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

The TeamThe TeamD Currow, P. Allcroft, T To,S Haynes,A Mowat, U CosicV MargitanovicA Greene.

Aim.Aim.

The aim of the study is to understand the role of endogenous

opioids in modulating breathlessness in vivo.

Objectives.Objectives.

In people with COPD during and after vigorous In people with COPD during and after vigorous exercise, the objectives of the study are to:exercise, the objectives of the study are to:

• explore the dynamic role of peripheral opioid explore the dynamic role of peripheral opioid receptors on the modulation of breathlessness;receptors on the modulation of breathlessness;

• explore changes in beta endorphin and adreno-explore changes in beta endorphin and adreno-cortico trophic hormone (ACTH) levels; and cortico trophic hormone (ACTH) levels; and

• further define differences in levels of intensity further define differences in levels of intensity and unpleasantness of breathlessness. and unpleasantness of breathlessness.

Study DesignStudy Design

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

Null hypothesis Null hypothesis

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

Exercise protocolExercise protocol

• After a baseline exercise test on a treadmill, After a baseline exercise test on a treadmill, each participant has four subsequent each participant has four subsequent standardised treadmill exercise sessions: standardised treadmill exercise sessions:

• one for further familiarisation in which one for further familiarisation in which bloods are taken before, at completion and bloods are taken before, at completion and 30 minutes after completion for beta 30 minutes after completion for beta endorphin and ACTH levels; and endorphin and ACTH levels; and

• three intervention studies preceded by a three intervention studies preceded by a double-blind injection 15 minutes before double-blind injection 15 minutes before exercise of the agent to which they were exercise of the agent to which they were randomised for that day. randomised for that day.

Primary outcome and its Primary outcome and its measurementmeasurement

• - Dyspnoea intensity measured at - Dyspnoea intensity measured at one minute intervals on 100mm VASone minute intervals on 100mm VAS

• - Dyspnoea unpleasantness - Dyspnoea unpleasantness measured at one minute intervals on measured at one minute intervals on 100mm VAS100mm VAS

Secondary outcomes and their Secondary outcomes and their

measurementsmeasurements..

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

Secondary Outcome Secondary Outcome MeasuresMeasures

• Oxygen consumption regression curve from analysis Oxygen consumption regression curve from analysis of expired gas looking at minute ventilation, oxygen of expired gas looking at minute ventilation, oxygen consumption, changes in oxygen concentration and consumption, changes in oxygen concentration and carbon dioxide generationcarbon dioxide generation

• Ventilatory effortVentilatory effort• Worst dyspnoea (100mm VAS)Worst dyspnoea (100mm VAS)• Participant preference blinded summary question Participant preference blinded summary question

after all three arms – ‘which was the worst arm?’after all three arms – ‘which was the worst arm?’• Descriptors of breathlessnessDescriptors of breathlessness• Beta endorphin and adreno-corticotrophin hormone Beta endorphin and adreno-corticotrophin hormone

levels taken immediately before exercise, at the levels taken immediately before exercise, at the conclusion of exercise and 30 minutes after conclusion of exercise and 30 minutes after exercise ceased exercise ceased on one study day onlyon one study day only..

What is problematicWhat 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. we feel like the cuckoo being in someone else’s nest . •Transporting our equipment across the hospital.•Working with interdepartmental staff dynamics leading toconflict in respiratory and cardiology

What is problematic contWhat is problematic cont

• The ongoing need to feed egos The ongoing need to feed egos

• We were all on a sharp learning curve We were all on a sharp learning curve

• Agreement from a host referring who then starts Agreement from a host referring who then starts recruiting to competing studies without telling recruiting to competing studies without telling

us .us .

• Unable to get the bloods tested in Australia Unable to get the bloods tested in Australia

• Weight of respiratory tubingWeight of respiratory tubing

• Cardiology Protocols –did not use modified BalkeCardiology Protocols –did not use modified Balke

What has worked or is What has worked or is working wellworking well• The inter- relationships between the nursing The inter- relationships between the nursing

teams across the 3 departments teams across the 3 departments • Support from biomedical engineering who set up Support from biomedical engineering who set up

our computer program, advised us on equipment our computer program, advised us on equipment and devised a pole to support respiratory tubing.and devised a pole to support respiratory tubing.

• The Palliative Care medical team members who The Palliative Care medical team members who volunteer for our roster every Friday afternoon. volunteer for our roster every Friday afternoon.

What has worked or is What has worked or is working wellworking well

• All staff gained an increase in skillsAll staff gained an increase in skills

• We get access to respiratory patients We get access to respiratory patients for our other respiratory studies.for our other respiratory studies.

• Bringing the patients into the unit for Bringing the patients into the unit for their eligibility medical their eligibility medical

What would be done What would be done differently next timedifferently next time

• Purchase some of the necessary Purchase some of the necessary equipmentequipment

• Run the study on healthy volunteers Run the study on healthy volunteers

• Have a practice run using all the Have a practice run using all the equipment before we bring in equipment before we bring in patients patients

Research Questions Research Questions

• There are two questions that will directly benefit There are two questions that will directly benefit from this work. In people with chronic refractory from this work. In people with chronic refractory breathlessness:breathlessness:

• Should we pursue the investigation of peripheral Should we pursue the investigation of peripheral opioid receptors with interventions such as opioid receptors with interventions such as nebulised opioids?nebulised opioids?

• Shoud we consider studying the new compound Shoud we consider studying the new compound pharmaceuticals (opioid agonist / peripheral pharmaceuticals (opioid agonist / peripheral opioid antagonists such as Targin R)?opioid antagonists such as Targin R)?

So why do the study ?

SignificanceSignificance

• These studies have the ability to These studies have the ability to influence directions for future basic influence directions for future basic science and Clinical research science and Clinical research

• Demonstrating that there is only a Demonstrating that there is only a central effect of opioid modulating central effect of opioid modulating dyspnoea would exclude further dyspnoea would exclude further studies of nebulized opioids for studies of nebulized opioids for dyspnoeadyspnoea