K. G. Wormsley

Review article : maintenance treatment with H2-receptor antagonists for peptic ulcer disease

In recent years a number of different strategies for managing patients with peptic ulcer disease have become available. The present review discusses the relative merits of each form of treatment. Intermittent treatment (whether given in response to symptoms or as a prophylactic regimen prescribed seasonally or at weekends) fails to prevent ulcer recurrence and leaves patients at risk of haemorrhage and perforation. Anti‐Helicobacter pylori therapy, although useful in certain circumstances, cannot be recommended for all patients with ulcer disease because of side effects and, in any case, requires further assessment of efficacy. Gastric surgery reduces ulcer recurrence and complications, but operations which have a low incidence of side effects are associated with higher rates of ulcer recurrence, particularly when patients are followed up for more than 10 years. Long‐term continuous maintenance treatment with H2‐receptor antagonists for 5 or more years effectively prevents ulcer recurrence in the majority of patients and significantly reduces the risk of ulcer complications. In addition, maintenance treatment has proved to be safe and is well tolerated by patients.

Nine years of maintenance treatment with ranitidine for patients with duodenal ulcer disease

Four hundred and sixty‐four patients with duodenal ulcer disease received continuous maintenance treatment with ranitidine for up to 9 years. Treatment failure was defined as either the first symptomatic recurrence of ulcer or the first ulcer recurrence accompanied by haemorrhage. Life tables were constructed using the Kaplan‐Meier product‐limit method; comparisons of survival curves were performed using the log‐rank test; and multivariate analysis was carried out using the Cox proportional hazards model.

The effects of cigarette smoking on plasma concentrations of gastric antisecretory drugs.

Plasma concentrations of cimetidine and ranitidine were measured after oral administration (n= 5 for cimetidine, n= 5 for ranitidine) or intravenous administration (n= 6 for cimetidine, n= 4 for ranitidine) in habitual smokers, once when cigarettes were smoked and again on a separate day when cigarettes were prohibited. After oral administration plasma concentrations of both drugs rose more rapidly and peak plasma concentrations were achieved earlier when cigarettes were smoked. However, plasma concentrations of the drugs subsequent to the peak were significantly lower when cigarettes were smoked. Cigarette smoking had no effect on plasma blood concentrations of either drug when administered intravenously. In eight healthy smokers cigarette smoking increased the gastric emptying of a liquid test meal by 28% compared with non‐smoking control rates. In habitual smokers cigarette smoking alters the blood concentrations of antisecretory drugs in a manner which appears attributable to an increase in the rate of gastric emptying. The observed changes in drug disposition may contribute to the loss of gastric secretory inhibition observed in duodenal ulcer patients who are smokers.

A placebo-controlled investigation of duodenal ulcer recurrence after withdrawal of long-term treatment with ranitidine.

Ninety‐two patients with duodenal ulcer disease, who had received long‐term continuous treatment with ranitidine for an average of 7.5 years, participated in a double‐blind, placebo‐controlled study to determine whether stopping ranitidine resulted in ulcer recurrence. Patients were randomized to continue with ranitidine (n= 46) or to receive placebo (n= 46) and were followed up for six months. Treatment failure was defined as the first symptomatic recurrence of ulcer. The occurrence of epigastric pain during the follow‐up period was significantly less frequent in the ranitidine group (13%) than in the placebo group (43%) (P= 0.001). At six months, 9% of the ranitidine group had developed ulcer recurrence, compared with 48 % in the placebo group (P < 0.001, logrank test). Multivariate analysis using the Cox proportional hazards model showed that younger age (P= 0.041) and a long history of ulcer disease (P= 0.025) were risk factors for ulcer recurrence but gender, smoking and duration or dose of previous ranitidine treatment were not predictive of relapse during treatment with placebo. In conclusion, withdrawal of ranitidine after more than five years of continuous treatment results in almost half of the patients developing symptomatic ulcer recurrence within six months. Thus, long‐term continuous therapy does not alter the natural history of duodenal ulcer disease. Younger patients and those with a long history of ulcer disease appear to be at increased risk of developing ulcer recurrence if long‐term treatment is withdrawn.

Review article: asymptomatic duodenal ulcers—implications of heterogeneity

The present review examines the evidence for the existence of an asymptomatic variant of duodenal ulcer disease, as well as its clinical significance and therapeutic implications. Asymptomatic duodenal ulcers have definitely been shown to occur only in patients treated with nonsteroidal anti‐inflammatory drugs (NSAIDs) and in patients who have previously suffered from ulcer disease, especially if the latter have been subjected to gastric surgery or are receiving long‐term continuous (maintenance) treatment with drugs. It seems likely (although conclusive evidence is not yet available) that NSAID‐associated asymptomatic duodenal ulcers are predisposed to haemorrhage or perforation and should therefore be healed and kept in remission. Asymptomatic duodenal ulcers discovered during maintenance treatment appear to be clinically innocuous and do not therefore indicate therapeutic failure, nor require modification of therapy.

Safety profile of ranitidine : a review

SummaryRanitidine has been used for the treatment of millions of patients during the past 10 years. A small proportion of patients have developed a reaction to the drug shortly after the start of treatment, usually as a result of ‘individual idiosyncrasy’. Reactions during continuous, long term treatment with ranitidine are uncommon, so that maintenance treatment of the chronic peptic diseases with ranitidine for more than 10 years has not been associated with significant iatrogenic disease.

Therapeutic achlorhydria and risk of gastric cancer

SummaryNew, powerful gastric secretory inhibitors, such as omeprazole, produce gastric cancer in rats. The mechanism by which the drugs elicit gastric carcinogenesis is considered to depend on the production of therapeutic achlorhydria, with subsequent release in to the circulation of peptides (such as gastrin) which are trophic to the gastric mucosa. It has been argued that the drugs do not pose a carcinogenic risk to man because the neoplastic response to gastric inhibitors in rats is a reaction to a ’toxic’ insult; or because rats and humans react differently to the drugs; or because the mechanisms of gastric carcinogenesis are different in the two species. In any case, since most of the powerful gastric secretory inhibitors produce carcinoid tumours in rats, and carcinoid tumours of the human stomach are rare and largely benign, there would be no risk even if the drugs did produce proliferative abnormalities of the human stomach. Not one of the above hypotheses has been confirmed or, indeed, even satisfactorily tested. The mechanisms of the drug-induced gastric carcinogenesis in rats has not been defined and consequently it is not even possible to attempt to guess the risk to man. Until information is available about the effects of the powerful gastric secretory inhibitors on the proliferative indices and patterns of the human gastric mucosa, the drugs must be categorized as too dangerous to use therapeutically, especially since the proposed therapeutic benefits are minimal.

Ranitidine maintenance treatment of non‐steroidal anti‐inflammatory drug‐induced duodenal ulceration

Fifty‐six patients who presented with non‐steroidal anti‐inflammatory drug‐associated duodenal ulcers received maintenance treatment with ranitidine. Forty‐eight of these patients stopped treatment with nonsteroidal anti‐inflammatory drugs. The cumulative symptomatic remission at the end of 5 years of maintenance treatment was 97.7%. While half the patients had presented with haemorrhage from the ulcer, only one patient bled during maintenance treatment, giving a cumulative risk of 2.3% in 5 years of maintenance treatment.

Maintenance therapy in duodenal and gastric ulcer disease : survey of practice amongst British gastroenterologists

We have used a postal questionnaire to obtain data on the practice of maintenance therapy for peptic ulcer disease by members of the British Society of Gastroenterology. Completed questionnaires were returned by 434 members. Ninety‐six per cent used maintenance therapy for patients with duodenal ulcer and 81 % for gastric ulcer. Maintenance therapy was considered to be safe (duodenal ulcer 91%; gastric ulcer 78%), acceptable to patients (duodenal ulcer gastric ulcer 89%; gastric ulcer 80%) and to reduce the incidence of ulcer complications (duodenal ulcer 81 %; gastric ulcer 68 %). There was consensus that increasing age of patient, current use of non‐steroidal anti‐inflammatory drugs, previous ulcer complications, and ulcer relapse after surgery were relatively strong indications for maintenance therapy. However, the proportion of patients who received maintenance therapy varied widely amongst respondents (from < 10% to > 50%). There was no agreement on the optimal duration of therapy, nor on management of patients who relapsed during maintenance therapy. It appears that the criteria for use of maintenance therapy need to be better defined, and that established knowledge about the practice of maintenance therapy should be better disseminated and acted upon.

Asymptomatic duodenal ulcers occurring during maintenance treatment with ranitidine.

Fifty‐seven patients who developed asymptomatic recurrence of duodenal ulceration during maintenance treatment with ranitidine were followed up to assess the risk of developing symptoms or complications of ulcer disease. The risk of development of symptomatic ulcer recurrence was 4% in the first year of follow‐up during continuous maintenance treatment, irrespective of whether or not the asymptomatic ulcer had been actively treated (by doubling the dose of ranitidine used for maintenance therapy). The asymptomatic duodenal ulceration during maintenance treatment did not predispose to complications such as haemorrhage or perforation. It seems, therefore, that patients receiving maintenance treatment for duodenal ulceration do not require endoscopic re‐examination unless symptoms have recurred, because the asymptomatic recurrences of duodenal ulceration occurring during maintenance treatment are clinically benign, usually heal spontaneously if maintenance treatment is continued, and do not require active medical intervention.