Differentiating the Effects of Substance P and Beta-endorphin
Condition: Chronic Obstructive Pulmonary Disease
MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
Study type: Interventional

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.
    

Intervention name(s): Aprepitant; Placebo
Intervention type(s): Drug; Drug
Other intervention name(s): aprepitant 125 mg capsule; inert capsule
Intervention MeSH terms: Aprepitant; Fosaprepitant
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Basic Science
Keywords: breathlessness; substance P; beta-endorphin