Proton pump inhibitors (PPIs) are the most potent. Long-term Effect of H 2 RA Therapy on Nocturnal Gastric Acid Breakthrough

Transcription

1 GASTROENTEROLOGY 2002;122: Long-term Effect of H 2 RA Therapy on Nocturnal Gastric Acid Breakthrough WILLIAM K. FACKLER, TINA M. OURS, MICHAEL F. VAEZI, and JOEL E. RICHTER Center for Swallowing and Esophageal Disorders, Department of Gastroenterology, Cleveland Clinic Foundation, Cleveland, Ohio Background & Aims: Adding histamine 2 receptor antagonists (H 2 RAs) to proton pump inhibitor (PPI) therapy is a common practice to block nocturnal acid breakthrough (NAB). Controversy exists over its efficacy because of H 2 RA intolerance. No prospective study has addressed this issue. Methods: Twenty-three healthy volunteers and 20 gastroesophageal reflux disease (GERD) patients were studied. Ambulatory ph monitoring was performed with one electrode in the gastric fundus and the other 5 cm above the lower esophageal sphincter. Baseline ph testing was performed and repeated after 2 weeks on PPI twice daily before meals (omeprazole 20 mg). All subjects then received 28 days of PPI plus H 2 RA Qhs (ranitidine 300 mg) with repeat ph testing on days 1, 7, and 28. Results: Eighteen controls and 16 GERD patients completed all 5 studies. Compared with baseline, all 4 medication regimens decreased supine % time ph < 4(P 0.001). The administration of PPI 1 day of H 2 RA was the only therapy that significantly decreased % time gastric ph < 4 for the supine period compared with PPI twice daily alone (P < 0.001). There was no difference in % time supine gastric ph < 4 between 2 weeks of PPI twice daily alone and either 1 week or 1 month of PPI bedtime H 2 RA. Conclusions: The combination of H 2 RA and PPI therapy reduced NAB only with the introduction of therapy. Because of H 2 RA tolerance, there is no difference in acid suppression between PPI twice daily and PPI twice daily H 2 RA after 1 week of combination therapy. Proton pump inhibitors (PPIs) are the most potent drugs currently available for the suppression of gastric acid secretion. Numerous studies have shown the superiority of PPIs over histamine 2 -receptor antagonists (H 2 RAs) for the treatment of acid-related disorders, such as the Zollinger-Ellison syndrome, erosive esophagitis, and peptic ulcer disease. 1 6 Nevertheless, even with the excellent acid control afforded by the PPIs, studies have consistently reported the inability to render the stomach achlorhydric. Kuo and Castell 7 reported that normal volunteers continue to secrete gastric acid after receiving omeprazole 40 mg/day. Leite et al. 8 showed persistent acid secretion in normal volunteers and patients with gastroesophageal reflux disease (GERD) while on omeprazole therapy. They showed that a number of these patients respond to increased doses of PPI with some improvement in the control of their gastric acidity and proposed the concept of omeprazole resistance. Recently, studies have identified a phenomenon of increasing gastric acidity at night in individuals receiving a PPI twice daily. 9,10 This event has been labeled nocturnal acid breakthrough (NAB) and is arbitrarily defined as the appearance of gastric acid, marked by a ph level of less than 4 in the fundus, for a period greater than 1 hour overnight during the administration of twice-daily PPI therapy. The prevalence of NAB ranges between 69% 79% in normal volunteers and patients with GERD and typically appears in the second 6-hour period after the evening dose of PPI when patients are sleeping. 9,11 There are important clinical implications of this phenomenon because of the potential for gastroesophageal reflux during this time period when the esophageal protective mechanisms of saliva production and esophageal motility are decreased. For example, some GERD patients with minimal acid exposure to the esophagus could develop ear, nose, and throat, or respiratory complaints, whereas others could manifest persistent nocturnal heartburn and acid regurgitation while on medical therapy and receive a diagnosis of refractory GERD. Hence, there is a clinical rationale for reducing or abolishing NAB. In a cross-over design study, NAB was essentially eliminated in normal volunteers with the addition of H 2 RAs (ranitidine 150 mg or 300 mg at bedtime) to omeprazole 20 mg orally twice daily. 12 This finding was supported by a trial investigating the prevalence of NAB in Japanese patients treated with lansoprazole and famotidine. 13 Because of these studies, it would appear advisable to treat patients Abbreviations used in this paper: GERD, gastroesophageal reflux disease; H 2 RA, histamine 2 -receptor antagonist; NAB, gastric nocturnal acid breakthrough; PPI, proton pump inhibitor by the American Gastroenterological Association /02/$35.00 doi: /gast

2 626 FACKLER ET AL. GASTROENTEROLOGY Vol. 122, No. 3 with difficult-to-control symptoms of GERD and documented NAB with H 2 RAs at bedtime to maintain their overnight gastric ph level above 4. Unfortunately, the long-term efficacy of suppressing gastric acid with histamine-antagonist therapy is lacking because the H 2 RAs were administered for only 1 day before ph level monitoring in the 2 studies showing nocturnal gastric acid control. 12,13 Documenting the suppression of gastric acid after such a brief period does not account for the possible development of H 2 RA tolerance. Multiple investigators have published data on the decreasing acid control provided by H 2 RAs when taken orally for periods as short as 7 days, whereas other studies have shown a decrease in drug effect after 1 to 2 months of continuous use Hence, the observation that H 2 RAs significantly reduce nocturnal gastric acid secretion has not been established for prolonged drug therapy. Therefore, the purpose of this study is to address the chronic effect of H 2 RA administration on the control of NAB. Materials and Methods Patients We prospectively evaluated 23 healthy volunteers and 20 patients with GERD. Patients were recruited to the Center for Swallowing and Esophageal Disorders through an advertisement campaign. All volunteers answered a questionnaire to determine medical histories and demographics. Healthy volunteers complained of no symptoms suggestive of GERD and had normal esophageal acid exposure by 24-hour ambulatory gastroesophageal ph level monitoring. Patients who described symptoms of GERD had either abnormal esophageal acid exposure with 24-hour ph level monitoring or a recent history of upper endoscopy with evidence of esophagitis per the Los Angeles classification. Individuals were excluded from the study if they were currently taking or had taken in the 2-week period before testing any of the following medications: PPIs, H 2 RAs, or promotility agents. Other exclusion criteria included a history of allergic response to either omeprazole or ranitidine, history of peptic ulcer disease, pregnancy, or the inability to tolerate either the manometry catheter or ph probe. Our study protocol was approved by the Institutional Review Board at the Cleveland Clinic Foundation in February All patients consented to the protocol before their enrollment in the study. Gastroesophageal Testing Esophageal manometry. All subjects underwent esophageal manometry after a 6-hour fast to locate the lower esophageal sphincter. We used a round polyvinyl catheter (diameter 4 mm; Arndorfer Medical Specialties Inc., Milwaukee, WI) continuously perfused with distilled water at a rate of 0.5 ml/minute by a low-compliance pneumohydraulic capillary infusion system. The station pull-through technique was used to determine the location of the sphincter. The lower esophageal sphincter pressures and locations were recorded by means of a computerized motility system (Synectics Gastrosoft Polygram, Milwaukee, WI). Ambulatory gastroesophageal ph monitoring. Twenty-four hour ph level monitoring was conducted in all participants. This was performed with 2.1-mm monocrystalline ph catheters with 2 antimony electrodes separated by 15 cm (Medtronic Functional Diagnostics Zinetics, Inc., Salt Lake City, UT). The reference electrode was internalized. The ph electrodes were calibrated at 37 C in buffer solutions of ph 7 and ph 1 (Fisher Scientific, Fairlawn, NJ) before each study. After calibration, the ph probe apparatus was passed nasally and positioned such that the distal electrode was in the gastric fundus, 10 cm below the proximal border of the lower esophageal sphincter. The probe apparatus was secured to the nose and cheek to prevent dislodgment. The ph electrodes were connected to a portable digital data recorder (Digitrapper Mark III Gold; Synectics) worn around the waist, which stored ph data samples every 4 seconds for up to 24 hours. Patients returned home with instructions to keep a diary recording meal times, time of lying down for sleep, and time of rising in the morning. Patients were encouraged to perform their normal daily activities, consume their customary diet without restrictions, and avoid sleeping for short periods during the day. They returned the following day after a minimum of 18 hours to have their probes removed and their diaries reviewed. Study Protocol During the initial visit, women of child-bearing potential underwent a urine pregnancy screen. After enrollment, the Helicobacter pylori status of each individual was checked by using a commercially available, whole-blood, immunoglobulin (Ig)G, serologic assay (FlexSure HP kit; SmithKline Diagnostics, Inc., San Jose, CA). All eligible participants were initially treated with omeprazole 20 mg orally twice daily for a total of 2 weeks. When this was completed, ranitidine 300 mg orally at bedtime was added to the omeprazole twice-daily regimen. All participants continued the revised medication regimen for a 4-week period. Participants were instructed to take the morning dose of PPI 30 minutes before breakfast, the evening dose of PPI 30 minutes before dinner, and the ranitidine within 30 minutes of the patient s bedtime. Medication adherence was measured by pill counts during interval visits throughout the 6-week study period. Patients were dropped from the study if adherence decreased below 75%. After the initial manometry, baseline gastroesophageal ph testing was performed before starting medications. The second ph study was conducted at the end of the first 2 weeks to assess the degree of acid suppression caused by PPI treatment alone. A third ph study was executed after 1 day of adding ranitidine to the PPI therapy. A fourth ph study was performed after a 1-week period of combined PPI and H 2 RA

3 March 2002 H2RA THERAPY 627 NAB was defined as an abrupt drop in esophageal ph to 4 or less, lasting for a period greater than 8 seconds. Jandel SigmaStat statistical software (Jandel Corp., San Rafeal, CA) was used for statistical analysis. Demographic differences between GERD patients and normal volunteers were compared with the Student t test and 2 analysis. Median percent time that ph level was less than 4 for each medication study period was calculated. The ph data for each study period was compared between GERD patients and normal volunteers with the Mann-Whitney Rank Sum test. The ph data comparisons between study periods was performed with paired analysis of variance on ranks. If differences were found between groups, individual groups were compared by using the Mann-Whitney Rank Sum test with a Bonferroni correction for multiple comparisons. For the later comparisons, a P value of less than 0.01 was considered significant. Figure 1. Study algorithm. All individuals were free of medication affecting gastric acid production for at least 2 weeks before enrolling in the study. H. pylori status was evaluated during the initial visit. The study period lasted a total of 6 weeks, with all participants taking omeprazole 20 mg orally twice daily and ranitidine 300 mg orally at bedtime for the final 4 weeks. A total of 34 individuals were able to complete all 5 gastroesophageal ph studies. treatment. After 4 weeks of continued H 2 RA, participants underwent the final ph study (Figure 1). Data Analysis After each study, ph data was downloaded onto an IBM-compatible computer for analysis by using a commercially available software package (Synectics Gastrosoft Esophagram). All ph data was reviewed and processed with meal times excluded because meals were not standardized in this study. Because the sleep period (i.e., time supine), was not standardized, the percent time that ph level was less than 4 for the gastric fundus and distal esophagus was analyzed for the total, upright, and supine periods and mean values were calculated. Median values with 25% 75% ranges were calculated from the group of means because the mean data distribution was nonparametric. The appearance of a NAB event was calculated directly from the minutes of time gastric ph level was less than 4 during the sleep period of the study. A cumulative time gastric ph level was less than 4 during the supine period, and greater than 60 minutes, defined nocturnal acid breakthrough. Concurrent gastroesophageal reflux during a period of Results Demographics Twenty-three normal volunteers (11 men, 12 women), mean age 32 years (range, years), and 20 patients with GERD (14 men, 6 women), mean age 41 years (range, years), were enrolled in the study protocol. Three volunteers were dropped because of medication noncompliance. Two volunteers and 4 GERD patients were unable to complete all 5 ph studies successfully. Therefore, complete data was analyzed on 34 participants, 18 normal volunteers and 16 GERD patients. Four of 18 normals had positive serologic results for IgG antibodies to H. pylori. Two of 16 GERD patients were positive for IgG antibodies to H. pylori. Gastric Acid Suppression Median percent time that gastric ph level was less than 4 for the supine period was similar between GERD patients and normal volunteers for all study periods: no medication (99% vs. 99.6%, respectively), PPI twice daily for 2 weeks (32.8% vs. 47.9%), PPI twice daily plus 1 day H 2 RA (2.5% vs. 0.3%), PPI twice daily plus 1 week H 2 RA (15.6% vs. 24.4%), and PPI twice daily plus 1 month H 2 RA (30.4% vs. 28.0%). Data was therefore combined for further analysis. Median percent time that gastric ph level was less than 4 during the supine period was statistically greater (P 0.001) for participants on no medications (99.3%) when compared with all medication regimens. When comparing specific drug regimens, the median percent time that supine gastric ph level was less than 4 was not different between studies after PPI alone (42.8%) and PPI with the addition of H 2 RA for either 1 week (16.0%, P 0.06) or 1 month (29.4%, P 0.08). However, the median percent time that ph level was less

4 628 FACKLER ET AL. GASTROENTEROLOGY Vol. 122, No. 3 Figure 2. Data for all study participants showing percentage that supine time gastric ph level was less than 4 for the 5 study periods. Medians (left) with 25% 75% ranges (right) are calculated and presented for the individual means. Median values for all medical periods are significantly less than the period of no medication. The median ph value after 1 day of PPI twice daily plus H 2 RA use is significantly less than any other drug regimen. There is no difference between median values for the period of PPI twice-daily use alone and PPI twice-daily plus H 2 RA use for either 1 week or 1 month. than 4 was significantly decreased (P 0.001) after 1 day of H 2 RA therapy (0.7%) when compared with all other drug regimens (Figure 2). The data analysis did not change if the ph values from the 6 participants who did not complete all studies were included. The development of NAB was similar between healthy volunteers and GERD patients for all study periods. When testing was completed on PPI twice-daily therapy alone, 79% of all participants exhibited NAB. This dropped to 18% after the addition of an evening H 2 RA for 1 night (P 0.001). With continued use of the H 2 RAs at bedtime, the number of NAB episodes increased. Fifty-nine percent of study participants manifested breakthrough after 1 week and 62% had recurrent events after 1 month of H 2 RA use. These values were statistically increased from 1-day H 2 RA therapy data (P 0.001), but were not statistically different from each other or from the occurrence of NAB after PPI therapy alone (Figure 3). Esophageal Acid Suppression Gastroesophageal reflux events and their association to NAB were assessed for the 16 GERD patients completing all 5 ph studies. During periods of NAB, median percent time that esophageal ph level was less than 4 during the supine period was not statistically different for patients on PPI twice daily (0.05%) when compared with the other medication regimens: PPI with the addition of H 2 RA for 1 day (0.0%), 1 week (0.0%), and 1 month (0.0%) (Figure 4). Figure 3. The presence of NAB for the 4 study periods on medication. Nocturnal acid breakthrough is defined as the presence of gastric ph level of less than 4 for at least 1 hour while sleeping. Comparisons for significance are made between all patients for each study period. A significant decrease (P 0.01) in nocturnal acid breakthrough is seen only for individuals taking PPI twice daily and H 2 RA for 1 day when compared with all other periods., GERD;, normals;, all patients. The number of patients who maintained a supine esophageal ph level of less than 4 for more than 3% of the time (the accepted upper limit of normal for supine acid exposure to the esophagus in controls) varied per drug regimen. Three individuals showed an abnormal percent time that ph level was less than 4 after PPI therapy alone, 1 after the addition of H 2 RA to PPI for 1 day, 3 after 1 week of H 2 RA, and 1 after 1 month of H 2 RA. All of these patients were different except for 1 individual who manifested a prolonged percent time that esophageal ph level was less than 4 at 1 day and 1 month of added H 2 RA to PPI therapy. Figure 4. Supine esophageal acid exposure periods of NAB for the 5 study groups. Abnormal esophageal acid exposure is defined as percent time that ph level is less than 4 of 3% or more during the supine period. Medians (left) with 25% 75% ranges (right) are calculated and presented from the individual means. All treatment regimens significantly decrease esophageal acid exposure. No statistical difference exists between any treatment regimens.

5 March 2002 H2RA THERAPY 629 Table 1. Demographics of 34 Patients Divided Into Response Type GERD Normals P value All patients Men/women 11/5 9/ Age (range) 40 (27 71) 31 (21 51) NS H. pylori 2 4 NS Group 1 H 2 RA tolerance response Men/women 7/1 2/5 NS Age (range) 35 (27 46) 31 (26 41) 0.02 H. pylori 1 0 NS Group 2 PPI response Men/women 1/2 Age (range) 31 (29 36) H. pylori 3 Group 3 H 2 RA response Men/women 3/1 2/1 NS Age (range) 47 (40 57) 26 (21 30) H. pylori 1 0 NS Group 4 unpredictable response Men/women 1/3 4/1 NS Age (range) 44 (31 71) 33 (31 35) NS H. pylori 0 1 NS NS, not specified. Post Hoc Analysis With such large variability in the mean percent time that gastric ph level was less than 4 existing between patients, we performed a post hoc analysis on the data to determine if identifiable patterns of response were present to the different drug regimens. This evaluation revealed 4 general patterns of gastric ph response when analyzing the 34 participants who completed all 5 gastroesophageal ph studies. Demographics of each group are presented in Table 1. The first subgroup experienced a decreasing effect of H 2 RA therapy over time (i.e., H 2 RA tolerance). A total of 15 of 34 participants (44%) showed a variable initial response to PPI dosing but with the addition of bedtime H 2 RA had resolution of NAB. The initial effect of gastric acid control with nighttime H 2 RA deteriorated after extended H 2 RA administration. All 15 patients experienced an increase in mean percent time that supine gastric ph level was less than 4 at 1 week or 1 month of H 2 RA administration and a return of nocturnal gastric acid for more than 60 minutes. The second subgroup was composed of 3 normal volunteers (9%) who had a dramatic response to PPI twicedaily therapy alone with no evidence of NAB (median percent time, 0%, range, 0% 9%). After the addition of H 2 RA medication to this population for any length of time, there was no significant increase in percent time that supine gastric ph level was less than 4. All 3 individuals in this group were H. pylori IgG positive. The third subgroup consisted of 7 of 34 participants (21%) who exhibited a sustained response to H 2 RA therapy. This subgroup was characterized by the presence of NAB on PPI therapy alone. When H 2 RA therapy was added, a reduction of percent time that supine gastric ph level was less than 4 resulted, and the NAB events were abolished in all participants. This effect persisted throughout the study period such that no differences in percent time that supine gastric ph level was less than 4 were observed after 1 day, 1 week, and 1 month of H 2 RA administration (0.6% vs. 4.0% vs. 0.7%, respectively). One of 7 were H. pylori IgG positive. No demographic differences were identified that effectively separated the H 2 RA responders from the other 3 groups. The fourth subgroup was marked by an unpredictable response to H 2 RA dosing in addition to PPI therapy in 9 participants (26%). The initial addition of bedtime H 2 RA to PPI twice daily resulted in a substantial reduction of nocturnal gastric acid and elimination of nocturnal acid breakthrough in 6 patients. However, after the addition of H 2 RA for 1 week, all individuals developed recurrent NAB. When H 2 RA was continued for 1 month, the percent time that supine gastric ph level was less than 4 decreased in all patients compared with 1 week of H 2 RA therapy, but only 3 participants had elimination of nocturnal acid breakthrough. Medication Adherence The median percent time that gastric ph level was less than 4 for each study period did not change significantly when increasing the drug compliance requirements from 75% to 90% for either omeprazole, ranitidine, or both (Table 2). Table 2. Effect of Drug Adherence on Nocturnal Gastric Acid Suppression Baseline PPI twice daily 2 wks PPI twice daily H 2 RA 1 day PPI twice daily H 2 RA1wk PPI twice daily H 2 RA1mo All patients 99.3% ( ) 42.8% ( ) 0.7% ( ) 16.0% ( ) 29.4% ( ) 90% PPI compliance 99.2% ( ) 45.8% ( ) 0.9% ( ) 15.5% ( ) 30.3% ( ) 90% H 2 RA compliance 99.2% ( ) 39.7% ( ) 0.3% ( ) 15.5% ( ) 30.7% ( ) 90% both compliance 99.9% ( ) 37.1% ( ) 0.4% ( ) 15.1% ( ) 30.2% ( )

6 630 FACKLER ET AL. GASTROENTEROLOGY Vol. 122, No. 3 Figure 5. The effect of drug adherence rates on the 4 identified subgroups of response to gastric acid suppression. The percentage of individuals showing either the H 2 RA tolerance response or PPI response patterns increases with more stringent adherence criteria whereas the percentage with either the H 2 RA response or unpredictable response decreases., 75% compliance;, 90% compliance. Interestingly, the subgroups showing a sustained response to H 2 RA therapy and an unpredictable response to the addition of H 2 RA had the greatest percentage of individuals excluded by this more stringent analysis (Figure 5). Forty-four percent of study participants comprised the H 2 RA tolerance subgroup with 75% medication adherence, but this increased to 59% of the individuals meeting 90% adherence. Conversely, 21% of individuals meeting the original 75% drug adherence requirements made up the subgroup responding to prolonged H 2 RA therapy, yet this dropped to 14% of those meeting 90% compliance standards. Likewise, the percentage of study patients forming the subgroup with an unpredictable response dropped from 26% to 14% with the increase in adherence standards. Discussion Our findings support earlier conclusions that the addition of an H 2 RA to twice-daily PPI therapy significantly reduces the appearance of nocturnal gastric acid; however, this phenomenon is temporary for most people. After only 1 week of continuous bedtime H 2 RA administration, there is a significant reduction in the acid inhibitory effect yielded by ranitidine at 1 day. After 1 month of uninterrupted H 2 RA therapy, gastric acidity has returned to pre-h 2 RA levels, and there is no meaningful reduction in the development of NAB for the majority of patients. Nonetheless, some individuals seem to respond to bedtime H 2 RAs. Our post hoc analysis reveals that 1 in 5 patients may derive at least 1 month of benefit from their use. Unfortunately, no demographic variables separate these responders from nonresponders. The most likely explanation for the inability of ranitidine to maintain its effect over a 1-month period is the development of tolerance. Studies have consistently shown that H 2 RAs lose their ability to inhibit acid secretion after prolonged administration. To date, the mechanisms behind the development of tolerance have not been clearly elucidated. 26 Most studies investigating tolerance focus on the interactions between H 2 RAs, intragastric ph, and changes in serum gastrin concentration. An increase in serum gastrin concentration occurs with the increase in gastric ph observed after H 2 RA therapy. 27 Proposed mechanisms for how this event results in a return of gastric acidity are: (1) gastrin increasing the acid secretory capacity of the stomach through its trophic effects on the parietal cell mass, (2) gastrin indirectly promoting acid secretion by stimulating the release of histamine from the enterochromaffin-like cell, or (3) gastrin directly stimulating acid production from the parietal cell through a gastrin receptor. 26,28,29 However, it is interesting that gastric ph level changes and gastrin concentration are not highly correlated. For example, Wilder- Smith et al. 18 showed the expected development of increased gastrin levels with a decrease in intragastric acidity after initial dosing with an H 2 RA. Yet, after prolonged dosing with H 2 RAs and the development of tolerance, this inverse relationship no longer held true. Rather, gastrin concentration did not show an expected decrease in association with the increase in gastric acidity. In fact, hypergastrinemia either remained stable or increased further with continued H 2 RA therapy, despite the lower intragastric ph level. This finding implies that a negative feedback loop between gastric acid and gastrin is not a simple relationship but instead is related through intermediary steps and may be influenced by other factors such as enterochromaffin-like cell hyperplasia 30 or through the up-regulation of the H 2 -receptor. This latter concept has recently gained more attention. In rabbit parietal cells after only 14 days of H 2 -receptor blockade by antagonists, there is an up-regulation of the receptor without a significant change in its binding affinity for histamine. 31 This may be accounted for by the nature of the H 2 -receptor interaction with an antagonist. It has been shown that with cimetidine and ranitidine, these antagonists actually act as inverse agonists by displaying some spontaneous agonist-independent H 2 -receptor activity. 32 These findings offer not only an explanation for tolerance to the use of H 2 -receptor antagonists but may also serve to explain some of the phenomenon of rebound hyperacidity with drug withdrawal.

7 March 2002 H2RA THERAPY 631 The influence of H 2 RA tolerance is further supported by our post hoc analysis of medication compliance patterns. With the initial 75% adherence requirement, the largest single subgroup of patients displayed a pattern of H 2 RA tolerance, yet almost 50% of patients either maintained suppression of gastric acid or showed an unpredictable response to H 2 RA therapy. When participants maintaining less than 90% adherence to medical treatment were excluded from the data analysis, the percentage of individuals with a sustained or unpredictable response to H 2 RA therapy dropped by almost half to 28%. In particular, the percentage of patients with a persistent benefit from the use of H 2 RAs decreased from 21% to 14%. This decrease was coupled with a substantial increase in the percentage of patients showing an H 2 RA tolerance effect from 44% to 59%. These results suggest tolerance develops in those who take the bedtime H 2 RAs with greatest frequency. Although the numbers of participants in this post hoc analysis are too small to disclose a statistically significant difference, the implication is apparent. One notable distinction between our study and the 2 earlier studies reporting the control of NAB with H 2 RAs is that the populations are different. The Peghini 12 and Katsube 13 trials enrolled healthy, asymptomatic volunteers whereas we included both healthy normal subjects and patients with GERD. Previous studies have shown that patients with acid-peptic disease, in particular duodenal ulcer disease, produce more gastric acid than normal subjects. 33 Interestingly, duodenal ulcer disease patients maintain a more sustained response to acid suppression with H 2 RAs. 34 Even though the pathophysiology of GERD differs from duodenal ulcer disease, one could hypothesize that acid hypersecretion plays a role in some GERD patients. 35 In this event, we would have expected a more long-standing, acid-suppressive effect from the addition of ranitidine to twice-daily PPIs. Instead, we found the opposite in the majority of patients. As well, comparisons of gastric acid profiles identified no differences between our normal and GERD populations. This study highlights a few important clinical observations. First, the addition of H 2 RAs on a regular schedule does not typically result in a lasting reduction of nocturnal gastric acid production; however, the intermittent use of H 2 RAs may provide a potential benefit for acid control on an as needed basis. Taking a bedtime H 2 RA when the patient is exposed to a refluxogenic situation (i.e., after a large fatty meal or a night of cocktails), may be the optimal approach for minimizing the theoretical damage from NAB. Second, it is extremely difficult to render individuals achlorhydric. In our trial, only 3 normal volunteers, all positive for H. pylori serology, had a sustained suppression of nocturnal gastric acidity. This inability to abolish gastric acid may help to explain the excellent safety profile of the PPI class of medications. Third, the use of PPIs provides good control of nighttime esophageal acid reflux. Because of the availability and safety of PPIs, primary care physicians are able to treat the vast majority of patients presenting with gastroesophageal reflux disease. More and more, gastroenterologists see patients with GERD because of difficult-to-manage symptoms or complications such as strictures or Barrett s esophagus. With persistent gastric acidity documented by ph testing, PPIs oftentimes are interchanged, doses are increased, or H 2 RAs are added to achieve optimal acid control. Unfortunately, it is extremely difficult to render the stomach devoid of acid with medical therapy alone, as exemplified by the appearance of NAB, and it appears that the addition of an H 2 RA at bedtime does little to change this fact for the majority of patients. Nevertheless, patients generally do well because all these regimens virtually eliminate reflux of acid into the esophagus. Therefore, we suggest returning our attention to esophageal ph parameters as the appropriate measure of successful acid control in difficult-to-manage patients. References 1. Delchier JC, Soule JC, Mignon M, Goldfain D, Cortot A, Travers B, Isal JP, Bader JP. Effectiveness of omeprazole in seven patients with Zollinger-Ellison resistant to histamine H 2 -receptor antagonists. Dig Dis Sci 1986;31: Lamers CBHW, Lind T, Moberg S, Jansen JBMJ, Olbe L. Omeprazole in Zollinger-Ellison syndrome. Effects of a single dose and of long-term treatment in patients resistant to histamine H 2 -receptor antagonists. N Engl J Med 1984;310: Ducrotte P, Guillemot F, Elouaer-Blanc L, Hirschauer C, Thorel JM, Petit A, Hochain P, Michel P, Cortot A, Colin R, Denis P. Comparison of omeprazole and famotidine on esophageal ph in patients with moderate to severe esophagitis: a cross over study. Am J Gastroenterol 1994;89: Bate CM, Keeling PWN, O Morain C, Wilkinson SP, Foster DN, Mountford RA, Temperley JM, Harvey RF, Thompson DG, Davis M, Forgacs IC, Bassett KS, Richardson PDI. Comparison of omeprazole and cimetidine in reflux esophagitis: symptomatic, endoscopic, and histologic evaluations. Gut 1990;31: Cooperative study group. Double blind comparative study of omeprazole and ranitidine in patients with duodenal or gastric ulcer: a multicentre trial. Gut 1990;31: Brunner G, Lreutzfeldt W, Harke U, Lamberts R. Therapy with omeprazole in patients with peptic ulcerations resistant to extended high-dose ranitidine treatment. Digestion 1988;39: Kuo B, Castell DO. Optimal dosing of omeprazole 40 mg daily: effects on gastric and esophageal ph and serum gastrin in healthy controls. Am J Gastroenterol 1996;91: Leite LP, Johnston BT, Just RJ, Castell DO. Persistent acid secretion during omeprazole therapy: a study of gastric acid profiles in patients demonstrating failure of omeprazole therapy. Am J Gastroenterol 1996;91:

8 632 FACKLER ET AL. GASTROENTEROLOGY Vol. 122, No 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. Gastro-esophageal reflux associated with nocturnal gastric acid breakthrough on proton pump inhibitors. Aliment Pharmacol Ther 1998;12: Fackler WK, Vaezi MF, Ours TM, Richter JE. Nocturnal acid breakthrough cannot be eliminated in patients with atypical gastroesophageal reflux disease (abstr). Gastroenterology 2000;118: A Peghini PL, Katz PO, Castell DO. Ranitidine controls nocturnal gastric acid breakthrough on omeprazole: a controlled study in normal subjects. Gastroenterology 1998;115: Katsube T, Adachi K, Kawamura A, Amano K, Uchida Y, Watanabe M, Kinoshita Y. Helicobacter pylori infection influences nocturnal gastric acid breakthrough. Aliment Pharmacol Ther 2000;14: Qvigstad G, Arnestad JS, Brenna E, Waldum HL. Treatment with proton pump inhibitors induces tolerance to H 2 -receptor antagonists in Helicobacter pylori-negative patients. Scand J Gastroenterol 1998;33: Netzer P, Gaia C, Sandoz M, Huluk T, Gut A, Halter F, Husler J, Inauen W. Effect of repeated injection and continuous infusion of omeprazole and ranitidine on intragastric ph over 72 hours. Am J Gastroenterol 1999;94: Wilder-Smith CH, Halter F, Merki HS. Tolerance and rebound to H 2 -receptor antagonists: intragastric acidity in patients with duodenal ulcer. Dig Dis Sci 1991;36: Lachman L, Howden CW. Twenty-four-hour intragastric ph: tolerance within 5 days of continuous ranitidine administration. Am J Gastroenterol 2000;95: Wilder-Smith C, Halter F, Ernest T, Gennoni M, Zeyen B, Varga L, Roehmel JJ, Merki HS. Loss of acid suppression during dosing with H 2 -receptor antagonists. Aliment Pharmacol Ther 1990; 4(Suppl 1): Nwokolo CU, Prewett EJ, Sawyerr AFM, Hudson M, Lim S, Pounder R. Tolerance during 5 months of dosing with ranitidine, 150 mg nightly: a placebo-controlled, double-blind study. Gastroenterology 1991;101: Labenz J, Peitz U, Leusing C, Tillenburg B, Blum AL, Borsch G. Efficacy of primed infusions with high dose ranitidine and omeprazole to maintain high intragastric ph in patients with peptic ulcer bleeding: a prospective randomised controlled study. Gut 1997;40: Merki HS, Wilder-Smith CH. Do continuous infusions of omeprazole and ranitidine retain their effect with prolonged dosing? Gastroenterology 1994;106: Wilder-Smith CH, Halter F, Hacki W, Merki HS. ph-feedback controlled infusions of ranitidine are no more effective than fixeddose infusions in reducing gastric acidity and variability in antisecretory responses. Br J Clin Pharmacol 1992;33: Wilder-Smith CH, Ernest T, Gennoni M, Zeyen B, Halter F, Merki HS. Tolerance to oral H 2 -receptor antagonists. Dig Dis Sci 1990; 35: Nwokolo CU, Smith JTL, Gavey C, Sawyerr A, Pounder RE. Tolerance during 29 days of conventional dosing with cimetidine, nizatidine, famotidine, or ranitidine. Aliment Pharmacol Ther 1990;4(Suppl 1): Mathot RAA, Geus WP. Pharmacodynamic modeling of the acid inhibitory effect of ranitidine in patients in an intensive care unit during prolonged dosing: characterization of tolerance. Clin Pharmacol Ther 1999;66: Sandevik AK, Brenna E, Waldum HL. Review article: the pharmacological inhibition of gastric acid secretion-tolerance and rebound. Aliment Pharmacol Ther 1997;11: Walsh JH, Richardson CT, Fordtran JS. ph dependence of acid secretion and gastrin release in normal and ulcer patients. J Clin Invest 1975;55: Neuburger P, Lewin M, Bontils S. Parietal and chief cell population in four cases of the Zollinger-Ellison syndrome. Gastroenterology 1972;63: Gerber JG, Payne NA. The role of gastric secretagogues in regulating gastric histamine release in vivo. Gastroenterology 1992; 102: Klinkenberg-Knol EC, Festen HP, Jansen JB, Lamers CB, Nelis F, Sael P, Luckers A, Dekkers CP, Havu N, Meuwissen SG. Longterm treatment with omeprazole for refractory reflux esophagitis: efficacy and safety. Ann Intern Med 1994;121: Takeuchi K, Kajimura M, Kodaira M, Lin S, Hanai H, Kaneko E. Up regulation of H 2 receptor and adenylate cyclase in rabbit parietal cells during prolonged treatment with H 2 -receptor antagonists. Dig Dis Sci 1999;44: Smit MJ, Leurs R, Alewijnse AE, Blauw J, Van NieuwAmerongen GP, Van De Vrede Y, Roovers E, Timmermen H. Inverse agonism of histamine H 2 antagonists accounts for the upregulation of spontaneously active H 2 receptors. Proc Natl Acad Sci USA 1996;93: Collen MJ, Abdulian JD, Chen YK. Age does not affect basal gastric acid secretion in normal subjects or in patients with acid-peptic disease. Am J Gastroenterol 1994;89: Savarino V, Mela GS, Zentilin P, Cutela P, Vigneri S, Termini R, Di Mario F, Ferrana M, Malesci A, Belicchi M, Celle G. Absence of tolerance in duodenal ulcer patients treated for 28 days with a bedtime dose of roxatidine or ranitidine. Fundam Clin Pharmacol 1996;10: Colleen MJ, Strong RM. Comparison of omeprazole and ranitidine in treatment of refractory gastroesophageal reflux disease in patients with gastric acid hypersecretion. Dig Dis Sci 1992;37: Received June 19, Accepted November 15, Address reprint requests to: Joel E. Richter, M.D., Department of Gastroenterology, A30, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio richtej@ccf.org; fax: (216) Supported by an educational grant from Astra-Zeneca and the Borra Family Endowment for Esophageal and Swallowing Disorders.