Effect of increased blood levels of β-endorphin on perception of breathlessness

Chest. 2013 May;143(5):1378-1385. doi: 10.1378/chest.12-1541.


Background: Although opioid receptors are expressed broadly in the CNS and in peripheral sensory nerve endings including bronchioles and alveolar walls of the respiratory tract, it is unknown whether the modulatory effect of endogenous opioids on breathlessness occurs in the CNS or in the peripheral nervous system. The purpose of this investigation was to examine whether increased blood levels of β-endorphin modify breathlessness by a putative effect of binding to peripheral opioid receptors in the respiratory tract.

Methods: Twenty patients with COPD (10 women and 10 men; age, 70 ± 8 years) inspired through resistances during practice sessions to identify an individualized target load that caused ratings of intensity and unpleasantness of breathlessness ≥ 50 mm on a 100-mm visual analog scale. At two interventions, blood levels of β-endorphin and adrenocorticotropic hormone (ACTH) were measured, ketoconazole (600 mg) or placebo was administered orally, and patients rated the two dimensions of breathlessness each minute during resistive load breathing (RLB).

Results: By inhibiting cortisol synthesis, ketoconazole led to significant increases in β-endorphin (mean change, 20% ± 4%) and ACTH (mean change, 21% ± 4%) compared with placebo. The intensity and unpleasantness ratings of breathlessness and the endurance time during RLB were similar in the two interventions.

Conclusions: The previously demonstrated modulatory effect of endogenous opioids on breathlessness appears to be mediated by binding to receptors within the CNS rather than to peripheral opioid receptors in the respiratory tract. An alternative explanation is that the magnitude of the β-endorphin response is inadequate to affect peripheral opioid receptors.

Trial registry: ClinicalTrials.gov; No.: NCT01378520; URL: www.clinicaltrials.gov.

Publication types

  • Controlled Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenocorticotropic Hormone / blood
  • Aged
  • Biomarkers / blood
  • Dyspnea / blood*
  • Dyspnea / drug therapy
  • Dyspnea / physiopathology*
  • Female
  • Humans
  • Ketoconazole / therapeutic use
  • Male
  • Middle Aged
  • Pulmonary Disease, Chronic Obstructive / blood*
  • Pulmonary Disease, Chronic Obstructive / drug therapy
  • Pulmonary Disease, Chronic Obstructive / physiopathology*
  • Receptors, Opioid / physiology
  • Respiratory System / physiopathology
  • Severity of Illness Index*
  • Substance P / blood
  • Treatment Outcome
  • beta-Endorphin / blood*


  • Biomarkers
  • Receptors, Opioid
  • Substance P
  • beta-Endorphin
  • Adrenocorticotropic Hormone
  • Ketoconazole

Associated data

  • ClinicalTrials.gov/NCT01378520