Abstract: 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 standardised mean post-treatment dyspnoea score was 0.32 points better in the opioid group compared to the placebo group (ranging from a 0.53 point reduction to a 0.10 point reduction) (12 RCTs, 338 participants, low quality evidence). The standardised mean change from baseline dyspnoea score was 0.11 points better in the opioids group compared to the placebo group (ranging from a 0.40 point reduction to a 0.19 increase) (six RCTs, 194 participants, very low quality evidence). A lower score indicates an improvement in breathlessness. 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.

Plain-language summary: We searched for studies up to 19 October 2015, and we included 26 studies with 526 people. These people had breathlessness from different types of lung disease. Some were given opioid drugs and some were given other drugs or a placebo, and studies compared the reporting of breathlessness to see if there was any difference. Some studies also looked at the amount of time people could exercise to see if there were any differences. Some people came from home, and some came from the hospital setting. There was some low quality evidence that showed a benefit of using oral or injectable opioid drugs for the treatment of the symptoms of breathlessness. There was no evidence for opioids by nebuliser. Some people experienced drowsiness, nausea, and vomiting. More research is needed using more people, and looking at effects on quality of life. We rated the quality of the evidence using one of the following grades: very low, low, moderate, or high. Very low quality evidence means we are uncertain about the results. High quality evidence means we are very certain about the results. For this Cochrane review, we found that the evidence was of low to very low quality. We included randomised controlled trials which were blinded, which means that participants and those people that assessed the results did not know whether the participants had received the opioid drug or a placebo. However, the trials were of small size, and some studies did not give enough information to allow us to assess whether they were of good quality.