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

Abstract

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.

Figures

Figure 1.

Change in “response feature”: bar labels refer to individual subject codes, as shown in Table 1. Bars depict change in breathing discomfort at the partial pressure of end-tidal carbon dioxide (PetCO2) that elicited a 60% rating on the Breathing Discomfort Visual Analog Scale (BDVAS) under baseline conditions on that day; thus, the maximal possible decrease would be 60%. IV = intravenous.

Figure 2.

Regression lines showing average perceptual and ventilatory responses. Top: Breathing discomfort versus partial pressure of end-tidal carbon dioxide (PetCO2) while minute ventilation was held constant at 0.13 L · minute−1 · kg−1. Bottom: Minute ventilation versus PetCO2 during unrestricted breathing. Dashed lines depict same-day baseline values before drug or placebo (because placebo had no effect, pre- and postinjection Breathing Discomfort Visual Analog Scale [BDVAS] regressions are superimposed). Average regression was obtained by averaging the slopes and intercepts for individual subjects’ regressions.