Dr W. C. Orr, Lynn Institute for Healthcare Research, 5300 N. Independence, Suite 130, Oklahoma City, OK, USA. E-mail: email@example.com
Background: It has been presumed that nocturnal acid breakthrough may pose a risk for the development of nocturnal gastro-oesophageal reflux.
Aim: To investigate the occurrence of gastro-oesophageal reflux and acid breakthrough during polygraphically monitored sleep under conditions of powerful acid suppression with omeprazole 20 mg b.d. and an additional dose of ranitidine at bedtime.
Methods: Nineteen individuals with symptomatic gastro-oesophageal reflux disease were studied. Each individual was studied on two occasions subsequent to 1 week of 20 mg of omeprazole treatment b.d. Subjects underwent 24-h oesophageal and gastric pH recording, with polysomnographic monitoring. Participants received either 150 mg ranitidine at bedtime or placebo, prior to a provocative meal.
Results: Ranitidine administration resulted in a significant (P < 0.01) reduction in the percentage of time the intragastric pH < 4.0. There was no significant difference with regard to measures of gastro-oesophageal reflux, and reflux events were not noted to occur with a significantly greater frequency during periods of nocturnal acid breakthrough compared with control intervals without acid breakthrough.
Conclusions: The administration of 150 mg ranitidine at bedtime did not significantly alter the occurrence of sleep-related gastro-oesophageal reflux.
There is much evidence available to support the concept that the occurrence of gastro-oesophageal reflux during the sleeping interval is an important element in the development of oesophagitis and other complications of gastro-oesophageal reflux.1–4 More recently, it has been demonstrated that, in the setting of powerful acid suppression with proton pump inhibitors, there remains substantial gastric acidity during the sleeping interval.5,6 The occurrence of a precipitous decline in intragastric pH during the sleeping interval has been called nocturnal acid breakthrough, and is defined as a gastric pH < 4.0 for more than 1 h during the sleeping interval.5,6 The clinical significance of this phenomenon has been postulated to be related to the putative occurrence of breakthrough gastro-oesophageal reflux during sleep, which may accordingly account for the observation that approximately 10% of patients with gastro-oesophageal reflux disease (GERD) treated with proton pump inhibitors show a poor clinical response.7
It would seem a logical extension of these ideas that the occurrence of nocturnal acid breakthrough would create a vulnerability to gastro-oesophageal reflux and the consequent complications of sleep-related gastro-oesophageal reflux. In an attempt to demonstrate the significance of nocturnal acid breakthrough with regard to the occurrence of sleep-related gastro-oesophageal reflux, Katz et al. have shown that an episode of gastro-oesophageal reflux coincident with nocturnal acid breakthrough is seen in 31% of patients with GERD, 50% of patients with Barrett's oesophagus and 9% of normal subjects.8 In a subsequent study, the same group of investigators defined oesophageal motility abnormalities in a group of patients in whom they had identified gastro-oesophageal reflux occurring during episodes of nocturnal acid breakthrough.9
Following the logic that nocturnal acid breakthrough may be an important provocative stimulus for the occurrence of nocturnal gastro-oesophageal reflux and its potentially dangerous consequences, several studies have been published which have addressed the issue of the most effective means of resolving nocturnal acid breakthrough. Peghini et al. have shown that 150 mg or 300 mg of ranitidine at bedtime is more effective than an additional 20 mg of omeprazole in reducing nocturnal acid breakthrough.10 Also of interest is a study by Khoury et al., in which it was demonstrated that a b.d. dose of omeprazole was significantly more effective in reducing nocturnal acid secretion than a 20-mg dose of omeprazole in the morning and a 150-mg dose of ranitidine at night.11 These data indicate that, given a single dose of 20 mg omeprazole in the morning, an additional dose of omeprazole with an evening meal is more effective than a dose of ranitidine at night in suppressing nocturnal gastric acid secretion. Thus, under these circumstances, the administration of omeprazole appears to be more effective than ranitidine, but the effect of these treatment regimens on nocturnal gastro-oesophageal reflux remains unclear. Furthermore, reliable and statistically meaningful comparisons are further hampered by the fact that gastro-oesophageal reflux episodes are relatively uncommon under conditions of powerful gastric acid suppression.
In the present study, we have attempted to reduce the ‘floor effect’ of a comparison of supplemental ranitidine at night on gastro-oesophageal reflux and nocturnal acid secretion by utilizing a provocative meal prior to bedtime to enhance gastric acid secretion. It was felt that this would induce substantially more reflux episodes in symptomatic GERD patients, which would allow a more valid comparison of the effects of ranitidine at night in reducing gastro-oesophageal reflux in patients treated with 20 mg b.d. of omeprazole.
Materials and methods
Subject recruitment and screening procedure
The participants in this study included 19 volunteers (six males and 13 females) with a mean age of 40.6 years (range, 25–62 years) and a mean body mass index of 29.4 kg/m2. All participants reported having heartburn at least four days a week and one night a week for a period of at least 6 months, and were currently using an over-the-counter antacid or an H2 blocker at least once a week. None of the subjects had a history of Barrett's oesophagus, gastric surgery, neurological disease or diabetes. All subjects were Helicobacter pylori negative. The study protocol was approved by the Western Institutional Review Board.
Procedures and experimental protocol
Subjects were withdrawn from any acid suppressive medication for a minimum of 3 days for an H2 blocker and 5 days for a proton pump inhibitor before participation. Each individual was studied on two occasions subsequent to 1 week of 20 mg omeprazole treatment b.d. with breakfast and evening meals. On each occasion, subjects underwent 24-h oesophageal and gastric pH recording, with polysomnographic monitoring taking place within the sleep laboratory on the night of the pH study.
Participants reported to the laboratory at 08.00 h on each study day, when they were intubated with a dual-channel pH probe. The pH probe was positioned such that the proximal sensor was located 5 cm above the proximal border of the lower oesophageal sphincter. The position of the lower oesophageal sphincter was determined manometrically during the first visit. The distal sensor was located approximately 10 cm below the proximal sensor in the stomach. The probe's distance from the nares was noted so that, on the second study day, the probe could be placed in an identical location.
Once the pH probe was in place, subjects were allowed to leave the laboratory and return to their daily routine. During this time, they kept a diary of their symptoms and daily habits (i.e. eating, lying down). They were asked to refrain from eating after 17.00 h. Participants reported back to the sleep laboratory at 20.30 h on the same night. Participants were given either 150 mg of ranitidine orally or placebo (identical in appearance), together with 10 mL of water, at approximately 21.00 h. The order of the experimental conditions (i.e. ranitidine vs. placebo) was randomly assigned, and the study was carried out in a double-blind fashion.
Participants were fed a standardized provocative meal at 21.00 h. The meal consisted of one slice of pizza, a 12-oz caffeine-free cola and a chocolate brownie (1 in2). The meal contained approximately 1100 kcal. Participants were instructed to eat as much of the provided meal as they would normally consume for dinner, and were required to eat an identical amount on each night.
At 22.00 h, subjects were prepared for polysomnography, which included a four-channel electroencephalogram, two-channel electro-oculogram, a submental electromyogram and an electrocardiogram. The lights were turned out and the polysomnographic recordings were started at approximately 23.00 h. All subjects were awakened by 06.30 h if spontaneous waking had not already occurred. During the course of the night, all subjects kept a log of arousals. The arousals were noted at the time of their occurrence by documenting whether or not they occurred with heartburn in a morning questionnaire. A visual analogue scale measuring subjective sleep quality was also completed at this time. Polysomnographic recordings were scored by an experienced technician using standardized criteria.12 Reflux events were noted by a drop in the oesophageal pH to below 4.0 for a period of at least 5 s. The duration of each reflux event was computed by noting the interval of time between the drop in oesophageal pH to below 4.0 until the pH had returned to 4.0 or greater for at least 60 s.
To compare the efficacy of a bedtime dose of ranitidine with placebo, data from the two nights were analysed using a dependent samples t-test. To examine the phenomenon of reflux during nocturnal acid breakthrough, the data from the placebo night were reviewed and the number of oesophageal reflux events was counted during a period in which the intragastric pH dropped below 4.0 for a minimum of 1 h. For each patient, a similar count was performed during an identical length of time without nocturnal acid breakthrough to serve as a control period. Care was taken to ensure that the patient was in the same position during both periods of time. These counts were compared using a dependent samples t-test. In addition, the Pearson product-moment correlation was calculated between intra-oesophageal and intragastric pH measures.
With regard to intragastric (distal) acidity, the ranitidine condition demonstrated a significant (P < 0.05) reduction in the percentage of the total recording time that the intragastric pH was less than 4.0, whereas no significant difference was noted in the oesophagus (proximal) (Figure 1). Examination of the questionnaire data revealed that the subjects experienced no significant improvement with regard to subjective measures of heartburn or sleep quality with ranitidine compared to placebo (Table 1).
Table 1. Questionnaire results
Values are expressed as the mean (S.E.M.).
Number of times awakened by heartburn
Sleep quality rating
Severity of heartburn
The results of the analysis of the polysomnographic data are presented in Table 2. No significant differences between ranitidine and placebo were found for any of the polysomnographic measures. Sleep efficiency was mildly reduced on both nights (a sleep efficiency of 90% or greater is generally obtained under normal conditions in a sleep laboratory setting), although this was not unexpected given the fact that the patients were sleeping with nasal intubation. Other parameters of sleep quality, including the rate of arousals, percentage of slow wave sleep and the percentage of rapid eye movement sleep, were also similar across the two conditions, with both nights' values being within normal expectations.
Table 2. Sleep measures
TIB, time in bed; TST, total sleeping.
Values are expressed as the mean (S.E.M.).
Total sleep time (min)
Sleep onset latency (min)
Sleep efficiency (TST/TIB)
Rapid eye movement sleep (%)
Slow wave sleep (%)
Turning to the issue of reflux and nocturnal acid breakthrough, reflux events were calculated during periods of intragastric pH < 4.0 for at least 1 h during the placebo condition. A similar interval of time was identified in each subject which did not qualify as a nocturnal acid breakthrough interval, and reflux events were assessed and compared with those occurring during periods of nocturnal acid breakthrough. A total of 16 of the 19 patients provided data for this analysis. No significant difference was noted in the number of reflux events (Figure 2). The correlation analysis results support these findings, with no significant correlations between intragastric pH and intra-oesophageal pH measures (r = 0.23, placebo; r = 0.30, ranitidine).
The results of this study indicate that, under the conditions of 20 mg omeprazole b.d. and a provocative reflux meal, 150 mg ranitidine at bedtime has no effect on the occurrence of gastro-oesophageal reflux during sleep. This is in spite of a significant reduction in intragastric acidity during the sleeping interval. This effect is likely to be transient based on a recent study by Fackler et al., in which it was shown that the effect of an H2 blocker (ranitidine 300 mg) at bedtime significantly increased the intragastric pH only after 1 day of administration in combination with omeprazole 20 mg b.d.13 This effect was reduced with continued administration of the H2 blocker, and was absent at 1 week and 1 month of follow-up. In addition, the results revealed no correlation between the intra-oesophageal and intragastric pH. When comparing comparable intervals of time with and without nocturnal acid breakthrough, no significant difference was found with regard to the occurrence of gastro-oesophageal reflux. On the basis of these data, there appears to be no evidence that the occurrence of nocturnal acid breakthrough provokes gastro-oesophageal reflux. Furthermore, it appears that ranitidine 150 mg at night has no particular advantage over omeprazole 20 mg b.d. with regard to the reduction of episodes of gastro-oesophageal reflux during the sleeping interval. No advantage was conveyed by the H2 blocker in terms of the objective measures of sleep. In contrast with the study by Xue et al.,14 we did not find that reflux events were significantly shorter during ranitidine treatment, nor did we find a significant correlation between intragastric and intra-oesophageal pH measures. This discrepancy could be explained by the fact that we correlated actual pH measures, whereas Xue et al. correlated the percentage of time the pH was less than 4.0. Also, only a small number of subjects were included in their analysis of two separate groups (i.e. 17 without and 13 with supplemental H2 blockers at bedtime). Given the inherent variability of the pH measures analysed, and the small numbers in our study and in that of Xue et al., definitive conclusions cannot be inferred from the conflicting data in these two studies.
The results of the study by Katz et al. showed that gastro-oesophageal reflux during nocturnal acid breakthrough was more frequent in patients with GERD or Barrett's oesophagus; they suggested that gastro-oesophageal reflux during nocturnal acid breakthrough may be more likely in patients with a weak anti-reflux barrier.8 In the study by Fackler et al., there was no difference in the median percentage of time the oesophageal pH was below 4.0 during episodes of nocturnal acid breakthrough with the addition of an H2 blocker at bedtime.13 Our study addresses the issue of whether or not a specific instance of nocturnal acid breakthrough, in and of itself, would serve as a provocative stimulus to the occurrence of gastro-oesophageal reflux; we feel that this more accurately reflects the vulnerability to gastro-oesophageal reflux. The results of our study suggest that this is not the case, at least with this population of symptomatic GERD patients. Furthermore, gastric acidity does not appear to correlate with oesophageal acidity from the results of our study. These data support the commonly held notion that gastro-oesophageal reflux is a phenomenon related to abnormal oesophageal motility (i.e. decreased lower oesophageal sphincter pressure or transient lower oesophageal sphincter relaxation), rather than to the specific acid environment of the stomach. It should also be mentioned that the control intervals used to compare reflux during the intervals of nocturnal acid breakthrough had intragastric pH levels below 4.0 for much of the comparative time interval. Thus, the differences in reflux events between the two time intervals could not be attributed to the fact that they would not be detected if the pH was above 4.0 during a substantial portion of the control interval.
As recounted in the ‘Introduction’ section, numerous studies have shown the occurrence of nocturnal acid breakthrough with potent acid suppression by proton pump inhibitors, and other studies have addressed the extent to which these nocturnal acid breakthrough episodes can be eliminated with either proton pump inhibitor treatment or the addition of an H2 blocker administered at night.5–11,13 These studies were conducted under the assumption that nocturnal acid breakthrough had some clinical significance with regard to the facilitation of gastro-oesophageal reflux, and that the elimination of these episodes of acid breakthrough would reduce the number of episodes of gastro-oesophageal reflux. Our study indicates that the addition of an H2 blocker (at bedtime) has no significant effect on the occurrence of gastro-oesophageal reflux, in spite of the fact that the additional acid suppressive medication further reduces the intragastric acidity. The demonstrated significance of ranitidine at night over an additional dose of omeprazole at night, noted in the study by Peghini et al., may be due to the fact that the evening omeprazole dose was not accompanied by a meal, thereby mitigating the effectiveness of omeprazole to induce acid suppression.5 Also, as noted previously, the data reported by Fackler et al. suggest that this is likely to be a transient effect.13 Thus, although there is clear evidence for the occurrence of nocturnal acid breakthrough in patients with profound acid suppression induced by a b.d. dose of omeprazole, questions remain with regard to the clinical significance of this phenomenon in GERD patients, as well as the most effective regimen for the elimination of nocturnal acid breakthrough. Another methodological consideration which must be taken into account when evaluating treatment regimens for the reduction of both nocturnal acid breakthrough and gastro-oesophageal reflux is the fact that only minimal oesophageal and gastric acid exposure exists with b.d. acid inhibition with proton pump inhibitors, and a statistical evaluation of further acid suppression is problematic. This is due to the ‘floor effect’ of acid suppression which precludes an appropriate statistical evaluation of pharmacological effects.
This study was supported by a research grant from Astra-Zeneca. The authors wish to thank Dr Frances Treadway for her invaluable contributions to the design of this study. The authors also acknowledge the very capable assistance of Ms Angie Bowles in the acquisition of the data for this study.