Tolerance to bronchodilation during treatment with long-acting beta-agonists, a randomised controlled trial.
BACKGROUND
Regular use of beta-agonists leads to tolerance to their bronchodilator effects. This can be demonstrated by measuring the response to beta-agonist following bronchoconstriction using methacholine. However most studies have demonstrated tolerance after a period of beta-agonist withdrawal, which is not typical of their use in clinical practice. This study assessed tolerance to the bronchodilator action of salbutamol during ongoing treatment with long-acting beta-agonist.


METHODS
Random-order, double-blind, placebo-controlled, crossover trial. After 1 week without beta-agonists, 13 asthmatic subjects inhaled formoterol 12 microg twice daily or matching placebo for 1 week. Eight hours after the first and last doses subjects inhaled methacholine to produce a 20% fall in FEV1. Salbutamol 100, 200 and 400 microg (cumulative dose) was then given at 5-minute intervals and FEV1 was measured 5 minutes after each dose. After a 1 week washout subjects crossed over to the other treatment. Unscheduled use of beta-agonists was not allowed during the study. The main outcome variable was the area under the salbutamol response curve.


RESULTS
The analysis showed a significant time by treatment interaction indicating that the response to salbutamol fell during formoterol therapy compared to placebo. After 1 week of formoterol the area under the salbutamol response curve was 48% (95% confidence interval 28 to 68%) lower than placebo. This reduction in response remained significant when the analyses were adjusted for changes in the pre-challenge FEV1 and dose of methacholine given (p = 0.001).


CONCLUSIONS
The bronchodilator response to salbutamol is significantly reduced in patients taking formoterol. Clinically relevant tolerance to rescue beta-agonist treatment is likely to occur in patients treated with long-acting beta-agonists.
Haney
Sarah
S
Freeman Hospital, Newcastle-upon-Tyne, UK. sas_haney@yahoo.co.uk
Hancox
Robert J
RJ
D000280:Administration, Inhalation; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage; D000328:Adult; D000420:Albuterol / Q000008:administration & dosage*; D001249:Asthma / Q000175:diagnosis* / Q000188:drug therapy* / Q000503:physiopathology; D001985:Bronchial Provocation Tests; D016084:Bronchoconstriction / Q000187:drug effects*; D001993:Bronchodilator Agents / Q000008:administration & dosage; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004361:Drug Tolerance; D004983:Ethanolamines / Q000008:administration & dosage*; D005260:Female; D000068759:Formoterol Fumarate; D006801:Humans; D008297:Male; D016210:Methacholine Chloride; D008875:Middle Aged; D016896:Treatment Outcome
D000318:Adrenergic beta-Agonists; D001993:Bronchodilator Agents; D004983:Ethanolamines; D016210:Methacholine Chloride; D000420:Albuterol; D000068759:Formoterol Fumarate