Morphine or Fentanyl for Refractory Dyspnea in COPD

COPD Clinical Trial

— MoreFoRCOPD  

Official title:

Morphine or Fentanyl for Refractory Dyspnea in COPD

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03834363
• Other study ID #: MoreFoRCOPD
• Status: Active, not recruiting
• Phase: Phase 4
• Start date: November 15, 2019
• Est. completion date: August 24, 2024

Study information

• Verified date: June 2024
• Source: University Medical Center Groningen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 59
• Est. completion date: August 24, 2024
• Est. primary completion date: May 24, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• COPD
• Dyspnea

Intervention

Drug:
• Fentanyl
Fentanylpatch 12 mcg/hr, change patch every three days.
• Morphine Retard
Morphine retard capsules 10 mg bid.
• Placebo patch
Placebo patch, change patch every three days.
• Placebo oral capsule
Placebo oral capsule bid

Locations

Country	Name	City	State
Netherlands	Noordwest Ziekenhuisgroep Alkmaar	Alkmaar	Noord-Holland
Netherlands	Wilhelmina Ziekenhuis Assen	Assen	Drenthe
Netherlands	Rode Kruis Ziekenhuis	Beverwijk	Noord-Holland
Netherlands	Medisch Spectrum Twente	Enschede	Overijssel
Netherlands	University Medical Center Groningen	Groningen
Netherlands	Spaarne Gasthuis	Haarlem	Noord-Holland
Netherlands	Elkerliek Ziekenhuis	Helmond	Noord-Brabant
Netherlands	Ikazia Ziekenhuis	Rotterdam	Zuid-Holland
Netherlands	Ommelander Ziekenhuis Groningen	Scheemda	Groningen
Netherlands	Isala Klinieken	Zwolle	Overijssel

Sponsors (3)

Lead Sponsor	Collaborator
Huib A.M. Kerstjens	Dutch Foundation for Asthma Prevention, Innovatiefonds Zorgverzekeraars

Country where clinical trial is conducted

Netherlands, 

References & Publications (12)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Survival	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.
Primary	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	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
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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
Secondary	Hypercapnia	Change in pCO2 in capillary blood gas analysis	4 times during the six week treatment period: baseline, 2 weeks, 4 weeks, 6 weeks.
Secondary	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
Secondary	Continued opioid use	Asked three months after the end of the treatment period	Once, three months after the end of the treatment period