Based in part on Practice Guidelines from the American College of Gastroenterology and Recommendations from the 2002 American Gastroenterological Association Consensus Development Panel-Improving the Management of GERD: evidence-based therapeutic strategies.

This report was reviewed for medical and scientific accuracy by Mark J. Sterling, MD, Assistant Professor of Medicine, and Interim Director, Division of Gastroenterology, University of Medicine & Dentistry of New Jersey (UMDNJ)-New Jersey Medical School, Newark, New Jersey

Introduction

According to recent recommendations from the American Gastroenterological Association Consensus Development Panel,¹ the combination of antacid and H₂ receptor antagonist (H₂RA) (famotidine/calcium carbonate—Pepcid Complete) provides an incremental improvement in efficacy compared to either individual ingredient in treating the symptoms of mild-to-moderate gastroesophageal reflux disease (GERD). Importantly, these recommendations reaffirm the role of over-the-counter (OTC) acid suppressants advocated as appropriate, initial patient-directed therapy for GERD in practice guidelines from the American College of Gastroenterology.²

From the patient's perspective, the impact of GERD is considerable. Studies show that GERD has a significant impact on quality of life, affecting the patient's sleep, work, and social life. A report published in 1998 showed that among 533 adults who had a history of heartburn lasting for a minimum of 6 months, patients with GERD reported significantly worse scores on physical function and well-being, as well as emotional well-being compared with the general population.³ In fact, patients with GERD reported worse emotional well-being than patients with diabetes or hypertension. Interestingly, quality-of-life scores for the GERD patients improved rapidly with successful treatment.

For the patient with mild-to-moderate GERD, there are a variety of safe and effective OTC treatment options to provide adequate relief of heartburn associated with GERD. Such options include antacids, H₂RAs, and the combination of antacid and H₂RA. After briefly reviewing the pathophysiology and clinical features of GERD, this Digestive Health Express Report will focus on the discussion of the available OTC treatment options, their advantages and disadvantages and their use in the treatment of mild-to-moderate GERD. For the purposes of this Digestive Health Express Report, the mild-to-moderate GERD patient is defined as experiencing mild symptoms that are adequately controlled by OTC therapy in conjunction with lifestyle/dietary modifications. For those patients who do not respond satisfactorily to OTC therapy or exhibit alarm symptoms, prescription strength H₂RAs, proton pump inhibitors (PPIs) and/or endoscopic examination would be clinically appropriate measures.

Perspective

GERD is one of the most common chronic disorders of the gastrointestinal tract.⁴ A systematic review of population studies of GERD symptoms (eg, heartburn) indicated a prevalence range between 10% and 48%.⁵ The socioeconomic impact of GERD is substantial given that 61 million adults in the United States experience heartburn at least once a month with 18 million individuals taking some form of medication for indigestion at least twice weekly,⁶ resulting in annual direct costs of $9.3 billion.⁷

Pathophysiology and Clinical Features of GERD

GERD occurs when the gastroesophageal sphincter malfunctions, allowing the stomach's contents to flow up into the esophagus resulting in its hallmark symptom—heartburn. Its pathogenesis has yet to be fully elucidated, but likely involves several factors^8,9 including:

• Antireflux barrier malfunction (eg, pressure relaxation of the lower esophageal sphincter [LES])
• Esophageal clearance failure (eg, peristalsis, gravity)
• Inadequate tissue resistance to acid (eg, esophageal epithelium, bicarbonate secretion, salivary pH)
• Abnormal characteristics and quantity of acid
• External features (eg, diet, smoking, select medications)

In its milder manifestation, the heartburn associated with GERD is typically transient. However, in some individuals, the heartburn is severe and typically is accompanied by prolonged episodes of reflux, particularly at night. Symptoms concurrent with heartburn may include regurgitation of gastric contents, nocturnal wheezing, coughing, hoarseness, and, with disease that is more advanced, dysphagia and bleeding. Atypical symptoms, such as angina-like pain or airway-induced symptoms occur rarely. In some GERD patients, lesions develop in the esophageal mucosa (reflux esophagitis). Reflux esophagitis is visible upon endoscopic exam, making the diagnosis more straightforward than that for endoscopy-negative GERD patients, who may have normal esophageal mucosa but experience similar reflux symptoms.

Treatment Options for Uncomplicated GERD

Resolving the patient's symptoms and maintaining an absence of symptoms are the primary goals of therapy for mild-to-moderate GERD. To achieve successful results, educating the patient about GERD and the factors that precipitate reflux are fundamentally important.

Lifestyle Modifications
Simple life-style modifications should be emphasized and incorporated into all stages of GERD treatment.² Such modifications include sleeping with the head of the bed elevated approximately 6 inches, smoking cessation, weight reduction, decreased fat intake, minimal alcohol consumption, avoidance of coffee, chocolate and peppermint, and avoidance of recumbency for 3 hours postprandially. Avoidance of medications that lower LES tone or decrease motility would require consultation from the physician or pharmacist. Medications associated with lowering the LES tone include nitrates, ethanol and anticholinergic agents;¹⁰ theophylline;¹¹ progesterone and tricyclic antidepressants;¹² and calcium channel blockers.^13,14 If symptoms are not resolved with lifestyle modifications, pharmacologic therapy with OTC medications is warranted.

Pharmacologic therapy is designed to decrease the amount of acid that refluxes from the stomach back into the esophagus or make the refluxed material less irritating to the esophageal lining by neutralizing the pH of the gastric acid. The OTC medications that have been shown to reduce the severity and frequency of GERD symptoms are considered rapid, effective, and safe when used for periods not exceeding 4 weeks.¹

Antacids
Antacids have been successful in neutralizing gastric acid and relieving symptoms of GERD. Antacids work primarily by increasing the pH of the stomach contents, thus resulting in less acidic material being refluxed into the esophagus. Undoubtedly, the most important therapeutic feature of antacids is their rapid effect. Patients need to be educated about the mechanism of action of antacids and their proper use. In order for antacids to be effective in relieving GERD symptoms, antacids must be administered every 2 to 4 hours. Antacids are considered to be safe and extremely well tolerated. However, many common antacids contain aluminum hydroxide and magnesium hydroxide (Maalox, Mylanta) or calcium carbonate (Tums) and potential drug interactions are of great importance. Antacids can interact with fluoroquinolones, tetracycline and ferrous sulfate.¹⁵ These interactions may be the result of an alteration in gastric pH, increase of urinary pH or resultant alteration of bioavailability with concomitant administration.¹⁵

Patients also need to be aware of potential adverse effects (Table 1). Aluminum hydroxide can cause constipation and magnesium hydroxide can cause diarrhea; although these effects are typically neutralized by concurrent administration. With aluminum and magnesium salts, particular care must be observed in renally-impaired patients. Nevertheless, many individuals do not tolerate the frequent administration of antacid required for the therapeutic relief of symptoms.

Antacid-alginate Combinations
Alginic acid is an ingredient in several antacid formulations. Rather than neutralizing gastric acid, alginic acid reacts with sodium bicarbonate in the saliva to form sodium alginate. Acting as a mechanical barrier, sodium alginate (Gaviscon) floats on top of the gastric contents to minimize exposure of the esophagus to refluxed material. Studies of sodium alginate in combination with low-dose antacid have shown a statistically significant benefit compared with placebo for relief of mild-to-moderate GERD symptoms.^16,17 While the combination of sodium alginate/antacid is superior to placebo, no study has demonstrated the superiority of sodium alginate/antacid to antacid alone.¹

H₂ Receptor Antagonists
The H₂RAs are a widely-accepted and effective treatment for the symptoms associated with mild-to-moderate GERD. There are four commercially available products: famotidine 10 mg (Pepcid AC), cimetidine 200 mg (Tagamet HB), ranitidine 75 mg (Zantac 75), and nizatidine 75 mg (Axid AR). The H₂RAs act through competitive binding to parietal cell H₂ receptors thereby inhibiting basal and stimulated-acid secretion and diminishing acid-dependent peptic activity. Numerous clinical trials have shown H₂RAs to be superior to placebo for efficacy, heartburn relief, and postprandial symptoms with mild-to-moderate GERD.¹

H₂RAs have a slower onset of action compared to antacids and thus are less useful for treating acute episodes of heartburn. However, H₂RAs have a significantly longer duration of effect and are able to provide excellent nocturnal acid control. The OTC H₂RAs are easy to use prophylactically, as they can be taken before a meal. Some H₂RAs have the potential to cause drug interactions; particularly with those medications whose absorption is gastric pH-dependent. Metabolic inhibition with cimetidine is dose-related, especially at doses above 400 mg daily.¹⁸ Interactions with propranolol, warfarin, theophylline, phenytoin, nifedipine, and diazepam are the most noteworthy.¹⁸ Increased or decreased prothrombin times have been reported during concurrent use of ranitidine and warfarin.¹⁹ No drug interactions have been identified with famotidine.²⁰

H₂RA/Antacid Combination
Given the effectiveness of single-agent treatment options for mild-to-moderate GERD, it is easy to see why researchers would want to investigate whether the combination of H₂RAs and antacid could synergistically improve symptom relief beyond the efficacy established by the separate components. The FACT Study was designed to answer that question.

The FACT (famotidine/antacid combination tablet—calcium carbonate 800 mg and magnesium hydroxide 165 mg) Study was a randomized, placebo-controlled clinical trial of 1640 GERD patients assigned to receive the FACT combination tablet (n = 410), H₂RA alone (n = 411), antacid alone (n = 411), or placebo (n = 115) for postcibal heartburn.¹ Analyses of efficacy were based on 6281 episodes of heartburn, 90% of which occurred during waking hours, between 7:01 am and 11:00 pm.

Results were reported on three areas of efficacy—time to onset of relief, duration of symptom relief, and a global assessment. FACT was found to be superior to placebo on all measures. While the FACT subjects essentially were equal to the antacid group for onset of relief, they were significantly faster than the placebo (odds ratio (OR) 1.59; 95% Confidence Interval (CI), 1.31-1.94; P<.001) or H₂RA alone (OR 1.42; 95% CI, 1.17-1.73; P = .001) groups.

Results on duration of relief indicate that the FACT group maintained relief from heartburn symptoms significantly longer than any of the other three groups (P<.05 for the H₂RA alone group and P<.001 for both the antacid and placebo groups). Odds-ratios indicate that the FACT group was more than twice as likely to sustain relief as any of the other three groups (H₂RA alone 95% CI, 1.26-1.92; antacid 95% CI, 1.31-1.95; and placebo 95% CI, 1.77-2.62). The finding that the FACT medication has a longer duration than H₂RA alone is notable and may suggest an incremental improvement in efficacy for the combination of H₂RA and antacid.

Overall symptom response was excellent or good in more FACT patients than in any other group. Eighty-one percent of the FACT subjects reported an "excellent/good" response (P≤.004) compared with 72% of subjects taking antacids or 65% taking an H₂RA alone—which is a statistically significant difference (P<.001). The FACT subjects also required fewer rescue antacids during the 8-hour postdose period. Rescue medications were used in 23% of the postdose heartburn episodes of the FACT group, in 34% of the H₂RA group, 36% of the antacid group, and 43% of the placebo group, indicating that FACT subjects were less likely to use the rescue antacid at an earlier time (P<.001 for all).

Future OTC Treatment: Proton Pump Inhibitors
Although not currently available OTC, PPIs offer longer-lasting acid suppression than H₂RAs but also have a slower onset of maximal acid suppression. For example, although the onset of antisecretory activity occurs within one hour for both famotidine and omeprazole, the inhibition of secretion with omeprazole is approximately 50% of maximum at 24 hours²¹ while the mean suppression of basal and nocturnal acid secretion with famotidine was 76% and 84%, respectively, 3 to 5 hours after administration.²⁰ They are, therefore, less optimal for treatment of acute episodes of heartburn but are very useful in controlling recurrent symptoms of GERD. They offer sustained meal-induced acid suppression, significant gastric pH elevation, and healing of gastric and duodenal ulcers when taken in prescription doses.

Omeprazole is expected to be the first PPI available as an OTC product.²² Patients will be instructed to take 20 mg daily for 14 days. Even at this full therapeutic dosage, however, some patients have indicated the need to treat breakthrough symptoms. In the May 2000 Gallup Study of Consumer's Use of Stomach Relief Products,²³ 45% of individuals taking PPIs also took OTC products, predominantly antacids, and half of those individuals took antacids daily.

While PPIs are considered safe, there is nevertheless the potential for interaction with drugs that are also CYP2C19 substrates. For example, since omeprazole inhibits CYP2C19 enzyme activity, medications that are metabolized through this system will be adversely affected. The concomitant administration of omeprazole with warfarin or phenytoin, which are both narrow therapeutic range medications and diazepam, would result in altered distribution of these agents.²¹ Medications, whose absorption is pH-dependent, when given with omeprazole would result in decreased absorption include ketoconazole, ampicillin, and iron salts.²¹

Conclusion

For the patient with mild-to-moderate GERD, there are a variety of safe and effective OTC treatment options to provide and maintain adequate relief of heartburn associated with GERD. Such options include antacids, H₂RAs, and the combination of antacid and H₂RA. Recent data suggest that the combination of antacid and H₂RA (famotidine/calcium carbonate) provides an incremental improvement in efficacy compared to either individual ingredient in treating the symptoms of mild-to-moderate GERD.

References

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16. McHardy G. A multicentric, randomized clinical trial of Gaviscon in reflux esophagitis. South Med J. 1978;71(suppl 1):16-21.
17. Stanciu C, Bennett JR. Alginate-antacid in the reduction of gastroesophageal reflux. Lancet. 1974;109-111.
18. Tagamet prescribing information [package insert]. GlaxoSmithKline. Available at http://corp.gsk.com. Accessed May 7, 2003.
19. Zantac prescribing information [package insert]. GlaxoSmithKline. Available at http://corp.gsk.com. Accessed May 7, 2003.
20. Pepcid prescribing information [package insert]. Merck & Co. Inc. Available at http://www.merck.com. Accessed May 7, 2003.
21. Prilosec prescribing information [package insert]. AstraZeneca. Available at http://www.astrazeneca-us.com. Accessed May 8, 2003.
22. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Memorandum from OTC Omeprazole Magnesium (Prilosec 1) Review Team. Available at http://www.fda.gov/ohrms/ dockets/ac/02/briefing/3861B1_02_A-Summary%20memo.pdf. Accessed May 8, 2003.
23. The Gallup Organization. 2000 Gallup Study of Consumers' Use of Stomach Relief Products, May 2000.

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Disclosure

Mark J. Sterling, MD
Has no significant relationships to disclose.

This report contains no information on commercial products that are unlabeled for use or investigational uses of products not yet approved.

This report is supported by an educational grant from Merck Consumer Pharmaceuticals Co.

The opinions expressed in this publication are those of the participating faculty and do not necessarily reflect the opinions or the recommendations of their affiliated institutions: University of Medicine & Dentistry of New Jersey; MMC, Inc.; or any other persons. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this publication should not be used by clinicians without evaluation of their patients' conditions, assessment of possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with the recommendation of other authorities. This Pain Management Express Report™ does not include discussion of treatment and indications outside of current approved professional labeling. This Pain Management Express Report™ was made possible through an educational grant from McNeil Consumer and Specialty Pharmaceuticals.

© 2003 Millennium Medical Communications, Inc. and UMDNJ-Center for Continuing and Outreach Education