Does blocking the body's own morphine-like chemicals during exercise change the perception of breathlessness?

INTERVENTION: The main object of the study is to compare the effects of i.v. administration of naloxone, methylnaltrexone and normal saline on ratings of dyspnoea during contant work rate treadmil exercise. 30 minutes prior to each test the participant will be administered 5mg of salbutamol in 2.5 of normal saline via a nebuliser. At visit 1( baseline) this test is for maximal incremental cardiopulmonary exercise test (iCPET) according to the modified Balke protocol. This iCPET may take up to 25 minutes depending on the participant's endurance but will be ceased when the individual’s perception of dyspnoea or leg fatigue prevents them from maintaining the required minimum speed. At the subsequent 4 weekly visits a constant rate cardio pulmonary exercise test (cCPET) of optimal training intensity, 75%WRmax will be undertaken to exhaustion with the aim that this will be at least 10 minutes of effort. Throughout each exercise test and for 30 minutes after stopping, the participant will be attached to a 12 lead cardiac safety monitor and their blood pressure will be recorded regularly. Ventilatory and metabolic measurements of exercise will be recorded using a portable gas exchange monitor (COSMED model) through which patients will breathe allowing physiologic and metabolic parameters to be recorded in real time. A medical officer, 2‐3 nurses and respiratory technician will be present throughout each visit and the tests will be performed in the cardiology department . Arm 1 ‐ once only dose of naloxone, 0.1mg/kg (10mg maximum) diluted to a standard volume, given intravenously 15 minutes a constant rate cardio pulmonary exercise test (cCPET) of optimal training intensity, 75%WRmax will be undertaken to exhaustion with the aim that this will be at least 10 minutes of effort. Arm 2 ‐once only dose methylnaltrexone,0.3mg/kg (30mg maximum) diluted to a standard volume, given intravenously 15 minutes prior to a constant rate cardio pulmonary exercise test (cCPET) of optimal training intensity, 75%WRmax will be undertaken to exhaustion with the aim that this will be at least 10 minutes of effort. There will be a 7 days wash out period between each arm and the placebo. CONDITION: Breathlessness during exercise in people with Chronic Obstructive Pulmonary Disease. PRIMARY OUTCOME: Intensity of dyspnoea measured by the Dyspnoea 100mm Visual Analogue Scale (VAS). Unpleasantness of dyspnoea measured by the Dyspnoea 100mm Visual Analogue Scale (VAS). SECONDARY OUTCOME: Oxygen consumption regression curve from analysis of expired gas looking at minute ventilation, oxygen consumption, changes in oxygen concentration and carbon dioxide generation.This will be measured and recorded by using a portable gas exchange monitor (COSMED model) through which patients will breath allowing physiologic and metabolic parameters to be recorded in real time. Participant preference blinded summary question after all three arms measured by asking the question, " on which day of the study was your breathlessness worst?" Plasma b‐endorphin and adrenocorticotorphic hormone levels will be measured by taking 3 samples of blood. Ventilatory effort will be measured by using a spirometer before and 30 minutes after inhaling 5mg of ventolin, a bronchodilator . INCLUSION CRITERIA: On stable medications for breathlessness over the prior one week except routine “as needed” medications. Able to provide written and dated informed consent.Moderate / severe COPD. (FEV1 30%‐80% of predicted for age in spirometry performed approximately 10‐15 minutes after the subject has self‐administered 4 inhalations (i.e., total 400mcg) of albuterol/salbutamol via a metered dose inhaler (MDI) with a valved‐holding chamber. The FEV1/FVC ratio and FEV1 percent predicted values will be calculated using NHANES III reference equations) [Hankinson 1999]. Subjects will have COPD which complies with the definition of the American Thoracic. Society/European Respiratory Society. [Celli, 2004). Modified Medical Research Council breathlessness scale of 3 or 4. >50 years of age. >10 pack year history of smoking (number of pack years = (number of cigarettes per day/20) x number of years smoked). Able to use a treadmill.