As-Needed Inhaled β2-Adrenoceptor Agonists in Moderate-to-Severe Asthma

Abstract

Intermediate-acting inhaled β₂-agonists (e.g. albuterol [salbutamol]), once recommended for round-the-clock bronchodilation, are now recommended to be used exclusively as-needed. Guidelines advise that asthma should be controlled with anti-inflammatory therapeutic strategies so that the as-needed requirement for inhaled β₂-agonists should be infrequent; ideally less than several times per week, up to once a day for exercise, and none at night. These recommendations are based upon the recognition that asthma is primarily an inflammatory condition and that the major thrust of therapy should be anti-inflammatory, including environmental control and administration of inhaled corticosteroids (ICS), leukotriene-receptor antagonists, and possibly oral theophylline and inhaled cromones; the cromones include cromolyn sodium (sodium cromogylcate) and nedocromil. While this is the primary rationale behind the as-needed infrequent prescription of the inhaled β₂-agonist paradigm, there are a number of detrimental effects that can be seen with regularly scheduled (or frequent as-needed) use of inhaled β₂-agonists. These include tolerance to the bronchodilator and particularly the bronchoprotective effects, increased airway responsiveness to allergen, worsened asthma control, and, probably most importantly, over-reliance on an excellent symptom reliever leading to undertreatment. Any or all of these could be responsible for the demonstrated dose-response relationship between inhaled β₂-agonist overuse and death from asthma. Several controlled clinical trials, which have included many patients with at least moderately severe asthma, have failed to demonstrate any obvious advantage to the regular scheduled use of inhaled β₂-agonists compared with as-needed inhaled β₂-agonists. On the other hand, despite no obvious advantage, regular use of albuterol 1000–1200 μg/day appears to be well tolerated and reasonably safe. When asthma is treated using an as-needed, infrequent inhaled β₂-agonist, the requirements for β₂-agonists become a useful marker of whether or not the asthma is adequately controlled. When inhaled β₂-agonists are required inordinately frequently (i.e. when asthma is not adequately controlled), after ensuring compliance with ICS, the most common strategy is to add one of the long-acting inhaled β₂-agonists twice daily. On the basis of the available evidence, the as-needed intermediate-acting inhaled β₂-agonist therapeutic strategy appears appropriate for patients with moderate-to-severe asthma.