Effect of opioids on outcomes of pulmonary rehabilitation

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Background Impaired exercise capacity and activity due to chronic obstructive pulmonary disease (COPD) is a major threat to the health of the individual and impacts on the community at large. About 330 million people have COPD worldwide and 235,000 people have moderate or severe disease in Australia alone. These people often suffer from disabling symptoms and reduced physical capacity for many years despite best medical management. Pulmonary rehabilitation is first-line treatment in people with symptomatic COPD with a strong evidence base for improved functional status, better exercise tolerance and better longer term outcomes. Recent laboratory data show that regular, low dose opioids (such as morphine) may decrease exertional breathlessness without impairing exercise capacity. Regular, low dose sustained release morphine is a potential new approach to improve further the established outcomes of pulmonary rehabilitation in COPD. Such an intervention has not been tested in a randomised clinical trial. It is important to establish that the overall net effect is positive and that benefits outweigh any harms encountered. A particular concern for many clinicians is the theoretical risk that opioids may cause respiratory depression. In steady state, at the relatively low regular doses proposed, there are no data to support this concern, but this study will specifically monitor this issue through careful collection of non-invasive measures of respiratory function, including end-tidal carbon dioxide, regularly throughout the study. Study design This is a phase III, multi-site, randomised, double-blind, parallel arm, fixed dose, placebo controlled trial of sustained release morphine (20 mg every 24 hours) or placebo during eight weeks of pulmonary rehabilitation for COPD. Randomisation will be stratified according to the mMRC score. During the study period, therapy for constipation is also given to participants with active therapy and identical appearing laxative placebo is given in the placebo arm. Data on 260 people will be required in order to complete the study with adequate power for the primary endpoint. Study population Suitable people with spirometry-verified COPD and breathlessness (between grade three and four on the mMRC scale), who are eligible for pulmonary rehabilitation and are able to give informed consent, will be recruited to participate in the study, provided they have no contraindication for opioid use. Objectives During eight weeks of pulmonary rehabilitation, the primary objective is to compare the efficacy for improving exercise capacity measured using the six minute walking test (6MWT) of sustained release morphine compared with placebo. Secondary objectives include effect on daily activity measured using an accelerometer, safety, breathlessness, quality of life (QOL), health care resource utilization, clinical and pharmacogenomic predictors of which individuals will achieve the greatest benefit from morphine, and to establish any blinded participant treatment preference. Treatment schedule Every day, participants will take three capsules (one Kapanol 20mg or placebo in the morning, and two capsules of docusate with senna or placebo). This will occur without titration and participants will continue the allocated treatment during eight weeks of pulmonary rehabilitation. ‘As needed’ open label docusate with senna will also be provided to all study participants. Assessments Week 1: demographic and clinical data, blood sample, 6MWT, daily activity (accelerometer for seven days), severity and characteristics of dyspnoea, twice daily diary, adverse events, quality of life, and blinded treatment preference. Outcome measures are repeated at the end of week eight of pulmonary rehabilitation. For 24 hours each week throughout the study: daily diary and adverse events. Definition of response: A response will be defined as an increase of 55m or more on the 6MWT. Primary endpoint: Change between week one and week eight of pulmonary rehabilitation in distance on a standardized 6MWT. Analysis: Longitudinal repeated measures mixed models with unstructured covariance matrices, two-sample t tests, and multivariable regression models will be used. Economic analysis: This will estimate incremental costs, effects and net benefit of oral sustained release morphine relative to placebo in addition to pulmonary rehabilitation from participant level data collected over eight weeks of follow up (survival to eight weeks or death, whichever is shorter) for: * resource use including bed days spent in hospital for inpatient admissions (index admission and readmissions); * professional community support utilised at home if discharged from hospital or enrolled at home, including general practitioner and specialty care service visits, * concomitant medication use; and * effects including days of survival with response, toxicity, adverse events, health related quality of life, and compliance. Bootstrapping of patient costs and effects data will be used to model decision making uncertainty related to the net benefit of oral sustained release morphine relative to placebo.

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