Table 1

Characteristics of meta-analyses of systemic opioids for breathlessness

Characteristic of meta-analysisJennings et al3Ekström et al6Barnes et al7
Design of included studies (n)Double-blind RCTsDouble-blind RCTsDouble-blind RCTs
N studies9 (all crossover trials)8 (all crossover trials)12 (1 parallel and 11 crossover trials)
N trial participants102118198
Population (n trial participants)COPD (n=80) Chronic heart failure (n=12) Cancer (n=10)COPD (n=113) Other (n=5)COPD (n=107) CHF (n=47) Cancer (n=41) Other (n=3)
InterventionOral or parenteral opioidOral or parenteral opioidOral or parenteral opioid
ComparisonPlaceboPlaceboPlacebo or any other pharmacological or non-pharmacological interventions that were directly compared with the opioid treatment (only two trials used non-placebo comparator)
Duration of treatment (n studies)Single or few doses (N=5); longer treatment of 1–6 weeks (n=4)Single dose or 1 day (n=3); 4 days to 6 weeks (n=5)Single dose or 1–2 days (n=7); 4 days to 6 weeks (n=5)
Statistical method for poolingRandom effects model.
Change on different scales compared as SMDs
Random effects model.
Change on different scales compared as SMDs
Fixed effect models.
Changes compared as MD when on the same scale and SMD when on separate scales, and separately for change from baseline and postscores.
Random effects model was used in a sensitivity analysis
Accounted for crossover designsYesYesNo (analysed data as from parallel trials)
Findings for whole study population
Pooled effect of opioids (95% CI; I2; n trial participants)*SMD −0.40 (−0.63 to −0.17; I2=42.3% ; n=102)SMD −0.34 (−0.58 to −0.10; I2=0%; n=118)Oral opioid, change from baseline: SMD 0.07 (−0.30 to 0.44; I2=65%; n=116)
Oral opioid, postscores: SMD −0.27 (−0.56 to 0.02; I2=0%; n=190)
Subcutaneous opioid, change from baseline: MD 0.20 (−2.50 to 2.90; n=20)
Stated quality of evidenceNot statedModerate (GRADE)Not stated for systemic opioids
For opioids overall: very low for change from baseline and low for postscores (GRADE)†
Findings in COPD participants
Pooled effect of opioids (95% CI; I2; n trial participants)*SMD −0.26 (−0.44 to 0.08; I2=23.6%; n=80)†SMD −0.34 (−0.58 to −0.10; I2=0%; n=118)Change from baseline: SMD −0.49 (−1.08 to 0.10; I2=0%; n=46)†
Postscores: SMD −0.21 (−0.45 to 0.04; I2=0%; n=262)†
Stated quality of evidence (criteria)Not statedModerate (GRADE)Not stated
Risk of bias assessmentUsing Jadad score of methods of randomisation and blinded. Most items were rated as unclearUsing the Cochrane risk of bias tool. Ratings were low or unclear for all items; no item was rated as highUsing the Cochrane risk of bias tool as well as an additional item based on study size: ≥200 (low risk), 50–199 (unclear risk) and <50 (high risk) participants in each treatment arm.
All items in the Cochrane risk of bias tool were rated as low or unclear except three items rated as high: performance bias (n=1), detection bias (n=1) and other bias (n=1).†
Risk of study size bias was rated as high risk for all studies
  • Characteristics are for trials included in each published meta-analysis.3 ,6 ,7

  • *Negative estimate indicates reduction in breathlessness by opioids compared with placebo.

  • †Included both trials of systemic and nebulised opioids which were not reported separately.

  • CHF, congestive heart failure; GRADE, Grading of Recommendations Assessment, Development, and Evaluation; I2, proportion of the total variance in effect estimates that are between studies; MD, mean difference; RCT, randomised controlled trial; SMD, standardised mean difference.