Morphine or Fentanyl for Refractory Dyspnea in COPD

NCT ID: NCT03834363

Last Updated: 2025-06-04

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE4

Total Enrollment

59 participants

Study Classification

INTERVENTIONAL

Study Start Date

2019-11-15

Study Completion Date

2024-08-24

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.

Detailed Description

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Conditions

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COPD

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

CROSSOVER

Crossover, double blind, double dummy Randomized Controlled Trial
Primary Study Purpose

TREATMENT

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors
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.)

Study Groups

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Morphine capsules and Placebo patch

Morphine retard 10 mg twice daily Placebo patch, change every three days.

Group Type ACTIVE_COMPARATOR

Morphine Retard

Intervention Type DRUG

Morphine retard capsules 10 mg bid.

Placebo patch

Intervention Type DRUG

Placebo patch, change patch every three days.

Placebo capsules and Fentanyl patch

Placebo capsules twice daily Fentanyl patch 12 mcg/hr, change every three days

Group Type EXPERIMENTAL

Fentanyl

Intervention Type DRUG

Fentanylpatch 12 mcg/hr, change patch every three days.

Placebo oral capsule

Intervention Type DRUG

Placebo oral capsule bid

Placebo capsules and Placebo patch

Placebo capsules twice daily Placebo patch, change every three days

Group Type PLACEBO_COMPARATOR

Placebo patch

Intervention Type DRUG

Placebo patch, change patch every three days.

Placebo oral capsule

Intervention Type DRUG

Placebo oral capsule bid

Interventions

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Fentanyl

Fentanylpatch 12 mcg/hr, change patch every three days.

Intervention Type DRUG

Morphine Retard

Morphine retard capsules 10 mg bid.

Intervention Type DRUG

Placebo patch

Placebo patch, change patch every three days.

Intervention Type DRUG

Placebo oral capsule

Placebo oral capsule bid

Intervention Type DRUG

Other Intervention Names

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Fentanyl Matrix Morphine

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
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Dutch Foundation for Asthma Prevention

UNKNOWN

Sponsor Role collaborator

Innovatiefonds Zorgverzekeraars

OTHER

Sponsor Role collaborator

Huib A.M. Kerstjens

OTHER

Sponsor Role lead

Responsible Party

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Huib A.M. Kerstjens

Full professor pulmonology, head of department pulmonology and tuberculosis, principal investigator.

Responsibility Role SPONSOR_INVESTIGATOR

Principal Investigators

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Huib AM Kerstjens, MD PhD

Role: PRINCIPAL_INVESTIGATOR

University Medical Center Groningen

Locations

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Wilhelmina Ziekenhuis Assen

Assen, Drenthe, Netherlands

Site Status

Elkerliek Ziekenhuis

Helmond, North Brabant, Netherlands

Site Status

Noordwest Ziekenhuisgroep Alkmaar

Alkmaar, North Holland, Netherlands

Site Status

Rode Kruis Ziekenhuis

Beverwijk, North Holland, Netherlands

Site Status

Spaarne Gasthuis

Haarlem, North Holland, Netherlands

Site Status

Medisch Spectrum Twente

Enschede, Overijssel, Netherlands

Site Status

Isala Klinieken

Zwolle, Overijssel, Netherlands

Site Status

Ommelander Ziekenhuis Groningen

Scheemda, Provincie Groningen, Netherlands

Site Status

Ikazia Ziekenhuis

Rotterdam, South Holland, Netherlands

Site Status

University Medical Center Groningen

Groningen, , Netherlands

Site Status

Countries

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Netherlands

References

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Blinderman CD, Homel P, Billings JA, Tennstedt S, Portenoy RK. Symptom distress and quality of life in patients with advanced chronic obstructive pulmonary disease. J Pain Symptom Manage. 2009 Jul;38(1):115-23. doi: 10.1016/j.jpainsymman.2008.07.006. Epub 2009 Feb 20.

Reference Type BACKGROUND
PMID: 19232893 (View on PubMed)

Wiseman R, Rowett D, Allcroft P, Abernethy A, Currow DC. Chronic refractory dyspnoea--evidence based management. Aust Fam Physician. 2013 Mar;42(3):137-40.

Reference Type BACKGROUND
PMID: 23529525 (View on PubMed)

Abernethy AP, Currow DC, Frith P, Fazekas BS, McHugh A, Bui C. Randomised, double blind, placebo controlled crossover trial of sustained release morphine for the management of refractory dyspnoea. BMJ. 2003 Sep 6;327(7414):523-8. doi: 10.1136/bmj.327.7414.523.

Reference Type BACKGROUND
PMID: 12958109 (View on PubMed)

Jennings AL, Davies AN, Higgins JP, Gibbs JS, Broadley KE. A systematic review of the use of opioids in the management of dyspnoea. Thorax. 2002 Nov;57(11):939-44. doi: 10.1136/thorax.57.11.939.

Reference Type BACKGROUND
PMID: 12403875 (View on PubMed)

Janssen DJ, de Hosson SM, bij de Vaate E, Mooren KJ, Baas AA. Attitudes toward opioids for refractory dyspnea in COPD among Dutch chest physicians. Chron Respir Dis. 2015 May;12(2):85-92. doi: 10.1177/1479972315571926. Epub 2015 Feb 12.

Reference Type BACKGROUND
PMID: 25676931 (View on PubMed)

Simon ST, Koskeroglu P, Gaertner J, Voltz R. Fentanyl for the relief of refractory breathlessness: a systematic review. J Pain Symptom Manage. 2013 Dec;46(6):874-86. doi: 10.1016/j.jpainsymman.2013.02.019. Epub 2013 Jun 4.

Reference Type BACKGROUND
PMID: 23742735 (View on PubMed)

Payne R, Mathias SD, Pasta DJ, Wanke LA, Williams R, Mahmoud R. Quality of life and cancer pain: satisfaction and side effects with transdermal fentanyl versus oral morphine. J Clin Oncol. 1998 Apr;16(4):1588-93. doi: 10.1200/JCO.1998.16.4.1588.

Reference Type BACKGROUND
PMID: 9552070 (View on PubMed)

Allan L, Hays H, Jensen NH, de Waroux BL, Bolt M, Donald R, Kalso E. Randomised crossover trial of transdermal fentanyl and sustained release oral morphine for treating chronic non-cancer pain. BMJ. 2001 May 12;322(7295):1154-8. doi: 10.1136/bmj.322.7295.1154.

Reference Type BACKGROUND
PMID: 11348910 (View on PubMed)

Johnson MJ, Bland JM, Oxberry SG, Abernethy AP, Currow DC. Clinically important differences in the intensity of chronic refractory breathlessness. J Pain Symptom Manage. 2013 Dec;46(6):957-63. doi: 10.1016/j.jpainsymman.2013.01.011. Epub 2013 Apr 19.

Reference Type BACKGROUND
PMID: 23608121 (View on PubMed)

Currow DC, McDonald C, Oaten S, Kenny B, Allcroft P, Frith P, Briffa M, Johnson MJ, Abernethy AP. Once-daily opioids for chronic dyspnea: a dose increment and pharmacovigilance study. J Pain Symptom Manage. 2011 Sep;42(3):388-99. doi: 10.1016/j.jpainsymman.2010.11.021. Epub 2011 Mar 31.

Reference Type BACKGROUND
PMID: 21458217 (View on PubMed)

Jensen D, Alsuhail A, Viola R, Dudgeon DJ, Webb KA, O'Donnell DE. Inhaled fentanyl citrate improves exercise endurance during high-intensity constant work rate cycle exercise in chronic obstructive pulmonary disease. J Pain Symptom Manage. 2012 Apr;43(4):706-19. doi: 10.1016/j.jpainsymman.2011.05.007. Epub 2011 Dec 14.

Reference Type BACKGROUND
PMID: 22168961 (View on PubMed)

Hui D, Kilgore K, Frisbee-Hume S, Park M, Liu D, Balachandran DD, Bruera E. Effect of Prophylactic Fentanyl Buccal Tablet on Episodic Exertional Dyspnea: A Pilot Double-Blind Randomized Controlled Trial. J Pain Symptom Manage. 2017 Dec;54(6):798-805. doi: 10.1016/j.jpainsymman.2017.08.001. Epub 2017 Aug 10.

Reference Type BACKGROUND
PMID: 28803087 (View on PubMed)

van Dijk M, Mooren KJM, van den Berg JK, van Beurden-Moeskops WJC, Heller-Baan R, de Hosson SM, Lam-Wong WY, Peters L, Pool K, Kerstjens HAM. Opioids in patients with COPD and refractory dyspnea: literature review and design of a multicenter double blind study of low dosed morphine and fentanyl (MoreFoRCOPD). BMC Pulm Med. 2021 Sep 10;21(1):289. doi: 10.1186/s12890-021-01647-8.

Reference Type DERIVED
PMID: 34507574 (View on PubMed)

Other Identifiers

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MoreFoRCOPD

Identifier Type: -

Identifier Source: org_study_id

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