We have recently shown that proton pump inhibitors

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1 GASTROENTEROLOGY 1998;115: Ranitidine Controls Nocturnal Gastric Acid Breakthrough on Omeprazole: A Controlled Study in Normal Subjects PAOLO L. PEGHINI, PHILIP O. KATZ, and DONALD O. CASTELL Department of Medicine Esophageal Laboratory, Graduate Hospital, Philadelphia, Pennsylvania Background & Aims: Proton pump inhibitors administered twice daily do not provide complete nocturnal acid suppression. Acid breakthrough, or decrease in intragastric ph to F4 for an hour or longer, occurs in three quarters of normal subjects and patients at night. We compared the effect of a third dose of omeprazole at bedtime with that of a dose of ranitidine at bedtime on residual nocturnal acid secretion in patients receiving omeprazole twice daily. Methods: Twelve volunteers underwent overnight intragastric ph monitoring after 7 days of treatment with omeprazole, 20 mg twice daily, followed by different treatment supplements at bedtime: placebo; additional omeprazole, 20 mg; ranitidine, 150 mg; and ranitidine, 300 mg. Results: Additional omeprazole at bedtime reduced the percentage of time with intragastric ph of F4 from 48% to 31% (P F 0.005) compared with omeprazole twice daily with placebo at bedtime. Ranitidine at bedtime reduced this parameter more, 5% with 150 mg and 6% with 300 mg (P F0.01 vs. omeprazole twice daily plus bedtime). Results for percentage of time with intragastric ph F3 were similar. Eleven subjects had acid breakthrough with placebo at bedtime; 7 with omeprazole at bedtime (P NS); 4 with ranitidine, 150 mg at bedtime; and 3 with ranitidine, 300 mg at bedtime (P F 0.05, ranitidine vs. placebo). Conclusions: Bedtime ranitidine is more effective than bedtime omeprazole on residual nocturnal acid secretion in patients receiving omeprazole twice daily. This finding suggests that fasting breakthrough nocturnal acid secretion in patients receiving omeprazole twice daily is most likely histamine related. We have recently shown that proton pump inhibitors given twice daily frequently do not suppress gastric acid secretion sufficiently overnight to prevent recovery of gastric acidity to potentially harmful ph levels. Nocturnal acid breakthrough, arbitrarily defined as intragastric ph 4 for more than 1 hour overnight, occurred in 73% of patients with gastroesophageal reflux and normal volunteers. 1 This decrease in intragastric ph occurs approximately 7.5 hours after intake of the evening dose of proton pump inhibitor, i.e., between 1 and 2 AM. In our experience, esophageal acid exposure occurs in approximately 70% of patients with chronic gastroesophageal reflux disease during this period of acid breakthrough and may be especially injurious because of delayed clearance at night. 2 Doubling of the dose or addition of proton pump inhibitor at bedtime did not prevent acid breakthrough in our experience. The temporal profile of the ph pattern overnight suggested that the desired effect might be achieved with a bedtime dose of an H 2 -receptor antagonist, a hypothesis supported by our observation in an initial patient with Barrett s esophagus and refractory nocturnal reflux. 3 Therefore, we conducted a double-blind, placebo-controlled, crossover study designed to compare the effect on overnight intragastric ph of 20 mg omeprazole twice daily plus 20 mg at bedtime with those of 20 mg omeprazole twice daily plus 150 or 300 mg ranitidine or placebo at bedtime. Subjects and Methods Subjects Twelve healthy, asymptomatic volunteers, with a mean age of 31 years (range, years; 7 men and 5 women; ethnic distribution: white, 9; black, 2; Asian, 1) were studied. All had negative serological results for immunoglobulin (Ig) G antibodies to Helicobacter pylori (FlexSure HP; SmithKline Diagnostics, Inc., San Jose, CA). Study Design Subjects were pretreated with oral omeprazole, 20 mg twice daily minutes before breakfast and dinner, for 7 days. Beginning on day 8, additional treatments with placebo, 150 mg ranitidine, 300 mg ranitidine, and an additional 20-mg dose of omeprazole were given at bedtime (10:30 PM). They were given in random sequence, with the exception that omeprazole was the last drug given to all subjects. This was chosen to avoid potential interference of the prolonged acidsuppressing effect of omeprazole on a study performed the subsequent night. Subjects were instructed to take the morning dose of omeprazole 15 minutes before breakfast on study days. Subjects were allowed to choose their own breakfast, but Abbreviations used in this paper: IQR, interquartile range; LES, lower esophageal sphincter by the American Gastroenterological Association /98/$3.00

2 1336 PEGHINI ET AL. GASTROENTEROLOGY Vol. 115, No. 6 it had to be the same meal at the same time on all 4 occasions. Evening doses of omeprazole were given 15 minutes before a standardized dinner eaten under supervision in the laboratory on study days. All 4 studies were completed over the next 4 21 days (median, 7 days). Treatment with omeprazole, 20 mg twice daily, was continued for the entire period. ph Monitoring Intragastric ph was recorded from 5 PM until 6:30 AM the next morning on each of the 4 study days. Before insertion of the ph probe, subjects were given 200 ml of a carbonated soft drink with a ph of 1.5 to acidify the stomach. This was done because of the anticipated daytime acid control of omeprazole. An antimony ph catheter with external reference electrode (Synectics Medical Inc., Irving, TX) was placed 10 cm below the proximal border of the manometrically identified lower esophageal sphincter (LES) as described previously. 4 A decrease in ph to 4 was taken as confirmation of intragastric placement. If the ph was 4, the probe was advanced cm and an additional ml of soft drink was given if needed. A decrease in ph to 4 for at least 2 minutes with either or both of these maneuvers was considered an indication for intragastric position, and the probe was pulled back to the study location 10 cm below the LES. If these maneuvers did not lead to a decrease in ph to 4, the probe was removed completely, reinserted again, and fixed at 10 cm below the LES, irrespective of the ph reading. After insertion of the ph probe, the evening dose of omeprazole was administered with 50 ml of water followed by a standardized dinner served 15 minutes later (6 PM) in the laboratory. After completion of dinner, subjects were allowed to return home. They were given the blinded study capsule with the instruction to take it with ml of water at 10:30 PM. No other food or liquids except water were allowed during the study. Subjects were instructed to remain upright until 10:30 PM, at which time they were required to go to bed and to remain in a recumbent position until 6:30 AM. Intragastric ph data were analyzed from intake of the study drug at 10:30 PM until 6:30 AM the next day using standard, commercially available software (Esophagram; Synectics Medical Inc.). Percentages of time with intragastric ph 4 and 3 and ph values were calculated automatically for each study. Acid breakthrough was defined arbitrarily as intragastric ph 4 for more than 1 hour. This point was identified visually on the ph tracing by an investigator blinded to the treatment sequence. Subjects were required to keep a diary on study days, marking time of intake of drugs, intake of meals, and upright and recumbent periods. The study was approved by the institutional Review Board of Allegheny University Hospitals, Graduate. Statistics Percentages of time with intragastric ph 4 and 3 and ph values were compared by use of Kruskal Wallis analysis of variance and Newman Keul s method for multiple comparisons. Categorical data were compared using Cochran s Figure 1. Median intragastric (IG) ph values with 4 treatments in 12 subjects. The 4 treatments were placebo (Pla), 150 mg ranitidine (Ran 150), 300 mg ranitidine (Ran 300), and 20 mg omeprazole (Ome 20) at bedtime in addition to 20 mg omeprazole twice daily. Horizontal bars represent median values for the whole group. a P vs. placebo and vs. omeprazole at bedtime; b P vs. placebo. Q test. For multiple comparisons of categorical data, Marascuilo s test was used. Two-tailed P values of 0.05 were considered significant. Statistics were calculated with True Epistat (4th ed.; Epistat Services, Richardson, TX). Results are expressed as medians and interquartile ranges (IQRs). Results Median intragastric ph values for the 8-hour overnight period were 4.2 (IQR, ) for omeprazole twice daily with placebo at bedtime; 5.7 (IQR, ) for the regimen with three doses of omeprazole (P vs. placebo); and 7.2 (IQR, ) and 7.2 (IQR, ) for 150 mg and 300 mg ranitidine, respectively, in addition to omeprazole twice daily (P vs. placebo and vs. additional omeprazole; Figure 1). These numbers suggest good acid control. However, the intragastric ph profile shows that acid suppression was not even throughout the night. Recovery of acid secretion occurred after midnight with 20 mg omeprazole twice daily and placebo at bedtime (Figure 2). A third dose of Figure 2. Summary ph profile. Median hourly intragastric (IG) ph in 12 subjects receiving 4 treatments (Pla, placebo; Ran 150, 150 mg ranitidine; Ran 300, 300 mg ranitidine; Ome 20, 20 mg omeprazole) given at bedtime in addition to 20 mg of omeprazole twice daily.

3 December 1998 RANITIDINE FOR NOCTURNAL ACID ON OMEPRAZOLE 1337 Figure 3. Median percentage of time with intragastric ph 4 and 3 from intake of the study medication at 10:30 PM until end of the study at 6:30 AM. The 4 treatments were placebo (Pla), 150 mg ranitidine (Ran 150), 300 mg ranitidine (Ran 300), and 20 mg omeprazole (Ome 20) in addition to 20 mg omeprazole twice daily. *P vs. placebo, **P 0.01 vs. omeprazole 20 for both ph 4 and ph 3. omeprazole at bedtime improved acid control, but the median ph still decreased to 4. The most effective method of nocturnal acid breakthrough suppression with omeprazole twice daily was addition of ranitidine at bedtime (Figure 2). Periods of poor acid control are better recognized by measurement of percentage of time with intragastric ph 4 and 3 and by assessment of frequency of acid breakthrough. Median percent times with intragastric ph 4 and 3 for all 4 treatments are shown in Figure 3. Intragastric ph was 4 for 48% (IQR, 35% 63%) of the overnight period with omeprazole, 20 mg twice daily, plus placebo at bedtime. A third dose of omeprazole at bedtime decreased this percentage to 31% (7% 36%; P 0.005). Better control of intragastric ph was observed with a bedtime dose of ranitidine. Percentages of time with ph 4 on 150 mg and 300 mg of ranitidine were 5% (0% 15%) and 6% (3% 11%), respectively. These were significantly lower than those with placebo (P 0.001) or additional omeprazole at bedtime (P 0.01). Similar results were found for the percentages of time with intragastric ph 3: placebo, 41% (24% 52%); omeprazole, 19% (3% 25%; P 0.005); 150 mg ranitidine, 3% (0% 11%); and 300 mg ranitidine, 1% (0% 2%). Each ranitidine dose resulted in significantly better ph control than either placebo (P ) or additional omeprazole at bedtime (P 0.01; Figure 3). Eleven of the 12 subjects had acid breakthrough on 20 mg of omeprazole twice a day with placebo at bedtime. A third dose of omeprazole at bedtime reduced this number to 7 (58%; P NS). Acid breakthrough occurred in 4 subjects (33%) who received 150 mg ranitidine at bedtime and 3 (25%) who received 300 mg ranitidine at bedtime (P 0.05 vs. placebo for both). High interindividual variability of nocturnal acid suppression was observed with omeprazole twice daily and placebo at bedtime and with three doses of omeprazole but not with ranitidine (Figure 4). This finding is consistent with our previous observations of marked variability of acid suppression with omeprazole. 4,5 Confirmation of intragastric placement of the ph probe at the beginning of the study, i.e., measurement of aph 4 for at least 2 minutes, could not be obtained in 8 of the 48 studies (17%). These 8 studies were equally distributed among all treatment groups: placebo, 3 studies; 150 mg ranitidine, 2 studies; 300 mg ranitidine, 1 study; and additional 20 mg omeprazole, 2 studies (P 0.1). They were not evenly distributed among the 12 subjects. Three incidences occurred in 1 subject, two in 2 subjects, and one in 1 subject (P 0.03). In 6 of the 8 studies in which an acidic ph reading could not be obtained at the beginning of the study, ph 4 occurred later during the study, indicating intragastric placement of the ph probe. Discussion This study confirms our previous findings of a high prevalence of nocturnal acid breakthrough in patients being treated with proton pump inhibitor twice daily. 1 Acid breakthrough, defined as a decrease in intragastric ph to 4 for 1 hour or more, occurred in more than 90% of the volunteers. Although this observation appears to be in conflict with general knowledge regarding acid suppression by omeprazole, the discrepancy is explained by differences in the way the acidinhibiting effect of omeprazole is expressed. Most studies have reported mean or median intragastric ph. We measured percentage of time with intragastric ph 4 and 3. If our data are expressed as median ph as shown in Figure 1, the values are similar to those of prior reports Figure 4. Percentages of time with nocturnal intragastric (IG) ph 4 for the 4 treatments for each of the 12 subjects. The 4 treatments were placebo (Pla), 150 mg ranitidine (Ran 150), 300 mg ranitidine (Ran 300), and 20 mg omeprazole (Ome 20) given at bedtime in addition to 20 mg omeprazole twice daily.

4 1338 PEGHINI ET AL. GASTROENTEROLOGY Vol. 115, No. 6 and none are 4. However, use of mean or median ph can be deceptive because periods of good acid control can offset periods of poor acid control. In this assessment, elevation of ph to counterbalances an equal decrease in ph to The former change, which probably is biologically insignificant, compensates for the latter, which converts an innocuous refluxate into a potentially damaging one. 6 Measurement of the fraction of time during which the ph drops below a critical level is not subject to this false impression of continuous good acid control and uncovers episodes of acid recovery. Therefore, this parameter is potentially clinically more useful than mean or median ph. Omeprazole, 20 mg twice daily, decreased the median percentage of time with intragastric ph 4 to 48% of the 8-hour overnight period. Addition of a third dose at bedtime reduced this parameter only to 31%, and 58% of subjects still had acid breakthrough. A much better effect was achieved by combining omeprazole twice daily with a relatively low dose of ranitidine at bedtime. With 150 mg of ranitidine, the time with intragastric ph 4 was only 5%, and the frequency of acid breakthrough only 33%. The surprising effectiveness of the nighttime dose of ranitidine suggests a major role of histamine in nocturnal acid secretion. Physiological acid secretion follows a circadian pattern, characterized by an increase in the evening hours, with a peak after midnight The drive for this pattern is not clear, but it is not paralleled by serum gastrin levels, suggesting that it is not gastrin mediated. 8,11 In contrast, cholinergic stimulation is clearly involved because vagotomy reduces basal acid secretion. 12 A role of histamine in basal acid secretion is supported by the fact that interprandial acid secretion can be reduced by H 2 -receptor antagonists. 12 However, the three mediators of acid secretion are interconnected, and histamine plays a crucial role. H 2 -receptor blockade markedly reduces acid secretion not only to histamine, but also to vagal and gastrinergic stimulation. 13 Therefore, inhibition of acid secretion by ranitidine does not necessarily imply a primarily histaminergic stimulus. A combination of histaminergic and vagal stimuli seems most likely to account for basal gastric acid secretion. 14 The limited effect of the bedtime dose of omeprazole could be related to the fact that it was not given with a meal. Proton pump inhibitors inhibit only actively secreting pumps in the secretory canaliculi, sparing those at rest in the tubulovesicles. 13 These drugs have a relatively short plasma half-life ( 50 minutes for 40 mg of omeprazole administered orally) Therefore, the fraction of active and hence proton pump inhibitor susceptible pumps during the short period of therapeutic plasma levels theoretically determines the efficacy of a dose of proton pump inhibitor. Food-related stimuli increase acid secretion, and hence active pumps, up to 10 times. 18 Because the bedtime dose of omeprazole was not accompanied by a meal or other stimulus for acid secretion, it is possible that this dose encountered mostly resting pumps, which it was unable to inhibit. These pumps may have responded later, after the proton pump inhibitor was cleared from the plasma, to any acidsecreting stimulus. The acid breakthrough that occurred in more than 90% of our subjects receiving omeprazole twice daily and in more than 50% receiving omeprazole twice daily and at bedtime clearly shows that the pumps were not completely inhibited at these seemingly large doses of omeprazole, allowing histamine or acetylcholine to activate the parietal cell. In contrast, the action of ranitidine does not depend on food intake. When given orally, it is absorbed rapidly, and absorption is not influenced by food ingestion. A dose of 150 mg has peak plasma concentrations within 1 3 hours and a duration of action of up to 12 hours. 19 These kinetics match the action profile required for a drug administered at bedtime to prevent nocturnal acid breakthrough, as illustrated in Figure 2. Can differences in omeprazole metabolism explain our observations? Slow (or poor), and rapid (or extensive) metabolizers are commonly distinguished. Because approximately 95% of a white population are phenotypically rapid metabolizers, they represent normal for this group. The corresponding percentages for black and Asian populations are approximately 98% and 75%, respectively. 20,21 Based on these data, there should have been 1 slow metabolizer among our 12 volunteers. Our results cannot be explained by a disproportionate fraction of slow metabolizers. A high proportion would have influenced our results toward a good omeprazole effect. The absence of slow metabolizers, on the other hand, would have meant that our group consisted only of normal subjects. A recent study suggests the existence of a third category of omeprazole metabolizer, the ultrarapid metabolizer. These subjects had no detectable concentrations of omeprazole in plasma collected 2 hours after intake of an oral dose, despite evidence of absorption of the drug in the form of measurable metabolites. This phenomenon occurred in 8 of 95 subjects (8.4%). 20 An excessive proportion of ultrarapid metabolizers in our study group could have generated results underscoring the limitations of omeprazole. However, the median overnight intragastric ph of 4.2. for the whole group receiving omeprazole twice daily with placebo at bedtime suggests susceptibility of our volunteers to the drug. Because the additional bedtime dose of omeprazole was

5 December 1998 RANITIDINE FOR NOCTURNAL ACID ON OMEPRAZOLE 1339 given last in all cases to avoid interference on a study done the following night, the study was not completely randomized, and an order effect cannot be excluded. However, we are not aware of any biological reason this should have occurred. In this study, we observed high interindividual variability in acid-suppressive responses to omeprazole, as reported previously. 4,5 This could be related to many factors, including individual variability in the rate of gastric acid secretion, differences in number of proton pumps activated and thus accessible to omeprazole, variable rates of generation of new proton pumps, and differences in elimination of the drug. The results of this study suggest that addition of ranitidine at bedtime may be useful for patients taking a proton pump inhibitor twice daily who remain symptomatic at night or in whom tight acid suppression may be considered desirable, i.e., patients with Barrett s esophagus. Our initial experience with an individual patient supports this conclusion. 3 In addition, these observations suggest that nocturnal acid breakthrough is largely dependent on histamine. References 1. Peghini PL, Katz PO, Bracy NA, Castell DO. Nocturnal recovery of gastric acid secretion with twice-daily dosing of proton pump inhibitors. Am J Gastroenterol 1998;93: Katz PO, Anderson C, Khoury R, Castell DO. Gastroesophageal reflux is associated with nocturnal gastric acid breakthrough on proton pump inhibitors BID. Aliment Pharmacol Ther (in press). 3. Peghini PL, Katz PO, Castell DO. Bedtime ranitidine decreases gastric acid secretion and eliminates esophageal acid exposure overnight in a patient with Barrett s esophagus taking omeprazole 20 mg BID (abstr). Am J Gastroenterol 1997;92: Kuo B, Castell DO. Optimal dosing of omeprazole 40 mg daily: effects on gastric acid and esophageal ph and serum gastrin in healthy controls. Am J Gastroenterol 1996;91: Mohiuddin MA, Pursnani KG, Katzka DA, Gideon RM, Castell JA, Castell DO. Effective gastric acid suppression after oral administration of enteric-coated omeprazole granules. Dig Dis Sci 1997; 42: Pursnani KG, Mohiuddin MA, Geisinger KR, Weinbaum G, Castell DO. Quantitative evaluation of the role of acid burden in production of feline esophagitis (abstr). Gastroenterology 1996; 110:A Moore JG, Englert E. Circadian rhythm of gastric acid secretion in man. Nature 1970;226: Moore JG, Halberg F. Circadian rhythm of gastric acid secretion in men with active duodenal ulcer. Dig Dis Sci 1986;31: Levin E, Kirsner JB, Palmer WL, Butler C. The variability and periodicity of the nocturnal gastric secretion in normal individuals. Gastroenterology 1948;10: Savarino V, Mela GS, Scalabrini P, Sumberaz A, Fera G. Celle G. 24-hour study of intragastric acidity in duodenal ulcer patients and normal subjects using continuous intraluminal ph-metry. Dig Sis Sci 1988;33: Moore JG, Wolfe M. The relation of plasma gastrin to the circadian rhythm of gastric acid secretion in man. Digestion 1973;9: Feldman M, Richardson CT. Total 24 hour gastric acid secretion in patients with duodenal ulcer. Comparison with normal subjects and effects of cimetidine and parietal cell vagotomy. Gastroenterology 1986;90: Hirschowitz BI, Keeling D, Lewin M, Okabe S, Parsons M, Sewing K, Wallmark B, Sachs G. Pharmacological aspects of acid secretion. Dig Dis Sci 1995;40:3S 23S. 14. DelValle J, Lucey MR, Yamada T. Gastric secretion. In: Yamada T, ed. Textbook of gastroenterology. 2nd ed. Philadelphia: Lippincott, 1995: Prichard PJ, Yeomans ND, Mihaly GW, Jones DB, Buckle PJ, Smallwood RA, Louis WJ. Omeprazole: a study of its inhibition of gastric ph and oral pharmacokinetics after morning or evening dosage. Gastroenterology 1985;88: Lind T, Cederberg C, Ekenved G, Haglund U, Olbe L. Effect of omeprazole a gastric proton pump inhibitor on pentagastrin stimulated acid secretion in man. Gut 1983;24: Cederberg C, Andersson T, Skanberg I. Omeprazole: pharmacokinetics and metabolism in man. Scand J Gastroenterol 1989; 24(suppl 166): Blair JA, Feldman M, Barnett C, Walsh JH, Richardson CT. Detailed comparison of basal and food-stimulated gastric acid secretion rates and serum gastrin concentrations in duodenal ulcer patients and normal subjects. J Clin Invest 1987;79: Zeldis JB, Friedman LS, Isselbacher KJ. Ranitidine: a new H 2 - receptor antagonist. N Engl J Med 1983;309: Balian JD, Sukhova N, Harris JW, Hewett J, Pickle L, Goldstein JA, Woosley RL, Flockhart DA. The hydroxylation of omeprazole correlates with S-mephenytoin metabolism: a population study. Clin Pharmacol Ther 1995;57: Marinac JS, Balian JD, Foxworth JW, Willsie SK, Daus JC, Owen R, Flockhart DA. Determination of CYP2C19 phenotype in black Americans with omeprazole: correlation with genotype. Clin Pharmacol Ther 1996;60: Received May 7, Accepted August 31, Address requests for reprints to: Donald O. Castell, M.D., Department of Medicine, Suite 501, Pepper Pavilion, Allegheny University Hospitals, Graduate, One Graduate Plaza, 1800 Lombard Street, Philadelphia, Pennsylvania Fax: (215) Supported by grants from the American College of Gastroenterology Institute of Research, from Glaxo Welcome, Inc., and from the Theodor and Ida Herzog-Egli Foundation, Zürich, Switzerland. Presented at the Annual Scientific Meeting of the American College of Gastroenterology, Chicago, Illinois, November 1997.