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Am Fam Physician. 2000;61(4):1151-1155

Salmeterol, a long-acting beta agonist, is recommended as second-line therapy for asthma when inhaled corticosteroid therapy fails to control the symptoms. It is classified as a controller medication in the asthma guidelines. Studies have shown that the combination of salmeterol and an inhaled corticosteroid is more effective in improving pulmonary function and symptoms than a doubled steroid dose. This may be due to the ability of the salmeterol to reduce bronchial responsiveness. Rosenthal and colleagues performed a double-blind, placebo-controlled study to evaluate the long-term effects of salmeterol on bronchial hyperresponsiveness in patients with moderate to severe asthma.

The 408 patients in the multicenter study were 12 years of age or older and had a baseline forced expiratory volume in one second (FEV1) of 70 percent or more of predicted value. Bronchial hyperreactivity was assessed by methacholine challenge tests, which were performed after four, 12 and 24 weeks of salmeterol therapy, as well as three and seven days after the completion of therapy. Pulmonary function tests were done at baseline, after four, eight, 12, 16, 20 and 24 weeks of treatment, and three and seven days after treatment.

Following a 15- to 30-day run-in period, patients were randomly assigned to receive salmeterol, in a dosage of 42 μg twice daily, or placebo, by means of a metered-dose inhaler. Patients were not allowed to use spacers. During the 24 weeks of therapy, patients were allowed to use albuterol on an as-needed basis.

Patients performed peak expiratory flow (PEF) measurements in the morning and evening and kept a diary of daytime asthma symptoms. Self-assessment of symptoms was based on a five-point scale for wheezing, shortness of breath and chest tightness. Patients also kept a log of nighttime awakening because of symptoms of asthma. Patients who required parenteral or inhaled steroids or the initiation of cromolyn therapy for acute exacerbations of asthma were withdrawn from the trial.

Of the 408 patients, 202 were randomized to salmeterol therapy and 206 to placebo. The mean age of subjects in the salmeterol and placebo groups was 29.3 years and 28.7 years, respectively. A total of 87 patients (34 in the salmeterol group and 53 in the placebo group) withdrew from the study.

Compared with the placebo group, patients who received salmeterol had less airway responsiveness on methacholine challenge tests after four, 12 and 24 weeks of treatment and again at three and seven days after treatment. In addition, the salmeterol group had significant increases in morning and evening PEF measurements compared with the placebo group. The mean morning PEF increased by 26.2 L per minute above baseline in patients receiving salmeterol, compared with an increase of 5.3 L per minute in the placebo group.

Salmeterol therapy was also associated with significant improvement in FEV1. Improvement was not observed on pulmonary function testing performed three and seven days after cessation of therapy.

Compared with baseline symptom scores, symptom scores of wheezing, shortness of breath and chest tightness were reduced a mean of 20 percent, 18 percent and 16 percent, respectively, among the patients who received salmeterol therapy. Nighttime awakenings also improved in the salmeterol group.

Adverse events were reported by a large number of patients in each group. In the salmeterol group, 149 (74 percent) reported adverse events, compared with 151 (73 percent) in the placebo group. The most common clinical adverse events were symptoms of an upper respiratory tract infection.

The authors conclude that long-term use of salmeterol produces sustained improvement in pulmonary function and control of asthma symptoms. It does not appear to increase bronchial hyperresponsiveness, lead to clinical instability or predispose patients to unpredictable asthma attacks.

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