Scottish Symposium-Peptic Ulceration
CIMETIDINE IN THE MANAGEMENT OF GASTRIC ULCERATION* D. G. Colin-Jones Queen Alexandra Hospital, Portsmouth
Gastric ulcers should be treated more actively than duodenal ulcers. They often occur in the older patient and since eating aggravates the pain, the patient may well eat less to the detriment of his health. Any complication is associated with a high mortality (e.g. acute haemorrhage from a gastric ulcer carries a mortality of about 17 per cent. (Johnston et al., 1973). Furthermore, approximately 6 per cent of apparently benign ulcers prove to be malignant (Lancet, 1976). Thus all gastric ulcers should be endoscoped, the ulcer biopsied and cytology undertaken. If medical treatment is decided upon, then complete healing should be confirmed, ideally by endoscopy, or alternatively by radiology. Choice of drug therapy To date carbenoxolone sodium is the best evaluated giving a healing rate of approximately 50 per cent in 4 weeks and 65 per cent in 8 weeks (Sircus, 1973). This drug has side effects in about half the patients receiving the drug (hypokalaemia, hypertension, fluid retention) and so is contraindicated in the elderly, and in cardiac or renal disease. Other drugs commonly used in this country are Caved-S and De-Nol, both of which have few side effects. However, the percentage healing rate for Caved-S is variable in the therapeutic trials utilising this drug-it is probably less effective than Carbenoxolone. De-Nol has been shown to heal 90 per cent of gastric ulcers in one trial (Boyes et al., 1975) but confirmation is needed before this bismuth compound can be advised as the drug of first choice. Many other drugs have been tried, and found wanting, relieving symptoms but not consistently healing ulcers (British Medical Journal, 1974). So clearly there is a need for a safe and effective drug for the treatment of gastric ulceration. Will Cimetidine fill that need? Mode of action of Cimetidine in Gastric Ulceration (Figs. 1 & 2) The most striking action of Cimetidine is to reduce acid output-so at first it might
N
o.u.
A M
A M
A
= Acid
Gu.
A
M
challenge
M = Mucosal
resistance
Fig. 1. Postulated relationship between acid/pepsin challenge against the mucosal resistance in normal patients, in duodenal ulcer patients (where the acid challenge is increased in many) and gastric ulcers where both the mucosal resistance and acid challenge may be reduced.
Gu.
GU +
Cimetidi ne healed ?
not healed ?
A M A =Acid
challenge
M = Mucosal resistance Fig. 2. Postulated basis for healing in treatment of gastric ulcers of Cimetidine where the acid challenge is reduced but in some patients perhaps not sufficiently (see text).
seem unlikely to help in a situation where an ulcer develops in the presence, on average, of a reduced acid secretion. Most workers consider that a gastric ulcer develops as a result of a combination of acid and pepsin digestion of the mucosa and a 295
Scottish Symposium-Peptic Ulceration
poor mucosal defence. This is represented in Figure 1 where the situation in duodenal ulcers is largely one of increased acid output, but in gastric ulceration of reduced acid mucosal defence. A tentative explanation for giving Cimetidine for gastric ulcers is to reduce further the acid output so that even the poor mucosal barrier can cope with the acid challenge and allow healing to occur (Fig. 2). In situations where healing does not take place it might be due to a very poor mucosa which cannot heal even if the acid secretion is greatly reduced (Fig. 2). To date there is no published data on this, and the figure is only a postulate. Results with Cimetidine The uncontrolled observations of Pounder et al. (1976) that all 10 of their cases healed, provided an impetus for 3 trials which have currently been published. Lambert et al. studied 53 patients in a multicentre trial (1977), 26 receiving 19. of Cimetidine in divided doses and 27 placebo. The groups were comparable and healing occurred in 18 of 26 patients (69%) after one month's treatment with Cimetidine and in 37 per cent in those on placebo. Although there was considerable symptomatic relief, the relationship between healing and relief of symptoms was not complete-for which there is no explanation at present. There was no consistent side effect. The Cambridge group (Ciclitira et al., 1977) also compared placebo with 19. of Cimetidine in divided doses over 4 weeks. Only patients who were unsuitable for Carbenoxolone therapy were entered. Sixteen patients received placebo (8 healed) and 19 patients received Cimetidine (15 healed) -p=0.069. Again symptoms were not invariably relieved when the ulcer was healed Included in this group were 4 anastomotic ulcers and 6 prepyloric ulcers, which may well behave differently from lesser curve gastric ulcers. This makes interpretation slightly more difficult. Our own group (Taylor et al., 1977), are comparing Carbenoxolone (300 mg. daily for. 1 week, then 150 mg. daily in divided doses) with Cimetidine (Ig. daily in divided doses) in benign gastric ulceration in the body of the stomach. Assessment of healing 296
was after 6 weeks' treatment using endoscopy; with the second endoscopist being ignorant of the treatment given. To date 32 patients have entered the trial, one defaulted from the Carbenoxolone; II of 15 patients in the Cimetidine group and 8 of 16 patients in the Carbenoxolone group healed their ulcers. This is not a statistically significant difference. In our study the correlation between ulcer healing and relief symptoms was good. Half of the Carbenoxolone group had significant side effects (7 had hypokalaemia) but of the 5 with side effects on Cimetidine none was serious. Conclusion Cimetidine clearly has a place in the treatment of gastric ulcer disease. Adding the results of the 3 trials quoted above gives an unusually consistent healing rate of 69 to 79 per cent (average 73%). Thus, in the short term it is at least comparable to other available drugs, and possibly better since it seems to be free from major side effects. At the present time there is no data on the all important question of relapse. About 45 per cent of patients will have a recurrence of their gastric ulcer in 2 years, but the relapse rate after a short course of Cimetidine is unknown, and the place of maintenance therapy has only just begun to be assessed. Much further work needs to be done to establish the place of Cimetidine in the management of gastric ulcer disease. REFERENCES
Boyes, B. E., Woolf, I. L., Wilson, R. Y., Cowley, D. J .. Dynock, I. W. (1975). Treatment of gastric ulceration with a bismuth preparation. Postgraduate Medical Journal 51, Supp!. 5, 29 British Medical Journal (1974). Editorial: Drugs for gastric ulceration. British Medical Journal, 2, 186 Ciclltira, P. J., Machell, R. J., Farthing, M. J., Dick, A. P., Hunter, J. O. (1977). Experience with Cim etidine in the treatment of gastric ulceration. Proceedings of British Society of Gastroenterology, April 1977: Gut (in press) Johnston, S. J., Jv'lJJ, P. F., Kyle, J., Needham, C. D. (1973). Epidemiology and cause of GI haemorrhage in N.E. Scotland. British Medical Journal, 3, 655 Lancet (1976). Editorial: When is a gastric ulcer really a cancer? Lancet, 1, 233
Scottish Symposium-Peptic Ulceration
Multicentre trial: Treatment of gastric ulcer by Cimetidine. Proceeds of second international symposium on H. receptor antagonists (1977). Excerpta Medica, p.287 Pounder, R. K, Hunt, R. H., Stekelman, M., MiltonThompson, G. J" Missiewicz, J. J. (1976). Healing of gastric ulcer during treatment with Cimetidine. Lancet, 1, 337
Sircus, W. (1973). Progress report: Carbenoxolone sodium. Gut, 13, 816 Taylor, R. H., Laidlow, J. M., Chapman R. G., Colin-Jones, D. G., Golding, P. L., Hunt, R. H., Vincent, S. H., Milton-Thomson, G. J., Missiewicz, J. J. (1977). Double-blind trial comparing Cimetidine with Carbenoxolone in the treatment of benign gastric ulcer. Gut (in press).
*Readers please note correspondence in Lancet and British Medical Journal (e.g. Brit. med. J., 1977,2,795).
CIMETIDINE IN THE TREATMENT OF PEPTIC OESOPHAGITIS
R. A. McCluskie Hairmyres Hospital, East Kilbride
No Summary Submitted
TREATMENT OF ACUTE UPPER GASTRO-INTESTINAL BLEEDING WITH CIMETIDINE
J. Y. Kang, P. W. Dykes, A. Hoare, C. F. Hawkins and Jane G. Mills The General Hospital and the Queen Elizabeth Hospital, Birmingham and Smith Kline and French Laboratories
Upper gastro-intestinal haemorrhage is a common medical emergency with many causes. Most patients suffer from ulcerative or erosive disease of the oesophagus, stomach, or duodenum, often associated with increased acid secretion from the stomach. Cimetidine, by inhibiting acid production, may therefore be expected to reduce the incidence of rebleeding and hence improve survival rates. We are currently carrying out a doubleblind controlled study of the use ofCimetidine in upper gastro-intestinal haemorrhage. In order to concentrate on patients with a greater chance of rebleeding we have excluded patients with minor degrees of haemorrhage and those under the age of 45 years. Patients with gastro-intestinal or widespread malignancies and those with significant liver, renal, or haematological disorders are also excluded. We stratified patients according to age and severity of haemorrhage, the latter being defined by clinical criteria. Patients were then entered consecutively into a predetermined randomised prescription list to be
given either Cimetidine or placebo. Treatment is given intravenously for 48 hours, at the rate of 200 mg. 4-hourly; oral treatment 400 mg. 6-hourly is then given and continued for 7 days. Endoscopy is carried out, usually within 24 hours of admission, to determine the site of bleeding. Standard transfusional therapy is given, and patients are referred for surgery when the usual indications exist. Treatment is deemed to have failed when there is evidence of significant re-bleeding, or when initial bleeding has not stopped. We have analysed the results for the first 63 patients who have completed the trial. Thirty-two have been treated with Cimetidine and 33 with placebo. The 2 groups are well balanced with respect to age, sex and severity of haemorrhage; there is, however, a marked imbalance in the distribution of gastric ulcers (Table I). Twenty patients rebled: 13 in the Placebo group and 7 in the Cimetidine group. All these occurred in patients shown to have gastric or duodenal ulcers: thus no rebleeding 297
CIMETIDINE IN THE MANAGEMENT OF GASTRIC ULCERATION* D. G. Colin-Jones Queen Alexandra Hospital, Portsmouth
Gastric ulcers should be treated more actively than duodenal ulcers. They often occur in the older patient and since eating aggravates the pain, the patient may well eat less to the detriment of his health. Any complication is associated with a high mortality (e.g. acute haemorrhage from a gastric ulcer carries a mortality of about 17 per cent. (Johnston et al., 1973). Furthermore, approximately 6 per cent of apparently benign ulcers prove to be malignant (Lancet, 1976). Thus all gastric ulcers should be endoscoped, the ulcer biopsied and cytology undertaken. If medical treatment is decided upon, then complete healing should be confirmed, ideally by endoscopy, or alternatively by radiology. Choice of drug therapy To date carbenoxolone sodium is the best evaluated giving a healing rate of approximately 50 per cent in 4 weeks and 65 per cent in 8 weeks (Sircus, 1973). This drug has side effects in about half the patients receiving the drug (hypokalaemia, hypertension, fluid retention) and so is contraindicated in the elderly, and in cardiac or renal disease. Other drugs commonly used in this country are Caved-S and De-Nol, both of which have few side effects. However, the percentage healing rate for Caved-S is variable in the therapeutic trials utilising this drug-it is probably less effective than Carbenoxolone. De-Nol has been shown to heal 90 per cent of gastric ulcers in one trial (Boyes et al., 1975) but confirmation is needed before this bismuth compound can be advised as the drug of first choice. Many other drugs have been tried, and found wanting, relieving symptoms but not consistently healing ulcers (British Medical Journal, 1974). So clearly there is a need for a safe and effective drug for the treatment of gastric ulceration. Will Cimetidine fill that need? Mode of action of Cimetidine in Gastric Ulceration (Figs. 1 & 2) The most striking action of Cimetidine is to reduce acid output-so at first it might
N
o.u.
A M
A M
A
= Acid
Gu.
A
M
challenge
M = Mucosal
resistance
Fig. 1. Postulated relationship between acid/pepsin challenge against the mucosal resistance in normal patients, in duodenal ulcer patients (where the acid challenge is increased in many) and gastric ulcers where both the mucosal resistance and acid challenge may be reduced.
Gu.
GU +
Cimetidi ne healed ?
not healed ?
A M A =Acid
challenge
M = Mucosal resistance Fig. 2. Postulated basis for healing in treatment of gastric ulcers of Cimetidine where the acid challenge is reduced but in some patients perhaps not sufficiently (see text).
seem unlikely to help in a situation where an ulcer develops in the presence, on average, of a reduced acid secretion. Most workers consider that a gastric ulcer develops as a result of a combination of acid and pepsin digestion of the mucosa and a 295
Scottish Symposium-Peptic Ulceration
poor mucosal defence. This is represented in Figure 1 where the situation in duodenal ulcers is largely one of increased acid output, but in gastric ulceration of reduced acid mucosal defence. A tentative explanation for giving Cimetidine for gastric ulcers is to reduce further the acid output so that even the poor mucosal barrier can cope with the acid challenge and allow healing to occur (Fig. 2). In situations where healing does not take place it might be due to a very poor mucosa which cannot heal even if the acid secretion is greatly reduced (Fig. 2). To date there is no published data on this, and the figure is only a postulate. Results with Cimetidine The uncontrolled observations of Pounder et al. (1976) that all 10 of their cases healed, provided an impetus for 3 trials which have currently been published. Lambert et al. studied 53 patients in a multicentre trial (1977), 26 receiving 19. of Cimetidine in divided doses and 27 placebo. The groups were comparable and healing occurred in 18 of 26 patients (69%) after one month's treatment with Cimetidine and in 37 per cent in those on placebo. Although there was considerable symptomatic relief, the relationship between healing and relief of symptoms was not complete-for which there is no explanation at present. There was no consistent side effect. The Cambridge group (Ciclitira et al., 1977) also compared placebo with 19. of Cimetidine in divided doses over 4 weeks. Only patients who were unsuitable for Carbenoxolone therapy were entered. Sixteen patients received placebo (8 healed) and 19 patients received Cimetidine (15 healed) -p=0.069. Again symptoms were not invariably relieved when the ulcer was healed Included in this group were 4 anastomotic ulcers and 6 prepyloric ulcers, which may well behave differently from lesser curve gastric ulcers. This makes interpretation slightly more difficult. Our own group (Taylor et al., 1977), are comparing Carbenoxolone (300 mg. daily for. 1 week, then 150 mg. daily in divided doses) with Cimetidine (Ig. daily in divided doses) in benign gastric ulceration in the body of the stomach. Assessment of healing 296
was after 6 weeks' treatment using endoscopy; with the second endoscopist being ignorant of the treatment given. To date 32 patients have entered the trial, one defaulted from the Carbenoxolone; II of 15 patients in the Cimetidine group and 8 of 16 patients in the Carbenoxolone group healed their ulcers. This is not a statistically significant difference. In our study the correlation between ulcer healing and relief symptoms was good. Half of the Carbenoxolone group had significant side effects (7 had hypokalaemia) but of the 5 with side effects on Cimetidine none was serious. Conclusion Cimetidine clearly has a place in the treatment of gastric ulcer disease. Adding the results of the 3 trials quoted above gives an unusually consistent healing rate of 69 to 79 per cent (average 73%). Thus, in the short term it is at least comparable to other available drugs, and possibly better since it seems to be free from major side effects. At the present time there is no data on the all important question of relapse. About 45 per cent of patients will have a recurrence of their gastric ulcer in 2 years, but the relapse rate after a short course of Cimetidine is unknown, and the place of maintenance therapy has only just begun to be assessed. Much further work needs to be done to establish the place of Cimetidine in the management of gastric ulcer disease. REFERENCES
Boyes, B. E., Woolf, I. L., Wilson, R. Y., Cowley, D. J .. Dynock, I. W. (1975). Treatment of gastric ulceration with a bismuth preparation. Postgraduate Medical Journal 51, Supp!. 5, 29 British Medical Journal (1974). Editorial: Drugs for gastric ulceration. British Medical Journal, 2, 186 Ciclltira, P. J., Machell, R. J., Farthing, M. J., Dick, A. P., Hunter, J. O. (1977). Experience with Cim etidine in the treatment of gastric ulceration. Proceedings of British Society of Gastroenterology, April 1977: Gut (in press) Johnston, S. J., Jv'lJJ, P. F., Kyle, J., Needham, C. D. (1973). Epidemiology and cause of GI haemorrhage in N.E. Scotland. British Medical Journal, 3, 655 Lancet (1976). Editorial: When is a gastric ulcer really a cancer? Lancet, 1, 233
Scottish Symposium-Peptic Ulceration
Multicentre trial: Treatment of gastric ulcer by Cimetidine. Proceeds of second international symposium on H. receptor antagonists (1977). Excerpta Medica, p.287 Pounder, R. K, Hunt, R. H., Stekelman, M., MiltonThompson, G. J" Missiewicz, J. J. (1976). Healing of gastric ulcer during treatment with Cimetidine. Lancet, 1, 337
Sircus, W. (1973). Progress report: Carbenoxolone sodium. Gut, 13, 816 Taylor, R. H., Laidlow, J. M., Chapman R. G., Colin-Jones, D. G., Golding, P. L., Hunt, R. H., Vincent, S. H., Milton-Thomson, G. J., Missiewicz, J. J. (1977). Double-blind trial comparing Cimetidine with Carbenoxolone in the treatment of benign gastric ulcer. Gut (in press).
*Readers please note correspondence in Lancet and British Medical Journal (e.g. Brit. med. J., 1977,2,795).
CIMETIDINE IN THE TREATMENT OF PEPTIC OESOPHAGITIS
R. A. McCluskie Hairmyres Hospital, East Kilbride
No Summary Submitted
TREATMENT OF ACUTE UPPER GASTRO-INTESTINAL BLEEDING WITH CIMETIDINE
J. Y. Kang, P. W. Dykes, A. Hoare, C. F. Hawkins and Jane G. Mills The General Hospital and the Queen Elizabeth Hospital, Birmingham and Smith Kline and French Laboratories
Upper gastro-intestinal haemorrhage is a common medical emergency with many causes. Most patients suffer from ulcerative or erosive disease of the oesophagus, stomach, or duodenum, often associated with increased acid secretion from the stomach. Cimetidine, by inhibiting acid production, may therefore be expected to reduce the incidence of rebleeding and hence improve survival rates. We are currently carrying out a doubleblind controlled study of the use ofCimetidine in upper gastro-intestinal haemorrhage. In order to concentrate on patients with a greater chance of rebleeding we have excluded patients with minor degrees of haemorrhage and those under the age of 45 years. Patients with gastro-intestinal or widespread malignancies and those with significant liver, renal, or haematological disorders are also excluded. We stratified patients according to age and severity of haemorrhage, the latter being defined by clinical criteria. Patients were then entered consecutively into a predetermined randomised prescription list to be
given either Cimetidine or placebo. Treatment is given intravenously for 48 hours, at the rate of 200 mg. 4-hourly; oral treatment 400 mg. 6-hourly is then given and continued for 7 days. Endoscopy is carried out, usually within 24 hours of admission, to determine the site of bleeding. Standard transfusional therapy is given, and patients are referred for surgery when the usual indications exist. Treatment is deemed to have failed when there is evidence of significant re-bleeding, or when initial bleeding has not stopped. We have analysed the results for the first 63 patients who have completed the trial. Thirty-two have been treated with Cimetidine and 33 with placebo. The 2 groups are well balanced with respect to age, sex and severity of haemorrhage; there is, however, a marked imbalance in the distribution of gastric ulcers (Table I). Twenty patients rebled: 13 in the Placebo group and 7 in the Cimetidine group. All these occurred in patients shown to have gastric or duodenal ulcers: thus no rebleeding 297
