Sucralfate versus placebo in treatment of non-ulcer dyspepsia

Sucralfate versus Placebo in Treatment of Non-Ulcer Dyspepsia One hundred fifty-one patients with non-ulcer dyspepsia, defined as chronic epigastric pain without concomitant symptoms of the irritable bowel syndrome and with no evidence of any organic disease other than macroscopic or microscopic gastritislduodenitis seen at endoscopy on entry into the trial, were randomly assigned to treatment for four weeks with sucraifate or a placebo, 1 g three times a day one-half hour before meals, according to a double-blind model. Seventy-nine patients received sucraifate and 72 patients received a placebo. According to patients’ subjective assessment of their symptoms at four weeks, 61 patients (77 percent) in the sucraifate group and 40 patients (56 percent) in the placebo group had become symptom-free or showed improvement, whereas the condition of 16 (23 percent) in the former group compared with 32 (44 percent) in the latter group remained unchanged or deteriorated. The difference between the groups was significant (p ~0.01). The best response to sucraifate treatment (64 percent or more symptom-free or improved) was achieved in patients with mild or moderate symptoms and without macroscopic or microscopic inflammation of their gastric mucosa-a typical patient with non-ulcer dyspepsia. Our results indicate that sucraifate is significantly more effective than placebo in the treatment of non-ulcer dyspepsia. MATTI I. KAIRALUOMA, M.D., Ph.D. RISTO HENTILAE, M.D. MART-R ALAVAIKKO, M.D., Ph.D. JUHANI KELLOSALO, M.D. MARKKU STAHLBERG, M.D., Ph.D. PEKKA JALOVAARA, M.D., Ph.D. MATTI OLSEN, M.Sc. PEKKA JAERVENSIVU, M.D. SEPPO LAITINEN, M.D., Ph.D. Oulu, Finland From the Departments of Surgery and Pathology, Oulu University Central Hospital, Oulu, Finland, and Farmos Group Ltd., Research Center, Oulu, Finland. Requests for reprints should be addressed to Dr. Matti I. Kairaluoma, Department of Surgery, Oulu University Central Hospital, Kajaanintie 50, SF-90220 Oulu 22, Finland. September Since the pathogenesis of non-ulcer dyspepsia is virtually unknown, the rationale for treatment directed at the neutralization or suppression of gastric acid is not well substantiated. A proven benefit, demonstrated in placebo-controlled clinical trials, should be a basic requirement for therapy recommendations. Only two such trials of antacids [1,2] and four of histamine (H&receptor blockers (2-51 in non-ulcer dyspepsia have been reported thus far, and all have failed to confirm any beneficial effects in this condition. Sucralfate is a new cytoprotective anti-ulcer drug that forms an adherent complex with proteins of the damaged and normal gastroduodenal mucosa and thus acts as an effective protective barrier against the deleterious actions of acid, pepsin, and bile salts (61. It also buffers acid, inhibits the action of pepsin, and adsorbs bile salts. Sucralfate speeds up healing of peptic ulcers and prevents their recurrence [7] and stimulates gastric and duodenal alkali secretion by local synthesis of prostaglandin Ez PI. Sucralfate is at least as effective as alginate/antacid in relieving symptoms and in healing macroscopic lesions in reflux esophagitis [9]. It possesses about the same bile acid binding capacity as antacids of the aluminum hydroxide type [IO]. In our preliminary study, sucralfate proved to 28, 1987 The American Journal of Medicine Volume 83 (suppl 38) 51 SYMPOSIUM ON SUCRALFATE-KAIRALUOMA ET AL be somewhat more effective than a placebo in the treatment of bile reflux gastritis [l 11. Based on these observations and as a consequence of its properties, sucralfate might also be useful in treating patients with non-ulcer dyspepsia. The aim of the current randomized, placebo-controlled trial was to evaluate the efficacy of sucralfate in the treatment of non-ulcer dyspepsia in a carefully circumscribed group of dyspeptic patients with a constellation of symptoms most likely originating in the stomach. Chronic epigastric pain without accompanying symptoms of the irritable bowel syndrome and the absence of detectable organic diseases (other than macroscopic or microscopic gastritis/duodenitis seen at endoscopy on entry into the trial) were the basic prerequisites for inclusion in the study. The primary effect variable in this study was the reduction of epigastric pain recorded according to patients’ subjective assessment of the treatment. PATIENTS AND METHODS Any patient with epigastric pain with a duration of at least three months referred for endoscopy to our outpatient clinic was eligible for inclusion in the study. Peptic ulcer disease and other organic lesions of the upper gastrointestinal tract, such as reflux esophagitis, were excluded by means of endoscopy and biopsy performed at the time of entry into the study. A history of peptic ulcer disease, previous gastric surgery, untreated biliary tract disease, organic large bowel disease, lactose intolerance, mental disturbances, lactation and pregnancy, alcohol abuse, or the presence of other concomitant diseases that could explain the symptoms led to exclusion from the trial, as did the presence of symptoms of the irritable bowel syndrome proposed by Manning et al [12]. From October 5, 1984 to May 14, 1986, a total of 1,663 patients underwent endoscopy for upper abdominal disorders at our outpatient clinic. Two hundred (12 percent) fulfilled the entry criteria. All patients were seen on an outpatient basis. The study was approved by the ethics committee of the medical faculty of the University of Oulu, and the trial was conducted in accordance with the principles of the Helsinki Dsclaration. Informed verbal consent was obtained from each patient. Study Design. This study was designed to detect a difference of 20 percent or more between placebo and sucralfate treatment, as it was believed that such a difference would be clinically important. For determination of sample size, it was estimated that the placebo would be 50 percent effective. Conventional risks of type I (alpha), and type II (beta) errors of 0.05 and 0.10, respectively, were accepted [13]. With these variables, demonstration that results with sucralfate were 20 percent better or worse than those with placebo required 60 patients in each group. The loss of patients by exclusion and withdrawal was estimated to be about 25 percent. Thus, a total of 200 patients was required to complete the trial. Study Protocol. Clinical investigations on entry into the trial included a careful symptom analysis, endoscopy with biopsy specimens taken from the body and distal antrum of the stomach and the first and second parts of the duodenum, 52 September 28, 1987 The American Journal of Medicine ultrasound scanning of the liver, biliary tract, and pancreas, and routine laboratory screening. In addition, liver function tests, determination of urine and serum amylase, serum urate, calcium, phosphate, ferritin, folic acid, vitamin B12, pepsinogen [14], and blood glucose, thyroid function tests (serum thyroxin, resin triiodothyronine uptake, and free thyroxin index), and the guaiac test for occult blood in stools (Fecatest) were performed. The determinations of serum folic acid and vitamin By2 and endoscopic biopsies of the second part of the duodenum were included in order to exclude malabsorption syndromes. In patients with symptoms suggesting large bowel diseases (constipation, diarrhea, blood in stools) or with a positive result on the Fecatest, air-contrast barium enema examination and sigmoidoscopy were carried out. Patients complaining of diarrhea underwent a lactose tolerance test. To confirm the diagnosis of non-ulcer dyspepsia, the following additional examinations were performed: 36 barium enemas, 26 sigmoidoscopies, 19 lactose tolerance tests, four intravenous pyelographs, three intravenous cholangiograms, one computed tomograph, one hepatic angiograph, and one laparoscopy. A double-blind trial design was used. On entry into the trial, patients were randomly allocated to treatment with either sucralfate or placebo. Sucralfate (Antepsin) 1 g, or placebo was given three times a day one-half hour before meals. The sucralfate and placebo tablets were similar in appearance. The constituents of the placebo tablets were lactose 803 mg, potato starch 428 mg, gelatin 20 mg, magnesium stearate 40 mg, and colloidal silicon oxide (Aerosil 200) 14 mg. On entry into the trial every patient received 100 tablets of sucralfate or placebo. Follow-up examinations were performed by the same investigator (RH) after four weeks. These examinations included a careful symptom analysis, scoring of epigastric pain from 1 to 3 (1 = mild; 2 = moderate; 3 = severe), and patients’ subjective assessment of the treatment (symptom-free, improved, unchanged, worse). The number of unused tablets was counted. Patients who had more than 40 tablets left after four weeks of treatment were deemed to have violated protocol. These patients were excluded from the analysis. Side effects were also recorded. Statistical Analysis. Differences between the groups were analyzed by the nonparametric chi-square test. Differences occurring with two-tailed probability p co.05 were considered to be significant. RESULTS Twenty-five of the 200 patients did not fulfill our inclusion criteria and were, therefore, excluded from the study. Ten patients had esophagitis, five had organic large bowel disease, three had biliary tract disease, two had irritable bowel syndrome, two had lactose intolerance, one had previous gastric surgery, one had thyrotoxicosis, and one had hepatic metastases of pulmonary cancer. Hospital records of one patient were missing. Twenty-three patients dropped out during the trial, 11 from the sucralfate group and 12 from the placebo group. Of these, six patients in the sucralfate group and four in the placebo group discontinued treatment because of side effects, four in the former group and six in the latter group did not follow the Volume 83 (suppl 38) SYMPOSIUM study protocol, and three patients were lost to follow-up. Thus, 151 patients completed the trial, 79 taking sucralfate and 72 taking placebo. The provisional-referral diagnosis was upper abdominal pain in 93 patients, gastritis in 14, duodenal ulcer and gallstones in nine patients each, reflux esophagitis in eight, gastroduodenitis and dyspepsia in six patients each, and gastric ulcer and irritable bowel syndrome in three patients each. The characteristics of these patients are summarized in Table I. The groups were similar with regard to age, sex, length of history, smoking, coffee and alcohol drinking habits, consumption of nonsteroidal anti-inflammatory drugs, mean serum pepsinogen value, mean severity score, and macroscopic signs of gastritis. Of all 151 patients, 47 had no histologic signs of gastritis or duodenitis, 22 in the sucralfate group and 25 in the placebo group; 67 patients had gastritis and 11 had duodenitis, 34 and seven in the sucralfate group and 33 and four in the placebo group, respectively. Twenty-five patients had both gastritis and duodenitis, 15 in the former group and 10 in the latter group. All 151 patients had epigastric pain. One hundred thirty patients (86 percent) complained of flatulence, 110 (73 percent) belching, 95 (64 percent) regurgitation, and 80 (53 percent) heartburn. Twenty patients (13 percent) had undergone a previous cholecystectomy and 15 (10 percent) had undergone a previous appendectomy. There were no differences in subjective symptoms between the groups. According to the patients’ subjective assessment of the treatment at four weeks, 61 patients (77 percent) in the sucralfate group and 40 (56 percent) in the placebo group had become symptom-free or showed improvement, whereas the condition of 18 patients (23 percent) in the former group compared with 32 patients (44 percent) in the latter group remained unchanged or became worse. The difference between the groups was significant (p ~0.01, chi-square = 7.031). Results related to the severity of patients’ subjective symptoms, macroscopic findings at endoscopy, and histologic diagnosis are given in Tables II, III, and IV. Severe symptoms were relieved less well than were mild or moderate symptoms. The improvement was less pronounced in patients with macroscopic or microscopic inflammation of their gastric mucosa. On review of the endoscopic biopsy specimens, the correlation between macroscopic endoscopic findings and histologic gastritis was poor. Of the 66 patients with macroscopic signs of gastritis at endoscopy, histologic examination of biopsy specimens revealed normal gastric and duodenal mucosa in 19 (29 percent) of them. Correspondingly, of the 35 patients with normal macroscopic findings at endoscopy, microscopic examination showed inflammatory changes in the gastroduodenal mucosa in 25 (71 percent). Eleven patients (13 percent) in the sucralfate group and September 28, 1987 TABLE I ON SUCRALFATE-KAIRALUOMA Characteristics of 151 Patients Characteristics Sucralfate Number of patients Men/women Mean age i- SD (years) Length of history (years) <l l-4 5-9 210 Mean * SD Smokers Coffee drinkers Reported use of alcohol Reported use of NSAlDs Mean serum pepsinogen ? SD* Mean severity score Macroscopic signs of gastritis NSAlDs *Normal ET AL Placebo 35144 472 12 72 29143 452 12 20 31 11 17 5+7 20 66 39 27 57 2 34 2.05 60 16 27 13 16 5?6 17 63 34 33 62 ? 31 2.07 53 79 = nonsteroidal anti-inflammatory drugs. values for pepsinogen were 20. to 66 pgiliter. 13 (17 percent) in the placebo group reported side effects. They were, however, mild complaints such as flatulence, diarrhea, fatigue, nausea, and constipation. The types of side effects were similar in both groups. COMMENTS Non-ulcer dyspepsia is a very common complaint in general practice [2,15]. The similarity of symptoms in many other functional and organic gastrointestinal disorders makes the definite diagnosis of non-ulcer dyspepsia difficult [16]. Thus, the diagnosis of non-ulcer dyspepsia can only be made by exclusion. In this study, non-ulcer dyspepsia was defined as chronic epigastric pain with a duration of at least three months without concomitant symptoms of the irritable bowel syndrome and with no evidence of organic disease, other than macroscopic or microscopic gastritis/duodenitis seen at endoscopy on entry into the trial. Neither the neutralization of gastric acid with antacids [1,2] nor its suppression by Hz-receptor blockers [2-51 is of clinical value in non-ulcer dyspepsia. We have previously found sucralfate effective in the treatment of reflux esophagitis [9] and promising in bile reflux gastritis [lO,l 11. Hence, we considered it warranted to also investigate the efficacy of sucralfate in the treatment of non-ulcer dyspepsia. The dropout rate during the trial was rather high but equally distributed in both groups. To ensure patient compliance, we did not carry out a pentagastrin-stimulated acid output test, which requires placement of a nasogastric tube, but determined a serum pepsinogen value that reflects parietal cell mass and acid secretion ability of the stomach quite well [14]. We have previously noticed that repeated endoscopic examinations are an obvious reason for dropouts [9]. Hence, in this study, we omitted repeated The American Journal of Medicine Volume 83 (suppl 38) 53 SYMPOSIUM TABLE II ON SUCRALFATE-KAIAALUOMA Results Related ET AL to Severity of Subjective Symptoms Mild Symptom-Free or Improved Sucralfate (percent) Placebo (percent) Chi-square value p value 16/l 9 (84) lo/16 (62) Moderate Unchanged or Worse Symptom-Free or Improved 3119 (16) 6116 (38) 32137 (86) 20135 (57) Severe Unchanged or Worse Symptom-Free or Improved 5137 (14) 15/35 (43) 1.157 NS 13/23 lo/21 (57) (48) 6.326 co.05 Unchanged or Worse lo/23 11/21 (43) (52) 0.06 NS NS = not significant. TABLE Ill Results Related to Macroscopic Findings at Endoscopy Gaetrltle/Duodenitis Symptom-Free or Improved Sucralfate (percent) Placebo (percent) Chi-square value p value 45161 (74) 33/55 (60) Normal hlucosa Unchanged or Worse Symptom-Free or Improved 16161 (26) 22/55 (40) Unchanged or Worse 16118 (89) 7/l 7 (41) 1.904 NS 2/18 (11) 10/17 (59) 6.842 co.01 NS = not significant. TABLE IV Results Related to Histologic Diagnosis Gastritie/Duodenitis Symptom-Free or Improved Sucralfate (percent) Placebo (percent) Chi-square value p value 42157 (74) 26147 (55) Normal Mucosa Unchanged or Worse 15/57 21/47 Symptom-Free or lmpmved (26) (45) 19/22 14/25 Unchanged or Worse (86) (56) 3.07 3/22 1 l/25 (14) (44) 3.81 NS NS NS = not significant. endoscopy during the follow-up visit and based the evaluation of the efficacy of the drug solely on patients’ subjective assessment of the treatment. This study focused on a group of patients who had symptoms confined to the epigastrium and no symptoms of the irritable bowel syndrome. Also, all patients with positive results on a lactose tolerance test were excluded. It must be emphasized that inferences from this study can be applied only to such patients. Admittedly, there are a considerable number of patients who had some symptoms applicable to the irritable bowel syndrome but who did not fulfill the criteria proposed by Manning et al [12] and also some patients with borderline results on the lactose tolerance test. One of the constituents of the placebo tablets was lactose. This might partly explain side effects in the placebo group. The study groups were, however, very similar. Thus, the internal validity of the trial was considered to be good. The next question that arises is whether the sample 54 September 28, 1987 The American Journal of Medicine studied was representative of the entire population with non-ulcer dyspepsia-the external validity. Inevitably, more severe cases were referred for endoscopy. Nyren et al [2] emphasize that those who experience relief with available remedies-e.g., antacids sold over the counterwill have less reason to consult a physician, and there may have been a selection of nonresponders presenting themselves for the investigation. Clearly, the implications of the current study for all dyspeptic patients who never seek medical advice are unknown. Therapeutic efforts should, however, be directed primarily at those who seek medical care. Almost all dyspeptic patients use antacids routinely for their abdominal symptoms [2,15]. However, the neutralization [1,2] or suppression of gastric acid [2-51 is of no clinical value compared with a placebo. In the current study, sucralfate, a cytoprotective drug that forms an effective protective mucosal barrier and also buffers acid, inhibits the action of pepsin, and adsorbs bile salts [6,7], Volume 83 (suppl 36) SYMPOSIUM was significantly more effective than placebo in the treatment of non-ulcer dyspepsia. The best treatment response was achieved in patients with mild or moderate symptoms and without macroscopic or microscopic inflammation of their gastric mucosa-a typical patient with non-ulcer dyspepsia. Valentini et al [17], Roesch [18], and Magnolfi et al [19] have recently reported similar results with pirenzepine and cisapride. Valentini and co-workers [17] emphasize that the cytoprotective activity of pirenzepine might be the most important factor for its efficacy in the treatment of non-ulcer dyspepsia. We have earlier suggested that the bile acid binding and locally active ON SUCRALFATE-KAIRALUOMA ET AL mucosal-protecting characteristics of sucralfate are the most important factors for the drug’s efficacy in bile reflux gastritis [l 11. Based on the aforementioned observations and in agreement with the opinion of Valentini et al [17], we emphasize that locally active mucosal-protecting and bile acid binding characteristics of sucralfate are most important for its efficacy in the treatment of non-ulcer dyspepsia. We conclude that sucralfate is significantly more effective than a placebo in the treatment of non-ulcer dyspepsia. As a safe, locally active agent with minimal side effects, it is highly suitable for this purpose. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Norrelund N, Helles A, Schmiegelow M: Ukarakteristisk dyspepsi i almen praksis. En kontrolleret undersokelse med et antacidum (Aluminox). Ugeskr Laeger 1980; 142: 17501753. Nyren 0, Adami HO, Bates S, et al: Absence of therapeutic benefit from antacids or cimetidine in non-ulcer dyspepsia. N Engl J Med 1986; 314: 339-343. La Brooy S, Lovell D, Misiewicz JJ: The treatment of non-ulcer dyspepsia. in: Wastell C, Lace P, eds. 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Stand J Gastroenterol 1985; 20: 229-232. Stahlberg M, Mokka R, Laitinen S, et al: Bile acid binding capac- September 28,1987 11. 12. 13. 14. 15. 16. 17. 18. 19. ity of sucralfate, cholestyramine and antacids (abstr). Stand J Gastroenterol 1983; 18 (suppl 86): 86. Kairaluoma Ml, Stahlberg M, Laitinen S, Hentilae R, Jalovaara P: A placebo-controlled double-blind, crossover study of sucralfate in postcholecystectomy bile reflux gastritis (abstr). Stand J Gastroenterol 1983; 18 (suppl 86): 35. Manning AP, Thompson WG, Heaton KW, Morris AF: Towards positive diagnosis in the irritable bowel. Br Med J 1978; 2: 653-654. Young MJ, Bresnitz EA, Strom BL: Sample size nomograms for interpreting negative clinical studies. Ann Intern Med 1983; 99: 248-251. Varis K, Samloff IM, lhamaeki T, Siurala M: An appraisal of tests for severe atrophic gastritis in relatives of patients with pernicious anemia. Dig Dis Sci 1979; 24: 187-191. Mead GM, Morris A, Webster GK, Langman MJS: Uses of barium meal examination in dyspeptic patients under 50. Br Med J 1977; 1: 1460-1461. Lindberg G: On the similarity of symptoms in peptic ulcer disease (PUD), non-ulcer dyspepsia (NUD) and the irritable bowel syndrome (IBS) (abstr). Dig Dis Sci 1986; 31 (suppl): 5. Valentini P, Caloni R, Leproux GR: Pirenzepine (PRZ) and nonulcer dyspepsia (NUD): results of an Italian multicenter trial (abstr). Dig Dis Sci 1986; 31 (suppl): 331. Roesch W: Cisapride in non-ulcer dyspepsia. A multi-center controlled trial (abstr). Dig Dis Sci 1986; 31 (suppl): 45. Magnolfi F, Agnolucci A, Rossi G, Caneschi F, Valentini P, Angioli D: Alcohol gastropathy: therapeutic experience with pirenzepine (abstr). Dig Dis Sci 1986; 31 (suppl): 332. The American Journal of Medicine Volume 83 (suppl3B) 55