10/8/03 Formoterol use thrice weekly does not induce tolerance to bronchoprotective effectsSummaryThe addition of inhaled long acting beta agonists (LABA) such as salmeterol (Salm) and formoterol (Form) to inhaled corticosteroids (ICS) has been used increasingly in the management of moderate persistent asthma. It has been repeatedly shown that this added LABA treatment allows asthma control with a reduction of about 50% in the dosage of ICS employed. However, some groups have raised concerns that the chronic daily use of inhaled LABA will lead to a tolerance to the protective effects of all beta agonists against bronchoconstrictive stimuli. Davis et al of the Royal Univ. Hospital in Saskatoon, Canada compared the effects of the thrice weekly use of inhaled Form (12mcg) vs placebo for one week. As a "positive control" in this double-blind crossover trial, the subjects were also evaluated after one week of daily Form (12 mcg) treatments. During a methacholine challenge on day 8 after each of the 3 types of treatment, a somewhat (but not significant) lower dose of methacholine was needed to induce bronchoconstriction following the week of daily Form treatments (when compared to placebo). There was no significant difference between the effects of thrice weekly Form vs placebo on the subsequent methacholine challenge pattern on day 8. The authors concluded that thrice weekly Form treatment does not result in the development of tolerance to bronchoprotection against a mechacholine stimulus. Reference Can Resp J 2003; 10:23-6 Editor's Comments This investigative group has been one of those raising strong concerns about the chronic use of inhaled beta agonists in asthma treatment. This concern, originally expressed about the short-acting agent albuterol, has been extended to the use of LABA. Several studies have shown that the bronchodilation effect of inhaled albuterol may be blunted somewhat in those treated chronically with LABA. However, most studies have shown no impressive evidence that the management of acute asthma flares is less effective or need for hospitalization was more frequent in those treated chronically with LABA plus ICS. It should be mentioned that a warning about chronic treatment with LABA has been raised based on an increased frequency of life-threatening asthma exacerbations in those receiving LABA in one study. Those raising concerns have still argued that the protective effect of inhaled beta agonists against methacholine-induced bronchoconstriction may be blunted in those treated chronically with LABA. They postulated that such blunted bronchoprotection may indicate a greater susceptibility to bronchoconstriction induced by a variety of stimulants, including irritants. I think the authors of the study described above were somewhat surprised by the findings in this study that no significant decrease in bronchoprotective capacity was found even in thos who were treated daily with form for 7 day. One would have liked to see a similar study carried out for longer than one week of Form vs placebo. Indeed, a recent meta-analysis (QJM 2003; 96:435-40) concluded that the chronic use of inhaled beta agonists by asthmatics (in addition to ICS) afforded a protective effect 0.8 doubling dilutions) on methacholine induced bronchoconstriction.
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