Inhaled steroids are the preferred treatment for chronic asthma because, in many patients, their anti-inflammatory effects greatly reduce the need for adjunctive therapies. Unfortunately, their long-term effects are still unknown, and the medications currently available are quite expensive. In the past, theophylline was widely used to treat asthma, but it is now less popular because of its side effects and apparent lack of anti-inflammatory activity. However, recent short-term studies have shown that, when used in combination with oral or inhaled steroids, theophylline improves pulmonary function. Evans and associates compared the effects of a regimen of inhaled steroids and low-dose theophylline with that of an increased dosage of steroids in patients who were already using budesonide on a daily basis.
Patients eligible for the study had the classic signs of asthma and fulfilled the criteria of the American Thoracic Society for a diagnosis of asthma. At the beginning of the study, all patients had to have a persistent cough, wheeze or breathlessness during the day or night, despite their current therapy of 800 to 1,000 mg of budesonide or an equivalent dosage of beclomethasone or fluticasone. During the initial screening, three measurements of peak expiratory flow (PEF), forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) were obtained. The greatest value obtained for each was used as the patient's baseline value. In addition, baseline theophylline levels and a morning cortisol level were measured in all patients.
A total of 62 patients were randomly assigned to one of two groups. The groups were similar in age, demographics and severity of asthma. The first group received 400 mg of budesonide plus 250 mg of theophylline or 375 mg of slow-release theophylline. The second group was given 800 mg of budesonide plus placebo. All medications were given twice a day. Patients were seen every three weeks during the 12-week treatment period and one week after the study ended. At each visit, PEF, FVC, FEV1 and theophylline levels were measured; a morning serum cortisol level was obtained at week 12. In addition, all patients kept a diary in which they recorded their own peak flow measurements, their use of albuterol and the severity of their symptoms using a four-point scale. The diaries were also used to record the number of exacerbations of asthma, which were subsequently classified as mild or severe based on the patient's symptom scores.
The therapies were well tolerated by both groups. Mean serum theophylline levels throughout the study were 8.7 mg per mL, which is lower than the usual therapeutic levels. Both groups showed improvements from baseline in FEV1, FVC and PEF that were sustained throughout the study. However, the patients who took theophylline showed greater improvements in both FEV1 and FVC. Both groups also decreased their daytime use of beta2 agonists, but patients in the theophylline group decreased their nighttime use of these drugs as well. Both groups recorded a decrease in the severity of symptoms. The number of exacerbations was small in both groups, with fewer reported in the theophylline group. Serum cortisol levels were much lower in patients in the high-dose steroid group but unchanged in the other group.
The authors concluded that therapy combining theophylline with low-dose inhaled steroids is as effective as therapy using high-dose inhaled steroids alone for treating asthma. Maintaining theophylline levels below 10 mg per mL appears to be beneficial and avoids the adverse side effects that occur at the usual therapeutic level of 10 to 20 mg per mL. Another advantage to this combination therapy is that the cost of theophylline and 800 mg of budesonide is about $60 per month, compared with about $100 per month for 1,600 mg of budesonide.