Differentiating the Effects of Substance P and Beta-endorphin

Not Applicable

Completed

Conditions: Chronic Obstructive Pulmonary Disease

Interventions: Drug: Aprepitant
Drug: Placebo

Registration Number: NCT01854177

Lead Sponsor: Dartmouth-Hitchcock Medical Center

Brief Summary: 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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 10

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 & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Aprepitant	Aprepitant	Aprepitant 125 mg
Placebo	Placebo	Inert capsule

Primary Outcome Measures

Name	Time	Method
Unpleasantness of Breathlessness	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)	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
Intensity of Breathlessness	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 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.

Secondary Outcome Measures