The etiology of exercise-induced bronchoconstriction in patients with asthma is not well understood but is thought to relate to cooling and drying of the airways, which stimulates the release of inflammatory mediators such as leukotrienes C4, D4 and E4. Leff and colleagues evaluated the effects of montelukast, a leukotriene receptor antagonist, on controlling airway hyperreactivity in response to exercise and methacholine challenge in patients with mild asthma.
The 12-week, double-blind, placebo-controlled study included 110 patients from 15 to 45 years of age (average age: 25 years) with at least a one-year history of asthma. Patients were nonsmokers and were receiving only inhaled beta agonists for therapy. All patients demonstrated a 20 percent or more decrease in forced expiratory volume in one second (FEV1) after a methacholine challenge and after a standardized exercise challenge on two occasions. None of the patients had used corticosteroids, long-acting antihistamines, theophylline, oral or long-acting beta adrenergic agonists or inhaled anticholinergics in the month before the study.
During the study, 54 patients received 10 mg of montelukast daily, and 56 received placebo. Patients were given an exercise challenge at baseline and four, eight and 12 weeks after beginning treatment; a methacholine challenge was given at baseline and at weeks 4 and 12. After 12 weeks of treatment, all patients received placebo for two weeks, and the exercise and methacholine challenges were again performed. The exercise challenge consisted of six minutes on a treadmill while inhaling compressed dry air at room temperature. Spirometry was performed at frequent intervals after the exercise challenge, beginning at zero minutes and then at five, 10, 15, 30, 45 and 60 minutes after exercise. If the FEV1 had not returned to within 5 percent of the pre-exercise value by 60 minutes, measurements were also obtained at 75 minutes and, if necessary, at 90 minutes after exercise. This process quantified the extent and duration of postexercise bronchoconstriction. For the methacholine challenges, the concentration of methacholine required to decrease the FEV1 by 20 percent was measured. After the 12 weeks of treatment, the patients were asked to evaluated the control of their asthma using a seven-point scale.
The mean FEV1 before exercise at baseline and at week 12 was similar in both groups. In response to the exercise challenges, patients receiving montelukast were found to have significantly greater protection from bronchospasm than patients receiving placebo. The treatment group also had significant improvement in the maximal decrease in FEV1 after exercise and in the interval between the maximal decrease in FEV1 and the return to within 5 percent of the pre-exercise FEV1. Two weeks after cessation of montelukast therapy, the mean values for FEV1 in the montelukast group were similar to those of the placebo group.
With the methacholine challenge, patients receiving montelukast required proportionately more double doses of methacholine than did the placebo group, although the difference did not reach statistical significance.
Scores on the self-assessment of symptoms after 12 weeks were much better in the montelukast group, with 73.1 percent characterizing the control of asthma as better. In contrast, 44.4 percent of patients in the placebo group described symptom control as better. The two groups did not differ significantly in the frequency of laboratory or clinical adverse events.
The authors conclude that montelukast at a daily dosage of 10 mg provides significant, consistent protection against exercise-induced bronchospasm. Unlike the short-acting inhaled beta agonist albuterol, montelukast does not appear to lead to the development of tolerance with prolonged use. Although the study demonstrated that montelukast offered no residual protective effect after cessation of therapy, no rebound worsening of symptoms was observed two weeks after discontinuation.