Differentiating the Effects of Substance P and Beta-endorphin
| Status: | Completed |
|---|---|
| Conditions: | Chronic Obstructive Pulmonary Disease, Pulmonary |
| Therapuetic Areas: | Pulmonary / Respiratory Diseases |
| Healthy: | No |
| Age Range: | 50 - 90 |
| Updated: | 11/1/2018 |
| Start Date: | July 2013 |
| End Date: | November 2013 |
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.
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.
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.
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.
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
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