Cimetidine for Gastric and Duodenal Ulcer?
M. J. S. LANGMAN,
M.D.
Nottingham, England
From the Department of Therapeutics, City Hospital, Nottingham, England. Requests for reprints should be addressed to Prof. M. J. S. Langman, Department of Therapeutics, City Hospital, Nottingham NG5 IPB, England. Manuscript accepted
September0, 197s.
The dictum no acid-no ulcer looked ill-founded as anticholinergic agents failed to demonstrate evidence of efficacy in the treatment of peptic ulceration and as carbenoxolone sodium showed itself to be a useful agent in aiding ulcer healing, although it lacked any obvious effect upon acid output. However, the pharmacologic approach which led to the development of beta adrenoreceptor blockade has been rewarded again by the introduction of histamine H2 antagonists which have powerful actions in blocking not only histamine-induced secretion, but also pentagastrin-induced and food-stimulated acid output. Clinical trials outside the U.S.A. have repeatedly shown that cimetidine, the successor to metiamide which was abandoned because of its bone marrow toxicity, will promote duodenal ulcer healing and will prevent relapse during continued treatment. The pattern of response in gastric ulcer has been less clear, but taken over-all there has been evidence of efficacy with two trials indicating superiority to placebo [ 1,2] and one, as yet incomplete, suggesting possible superiority to carbenoxolone. with a fourth trial showing no real difference from placebo [ 31. Results in the U.S.A. in the treatment of duodenal ulcer have been disappointing [4,5] (and those in gastric ulcer seem no different). The reasons are unclear, but there has been similar difficulty in the past. notably with carbenoxolone, in demonstrating clinical efficacy. A high response rate to placebo therapy has been found, and this may reflect the use of much higher antacid doses concurrently than has been the custom elsewhere. Other possible explanations include a higher natural healing rate for ulcer occurring elsewhere, and perhaps the inclusion of patients with relatively transitory symptoms who might not have been seen and considered for inclusion in trials in other countries. Since cimetidine is such a potent antisecretory drug, its ability to induce ulcer healing is to be expected. Answers to two other important questions are needed: what happens to the ulcers when treatment stops, and what are the adverse consequences of treatment? Only oartial reolies are available. ’ It is already clear that the recurrence of duodenal ulcer is prompt and frequent if treatment ceases after a single course designed to heal the ulcer. This is only to be expected. The fact that the range of acid outputs of ulcer patients and of people without ulcer overlap greatly
December
1978
The American
Journal of Medicine
Volume 65
585
CIMETIDINE FOR GASTRIC AND DUODENAL ULCER-LANGMAN
is sufficient in itself to indicate that ulceration is neither solely nor mainly due to an abnormality of acid production. Furthermore, even if it were, then a temporary interruption of the mechanisms of acid production would very unlikely prevent the return of ulceration when treatment ceased. Maintenance treatment will reduce the chances of relapse, but it is becoming clear that its continuance is likely to be needed for at least six to 12 months. We have found that only about a third of the patients who received a six months’ course of maintenance treatment with cimetidine were “relapse-free” eight months after completing that course, and in a study in Denmark rather less than one in two patients remained symptom-free three months after completing a year’s treatment for duodenal ulcer [6]. Similar findings have been recorded in Scotland [ 71. There is now ample evidence that the short-term use of cimetidine is reasonably safe; in particular, it is substantially free of idiosyncratic severe adverse effects such as acute hepatic necrosis and bone marrow failure. Adverse reactions not necessitating withdrawal of treatment have been noted in a fifth of the patients receiving cimetidine in clinical trials and in about the same proportion of control subjects. Withdrawal of treatment has been thought necessary in less than one in 50 treated patients and in much the same proportion of control subjects. Examination of the pattern of individual symptoms such as headache, tiredness, nausea and muscular pain shows nothing to suggest that specific complaints might be particularly likely to be drug induced. Increases in serum creatinine and transaminase concentrations have been noted during treatment. The changes in creatinine have been small, unaccompanied by other evidence of renal dysfunction, and they are common and vanish when treatment stops. Changes in serum concentrations of liver enzymes have usually been small, with similar proportions of cimetidine- and placebo-treated-patients having rises detected. In a few subjects higher values of possible clinical significance have been noted, but it is unclear as yet whether such findings represent drug toxicity or coincidental liver disease. Endocrine changes of gynecomastia and galactorrhea have also occurred with cimetidine therapy, the former being reported more frequently than the latter. Rises in serum prolactin levels have also been reported by some but not others, and in some, but not all, patients with gynecomastia. Whether the endocrine changes are of clinical importance is doubtful; increases in serum prolactin have been noted with other drugs in widespread use, including chlorpromazine and metoclopramide. We still need to know about two other major groups of adverse effects. Firstly, will long continued use lead
666
December1976
The American Journal of Medicine
to changes in gastric secretory function? The possibilities include hypergastrinemia causing rebound acid hypersecretion on stopping treatment, and gastric atrophy consequent upon long-continued suppression of parietal cell activity. On the one hand, elevated serum gastrin levels have been reported after prolonged treatment; by contrast, diminished responses to pentagastrin stimulation have also been suggested. In isolated clinical reports it has been proposed that ulcer perforation may coincide with stopping treatment, but there is no means of knowing whether these events were more or less common than might have been expected in any ordinary population of patients with ulcer. Information about the effects of continued treatment on gastric function is limited, but so far there is no reason to believe that any dramatic changes ensue with longcontinued treatment. During treatment, gastric acid output is diminished, it is, therefore, possible that conditions in the stomach favor bacterial overgrowth and conversion of nitrates and nitrites to nitrosamines with the risk consequently of gastric cancer. This is pathophysiologic speculation; a more immediate difficulty lies in deciding whether a wide range of other possible adverse events reported, such as mental confusion, stroke and myocardial infarction, were drug induced or not. Histamine H2 receptors are distributed throughout the body, and their importance is largely undetermined. Interference with their function could be harmful; the difficulty lies in deciding whether (say) myocardial infarction in patients taking cimetidine was drug induced or coincidental. No simple post hoc adverse reaction reporting system could decide between these choices, and a prospective registering system with noncimetidine-treated control subjects would be needed to decide on the absolute frequency and the relative risk compared with an untreated population. How then should cimetidine be used? The first attack of duodenal ulcer symptoms should reasonably be managed by conventional conservative means; a second attack might justify a restricted course, say six weeks, of cimetidine therapy, the third attack perhaps another course, then possibly surgery. Maintenance treatment is harder to justify, except in patients in whom surgery is unduly risky, until either a fixed course of, say, one year is shown to alter the natural history of the disease-and this looks unlikely-or adverse effects of prolonged treatment can be discounted; this will take time. Gastric ulcer could well be managed in the same way with earlier recourse to surgery, bearing in mind the risk of cancer misdiagnosed as ulcer, and that cimetidine treatment may induce apparent healing in malignant ulcers. Do other drugs offer advantages? Competition in the U.S.A. is virtually limited to vigorous antacid treatment,
Volume 65
CIMETIDINE
and it is questionable whether the average patient would tolerate the high and frequent dosage required. Two other drugs, carbenoxolone and chelated bismuth, would be considered elsewhere. The former has common adverse effects on the blood pressure and electrolyte balance, although these are predictable and controllable. The latter seems substantially free of side
FOR GASTRIC AND DUODENAL ULCER-LANGMAN
effects, but a question still remains as to whether it is really devoid of a tendency to cause encephalopathy like, for instance, bismuth subnitrate. Cimetidine therapy offers rational control of acid secretion, but this is not necessarily treatment of the ulcer. The ulcers heal, but may recur, and the long-term effects need better assessment.
REFERENCES Frost F, Rahbek I, Rune SJ, et al.: Cimetidine in patients with gastric ulcer: a multicentre controlled trial. Br Med J 2: 795, 1977. Multicentre Trial: Treatment of gastric ulcer with cimetidine, Cimetidine, Proceedings of the Second International Symposium on Histamine H2 Antagonists, (Burland WL, Simkins MA, eds), Amsterdam, Excerpta Medica, 1977, p 287. Ciclitira PJ, Machell RJ, Farthing MJ, et al.: A controlled trial of cimetidine in the treatment of gastric ulcer in man. Cimetidine, Proceedings of the Second International Symposium on Histamine H2 Antagonists, (Burland WL, Simkins
4.
5.
6.
7.
MA, eds), Amsterdam, Excerpta Medica, 1977, p 283. Binder HJ, Cocco A, Crossley RJ, et al.: Cimetidine in the treatment of duodenal ulcer. A multicentre double blind study. Gastroenterology 74: 380, 1978. lppoliti AF, Sturdevant RAL, lsenberg JI, et al.: Cimetidine versus intensive antacid therapy for duodenal ulcer. A multicentre trial. Gastroenterology 74: 393, 1978. Gudmand-l-kiyer E, Jensen BK, Krag E, et al.: Prophylactic effect of cimetidine in duodenal ulcer disease. Br Med J 1: 1095, 1978. Wormsley KG: Unpublished observations, 1978.
December 1978
The American Journal of Medlclne
Volume 85
887
M. J. S. LANGMAN,
M.D.
Nottingham, England
From the Department of Therapeutics, City Hospital, Nottingham, England. Requests for reprints should be addressed to Prof. M. J. S. Langman, Department of Therapeutics, City Hospital, Nottingham NG5 IPB, England. Manuscript accepted
September0, 197s.
The dictum no acid-no ulcer looked ill-founded as anticholinergic agents failed to demonstrate evidence of efficacy in the treatment of peptic ulceration and as carbenoxolone sodium showed itself to be a useful agent in aiding ulcer healing, although it lacked any obvious effect upon acid output. However, the pharmacologic approach which led to the development of beta adrenoreceptor blockade has been rewarded again by the introduction of histamine H2 antagonists which have powerful actions in blocking not only histamine-induced secretion, but also pentagastrin-induced and food-stimulated acid output. Clinical trials outside the U.S.A. have repeatedly shown that cimetidine, the successor to metiamide which was abandoned because of its bone marrow toxicity, will promote duodenal ulcer healing and will prevent relapse during continued treatment. The pattern of response in gastric ulcer has been less clear, but taken over-all there has been evidence of efficacy with two trials indicating superiority to placebo [ 1,2] and one, as yet incomplete, suggesting possible superiority to carbenoxolone. with a fourth trial showing no real difference from placebo [ 31. Results in the U.S.A. in the treatment of duodenal ulcer have been disappointing [4,5] (and those in gastric ulcer seem no different). The reasons are unclear, but there has been similar difficulty in the past. notably with carbenoxolone, in demonstrating clinical efficacy. A high response rate to placebo therapy has been found, and this may reflect the use of much higher antacid doses concurrently than has been the custom elsewhere. Other possible explanations include a higher natural healing rate for ulcer occurring elsewhere, and perhaps the inclusion of patients with relatively transitory symptoms who might not have been seen and considered for inclusion in trials in other countries. Since cimetidine is such a potent antisecretory drug, its ability to induce ulcer healing is to be expected. Answers to two other important questions are needed: what happens to the ulcers when treatment stops, and what are the adverse consequences of treatment? Only oartial reolies are available. ’ It is already clear that the recurrence of duodenal ulcer is prompt and frequent if treatment ceases after a single course designed to heal the ulcer. This is only to be expected. The fact that the range of acid outputs of ulcer patients and of people without ulcer overlap greatly
December
1978
The American
Journal of Medicine
Volume 65
585
CIMETIDINE FOR GASTRIC AND DUODENAL ULCER-LANGMAN
is sufficient in itself to indicate that ulceration is neither solely nor mainly due to an abnormality of acid production. Furthermore, even if it were, then a temporary interruption of the mechanisms of acid production would very unlikely prevent the return of ulceration when treatment ceased. Maintenance treatment will reduce the chances of relapse, but it is becoming clear that its continuance is likely to be needed for at least six to 12 months. We have found that only about a third of the patients who received a six months’ course of maintenance treatment with cimetidine were “relapse-free” eight months after completing that course, and in a study in Denmark rather less than one in two patients remained symptom-free three months after completing a year’s treatment for duodenal ulcer [6]. Similar findings have been recorded in Scotland [ 71. There is now ample evidence that the short-term use of cimetidine is reasonably safe; in particular, it is substantially free of idiosyncratic severe adverse effects such as acute hepatic necrosis and bone marrow failure. Adverse reactions not necessitating withdrawal of treatment have been noted in a fifth of the patients receiving cimetidine in clinical trials and in about the same proportion of control subjects. Withdrawal of treatment has been thought necessary in less than one in 50 treated patients and in much the same proportion of control subjects. Examination of the pattern of individual symptoms such as headache, tiredness, nausea and muscular pain shows nothing to suggest that specific complaints might be particularly likely to be drug induced. Increases in serum creatinine and transaminase concentrations have been noted during treatment. The changes in creatinine have been small, unaccompanied by other evidence of renal dysfunction, and they are common and vanish when treatment stops. Changes in serum concentrations of liver enzymes have usually been small, with similar proportions of cimetidine- and placebo-treated-patients having rises detected. In a few subjects higher values of possible clinical significance have been noted, but it is unclear as yet whether such findings represent drug toxicity or coincidental liver disease. Endocrine changes of gynecomastia and galactorrhea have also occurred with cimetidine therapy, the former being reported more frequently than the latter. Rises in serum prolactin levels have also been reported by some but not others, and in some, but not all, patients with gynecomastia. Whether the endocrine changes are of clinical importance is doubtful; increases in serum prolactin have been noted with other drugs in widespread use, including chlorpromazine and metoclopramide. We still need to know about two other major groups of adverse effects. Firstly, will long continued use lead
666
December1976
The American Journal of Medicine
to changes in gastric secretory function? The possibilities include hypergastrinemia causing rebound acid hypersecretion on stopping treatment, and gastric atrophy consequent upon long-continued suppression of parietal cell activity. On the one hand, elevated serum gastrin levels have been reported after prolonged treatment; by contrast, diminished responses to pentagastrin stimulation have also been suggested. In isolated clinical reports it has been proposed that ulcer perforation may coincide with stopping treatment, but there is no means of knowing whether these events were more or less common than might have been expected in any ordinary population of patients with ulcer. Information about the effects of continued treatment on gastric function is limited, but so far there is no reason to believe that any dramatic changes ensue with longcontinued treatment. During treatment, gastric acid output is diminished, it is, therefore, possible that conditions in the stomach favor bacterial overgrowth and conversion of nitrates and nitrites to nitrosamines with the risk consequently of gastric cancer. This is pathophysiologic speculation; a more immediate difficulty lies in deciding whether a wide range of other possible adverse events reported, such as mental confusion, stroke and myocardial infarction, were drug induced or not. Histamine H2 receptors are distributed throughout the body, and their importance is largely undetermined. Interference with their function could be harmful; the difficulty lies in deciding whether (say) myocardial infarction in patients taking cimetidine was drug induced or coincidental. No simple post hoc adverse reaction reporting system could decide between these choices, and a prospective registering system with noncimetidine-treated control subjects would be needed to decide on the absolute frequency and the relative risk compared with an untreated population. How then should cimetidine be used? The first attack of duodenal ulcer symptoms should reasonably be managed by conventional conservative means; a second attack might justify a restricted course, say six weeks, of cimetidine therapy, the third attack perhaps another course, then possibly surgery. Maintenance treatment is harder to justify, except in patients in whom surgery is unduly risky, until either a fixed course of, say, one year is shown to alter the natural history of the disease-and this looks unlikely-or adverse effects of prolonged treatment can be discounted; this will take time. Gastric ulcer could well be managed in the same way with earlier recourse to surgery, bearing in mind the risk of cancer misdiagnosed as ulcer, and that cimetidine treatment may induce apparent healing in malignant ulcers. Do other drugs offer advantages? Competition in the U.S.A. is virtually limited to vigorous antacid treatment,
Volume 65
CIMETIDINE
and it is questionable whether the average patient would tolerate the high and frequent dosage required. Two other drugs, carbenoxolone and chelated bismuth, would be considered elsewhere. The former has common adverse effects on the blood pressure and electrolyte balance, although these are predictable and controllable. The latter seems substantially free of side
FOR GASTRIC AND DUODENAL ULCER-LANGMAN
effects, but a question still remains as to whether it is really devoid of a tendency to cause encephalopathy like, for instance, bismuth subnitrate. Cimetidine therapy offers rational control of acid secretion, but this is not necessarily treatment of the ulcer. The ulcers heal, but may recur, and the long-term effects need better assessment.
REFERENCES Frost F, Rahbek I, Rune SJ, et al.: Cimetidine in patients with gastric ulcer: a multicentre controlled trial. Br Med J 2: 795, 1977. Multicentre Trial: Treatment of gastric ulcer with cimetidine, Cimetidine, Proceedings of the Second International Symposium on Histamine H2 Antagonists, (Burland WL, Simkins MA, eds), Amsterdam, Excerpta Medica, 1977, p 287. Ciclitira PJ, Machell RJ, Farthing MJ, et al.: A controlled trial of cimetidine in the treatment of gastric ulcer in man. Cimetidine, Proceedings of the Second International Symposium on Histamine H2 Antagonists, (Burland WL, Simkins
4.
5.
6.
7.
MA, eds), Amsterdam, Excerpta Medica, 1977, p 283. Binder HJ, Cocco A, Crossley RJ, et al.: Cimetidine in the treatment of duodenal ulcer. A multicentre double blind study. Gastroenterology 74: 380, 1978. lppoliti AF, Sturdevant RAL, lsenberg JI, et al.: Cimetidine versus intensive antacid therapy for duodenal ulcer. A multicentre trial. Gastroenterology 74: 393, 1978. Gudmand-l-kiyer E, Jensen BK, Krag E, et al.: Prophylactic effect of cimetidine in duodenal ulcer disease. Br Med J 1: 1095, 1978. Wormsley KG: Unpublished observations, 1978.
December 1978
The American Journal of Medlclne
Volume 85
887
