Morphine or Fentanyl for Refractory Dyspnea in COPD (MoreFoRCOPD)

May 30, 2025 updated by: Huib A.M. Kerstjens

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

59

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Netherlands
      • Groningen, Netherlands, 9713GZ
        • University Medical Center Groningen
    • Drenthe
      • Assen, Drenthe, Netherlands, 9401 RK
        • Wilhelmina Ziekenhuis Assen
    • Groningen
      • Scheemda, Groningen, Netherlands, 9676 BJ
        • Ommelander Ziekenhuis Groningen
    • Noord-Brabant
      • Helmond, Noord-Brabant, Netherlands, 5707 HA
        • Elkerliek Ziekenhuis
    • Noord-Holland
      • Alkmaar, Noord-Holland, Netherlands, 1815 JD
        • Noordwest Ziekenhuisgroep Alkmaar
      • Beverwijk, Noord-Holland, Netherlands, 1942 LE
        • Rode Kruis Ziekenhuis
      • Haarlem, Noord-Holland, Netherlands, 2035 RC
        • Spaarne Gasthuis
    • Overijssel
      • Enschede, Overijssel, Netherlands, 7512 KZ
        • Medisch Spectrum Twente
      • Zwolle, Overijssel, Netherlands, 8025 AB
        • Isala Klinieken
    • Zuid-Holland
      • Rotterdam, Zuid-Holland, Netherlands, 3083 AN
        • Ikazia Ziekenhuis

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Morphine capsules and Placebo patch
Morphine retard 10 mg twice daily Placebo patch, change every three days.
Drug: Morphine Retard
Morphine retard capsules 10 mg bid.
Other Names:
  • Morphine
Drug: Placebo patch
Placebo patch, change patch every three days.
Experimental: Placebo capsules and Fentanyl patch
Placebo capsules twice daily Fentanyl patch 12 mcg/hr, change every three days
Drug: Fentanyl
Fentanylpatch 12 mcg/hr, change patch every three days.
Other Names:
  • Fentanyl Matrix
Drug: Placebo oral capsule
Placebo oral capsule bid
Placebo Comparator: Placebo capsules and Placebo patch
Placebo capsules twice daily Placebo patch, change every three days
Drug: Placebo patch
Placebo patch, change patch every three days.
Drug: Placebo oral capsule
Placebo oral capsule bid

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in dyspnea sensation
Time Frame: Daily during the six week treatment period
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)
Time Frame: Daily during the six week treatment period
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)
Time Frame: 4 times during the six week treatment period: baseline, 2 weeks, 4 weeks, 6 weeks.
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)
Time Frame: 4 times during the six week treatment period: baseline, 2 weeks, 4 weeks, 6 weeks.
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)
Time Frame: 4 times during the six week treatment period: baseline, 2 weeks, 4 weeks, 6 weeks.
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
Time Frame: Daily during the six week treatment period
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
Time Frame: 4 times during the six week treatment period: baseline, 2 weeks, 4 weeks, 6 weeks.
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
Time Frame: Daily during the six week treatment period
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
Time Frame: Once, three months after the end of the treatment period
Asked three months after the end of the treatment period
Once, three months after the end of the treatment period

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Survival
Time Frame: One week after the end of the treatment period, which is 7 weeks after start of the study.
Measured one week after the end of the treatment period
One week after the end of the treatment period, which is 7 weeks after start of the study.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Huib A.M. Kerstjens

Collaborators

Innovatiefonds Zorgverzekeraars
Dutch Foundation for Asthma Prevention

Investigators

  • Principal Investigator: Huib AM Kerstjens, MD PhD, University Medical Center Groningen

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 15, 2019

Primary Completion (Actual)

May 24, 2024

Study Completion (Actual)

August 24, 2024

Study Registration Dates

First Submitted

January 11, 2019

First Submitted That Met QC Criteria

February 6, 2019

First Posted (Actual)

February 7, 2019

Study Record Updates

Last Update Posted (Actual)

June 4, 2025

Last Update Submitted That Met QC Criteria

May 30, 2025

Last Verified

May 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • MoreFoRCOPD

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Upon request

IPD Sharing Time Frame

After publication of results Unlimited

IPD Sharing Access Criteria

Clear description of goals for asking

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • ICF

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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