The role of peripheral opioid receptors in modulating breathlessness.

1. The role of peripheral opioid receptors in modulating breathlessness. An in vivo placebo controlled, cross over, double blind study of naloxone and methylnatlrexone on breathlessness during exercise in people with chronic obstructive pulmonary disease

2. The Team D Currow, P. Allcroft, T To, S Haynes, A Mowat, U Cosic V Margitanovic A Greene.

3. Aim. The aim of the study is to understand the role of endogenous opioids in modulating breathlessness in vivo.

4. Objectives. In people with COPD during and after vigorous exercise, the objectives of the study are to: • explore the dynamic role of peripheral opioid receptors on the modulation of breathlessness; • explore changes in beta endorphin and adreno-cortico trophic hormone (ACTH) levels; and • further define differences in levels of intensity and unpleasantness of breathlessness.

5. Study Design • Double-blind, randomised, triple arm, cross over study. The intervention arms are intravenous methylnaltrexone, naloxone and placebo (normal saline) in the setting of the intensity of breathlessness and oxygen consumption in response to a constant work rate test.

6. Null hypothesis • The null hypothesis is that there is no difference between the subjective unpleasantness of dyspnoea experienced during an individually standardised exercise protocol when each of normal saline, naloxone and methylnaltrexone are administered in people with moderate to severe COPD.

7. Exercise protocol • After a baseline exercise test on a treadmill, each participant has four subsequent standardised treadmill exercise sessions: • one for further familiarisation in which bloods are taken before, at completion and 30 minutes after completion for beta endorphin and ACTH levels; and • three intervention studies preceded by a double-blind injection 15 minutes before exercise of the agent to which they were randomised for that day.

8. Primary outcome and its measurement • - Dyspnoea intensity measured at one minute intervals on 100mm VAS • - Dyspnoea unpleasantness measured at one minute intervals on 100mm VAS

11. Secondary outcomes and their measurements. • To describe any difference between placebo and methylnaltrexone, and to describe the difference between methylnaltrexone and naloxone in subjective dyspnoea at the same work effort for people with COPD.

12. Secondary Outcome Measures • Oxygen consumption regression curve from analysis of expired gas looking at minute ventilation, oxygen consumption, changes in oxygen concentration and carbon dioxide generation • Ventilatory effort • Worst dyspnoea (100mm VAS) • Participant preference blinded summary question after all three arms – ‘which was the worst arm?’ • Descriptors of breathlessness • Beta endorphin and adreno-corticotrophin hormone levels taken immediately before exercise, at the conclusion of exercise and 30 minutes after exercise ceased on one study day only.

15. What is problematic • The study commencement was protracted as we had little control over • equipment and room availability • Cardiology supplies • Borrowing equipment for prolonged periods of time due to budget constraints. • Palliative Care research team members working in the cardiology department.wefeel like the cuckoobeing in someone else’s nest . • Transporting our equipment across the hospital. • Working with interdepartmental staff dynamics leading to • conflict in respiratory and cardiology

16. What is problematic cont • The ongoing need to feed egos • We were all on a sharp learning curve • Agreement from a host referring who then starts recruiting to competing studies without telling us . • Unable to get the bloods tested in Australia • Weight of respiratory tubing • Cardiology Protocols –did not use modified Balke

20. What has worked or is working well • The inter- relationships between the nursing teams across the 3 departments • Support from biomedical engineering who set up our computer program, advised us on equipment and devised a pole to support respiratory tubing. • The Palliative Care medical team members who volunteer for our roster every Friday afternoon.

21. What has worked or is working well • All staff gained an increase in skills • We get access to respiratory patients for our other respiratory studies. • Bringing the patients into the unit for their eligibility medical

24. What would be done differently next time • Purchase some of the necessary equipment • Run the study on healthy volunteers • Have a practice run using all the equipment before we bring in patients

25. Research Questions • There are two questions that will directly benefit from this work. In people with chronic refractory breathlessness: • Should we pursue the investigation of peripheral opioid receptors with interventions such as nebulised opioids? • Shoud we consider studying the new compound pharmaceuticals (opioid agonist / peripheral opioid antagonists such as Targin R)?

26. So why do the study ?

27. Significance • These studies have the ability to influence directions for future basic science and Clinical research • Demonstrating that there is only a central effect of opioid modulating dyspnoea would exclude further studies of nebulized opioids for dyspnoea