Meta-Analysis: Respiratory Tolerance to Regular β₂-Agonist Use in Patients with Asthma

BACKGROUND: The regular administration of beta2-agonists may be associated with the development of tolerance to their effects. PURPOSE: To assess the effect of regular beta2-agonist use on respiratory function and beta2-receptor function in asthmatic patients. DATA SOURCES: Comprehensive searches of the EMBASE, MEDLINE, and CINAHL databases from 1966 to June 2003 and references of identified articles and reviews. STUDY SELECTION: Randomized, placebo-controlled trials that studied at least 1 week of regular beta2-agonist administration in patients with asthma and did not allow "as-needed" beta2-agonist use in the placebo group. DATA EXTRACTION: Outcomes measured in the active treatment and placebo groups were the change in FEV1 in response to treatment and subsequent beta2-agonist administration, the provocative concentration of bronchoconstrictive agents causing a 20% reduction in FEV1 (PC20), and in vitro variables of leukocyte beta2-receptor function. DATA SYNTHESIS: Pooled results of 22 trials showed that regular beta2-agonist use, compared with placebo, did not change the mean FEV1 after treatment or the net FEV1 treatment effect but substantially reduced the following: the peak FEV1 response to subsequent beta2-agonist administration (change, -17.8% [95% CI, -27.2% to -8.5%]); the FEV1 dose response to subsequent beta2-agonists (-34.8% [CI, -45.7% to -24%]); the PC20 to combined bronchoconstrictive stimuli (-26% [CI, -37% to -11%]); and leukocyte beta2-receptor density (-18.3% [CI, -31.6% to -5.1%]), binding affinity (-23.1% [CI, -39.4% to -6.8%]), and in vitro response to isoproterenol (-32.7% [CI, -56.5% to -9.0%]). CONCLUSION: Regular beta2-agonist use for at least 1 week in patients with asthma results in tolerance to the drug's bronchodilator and nonbronchodilator effects and may be associated with poorer disease control compared with placebo.