Nocturnal Asthma Therapy: Inhaled Bitolterol versus Sustained-release Theophylline

Abstract Many asthmatics complain of increased symptoms, awakenings, and need for additional medications during the sleeping hours. Sustained-release theophylline (THEO) may be superior to conventional inhaled bronchodilators in preventing nocturnal asthma symptoms and the early morning decrement in lung function common to this population. However, recent studies have demonstrated that THEO may delay sleep onset and perturb sleep stage distribution. No previous study has evaluated electroencephalographic, cardiac, and gas exchange indices during sleep in asthmatics treated with THEO compared with a long-acting inhaled beta2-agonist. The study goals were to determine if theophylline perturbed sleep when compared with beta2-agonists and to determine which agent achieved best control of daytime and nocturnal pulmonary symptoms and lung dysfunction. We evaluated 26 subjects with mild to moderate asthma and a history of frequent nocturnal symptoms who previously demonstrated decrements in AM lung function. THEO was compared with 3 puffs every 8 h (6 a.m., 2 p.m., and 10 p.m.) of bitolterol (BITOL), a long-acting beta2-agonist, in a randomized, double-blind, placebo-controlled cross-over study. Each drug was administered for a 2-wk period ending with two consecutive nights of sleep evaluation followed by cross-over to the alternate drug regimen. During THEO administration, plasma concentrations on awakening were 11.4 ± 0.69 µg/ml as compared with 0.00 µg/ml during BITOL. THEO was not found to disrupt sleep as sleep latency, total sleep time, percentage of total sleep time spent in Stages 1, 2, and 3/4 and in REM sleep were similar during each regimen. Sleep efficiency, sleep stage changes per hour, apneas, and hypopneas were similar between regimens. However, time spent with an oxyhemoglobin saturation of 4% or more below the control level occurred for 2 ± 0.7 min during THEO and 18.6 ± 7.6 min (p = 0.04) during BITOL. Morning FEV1 was 2.47 ± 0.16 during THEO and 1.79 ± 0.17 (p = 0.001) during BITOL. Asthmatics had significantly fewer daytime complaints of wheezing, cough, and dyspnea, claimed better sleep quality, and showed an overall preference for THEO over BITOL. Thus, THEO appears to be superior to BITOL given every 8 h in controlling symptoms, sleeping gas exchange abnormalities, and lung dysfunction in asthmatics.