Scottish Symposium-Peptic Ulceration
SUMMARIES SUBMITTED BY PRINCIPAL DISCUSSANTS THERAPEUTIC USES OF CIMETIDINE T. J. Thomson StobhiII General Hospital, Glasgow
I have been asked to give an account of my views on the therapeutic uses of Cimetidine and, in particular, views about the need for prospective trials. When expressing an opinion about any therapy in the treatment of peptic ulcer, I think it is of fundamental importance to consider the treatment under the following headings: A Of symptomatic value? B Does it heal the ulcer? C Does it prevent recurrence? It is perhaps not uncommon practice to continue with a therapy which gives symptomatic relief after the symptoms have subsided. Similarly, treatment which has co-incided with the healing of an ulcer is not infrequently continued on the assumption that it must be of benefit to the patient. For many years this attitude persisted in relation to bland diet and antacids and even today there are those who would advise that abstinence from smoking cigarettes or drinking alcohol will increase the interval between relapses in peptic ulceration. The decision to prescribe a particular drug depends on many factors including, where possible, a knowledge of the pharmacological action in man, the side effects, the availability of alternative therapies and the relative costs. With these background thoughts in mind it is worthwhile to consider the place of Cimetidine in named conditions associated with dyspepsia. Chronic duodenal ulcer There is no doubt that in oral dosage of 1 g. daily for 1 month Cimetidine can cause healing of a high percentage of duodenal ulcers. The question of maintenance therapy in such patients in order to prevent recurrence remains unanswered. A variety of dose schedules given under conditions of doubleblind controlled trials stilI require to be tried. 300
In this way we could gain information about the optimum dosage, duration of therapy, the times of administration, which may prove to be an intermittent regimen; and also information on the occurrence of unexpected side effects. Such trials should be planned to last for not less than 1 year in the individual patient, in view of the known variability of the natural history of chronic duodenal ulcer. Such trials should also afford the opportunity for studies to be made of the levels of pepsin and gastrin as well as gastric acid, both during Cimetidine therapy and on withdrawal. At the present time I believe that a patient with duodenal ulcer, in routine circumstances, should be treated along traditional lines. Only when the symptoms fail to respond to such measures should a course of Cimetidine be given. The optimal duration of such a course is still not clear. This raises again the question of whether we are providing symptomatic therapy or healing the ulcer. In the case of the patient who is being considered for surgical treatment of uncomplicated duodenal ulcer, I consider that a course of Cimetidine in full dosage for one month should be given. *Chronic gastric ulcer The present situation appears clearer in the case of gastric ulcer. To date Cimetidine does not appear to have any distinct advantage over drugs which have been shown to accelerate the rate of healing in chronic gastric ulcer, e.g. Carbenoxolone Sodium or Deglycyrrhizinised Liquorice. It will be necessary to have extended double-blind trials comparing Cimetidine with these accepted remedies before the additional cost of using Cimetidine can be justified. This refers only to healing of gastric ulcer and the position regarding prevention of recurrence is still to be examined. It may be that Cimetidine has a place to play here.
Scottish Symposium-Peptic Ulceration
Gastro-oesophageal reflux There is a large amount of information available on the value of Cimetidine in the treatment of severe oesophagi tis due to gastro-oesophageal reflux. This evidence is largely based on open trials of the drug by experienced observers. It will be necessary, however, to perform controlled double-blind trials on the value of this drug in this condition before it can be unreservedly recommended. Acute erosive gastritis Although there was some preliminary evidence that Metiamide was useful in the treatment of upper gastro-intestinal bleeding, due to acute erosive gastritis, I understand from a trial which is being conducted in Birmingham at present that the preliminary results do not show a trend towards Cimetidine being of superior value to a placebo in the treatment of this condition. The results of this trial and possibly others are awaited with great interest. Zollinger-Ellison syndrome Cimetidine is of great value in the sympto-
matic treatment of this condition and in the investigation and preparation of patients for surgical treatment. These views are given in the knowledge and appreciation of the major advance which has been made with the discovery of the H 2receptor antagonists. This work has added greatly to our knowledge of human physiology and contributed significantly to the treatment of conditions related to the presence of acid in the stomach. It is appreciated that there may be other H 2 receptor sites in the human body and it is hoped that every attempt will be made to identify these. In this way, it should be possible to predict or at least watch for, expectantly, any undesirable side effects of this group of drugs. With particular reference to side effects, I believe that there is a case for mounting a positive monitoring system, which would record answers to specific questions about named possible side effects in perhaps 1,000 or 2,000 patients. In this way the unexpected side effect might well come to light at an earlier stage than would otherwise be possible.
*Editor's Note.- see paper by Frost et al. (1977) British Medical Journal, 2, 795.
CIMETIDINE-IS IT THE FINAL COMMON PATHWAY FOR DUODENAL ULCERS S. N. Joffe Royal Infirmary, Glasgow
Cimetidine is a potent inhibitor of gastric secretion in man when tested in a variety of conditions. More important in several controlled clinical trials, it has been found to be an effective drug in the healing of duodenal ulcers when compared to a placebo (Gillespie et al., 1977; Semb et al., 1977; Multicentre Trial, 1977). This assumes that there is no other effective form of treatment. The patients investigated in these studies had symptoms of duodenal ulceration for a mean period of 8-12 years and a range up to 27 years. These patients probably would hav
been referred for elective duodenal ulcer surgery had Cimetidine not been available. In other words, it appears that a comparison should be made, not so much regarding cimetidine and an inert placebo, but rather cimetidine versus a 'physiological' method of surgicaIly treating duodenal ulceration by a highly selective vagotomy (parietal cell vagotomy). Both the pharmacological and surgical forms of treatment reduce acid secretion to a similar extent and the mode of action is, by either producing an effective antagonism or 301
SUMMARIES SUBMITTED BY PRINCIPAL DISCUSSANTS THERAPEUTIC USES OF CIMETIDINE T. J. Thomson StobhiII General Hospital, Glasgow
I have been asked to give an account of my views on the therapeutic uses of Cimetidine and, in particular, views about the need for prospective trials. When expressing an opinion about any therapy in the treatment of peptic ulcer, I think it is of fundamental importance to consider the treatment under the following headings: A Of symptomatic value? B Does it heal the ulcer? C Does it prevent recurrence? It is perhaps not uncommon practice to continue with a therapy which gives symptomatic relief after the symptoms have subsided. Similarly, treatment which has co-incided with the healing of an ulcer is not infrequently continued on the assumption that it must be of benefit to the patient. For many years this attitude persisted in relation to bland diet and antacids and even today there are those who would advise that abstinence from smoking cigarettes or drinking alcohol will increase the interval between relapses in peptic ulceration. The decision to prescribe a particular drug depends on many factors including, where possible, a knowledge of the pharmacological action in man, the side effects, the availability of alternative therapies and the relative costs. With these background thoughts in mind it is worthwhile to consider the place of Cimetidine in named conditions associated with dyspepsia. Chronic duodenal ulcer There is no doubt that in oral dosage of 1 g. daily for 1 month Cimetidine can cause healing of a high percentage of duodenal ulcers. The question of maintenance therapy in such patients in order to prevent recurrence remains unanswered. A variety of dose schedules given under conditions of doubleblind controlled trials stilI require to be tried. 300
In this way we could gain information about the optimum dosage, duration of therapy, the times of administration, which may prove to be an intermittent regimen; and also information on the occurrence of unexpected side effects. Such trials should be planned to last for not less than 1 year in the individual patient, in view of the known variability of the natural history of chronic duodenal ulcer. Such trials should also afford the opportunity for studies to be made of the levels of pepsin and gastrin as well as gastric acid, both during Cimetidine therapy and on withdrawal. At the present time I believe that a patient with duodenal ulcer, in routine circumstances, should be treated along traditional lines. Only when the symptoms fail to respond to such measures should a course of Cimetidine be given. The optimal duration of such a course is still not clear. This raises again the question of whether we are providing symptomatic therapy or healing the ulcer. In the case of the patient who is being considered for surgical treatment of uncomplicated duodenal ulcer, I consider that a course of Cimetidine in full dosage for one month should be given. *Chronic gastric ulcer The present situation appears clearer in the case of gastric ulcer. To date Cimetidine does not appear to have any distinct advantage over drugs which have been shown to accelerate the rate of healing in chronic gastric ulcer, e.g. Carbenoxolone Sodium or Deglycyrrhizinised Liquorice. It will be necessary to have extended double-blind trials comparing Cimetidine with these accepted remedies before the additional cost of using Cimetidine can be justified. This refers only to healing of gastric ulcer and the position regarding prevention of recurrence is still to be examined. It may be that Cimetidine has a place to play here.
Scottish Symposium-Peptic Ulceration
Gastro-oesophageal reflux There is a large amount of information available on the value of Cimetidine in the treatment of severe oesophagi tis due to gastro-oesophageal reflux. This evidence is largely based on open trials of the drug by experienced observers. It will be necessary, however, to perform controlled double-blind trials on the value of this drug in this condition before it can be unreservedly recommended. Acute erosive gastritis Although there was some preliminary evidence that Metiamide was useful in the treatment of upper gastro-intestinal bleeding, due to acute erosive gastritis, I understand from a trial which is being conducted in Birmingham at present that the preliminary results do not show a trend towards Cimetidine being of superior value to a placebo in the treatment of this condition. The results of this trial and possibly others are awaited with great interest. Zollinger-Ellison syndrome Cimetidine is of great value in the sympto-
matic treatment of this condition and in the investigation and preparation of patients for surgical treatment. These views are given in the knowledge and appreciation of the major advance which has been made with the discovery of the H 2receptor antagonists. This work has added greatly to our knowledge of human physiology and contributed significantly to the treatment of conditions related to the presence of acid in the stomach. It is appreciated that there may be other H 2 receptor sites in the human body and it is hoped that every attempt will be made to identify these. In this way, it should be possible to predict or at least watch for, expectantly, any undesirable side effects of this group of drugs. With particular reference to side effects, I believe that there is a case for mounting a positive monitoring system, which would record answers to specific questions about named possible side effects in perhaps 1,000 or 2,000 patients. In this way the unexpected side effect might well come to light at an earlier stage than would otherwise be possible.
*Editor's Note.- see paper by Frost et al. (1977) British Medical Journal, 2, 795.
CIMETIDINE-IS IT THE FINAL COMMON PATHWAY FOR DUODENAL ULCERS S. N. Joffe Royal Infirmary, Glasgow
Cimetidine is a potent inhibitor of gastric secretion in man when tested in a variety of conditions. More important in several controlled clinical trials, it has been found to be an effective drug in the healing of duodenal ulcers when compared to a placebo (Gillespie et al., 1977; Semb et al., 1977; Multicentre Trial, 1977). This assumes that there is no other effective form of treatment. The patients investigated in these studies had symptoms of duodenal ulceration for a mean period of 8-12 years and a range up to 27 years. These patients probably would hav
been referred for elective duodenal ulcer surgery had Cimetidine not been available. In other words, it appears that a comparison should be made, not so much regarding cimetidine and an inert placebo, but rather cimetidine versus a 'physiological' method of surgicaIly treating duodenal ulceration by a highly selective vagotomy (parietal cell vagotomy). Both the pharmacological and surgical forms of treatment reduce acid secretion to a similar extent and the mode of action is, by either producing an effective antagonism or 301
