Rapid onset of tolerance to beta-agonist bronchodilation

Introduction: Regular use of beta-agonists leads to tolerance to their bronchoditator effects. This is easily demonstrated if dilation is tested following methacholine challenge. It is not known how quickly tolerance develops or how tong it lasts after stopping beta-agonist therapy. Methods: Ten subjects with stable asthma were studied. Following 2 weeks without beta-agonists, methacholine was inhaled to induce a 20% reduction in FEV1. The response to inhaled salbutamol (100, 100, 200 mu g at 5-min intervals) was then measured. This procedure was repeated 24 h after one dose and 24 h after 3, 7 and 14 days of inhaled formoterol 12 mu g twice daily, and 3 and 5 days after formoterol was discontinued. Unscheduled use of beta-agonists was not permitted. Results: Bronchoditator tolerance, assessed by a reduction of the area under the salbutamol dose-response curve, occurred after 1 dose of formoterol (28% reduction, 95% Cl 12, 45%), increased up to 1 week and plateaued between 1 and 2 weeks (58% reduction, 95% Cl 38, 78%). Three days after stopping formoterol, the response to salbutamol was similar to baseline (12% reduction, 95% Cl -9, 33%). The first dose of formoterol provided significant bronchoprotection to methacholine (1.6 doubling doses, P = 0.007). This diminished with regular treatment and by 2 weeks the PD20 methacholine was not significantly different to baseline. Conclusions: Bronchoditator tolerance occurs after a single dose and reaches a maximum after 1 week of regular formoterol. Sensitivity recovers 3 days after stopping treatment. (c) 2004 Elsevier Ltd. All rights reserved.