Current issues of ACP Journal Club are published in Annals of Internal Medicine


Theophylline withdrawal had an unfavorable effect in chronic obstructive pulmonary disease

ACP J Club. 1994 Mar-April;120:29. doi:10.7326/ACPJC-1994-120-2-029

Source Citation

Kirsten DK, Wegner RE, Jorres RA, Magnussen H. Effects of theophylline withdrawal in severe chronic obstructive pulmonary disease. Chest. 1993 Oct;104:1101-7.



To determine the effect of theophylline therapy withdrawal in patients with severe chronic obstructive pulmonary disease (COPD).


Randomized, double-blind, placebo-controlled trial lasting 6 days.


A hospital in Germany.


39 patients (mean age 66 y) who were hospitalized with severe COPD and had a history of smoking, gradual progression of dyspnea on exertion over many years, no history of atopy, stable clinical condition with optimized therapy, absence of other major medical problems, theophylline treatment ≥ 1 week, and forced expiratory volume in 1 second of < 60% of predicted. Follow-up was 97%.


Patients were allocated to a theophylline group (n = 21), receiving theophylline for 6 days, or a placebo group (n = 18), receiving theophylline for the first 2 days and placebo for the last 4 days.

Main outcome measures

Serum levels of theophylline and potassium, lung function, arterial blood gas tensions, heart rate and arrhythmia, 6-minute walking distance, quality of life, and symptom scores were measured during the first 2 days and last 2 days of treatment.

Main results

6-minute walking distance increased for patients in the theophylline group between days 1 and 2 and days 5 and 6 (mean change 27 m) and decreased for patients in the placebo group (mean change -20 m). The absolute difference in change between groups was 47 meters (P = 0.006). The difference in change in the Medical Research Council dyspnea score was 0.4 in favor of the theophylline group (P < 0.05). Other measures showed trends in favor of the active drug that did not reach statistical significance.


Theophylline therapy withdrawal had unfavorable effects on 6-minute walking distance and dyspnea scores in patients hospitalized with severe chronic obstructive pulmonary disease.

Source of funding: Not stated.

For article reprint: Dr. H. Magnussen, Hospital Grosshansdorf, Wohrendamm 80, D(W) 2070 Grosshansdorf, Germany. FAX 49-4102-601245.


No specific laboratory tests predict clinical response to bronchodilators, including theophylline. The response in lung function to an inhaled bronchodilator (e.g., albuterol) does not provide satisfactory test-retest reliability nor does it predict which patients might improve (1). The study by Kirsten and colleagues examined physiologic and subjective responses to the withdrawal of theophylline in patients hospitalized with severe COPD. In this short, 6-day study, approximately 50% of the patients deteriorated when theophylline was withdrawn and were labeled "theophylline responders." The investigators propose determining the effectiveness of theophylline by its withdrawal after optimal therapy has been achieved.

Theophylline is now considered the third line of therapy for the treatment of COPD. Many patients with moderate-to-severe COPD, however, continue to have dyspnea on exertion and have functional limitations despite the use of inhaled β2-adrenergic agonist and inhaled ipratropium bromide. The investigators recommend that a trial of theophylline be done in patients who remain symptomatic if no contraindication to its use exists. An individual (n of 1) randomized, controlled trial may be applied to examine clinical efficacy of theophylline by either the addition or the withdrawal of that medication compared with placebo therapy (2). In an individual, randomized, controlled trial, it is important to measure symptoms, particularly dyspnea, and functional status in addition to lung function. Several instruments are available for quantifying the severity of dyspnea (3).

Donald A. Mahler, MD
Dartmouth-Hitchcock Medical CenterLebanon, New Hampshire, USA


1. Guyatt GH, Townsend M, Nogradi S, et al. Acute response to bronchodilator.An imperfect guide for bronchodilator therapy in chronic airflow limitation. Arch Intern Med. 1988;148:1949-52.

2. Patel A, Jaeschke R, Guyatt GH, Keller JL, Newhouse MT. Clinical usefulness of n-of-1 randomized controlled trials in patients with nonreversible chronic airflow limitation. Am Rev Respir Dis. 1991;144:962-4.

3. Mahler DA, Harver A. Clinical measurement of dyspnea. In: Mahler DA, ed. Dyspnea. Mount Kisco, New York: Futura Publishing; 1990:75-126.