Bronchodilator subsensitivity to salbutamol after twice daily salmeterol in asthmatic patients

In view of current concerns about use of regular beta-2 agonists, and the place of the newer long-acting drugs, we decided to evaluate whether continuous exposure to twice daily salmeterol results in a blunting of the acute bronchodilator response to repeated doses of salbutamol, as might be administered in the management of an acute asthma attack. After a 2 week run-in without beta-2 agonists, 17 asthmatic patients (mean [SE] age 34 [3] years, mean forced expiratory volume in 1 s [FEV1] 64 [2·7]% of predicted) were randomised to receive salmeterol 50 μg twice daily or placebo for 4 weeks in a double-blind crossover fashion. A histamine challenge test was done 12 h after the last dose of each treatment period, and dose-response curves to inhaled salbutamol (200-3200 μg) were constructed 36 h after the last dose. Patients treated with salmeterol had reduced bronchodilator responses to salbutamol in terms of FEV1 and peak expiratory flow rate (PEFR) than those treated with placebo. The reduction in response equated with a 2·5-fold and a fourfold greater dose of salbutamol being required to produce a given FEV1 and PEFR, respectively. There was a significant reduction in lymphocyte beta-2 adrenoceptor density after salmeterol compared with placebo and run-in. Salmeterol remained effective in terms of disease control, with a significant improvement in morning PEFR compared with placebo that was maintained over the 4 week treatment period. Continuous exposure to salmeterol 50 μg twice daily results in subsensitivity to the acute bronchodilator response to repeated doses of inhaled salbutamol. Thus patients receiving regular treatment with salmeterol might require higher doses of salbutamol when used for relief of acute bronchoconstriction.