Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Meta-Analysis
. 2016 Oct 20;10(10):CD007354.
doi: 10.1002/14651858.CD007354.pub3.

Benzodiazepines for the relief of breathlessness in advanced malignant and non-malignant diseases in adults

Steffen T Simon  1 , Irene J Higginson, Sara Booth, Richard Harding, Vera Weingärtner, Claudia Bausewein
Affiliations
Meta-Analysis

Benzodiazepines for the relief of breathlessness in advanced malignant and non-malignant diseases in adults

Steffen T Simon et al. Cochrane Database Syst Rev. .

Abstract

Background: This is an updated version of the original Cochrane review published in Issue 1, 2010, on 'Benzodiazepines for the relief of breathlessness in advanced malignant and non-malignant diseases in adults'. Breathlessness is one of the most common symptoms experienced in the advanced stages of malignant and non-malignant disease. Benzodiazepines are widely used for the relief of breathlessness in advanced diseases and are regularly recommended in the literature. At the time of the previously published Cochrane review, there was no evidence for a beneficial effect of benzodiazepines for the relief of breathlessness in people with advanced cancer and chronic obstructive pulmonary disease (COPD).

Objectives: The primary objective of this review was to determine the efficacy of benzodiazepines for the relief of breathlessness in people with advanced disease. Secondary objectives were to determine the efficacy of different benzodiazepines, different doses of benzodiazepines, different routes of application, adverse effects of benzodiazepines, and the efficacy in different disease groups.

Search methods: This is an update of a review published in 2010. We searched 14 electronic databases up to September 2009 for the original review. We checked the reference lists of all relevant studies, key textbooks, reviews, and websites. For the update, we searched CENTRAL, MEDLINE, and EMBASE and registers of clinical trials for further ongoing or unpublished studies, up to August 2016. We contacted study investigators and experts in the field of palliative care asking for further studies, unpublished data, or study details when necessary.

Selection criteria: We included randomised controlled trials (RCTs) and controlled clinical trials (CCTs) assessing the effect of benzodiazepines compared with placebo or active control in relieving breathlessness in people with advanced stages of cancer, chronic obstructive pulmonary disease (COPD), chronic heart failure (CHF), motor neurone disease (MND), and idiopathic pulmonary fibrosis (IPF).

Data collection and analysis: Two review authors independently assessed identified titles and abstracts. Three review authors independently performed assessment of all potentially relevant studies (full text), data extraction, and assessment of methodological quality. We carried out meta-analysis where appropriate.

Main results: Overall, we identified eight studies for inclusion: seven in the previous review and an additional study for this update. We also identified two studies awaiting classification in this update. The studies were small (a maximum number of 101 participants) and comprised data from a total of 214 participants with advanced cancer or COPD, which we analysed. There was only one study of low risk of bias. Most of the studies had an unclear risk of bias due to lack of information on random sequence generation, concealment, and attrition. Analysis of all studies did not show a beneficial effect of benzodiazepines for the relief of breathlessness (the primary outcome) in people with advanced cancer and COPD (8 studies, 214 participants) compared to placebo, midazolam, morphine, or promethazine. Furthermore, we observed no statistically significant effect in the prevention of episodic breathlessness (breakthrough dyspnoea) in people with cancer (after 48 hours: risk ratio of 0.76 (95% CI 0.53 to 1.09; 2 studies, 108 participants)) compared to morphine. Sensitivity analyses demonstrated no statistically significant differences regarding type of benzodiazepine, dose, route and frequency of delivery, duration of treatment, or type of control. Benzodiazepines caused statistically significantly more adverse events, particularly drowsiness and somnolence, when compared to placebo (risk difference 0.74 (95% CI 0.37, 1.11); 3 studies, 38 participants). In contrast, two studies reported that morphine caused more adverse events than midazolam (RD -0.18 (95% CI -0.31, -0.04); 194 participants).

Authors' conclusions: Since the last version of this review, we have identified one new study for inclusion, but the conclusions remain unchanged. There is no evidence for or against benzodiazepines for the relief of breathlessness in people with advanced cancer and COPD. Benzodiazepines caused more drowsiness as an adverse effect compared to placebo, but less compared to morphine. Benzodiazepines may be considered as a second- or third-line treatment, when opioids and non-pharmacological measures have failed to control breathlessness. There is a need for well-conducted and adequately powered studies.

PubMed Disclaimer

Conflict of interest statement

STS: none known. STS is a specialist in palliative care and works as a physician caring for patients with life‐limiting diseases.

IJH: none known. IJH is a specialist in palliative care and works as a researcher and physician caring for patients with life‐limiting diseases.

SB: none known. SB worked as a specialist in palliative care and and now supports patients with chronic illness.

RH: none known. RH is a reader in palliative care and works as a researcher in palliative care with focus on HIV/AIDS, Sub‐Saharan Africa and Global Health.

VW received reimbursement of travel costs from Teva Pharmaceutical Industries Ltd. for the 8th World Research Congress of the European Association of Palliative Care (Lleida, Spain, 2014) outside the submitted work. VW is a health economist with experience in research in palliative care (2011‐2015) and works as a research associate at an institute of quality and efficiency in health care (since 2015).

CB: none known. CB is a specialist in palliative care and works as a physician caring for patients with life‐limiting diseases.

Figures

1
1
Study flow diagram.
2
2
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
3
3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
4
4
Forest plot of comparison: 1 Overall, outcome: 1.1 Placebo‐controlled/cross‐over design.
5
5
Forest plot of comparison: 1 Overall, outcome: 1.2 Morphine‐controlled/parallel design.
6
6
Forest plot of comparison: 5 Secondary outcomes, outcome: 5.1 Adverse effects (placebo‐controlled).
1.1
1.1. Analysis
Comparison 1 Overall, Outcome 1 Placebo‐controlled/cross‐over design.
1.2
1.2. Analysis
Comparison 1 Overall, Outcome 2 Morphine‐controlled/parallel design.
2.1
2.1. Analysis
Comparison 2 Disease, Outcome 1 COPD.
2.2
2.2. Analysis
Comparison 2 Disease, Outcome 2 Cancer ‐ placebo‐controlled.
2.3
2.3. Analysis
Comparison 2 Disease, Outcome 3 Cancer ‐ morphine‐controlled.
3.1
3.1. Analysis
Comparison 3 Intervention, Outcome 1 Benzodiazepines ‐ alprazolam.
3.2
3.2. Analysis
Comparison 3 Intervention, Outcome 2 Benzodiazepines ‐ diazepam.
3.3
3.3. Analysis
Comparison 3 Intervention, Outcome 3 Benzodiazepines ‐ midazolam.
3.4
3.4. Analysis
Comparison 3 Intervention, Outcome 4 Benzodiazepines ‐ temazepam.
3.5
3.5. Analysis
Comparison 3 Intervention, Outcome 5 Benzodiazepines ‐ ultra short‐acting.
3.6
3.6. Analysis
Comparison 3 Intervention, Outcome 6 Benzodiazepines ‐ intermediate‐acting.
3.7
3.7. Analysis
Comparison 3 Intervention, Outcome 7 Benzodiazepines ‐ long‐acting.
3.8
3.8. Analysis
Comparison 3 Intervention, Outcome 8 Benzodiazepines ‐ short duration of treatment (≦ 24 hours).
3.9
3.9. Analysis
Comparison 3 Intervention, Outcome 9 Benzodiazepines ‐ long duration of treatment (5 to 14 days).
3.10
3.10. Analysis
Comparison 3 Intervention, Outcome 10 Benzodiazepines ‐ morphine + midazolam‐controlled.
3.11
3.11. Analysis
Comparison 3 Intervention, Outcome 11 Benzodiazepines ‐ promethazine‐controlled.
4.1
4.1. Analysis
Comparison 4 Primary outcome, Outcome 1 Breathlessness ‐ no relief (placebo‐controlled).
4.2
4.2. Analysis
Comparison 4 Primary outcome, Outcome 2 Breathlessness ‐ no relief (morphine‐controlled).
4.3
4.3. Analysis
Comparison 4 Primary outcome, Outcome 3 Breathlessness ‐ episodic after 48 hours.
4.4
4.4. Analysis
Comparison 4 Primary outcome, Outcome 4 Breathlessness ‐ episodic after 24 hours.
5.1
5.1. Analysis
Comparison 5 Secondary outcomes, Outcome 1 Adverse effects (placebo‐controlled).
5.2
5.2. Analysis
Comparison 5 Secondary outcomes, Outcome 2 Adverse effects (morphine‐controlled).
5.3
5.3. Analysis
Comparison 5 Secondary outcomes, Outcome 3 Adverse effects ‐ clinical relevance only (morphine‐controlled).
5.4
5.4. Analysis
Comparison 5 Secondary outcomes, Outcome 4 Adverse effects ‐ drowsiness and somnolence only (placebo‐controlled).
5.5
5.5. Analysis
Comparison 5 Secondary outcomes, Outcome 5 Adverse effects ‐ drowsiness and somnolence only (morphine‐controlled).
5.6
5.6. Analysis
Comparison 5 Secondary outcomes, Outcome 6 Attrition (placebo‐controlled).
5.7
5.7. Analysis
Comparison 5 Secondary outcomes, Outcome 7 Attrition (morphine‐controlled).
5.8
5.8. Analysis
Comparison 5 Secondary outcomes, Outcome 8 Deaths (placebo‐controlled).
5.9
5.9. Analysis
Comparison 5 Secondary outcomes, Outcome 9 Deaths (morphine‐controlled).
See this image and copyright information in PMC

Update of

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

References to studies included in this review

Eimer 1985 {published data only}
    1. Eimer M, Cable T, Gal P, Rothenberg LA, McCue JD. Effects of clorazepate on breathlessness and exercise tolerance in patients with chronic airflow obstruction. Journal of Family Practice 1985;21:359‐62. - PubMed
Harrison (unpublished) {unpublished data only}
    1. Harrison TJR. A comparison of the effectiveness of oral lorazepam and placebo in relieving breathlessness associated with advanced cancer. (MSc thesis, 2004).
Man 1986 {published data only}
    1. Man GCW, Hsu K, Sproule BJ. Effect of alprazolam on exercise and dyspnea in patients with chronic obstructive pulmonary disease. Chest 1986;90:832‐6. - PubMed
Navigante 2006 {published data only}
    1. Navigante AH, Cerchietti LC, Castro MA, Lutteral MA, Cabalar ME. Midazolam as adjunct therapy to morphine in the alleviation of severe dyspnea perception in patients with advanced cancer. Journal of Pain and Symptom Management 2006;31:38‐47. - PubMed
Navigante 2010 {published and unpublished data}
    1. Navigante AH, Castro MA, Cerchietti LC. Morphine versus midazolam as upfront therapy to control dyspnea perception in cancer patients while its underlying cause is sought or treated. Journal of Pain and Symptom Management 2010;39(5):820‐30. - PubMed
Shivaram 1989 {published data only}
    1. Shivaram U, Cash M, Finch P. Effects of alprazolam on gas exchange, breathing pattern, and lung function in COPD patients with anxiety. Respiratory Care 1989;34:196‐200.
Stege 2010 {published data only}
    1. Stege G, Heijdra YF, Elshout FJ, Ven MJ, Bruijn PJ, Sorge AA, et al. Temazepam 10 mg does not affect breathing and gas exchange in patients with severe normocapnic COPD. Respiratory Medicine 2010;104(4):518‐24. - PubMed
Woodcock 1981 {published data only}
    1. Woodcock AA, Gross ER, Geddes DM. Drug treatment of breathlessness: contrasting effects of diazepam and promethazine in pink puffers. British Medical Journal 1981;283:343‐6. - PMC - PubMed

References to studies excluded from this review

Allcroft 2013 {published data only}
    1. Allcroft P, Margitanovic V, Greene A, Agar MR, Clark K, Abernethy AP, et al. The role of benzodiazepines in breathlessness: a single site, open label pilot of sustained release morphine together with clonazepam. Journal of Palliative Medicine 2013;16(7):741‐4. [PUBMED: 23597092] - PubMed
Allen 1984 {published data only}
    1. Allen SC. Treatment of dyspnoea: the role of drugs. Drugs of Today 1984;8:397‐403.
Anonymous 1980a {published data only}
    1. Anonymous (Lancet). Diazepam and breathlessness. Lancet 1980;2:242‐3. - PubMed
Anonymous 1980b {published data only}
    1. Anonymous (British Medical Journal). Centrally acting drugs in chronic airways obstruction. British Medical Journal 1980;281:1232‐3. - PMC - PubMed
Appel 1989 {published data only}
    1. Appel M, Bron HN, Hooymans PM, Janknegt R. Efficacy of flumazenil in COPD patient with therapeutic diazepam levels. The Lancet 1989;1:392. - PubMed
Argyropoulou 1993 {published data only}
    1. Argyropoulou P, Patakas D, Koukou A, Vasiliadis P, Georgopoulos D. Buspirone effect on breathlessness and exercise performance in patients with chronic obstructive pulmonary disease. Respiration 1993;60:216‐20. - PubMed
Bar‐Or 1982 {published data only}
    1. Bar‐Or D, Marx JA, Good J. Breathlessness, alcohol, and opiates. The New England Journal of Medicine 1982;306(22):1363‐4. - PubMed
Beaupre 1988 {published data only}
    1. Beaupre A, Soucy R, Phillips R, Bourgouin J. Respiratory center output following zopiclone or diazepam administration in patients with pulmonary disease. Respiration 1988;54(4):235‐40. - PubMed
Borson 1992 {published data only}
    1. Borson S, McDonald GJ, Gayle T, Deffebach M, Lakshminarayan S, VanTuinen C. Improvement in mood, physical symptoms, and function with nortriptyline for depression in patients with chronic obstructive pulmonary disease. Psychosomatics 1992;33(2):190‐201. - PubMed
Bottomley 1990 {published data only}
    1. Bottomley DM, Hanks GW. Subcutaneous midazolam infusion in palliative care. Journal of Pain and Symptom Management 1990;5:259‐61. - PubMed
Boyden 2015 {published data only}
    1. Boyden JY, Connor SR, Otolorin L, Nathan SD, Fine PG, Davis MS, et al. Nebulized medications for the treatment of dyspnea: A literature review. Journal of Aerosol Medicine and Pulmonary Drug Delivery 2015; Vol. 28, issue 1:1‐19. [1941‐2711] - PubMed
Catchlove 1971a {published data only}
    1. Catchlove RF, Kafer ER. The effects of diazepam on the ventilatory response to carbon dioxide and on steady‐state gas exchange. Anesthesiology 1971;34(1):9‐13. - PubMed
Catchlove 1971b {published data only}
    1. Catchlove RF, Kafer ER. The effects of diazepam on respiration in patients with obstructive pulmonary disease. Anesthesiology 1971;34(1):14‐8. - PubMed
Cherny 2014 {published data only}
    1. Cherny NI. ESMO clinical practice guidelines for the management of refractory symptoms at the end of life and the use of palliative sedation. Annals of Oncology 2014; Vol. 25:iii143‐52. [0923‐7534] - PubMed
Clark 1971 {published data only}
    1. Clark TJH. Respiratory depression caused by nitrazepam in patients with respiratory failure. The Lancet 1971;2:737‐8. - PubMed
Clemens 2011 {published data only}
    1. Clemens KE, Klaschik E. Dyspnoea associated with anxiety ‐ symptomatic therapy with opioids in combination with lorazepam and its effect on ventilation in palliative care patients. Supportive Care in Cancer 2011; Vol. 19, issue 12:2027‐33. [1433‐7339] - PubMed
Cohn 1992 {published data only}
    1. Cohn MA, Morris DD, Juan D. Effects of estazolam and flurazepam on cardiopulmonary function in patients with chronic obstructive pulmonary disease. Drug Safety 1992;7(2):152‐8. - PubMed
Daubert 2014 {published data only}
    1. Daubert E, Bolesta S. Effect of lorazepam versus morphine on quality of life in hospice patients with dyspnea and anxiety. Journal of the American Pharmacists Association 2014, issue 2:e193.
Denaut 1974 {published data only}
    1. Denaut M, Yernault JC, De CA. Double‐blind comparison of the respiratory effects of parenteral lorazepam and diazepam in patients with chronic obstructive lung disease. Current Medical Research and Opinion 1974;2:611‐5. - PubMed
De Sousa 1988 {published data only}
    1. Sousa E, Jepson BA. Midazolam in terminal care. The Lancet 1988;331:67‐8. - PubMed
Dolly 1982 {published data only}
    1. Dolly FR, Block AJ. Effect of flurazepam on sleep‐disordered breathing and nocturnal oxygen desaturation in asymptomatic subjects. American Journal of Medicine 1982;73(2):239‐43. - PubMed
Dowson 2004 {published data only}
    1. Dowson CA, Kuijer RG, Mulder RT. Anxiety and self‐management behaviour in chronic obstructive pulmonary disease: what has been learned?. Chronic Respiratory Disease 2004;1(4):213‐20. - PubMed
Ekstrom 2015 {published data only}
    1. Ekstrom MP, Abernethy AP, Currow DC. The management of chronic breathlessness in patients with advanced and terminal illness. BMJ (Online) 2015; Vol. 349, issue g7617. [0959‐8146] - PubMed
Fonsmark 2015 {published data only}
    1. Fonsmark L, Hein L, Nibroe H, Bundgaard H, Haas I, Iversen S, et al. Danish national sedation strategy. Targeted therapy of discomfort associated with critical illness. Danish Society of Intensive Care Medicine (DSIT) and the Danish Society of Anesthesiology and Intensive Care Medicine (DASAIM). Danish Medical Journal 2015; Vol. 62, issue 4:1‐5. - PubMed
Forster 1983 {published data only}
    1. Forster A, Morel D, Bachmann M, Gemperle M. Respiratory depressant effects of different doses of midazolam and lack of reversal with naloxone: a double‐blind randomized study. Anesthesia Analgesia 1983;62:920‐4. - PubMed
Gaddie 1972 {published data only}
    1. Gaddie J, Legge JS, Palmer KNV, Petrie JC, Wood RA. Effect of nitrazepam in chronic obstructive bronchitis. British Medical Journal 1972;2:688‐9. - PMC - PubMed
Garrett 2015 {published data only}
    1. Garrett Key R. Psychiatric care of lung cancer patients. Oncology 2015; Vol. 29, issue 3. [0890‐9091] - PubMed
Geddes 1976 {published data only}
    1. Geddes DM, Rudolf M, Saunders KB. Effect of nitrazepam and flurazepam on the ventilatory response to carbon dioxide. Thorax 1976;31:548‐51. - PMC - PubMed
Gomutbutra 2013 {published data only}
    1. Gomutbutra P, O'Riordan DL, Pantilat SZ. Management of moderate‐to‐severe dyspnea in hospitalized patients receiving palliative care. Journal of Pain and Symptom Management 2013; Vol. 45, issue 5:885‐91. [1873‐6513] - PubMed
Greene 1989 {published data only}
    1. Greene JG, Pucino F, Carlson JD, Storsved M. Effects of alprazolam on respiratory drive, anxiety, and dyspnea in chronic airflow obstruction: a case study. Pharmacotherapy 1989;9:34‐8. - PubMed
Guilleminault 1993 {published data only}
    1. Guilleminault C, Clerk A, Labanowski M, Simmons J, Stoohs R. Cardiac failure and benzodiazepines. Sleep 1993;16(6):524‐8. - PubMed
Guz 1980 {published data only}
    1. Guz A, Minty K, Adams L, Rosser R. Quantifying dyspnoea and the use of drugs to alleviate the symptom. Clinical Respiratory Physiology 1980;16:209.
Heinonen 1972 {published data only}
    1. Heinonen J, Muittari A. The effect of diazepam on airway resistance in asthmatics. Anaesthesia 1972;27:37‐40. - PubMed
Hoeijer 1994 {published data only}
    1. Hoeijer U, Hedner J, Ejnell H, Grunstein R, Odelberg E, Elam M. Nitrazepam in patients with sleep apnoea: a double‐blind placebo‐controlled study. European Respiratory Journal 1994;7(11):2011‐5. - PubMed
Horfarter 2006 {published data only}
    1. Horfarter B, Weixler D. Symptom control and ethics in final stages of COPD. Wiener Medizinische Wochenschrift 2006;156:275‐82. - PubMed
Hosaka 1996 {published data only}
    1. Hosaka M, Hoshimyama Y. Effects of diazepam on quality of life in patients receiving home oxygen therapy: a double‐blind, cross‐over, placebo‐controlled clinical trial [Japanese]. Journal of the Showa Medical Association 1996;5:522‐9.
Huttemann 1971 {published data only}
    1. Huttemann U, Kunkel G, Lode H, Hass E. The influence of laevomepromazine and prometazine on respiration in healthy subjects and patients with pulmonary emphysema. Arzneimittelforschung 1971;21(10):1594‐8. - PubMed
Johanson 1993 {published data only}
    1. Johanson GA. Midazolam in terminal care. American Journal of Hospice and Palliative Care 1993;10:13‐4. - PubMed
Jokinen 1984 {published data only}
    1. Jokinen K. Flupenthixol versus diazepam in the treatment of psychosomatic disorders: a double‐blind, multi‐centre trial in general practice. Pharmatherapeutica 1984;3(9):573‐81. - PubMed
Jolly 1996 {published data only}
    1. Jolly E, Aguirre L, Jorge E, Luna C. Acute effect of lorazepam on respiratory muscles in stable patients with chronic obstructive pulmonary disease. Medicina (B Aires) 1996;56:472‐8. - PubMed
Jones 1985 {published data only}
    1. Jones AL, Cameron IR. The effect of promethazine and diazepam on respiratory control in breathless patients (abstract). Clinical Science 1985;69:6.
Kaltsas 2014 {published data only}
    1. Kaltsas K, Anevlavis S, Bouros D. Safety of opioids and benzodiazepines in patients with breathlessness and respiratory failure associated with chronic obstructive pulmonary disease. Pneumon 2014; Vol. 27, issue 3:197‐9. [1105‐848X]
Kann 1968 {published data only}
    1. Kann J, Jokl H. On the therapy of asthmatic dyspnea. Medizinische Klinik 1968;63(45):1814‐8. - PubMed
Kronenberg 1975 {published data only}
    1. Kronenberg RS, Cosio MG, Stevenson JE, Drage CW. The use of oral diazepam in patients with obstructive lung disease and hypercapnia. Annals of Internal Medicine 1975;83(1):83‐4. - PubMed
Lakshminarayan 1976 {published data only}
    1. Lakshminarayan S, Sahn SA, Hudson LD, Weil JV. Effect of diazepam on ventilatory responses. Clinical Pharmacology and Therapeutics 1976;20(2):178‐83. - PubMed
Lareau 1999 {published data only}
    1. Lareau SC, Meek PM, Press D, Anholm JD, Roos PJ. Dyspnea in patients with chronic obstructive pulmonary disease: does dyspnea worsen longitudinally in the presence of declining lung function?. Heart & Lung 1999;28(1):65‐73. - PubMed
Laros 1982 {published data only}
    1. Laros CD, Bergstein PG. Relief of breathlessness in a case of progressive pulmonary fibrosis. Respiration 1982;43(6):452‐7. - PubMed
Lichterfeld 1967 {published data only}
    1. Lichterfeld A. Controlled therapeutic comparison of antiasthmatics in out‐patients in a double‐blind experiment. Arzneimittel‐Forschung 1967;17:1318‐21. - PubMed
Light 1996 {published data only}
    1. Light RW, Stansbury DW, Webster JS. Effect of 30 mg of morphine alone or with promethazine or prochlorperazine on the exercise capacity of patients with COPD. Chest 1996;109(4):975‐81. - PubMed
Marin 1987 {published data only}
    1. Marin I, Andrieu J‐M, Chretien J. Bronchopulmonary carcinoma: a medical approach to the last weeks of life; a study of 191 cases. Annales de Medecine Interne 1987;138(2):90‐5. - PubMed
McIver 1994 {published data only}
    1. McIver B, Walsh D, Nelson K. The use of chlorpromazine for symptom control in dying cancer patients. Journal of Pain and Symptom Management 1994;9(5):341‐5. - PubMed
Mitchell‐Heggs 1980a {published data only}
    1. Mitchell‐Heggs P, Murphy K, Minty K, Guz A, Patterson SC, Minty PS, et al. Diazepam in the treatment of dyspnoea in the 'Pink Puffer' syndrome. Quarterly Journal of Medicine 1980;49:9‐20. - PubMed
Mitchell‐Heggs 1980b {published data only}
    1. Mitchell‐Heggs P, Guz A. Dyspnoea in 'pink puffers': the place of diazepam. British Journal of Diseases of the Chest 1980;74(4):418.
Mouzi 2014 {published data only}
    1. Mouzi L, Ashutosh W. Anesthetic management during labor and delivery of a multiparous patient terminally ill with metastatic breast cancer. A&A Case Reports 2014; Vol. 2, issue 4:48‐9. - PubMed
Murciano 1990 {published data only}
    1. Murciano D, Aubier M, Palacios S, Pariente R. Comparison of zolpidem (Z), triazolam (T), and flunitrazepam (F) effects on arterial blood gases and control of breathing in patients with severe chronic obstructive pulmonary disease (COPD) (abstract). Chest 1990;97:51S‐2S. - PubMed
Murciano 1993 {published data only}
    1. Murciano D, Armengaud MH, Cramer PH, Neveux E, L'Heritier C, Pariente R, et al. Acute effects of zolpidem, triazolam and flunitrazepam on arterial blood gases and control of breathing in severe COPD. European Respiratory Journal 1993;6:625‐9. - PubMed
Navigante 1997 {published data only}
    1. Navigante AH, Sauri A, Palazzo F, Coppola M, De CO, Kirchuk R, et al. Compared and randomized prospective trial between oxygenotherapy vs. morphine chlorhydrate + midazolam by subcutaneous route in patients with advanced cancer and dyspnea. Prensa Medica Argentina 1997;84:474‐6.
Navigante 2003 {published data only}
    1. Navigante AH, Cerchietti LCA, Cabalar ME. Morphine plus midazolam versus oxygen therapy on severe dyspnea management in the last week of life in hipoxemic advanced cancer patients. Medicina Paliativa 2003;10:14‐9.
NCT01687751 {unpublished data only}
    1. NCT01687751. Pilot study comparing treatment with dexmedetomidine to midazolam for symptom control in advanced cancer patients. clinicaltrials.gov/show/NCT01687751.
Nordt 1997 {published data only}
    1. Nordt SP, Clark RF. Midazolam: a review of therapeutic uses and toxicity. Journal of Emergency Medicine 1997;15(3):357‐65. - PubMed
O'Donnell 1992 {published data only}
    1. O'Donnell DE, Webb KA. Breathlessness in patients with severe chronic airflow limitation. Physiologic correlations. Chest 1992;102(3):824‐31. - PubMed
O'Donnell 1994 {published data only}
    1. O'Donnell DE. Breathlessness in patients with chronic airflow limitation. Mechanisms and management. Chest 1994;106(3):904‐12. - PubMed
O'Donnell 1998 {published data only}
    1. O'Donnell DE. Dyspnea in advanced chronic obstructive pulmonary disease. Journal of Heart & Lung Transplantation 1998;17(6):544‐54. - PubMed
O'Neill 1985 {published data only}
    1. O'Neill PA, Morton PB, Stark RD. Chlorpromazine ‐ a specific effect on breathlessness?. British Journal of Clinical Pharmacology 1985;19:793‐7. - PMC - PubMed
Rao 1973 {published data only}
    1. Rao S, Sherbaniuk RW, Prasad K, Lee SJ, Sproule BJ. Cardiopulmonary effects of diazepam. Clinical Pharmacology & Therapeutics 1973;14(2):182‐9. - PubMed
Rapoport 1991 {published data only}
    1. Rapoport DM, Greenberg HE, Goldring RM. Differing effects of the anxiolytic agents buspirone and diazepam on control of breathing. Clinical Pharmacology and Therapeutics 1991;49:394‐401. - PubMed
Rice 1986 {published data only}
    1. Rice KL. Treatment of dyspnea with psychotropic agents. Chest 1986;90:789‐90. - PubMed
Rice 1987 {published data only}
    1. Rice KL, Kronenberg RS, Hedemark LL, Niewoehner DE. Effects of chronic administration of codeine and promethazine on breathlessness and exercise tolerance in patients with chronic airflow obstruction. British Journal of Disease of the Chest 1987;81(3):287‐92. - PubMed
Rodriguez‐Roisin 2014 {published data only}
    1. Rodriguez‐Roisin R, Garcia‐Aymerich J. Should we exercise caution with benzodiazepine use in patients with COPD?. European Respiratory Journal 2014; Vol. 44, issue 2:284‐6. [0903‐1936] - PubMed
Rose 2002 {published data only}
    1. Rose C, Wallace L, Dickson R, Ayres J, Lehman R, Searle Y. The most effective psychologically‐based treatments to reduce anxiety and panic in patients with chronic obstructive pulmonary disease (COPD): a systematic review. Patient Education Counseling 2002;47(4):311‐8. - PubMed
Rudolf 1978 {published data only}
    1. Rudolf M. Depression of central respiratory drive by nitrazepam. Thorax 1978;33:97‐100. - PMC - PubMed
Runo 2001 {published data only}
    1. Runo JR, Ely EW. Treating dyspnea in a patient with advanced chronic obstructive pulmonary disease. Western Journal of Medicine 2001;175(3):197‐201. - PMC - PubMed
Schultze‐Werninghaus 2007 {published data only}
    1. Schultze‐Werninghaus G, Steinkamp G, Gillissen A, Pfeifer M, Lorenz J, Worth H, et al. The critically ill patient with COPD. Pneumologie 2007;61(6):410‐9. - PubMed
Sen 1983 {published data only}
    1. Sen D, Jones G, Leggat PO. The response of the breathless patient treated with diazepam. British Journal of Clinical Practice 1983;37:232‐3. - PubMed
Singh 1993 {published data only}
    1. Singh NP, Despars JA, Stansbury DW, Avalos K, Light RW. Effects of buspirone on anxiety levels and exercise tolerance in patients with chronic airflow obstruction and mild anxiety. Chest 1993;103(3):800‐4. - PubMed
Smith 2015 {published data only}
    1. Smith TJ. Symptom management in the older adult. 2015 Update. Clinics in Geriatric Medicine 2015; Vol. 31, issue 2:155‐75. [0749‐0690] - PMC - PubMed
Stark 1981a {published data only}
    1. Stark RD, Gambles SA. Does diazepam reduce breathlessness in healthy subjects? (abstract). British Journal of Clinical Pharmacology 1982;13:600.
Stark 1981b {published data only}
    1. Stark RD, Gambles SA, Lewis JA. Methods to assess breathlessness in healthy subjects: a critical evaluation and application to analyse the acute effects of diazepam and promethazine on breathlessness induced by exercise or by exposure to raised levels of carbon dioxide. Clinical Science 1981;61:429‐39. - PubMed
Stark 1983 {published data only}
    1. Stark RD, O'Neill PA. Dihydrocodeine for breathlessness in pink puffers. British Journal of Medicine 1983;286:1280‐1. - PMC - PubMed
Stark 1988 {published data only}
    1. Stark RD. Dyspnoea: Assessment and pharmacological manipulation. European Respiratory Journal 1988;1(3):280‐7. - PubMed
Steens 1993 {published data only}
    1. Steens RD, Pouliot Z, Millar TW, Kryger MH, George CF. Effects of zolpidem and triazolam on sleep and respiration in mild to moderate chronic obstructive pulmonary disease. Sleep 1993;16:318‐26. - PubMed
Tenorio 2012 {published data only}
    1. Tenorio Carmona B, Ramirez Rodriguez G, Rangel Selvera OA, Ales Siles I, Sanchez Del Corral Usaola F, Ruiperez Cantera I. Associated symptoms to terminality in elderly patient and the necessity of subcutaneous application at the home care assistance. European Geriatric Medicine 2012; Vol. 3:S47. [1878‐7649]
Timms 1988 {published data only}
    1. Timms RM, Dawson A, Hajdukovic RM, Mitler MM. Effect of triazolam on sleep and arterial oxygen saturation in patients with chronic obstructive pulmonary disease. Archives of Internal Medicine 1988;148:2159‐63. - PubMed
Vozoris 2013 {published data only}
    1. Vozoris NT, Fischer HD, Wang X, Anderson GM, Bell CM, Gershon AS, et al. Benzodiazepine use among older adults with chronic obstructive pulmonary disease: a population‐based cohort study. Drugs & Aging 2013; Vol. 30, issue 3:183‐92. [1170‐229X] - PubMed
Walsh 1993 {published data only}
    1. Walsh D. Dyspnoea in advanced cancer. The Lancet 1993;342:450‐1. - PubMed
Wanrooij 2005 {published data only}
    1. Wanrooij B, Koelewijn M. Dyspnea relief in the palliative phase. Huisarts en Wetenschap 2005;48(5):239‐45.
Wiedemann 1995 {published data only}
    1. Wiedemann K, Diestelhorst C. The effect of sedation on pulmonary function. Anaesthetist 1995;44:588‐93. - PubMed
Wilson 1954 {published data only}
    1. Wilson RH, Hoseth W, Dempsey ME. Respiratory acidosis. I. Effects of decreasing respiratory minute volume in patients with severe chronic pulmonary emphysema, with specific reference to oxygen, morphine and barbiturates. American Journal of Medicine 1954;17(4):464‐70. - PubMed
Woodcock 1981a {published data only}
    1. Woodcock AA, Gross ER, Gellert A, Shah S, Johnson M, Geddes DM. Effects of dihydrocodeine, alcohol, and caffeine on breathlessness and exercise tolerance in patients with chronic obstructive lung disease and normal blood gases. The New England Journal of Medicine 1981;305(27):1611‐6. - PubMed
Woodcock 1981b {published data only}
    1. Woodcock AA, Gross ER, Geddes DM. Oxygen relieves breathlessness in "pink puffers". The Lancet 1981;317(8226):907‐9. - PubMed

References to studies awaiting assessment

Hardy 2016 {published data only}
    1. Hardy J, Randall C, Pinkerton E, Flatley C, Gibbons K, Allan S. A randomised, double‐blind controlled trial of intranasal midazolam for the palliation of dyspnoea in patients with life‐limiting disease. Support Care Cancer 2016;24:3069. [DOI: 10.1007/s00520-016-3125-2] - DOI - PubMed
Hart 2012 {published data only (unpublished sought but not used)}
    1. Hart DE, Corna NE, Horwood F, Maingay G. Randomised control trial of intranasal midazolam or oral lorazepam for the relief of dyspnoea in severe respiratory disease [Abstract]. American Journal of Respiratory and Critical Care Medicine 2012;185:A2953.

Additional references

Abernethy 2008
    1. Abernethy AP, Uronis HE, Wheeler JL, Currow DC. Pharmacological management of breathlessness in advanced disease. Progress in Palliative Care 2008;16(1):15‐20.
Altose 1985
    1. Altose MD. Assessment and management of breathlessness. Chest 1985;88:77S‐83S. - PubMed
Bausewein 2008
    1. Bausewein C, Booth S, Gysels M, Higginson IJ. Non‐pharmacological interventions for breathlessness in advanced stages of malignant and non‐malignant diseases. Cochrane Database of Systematic Reviews 2008, Issue 2. [DOI: 10.1002/14651858.CD005623.pub2] - DOI - PubMed
Beach 2006
    1. Beach D, Schwartzstein RM. The genesis of breathlessness ‐ what do we understand?. In: Booth S, Dudgeon D editor(s). Dyspnoea in Advanced Disease ‐ a Guide to Clinical Management. 1st Edition. Oxford: Oxford University Press, 2006:1‐18.
Booth 2006
    1. Booth S, Dudgeon D, editors. Dyspnoea in Advanced Disease ‐ a Guide to Clinical Management. 1st Edition. Oxford: Oxford University Press, 2006.
Booth 2008
    1. Booth S, Moosavi SH, Higginson IJ. The etiology and management of intractable breathlessness in patients with advanced cancer: a systematic review of pharmacological therapy. Nature Clinical Practice Oncology 2008;5:90‐100. - PubMed
Bruera 2006
    1. Bruera E, Higginson IJ, Robb SD, Gunten CF. Textbook of Palliative Medicine. 1st Edition. London: Hodder Arnold, 2006.
Cranston 2008
    1. Cranston JM, Crockett A, Currow D. Oxygen therapy for dyspnoea in adults. Cochrane Database of Systematic Reviews 2008, Issue 3. [DOI: 10.1002/14651858.CD004769.pub2] - DOI - PubMed
Currow 2010
    1. Currow DC, Smith J, Davidson PM, Newton PJ, Agar MR, Abernethy AP. Do the trajectories of dyspnea differ in prevalence and intensity by diagnosis at the end of life? A consecutive cohort study. Journal of Pain and Symptom Management 2010;39(4):680‐90. - PubMed
Davis 1997
    1. Davis CL. ABC of palliative care. BMJ 1997;315(7113):931‐4. - PMC - PubMed
Davis 2005
    1. Davis C. Drug therapies. In: Ahmedzai SH, Muers MF editor(s). Supportive Care in Respiratory Disease. 1st Edition. Oxford: Oxford University Press, 2005:147‐63.
De Conno 1991
    1. Conno F, Spoldi E, Caraceni A, Ventafridda V. Does pharmacological treatment affect the sensation of breathlessness in terminal cancer patients?. Palliative Medicine 1991;5:237‐43.
Dorman 2009
    1. Dorman S, Jolley C, Abernethy A, Currow D, Johnson M, Farquhar M, et al. Researching breathlessness in palliative care: consensus statement of the National Cancer Research Institute Palliative Care Breathlessness Subgroup. Palliative Medicine 2009;23(3):213‐27. - PubMed
Edwards 2001
    1. Edwards A, Elwyn G, Covey J, Matthews E, Pill R. Presenting risk information ‐ a review of the effects of "framing" and other manipulations on patient outcomes. Journal of Health Communication 2001;6(1):61‐82. [PUBMED: 11317424] - PubMed
Edwards 2003
    1. Edwards A, Unigwe S, Elwyn G, Hood K. Personalised risk communication for informed decision making about entering screening programs. Cochrane Database of Systematic Reviews 2003, Issue 4. [DOI: 10.1002/14651858.CD001865.pub2] - DOI - PubMed
Ekstrom 2014
    1. Ekstrom MP, Bornefalk‐Hermansson A, Abernethy AP, Currow DC. Safety of benzodiazepines and opioids in very severe respiratory disease: national prospective study. BMJ 2014;348:g445. - PMC - PubMed
Elbourne 2002
    1. Elbourne DR, Altman DG, Higgins JPT, Curtin F, Worthington HV, Vail A. Meta‐analyses involving cross‐over trials: methodological issues. International Journal of Epidemiology 2002;31:140‐9. - PubMed
GOLD 2007
    1. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management and prevention of COPD (2007). http://www.goldcopd.org (accessed 31 January 2008).
Hardman 2005
    1. Hardman JG, Limbird LE. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 11th Edition. New York: McGraw‐Hill, 2005.
Higgins 2011
    1. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions, The Cochrane Collaboration. Available from www.cochrane‐handbook.org Version 5.1.0 [updated March 2011].
Higginson 2004
    1. Higginson IJ, Addington‐Hall J. The epidemiology of death and symptoms. In: Doyle D, Hanks G, Cherny N, Calman K editor(s). Oxford Textbook of Palliative Medicine. 3rd Edition. Oxford: Oxford University Press, 2004:14‐24.
Jennings 2001
    1. Jennings AL, Davies AN, Higgins JP, Broadley K. Opioids for the palliation of breathlessness in terminal illness. Cochrane Database of Systematic Reviews 2001, Issue 4. [DOI: 10.1002/14651858.CD002066] - DOI - PubMed
Lanken 2008
    1. Lanken PN, Terry PB, Delisser HM, Fahy BF, Hansen‐Flaschen J, Heffner JE, et al. An official American Thoracic Society clinical policy statement: palliative care for patients with respiratory diseases and critical illnesses. Journal of Respiratory and Critical Care Medicine 2008;177(8):912‐27. - PubMed
Manning 1995
    1. Manning HL, Schwartzstein RM. Pathophysiology of dyspnea. The New England Journal of Medicine 1995;333:1547‐53. - PubMed
Manning 2000
    1. Manning HL. Dyspnea treatment. Respiratory Care 2000;45(11):1342‐50. - PubMed
Moens 2014
    1. Moens K, Higginson IJ, Harding R. Are there differences in the prevalence of palliative care‐related problems in people living with advanced cancer and eight non‐cancer conditions? A systematic review. Journal of Pain and Symptom Management 2014; Vol. 48, issue 4:660‐77. [PUBMED: 24801658] - PubMed
Neuman 2006
    1. Neuman A, Gunnbjornsdottir M, Tunsater A, Nystrom L, Franklin KA, Norrman E, et al. Dyspnea in relation to symptoms of anxiety and depression: a prospective population study. Respiratory Medicine 2006;100:1843‐9. - PubMed
Nordgren 2003
    1. Nordgren L, Sorensen S. Symptoms experienced in the last six months of life in patients with end‐stage heart failure. European Journal of Cardiovascular Nursing 2003;2:213‐7. - PubMed
Parshall 2012
    1. Parshall MB, Schwartzstein RM, Adams L, Banzett RB, Manning HL, Bourbeau J, et al. An Official American Thoracic Society Statement: Update on the Mechanisms, Assessment, and Management of Dyspnea. American Journal of Respiratory and Critical Care Medicine 2012;185(4):435‐52. - PMC - PubMed
RevMan 2008 [Computer program]
    1. The Nordic Cochrane Centre. The Cochrane Collaboration. Review Manager (RevMan). Version 5.0. Copenhagen: The Nordic Cochrane Centre. The Cochrane Collaboration, 2008.
RevMan 2014 [Computer program]
    1. The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.
Ripamonti 1999
    1. Ripamonti C. Management of dyspnea in advanced cancer patients. Supportive Care in Cancer 1999;7(4):233‐43. - PubMed
Rocker 2007
    1. Rocker GM, Sinuff T, Horton R, Hernandez P. Advanced chronic obstructive pulmonary disease: innovative approaches to palliation. Journal of Palliative Medicine 2007;10(3):783‐97. - PubMed
Seow 2011
    1. Seow H, Barbera L, Sutradhar R, Howell D, Dudgeon D, Atzema C, et al. Trajectory of performance status and symptom scores for patients with cancer during the last six months of life. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 2011;29(9):1151‐8. - PubMed
Simon 2012
    1. Simon ST, Higginson IJ, Benalia H, Gysels M, Murtagh FE, Spicer J, et al. Episodic and continuous breathlessness: a new categorization of breathlessness. Journal of Pain and Symptom Management 2012;45(6):1019‐29. - PubMed
Simon 2014
    1. Simon ST, Weingärtner V, Higginson IJ, Voltz R, Bausewein C. Definition, categorization, and terminology of episodic breathlessness: consensus by an International Delphi Survey. Journal of Pain and Symptom Management 2014;47(5):828‐38. - PubMed
Thomas 2002
    1. Thomas JR, Gunten CF. Clinical management of dyspnoea. The Lancet Oncology 2002;3(4):223‐8. - PubMed
Tobin 1990
    1. Tobin MJ. Dyspnoea. Archives of Internal Medicine 1990;150:1604‐13. - PubMed
Viola 2008
    1. Viola R, Kiteley C, Lloyd NS, Mackay JA, Wilson J, Wong RK, the Guideline Group. The management of dyspnea in cancer patients: a systematic review. Supportive Care Cancer 2008;16(4):329‐37. - PubMed
Williams 2006
    1. Williams CM. Dyspnea. Cancer Journal 2006;12(5):365‐73. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources