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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

Background  H2-receptor antagonists are widely used with proton pump inhibitors.

Aim  To determine if H2-receptor antagonists used in conjunction with proton pump inhibitors were effective for nocturnal heartburn in patients taking proton pump inhibitors.

Methods  We evaluated 386 patients with erosive oesophagitis documented at endoscopy who were receiving single daily maintenance proton pump inhibitor therapy to determine if they had symptoms of nocturnal heartburn. Patients with two or more episodes of night-time a week were invited to participate in the study. Patients were randomly assigned to a single dose of an over-the-counter preparation of ranitidine 75 mg at bedtime or matching placebo for 14 days.

Results  The prevalence of nocturnal symptoms was 10.6%. Mean symptom scores on the first day of the trial (baseline) were similar between the treatment group (1.1 ± 0.9) and the placebo group (1.1 ± 1.1). On day 3, symptom scores were significantly lower in the ranitidine group (0.71 ± 0.69) compared with the control group (1.4 ± 1.2; P = 0.045). On day 14, mean symptom scores were similar in the ranitidine group (0.82 ± 0.95) and the control group (1 ± 0.84).

Conclusions  Nocturnal heartburn is uncommon on proton pump inhibitor therapy; the addition of ranitidine at bedtime resulted in a decrease in symptom scores on day 3 but there were no differences on day 14.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

Night-time heartburn is a common symptom in untreated patients with reflux disease and has a significant impact on quality of life. Reflux during the nocturnal period may also have significant consequences as protective mechanisms such as peristalsis are inhibited during sleep. Acid contact time may therefore be higher at night and the adverse consequences of nocturnal reflux may be potentially greater. Recent studies that measure intragastric pH in individuals on once daily or twice daily therapy with proton pump inhibitors (PPI) have shown that there is a significant drop in intragastric pH at night in some subjects, despite PPI therapy. Intragastric pH studies have also demonstrated that the addition of a small dose of a histamine-2 (H2)-receptor antagonist at bedtime can decrease or abolish the nocturnal drop in intragastric pH. There is little information, however, on the prevalence of nocturnal heartburn in patients taking regular PPI therapy for gastro-oesophageal reflux disease (GERD) and no data on the effectiveness of H2-receptor antagonists in controlling nocturnal symptoms in this group of patients. We therefore performed a randomized placebo-controlled trial that evaluated the efficacy of bedtime H2-receptor antagonist therapy in the treatment of nocturnal heartburn in patients taking daily PPI therapy.

Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

We evaluated 386 patients with erosive oesophagitis documented at endoscopy who were receiving daily maintenance PPI therapy to determine if they had symptoms of nocturnal heartburn. Patients were identified from a database and contacted to determine if they had nocturnal heartburn. Patients presenting for annual follow-up visits on maintenance therapy with PPIs were also interviewed and offered entry if eligible. All patients had received at least 8 weeks of the same dose of the PPI. All patients were taking a single daily dose of the PPI half an hour before breakfast daily. Patients with two or more episodes of night-time a week were invited to participate in the study.

After written informed consent was obtained, the patients were randomly assigned to a single dose of an over-the-counter preparation of ranitidine tablets 75 mg (Pfizer Consumer Healthcare, Morris Plains, NJ, USA) at bedtime or matching placebo for 14 days. Randomization was performed using a random number chart with concealed allocation using opaque envelopes so that neither the investigator nor the patient was aware of the medication they were receiving. Proton pump inhibitor therapy remained unchanged in timing and dose. Daytime heartburn was evaluated using a validated 4-point Likert scale (none, mild, moderate, severe) for heartburn severity at baseline and every morning at the approximately the same time for the 14 days of the trial. Nocturnal heartburn was measured daily as a dichotomous response (yes/no) because severity measures are of limited utility in the nocturnal period because of recall bias.

Statistics

Results are presented as mean values of the 4-point scale for daytime heartburn and proportion responding yes for nocturnal heartburn with 95% confidence intervals. Planned comparisons were made between the groups at baseline (day 1) on day 3 and day 14. These time points were chosen because intragastric pH data suggest that the effect of adding H2-receptor antagonists is pronounced in first week of therapy but the effect disappeared after more prolonged use.

Human subjects

The human subjects review board at Aurora Sinai Medical Center, approved the protocol and all participating patients gave written informed consent (the study was sponsored by Pfizer Inc.).

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

Forty-one of the 386 patients (10.6%) surveyed had nocturnal symptoms of heartburn at least twice a week. By self-report, all patients were taking their PPIs daily half an hour before breakfast. All 41 had erosive oesophagitis demonstrated at endoscopy prior to the initiation of PPI therapy (Los Angeles A or B in 40 patients and Los Angeles grade C in one patient). The prevalence of nocturnal symptoms in this population was 10.6%. Thirty-three of the 41 patients agreed to participate in the study. The remaining eight patients wished to have additional therapy without the possibility of receiving a placebo and refused to participate. Sixteen patients were randomized to placebo and 17 patients were randomized to ranitidine 75 mg at bedtime. At baseline, seven of 16 patients in the placebo group and eight of 17 in the ranitidine group reported symptoms of nocturnal heartburn. Mean symptom scores did not change significantly over time and there were no significant differences between the groups. Mean daytime symptom scores on the first day of the trial (baseline) were similar between the treatment group (1.1 ± 0.9) and the placebo group (1.1 ± 1.1). On day 3, symptom scores were significantly lower in the ranitidine group (0.71 ± 0.69) compared with the control group (1.4 ± 1.2; P = 0.045; Fig. 1). On day 14, mean symptom scores were similar in the ranitidine group (0.82 ± 0.95) and the control group (1 ± 0.84; Fig. 1). There were no significant differences in proportion of subjects reporting nocturnal heartburn between the two groups (Fig. 2).

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Figure 1. Mean daytime symptom score with 95% confidence interval (CI). Day 1 is the baseline measurement before administration of ranitidine 75 mg or matched placebo. Patients received ranitidine or placebo at bedtime on day 1 and every night thereafter. Symptom assessments for the preceding day and night were performed in the morning.

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image

Figure 2. Proportion of subjects with nocturnal heartburn. Patients received ranitidine or placebo at bedtime on day 1 and every night at bedtime thereafter. Symptom assessments for the preceding day and night were performed in the morning.

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Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

Nocturnal symptoms of heartburn are common in the general population and have been shown to be associated with a significant decrease in the quality of life. There is little information on the prevalence of nocturnal heartburn in patients with erosive oesophagitis who are receiving PPI therapy. The results of this study show that nocturnal heartburn is reported by approximately 10% of patients with erosive oesophagitis on PPI therapy. This is probably an underestimate of the number of patients who actually have nocturnal reflux because many reflux episodes are not recognized or reported by the patient.1 Our study population was chosen to be well-characterized and therefore only patients with previously documented erosive oesophagitis were studied. The prevalence of nocturnal symptoms may be different in other populations of patients with reflux symptoms, e.g. non-erosive reflux disease.

We studied Zantac 75 tablets as this preparation is widely available over-the-counter throughout the world (the USA, Canada, Australia, New Zealand, Denmark, the UK) and is frequently used by patients for control of heartburn. In a recent report on the over-the-counter acid-blocker drugs, ranitidine 75 was one of the top three (along with famotidine and omeprazole) over-the-counter acid inhibitors purchased in the United States.2 We also chose low-dose ranitidine because it has been shown to be effective in increasing nocturnal intragastric pH and because it can have an effect that can be detected up to 15 h after a single dose in gastric pH studies.3 In some studies ranitidine 75 mg has been more effective than famotidine 10 mg and its effects on pH were more pronounced in the first 2.5 h after dosing.4 Robinson et al. studied a group of patients with heartburn who were given a single daily dose of omeprazole and demonstrated that addition of bedtime ranitidine in a dose of 75 mg eliminated night-time gastric acidity but oesophageal acid exposure was not significantly changed because the patients no longer had nocturnal acid exposure in the oesophagus after receiving omeprazole.5 In another intragastric pH study, bedtime ranitidine (150 mg) was more effective than bedtime omeprazole in controlling night-time acid in normal subjects.6 In GERD patients, addition of an H2-receptor antagonist to a regimen of twice a day omeprazole therapy improved intragastric pH values.7 None of these studies, however, established a clear link between changes in intragastric pH and intraoesophageal pH or symptoms. Ours et al. studied GERD patients randomized to four treatments: (i) omeprazole 20 mg twice daily for 2 weeks; (ii) omeprazole 20 mg twice daily for 2 weeks with ranitidine 300 mg at bedtime for 4 weeks; (iii) omeprazole 20 mg before breakfast and before dinner for 2 weeks and (iv) omeprazole 20 mg every 8 h for 2 weeks. Although all the regimens improved intragastric pH parameters compared with baseline, no single treatment regimen resulted in more significant suppression of nocturnal acid than the others. Oesophageal acid reflux and patient symptoms were well controlled despite acid being present in the stomach.8 In another pH study, addition of ranitidine 150 mg at bedtime did not alter oesophageal acid exposure during sleep in patients taking omeprazole 20 mg twice daily.9 In a long-term study of the effects of adding H2-receptor antagonists to a regimen of PPIs, Fackler et al. showed that intragastric pH values improved in patients receiving H2-receptor antagonists but that these effects were short-lived and were no longer apparent at 1 week presumably because of the development of tachyphylaxis.10

Drug tolerance is said to have occurred when, after prior exposure to a drug, an individual requires an unusually large dose of that drug to achieve the usual effect.11 Tolerance to H2-receptor antagonists has been studied in healthy volunteers and in patients with duodenal ulcer. In volunteers, the reduction in acid inhibition is related to the dose of the H2-receptor antagonist administered.12 Despite the absence of clinical data on symptoms in patients with GERD, the concept of adding H2-receptor antagonists to PPI therapy has gained wide attention and these combinations of therapy are frequently prescribed by primary care doctors.13 Our study demonstrates that symptom scores improve at day 3 but the effect is short-lived and is not seen on day 14. The greatest loss of efficacy in acid inhibition in intragastric pH studies in volunteers is in the first few days after initiation of therapy and is well-established by 1 week.11 Our results are therefore in keeping with pH studies. From a clinical standpoint, one may interpret our data and the available intragastric pH data to suggest that there is short-term efficacy in nocturnal heartburn relief with over-the-counter doses of H2-receptor antagonists. Given the clinical profile of these agents the optimal use of an H2-receptor antagonist in a patient taking a PPI would be in intermittent courses that are <1 week in duration. Continuous use is probably associated with the development of tolerance and a disappearance of the clinical effect. Because of the rapidity with which the H2-receptor antagonists act, they seem well suited for patients who are generally well maintained on PPI therapy but develop nocturnal heartburn under special circumstances, e.g. a late evening meal or the ingestion of alcohol with the meal. In these instances, tolerance would not play a role as the H2-receptor antagonist would be taken infrequently when these specific circumstances arose. In this context, H2-receptor antagonists have another advantage in that they are rapidly effective even when taken after a meal.14 Finally, theoretical concerns that the H2-receptor antagonist might affect next day activity of PPIs have been allayed by pH studies which have shown no effect on next day acid control with the PPI.15 Other preparations of over-the-counter medications are also available such as the effervescent formulation of ranitidine 75. These compounds have a more rapid onset of effect and may offer further advantages in symptom relief but were not evaluated in this study.16

Our study has some limitations. The numbers of patients randomized are small and this was due to the paucity of patients reporting nocturnal heartburn on single daily doses of PPIs. The possibility of a type 1 error exists but a small effect on symptoms is probably of little clinical significance. Our study is, however, the only randomized-controlled trial addressing symptoms with this combination of drugs. We believe that a more thorough appraisal of combination therapy is necessary before it becomes widely used in clinical practice. Such studies would have to consider a higher dose of an H2-receptor antagonist but the development of tolerance is still a problem with these agents.17 Our study also points out the limitations of intragastric pH studies when they are extrapolated to clinical conditions. These studies are performed with an intragastric pH electrode that measures pH but does not measure gastric volume. Therefore, these studies do not necessarily predict intraoesophageal pH changes or the development of symptoms.

Acknowledgement

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

The study was supported by a grant from Pfizer Pharmaceuticals.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References
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    Levy S. Antacids/Laxatives: Catering to a Loyal Customer Base. Drug Topics. Available at: http://www.drugtopics.com/drugtopics/article/articleDetail.jsp?id=123688, accessed on 9 December 2005.
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    Hamilton MI, Sercombe J, Pounder RE. Decrease of intragastric acidity in healthy subjects dosed with ranitidine 75 mg, cimetidine 200 mg, or placebo. Dig Dis Sci 2002; 47: 547.
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    Robinson M, Rodriguez-Stanley S, Ciociola AA, et al. Control of nocturnal gastric acidity: a role for low dose bedtime ranitidine to supplement daily omeprazole. Dig Dis Sci 2002; 47: 26573.
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    Ours TM, Fackler WK, Richter JE, Vaezi MF. Nocturnal acid breakthrough: clinical significance and correlation with esophageal acid exposure. Am J Gastroenterol 2003; 98: 54550.
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    Orr WC, Harnish MJ. The efficacy of omeprazole twice daily with supplemental H2 blockade at bedtime in the suppression of nocturnal oesophageal and gastric acidity. Aliment Pharmacol Ther 2003; 17: 15538.
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    Fackler WK, Ours TM, Vaezi MF, Richter JE. Long-term effect of H2RA therapy on nocturnal gastric acid breakthrough. Gastroenterology 2002; 122: 62532.
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    Wilder-Smith C, Merki H. Tolerance during dosing with H2 receptor antagonists. Scand J Gastroenterol 1992; 27 (Suppl. 193): 149.
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    Khoury RM, Katz PO, Castell DO. Post-prandial ranitidine is superior to post-prandial omeprazole in control of gastric acidity in healthy volunteers. Aliment Pharmacol Ther 1999; 13: 12114.
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    Tutuian R, Katz PO, Ahmed F, Korn S, Castell DO. Over-the-counter H(2)-receptor antagonists do not compromise intragastric pH control with proton pump inhibitors. Aliment Pharmacol Ther 2002; 16: 4737.
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    Smout AJ, Jonkman JH, Peeters PA, De Bruin H. Effect of an evening dose of regular and effervescent formulations of ranitidine or cimetidine on intragastric pH in healthy volunteers. Aliment Pharmacol Ther 1995; 9: 516.
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    Nwokolo CU, Prewett EJ, Sawyer AM, Hudson M, Lim S, Pounder RE. Tolerance during 5 months of dosing with ranitidine, 150 mg nightly: a placebo-controlled, double-blind study. Gastroenterology 1991; 101: 94853.