Long-Term Treatment of Exercise-Induced Asthma

Abstracts & Commentary

Synopsis: The treatment of exercise-induced asthma was examined by Nelson and colleagues, who demonstrated that the persistent protective effect of Salmeterol inhalation was maintained more than one month early but not late in the day. Leff and associates reported that Montelukast was more effective given once a day than placebo in moderating exercise-induced asthmatic symptoms over a 12-week period.

Sources: Nelson JA, et al. N Engl J Med 1998;339:141-146; Leff JA, et al. N Engl J Med 1998;339:147-152; Hansen-Flaschen J, et al. N Engl J Med 1998;339:191-194.

Asthma is an extremely common condition affecting between 10-20% of the population. This condition is associated with a significant loss of time from work and school, and increased mortality in the elderly in urban and low-income populations. Although exercise-induced asthma was at one time thought to be a unique "syndrome," it is now recognized that all asthmatics have some component of activity-induced symptoms.1,2 It is thought that rapid water vapor and heat exchange, which occurs during exercise as well as drying of the airway mucosa, results in release of inflammatory mediators, including cysteinyl leukotrienes and slower acting prostaglandins. After an asthmatic starts exercising and abruptly stops (5 minutes), airflow obstruction results, peaking at 10 minutes at 50% below pre-exercise levels. Gradually, airflow improves over 1-2 hours. This is a common cause for individuals with asthma to seek medical attention and contributes to a reduced participation in sports by many whose asthma is only mild.

Two recent papers published in the New England Journal of Medicine by Nelson et al and Leff et al add to the practical body of knowledge enabling physicians to manage the exercise-related symptoms of asthma. In the first paper, investigators from Case Western Reserve University School of Medicine performed a randomized, double-blind crossover trial in 20 patients with exercise-induced asthma (age 29 ± 2 years). Subjects received either inhaled Salmeterol 42 mcg or placebo twice a day for one month and then crossed-over after a one-week wash-out. The exercise-induced stress included frigid air administered during cycling, 30 minutes and nine hours after the morning dose of Salmeterol. Evaluations were repeated on days 1, 14, and 29. Although Salmeterol continued to protect asthmatics over the course of study following the morning challenge, duration of protection throughout the day decreased with long-term use. Nelson et al point out that while initial protection was maintained, the duration of protection from Salmeterol decreased, suggesting that while B2-adrenergic receptors probably did not change in their functional activity, perhaps the clearance of Salmeterol increased with time.

In the study by Leff et al, Montelukast (10 mg), a leukotriene-receptor antagonist, was administered once daily to patients with mild asthma between 15-45 years of age who had demonstrated a decrease in FEV1 of 20% or more after exercise on two occasions. Exercise challenge included: six minutes of treadmill while inhaling compressed dry air at room temperature. Measures of obstruction included area under the curve of FEV1 (60 minutes after exercise), as well as the maximal decrease in FEV1, and the time to return to baseline pulmonary function. Leff et al found the degree of protection against airway constriction at 12 weeks was significantly increased compared to placebo. In addition, Montelukast also improved maximum decrease in FEV1 and the time to return to baseline compared to placebo. Asthma control, as assessed by the patient’s global assessment, improved in 73% of patients. In 21%, it was unchanged, and in 6%, it was worse.

Comment by Alan M. Fein, MD

While asthma can be fatal, more often it limits activity, lifestyle, and the ability to contribute at work and school. In these groups of young asthmatics, average age younger than 30, both Salmeterol (inhaled medication) and Montelukast (oral medication) demonstrated a significant ability to improve exercise-induced measures of airway obstruction over prolonged periods of time. Although inhaled B2-agonist and the anti-inflammatory agents Nedocromil and Cromolyn have been demonstrated to offer some protection, these drugs are impractical because they require inhalation shortly before exercise. Salmeterol, a long acting B2-agonist lasting up to 12 hours, offered substantial and long-term protection against what is a "real world" bronchoconstrictive stimuli (cold air and bicycling). The early protective effect of Salmeterol was maintained over the one-month course of study while the duration throughout the day waned (i.e., the protective effect after 9 hours was reduced as compared to that at 30 minutes by day 14). By day 29, late protection was not significantly different than placebo. Montelukast offers another protective pharmacologic intervention. The protection persisted over the 12 weeks of study and supports the hypothesis that the exercise-induced asthma is mediated via inflammatory mediators, especially leukotrienes. In practical terms, both agents offer the potential of treatment at a time relatively remote from the exercise. This limits the problems so often associated with compliance and the embarrassment that patients feel when forced to use inhalers immediately prior to their exercise. Both strategies offer young individuals with relatively mild asthma the potential to enhance quality of life and participation in sports. (Dr. Fein is Director, Center for Pulmonary and Critical Care, Northshore University Hospital, Manhasset, NY.)

References

1. McFadden ER Jr. Clin Chest Med 1995;16:671-682.

2. Randolph C. Curr Probl Pediatr 1997;27:53-77.