Long-acting β2-adrenoceptor agonists and exercise-induced asthma: Lessons to guide us in the future

The safety and efficacy of long-acting β2-adrenoceptor agonists (LABAs) taken intermittently for the prevention of exercise-induced asthma (EIA) in children is well established. However, the safety and efficacy of LABAs taken twice daily, either alone or in combination with inhaled corticosteroids, for the prevention of EIA is not as clear because of issues of tolerance (defined as being less responsive to the influence of LABAs). There have been many observations on short-acting β2-adrenoceptor agonists (SABAs) and EIA that should have alerted us to the potential for tolerance and desensitization to occur with LABAs. For example, we expected that the use of LABAs for EIA would overcome the problem of the short duration of protection of SABAs, and to some extent they have. The protective period of a LABA is two to three times longer in duration than that of a SABA. However, when a LABA is taken daily it is apparent that the duration of its protective effect is reduced and there is a risk of EIA occurring well within the 12-hour administration schedules. Furthermore, daily use of LABAs attenuates the bronchodilator effect of SABAs, an effect that is greater the more severe the bronchoconstriction. This 'tolerance' increases both the time and the amount of therapy that is needed to recover from bronchoconstriction, and thus, could potentially impact on the success of rescue therapy should severe EIA occur. The daily use of LABAs also increases the sensitivity of the bronchial smooth muscle to contractile agents. This increase in sensitivity is almost equivalent to the extent to which inhaled corticosteroids reduce sensitivity to the same contractile agents. The increased sensitivity to contractile agents may occur either by a reduction in the inhibitory effect of β2- adrenoceptor agonists on release of mediators from mast cells or by a direct effect on the bronchial smooth muscle. These unwanted effects of LABAs are not necessarily reduced by concomitant treatment with inhaled corticosteroids. As the number of children being treated with LABAs increases, it is predicted that problems with breakthrough EIA will also increase. We need to know the percentage of children taking a LABA daily who are requiring either extra doses of a β2-adrenoceptor agonist to prevent (or reverse) EIA or other provocative stimuli. If this percentage is significant then we may need to reconsider the position of LABAs in the treatment of children with asthma who regularly perform strenuous physical activity.