Morphine or Fentanyl for Refractory Dyspnea in COPD

NCT03834363 | Completed Phase 4

• 1 other identifier: MoreFoRCOPD
• Study Type: interventional
• Target: 59
• Locations: 1 country
• Sites: 10

Brief Summary

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.

Conditions

COPD

Keywords

COPD; Refractory Dyspnea; Morphine; Fentanyl

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (8)

• Change in CCQ (HR-QoL)

  Daily during the six week treatment period

• Change in CRQ (HR-QoL)

  4 times during the six week treatment period: baseline, 2 weeks, 4 weeks, 6 weeks.

• Change in CRQ mastery (HR-QoL)

  4 times during the six week treatment period: baseline, 2 weeks, 4 weeks, 6 weeks.

• Change on the HADS-A questionnaire (Anxiety)

  4 times during the six week treatment period: baseline, 2 weeks, 4 weeks, 6 weeks.

• Side effects

  Daily during the six week treatment period

Other Outcomes (1)

• Survival

  One week after the end of the treatment period, which is 7 weeks after start of the study.

Study Arms (3)

Morphine capsules and Placebo patch

ACTIVE COMPARATOR

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

Drug: Morphine Retard; Drug: Placebo patch

Placebo capsules and Fentanyl patch

EXPERIMENTAL

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

Drug: Fentanyl; Drug: Placebo oral capsule

Placebo capsules and Placebo patch

PLACEBO COMPARATOR

Placebo capsules twice daily Placebo patch, change every three days

Drug: Placebo patch; Drug: Placebo oral capsule

Interventions

Fentanyl DRUG

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

Also known as: Fentanyl Matrix

Placebo capsules and Fentanyl patch

Morphine Retard DRUG

Morphine retard capsules 10 mg bid.

Also known as: Morphine

Morphine capsules and Placebo patch

Placebo patch DRUG

Placebo patch, change patch every three days.

Morphine capsules and Placebo patch; Placebo capsules and Placebo patch

Placebo oral capsule DRUG

Placebo oral capsule bid

Placebo capsules and Fentanyl patch; Placebo capsules and Placebo patch

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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

Sponsors & Collaborators

• Huib A.M. Kerstjens: lead
• Dutch Foundation for Asthma Prevention: collaborator
• Innovatiefonds Zorgverzekeraars: collaborator

Study Sites (10)

Wilhelmina Ziekenhuis Assen

Assen, Drenthe, 9401 RK, Netherlands

Location

Elkerliek Ziekenhuis

Helmond, North Brabant, 5707 HA, Netherlands

Location

Noordwest Ziekenhuisgroep Alkmaar

Alkmaar, North Holland, 1815 JD, Netherlands

Location

Rode Kruis Ziekenhuis

Beverwijk, North Holland, 1942 LE, Netherlands

Location

Spaarne Gasthuis

Haarlem, North Holland, 2035 RC, Netherlands

Location

Medisch Spectrum Twente

Enschede, Overijssel, 7512 KZ, Netherlands

Location

Isala Klinieken

Zwolle, Overijssel, 8025 AB, Netherlands

Location

Ommelander Ziekenhuis Groningen

Scheemda, Provincie Groningen, 9676 BJ, Netherlands

Location

Ikazia Ziekenhuis

Rotterdam, South Holland, 3083 AN, Netherlands

Location

University Medical Center Groningen

Groningen, 9713GZ, Netherlands

Location

Related Publications (13)

• 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.

  PMID: 19232893 BACKGROUND

• 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.

  PMID: 23529525 BACKGROUND

• 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.

  PMID: 12958109 BACKGROUND

• 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.

  PMID: 12403875 BACKGROUND

• 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.

  PMID: 25676931 BACKGROUND

• 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.

  PMID: 23742735 BACKGROUND

• 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.

  PMID: 9552070 BACKGROUND

• 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.

  PMID: 11348910 BACKGROUND

• 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.

  PMID: 23608121 BACKGROUND

• 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.

  PMID: 21458217 BACKGROUND

• 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.

  PMID: 22168961 BACKGROUND

• 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.

  PMID: 28803087 BACKGROUND

• 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.

  PMID: 34507574 DERIVED

MeSH Terms

Conditions

Pulmonary Disease, Chronic Obstructive; Dyspnea

Interventions

Fentanyl; Morphine

Condition Hierarchy (Ancestors)

Lung Diseases, Obstructive; Lung Diseases; Respiratory Tract Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Respiration Disorders; Signs and Symptoms, Respiratory; Signs and Symptoms

Intervention Hierarchy (Ancestors)

Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Morphine Derivatives; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds

Study Officials

• Huib AM Kerstjens, MD PhD

  University Medical Center Groningen

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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.)
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Full professor pulmonology, head of department pulmonology and tuberculosis, principal investigator.

Model Details: Crossover, double blind, double dummy Randomized Controlled Trial

Study Record Dates

• First Submitted: January 11, 2019
• First Posted: February 7, 2019
• Study Start: November 15, 2019
• Primary Completion: May 24, 2024
• Study Completion: August 24, 2024
• Last Updated: June 4, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF
• Time Frame: After publication of results Unlimited
• Access Criteria: Clear description of goals for asking

Locations

NL (10)