Meta-Analysis: Respiratory Tolerance to Regular ß₂-Agonist Use in Patients with Asthma

18 May 2004 | Volume 140 Issue 10 | Pages 802-813

Background: The regular administration of ß₂-agonists may be associated with the development of tolerance to their effects.

Purpose: To assess the effect of regular ß₂-agonist use on respiratory function and ß₂-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 ß₂-agonist administration in patients with asthma and did not allow "as-needed" ß₂-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 ß₂-agonist administration, the provocative concentration of bronchoconstrictive agents causing a 20% reduction in FEV₁ (PC₂₀), and in vitro variables of leukocyte ß₂-receptor function.

Data Synthesis: Pooled results of 22 trials showed that regular ß₂-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 ß₂-agonist administration (change, –17.8% [95% CI, –27.2% to –8.5%]); the FEV₁ dose response to subsequent ß₂-agonists (–34.8% [CI, –45.7% to –24%]); the PC₂₀ to combined bronchoconstrictive stimuli (–26% [CI, –37% to –11%]); and leukocyte ß₂-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 ß₂-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.

Editors' Notes Context Although ß2-agonists are an important component of asthma therapy, studies indicate that tachyphylaxis may make regular use of these agents counterproductive. Contribution Pooled data from 22 trials of regular ß2-agonist use versus placebo showed that regular use leads to decreased responsiveness to both the bronchodilator and nonbronchodilator effects of subsequent ß2-agonist administration and increased airway inflammation. Implications Patients with asthma who use ß2-agonists regularly may not respond to subsequent doses of ß2-agonists as well as do patients who had not previously been using these agents, and they may have increased airway inflammation compared with those not taking the medicine at all. –The Editors

 

Author and Article Information

From Stanford University School of Medicine, Stanford, and Santa Clara Valley Medical Center, San Jose, California; and Cornell University, Ithaca, New York.

Acknowledgments: The authors thank Donald Miller for graphical assistance and Christopher Stave for coordinating the trials search.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Shelley R. Salpeter, MD, Santa Clara Valley Medical Center, 751 S. Bascom Avenue, San Jose, CA 95128; e-mail, salpeter{at}stanford.edu.

Current Author Addresses: Drs. S.R. Salpeter and Ormiston: Santa Clara Valley Medical Center, 751 S. Bascom Avenue, San Jose, CA 95128.

Dr. E. Salpeter: Center for Radiophysics and Space Research, 612 Space Sciences Building, Cornell University, Ithaca, NY 14853.

Read all Rapid Responses

Susceptibility to Tolerance and ß₂-Adrenoceptor Polymorphism

Daniel K C Lee, et al.

Annals Online, 27 Jul 2004 [Full text]