Wright and Sarich's recommendation to reserve long-term omeprazole therapy for patients with severe, erosive esophageal disease who cannot be managed with other available therapies would be reasonable if the alternative long-term therapies for less severe disease were equally efficacious, safe, and cost-effective. This recommendation, however, would exclude promotility drugs (because of their reduced efficacy and unknown long-term safety) and histamine-2-receptor antagonists in standard doses (because of their reduced efficacy) and in high doses (because of probable reduced efficacy, unknown long-term safety, and increased cost compared with omeprazole).

The combination of serum gastrin determinations every 3 months and yearly gastroscopies should not be recommended without evidence that the associated costs will be offset by improved safety. Gastrin levels may vary sixfold in persons tested every 3 or 4 months during long-term omeprazole therapy, and yearly testing is as likely as thrice-yearly testing to identify patients with gastrin levels greater than 400 pg/mL [1]. Graham's extraordinary recommendation that gastroscopies be done annually during omeprazole therapy was based on his observation of gastric mucosal nodularity in some patients [2]. The nodules have since been shown to be mucosal cysts of no known clinical relevance [3].

Regardless of their rate of omeprazole metabolism, patients with high gastrin levels should have a trial of low-dose omeprazole or histamine-2 blockers because they may not need a high degree of gastric acid inhibition. Meanwhile, the effects of slow omeprazole metabolism on acid secretion, gastrin levels, and vitamin B₁₂ absorption should be measured. Such pharmacodynamics data will be more useful than pharmacokinetics data in the creation of sound clinical recommendations.

Waldum and Brenna's observation that the maximum trophic effects of gastrin are reached at concentrations of less than 500 pM underscores the importance of an additional factor operating in patients with pernicious anemia and the Zollinger-Ellison syndrome in whom gastric carcinoid tumors develop; that is, hypergastrinemia appears to be necessary but not necessary and sufficient. The additional factor, possibly related to the multiple endocrine neoplasia type I gene in patients with the Zollinger-Ellison syndrome and to chronic inflammation in patients with pernicious anemia appears to trigger a transformation from ECL-cell hyperplasia to dysplasia and neoplasia.

To deny that safety concerns about omeprazole are diminishing is to ignore facts. Since the discovery of omeprazole-induced gastric carcinoid tumors in rats nearly a decade ago, regulatory agencies throughout the world have approved the use of omeprazole, including its long-term use in several countries. These developments reflect an increased understanding of the mechanism of carcinoid formation, the absence of omeprazole-induced ECL-cell dysplasia or carcinoid tumors in long-term clinical trials, and the absence of carcinoid tumors in surveillance studies among the estimated 60 million patients who have been treated with omeprazole. It is also reassuring that gastric carcinoids are not known to occur years after gastric vagotomy, which causes gastrin elevations greater than those resulting from omeprazole therapy [4].

Safety concerns persist, of course, and continued surveillance is necessary. Meanwhile, clinicians can use omeprazole to treat patients with recurrent esophagitis and can know that they are practicing within the experience of excellent long-term safety trials such as those of Lamberts and colleagues [5] and Klinkenberg-Knol and colleagues.