A double-blind, placebo-controlled comparison of the efficacy of standard and individually titrated doses of theophylline in patients with chronic asthma

Forty adult patients with chronic asthma completed a 3-month double-blind crossover study to compare the effect of sustained-release theophylline given both as a fixed 300 mg twice daily dose (standard) and an individually titrated dose (titrated) with placebo. Theophylline was given in addition to other usual therapy, inhaled bronchodilators, inhaled steroids and, in 12 patients, oral steroids. The 3-month period was preceded by a run-in phase to determine the dose of theophylline which each subject required to achieve peak serum levels of 12–20 mg/litre and trough levels of 8–12 mg/litre. Doses ranged from 300 mg to 700 mg twice daily. Twenty-one patients needed more than the standard dose to achieve satisfactory serum levels. Patients recorded daily peak flow rates and symptom scores and were seen at monthly intervals to measure lung function, check serum theophylline levels and change treatments, which were given in random order. FEV₁ was significantly higher for the whole group after standard (2.11 litres) and titrated (2.15 litres) theophylline therapy than after placebo (1.89 litres), as was FVC, but in the large subgroup whose titrated dose was greater than the standard dose, the FEV₁ only improved with the titrated dose. Peak flow measurements at home showed the same pattern. Patients taking oral steroids appeared to derive less benefit from theophylline than others. It is concluded that theophylline can usefully be added as a third-line drug in chronic asthma, but that since half the patients are likely only to benefit from a dose greater than 300 mg twice daily, while the other half may have high serum levels above this dose, it is essential to measure serum levels in order to use the drug effectively and safely.