Differentiating the Effects of Substance P and Beta-endorphin

Study 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.

Primary Outcome

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 unpleasan

Interventions

• DRUG Placebo
• DRUG Aprepitant