Oral theophylline for chronic obstructive pulmonary disease

Background: Oral theophylline has, for many years, been used as a bronchodilator in patients with COPD. Despite the introduction of new drugs, and its narrow therapeutic index, theophylline is still recommended for COPD treatment.

Objectives: To determine the effectiveness of oral theophylline when compared to placebo in patients with stable COPD.

Search strategy: The Cochrane Airways Review Group and Cochrane Controlled Clinical Registers were searched.

Selection criteria: All studies were randomised controlled trials (RCTs).

Data collection and analysis: Data were independently abstracted and the methodological quality assessed by two reviewers.

Main results: Twenty RCTs met the inclusion criteria. Concomitant therapy varied from none to any other bronchodilator plus corticosteroid (oral and inhaled). The following outcomes were significantly different when compared to placebo. FEV1 improved with treatment: Weighted Mean Difference (WMD) 100 ml; 95% Confidence Interval (95%CI) 40, 160 ml. Similarly for FVC: WMD 210 ml 95%CI 100, 320. Two studies reported an improvement in VO2max; WMD 195 ml/min, 95%CI 113,27). At rest, PaO2 and PaCO2 both improved with treatment (WMD 3.2 mmHg; 95%CI = 1.2, 5., and WMD -2.4 mmHg; 95%CI = -3.5, -1.2, respectively). Walking distance tests did not improve (4 studies, Standardised Mean Difference 0.30, 95%CI -0.01, 0.62), neither did Visual Analogue Score for breathlessness isn two small studies (WMD 3.6, 95%CI -4.6, 11.8). The Relative Risk (RR) of nausea was greater with theophylline (RR 7.7; 95%CI 1.5, 39.9). However, patients' preference for theophylline was greater than that for placebo (RR 2.27; 95%CI = 1.26, 4.11). Very few patient withdrew from these studies for any reason.

Reviewer's conclusions: Theophylline has a modest effect on FEV1 and FVC and slightly improves arterial blood gas tensions in moderate to severe COPD. These benefits were seen in patients receiving a variety of different concomitant therapies. Improvement in exercise performance depended on the method of testing. There was a very low dropout rate in the studies that could be included in this review, which suggests that recruited patients may have been known by the investigators to be theophylline tolerant. This may limit the generalisability of these studies.