Meta-analysis:: Respiratory tolerance to regular β2-agonist use in patients with asthma

Background: The regular administration of beta(2)-agonists may be associated with the development of tolerance to their effects. Purpose: To assess the effect of regular beta(2)-agonist use on respiratory function and beta(2)-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 beta(2)-agonist administration in patients with asthma and did not allow as-needed beta(2)-agonist use in the placebo group. Data Extraction: Outcomes measured in the active treatment and placebo groups were the change in FEV, in response to treatment and subsequent beta(2)-agonist administration, the provocative concentration of bronchoconstrictive agents causing a 20% reduction in FEV1 (PC20), and in vitro variables of leukocyte beta(2)-receptor function. Data Synthesis: Pooled results of 22 trials showed that regular beta(2)-agonist use, compared with placebo, did not change the mean FEV, after treatment or the net FEV, treatment effect but substantially reduced the following: the peak FEV, response to subsequent beta(2)-agonist administration (change, -17.8% [95% CI, -27.2% to -8.5%]); the FEV, dose response to subsequent beta(2)agonists (-34.8% [CI, -45.7% to -24%]); the PC20 to combined bronchoconstrictive stimuli (-26% [CI, -37% to -11%]); and leukocyte beta(2)-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 beta(2)-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.