Dyspnea is the most reported symptom of patients with advanced Chronic Obstructive Pulmonary Disease (COPD) and is undertreated. Morphine is an effective treatment for dyspnea and is recommended in clinical practice guidelines, but questions concerning benefits and concerns about respiratory adverse effects remain. For example, the effect on health-related quality of life and functional capacity is unknown. In one-third of the patients oral sustained release morphine (morphine SR) doesn't relieve dyspnea and it remains unknown whether severity and descriptors of breathlessness may predict a response to morphine. Finally, cost-effectiveness of morphine SR in this patient group is unknown. Therefore, prescription of morphine to patients with COPD is limited.

Objectives of this double blind randomized controlled trial are to study the effect of oral administration of morphine SR on health-related quality of life, respiratory adverse effects, and functional capacity; to explore whether description and severity of breathlessness are related with a clinically relevant response to morphine and to analyse the cost-effectiveness of morphine SR. The study population will consist of 124 clinically stable outpatients with COPD and severe dyspnea despite optimal pharmacological and non-pharmacological treatment.

Participants will be outpatients with a confirmed diagnosis of COPD, who suffer from severe dyspnea despite optimal pharmacological and non-pharmacological treatment. Participants will be recruited at CIRO, a center for pulmonary rehabilitation in the Netherlands after they completed a pulmonary rehabilitation program. After providing informed consent, patients will be randomized. Members of the research team who perform measurements will be blinded for treatment allocation.

Patients in the intervention group will receive regular clinical care and morphine SR 10mg, administered twice daily (20mg/24h), which can be increased after one or two weeks to three times per day 10mg (30mg/24h) in non-responders. Patients will be defined as non-responders if the mean dyspnea numeric rating scale (NRS) score was not reduced by 1 point in comparison with baseline. The control group will receive regular clinical care and placebo medication. Patients will receive morphine or placebo for four weeks. In addition, both groups will receive a prescription for a laxative and metoclopramide at the start of the intervention and will be instructed to adjust the dose as needed.

When the intervention period has ended, participants can choose to continue morphine treatment. They will be followed for twelve weeks to assess their healthcare use, use of morphine and number of adverse effects and exacerbations.

Measurements at baseline will include: demographics, medical history, medication, co-morbidities, exercise capacity, respiratory parameters, generic and disease-specific health-related quality of life (HRQoL), severity of dyspnea, sensory and affective dimensions of dyspnea, impact of dyspnea, cognition, level of daytime sleepiness, and functional capacity. A member of the research team will visit patients after 1 and 2 weeks in their home environment to assess adverse effects, compliance, exacerbations, disease-specific HRQoL, mobility, severity of dyspnea, and some respiratory parameters. A member of the research team will call the patient after 2 days and 3 weeks to assess adverse effects, compliance, exacerbations, and severity of dyspnea. After 4 weeks the following measurements will be performed: respiratory parameters, exercise capacity, general and disease-specific HRQoL, sensory and affective dimensions of dyspnea, impact of dyspnea, functional capacity, and adverse effects. Overnight oximetry will be performed in the home environment at baseline and after four weeks. A diary for costs and healthcare use will be filled in during four weeks.

Measurements during the twelve weeks following the intervention include: retrospective cost questionnaire, generic and disease-specific quality of life severity of dyspnea and adverse effects.

Statistical analyses Baseline characteristics will be compared between the intervention and control group using descriptive statistics. Chi square tests will be used for categorical variables. Independent sample T-tests and Mann-Whitney U-tests will be used for continuous variables, according to the variable distribution. Change in CAT-score, respiratory parameters and 6MWD between baseline and four weeks will be compared between patients in the intervention and the control group. First, mean change in CAT-score, respiratory parameters and 6MWD will be compared between the two groups using an independent sample T-test or Mann-Whitney U test, according to the variable distribution. Afterwards, multivariate analyses for longitudinal data will be performed. Analyses will be done using an intention-to-treat approach. The relationship between response to opioids and severity of dyspnea and descriptors of breathlessness will be explored using univariate analysis, followed by a binary logistic regression model. A trial-based economic evaluation will be performed, based on empirical data obtained in the RCT. The economic evaluation will be performed from the societal and healthcare perspective, the first including costs inside and outside the health care sector, and will follow published international guidelines. The time horizon of the trial-based economic evaluation will be four weeks. The outcomes of the twelve weeks following the intervention will be used in the model-based economic evaluation. The model will probably take the form of a Markov model; however this will be decided upon during the study.

Inclusion Criteria:

• Diagnosis of COPD according to the current Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (GOLD);
• Optimal pharmacological treatment, including including treatment with a combination of a long-acting muscarinic antagonist and an ultra-long-acting β-agonist;
• Grade 3 or 4 dyspnea on the mMRC dyspnea scale;
• Optimal non-pharmacological treatment defined as completed a comprehensive pulmonary rehabilitation program.

Exclusion Criteria:

• History of substance misuse;
• Exacerbation of COPD within two weeks of study enrolment;
• Waiting list for lung transplantation;
• Pregnant or childbearing potential not using contraception;
• Renal failure (creatinine clearance <15mL/min);
• Not being able to read or fill in the questionnaires or diary;
• Allergy for morphine or its excipients;
• Concomitant use of irreversible MAO blockers;
• Use of opioids;
• History of convulsions;
• Head injury;
• Intestinal obstruction;
• Gastroparesis;
• Liver disease.