Asthma is characterized by hyperresponsiveness of the airways to bronchoconstrictive stimuli. Long-acting β₂-adrenoceptor agonists have been introduced as a new therapeutic approach, but there is growing concern about whether control of asthma may deteriorate with the regular use of these agents. We investigated the long-term effects of the β₂-agonist salmeterol on bronchodilation and on airway hyperresponsiveness to the bronchoconstrictive agent methacholine in mild asthma.

In a parallel, double-blind study, 24 patients with mild asthma were randomly assigned to treatment with either inhaled salmeterol (50 μg, twice daily) (n = 12) or placebo (n = 12) during an eight-week trial. Methacholine challenge was performed before, during, and after the treatment period. Methacholine responsiveness was measured as the provocative concentration (PC₂₀) that caused a 20 percent decrease in the forced expiratory volume in one second (FEV₁).

There was a significant increase in FEV₁ one hour after the inhalation of salmeterol (P = 0.006), which did not differ significantly on days 0, 28, and 56 of the treatment period (increase, 9.8, 9.4, and 8.8 percent of predicted FEV₁, respectively; P = 0.91). On the first treatment day, salmeterol afforded significant protection against methacholine-induced bronchoconstriction, as shown by a 10-fold increase in the PC₂₀ as compared with the value at entry (P<0.001). After four and eight weeks of treatment, however, the salmeterol-induced change in the PC₂₀ was significantly attenuated (P<0.001) to only a twofold increase. Two and four days after treatment ended, the PC₂₀ was not significantly different from the value before treatment (P = 0.15).

Regular treatment of patients with mild asthma with salmeterol leads to tolerance to its protective effects against a bronchoconstrictor stimulus, in this case inhaled methacholine, despite well-maintained bronchodilation. This finding raises concern about the effectiveness of prolonged therapy with long-acting β₂-adrenoceptor agonists in asthma. (N Engl J Med 1992;327:1198–203.)