Theophylline Soothes Esophageal Pain

IOWA CITY, Iowa, May 10 -- Noncardiac esophageal pain, often mistaken for angina or a myocardial infarction, can be eased by theophylline, said investigators here.

In two small double-blind studies, intravenous formulations of theophylline relaxed esophageal walls and decreased the hypersensitivity, while oral theophylline decreased the number and duration of chest-pain episodes, said Satish S.C. Rao, M.D., Ph.D., and colleagues of the University of Iowa.

The authors postulated that the neurohumoral mediator adenosine may play a key role in chest pain caused by esophageal hypersensitivity, and that theophylline, an adenosine receptor antagonist, might relieve esophageal pain, the investigators wrote in the May issue of the American Journal of Gastroenterology.

In previous studies, adenosine infusions have been shown to provoke chest pain similar to that experience in a cardiac ischemic event, but not when patients were pre-treated with oral theophylline, the authors noted.

In the first of the double-blind studies, 16 patients with chest pain from esophageal hypersensitivity were assessed for sensory and biomechanical properties of the esophagus. The patients were randomly assigned to theophylline at 0.5 L/kg body weight x average body weight x 15 mg/L, or 0.9% saline placebo.

Thirty minutes after the end of the infusion, the patients underwent esophageal balloon distention using impedance planimetry.

The authors found that compared with placebo, patients who were pretreated with intravenous theophylline had significantly higher chest pain thresholds (P=0.027) and esophageal cross-sectional area (P=0.03), and the esophageal wall became significantly more distensible (P=0.04), indicating that theophylline relieved pain in part by relaxing the esophageal wall.

In the second study, the authors enrolled 24 patients who had functional chest pain and esophageal hypersensitivity. After a two-week baseline screening period in which the patients kept diaries rating their daily pain episodes, they were randomly assigned to receive either placebo or oral theophylline, 200 mg b.i.d. for four weeks after meals.

Following a one-week washout period, the patients were then crossed over to the alternate treatment for an additional four weeks. At the end of each treatment period the patients were asked to rate their symptoms as improved, unchanged, or worse.

The investigators found that patients on theophylline had significantly fewer painful days, with a median of five (range zero to 10) compared with placebo (median 10, range three to 14, P=0.03).

Patients on theophylline also had significantly fewer episodes of chest pain (eight, range three to 15 compared with 16, range one to 25, P=0.025).

Theophylline was also associated with significantly less severe chest pain (P=0.031), and with a lower proportion of patients reporting pain severity of three on a four-point scale of 0-4 (P=0.047).

Median chest-pain duration was about 2 minutes shorter among theophylline treated patients (6.5, range 1-11.5 minutes, vs. 8.5, range 3-25 minutes for placebo P=0.002).

"Eleven patients (58%) reported that their overall symptoms (when compared with baseline) were better, four (21%) felt worse, and four (21%) other patients felt that their symptoms were unchanged after theophylline treatment," the authors wrote. "Thirteen patients (68%) reported that their symptoms were unchanged, five (26%) felt worse, and only one (6%) felt better after placebo treatment. The overall change in symptoms differed significantly between theophylline and placebo (P=0.027)."

The authors noted that while esophageal chest pain associated with gastroesophageal reflux disease responds well to treatment with proton-pump inhibitors, there is no approved therapy for pain from esophageal hypersensitivity in the absence of reflux.

"Esophageal chest pain can be a frustrating and a challenging clinical problem, and both cardiac and other nonesophageal sources may mimic this pain," they wrote. "Hence, a thoughtful appraisal is required before embarking on therapy. If a cardiac, pulmonary, musculoskeletal, or esophageal source such as acid reflux disease can be excluded, our findings suggest that a trial of theophylline may be effective in relieving chest pain."

They cautioned, however, that theophyilline could itself exacerbate gastroesophageal reflux, thereby worsening chest pain.

"Hence, caution should be exercised when prescribing theophylline and patients should be carefully followed up," they recommended.