Abstract: We included 53 trials consisting of 1139 participants. Forty-eight studies used a cross-over design, and five were performed in accordance with a parallel-group design. Forty-five studies addressed the effect of a single beta2-agonist administration, and eight focused on long-term treatment. We addressed these two different intervention regimens as different comparisons. Among primary outcomes for short-term administration, data on maximum fall in forced expiratory volume in 1 second (FEV1) showed a significant protective effect for both short-acting beta-agonists (SABA) and long-acting beta-agonists (LABA) compared with placebo, with a mean difference of -17.67% (95% confidence interval (CI) -19.51% to -15.84%, P = 0.00001, 799 participants from 72 studies). The subgroup analysis of studies performed in adults compared with those performed in children showed high heterogeneity confined to children, despite the comparable mean bronchoprotective effect. Secondary outcomes on other pulmonary function parameters confirmed a more positive and protective effect of beta2-agonists on EIA compared with placebo. Occurrence of side effects was not significantly different between beta2-agonists and placebo. Overall evaluation of the included long-term studies suggests a beta2-agonist bronchoprotective effect for the first dose of treatment. However, long-term use of both SABA and LABA induced the onset of tolerance and decreased the duration of drug effect, even after a short treatment period. Evidence of low to moderate quality shows that beta2-agonists, both SABA and LABA, when administered in a single dose, are effective and safe in preventing EIA. Long-term regular administration of inhaled beta2-agonists induces tolerance and lacks sufficient safety data. This finding appears to be of particular clinical relevance in view of the potential for prolonged regular use of beta2-agonists as monotherapy in the pretreatment of EIA, despite the warnings of drug agencies (FDA, EMA) regarding LABA.

Plain-language summary: We found 53 trials consisting of 1139 participants. Forty-eight studies used a cross-over design, which meant that each person in the trial received two or more treatments－one or more active treatments, the beta-agonist and a placebo in random order. The rest were parallel-group trials, meaning that people received either the active treatment or a placebo. Most of the studies addressed the effect of a giving a single beta2-agonist treatment before exercise and recorded the effect on lung function following exercise. Only eight focused on longer treatment－longer treatments would be needed to assess whether these treatments were harmful over the longer term. Studies in which people received a single administration of a beta-agonist showed that FEV1 (a measure of lung function) fell significantly less for people taking SABA or LABA compared with placebo (mean difference (MD) -17.67%; 95% confidence interval (CI) -19.51% to -15.84%). Other lung function measures confirmed that beta2-agonists were more beneficial compared with placebo. No significant difference in the number of side effects was noted in people taking SABA or LABA compared with people taking placebo. However, it is unlikely that people would be prescribed an inhaler for a single treatment, so we must consider longer-term studies to get a true measure of the side effects that inhalers can cause. We found that included longer-term studies showed that beta2-agonists were helpful in terms of lung function for the first dose of treatment. However, studies that provided longer-term treatment with SABA or LABA showed that over time, people built up a tolerance to the effects of treatments, and the beneficial effects lasted for shorter periods of time. Overall, we believe that the evidence was of low to moderate quality. This review shows that beta2-agonists－both SABA and LABA－when administered in a single dose, are effective and safe in preventing the symptoms of EIA. Longer-term administration of inhaled beta2-agonists induces tolerance and lacks sufficient safety data. It is important to note that taking LABA without background inhaled steroids is considered unsafe and is not currently recommended in most of the clinical guidelines for asthma. We recommend that more studies are needed to determine whether it is safe to administer inhaled beta2-agonists alone to people who experience asthma symptoms when exercising. This review is current as of August 2013.