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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. References

Background

: Episodic heartburn is a common problem, affecting over 40 million Americans. Although omeprazole provides excellent acid suppression when used daily, the use of omeprazole as on-demand therapy for episodic symptoms has not been extensively studied.

Aim

: To compare the onset and duration of post-prandial gastric acid suppression by omeprazole (10 and 20 mg) or ranitidine (75 and 150 mg) taken as single doses in healthy volunteers.

Methods

: Twenty-four healthy volunteers (14 male, 10 female, mean age 33.4 years, range 18–56 years) were given ranitidine (RAN) 75 mg or 150 mg vs. omeprazole (OME) 10 mg or 20 mg when pH returned to below 2 after breakfast, in a randomized open label crossover design, with a washout of at least 2 days between medications. Intragastric pH was monitored for 6 h. The time between drug ingestion and rise of gastric pH > 3 and 4, and total time pH remained > 3 and 4 during the 6 h post drug, was compared between groups using two way ANOVA and Wilcoxon matched pairs test.

Results

: The median time needed to pH > 4 was 204.5 min for RAN 75 mg, 186 min for RAN 150 mg and > 360 min for both OME 10 and 20 mg (< 0.001 between the four groups). The median time that pH remained > 4 was 93 min for RAN 75 mg, 143.5 min for RAN 150 mg and 0 min for both OME 10 and 20 mg (< 0.001 between the four groups). Both doses of RAN were significantly superior to both doses of OME, although no significant difference was found between the high and the low doses of either drugs. Similar results were found for pH > 3.

Conclusion

: Ranitidine 75 or 150 mg provides more rapid increase in gastric pH to > 3 and > 4 compared to omeprazole 10 or 20 mg when taken at the end of the post-prandial period. These data suggest that ranitidine may be more effective for episodic post-prandial heartburn than omeprazole.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. References

Heartburn, the cardinal symptom of gastro-oesophageal reflux disease is present in 10% of the US population daily, and up to 40% monthly.1 Current data suggest that over 20 million people use intermittent antacids or other over the counter products for treatment of this symptom. The ideal medication for on-demand treatment should have rapid onset of action for prompt symptom relief and last long enough to relieve recurrent symptoms. Multiple agents are currently available for over the counter use for heartburn, including antacids and H2-receptor antagonists.2 Proton pump inhibitors are the most potent inhibitors of gastric acidity when used regularly.3 The effect of intermittent single dose proton pump inhibitor for on-demand treatment is not clear, and a recent study suggested that H2-blockers might be a better choice in this situation.4 The current study was designed to compare the acute effect on intragastric pH of ranitidine 75 and 150 mg with omeprazole 10 and 20 mg, each given as a single dose after breakfast.

SUBJECTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. References

The study was an open-label, randomized, crossover study of 24 healthy volunteers, who were not users of acid suppressive medications including antacids, H2-receptor antagonists and/or proton pump inhibitors. Female subjects had a negative urine pregnancy test, and were required to use effective birth control during the course of the study.

Stationary oesophageal manometry was performed to determine the location of the lower oesophageal sphincter (LES). A pH catheter with external reference electrode (Synectics Medical Inc.) was placed transnasally with the antimony electrode placed 10 cm below the proximal border of the LES at 08.00 hours followed within 15 min by a standardized meal consisting of a breakfast sandwich with one egg and sausage in a croissant and an 8 oz. cup of caffeinated coffee. Subjects were observed in the laboratory until intragastric pH fell to < 4 continuously for more than 10 min at which time the study medication was given with a glass of water. Gastric pH monitoring was continued for 6 h after intake of the medication (Figure 1).

image

Figure 1. . Schematic of study design.

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All subjects received 75 and 150 mg ranitidine, and 10 and 20 mg omeprazole in random sequence. All four arms were completed with a washout period of at least 2 days between each study. Data were analysed using established software (Esophagram; Synectics Medical Inc., Irving, TX). The effects of the different dosage regimens for each medication were compared for the time (in minutes) required for the pH to rise to > 3 and 4 for at least 10 min after ingestion of the study drug. The time for which intragastric pH remained above 3 and 4, respectively, during the 6 h monitoring period after taking the study drug was also measured. Subjects were required to keep a diary on the study days, marking time of intake of drugs and meals.

Statistics

Two-way ANOVA and Wilcoxon matched pairs test were used as appropriate. Two tailed P-values < 0.05 were considered significant. Statistical analyses were performed with Prism (GraphPad, CA). Results are expressed as medians and interquartile range (IQR).

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. References

Twenty-four subjects, mean age 33.4 years (range 18–56 years, 14 male, 10 female) completed the study.

Time until pH rise ≥ 4

Ranitidine 75 and 150 mg provided faster increase in time to pH > 4 (median: 204.5 and 186 min, respectively) compared to both doses of omeprazole (median: > 360 min for both; < 0.05); 150 mg of ranitidine was superior to 75 mg of ranitidine (< 0.05) in time to pH > 4. No significant difference was found between 10 and 20 mg of omeprazole (Figure 2).

image

Figure 2. . Time from taking the study drug until pH  4 for volunteers after ranitidine 75, 150 mg, omeprazole 10 and 20 mg (< 0.05 for ranitidine 75 mg and 150 mg vs. omeprazole).

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Duration for which pH remained at ≥ 4

Ranitidine 75 and 150 mg provided longer duration of pH control during the 6 h study period (median: 93 and 143.5 min, respectively) compared to both doses of omeprazole (median: 0 min for both; < 0.05). No significant difference was found between 75 and 150 mg of ranitidine, or 10 and 20 mg of omeprazole (Figure 3).

image

Figure 3. . Time for which pH remained > 4 after ranitidine 75, 150 mg, omeprazole 12 and 20 mg (< 0.05 for ranitidine 75 mg and 150 mg vs. omeprazole).

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Time until pH rise ≥ 3

Ranitidine 75 and 150 mg resulted in a faster increase in pH > 3 (median: 178 and 145.5 min, respectively) compared to both doses of omeprazole (median: > 360 min for both; < 0.05); 150 mg of ranitidine was superior to 75 mg of ranitidine (P=0.005). No significant difference was found between 10 and 20 mg of omeprazole (Figure 4).

image

Figure 4. . Time from taking the study drug until pH rise > 3 for volunteers on ranitidine 75, 150 mg, omeprazole 10 mg and 20 mg (< 0.05 for ranitidine 75 mg and 150 mg vs. omeprazole).

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Duration for which pH remained at ≥ 3

Ranitidine 75 and 150 mg provided longer duration pH > 3 (median: 110 and 166 min, respectively) compared to both doses of omeprazole (median: 0 min for both; < 0.05); 150 mg of ranitidine was superior to 75 mg of ranitidine (P=0.006). No significant difference was found between 10 and 20 mg of omeprazole (Figure 5).

image

Figure 5. . Time pH remained > 3 in volunteers on ranitidine 75, 150 mg, omeprazole 10 and 20 mg (< 0.05 for ranitidine 75 mg and 150 mg vs. omeprazole).

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DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. References

The ideal medication for treatment of episodic heartburn should have the rapid onset needed for on-demand treatment, combined with sufficient duration of action to assure continued relief of post-prandial symptoms. This study shows that both ranitidine 75 and 150 mg tablets raise intragastric pH significantly faster and for a longer period than omeprazole 10 or 20 mg capsules when given as a single dose when pH drops to less than 2 after breakfast. This is compatible with results reported by Arnestad et al. and Hedenstrom et al. who found that a single dose of ranitidine effervescent tablets given after breakfast had a significantly more rapid onset of control of intragastric pH than lansoprazole capsules.4, 5

Intragastric pH failed to rise to pH 4.0 in the majority of subjects after omeprazole treatment (18 out of 24 with 10 mg and 16 out of 24 with 20 mg). This is consistent with the results of Hurlimann et al. who found that intragastric pH control with proton pump inhibitors increases steadily during the first week of daily treatment,6 a result also found by Tolman et al. after 5 days of treatment with either omeprazole or lansoprazole.7 Both studies were carried out in healthy volunteers. Surprisingly, a minority also failed to reach pH > 4 with ranitidine (7 out of 24 with 75 mg and 2 out of 24 with 150 mg), though both doses were clearly superior to omeprazole.

The superiority of 150 mg to 75 mg of ranitidine in time to and duration of pH > 3 and 4 suggests a potentially clinically important dose response. Taking the medication after breakfast may have decreased the efficacy of both agents as the onset of action of H2-blockers on gastric acidity is attenuated by taking it after as opposed to before a meal.8 Similarly the proton pump inhibitors have their maximal acid suppressive effect when taken before meals.9 The present study shows that ranitidine 75 or 150 mg results in superior control of gastric pH compared to omeprazole 10 or 20 mg when taken as a single dose after pH returns to below 2 following breakfast and suggests that ranitidine should be more effective for on-demand treatment of heartburn. Ranitidine taken as 150 mg may be more efficacious than 75 mg for episodic heartburn.

References

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. References
  • 1
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    Hatlebakk J & Berstad A. Pharmacokinetic optimization in the treatment of Gastro-Oesophageal reflux disease. Clin Pharmacokinet 1996; 31: 386 406.
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    Burget DW, Chiverton SG, Hunt RH. Is there an optimal degree of acid suppression for healing of duodenal ulcers? A model of the relationship between ulcer healing and acid suppression. Gastroenterology 1990; 99: 345 51.
  • 4
    Arnestad JS, Kleveland PM, Waldum HL. In single doses ranitidine effervescent is more effective than lansoprazole in decreasing gastric acidity. Aliment Pharmacol Ther 1997; 11: 355 8.
  • 5
    Hedenstrom H, Alm C, Kraft M, et al.Intragastric pH after administration of single doses of effervescent ranitidine, omeprazole capsules and famotidine fast dissolving tablets to healthy volunteers. Scand J Gastroenterol 1995; 30: P032P032.
  • 6
    Hurlimann S, Abbuhl B, Inauen E, et al.Comparison of acid inhibition by either oral high-dose ranitidine or omeprazole. Aliment Pharmacol Ther 1994; 8: 193 201.
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    Tolman KG, Sanders SW, Buchi KN, Karol MD, Jennings DE, Ringham GL. The effect of oral doses of lansoprazole and omeprazole on gastric pH. J Clin Gastro 1997; 24: 65 70.
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    Merki HS, Halter F, Wilder-Smith C, et al.Effect of food on H2-receptor blockade in normal subjects and duodenal ulcer patients . Gut 1990; 31: 148 50.
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    Hatlebakk JG, Katz PO, Castell DO. Proton pump inhibitors should be taken with meals for optimal control of gastric acidity. Gastroenterology 1998; 114: G0592G0592 (part 2, abstract).