investigators: Principal Investigator: Donald A Mahler, M.D., Dartmouth-Hitchcock Medical Center

Study record dates

Study Major Dates

• Study Start: July 1, 2013
• Primary Completion (Actual): November 1, 2013
• Study Completion (Actual): November 1, 2013

Study Registration Dates

• First Submitted: May 13, 2013
• First Submitted That Met QC Criteria: May 14, 2013
• First Posted (Estimate): May 15, 2013

Study Record Updates

• Last Update Posted (Actual): October 30, 2018
• Last Update Submitted That Met QC Criteria: September 30, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: breathlessness; substance P; beta-endorphin
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Antiemetics; Gastrointestinal Agents; Neurokinin-1 Receptor Antagonists; Aprepitant; Fosaprepitant
• Other Study ID Numbers: CPHS#23992