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

Shelley R. Salpeter, MD; Thomas M. Ormiston, MD; and Edwin E. Salpeter, PhD
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From Stanford University School of Medicine, Stanford, and Santa Clara Valley Medical Center, San Jose, California; and Cornell University, Ithaca, New York.

Ann Intern Med. 2004;140(10):802-813. doi:10.7326/0003-4819-140-10-200405180-00018
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Background: The regular administration of β2-agonists may be associated with the development of tolerance to their effects.

Purpose: To assess the effect of regular β2-agonist use on respiratory function and β2-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 β2-agonist administration in patients with asthma and did not allow “as-needed” β2-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 β2-agonist administration, the provocative concentration of bronchoconstrictive agents causing a 20% reduction in FEV1 (PC20), and in vitro variables of leukocyte β2-receptor function.

Data Synthesis: Pooled results of 22 trials showed that regular β2-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 β2-agonist administration (change, −17.8% [95% CI, −27.2% to −8.5%]); the FEV1 dose response to subsequent β2-agonists (−34.8% [CI, −45.7% to −24%]); the PC20 to combined bronchoconstrictive stimuli (−26% [CI, −37% to −11%]); and leukocyte β2-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 β2-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.


asthma ; agonists


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Figure 1.
FEV 1 response to a course of β 2 -agonist or placebo.
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Figure 2.
Acute FEV 1 response to β 2 -agonist administration after a course of β 2 -agonist or placebo.
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Figure 3.
Provocative concentration causing a 20% reduction in FEV 1 (PC 20 ) to bronchoconstrictive stimuli, measured after a course of β 2 -agonist or placebo.

AMP = adenosine monophosphate.

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Figure 4.
Provocative concentration causing 20% reduction in FEV 1 (PC 20 ) to bronchoconstrictive stimuli with β 2 -agonist treatment, measured as the change from first to last dose.

AMP = adenosine monophosphate.

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Figure 5.
In vitro variables of leukocyte β 2 -receptor function after a course of β 2 -agonist or placebo.

AMP = adenosine monophosphate.

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Submit a Comment/Letter
Susceptibility to Tolerance and 2-Adrenoceptor Polymorphism
Posted on July 26, 2004
Daniel K C Lee
Department of Respiratory Medicine, Ipswich Hospital, Heath Road, Ipswich IP4 5PD, Suffolk, England
Conflict of Interest: None Declared

Salpeter and colleagues examined the development of tolerance to the effects of regular ß2-agonist therapy in patients with asthma (1). However, the authors failed to mention the important influence of ß2- adrenoceptor polymorphism on the propensity for desensitization of response following regular ß2-agonist use. In particular, patients with the homozygous arginine-16 ß2-adrenoceptor genotype have been shown to have poorer outcomes of asthma control following regular albuterol use (2).

In asthmatic patients who were washed out of the effects of ß2- agonist therapy, acute systemic ß2-adrenoceptor-mediated responses to a single bolus of inhaled albuterol were enhanced in subjects expressing the homozygous arginine-16/glutamine-27 haplotype, which in turn suggested a greater propensity for desensitization of response on chronic exposure (3). In asthmatic patients receiving concomitant inhaled corticosteroids, the greatest degree of desensitization of response for protection against bronchoconstriction was observed in association with the arginine-16 polymorphism, especially with the homozygous arginine-16/glutamine-27 haplotype, following regular exposure to long-acting ß2-agonist therapy (4). In the same study, there was greater tolerance with formoterol compared to salmeterol, which occurred in patients expressing the arginine -16 polymorphism, for protection against bronchoconstriction. This phenomenon may be explained by a higher degree of ß2-adrenoceptor intrinsic activity in the former compared to the latter, whereby prolonged 24-hour receptor occupancy would result in enhanced agonist-induced receptor down-regulation and desensitization of response (5).

Thus, while it is tempting to evaluate mean data from the meta- analysis of Salpeter and colleagues, it is more clinically relevant to consider individual responses, particularly as susceptibility to tolerance is genetically determined by ß2-adrenoceptor polymorphism. Indeed in the real life clinical situation, one sees an individual rather than an average patient.

Daniel K C Lee, MBBCh, MRCP, MD, Department of Respiratory Medicine, Ipswich Hospital, Heath Road, Ipswich IP4 5PD, England, UK

Graeme P Currie, MBChB, DCH, MRCP, MD, Department of Respiratory Medicine, Aberdeen Royal Infirmary, Foresterhill, Aberdeen AB25 2ZN, Scotland, UK

Catherine M Jackson, MBChB, MRCGP, Tayside Centre for General Practice, University of Dundee, Kirsty Semple Way, Dundee DD2 4BF, Scotland, UK

Kean C Khoo, MBBCh, MRCP, Department of Respiratory Medicine, Llandough Hospital, Penlan Road, Penarth CF64 2XX, Wales, UK

Brian J Lipworth, BMedSci, MBChB, MD, FRCP, FRCPE, Asthma and Allergy Research Group, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, UK


1. Salpeter SR, Ormiston TM, Salpeter EE. Meta-analysis: respiratory tolerance to regular beta2-agonist use in patients with asthma. Ann Intern Med. 2004;140:802-13.

2. Israel E, Drazen JM, Liggett SB, Boushey HA, Cherniack RM, Chinchilli VM et al. The effect of polymorphisms of the beta2-adrenergic receptor on the response to regular use of albuterol in asthma. Am J Respir Crit Care Med. 2000;162:75-80.

3. Lee DK, Bates CE, Lipworth BJ. Acute systemic effects of inhaled salbutamol in asthmatic subjects expressing common homozygous beta2- adrenoceptor haplotypes at positions 16 and 27. Br J Clin Pharmacol. 2004;57:100-104.

4. Lee DK, Currie GP, Hall IP, Lima JJ, Lipworth BJ. The arginine-16 beta2-adrenoceptor polymorphism predisposes to bronchoprotective subsensitivity in patients treated with formoterol and salmeterol. Br J Clin Pharmacol. 2004;57:68-75.

5. Linden A, Bergendal A, Ullman A, Skoogh BE, Lofdahl CG. Salmeterol, formoterol, and salbutamol in the isolated guinea pig trachea: differences in maximum relaxant effect and potency but not in functional antagonism. Thorax. 1993;48:547-53.

Conflict of Interest:

None declared

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Summary for Patients

Tolerance to Beta2-Agonist Treatment after Regular Use in People with Asthma

The summary below is from the full report titled “Meta-Analysis: Respiratory Tolerance to Regular β2-Agonist Use in Patients with Asthma.” It is in the 18 May 2004 issue of Annals of Internal Medicine (volume 140, pages 802-813). The authors are S.R. Salpeter, T.M. Ormiston, and E.E. Salpeter.


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