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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Protocol
  6. Oesophageal and gastric pH monitoring technique
  7. Data analysis
  8. Statistics
  9. Results
  10. Effect of rabeprazole on oesophageal acid exposure
  11. Effect of rabeprazole on gastric acidity
  12. Occurrence of nocturnal supine gastro-oesophageal reflux during periods of nocturnal gastric acid breakthrough
  13. Effect of rabeprazole on heartburn symptoms
  14. Discussion
  15. Acknowledgements
  16. References

Aim:  To assess the effect of timing of rebeprazole (RB) 20 mg/d administration on oesophageal acid exposure and nocturnal gastric acid breakthrough (NGAB) in patients with GERD.

Methods:  20 GERD patients received two 7-day treatments of RB in the morning (a.m.) or in the evening (p.m.) hours. The regimens were randomized in a double-blind fashion and separated by a 7-day washout period. The tablets were taken 30 min before standardized meals. A combined (oesophageal & gastric) 24-hour pH monitoring was performed before and on day 7 of each treatment.

Results:  Total oesophageal acid exposure was normalized in 10/14 (71.4%) patients with RB p.m. and in 6/15 (42.8%) with RB a.m. RB p.m. significantly decreased the nocturnal supine oesophageal acid exposure vs. RB a.m., 0.2% vs. 3.4%. The mean NGAB duration was significantly shortened with RB a.m. and p.m. vs. the baseline recording, 4.1±1.8 and 3.4±1.5 hours vs. 7.8±1.7 hours.

Conclusions:  Rabeprazole significantly reduced the NGAB duration and significantly increased the mean nocturnal gastric pH; RB p.m. normalized more effectively the total oesophageal exposure than RB-a.m.; RB p.m. provided significantly better control of nocturnal supine gastro-oesophageal reflux than a.m. dosing. These data suggest that administration of a PPI before the evening meal maximizes acid control and would be the preferred dosing schedule in GERD patients, particularly those with nocturnal symptoms.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Protocol
  6. Oesophageal and gastric pH monitoring technique
  7. Data analysis
  8. Statistics
  9. Results
  10. Effect of rabeprazole on oesophageal acid exposure
  11. Effect of rabeprazole on gastric acidity
  12. Occurrence of nocturnal supine gastro-oesophageal reflux during periods of nocturnal gastric acid breakthrough
  13. Effect of rabeprazole on heartburn symptoms
  14. Discussion
  15. Acknowledgements
  16. References

The nocturnal gastro-oesophageal reflux of acid poses a significant challenge for the successful control of gastro-oesophageal reflux disease (GERD). Patients with reflux symptoms at night have a significantly higher risk of developing complications of GERD, including oesophageal adenocarcinoma, than controls from the general population.1 Nocturnal gastric acid breakthrough in GERD patients treated with proton pump inhibitors has evoked new questions and warranted a closer look at the effectiveness of this group of medications. It has been hypothesized that nocturnal gastric acid breakthrough is linked to the occurrence of GERD.2, 3 In addition to increasing the drug dose, another possible means of enhancing efficacy is changing the timing of administration. This strategy has not been investigated fully in terms of the better control of oesophageal pH exposure or nocturnal gastric acid breakthrough in GERD patients. Omeprazole, 40 mg at dinnertime, has been proven to be more effective in the prevention of nocturnal gastric acid breakthrough than the same dose administered in the morning.4 Another proton pump inhibitor, rabeprazole, has been proven to be as effective in controlling oesophageal acid exposure as omeprazole when given in the morning,5 and a single daily dose of 20 mg rabeprazole has been shown to be well tolerated and effective in preventing the relapse of erosive or ulcerative GERD.6

Our aim was to evaluate the effect of two different time schemes of administration of rabeprazole, 20 mg/day, on the oesophageal pH profile and nocturnal gastric acid breakthrough during a circadian cycle in patients with abnormal combined and/or nocturnal gastro-oesophageal reflux of acid.

Materials and methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Protocol
  6. Oesophageal and gastric pH monitoring technique
  7. Data analysis
  8. Statistics
  9. Results
  10. Effect of rabeprazole on oesophageal acid exposure
  11. Effect of rabeprazole on gastric acidity
  12. Occurrence of nocturnal supine gastro-oesophageal reflux during periods of nocturnal gastric acid breakthrough
  13. Effect of rabeprazole on heartburn symptoms
  14. Discussion
  15. Acknowledgements
  16. References

Twenty-seven consecutive individuals were enrolled and screened by pH monitoring for eventual inclusion in the treatment stage of the study on the basis of a history of night-time heartburn occurring more than three times per week in the late evening and night hours. All patients were recruited from the Gastroenterology Clinics and Gastrointestinal Endoscopy Unit of the University of Kansas Medical Center, Kansas City, KS, USA. Twenty patients (six males and 14 females; mean age, 45.4 ± 9.2 years) met the pH monitoring inclusion criteria and completed the treatment stage of the study (see Table 1 for endoscopy data). The protocol was approved by the Human Investigation Committee of the University of Kansas Medical Center. All subjects signed an informed consent prior to participating in the study.

Table 1.  Demographic and endoscopic findings of 20 (intention-to-treat) patients
Mean age ± s.d. (years)45.4 ± 9.2
Gender (male/female)6/14
Endoscopic findings
 Non-erosive reflux disease5
 Oesophagitis grade A (Los Angeles classification)7
 Oesophagitis grade B (Los Angeles classification)2
 Oesophagitis grade D (Los Angeles classification)2
 Barrett's oesophagus2
Unknown (no endoscopy)1

Protocol

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Protocol
  6. Oesophageal and gastric pH monitoring technique
  7. Data analysis
  8. Statistics
  9. Results
  10. Effect of rabeprazole on oesophageal acid exposure
  11. Effect of rabeprazole on gastric acidity
  12. Occurrence of nocturnal supine gastro-oesophageal reflux during periods of nocturnal gastric acid breakthrough
  13. Effect of rabeprazole on heartburn symptoms
  14. Discussion
  15. Acknowledgements
  16. References

Proton pump inhibitors and H2-receptor antagonists were discontinued for 14 and 7 days, respectively, prior to the screening 24-h oesophageal and gastric pH monitoring study. All other medications which could influence gastric acid secretion or gastrointestinal motility were excluded during the study. In the case of reflux complaints, patients were free to use antacids as a rescue medication at their discretion. However, during pH recording, antacids were not allowed. In addition to oesophageal and gastric pH, the patients' blood was screened for major health problems. Patients with previous anti-reflux or major abdominal surgery were excluded. The enrolment criteria for treatment with rabeprazole included a heartburn frequency as listed above lasting for > 3 months, plus a total oesophageal acid exposure below pH 4 of > 5% and a nocturnal supine exposure of > 1.5%, established by pH monitoring at entry to the study.7 On meeting these criteria, patients were randomly allocated to one of two groups: rabeprazole a.m. group, involving a 7-day treatment with rabeprazole 20 mg in the morning 30 min before breakfast (07.00–07.30 h); rabeprazole p.m. group, involving a 7-day treatment with rabeprazole 20 mg administered 30 min before dinner (19.00–19.30 h). Blinding of the patients and researcher in terms of the active medication was guaranteed by providing an additional placebo tablet, which was taken 12 h apart from the real medication, i.e. in the evening for the rabeprazole a.m. group and in the morning for the rabeprazole p.m. group. Patients were instructed to ingest a major meal 30 min after the study medication. A list of four menu choices for a 400-kcal breakfast (55 g carbohydrate, 16 g protein and 12 g fat) and a 600-kcal dinner (80 g carbohydrate, 27 g protein and 18 g fat) was provided to the patients. On the seventh day of the first leg of the study, patients underwent combined (oesophageal and gastric) ambulatory 24-h pH monitoring, followed by a 7-day washout period. After completion of the latter, patients started another 7-day treatment period with the alternative regimen. Another combined 24-h pH monitoring study was performed on the last day of this period. Patients were instructed to follow their daily activities as closely as possible, to indicate all food ingestion on a log and to go to bed around 22.30–23.00 h.

Oesophageal and gastric pH monitoring technique

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Protocol
  6. Oesophageal and gastric pH monitoring technique
  7. Data analysis
  8. Statistics
  9. Results
  10. Effect of rabeprazole on oesophageal acid exposure
  11. Effect of rabeprazole on gastric acidity
  12. Occurrence of nocturnal supine gastro-oesophageal reflux during periods of nocturnal gastric acid breakthrough
  13. Effect of rabeprazole on heartburn symptoms
  14. Discussion
  15. Acknowledgements
  16. References

Pull-through manometry was performed at the first visit to locate the lower oesophageal sphincter after topical anaesthesia of the nostril and oro-pharynx with 2% lignocaine (lidocaine) and 20% benzocaine spray, respectively. A dual pH probe with sensors 15 cm apart (Medtronic Functional Diagnostics Zinectics, Inc., Salt Lake City, UT, USA) was placed transnasally in the oesophagus so that the proximal pH sensor was 5 cm above the upper edge of the lower oesophageal sphincter, and the distal sensor was in the stomach 6–7 cm below the lower margin of the lower oesophageal sphincter. The pH catheter was secured with tape to the nose. The patient was instructed on how to use event buttons on the recording device (Synectics Digitrapper Mk III, Stockholm, Sweden) and was allowed to go home and return the next morning when the device was removed.

Data analysis

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Protocol
  6. Oesophageal and gastric pH monitoring technique
  7. Data analysis
  8. Statistics
  9. Results
  10. Effect of rabeprazole on oesophageal acid exposure
  11. Effect of rabeprazole on gastric acidity
  12. Occurrence of nocturnal supine gastro-oesophageal reflux during periods of nocturnal gastric acid breakthrough
  13. Effect of rabeprazole on heartburn symptoms
  14. Discussion
  15. Acknowledgements
  16. References

pH tracings were reviewed blindly by one investigator (N.D.P.). Tracings were analysed by means of a commercial program package (Medtronic Polygram function testing software EsopHogram Analysis 2.0 for Windows, Stockholm, Sweden). Meal episodes were excluded from the final analysis to avoid including erroneous gastro-oesophageal reflux episodes, as recommended by others.8 The following parameters were analysed separately for upright and nocturnal supine periods: number of acid gastro-oesophageal reflux episodes, number of reflux episodes lasting for > 5 min, duration of the longest reflux episode and oesophageal exposure to pH < 4. In the medical literature, nocturnal gastric acid breakthrough is defined as a drop in gastric pH to less than pH 4 during the nocturnal supine period lasting for more than 1 h between 22.00 and 06.00 h, and can include awake or asleep periods.4 For the purposes of the current investigation, only nocturnal gastric acid breakthrough during the nocturnal supine period was taken into consideration. In this study, the nocturnal supine period was defined as that between 22.30 and 06.30 h. Patients were instructed to remain in bed during this period of the night regardless of whether they were awake or asleep. Thus, the collected data referred to similar postural and physiological conditions of the patients. In the case of more than one nocturnal gastric acid breakthrough episode occurring during the same night, a cumulative duration of all episodes was calculated and analysed. The duration of nocturnal gastric acid breakthrough was expressed as a proportion (%) of the whole nocturnal supine period. Furthermore, the mean gastric pH during nocturnal gastric acid breakthrough and the mean gastric pH during the entire nocturnal supine period were calculated.

Statistics

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Protocol
  6. Oesophageal and gastric pH monitoring technique
  7. Data analysis
  8. Statistics
  9. Results
  10. Effect of rabeprazole on oesophageal acid exposure
  11. Effect of rabeprazole on gastric acidity
  12. Occurrence of nocturnal supine gastro-oesophageal reflux during periods of nocturnal gastric acid breakthrough
  13. Effect of rabeprazole on heartburn symptoms
  14. Discussion
  15. Acknowledgements
  16. References

The demographic data of all intention-to-treat patients who completed the treatment stage of the study are presented as the mean and standard deviation (s.d.), as are the nocturnal gastric acid breakthrough parameters. The oesophageal pH variables are presented as the median and interquartile range due to a lack of normality in data distribution. The paired two-tailed t-test and Wilcoxon test were applied to compare the oesophageal and gastric parameters from the two different treatment regimens and baseline. P values of less than 0.05 were considered to indicate statistical significance. Pearson's product moment correlation was used to analyse the association between the duration of the nocturnal gastric acid breakthrough period, on the one hand, and the number of reflux episodes, number of reflux episodes lasting for > 5 min and duration of the longest reflux episode, measured for both the time of the corresponding nocturnal gastric acid breakthrough and for the whole nocturnal supine episode, on the other.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Protocol
  6. Oesophageal and gastric pH monitoring technique
  7. Data analysis
  8. Statistics
  9. Results
  10. Effect of rabeprazole on oesophageal acid exposure
  11. Effect of rabeprazole on gastric acidity
  12. Occurrence of nocturnal supine gastro-oesophageal reflux during periods of nocturnal gastric acid breakthrough
  13. Effect of rabeprazole on heartburn symptoms
  14. Discussion
  15. Acknowledgements
  16. References

According to the analysis generated by the program, the tracings of six patients revealed artefacts lasting for more than 4 h on one or more of the 24-h pH recordings. In the majority of the cases, the reason for these artefacts was technical failure (temporary loss of the signal), possibly due to the temporary loss of connection between the pH probe and recording device. All 18 tracings of these six patients were excluded from the analysis. The tracings of the remaining 14 patients were analysed blindly before breaking the code.

The mean durations of the three pH recordings for each patient during the study (one baseline and two on medication) did not differ significantly (P > 0.05). The mean (± s.d.) nocturnal supine periods of the pH recordings during the rabeprazole a.m. and p.m. regimens were similar: 7.8 ± 1.3 and 7.1 ± 1.2 h, respectively (P > 0.05). However, the mean baseline supine period on the non-treatment day was significantly longer in comparison with the supine period whilst the patients were on the rabeprazole p.m. regimen: 8.7 ± 1.1 vs. 7.1 ± 1.2 h, respectively (P = 0.001).

Effect of rabeprazole on oesophageal acid exposure

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Protocol
  6. Oesophageal and gastric pH monitoring technique
  7. Data analysis
  8. Statistics
  9. Results
  10. Effect of rabeprazole on oesophageal acid exposure
  11. Effect of rabeprazole on gastric acidity
  12. Occurrence of nocturnal supine gastro-oesophageal reflux during periods of nocturnal gastric acid breakthrough
  13. Effect of rabeprazole on heartburn symptoms
  14. Discussion
  15. Acknowledgements
  16. References

The rabeprazole p.m. regimen normalized the total (24-h) oesophageal acid exposure to < 5% in 10 of 14 patients (71.4%) vs. six of 14 patients (42.8%) with a.m. administration. All patients who showed normalized oesophageal acid exposure with the rabeprazole a.m. regimen had normal oesophageal acid exposure with p.m. administration; however, the reverse was not true. The four patients in whom rabeprazole p.m. 20 mg did not control either the daytime or nocturnal gastro-oesophageal reflux had significantly higher total oesophageal acid exposure at baseline (17.1%; 15.5–18.9%) in comparison with the baseline data of the 10 patients who showed a normalized pH with rabeprazole (9.7%; 5.9–13.1%) (P = 0.01).

The median total (24-h) oesophageal acid exposure at baseline (without treatment) was 11.6% (8.9–15.6%). Rabeprazole a.m. and p.m. regimens reduced it to 6.4% (3.5–15.7%) and 3.3% (1.5–14.0%), respectively (P > 0.05). However, the median nocturnal supine oesophageal acid exposure was significantly decreased by rabeprazole 20 mg administered in the evening in comparison with the morning regimen: 0.2% vs. 3.4%, respectively (Figure 1). Rabeprazole p.m. also significantly reduced the number of nocturnal gastro-oesophageal reflux episodes (median of 6.0) in comparison with baseline and rabeprazole a.m. (medians of 32.5 and 28.0, respectively) (Figure 2). Statistical analysis failed to demonstrate a significant difference when the rabeprazole a.m. and p.m. regimens were compared in terms of the number of long (> 5 min) gastro-oesophageal reflux episodes and the duration of the longest reflux episode. Despite the lack of statistical significance, these two pH parameters demonstrated a trend towards a larger reduction of prolonged nocturnal acid reflux with rabeprazole p.m. rather than a.m. (see Table 2 for details).

image

Figure 1. Supine oesophageal exposure at baseline and for the two rabeprazole regimens. Note that the nocturnal acid exposure is significantly lower with the rabeprazole p.m. regimen (*) in comparison with the rabeprazole a.m. regimen. Data are presented as median values. See also Table 1.

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image

Figure 2. Number of supine reflux episodes at baseline and for the two rabeprazole regimens. Note the significant difference in the number of reflux episodes between the evening dose of rabeprazole (*) and baseline (no medication). Data are presented as median values. See also Table 1.

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Table 2.  Summary of 24-h oesophageal pH monitoring in 14 patients treated with rabeprazole 20 mg in a.m. and p.m. regimens. Data are presented as the median and interquartile range in parentheses
 BaselineRabeprazole a.m.Rabeprazole p.m.
  • P < 0.05 vs. baseline.

  • † 

    P < 0.05 vs. rabeprazole a.m.

No. of reflux episodes
 Upright109.0 (62–180)76.0 (48–108)50.0 (23–92)*
 Supine32.5 (19–57)28.0 (5–55)6.0 (0–13)*
No. of long episodes (> 5 min)
 Upright2.0 (1–5)1.0 (0–2)1.0 (0–4)
 Supine1.0 (1–3)0.5 (0–3)0.0 (0–1)
Longest episode (min)
 Upright21.0 (5–35)6.5 (4–16)*12.0 (4–21)
 Supine15.0 (8–26)4.5 (0–23)0.0 (0–12)
% of time pH < 4
 Upright12.4 (5.7–19.4)4.9 (2.5–10.2)4.3 (1.9–14.2)
 Supine5.8 (4.6–12.2)3.4 (0.5–16.0)0.2 (0.0–6.0)

Effect of rabeprazole on gastric acidity

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Protocol
  6. Oesophageal and gastric pH monitoring technique
  7. Data analysis
  8. Statistics
  9. Results
  10. Effect of rabeprazole on oesophageal acid exposure
  11. Effect of rabeprazole on gastric acidity
  12. Occurrence of nocturnal supine gastro-oesophageal reflux during periods of nocturnal gastric acid breakthrough
  13. Effect of rabeprazole on heartburn symptoms
  14. Discussion
  15. Acknowledgements
  16. References

Without treatment, e.g. at baseline, all patients had a gastric pH < 4.0 for the greater part of the nocturnal supine recording: 88.7 ± 11.8%. The nocturnal gastric acid breakthrough duration with rabeprazole a.m. and p.m. was significantly shorter than the percentage of time for which the gastric pH was below pH 4.0 at baseline conditions (Table 3). Although there was no statistical difference between rabeprazole a.m. and p.m., there was a trend towards a shorter nocturnal gastric acid breakthrough with the p.m. regimen during the nocturnal supine period. However, all patients but one still revealed nocturnal gastric acid breakthrough despite rabeprazole treatment.

Table 3.  Summary of 24-h gastric pH monitoring results in 14 patients treated with rabeprazole 20 mg in a.m. and p.m. regimens. Data are presented as the mean ± standard deviation
 BaselineRabeprazole a.m.Rabeprazole p.m.
  • NGAB, nocturnal gastric acid breakthrough.

  • P < 0.05 vs. baseline.

Duration of supine NGAB (h)7.8 ± 1.74.1 ± 1.8*3.4 ± 1.5*
NGAB duration/nocturnal supine period duration (%)88.7 ± 11.852.1 ± 21.7*48.0 ± 18.3*
Mean pH during supine NGAB (pH units)1.2 ± 0.22.0 ± 0.7*1.9 ± 0.8*
Mean pH during nocturnal supine period (pH units)1.4 ± 0.53.3 ± 0.9*3.4 ± 1.0*
Time pH < 4 during daytime period (%)87.9 ± 10.639.7 ± 20.9*48.8 ± 21.3*

Rabeprazole a.m. and p.m. also significantly increased the mean gastric pH (to pH 2.0 and pH 1.9, respectively) during the nocturnal supine period in comparison with that at baseline before treatment (pH 1.2). Similarly, the mean gastric pH values measured during the nocturnal gastric acid breakthrough periods were significantly higher with both treatment regimens in comparison with baseline acid exposure. In addition, rabeprazole significantly reduced the daytime gastric exposure to pH < 4 (see Table 3 for details).

Occurrence of nocturnal supine gastro-oesophageal reflux during periods of nocturnal gastric acid breakthrough

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Protocol
  6. Oesophageal and gastric pH monitoring technique
  7. Data analysis
  8. Statistics
  9. Results
  10. Effect of rabeprazole on oesophageal acid exposure
  11. Effect of rabeprazole on gastric acidity
  12. Occurrence of nocturnal supine gastro-oesophageal reflux during periods of nocturnal gastric acid breakthrough
  13. Effect of rabeprazole on heartburn symptoms
  14. Discussion
  15. Acknowledgements
  16. References

We investigated the potential connection between the frequency and length of the nocturnal supine gastro-oesophageal reflux and the duration of nocturnal gastric acid breakthrough. The length of the gastro-oesophageal acid reflux episodes during the nocturnal supine period did not necessarily coincide with the whole duration of the nocturnal gastric acid breakthrough period. With the rabeprazole a.m. regimen, only 20.3 ± 31.2% (mean ± s.d.) of the nocturnal gastric acid breakthrough duration coincided with oesophageal acid reflux, and only 11.1 ± 21.1% of the nocturnal gastric acid breakthrough duration was associated with reflux with the rabeprazole p.m. regimen. However, the number of longer episodes of gastro-oesophageal reflux, e.g. reflux episodes longer than 5 min, had a stronger correlation with the nocturnal gastric acid breakthrough duration. With the rabeprazole a.m. regimen, reflux episodes > 5 min correlated better with the nocturnal gastric acid breakthrough duration (r = 0.60, P = 0.02) than with the duration of the supine nocturnal period as a whole (r = 0.07, P > 0.05). Similarly, with the rabeprazole p.m. regimen, the correlation between the number of reflux episodes > 5 min and the duration of nocturnal gastric acid breakthrough was stronger (r = 0.54, P = 0.04) than with the duration of the nocturnal supine period as a whole (r = 0.19, P = 0.51).

Effect of rabeprazole on heartburn symptoms

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Protocol
  6. Oesophageal and gastric pH monitoring technique
  7. Data analysis
  8. Statistics
  9. Results
  10. Effect of rabeprazole on oesophageal acid exposure
  11. Effect of rabeprazole on gastric acidity
  12. Occurrence of nocturnal supine gastro-oesophageal reflux during periods of nocturnal gastric acid breakthrough
  13. Effect of rabeprazole on heartburn symptoms
  14. Discussion
  15. Acknowledgements
  16. References

All but two patients had heartburn symptoms on the non-medication (baseline) day of pH monitoring. Nine of 14 patients and 10 of 14 patients on the rabeprazole a.m. and p.m. regimens, respectively, were asymptomatic during the recordings on the corresponding investigational days. Surprisingly, three of the four patients who failed to normalize acid oesophageal exposure below 5% of the recorded time were asymptomatic for both regimens of rabeprazole. The median heartburn events registered during the upright and whole recording periods on the three investigational days were significantly decreased with both the rabeprazole p.m. and a.m. regimens compared with baseline (P < 0.05) (Table 4).

Table 4.  Summary of the heartburn events registered in 14 patients during the three investigational days (at baseline and with rabeprazole 20 mg in a.m. and p.m. regimens). Data are presented as the median and interquartile range in parentheses
 BaselineRabeprazole a.m.Rabeprazole p.m.
  • *

     P < 0.05 vs. baseline.

Upright period4 (2–11)0 (0–2)*0 (0–2)*
Nocturnal supine period0 (0–3)0 (0–0)0 (0–0)
Whole recording4 (3–14)0 (0–2)*0 (0–2)*

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Protocol
  6. Oesophageal and gastric pH monitoring technique
  7. Data analysis
  8. Statistics
  9. Results
  10. Effect of rabeprazole on oesophageal acid exposure
  11. Effect of rabeprazole on gastric acidity
  12. Occurrence of nocturnal supine gastro-oesophageal reflux during periods of nocturnal gastric acid breakthrough
  13. Effect of rabeprazole on heartburn symptoms
  14. Discussion
  15. Acknowledgements
  16. References

Our study evaluated possible means of increasing the efficacy of proton pump inhibitor therapy without changing the dose. Some of the factors which may influence the gastric acid suppression in this situation are the time of proton pump inhibitor administration and food intake. The Physicians' Desk Reference (Edition 2002) indicates no specific directions for the administration of proton pump inhibitors with regard to timing and prandial status. However, our observations and those of others9, 10 indicate that physicians generally advise GERD patients to take proton pump inhibitors whilst still fasting in the morning. A previous study of a single dose of omeprazole 20 mg concluded that morning administration was optimal for gastric acid suppression.10 Conversely, another study in healthy volunteers concluded that dinnertime or split administration of omeprazole 40 mg was significantly more effective than administration before breakfast in preventing nocturnal gastric acid breakthrough and controlling gastric acid.4 Rabeprazole is a proton pump inhibitor approved for the treatment of GERD at a dose of 20 mg administered once daily; however, the optimal time of administration has not been researched. The timing of administration of a proton pump inhibitor in relation to dinner might be preferable to taking it in relation to breakfast based on the duration of action of a proton pump inhibitor and the need in GERD to provide effective overnight gastric acid inhibition.9 Therefore, it was our working hypothesis that the intake of a proton pump inhibitor should be before the evening meal in GERD patients with predominantly nocturnal reflux in order to maximize the gastric acid suppression when this is most needed, i.e. from 22.00 h until morning.

In addition to the timing of administration, the role of a meal is also a significant factor in the improvement of proton pump inhibitor efficacy. Gastric acid suppression was significantly improved when proton pump inhibitor administration was followed by a meal rather than without a meal.9 However, our clinical experience is that it is common practice for patients, at least in the USA, not to have a significant caloric meal for breakfast or indeed have breakfast at all. Rather, the major meal is usually dinner and everyone has some caloric intake for this evening meal. It is known that nocturnal reflux may increase the risk of high-grade oesophagitis.11

We studied GERD patients with night-time heartburn and pH-proven combined, i.e. day and night, or predominantly nocturnal gastro-oesophageal reflux. Most also had erosive oesophagitis and hiatal hernia. In order to study the effect of the different timing of rabeprazole 20 mg/day, we standardized the caloric content of the meals and pre-set hours for drug administration. Our data showed that rabeprazole was effective in reducing abnormal gastro-oesophageal reflux, as reported by others.5, 6 Seventy-one per cent of our patients showed normalized total (24-h) acid exposure (< 5%) with a single 20-mg tablet of rabeprazole administered before dinner. However, if rabeprazole was taken before breakfast, the percentage of patients who showed reflux within the normal range was lower: 43%. More specifically, the nocturnal supine oesophageal acid exposure to pH < 4 was significantly reduced with the p.m. regimen in comparison with a.m. administration. In addition to the timing of administration, another potential reason for the better efficacy of the p.m. rabeprazole administration in this study could be the higher caloric intake at dinner compared with breakfast — a 200-kcal difference. Theoretically, the more potent the stimulus, the more proton pumps that will be exposed for consecutive inhibition by the medication. On the other hand, it is still unclear whether the proton pump inhibitor effect is directly proportional to the caloric stimulus. In this regard, a 200-kcal difference between the morning and evening meals is a feasible factor contributing to the greater effect of the p.m. over the a.m. regimen of rabeprazole, but it is difficult to estimate its contribution. In the USA, patients normally eat a large evening meal, and the caloric intake at this meal will be more than 200 kcal greater than their breakfast intake.

The higher efficacy of rabeprazole p.m. in suppressing nocturnal oesophageal exposure corresponded to a trend towards shorter nocturnal gastric acid breakthrough periods. Both rabeprazole regimens achieved significantly higher gastric pH during the nocturnal hours in comparison with baseline, but there was no significant difference between a.m. and p.m. administration of the drug. The mean gastric pH of nocturnal gastric acid breakthrough during treatment with rabeprazole corresponded to previously published data.12 Despite the reduced time at gastric pH < 4, only one patient was free of nocturnal gastric acid breakthrough during treatment with rabeprazole. However, the relationship between nocturnal gastric acid breakthrough and acid gastro-oesophageal reflux still remains controversial.13 Despite evidence of nocturnal gastric acid breakthrough, we found no direct correlation with simultaneous acid reflux into the oesophagus. Oesophageal acid events occurred during only 11–20% of the total recorded nocturnal gastric acid breakthrough time. The number of nocturnal supine gastro-oesophageal reflux episodes longer than 5 min correlated well with the duration of nocturnal gastric acid breakthrough. In our view, the presence of an acid environment in the stomach is an indispensable condition for the occurrence of gastro-oesophageal acid reflux; however, the motility abnormalities linked to gastro-oesophageal reflux determine the degree of nocturnal oesophageal reflux.

Our results showed a significant decrease in the number of heartburn symptoms for the upright and whole recording periods with rabeprazole. On the other hand, surprisingly, three of the four patients who failed to normalize their acid gastro-oesophageal reflux with a.m. and p.m. rabeprazole regimens were asymptomatic with treatment despite ongoing reflux. A possible explanation for these anomalies could be the well-known disparity between heartburn symptoms and gastro-oesophageal reflux. A deep sleep could also preclude perception of the reflux symptoms by patients during the night. However, it is well accepted that heartburn is an unreliable criterion for the assessment of nocturnal reflux and the ‘gold standard’ is 24-h oesophageal pH monitoring. Nevertheless, in clinical practice, physicians rely on regurgitation and heartburn to wake up the patient and do not routinely monitor 24-h results.

The suppression of gastro-oesophageal reflux by rabeprazole in our study was slightly inferior to that found by others.5, 14 Different responses to treatment with proton pump inhibitors, with regard to the suppression of gastro-oesophageal reflux over 24 h, may stem from genotypic differences in drug metabolism, described recently in experiments with rabeprazole and other proton pump inhibitors.15 This also corresponds to the observations of other investigators that, in some cases, proton pump inhibitors, even at the doses approved for GERD treatment, do not effectively control gastric acidity over 24 h.16 However, neither our study, nor previous publications investigating rabeprazole in the treatment of GERD, have tested patients for genotype status. Another aspect is the inter-subject variability in acid control exerted by rabeprazole; other investigators assessing proton pump inhibitor treatment by pH recordings have also experienced analogous difficulties.9 Other drawbacks inherent to pH monitoring as a method of investigation may also be the source of differences.17 A potential criticism of this study is the small study population. This was due to the number of patients excluded from the analysis due to artefacts. In order to prevent accidental bias, we preferred to exclude the whole batch of recordings of a particular patient, rather than ‘cut’ the distorted information and include the rest in the analysis.

In conclusion, rabeprazole a.m. and p.m. significantly reduced nocturnal gastric acid breakthrough. Rabeprazole administration before dinner provided a better control of the nocturnal supine gastro-oesophageal reflux in GERD patients than did a.m. administration. These data suggest that giving a proton pump inhibitor before the evening meal has advantages compared with morning administration in patients with gastro-oesophageal reflux, and even more so if there is predominantly nocturnal gastro-oesophageal acid reflux or if the daily eating habits or professional activities require the evening meal to be the largest.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Protocol
  6. Oesophageal and gastric pH monitoring technique
  7. Data analysis
  8. Statistics
  9. Results
  10. Effect of rabeprazole on oesophageal acid exposure
  11. Effect of rabeprazole on gastric acidity
  12. Occurrence of nocturnal supine gastro-oesophageal reflux during periods of nocturnal gastric acid breakthrough
  13. Effect of rabeprazole on heartburn symptoms
  14. Discussion
  15. Acknowledgements
  16. References

We acknowledge the invaluable support of Sandra Sostarich, R.N., faculty physicians and Gastrointestinal Fellows at the Division of Gastroenterology and Hepatology, as well as the staff of the Gastrointestinal Endoscopy Unit, at the University of Kansas Medical Center, Kansas City, KS, USA.

This study was supported by a research grant from Eisai Inc., Teaneck, NJ, USA and Janssen Pharmaceutica Inc., Titusville, NJ, USA.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Protocol
  6. Oesophageal and gastric pH monitoring technique
  7. Data analysis
  8. Statistics
  9. Results
  10. Effect of rabeprazole on oesophageal acid exposure
  11. Effect of rabeprazole on gastric acidity
  12. Occurrence of nocturnal supine gastro-oesophageal reflux during periods of nocturnal gastric acid breakthrough
  13. Effect of rabeprazole on heartburn symptoms
  14. Discussion
  15. Acknowledgements
  16. References
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