Morphine, Dyspnea, Exercise and COPD

The investigators are studying the effect of a single dose Opioid drug (Morphine) on dyspnea and exercise tolerance in COPD patients.

"Dyspnea" refers to the subjective awareness of breathing discomfort that typically accompanies an increase in physical activity, particularly in patients with Chronic Obstructive Pulmonary Disease (COPD). In these patients, the symptom of dyspnea contributes significantly to exercise intolerance and an impoverished health-related quality of life. Alleviating dyspnea and improving functional capacity are, therefore, among the principal goals of COPD management, i.e., response to therapy. Nevertheless, the effective management of dyspnea and exercise intolerance remains an elusive goal for healthcare providers and current strategies aimed at reversing the patients' underlying chronic disease (e.g., bronchodilators, corticosteroids, supplemental oxygen) are only partially successful in this regard. Evidence-based clinical practice guidelines recommend that, under these circumstances, pain-relieving (opioid) medications may be used for the pharmacologic management of refractory dyspnea and activity-limitation in COPD. Indeed, a handful of published studies provide evidence to suggest that single-dose treatment with morphine or dihydrocodeine improves dyspnea and exercise performance by \~20% in patients with COPD. Nevertheless, little information is available on the physiological mechanisms by which opioid drugs contribute to these improvements in such patients. From a clinical management perspective, this information becomes crucial if we are to optimize the management of exertional symptoms in patients with advanced COPD who remain incapacitated by dyspnea, despite receiving optimal care from their healthcare provider for their underlying disease. Therefore, the purpose of the proposed randomized, double-blind, placebo-controlled, cross-over study is (1) to test the hypothesis that single-dose administration of oral morphine sulphate will improve exertional dyspnea and exercise tolerance in patients with advanced COPD and (2) elucidate the physiological underpinnings of these improvements. To this end, we will compare the effects of single-dose administration of oral morphine sulphate (0.1 mg/kg, equivalent to 7.5 mg for an average 75 kg man) and placebo on dyspnea (sensory intensity and affective responses) and exercise endurance time during symptom-limited constant-work-rate cardiopulmonary cycle exercise testing in symptomatic patients with severe-to-very severe COPD. To explore possible physiological mechanisms of symptom relief, we will measure spirometry parameters, plethysmographic lung volumes and plasma morphine concentrations; perform detailed assessments of central neural respiratory motor drive (i.e., diaphragm electromyography), contractile respiratory muscle function (i.e., esophageal, gastric and transdiaphragmatic pressures), operating lung volumes, ventilation, breathing pattern, pulmonary gas exchange and cardio-metabolic function during exercise; and employ a novel multi-dimensional evaluation technique that permits simultaneous measurement of the sensory intensity and affective dimensions of dyspnea.

Eligibility Criteria:
Inclusion Criteria:

* sever or very sever COPD, i.e. post B2 agonist FEV1\<50% predicted
* age \>= 40 years
* cigarette smoking history \> 2 pack yrs
* ever chronic activity-related dyspnea defined by the combination of A BDI focal score \<=6, Modified MRC dyspnea scale \>=3 and an OCD rating \<=50
* no change in medication dosage \& frequency in the preceding 6 weeks
* no hospitalization or exacerbation in the preceding 6 weeks

Exclusion Criteria:

* active cardiopulmonary disease other than COPD
* contraindication to Cardiopulmonary exercise testing
* use of daytime oxygen
* exercise-induced oxyhemoglobin desaturation to \<80% on room air
* Body mass index \<18.5 or \>30 kg/m2
* use of antidepressant drugs in the preceding 2 weeks
* use of opioid drugs in the preceding 4 weeks
* partial pressure of carbon dioxide PCo2 of \>50 mmHg on capillary blood gas