Using laboratory models to test treatment: morphine reduces dyspnea and hypercapnic ventilatory response

Am J Respir Crit Care Med. 2011 Oct 15;184(8):920-7. doi: 10.1164/rccm.201101-0005OC. Epub 2011 Jul 21.


Rationale: Opioids are commonly used to relieve dyspnea, but clinical data are mixed and practice varies widely.

Objectives: Evaluate the effect of morphine on dyspnea and ventilatory drive under well-controlled laboratory conditions.

Methods: Six healthy volunteers received morphine (0.07 mg/kg) and placebo intravenously on separate days (randomized, blinded). We measured two responses to a CO(2) stimulus: (1) perceptual response (breathing discomfort; described by subjects as "air hunger") induced by increasing partial pressure of end-tidal carbon dioxide (Pet(CO2)) during restricted ventilation, measured with a visual analog scale (range, "neutral" to "intolerable"); and (2) ventilatory response, measured in separate trials during unrestricted breathing.

Measurements and main results: We determined the Pet(CO2) that produced a 60% breathing discomfort rating in each subject before morphine (median, 8.5 mm Hg above resting Pet(CO2)). At the same Pet(CO2) after morphine administration, median breathing discomfort was reduced by 65% of its pretreatment value; P < 0.001. Ventilation fell 28% at the same Pet(CO2); P < 0.01. The effect of morphine on breathing discomfort was not significantly correlated with the effect on ventilatory response. Placebo had no effect.

Conclusions: (1) A moderate morphine dose produced substantial relief of laboratory dyspnea, with a smaller reduction of ventilation. (2) In contrast to an earlier laboratory model of breathing effort, this laboratory model of air hunger established a highly significant treatment effect consistent in magnitude with clinical studies of opioids. Laboratory studies require fewer subjects and enable physiological measurements that are difficult to make in a clinical setting. Within-subject comparison of the response to carefully controlled laboratory stimuli can be an efficient means to optimize treatments before clinical trials.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Analgesics, Opioid / pharmacology
  • Analgesics, Opioid / therapeutic use*
  • Double-Blind Method
  • Dyspnea / drug therapy*
  • Female
  • Humans
  • Hypercapnia / etiology
  • Male
  • Middle Aged
  • Morphine / pharmacology
  • Morphine / therapeutic use*
  • Pulmonary Ventilation / drug effects


  • Analgesics, Opioid
  • Morphine