Hayley Barnes, Julie McDonald, Natasha Smallwood, Renée Manser

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. 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. 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. 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. 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. 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. 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.