Does blocking the body's own morphine-like chemicals during exercise change the perception of breathlessness?
The role of peripheral opioid receptors in modulating breathlessness. An in vivo placebo controlled, triple arm, cross over , double blind study of naloxone and methylnaltrexone on breathlessness during exercise in people with Chronic Obstructive Airway Disease.
Flinders University- Deptment of Palliative and Supportive Services
30 participants
Nov 11, 2011
Interventional
Conditions
Summary
The aim of the study is to understand the role of endogenous opioids ( the body's own morphine-like chemicals) in regulating breathlessness in people with Chronic Obstructive Airways Disease and to answer the question "Does blocking these endogenous opioids during exercise change the perseption of breathlessness. Trial details Participants with moderate to severe Chronic Obstructive Pulmonary Airways (COPD) disease, if eligible will be asked to attend the clinic up to 5 times over the study period and each visit will take about 2 hours. After a baseline exercise test on a treadmill participants will have 4 subsequent standardised treadmill exercise sessions.Each test will comprise of up to 15 minutes on the treadmill with the aim of walking as far as possilbe at a steady pace. Visits will be weeklyand a doctor and nurse will be present at all times during the proceedure. Bloods will be taken on visit 3 to measure two chemicals that the body routinely makes- beta endorphin and adrenocorticotrophin. 30 minutes before each exercise test the participant will be administered 5mg of salbutamol through an inhaler. On the 3th,4th and 5th exercise test participants will receive a double blind injection on different visits of each of saline, methylnaltrexone and naloxone, in a random ( by chance) order. During the 15 minute exercise tests, participants will be asked to record the intensity and unpleasantness of their breathlessness and how tired their legs feel, every minute by means of a touch pad screen. Throughout each test and for 30 minutes after stopping the participant will be attached to cardiac monitor and their blood pressure will be monitored regularly.
Eligibility
Inclusion Criteria1
- 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.
Exclusion Criteria6
- On regular or ‘as needed’ opioids in the week before commencing the study and at any time during the study.
- Unable to give informed consent or complete evaluation tool entries. Cognitively impaired (Mini Mental State < 24). [Folstein]. Calculated creatinine clearance of < 30mls using MDRD. [Levey 1999] . Known or suspected bowel obstruction (specific contra-indications in methylnaltrexone) or known or suspected GI lesions.
- Participants with any of the following clinical conditions:
- a history of myocardial infarction, unstable angina or untreated severe left anterior descending coronary artery compromise within 1 year of screening visit, cardiac arrhythmia causing symptoms or haemodynamic compromise, atrioventricular block, hospitalized for heart failure within the past year, claudication, known active tuberculosis or other chronic lung infection, a history of life-threatening pulmonary obstruction, a history of cystic fibrosis, clinically evident bronchiectasis.
- Contraindications for exercise testing which would include
- active endocarditis, myocarditis or pericarditis, hypertrophic cardiomyopathy, symptomatic moderate to severe aortic stenosis, severe untreated arterial hypertension (>160 mmHg systolic, >110 mmHg diastolic), significant pulmonary hypertension, untreated venous thromboembolism, active systemic infection, uncontrolled hyperthyroidism, body mass index (BMI) >35, physical limitations due to arthritis, joint replacement, people on monoamine oxidase inhibitors. Participants who are currently under going pulmonary rehabilitation or have completed a pulmonary rehabilitation program in the previous six weeks. Participants with an endurance time > 25 minutes during the training (visit 2)
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Interventions
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.
Locations(1)
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ACTRN12611001182987