Morphine or Fentanyl for Refractory Dyspnea in COPD

Study Overview
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Brief Summary
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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.

Official Title
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Morphine or Fentanyl for Refractory Dyspnea in COPD

Conditions
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COPD

Intervention / Treatment
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* Drug: Fentanyl
* Drug: Morphine Retard
* Drug: Placebo patch
* Drug: Placebo oral capsule


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Crossover, double blind, double dummy Randomized Controlled Trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Morphine capsules and Placebo patch<br>Morphine retard 10 mg twice daily Placebo patch, change every three days. | Drug: Morphine Retard<br>* Morphine retard capsules 10 mg bid.<br>* Other names: Morphine;Drug: Placebo patch<br>* Placebo patch, change patch every three days.<br>|
| Experimental: Placebo capsules and Fentanyl patch<br>Placebo capsules twice daily Fentanyl patch 12 mcg/hr, change every three days | Drug: Fentanyl<br>* Fentanylpatch 12 mcg/hr, change patch every three days.<br>* Other names: Fentanyl Matrix;Drug: Placebo oral capsule<br>* Placebo oral capsule bid<br>|
| Placebo Comparator: Placebo capsules and Placebo patch<br>Placebo capsules twice daily Placebo patch, change every three days | Drug: Placebo patch<br>* Placebo patch, change patch every three days.<br>Drug: Placebo oral capsule<br>* Placebo oral capsule bid<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in dyspnea sensation | Change in dyspnea sensation measured on a Numeric Rating Scale from 0 to 10. A lower score represents a better outcome. | Daily during the six week treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in CCQ (HR-QoL) | Change in HR-QoL measured with the Clinical COPD Questionnaire. Scores range from 0 to 6. Lower values represent a better outcome. | Daily during the six week treatment period | 
| Change in CRQ (HR-QoL) | Change in HR-QoL measured with Chronic Respiratory Disease Questionnare. Scores range from 1 to 7. A higher score represents a better outcome. | 4 times during the six week treatment period: baseline, 2 weeks, 4 weeks, 6 weeks. | 
| Change in CRQ mastery (HR-QoL) | Change in HR-QoL measured with Chronic Respiratory Disease Questionnare, domain Mastery. Scores range from 1 to 7. A higher score represents a better outcome. | 4 times during the six week treatment period: baseline, 2 weeks, 4 weeks, 6 weeks. | 
| Change on the HADS-A questionnaire (Anxiety) | Change on the Hospital Anxiety and Depression Scale-anxiety subscale. Scores range from 0 to 21. A lower score represents a better outcome. | 4 times during the six week treatment period: baseline, 2 weeks, 4 weeks, 6 weeks. | 
| Side effects | Reported spontaneously in a daily patient diary and specifically, both open and named side effects at planned visits. | Daily during the six week treatment period | 
| Hypercapnia | Change in pCO2 in capillary blood gas analysis | 4 times during the six week treatment period: baseline, 2 weeks, 4 weeks, 6 weeks. | 
| Sleep quality | Change on a Numeric Rating Scale from 0 to 10. A lower score represents a better outcome. | Daily during the six week treatment period | 
| Continued opioid use | Asked three months after the end of the treatment period | Once, three months after the end of the treatment period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COPD, Refractory Dyspnea, Morphine, Fentanyl