Tolerance to the Protective Effect of Salmeterol on Allergen Challenge

¹ From the Second Institute of Internal Medicine, Respiratory Pathophysiology, Pisa, Italy

Long-term treatment with inhaled β₂-agonists may be associated with a deterioration in asthma control, potentially due to tolerance. Regular use of short-acting β₂-agonists has been shown to induce tolerance to allergen or adenosine 5'-monophosphate challenge. The aim of the study was to detect the efficacy of a single dose and a short-term treatment with salmeterol, a long-acting β₂-agonist, to protect against early asthmatic reaction (EAR) to allergen. Eight subjects with mild allergic asthma underwent two treatment periods in which subjects performed an allergen challenge (specific bronchial provocation test) protected by a single dose (50 µg) of salmeterol (Salm-1) followed by a second specific bronchial provocation test after regular treatment with salmeterol for 1 week (Salm-2), or a single dose of placebo (Plac-1) and regular treatment (1 week) with placebo (Plac-2). Each subject performed both treatments in a randomized order. Each time allergen challenge was performed 1 h after last drug inhalation and it was stopped when the same provocative dose of allergen of a previous screening allergen challenge was achieved. The maximum decrease in FEV₁ and area under curve in the first hour after allergen inhalation were significantly lower in Salm-1 (max FEV₁ %, median [range]: 4%[0 to 9]) with respect to Salm-2, Plac-1, Plac-2 (24%[13 to 38], 31%[19 to 50], 30%[6 to 44], respectively, p<0.001); there was no difference among Salm-2, Plac-1 and Plac-2. In Salm-1, all subjects were protected against EAR, whereas in Salm-2 only 2 subjects showed a partial protection. In conclusion the protective effect of a single dose of salmeterol against allergen-induced EAR was lost after regular treatment with salmeterol for 1 week. The clinical relevance of this mechanism remains to be elucidated.

Key Words: asthma allergen challenge • β₂-agonist • salmeterol • tolerance

Submitted on April 9, 1996
Accepted on July 5, 2007

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