GASTROENTEROLOGY. Official Publication of the America" Gastroenterological Association

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1 GASTROENTEROLOGY Official Publication of the America" Gastroenterological Association COPYRIGHT 1977 THE WILLIAMS & WILKINS CO. Vol. 72 January 1977 Number 1 ALIMENTARY TRACT ANTACID AND PLACEBO PRODUCED SIMILAR PAIN RELIEF IN DUODENAL ULCER PATIENTS RICHARD A. L. STURDEVANT, M.D., M.P.H., JON I. ISENBERG, M.D., DONALD SECRIST, M.D., AND JAMES ANSFIELD, M.D. Medical and Research Services, Veterans Administration Wadsworth Hospital Center and the Department of Medicine, University of California at Los Angeles, Los Angeles, California The effectiveness of antacid and placebo in relieving single episodes of spontaneous duodenal ulcer pain were compared in two double blind, controlled, randomized trials. The trials compared the effects on ulcer pain of individual doses of a liquid antacid and placebo, rather than the effects of therapeutic regimens with antacid or placebo. Thirty patients were studied. There were no significant differences between antacid and placebo in time to onset, degree, or duration of pain relief. These results suggest that factors other than gastric acid neutralization are important in acute relief of spontaneous duodenal ulcer pain. Antacids are generally accepted as effective in the relief of pain arising from duodenal ulcer. 1-3 However, we are unaware of double blind, controlled, randomized studies supporting this belief. Relief of ulcer pain by antacid can be defined as either: (1) alleviation (partial or complete, temporary or permanent) of pain after a dose of antacid, or (2) decreased frequency, severity, or both, of pain after repeated ingestion of antacid. The purpose of these studies was to compare the effects of a liquid antacid and placebo in acute relief of spontaneous duodenal ulcer pain (definition 1). Methods The Wadsworth VA Hospital Research Committee approved these studies, and written informed consent was obtained from each patient. Two studies were performed. Received May 6, Accepted July 6, Address requests for reprints to: R. A. L. Sturdevant, M.D., Gastroenterology Section, Veterans Administration Wadsworth Hospital Center, Los Angeles, California Supporting funds were provided by Warner-Lambert, the Veterans Administration, and Center for Ulcer Research and Education Grant AM17328 from the National Institute for Arthritis, Metabolism and Digestive Diseases. The placebo was prepared by Warner-Lambert Research Laboratories, Morris Plains, New Jersey. Morton I. Grossman provided advice regarding experimental design.!. Michael Samloff measured the effect of the placebo on gastric juice pepsin activity. Janet Elashoff provided statistical assistance. Frances Turner and Anne Husz provided secretarial assistance. Study A. Criteria necessary for entry of patients included all of the following: (1) epigastric pain, considered characteristic of duodenal ulcer, i.e., having onset before meals, relieved by intake of food, antacids, or both, with a history of exacerbations and remissions, occurring for at least 2 hr daily during the week before entry into the study, and severe enough to interfere with the usual activities of daily living; (2) a duodenal ulcer crater demonstrated by radiographs obtained within 48 hr before entry into the study; (3) willingness to be hospitalized for 5 days; (4) ability to maintain a diary regarding the relationship of pain relief to the intake of study drugs. Patients with gastric ulcer, retrosternal burning pain suggestive of gastroesophageal reflux, or previous gastric surgery were not enrolled. Twelve male patients were enrolled. Ten (mean age 44 years: range 25 to 66 years) completed the study. Two patients were deleted from analysis: one because he became pain-free after selection but before receiving any study drug, and the other because he became pain-free after receiving only one dose of study drug (placebo). The mean (±SE) time from onset of duodenal ulcer symptoms to entry into the study was 7.5 ± 2.0 years. The mean ( ± SE) duration of the current exacerbation of symptoms before entry into the study was 46.5 ± 17.8 days. All patients became pain-free during this hospitalization, none had evidence of complications of ulcer, and none required surgery. The antacid preparation was a locally prepared liquid antacid containing 13% aluminum hydroxide (aluminum oxide 3.2%), 12% magnesium trisilicate, and small amounts of low viscosity carboxymethyl cellulose, methylparaben, propylparaben, saccharin sodium, cyclamate calcium, propylene glycol, and peppermint oil. Its in vitro acid neutralizing capacity as determined by the method of Fordtran et al. was 20.3 ml

2 2 STURDEVANT ET AL. Vol. 72, No.1 of 0.1 N hydrochloric acid per ml of antacid in 120 min. Fifteen milliliters of antacid were capable of buffering 30 meq of hydrochloric acid. The commercial antacids Gelusil-M, Riopan, Amphogel, and A-M-T have similar acid-buffering capacities. 4 The placebo was similar in appearance, consistency, and flavor to the antacid. One milliliter had an in vitro neutralizing capacity of less than 0.2 ml of 0.1 N hydrochloric acid. When tested in vitro the placebo had no effect on gastric juice pepsin activity. It contained carboxymethyl cellulose (9%), parabens (0.004%), peppermint oil, and water. Patients were hospitalized on a gastroenterology ward for the study. Each patient was assigned a carton of coded test medications containing ml doses of antacid and ml doses of placebo. The order of doses was randomized in 10 sets of six, each containing three antacid and three placebo doses. Patients were instructed to obtain a dose of medication whenever their ulcer pain occurred, but no more often than every 30 min. Thirty minutes was selected, consistent with previous reports, 5. 6 as a time interval long enough to permit antacid to produce pain relief. Randomization in sets of six provided that if the patient required medication every 30 min, the longest possible time interval between two antacid doses would be 3.5 hr-three placebo doses of one set followed by three placebo doses of the following set. This randomization schedule ensured that the results would not be significantly confounded by time-related variables. The coded medications were kept at the nurses' station, and were dispensed dose-by-dose by one nurse on each of the three daily 8-hr hospital shifts. The dose was swallowed under the direct supervision of the nurse. A written record of each dose was maintained. The nurse recorded bottle number, time of ingestion, and date. The patient recorded degree (none, partial, or complete) and time of pain relief. Partial relief meant decrease without disappearance of ulcer pain. Patients were instructed and encouraged to obtain medication every 30 min if they had less than complete relief after the previous dose. Before administering the next dose, the nurse reviewed the patient's pain chart to be certain that the time and degree of relief had been recorded. The medication record' and pain chart were reviewed daily by one of the "blinded" investigators with the patient and the nursing staff. Each day the patients were encouraged by a physician to be conscientious and accurate regarding the time and type of pain relief. The study ended after 5 days or after ingestion of all 60 doses, whichever occurred first. Patients received a regular diet, except that milk was excluded. Anticholinergics, hypnotics, tranquilizers, analgesics, or corticosteroids were not given. Two patients received additional medication: isoniazid in one case, probenecid and colchicine in the other. Study B. Twenty additional male patients (mean age 48 years, range 29 to 67 years) were studied. Criteria for entry included epigastric pain (as in study A) and evidence of duodenal ulcer by barium meal or endoscopy. Excluding criteria were the same as in study A. The purpose of study B was to contrast the effect of only one dose of a highly potent antacid with one dose of placebo on spontaneous duodenal ulcer pain under blind randomized conditions. Patients were given two bottles, one containing 30 ml of antacid and the other 30 ml of placebo. They were instructed to ingest the contents of a bottle when their next two typical episodes of ulcer pain occurred (bottle A for the first episode, B for the second) and to record the degree of pain relief at 5-min intervals over the next 30 min on a form as follows: 0, no relief; 1, little relief (less than 25% decrease from initial severity); 2, moderate relief (25 to 75% decrease); 3, marked relief (76 to 99% decrease); 4, complete relief. Seven patients were hospitalized, and 13 were not hospitalized, when studied. Eight patients ingested both antacid and placebo, and recorded the results, in the presence of a physician observer. This was done to minimize the possibility of patient error in identifying ulcer pain or in performing the test. The order of ingestion of antacid and placebo was randomized: 10 patients had antacid first, 10 had placebo first. A commercial antacid was used; 30 ml contained 2.4 g of aluminum hydroxide (equivalent to dried gel, USP), 1.6 g of magnesium hydroxide, and 120 ml of simethicone. One milliliter of antacid was capable of neutralizing 41.4 ml of 0.1 N hydrochloric acid. Therefore, 30 ml were able to neutralize 124 meq of hydrochloric acid.' The placebo was the same material used in study A. Because the placebo was designed to mimic the antacid in study A, it differed in taste from the study B antacid. Patients in both studies were told that we were comparing the effects of two different preparations on ulcer pain. 7 The X 2 test, Student's t-test, the Mann-Whitney test, and the sign test were used in the statistical analysis of the data. 8, 9 Results Study A (5-day multiple dose inpatient study). No differences were observed between antacid and placebo in ability to relieve pain (tables 1 to 5). For analysis of individual patient's results, an "antacid-positive" score was calculated by adding the number of doses of antacid followed by complete pain relief to the number of doses of placebo followed by no pain relief (table 1). Similarly, a "placebo-positive" score was obtained by adding the number of doses of antacid followed by no pain relief to the number of doses of placebo followed by complete pain relief. The antacid-positive score was greater in 4 patients, the placebo-positive score was greater in 3 patients, and the scores were equal in 3 patients. Only 1 patient, no. 6, responded significantly better to antacid than to placebo (P < 0.05, table 1). (One of Cochran's modifications of x 2 was used for this test. 9 No relief was scored as 0, partial relief as 1, and complete relief as 2.) In an attempt to reduce the possible effect of hospitalization on pain relief, data for the first 2 days were analyzed separately. Evidence for greater effectiveness TABLE 1. Study A: number of doses of antacid (A) or placebo (P) providing various levels of pain relief in 10 hospitalized symptomatic duodenal ulcer patients Patient No relief Partial relief Complete relief A P A P A P

3 January 1977 RELIEF OF ULCER PAIN 3 TABLE 2. Study A: number of doses of antacid or placebo producing various levels of pain relief in 10 hospitalized symptomatic duodenal ulcer patients P ain relief Complete Antacid Placebo Partial Antacid Placebo None Antacid Placebo Antacid Placebo TABLE 3. Study A: minutes (mean ± SE) after ingestion of antacid or placebo before complete relief of pain occurred in 10 hospitalized symptomatic duodenal ulcer patients (complete relief occurred after 51 antacid, and 50 placebo, doses (table 1)' Agent Antacid 11.1 ± ± ± ± ± 3.0 Placebo 8.4 ± ± ± ± ± 3.7 P > 0.2 for each day (t-test). TABLE 4. Study A: number of doses of antacid or placebo followed by complete relief of given duration in 10 symptomatic hospitalized duodenal ulcer patients Antacid Placebo o Minutes of antacid than of placebo during the first 2 days was minimal. The antacid-positive score was greater in 5 patients, the placebo-positive score was greater in 3 patients, and the scores were equal in 2 patients. There were no significant differences between antacid and placebo in: (1) doses per day; (2) likelihood of producing complete, partial, or no pain relief on anyone of the 5 days or during the entire 5-day period; (3) mean time required to produce complete pain relief; (4) median duration of complete pain relief (median, rather than mean, duration of pain relief was analyzed because the data were skewed by the prolonged duration of relief which occurred after the last dose before falling asleep); (5) number of doses that produced similar duration of complete pain relief (tables 2 to 5). For these analyses, the individual doses were the experimental unit, and were assumed to be independent. Study B(single 30-ml doses of a potent antacid versus placebo). The time course and degree of pain relief in study B did not differ significantly between antacid and placebo treatments (tables 6 to 8). Nine patients had complete relief of pain by 30 min-5 with antacid only, 2 with placebo only, and 2 with both treatments. Ten patients reported a greater degree of relief at 30 min after antacid and 4 after placebo, and 6 reported no difference. At 30 min, 6 patients reported differences in pain relief of two or more categories (0 = no relief; 1 = 1 to 24% relief; 2 = 25 to 75 %; 3 = 76 to 99%; 4 = complete relief; table 6); 3 of these patients had more relief with antacid, and 3 with placebo. Estimated pain relief of 75% or more was reported by 12 patients after antacid, and by 10 patients after placebo. Seven patients had less than 25% relief after antacid; 8 had similar failure to obtain relief after placebo. Combined data. Data from the two studies were combined in two ways. First (minimal criteria), patients were classified as responding better to antacid if (study A) their antacid-positive score was greater than their placebo-positive score (table 1), or (study B) they reported more pain relief at 30 min after antacid than after placebo (table 7). Patients responding better to placebo, or equally to antacid and placebo, were classified similarly. Second (strict criteria), patients were classified as responding better to antacid if (study A) their antacidpositive score was significantly greater than their placebo-positive score (table 1), or (study B) they reported relief 2 or more categories greater after antacid than after placebo (table 8). Patients responding better to placebo, TABLE 5. Study A: median duration (minutes) of complete pain relief after ingestion of antacid or placebo in 10 symptomatic hospitalized duodenal ulcer patients' Agent Antacid 9, Placebo P > 0.05 for each day (Mann-Whitney test). TABLE 6. Study B: comparison of degree of pain relief produced by single doses of antacid (A) and placebo (P) in 20 symptomatic duodenal ulcer patients' Degree of pain relief 5min 10 min 15 min 20 min 25 min 30min A p A P A P A P A P A P Patients' estimates of degree of relief: 0 ~ none, 1+ ~ 1 to 24%, 2+ ~ 25 to 75%, 3+ ~ 76 to 99%, 4 + ~ 100%. The numbers of patients with various degrees of pain relief at 5-min intervals after ingestion of the test drug are shown.

4 4 STURDEVANT ET AL. Vol. 72, No.1 TABLE 7. Number of patients reporting differences or equality in pain relief between antacid and placebo at 5-min intervals after ingestion Time after Antacid better Placebo better No ingestion than placebo than antacid difference min TABLE 8. Number of patients reporting differences in pain relief between antacid and placebo of two or more categories (scale in table 6) at each 5-min interval after ingestion Time after Antacid better than Placebo better than ingestion placebo antacid mm or equally to antacid and placebo, were classified similarly. The minimal criteria classified 14 patients as having better pain relief with antacid, 7 as better with placebo, and 9 as no preference. The strict criteria classified 4 patients as better with antacid, 3 as better with placebo, and 23 as no preference. Neither classification method resulted in statistically significant differences between antacid and placebo. Discussion Failure of antacid to produce either consistent marked relief of pain or significantly better relief than placebo indicates that factors other than acid neutralization are important in the acute relief of duodenal ulcer pain. Although some previous studies have reported antacid effective in relieving pain, 5, 6, 10 those studies used experimental designs inadequate by current standards to control for unconscious bias or time-related confounding variables. The finding that I5-ml doses of antacid or of placebo produced similar pain relief in 10 hospitalized symptomatic duodenal ulcer patients (study A) was not anticipated. Failure to observe differences in study A might have been caused by biasing effects of several factors, including hospitalization, the rather low dose of antacid used (i.e., neutralizing capacity of 30 meq of hydrochloric acid), the serial randomized dose design, or other unrecognized variables. To obviate some of these factors we performed study B, comparing a large dose of antacid (neutralizing capacity of 120 meq of hydrochloric acid) with placebo. Again, no distinct differences in pain relief were observed, either in the entire group or in the subgroups (hospitalized versus outpatients; physician observer versus no physician observer; antacid first versus placebo first; any of the 5-min. intervals). In a double blind study of treatment of duodenal ulcer with calcium-containing antacid or placebo tablets, the proportion of patients pain-free after 1 month of treatment was not significantly different between the antacid and placebo groups. 11 This observation agrees with ours, but is not necessarily directly comparable, as the mechanism of persistent pain despite chronic treatment may be different from that for persistent pain despite acute antacid ingestion. Studies comparing relief of gastric ulcer pain by chronic antacid or placebo treatment have reported conflicting results. 11, 12 Because antacid was arithmetically, but not statistically, more effective than placebo in our studies, it is reasonable to postulate that study of larger numbers of patients might produce statistical evidence for antacid effectiveness. That is, antacids may indeed be more effective than placebo in relief of duodenal ulcer pain, but the differences are not great and only become apparent if large groups of patients are studied. Pain has two components, the stimulus and the affective response. 13 Our results, and earlier results, are compatible with the hypothesis that patients' expectation of relief, whether by ingestion of a thick white suspension, by removal of gastric contents, or by instmation of neutralizing solutions into the stomach, modifies the affective response to produce pain relief in duodenal ulcer patients. Separation of postulated pain relief due to acid neutralization from pain relief due to placebo might be achieved by using placebo and acid-neutralizing preparations that do not resemble commercial antacids. Relief of duodenal ulcer pain by antacids is regularly reported by patients, accepted by most authorities, and supported by earlier studies. The results of the present study do not necessarily prove that antacids have no effect on duodenal ulcer pain, but they do indicate that factors other than gastric acid neutralization are important in relief of ulcer pain. Because millions of dollars are spent each year for antacids in the treatment of duodenal ulcer, and because antacids have some inherent (usually mild) untoward side effects, our findings suggest the need for further clinical trials to define the efficacy, if any, of antacids in treatment of duodenal ulcer. REFERENCES 1. Walker CO: Chronic duodenal ulcer. In Gastrointestinal Disease, Pathophysiology, Diagnosis, Management. Edited by MH Sleisenger, JS Fordtran. Philadelphia, WE Saunders, 1973, p Baron JH, Wastell C: Medical treatment. In Chronic Duodenal Ulcer. Edited by C Wastell. New York, Appleton-Century-Crofts, 1972, p Harvey SC: Gastric antacids and digestants. In The Pharmacological Basis of Therapeutics. Fourth Edition. Edited by LS Goldman, A Gilman. London, Macmillan, 1970, p Fordtran JS, Morawski SG, Richardson CT: In vivo and in vitro

5 January 1977 RELIEF OF ULCER PAIN 5 evaluation 0f liquid antacids. N Engl J Med 288: , Palmer WL: The "acid test" in gastric and duodenal ulcer. JAMA 88: , Lawrence JS: Dietetic and other methods in the treatment of peptic ulcer. Lancet 1: , Vere DW, Chaput de Saintonge DM: Double-blind trials. Lancet 1: 546, Snedecor GW, Cochran WG : Statistical Methods. Sixth Edition. Ames, Iowa, Iowa State University Press, Cochran WG: Some methods for strengthening the common chi-square tests. Biometrics 10: , Bonney, GLW, Pickering GW: Observations on the mechanism of pain in ulcer of the stomach and duodenum. Clin Sci 6:63-89, Hollander D, Harlan J: Antacids vs placebo in peptic ulcer therapy: a controlled double-blind investigation. JAMA 226: , Butler ML, Gersh H: Antacid vs placebo in hospitalized gastric ulcer patients: a controlled therapeutic study. Am J Dig Dis 20: , Beecher HK: The measurement of pain. Prototype for the quantitative study of subjective responses. Pharmacol Rev 9:59-209, 1957

The Effect of Glycopyrrolate on the Course of Symptomatic Duodenal Ulcer

The Effect of Glycopyrrolate on the Course of Symptomatic Duodenal Ulcer HECTOR TREVlNO, M.D.,* JUAN ANDERSON, M.D., t PAULA G. DAVEY, M.D., + and KEITH S. HENLEY, M.D. x HAS BEEN snowy by Sun 1 that the