Simon, S.T., Higginson, I.J., Booth, S., Harding, R., Weingartner, V., & Bausewein, C. (2016). Benzodiazepines for the relief of breathlessness in advanced malignant and non-malignant diseases in adults. Cochrane Database of Systematic Reviews, 10, CD007354. 

DOI Link

Purpose

STUDY PURPOSE: To evaluate the effectiveness of benzodiazepines in relieving dyspnea in individuals with advanced disease; in addition, to compare the effectiveness of different benzodiazepines and different dosages, routes of administration, side effects, as well as a comparison of effectiveness in various diseases

TYPE OF STUDY: Meta-analysis and systematic review

Search Strategy

DATABASES USED: CENTRAL, MEDLINE, EMBASE used in update since 2010 and the following registers: ClinicalTrials.gov, metaRegister of Controlled Trials, WHO International Clinical Trials Registry Platform; 14 databases used in original review: the Cochrane Pain, Palliative and Supportive Care Trials Register, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, MEDLINE, EMBASE, CINAHL, PsycINFO, American College of Physicians Journal Club, Health Technology Assessment Database, NHS Economic Evaluation Database, Database of Halley Stewart Library, International Pharmaceutical Abstracts, Iowa Drug Information System
 
YEARS INCLUDED: Overall for all databases, 1,806 through September 2016 (PsycINFO includes data from the 1880s)
 
INCLUSION CRITERIA: Randomized, controlled trials and controlled clinical trials evaluating the comparison of benzodiazepines to placebo or active control in relief of dyspnea in individuals with advanced cancer, chronic obstructive pulmonary disease (COPD), heart failure (HF), motor neuron disease (MND), and idiopathic pulmonary fibrosis (IPF) in any setting (hospital or home) and participants on oxygen if used in both arms (intervention and control)
 
EXCLUSION CRITERIA: Acute or chronic asthma, pneumonia, or other potentially curable diseases

Literature Evaluated

TOTAL REFERENCES RETRIEVED: 2,010 articles were included in the review. The total N was 1,309, and 1,102 met inclusion criteria. Of these, 79 articles were reviewed in more detail, and 7 of these met the inclusion criteria. In the 2016 updated review 1,884 records were retrieved (2009–2016), and 1,769 were screened after the removal of duplicates. Nineteen articles and one study register record were assessed for eligibility. Eight studies were included in qualitative synthesis, and seven studies were included in meta-analysis (quantitative synthesis). 
 
EVALUATION METHOD AND COMMENTS ON LITERATURE USED: This publication was an update of earlier review published in 2010. The earlier review searched 14 databases and identified 1,102 relevant articles. Seventy-nine articles were evaluated in detail; 5 met inclusion criteria, and data from 2 unpublished studies were included for evaluation. The updated review (2009–2016) included one new study to the seven studies in the original review published in 2010 after a search of three databases and hand searching of relevant references, textbooks, and websites. Data of one previously included unpublished study were updated for the updated review. The authors independently assessed all selected studies for methodological quality using the Risk of Bias table according to Cochrane Handbook for Systematic Reviews of Interventions and the Edwards Method Score. One study was excluded from meta-analysis because of a low score on methodological quality.

Sample Characteristics

  • FINAL NUMBER STUDIES INCLUDED =  8 studies in qualitative synthesis and 7 studies in quantitative synthesis
  • TOTAL PATIENTS INCLUDED IN REVIEW = 214 with advanced cancer and COPD
  • SAMPLE RANGE ACROSS STUDIES: 5–101
  • KEY SAMPLE CHARACTERISTICS: Adults suffering from dyspnea related to advanced malignant and nonmalignant diseases. Advanced diseases meeting inclusion criteria were cancer, COPD GOLD stage III or IV, HF NYHA class III or IV, MND, and IPF; however, all relevant studies included only individuals with cancer and COPD. The interventions included the use of any benzodiazepines at any dose, frequency, route, duration, or route.

Phase of Care and Clinical Applications

PHASE OF CARE: Multiple phases of care
 
APPLICATIONS: Elder care, palliative care

Results

1. Placebo-controlled and morphine-controlled study data were analyzed separately, showing no statistically significant benefit of using benzodiazepines for the relief of dyspnea at rest.
a. Pooled placebo-controlled studies: Standard mean difference (SMD) = –0.1, 95% confidence interval (CI) [–0.42, 0.21], p = 0.53
b. Pooled morphine-controlled studies: SMD = –0.68, 95% CI [–2.21, 0.84], p = 0.38
c. No statistical difference on third arm comparing midazolam to midazolam plus morphine
d. One study (Navigante, 2010) looking at episodic breathlessness in cancer showed a statistically significant benefit in the use of midazolam over morphine; however, when data were pooled with (Navigante, 2006) a study by same author, significant difference existed because of conflicting data.
 
2. Secondary outcomes using benzodiazepines
a. Anxiety: 4 of 7 studies; no reduction with benzodiazepines
b. Depression: 3 of 7 studies; no statistical significance in levels of depression
c. Adverse effects: 7 of 7 studies; statistically significant increase in somnolence when comparing benzodiazepines to placebo control (overall effect = 0.44 [0.69, 0.94]). When comparing morphine to midazolam, statistically significant increase in somnolence with morphine
d. Exercise tolerance: 3 of 7; no significance
e. Quality of life: Not included in any studies
 
3. No statistically significant differences were identified when comparing benzodiazepines, route, duration, or schedule of administration.

Conclusions

There is currently insufficient evidence to recommend the use of benzodiazepines for the prevention or relief of dyspnea in individuals with cancer and COPD. The adverse effects of somnolence is more prevalent with benzodiazepines than placebo; however, somnolence is more prevalent when treating dyspnea with morphine compared to benzodiazepines. Results must be interpreted with caution because of limited quality and high heterogeneity in the studies evaluated.

Limitations

  • No quality evaluation
  • High heterogeneity
  • Low sample sizes
  • Heterogeneity in the benzodiazepine group, disease group, control group, and others

Nursing Implications

Additional high quality studies are needed to fully evaluate the impact of benzodiazepines on dyspnea. Treatment of dyspnea with benzodiazepines does have side effects with potentially no benefit. Given uncertain benefits of treating dyspnea with benzodiazepines, interventions for management of dyspnea should include nonpharmacological approaches as first-line when appropriate. Assessment of response to benzodiazepines administered to treat dyspnea should include knowledge of potential benefits and potential burdens of the medication and their impact on overall quality of life; for example, drowsiness may be an acceptable side effect for some but not others.

Legacy ID

6455