Association between medications that relax the lower esophageal sphincter and risk for esophageal adenocarcinoma

Ann Intern Med. 2000 Aug 1;133(3):165-75. doi: 10.7326/0003-4819-133-3-200008010-00007.


Background: The incidence of esophageal adenocarcinoma is increasing rapidly. Gastroesophageal reflux is a strong risk factor for this disease. The increase in incidence of esophageal adenocarcinoma coincided with the introduction of medications that promote reflux by relaxing the lower esophageal sphincter (LES), such as nitroglycerin, anticholinergics, beta-adrenergic agonists, aminophyllines, and benzodiazepines.

Objective: To test the possible association between use of LES-relaxing medications and risk for adenocarcinoma of the esophagus and gastric cardia.

Design: A nationwide population-based case-control study with in-person interviews.

Setting: Sweden, 1995 through 1997.

Patients: 189 patients with newly diagnosed esophageal adenocarcinoma, 262 with adenocarcinoma of the gastric cardia, and 167 with esophageal squamous-cell carcinoma were compared with 820 population-based controls.

Measurements: Estimated incidence rate ratios, calculated by using multivariate logistic regression from case-control data with adjustment for potential confounding.

Results: Past use of LES-relaxing drugs was positively associated with risk for esophageal adenocarcinoma. Among daily, long-term users (>5 years) of LES-relaxing drugs, the estimated incidence rate ratio was 3.8 (95% CI, 2.2 to 6.4) compared with persons who had never used these drugs. Drugs of all classes contributed to the increased risk, but the association was particularly strong for anticholinergics. Short-term use of other types of LES-relaxing drugs did not seem to be strongly associated with risk. The association almost disappeared after adjustment for reflux symptoms, indicating that promotion of reflux is the link between use of LES-relaxing drugs and esophageal adenocarcinoma. If 15,490 men in any age group take LES-relaxing drugs daily for 5 years, 1 additional case of adenocarcinoma would be expected (number needed to treat for harm); in men older than 60 years of age, the number needed to treat for harm is 5,570. Assuming a causal relation, about 10% of the esophageal adenocarcinomas occurring in the population may be attributable to intake of LES-relaxing drugs. Cardia adenocarcinoma and esophageal squamous-cell carcinoma were not associated with use of LES-relaxing drugs.

Conclusions: The widespread use of LES-relaxing drugs may have contributed to the increasing incidence of esophageal adenocarcinoma.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenocarcinoma / etiology*
  • Adrenergic beta-Agonists / adverse effects
  • Aminophylline / adverse effects
  • Benzodiazepines / adverse effects
  • Carcinoma, Squamous Cell / etiology
  • Cardia
  • Case-Control Studies
  • Cholinergic Antagonists / adverse effects
  • Confounding Factors, Epidemiologic
  • Esophageal Neoplasms / etiology*
  • Esophagogastric Junction / drug effects*
  • Gastroesophageal Reflux / chemically induced*
  • Gastroesophageal Reflux / complications
  • Humans
  • Interviews as Topic
  • Male
  • Nitroglycerin / adverse effects
  • Regression Analysis
  • Risk Factors
  • Stomach Neoplasms / etiology
  • Vasodilator Agents / adverse effects


  • Adrenergic beta-Agonists
  • Cholinergic Antagonists
  • Vasodilator Agents
  • Benzodiazepines
  • Aminophylline
  • Nitroglycerin