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Low-dose oral theophylline plus budesonide was as effective as high-dose budesonide for treatment of moderate asthma

ACP J Club. 1998 May-June;128:66. doi:10.7326/ACPJC-1998-128-3-066

Source Citation

Evans DJ, Taylor DA, Zetterstrom O, et al. A comparison of low-dose inhaled budesonide plus theophylline and high-dose inhaled budesonide for moderate asthma. N Engl J Med. 1997 Nov 13;337:1412-8.



To compare the effectiveness of oral theophylline added to inhaled budesonide for patients with persistent asthma symptoms despite the use of an inhaled glucocorticoid.


3-month, randomized, double-blind, placebo-controlled trial.


2 U.K. and Swedish clinical centers.


66 adults were enrolled, and 62 (mean age 39 y, 60% women) completed the study. Patients had asthma (American Thoracic Society criteria); were symptomatic despite treatment with inhaled budesonide, 800 to 1000 µg/d, or equivalent doses of beclomethasone or fluticasone; had an FEV1> 50% of predicted value; and had abormalities that were reversed with albuterol. Exclusion criteria were frequent or recent previous use of oral glucocorticoids or recent use of theophylline, asthma exacerbations during baseline evaluation, or other serious illness.


Patients received inhaled budesonide, 800 µg/d for a 2-week run-in period, and then either budesonide, 800 µg/d, and theophylline, 250 or 375 mg based on body weight twice daily, or budesonide, 1600 µg/d. 31 patients in each group finished the trial.

Main outcome measures

FEV1, forced vital capacity (FVC), peak expiratory flow (PEF), severity of symptoms, exacerbations, and albuterol use.

Main results

Patients who received both drugs showed improvements from baseline in FEV1, FVC, and PEF and reduced PEF variation (P for all ≤ 0.009) (Table). Patients who received high-dose budesonide showed improvement from baseline in PEF (P = 0.02) (Table) and PEF variation (P = 0.03). The groups did not differ significantly for day and night symptoms, use of albuterol, exacerbations, or side effects (5 gastrointestinal upsets in the theophylline group vs 2 in the high-dose budesonide group). Budesonide plus theophylline increased FEV1 and FVC (P for both = 0.03) more than high-dose budesonide.


For patients with moderate asthma and persistent symptoms, oral theophylline plus inhaled budesonide was at least as effective as an increased dose of budesonide.

Source of funding: Byk Gulden.

For article reprint: Dr. P.J. Barnes, Department of Thoracic Medicine, National Heart and Lung Institute, Imperial College School of Medicine, Dovehouse Street, London SW3 6LY, UK. FAX 44-171-351-5675.

Table. Theophylline plus budesonide vs high-dose budesonide for asthma*

Outcomes at 12 wk Theophylline plus budesonide High-dose budesonide Between-group differences
FEV1 2.69 L† (baseline 2.48) 2.61 L† (baseline 2.50) P = 0.03
FVC 3.78 L† (baseline 3.52) 3.67 L (baseline 3.49) P = 0.03
PEF 453 L/min† (baseline 430) 436 L/min† (baseline 411) Not significant

*FVC = forced vital capacity; PEF = peak expiratory flow.
†Significant increase from baseline.


Formoterol and budesonide reduced exacerbations and improved lung function in patients with stable asthma

Patients with chronic asthma whose symptoms persist despite low-dose inhaled corticosteroid therapy have many options for maintenance: increasing the dose of inhaled corticosteroids; adding long-acting inhaled β2 agonists, such as formoterol; and adding theophylline. Evans and Pauwels and their colleagues evaluate these options using controlled trials.

Theophylline has anti-inflammatory and immunomodulatory activity (1) and provides a compliance advantage over inhaled medications (2). However, we need further information on the additive benefit of theophylline at concentrations that are lower than conventional therapeutic levels (3). The study by Evans and colleagues provides data for this question—their median level of theophylline was 8.7 µg/mL. The durability of the benefit of long-acting β2 agonists has also been questioned because of tolerance, and the 12-month study by Pauwels and colleagues addresses this issue. Because the exclusion criteria included recent courses of oral corticosteroids, the results of both studies are most relevant to patients with moderate rather than severe asthma.

The studies showed improvements of similar magnitude in many clinically important subjective and objective outcomes for both additive approaches. In general, theophylline was at least as effective as higher-dose budesonide and was associated with statistically, but not clinically, significant improvements in FEV1 and FVC that were not evident with higher-dose budesonide.

It is important to note that the benefits in the patients who received theophylline were obtained at median serum levels that were below conventional levels; theophylline also did not cause adverse reactions in most patients. Controlled studies of academic performance and behavior that include toxicity assessments have been reported and are reassuring, particularly because the study by Evans and colleagues shows that the additive benefits were obtained at low levels (3). Adverse effects may also be further reduced by a gradual stepwise introduction of theophylline.

The comments by Evans and colleagues on the relative cost of the various therapeutic options are welcome and suggest a cost advantage for theophylline. However, therapy with theophylline requires that both the clinician and the patient have adequate knowledge of the potential for toxicity and drug interactions; risk factors include lack of continuity of care and older age (4).

The strength of the conclusions from the study by Evans and colleagues is limited, however, by the flat dose-response profile of budesonide. Higher-dose budesonide cannot be assumed to provide much greater benefit in all patients, and the 2-week run-in period may have been insufficient to attain full beneficial effect on lung function. Given the absence of an appropriate control group, subsequent improvements in either therapeutic group are difficult to interpret.

The study by Pauwels and colleagues achieved a follow-up of > 80% of patients over 12 months and showed reductions in moderate and severe exacerbations that were independent and additive for formoterol and for an increased dose of budesonide. Patients did not build up a tolerance to the long-acting inhaled β2 agonist at 12 months.

Formoterol was superior to higher-dose budesonide for increasing the number of episode-free days. Improvements in most other outcomes were at least similar for formoterol as for higher-dose budesonide, and adverse effects were infrequent.

In summary, theophylline was well tolerated in most patients, outcomes with theophylline were at least similar to higher-dose budesonide, compliance with theophylline may be superior to that with inhaled therapies, and theophylline is less expensive than budesonide. In selected patients, therefore, an argument can be made for the careful addition of theophylline to low-dose inhaled corticosteroids when symptoms persist. If adverse effects occur, prompt consideration must be given to switching to a higher dose of inhaled corticosteroids or adding long-acting inhaled β2 agonists. Such additive approaches may reduce adverse effects because each drug may be used within a safer dose range rather than in the higher doses required for monotherapy.

Neither study was designed to comprehensively evaluate potential long-term or rare adverse effects. These issues warrant further evaluation.

Brian J. Smith, MBBS
Queen Elizabeth HospitalWoodville, South Australia, Australia


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3. Weinberger M, Hendeles L. Drug Therapy: Theophylline in Asthma. N Engl J Med. 1996;334:1380-8.

4. Shannon M. Predictors of major toxicity after theophylline overdose. Ann Intern Med. 1993; 119:1161-7.