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Cited by 282Pain Management and Opioid UsePalliative Care and End-of-Life IssuesPalliative and Oncologic Care

Opioids for the palliation of refractory breathlessness in adults with advanced disease and terminal illness

Open access
Barnes, Hayley, McDonald, Julie, Smallwood, Natasha, Manser, Renée·2016·Cochrane Database of Systematic Reviews
DOI 10.1002/14651858.cd011008.pub2PMC PMC6485401
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Abstract

BACKGROUND: Breathlessness is a common and disabling symptom which affects many people with advanced cardiorespiratory disease and cancer. The most effective treatments are aimed at treating the underlying disease. However, this may not always be possible, and symptomatic treatment is often required in addition to maximal disease-directed therapy. Opioids are increasingly being used to treat breathlessness, although their mechanism of action is still not completely known. A few good sized, high quality trials have been conducted in this area. OBJECTIVES: To determine the effectiveness of opioid drugs in relieving the symptom of breathlessness in people with advanced disease due to malignancy, respiratory or cardiovascular disease, or receiving palliative care for any other disease. SEARCH METHODS: We performed searches on CENTRAL, MEDLINE, EMBASE, CINAHL, and Web of Science up to 19 October 2015. We handsearched review articles, clinical trial registries, and reference lists of retrieved articles. SELECTION CRITERIA: We included randomised double-blind controlled trials that compared the use of any opioid drug against placebo or any other intervention for the relief of breathlessness. The intervention was any opioid, given by any route, in any dose. DATA COLLECTION AND ANALYSIS: We imported studies identified by the search into a reference manager database. We retrieved the full-text version of relevant studies, and two review authors independently extracted data. The primary outcome measure was breathlessness and secondary outcome measures included exercise tolerance, oxygen saturations, adverse events, and mortality. We analysed all studies together and also performed subgroup analyses, by route of administration, type of opioid administered, and cause of breathlessness. Where appropriate, we performed meta-analysis. We assessed the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach and created three 'Summary of findings' tables. MAIN RESULTS: We included 26 studies with 526 participants. We assessed the studies as being at high or unclear risk of bias overall. We only included randomised controlled trials (RCTs), although the description of randomisation was incomplete in some included studies. We aimed to include double blind RCTs, but two studies were only single blinded. There was inconsistency in the reporting of outcome measures. We analysed the data using a fixed-effect model, and for some outcomes heterogeneity was high. There was a risk of imprecise results due to the low numbers of participants in the included studies. For these reasons we downgraded the quality of the evidence from high to either low or very low.For the primary outcome of breathlessness, the mean change from baseline dyspnoea score was 0.09 points better in the opioids group compared to the placebo group (ranging from a 0.36 point reduction to a 0.19 point increase) (seven RCTs, 117 participants, very low quality evidence). A lower score indicates an improvement in breathlessness. The mean post-treatment dyspnoea score was 0.28 points better in the opioid group compared to the placebo group (ranging from a 0.5 point reduction to a 0.05 point increase) (11 RCTs, 159 participants, low quality evidence).The evidence for the six-minute walk test (6MWT) was conflicting. The total distance in 6MWT was 28 metres (m) better in the opioids group compared to placebo (ranging from 113 m to 58 m) (one RCT, 11 participants, very low quality evidence). However, the change in baseline was 48 m worse in the opioids group (ranging from 36 m to 60 m) (two RCTs, 26 participants, very low quality evidence).The adverse effects reported included drowsiness, nausea and vomiting, and constipation. In those studies, participants were 4.73 times more likely to experience nausea and vomiting compared to placebo, three times more likely to experience constipation, and 2.86 times more likely to experience drowsiness (nine studies, 162 participants, very low quality evidence).Only four studies assessed quality of life, and none demonstrated any significant change. AUTHORS' CONCLUSIONS: There is some low quality evidence that shows benefit for the use of oral or parenteral opioids to palliate breathlessness, although the number of included participants was small. We found no evidence to support the use of nebulised opioids. Further research with larger numbers of participants, using standardised protocols and with quality of life measures included, is needed.

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Research works printed but not linked: 10

  1. Chahl 1996 Chahl LA. Opioids -mechanisms of action. Australian Prescriber 1996;19:63-5.
  2. Fitzgerald RS, Lahiri S. Reflex response to chemoreceptor stimulation. In: Cherniack NS, Widdicombe JG editor(s). Handbook of Physiology, Section 3: The Respiratory System, Vol. 2. Control of Breathing. Bethesda: American Physiological Society, 1986:313-62.
  3. Mahler DA. Opioids for refractory dyspnoea. Expert Review of Respiratory Medicine 2013;7(2):123-35.
  4. Nattie E. Central chemoreceptors. In: Dempsey JA, Pack AL editor(s). Regulation of Breathing. 2nd Edition. New York: Marcel Dekker, 1995:473-510.
  5. Johnson MJ, Bland JM, Oxberry SG, Abernethy AP, Currow DC. Clinically important differences in the intensity of chronic refractory breathlessness. Journal of Pain and Symptom Management. 2013 Dec;46(6):957-63.
  6. Johnson M, Hui D, Currow D. Opioids, Exertion, and Dyspnea: A Review of the Evidence. American Journal of Hospice and Palliative Medicine 2016;33(2):194-200.
  7. 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 (20 participants) · DOI
  8. Janowiak P, Krajnik M, Podolec Z, Bandurski T, Damps-Konstańska I, Sobański P, Currow DC, Jassem E. Dosimetrically administered nebulized morphine for breathlessness in very severe chronic obstructive pulmonary disease: a randomized, controlled trial. BMC Pulm Med. 2017 Dec 11;17(1):186 (10 participants
  9. Currow D, Watts GJ, Johnson M, McDonald CF, Miners JO, Somogyi AA, Denehy L, McCaffrey N, Eckert DJ, McCloud P, Louw S, Lam L, Greene A, Fazekas B, Clark KC, Fong K, Agar MR, Joshi R, Kilbreath S, Ferreira D, Ekström M; Australian national Palliative Care Clinical Studies Collaborative (PaCCSC). A pragmatic, phase III, multisite, double-blind, placebo-controlled, parallel-arm, dose increment randomised trial of regular, low-dose extended-release morphine for chronic breathlessness: Breathlessness, Exertion And Morphine Sulfate (BEAMS) study protocol. BMJ Open. 2017 Jul 17;7(7):e018100 (aim: 171 participants)
  10. Verberkt CA, van den Beuken-van Everdingen MH, Franssen FM, Dirksen CD, Schols JM, Wouters EF, Janssen DJ. A randomized controlled trial on the benefits and respiratory adverse effects of morphine for refractory dyspnea in patients with COPD: Protocol of the MORDYC study. Contemp Clin Trials. 2016 Mar;47:228-34 (aim: 124 participants)

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Authors
Barnes, H., McDonald, J., Smallwood, N., & Manser, R.
Affiliations
  • The Alfred Hospital (AU)
  • University Health Network (CA)
  • The Royal Melbourne Hospital (AU)
  • and Department of Respiratory Medicine, Royal Melbourne Hospital; Department of Haematology and Medical Oncology, Peter MacCallum Cancer Institute, St Andrew's Place, East Melbourne 3002, Victoria; 305 Grattan Street Melbourne Australia 3000
ORCID
Venue
Cochrane Database of Systematic Reviews
Publisher
Wiley
Published
2016-03-31
Volume
2019
Issue
7
Pages
CD011008-CD011008
ISSN
  • 1361-6137 (ISSN-L)
  • 1465-1858
DOI
10.1002/14651858.cd011008.pub2
PMC
PMC6485401
OpenAlex
W1598113675
Cited by
280
References
86
Citations by year
2026: 8 · 2025: 17 · 2024: 19 · 2023: 26 · 2022: 24 · 2021: 43 · 2020: 31 · 2019: 31 · 2018: 31 · 2017: 37 · 2016: 10 · 2014: 2 · 2012: 1
FWCI
6.80
Type
journal article
Language
en
Open access
Locations
  • Cochrane Database of Systematic Reviews (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institute for Health and Care Research
  • Evidence Synthesis Programme
Topics
  • Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Opioid Use
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Palliative Care and End-of-Life Issues
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Palliative and Oncologic Care
Keywords
opioids, dyspnea, palliative care, advanced disease, terminal illness, cancer, cardiopulmonary disease, symptom management, route of administration, exercise tolerance, oxygen saturation, adverse events, mortality, opioid analgesics, opioid agonists, opioid antagonists, opioid side effects, opioid use disorder, opioid withdrawal
MeSH terms
Adult, Analgesics, Opioid, Dyspnea, Humans, Morphine, Palliative Care, Quality of Life, Terminal Care, Time Factors, Randomized Controlled Trials as Topic, Walking, Exercise Tolerance

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