Purpose of the Study
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. They studied whether the frequency or dose of treatment with a long-acting β2-agonist (formoterol) effects the degree of bronchoprotection afforded against methacholine challenge and to compare this with the effects of a short-acting β2-agonist (terbutaline).
Study Population 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% decrease 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.
Each of the four active treatments exhibited significant tachyphylaxis (P < .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.
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.
I always have a tough time knowing if there is clinical importance to these kinds of studies, especially regarding long-term usage. Based on clinical observation, it would not appear (at least to me) that patients using these medications develop greater bronchial reactivity over time. Nevertheless, other long-acting inhaled bronchodilators (eg, salmeterol) can show this kind of tachyphylaxis to bronchoprotection against methacholine and exercise, while maintaining their bronchodilator effects. This article was accompanied by a related editorial (Abishenganden J. Am J Med.1998;104:494–497).