It is generally believed that omeprazole, particularly in high doses, reliably and completely suppresses gastric acid production. We describe a patient with severe gastroesophageal reflux disease who continued to have gastric acid production and markedly abnormal esophageal acid exposure while receiving omeprazole in daily doses as high as 180 mg.

A 43-year-old man presented with an 11-year history of dysphagia, regurgitation, and heartburn. His physical examination was normal. A barium esophagram showed no stricture. Esophageal manometry showed poor peristalsis and a lower esophageal sphincter pressure of 23 mm Hg with complete relaxation. The patient was given omeprazole at 40 mg twice daily. His total 24-hour distal esophageal and gastric acid exposures (pH <4.0) were 10.5% and 99.5%, respectively (Figure 1). The omeprazole dose was increased to 60 mg three times daily, yielding acid exposures of 11.7% and 35.1%, respectively, with persistent heartburn. Basal serum gastrin level (94 pg/mL), gastric acid analysis (basal acid output, 2.52 mEq H^+/1), secretin test results, and gastric emptying studies were all normal. At an omeprazole dose of 20 mg twice daily for 10 days, omeprazole and its sulphone metabolite, measured by high-pressure liquid chromatography, were normal [1]. The patient was given nizatidine, 150 mg every 2 hours, and showed a decrease in heartburn and dramatic improvement in daytime distal esophageal and gastric acid exposure. Acid production increased overnight while the patient was asleep and not receiving medication (Figure 1).

View larger version (37K): [in this window] [in a new window]   Figure 1. Dual electrode pH monitoring in a patient receiving omeprazole for gastroesophageal reflux disease. Top. Lighter tracing is 5 cm above the lower esophageal sphincter, and bold tracing is 10 cm below it. Data shown while the patient received omeprazole at 40 mg twice daily. Gastric pH remained less than 4.0 for the entire 24-hour study period, and frequent reflux was seen. Bottom. Monitoring of pH while the patient received nizatidine (150 mg every 2 hours while the patient was awake). Gastric pH was consistently elevated during the day and subsequently decreased overnight. Reflux occurred when the patient was asleep and could not take the medication. O = omeprazole; N = nizatidine.

By excluding gastroparesis, a hypersecretory state, altered metabolism, and decreased absorption of the drug, we hypothesize that either a variant H^+/K+ adenosine triphosphate structure with altered binding or rapid enzyme turnover may explain the mechanism of omeprazole resistance in this patient. This hypothesis is also supported by the ability of nizatidine to suppress this patient's gastric acid, given that histamine-2 antagonists act by a mechanism different from that of omeprazole [2, 3]. We are now studying 12 patients with similar omeprazole resistance. It should be noted that treating a patient with high-dose omeprazole does not ensure complete gastric acid suppression.