Rationale: The most important complaint in severe COPD is dyspnea which is associated with a diminished exercise tolerance, reduced quality of life and can lead to anxiety and depression. If dyspnea continues to exist despite optimal therapy it is called refractory dyspnea. There is evidence that morphine is effective and can safely be prescribed for treating refractory dyspnea.

However, a Dutch study recently showed that few pulmonologists actually prescribe opioids for this indication. The main reasons for this are concerns about side effects and respiratory insufficiency as well as negative emotions for the patient and families at the thought of using morphine.

Most studies investigating opioids for treatment of dyspnea are conducted with morphine tablets, and only a part of these patients suffered from COPD. To our knowledge there has not been a randomized controlled trial investigating fentanyl patches for refractory dyspnea in COPD patients. However, studies comparing fentanyl and morphine in pain management show that patients may prefer fentanyl patches and have less problems with obstipation.

Objective: There are three main objectives for this study.

First, the investigators will investigate the following hypothesis: Both fentanyl and morphine provide a reduction of dyspnea which is better than placebo. Fentanyl has less side effects than morphine.

Secondly, with this Dutch multi-center study the investigators would like to enlarge the evidence base and contribute to the experience with opioids for refractory dyspnea in COPD thereby greatly facilitating its implementation in the Netherlands.

Finally, the investigators will develop and evaluate educational material about opioid use for dyspnea in COPD.

Study design: This is a multi-center double blind, double-dummy cross-over randomized placebo-controlled trial with three study arms. A total of 60 COPD patients will be included in this study.

Participants will be treated sequentially with three combinations of medication and/or placebo medication in a random order. They will receive either a Fentanyl patch in combination with placebo tablets, a placebo patch with Morphine Slow release tablets or a placebo patch with placebo tablets. Main study parameters/endpoints: The primary endpoint is change in dyspnea sensation Secondary endpoints are change in HR-QoL, anxiety, sleep quality, hypercapnia and the number and seriousness of side effect.

Inclusion Criteria:

• Age ≥ 40 years.
• Read, understood and signed the Informed Consent form.
• COPD GOLD class III or IV, according to GOLD criteria (Post-bronchodilation FEV/FVC <70% and FEV1 < 50%pred.
• Complaints of refractory dyspnea as established by patient and doctor.
• mMRC score ≥ 3.
• Life expectancy of ≥ 2 months.
• Optimized standard therapy according to Dutch LAN guideline for diagnosis and treatment of COPD.

Exclusion Criteria:

• Other severe disease with chronic pain or chronic dyspnea (a non substantial component of left sided heart failure is acceptable).
• Current use of opioids for whatever indication.
• Allergy / intolerance for opioids
• Psychiatric disease, not related to severe COPD.
• Exacerbation of COPD 8 weeks prior to inclusion or between screening and randomization.
• Problematic (leading to medical help or social problems) substance abuse during the last five years.
• Active malignancy, with the exception of planocellular or basal cell carcinoma of the skin.
• eGFR <15 ml/min

Upon request

After publication of results Unlimited

Clear description of goals for asking

For both morphine retard capsules as fentanyl patches there is a placebo available. Participants will be treated in each period with both tablets and a patch. (morphine capsules+placebo patch, placebo capsules+fentanyl patch, placebo capsules+ placebo patch.)