A high dose of albuterol does not overcome bronchoprotective subsensitivity in asthmatic subjects receiving regular salmeterol or formoterol

J Allergy Clin Immunol. 1999 Jan;103(1 Pt 1):88-92. doi: 10.1016/s0091-6749(99)70530-0.


Background: Regular treatment with inhaled, long-acting beta2 -agonists is associated with subsensitivity for bronchoprotective effects. It is not known whether a high dose of short-acting beta2 -agonist could overcome this subsensitivity.

Objectives: The objective of this study was to investigate the acute effects of a high dose of inhaled albuterol on methacholine-induced bronchoconstriction in patients receiving regular treatment with salmeterol or formoterol.

Methods: Ten stable asthmatic subjects (mean age, 34 years; FEV1, 77% of predicted value), all taking inhaled corticosteroids (methacholine PD20 < 500 microg), were recruited into a randomized, single-blind, crossover study. After an initial 1-week run-in period, subjects underwent 3 separate treatment periods each of 9 days (separated by a washout of at least 5 days) comprising inhaled placebo twice daily, inhaled salmeterol dry powder 50 microg twice daily, or inhaled formoterol dry powder 12 microg twice daily. Methacholine challenge was performed 1 hour after the first dose and after 7 days of treatment. After 9 days of treatment, a third methacholine challenge was performed 1 hour after inhalation of a single 1600 microg dose of albuterol dry powder.

Results: There was significant (P <.001) improvement in geometric mean PD20 after the first dose of active treatment as compared with placebo (78 microg) versus salmeterol (266 microg, a 3.4-fold difference [95% CI 1.9 to 6.1]) and versus formoterol (318 microg, a 4.1-fold difference [95% CI 2.3 to 7.3]). This bronchoprotection diminished with regular treatment, although it remained significant (P <.01) compared with placebo (68 microg) versus salmeterol (144 microg, a 2.1-fold difference [95% CI 1.2 to 3.8]) and versus formoterol (230 microg, 3.4-fold difference [95% CI 1.9 to 6.2]). After 9 days, the protection afforded by a single dose of albuterol after placebo pretreatment (889 microg) was significantly (P =.005) higher in comparison with albuterol protection after salmeterol pretreatment (338 microg, a 2.7-fold difference [95% CI 1.1 to 6.8]) and after formoterol pretreatment (247 microg, a 3.6-fold difference [95% 1.4 to 9.1]).

Conclusions: Thus in stable asthmatic subjects receiving regular salmeterol or formoterol, bronchoprotective subsensitivity was not overcome by administering a high dose of albuterol. Further studies are required to evaluate the clinical relevance of this pharmacologic phenomenon when albuterol is used in acute asthma.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Inhalation
  • Adrenergic beta-Agonists / therapeutic use*
  • Adult
  • Albuterol / administration & dosage*
  • Albuterol / analogs & derivatives*
  • Albuterol / therapeutic use
  • Asthma / diagnosis
  • Asthma / physiopathology*
  • Bronchial Provocation Tests / methods
  • Bronchoconstriction / drug effects
  • Bronchodilator Agents / therapeutic use*
  • Cross-Over Studies
  • Dose-Response Relationship, Drug
  • Ethanolamines / therapeutic use*
  • Female
  • Formoterol Fumarate
  • Humans
  • Male
  • Methacholine Chloride / pharmacology
  • Salmeterol Xinafoate
  • Single-Blind Method
  • Spirometry
  • Time Factors


  • Adrenergic beta-Agonists
  • Bronchodilator Agents
  • Ethanolamines
  • Methacholine Chloride
  • Salmeterol Xinafoate
  • Albuterol
  • Formoterol Fumarate