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Notes: Background: The proton pump inhibitors (omeprazole and lansoprazole) are the drugs of choice for the medical management of gastric acid hypersecretion in Zollinger–Ellison syndrome (ZES). These drugs are safe for long-term therapy but are acid-labile and high doses are expensive. The recommended starting dose of omeprazole is 60 mg/day. However, it has been shown in recent studies that the maintenance dose of omeprazole could be safely reduced to 20 mg once or twice a day in more than two-thirds of patients with ZES. The purpose of this study is to determine if an initial starting dose of omeprazole 20 mg/day is safe and effective in patients with ZES. Methods: Forty-nine consecutive patients with ZES being treated with ranitidine for at least 2 weeks were admitted to the NIH. Omeprazole 20 mg was started on day 1 of the admission and ranitidine discontinued 4 h after the first dose. Gastric acid output was measured for 1 h prior to the next omeprazole dose on day 2, then on day 3 if the value was 〉 10 mmol/h on the previous day. If acid-peptic symptoms developed or the gastric acid output remained 〉 10 mmol/h on day 3, the patient was considered to have failed omeprazole 20 mg/day initial therapy and the dose titrated daily to achieve adequate control of acid-peptic symptoms and gastric secretion. Results: In 33 of the 49 patients (68%) omeprazole 20 mg/day was successful as initial therapy. Sixteen patients (32%) failed this initial omeprazole dose (eight patients owing to persistent peptic symptoms and eight patients owing to inadequate acid control). The final daily omeprazole dose required in these patients was 40 mg in eight patients (16%), 60 mg in one patient (2%) and 80 mg in seven patients (14%). Basal acid output (BAO) was the only clinical or laboratory feature that was significantly different between the two groups in which low dose initial omeprazole therapy was or was not successful: all patients with basal acid output 〈 20 mmol/h had a successful outcome. Conclusions: Because of the need to rapidly control gastric acid hypersecretion owing to the high risk of complications from peptic ulcer disease, patients with ZES should continue to be started on omeprazole 60 mg/day and the dose adjusted by acute titration methods as is currently recommended. After a maintenance dose is established, attempts should be undertaken to reduce the dose to 20 mg/day once or twice a day. Only the minority of patients with ZES in whom basal acid output is known to be 〈 20 mmol/h (20% of patients) should be started on a low initial omeprazole dose.