PURPOSE: In addition to their bronchodilatory effects, β2-agonists protect against bronchoconstriction, such as that caused by methacholine
challenge. However, tachyphylaxis to this beneficial effect develops after chronic
use of β2-agonists. We studied whether the frequency or dose of treatment with a long-acting
β2-agonist (formoterol) affects the degree of bronchoprotection afforded against methacholine
challenge and to compare this with the effects of a short-acting β2-agonist (terbutaline).
PATIENTS AND METHODS: In a randomized, parallel group, double-blind study at two centers,
patients with stable asthma of mild to moderate severity who were treated with inhaled
corticosteroids were treated with formoterol 6 μg twice daily, 24 μg twice daily,
12 μg once daily; terbutaline 500 μg four times daily; or placebo. Treatments were
given by dry powder inhaler for a period of 2 weeks. Of the 72 patients who were enrolled,
67 completed the study. Methacholine challenge was performed to calculate the provocative
dose that caused a 20% fall in forced expiratory volume in 1 second at baseline (unprotected)
after an initial 1-week run-in without β2-agonists, 1 hour after the first dose of study treatment, and again 1 hour after
7 and 14 days of study treatment.
RESULTS: Each of the four active treatments exhibited significant tachyphylaxis (P <0.05) to protection against methacholine challenge when comparing first/last dose
(as geometric mean protection ratio versus baseline): formoterol 24 μg twice daily
(9.6-fold/1.6-fold), 12 μg once daily (7.1-fold/2.2-fold), 6 μg twice daily (6.2-fold/2.3-fold),
and terbutaline 500 μg four times daily (2.9-fold/2.0-fold). There were no significant
differences among treatments after 2 weeks in bronchoprotection against methacholine
challenge. For all formoterol regimens, the bronchodilator response 1 hour after inhalation
was maintained over the 2-week treatment period. Diurnal control of morning and evening
peak flow was significantly better with formoterol 24 μg twice daily than with terbutaline.
CONCLUSIONS: Tachyphylaxis to bronchoprotection against methacholine challenge develops
after 2 weeks of therapy with formoterol, a long-acting β2-agonist, at all three dosage regimens that were tested. In contrast, the bronchodilator
effects of formoterol were maintained during the 2 weeks of treatment.