Whether due to fast food, obesity, and/or loss of protective Helicobacter pylori (the latter is controversial), heartburn seems to be reaching epidemic proportions. High heartburn prevalence has led to substantial use of over-the-counter (OTC) and prescription medications.
Almost by definition, intermittent heartburn is a condition amenable to self-treatment with OTC remedies. It has been argued that heartburn as often as twice weekly could indicate a serious pathological process (thus converting the perception of a mild malady amenable to self-management to a presumably life-threatening disease). However, the heartburn frequency and severity of do not correlate with presence or extent of esophageal mucosal injury, a traditional hallmark of gastroesophageal reflux disease (GERD). Even very frequent heartburn (5 or more episodes per week) can be associated with insignificant pathology and a benign prognosis. On the other hand, erosive esophagitis and other severe reflux complications may occur with little or no heartburn (silent GERD). It seems logical that response to patient-directed treatment (OTC self-treatment or on-demand treatment) might be a better identifier of significant pathology than any arbitrary number or severity of heartburn episodes.
In the absence of documented or suspected reflux complications, the primary treatment aim for heartburn sufferers should be effective symptom relief. With the recent availability of omeprazole as the first OTC proton-pump inhibitor (PPI), there is now a wide range of potential self-treatments working by different mechanisms. This report reviews current concepts of heartburn, self-treatment options, and stepwise management approaches for refractory symptoms.
Approximately 20% of adults in the United States suffer from heartburn or acid regurgitation at least once weekly, with an additional 20% experiencing less frequent episodes. Frequent heartburn may restrict normal activities and lead to significant decrements in health-related quality of life.[3,4]
Risk factors for frequent reflux symptoms include obesity and a positive family history. There may be a genetic predisposition for gastroesophageal reflux. Eradication of H pylori infection may or may not promote GERD onset or exacerbation.[7,8]
Physiology of Heartburn
Heartburn is virtually always due to reflux of acidic gastric contents into the esophagus. Transient lower esophageal sphincter relaxations (tLESRs) often underlie both normal and pathological reflux. In healthy individuals, gravity and peristalsis rapidly clear refluxate, whereas swallowed saliva neutralizes remaining adherent esophageal acid. Heartburn occurs when these protective mechanisms and/or endogenous mucosal defenses are impaired. Other etiologic factors include an increased frequency of inappropriate tLESRs and prolonged acid contact time.
Depending on the study, 53% to 71% of heartburn sufferers have endoscopically normal esophageal mucosa.[1,9,10] Such patients with nonerosive reflux disease (NERD) or symptomatic GERD have only minimally impaired esophageal motility. Pathogenic factors in NERD might include postprandial hypersecretion and/or mucosal hypersensitivity to physiologic amounts of acid exposure.[10,12]
Therapies for Intermittent Heartburn
Patient-directed OTC therapies now include a PPI and antacids and histamine-2 receptor antagonists (H2RAs), alone or in combination (Table).
Table. Selected OTC Medications for Intermittent Heartburn
Abbreviations: Al(OH)3, aluminum hydroxide; CaCO3, calcium carbonate; H2RA, histamine-2 receptor antagonist; Mg(OH)2, magnesium hydroxide; OTC, over the counter; PPI, proton pump inhibitor.
Whereas we once thought antacids acted in the gastric lumen by reducing gastric acidity, we now know that they largely or completely work within the esophageal lumen. Antacids rapidly elevate esophageal pH and neutralize esophageal acid for up to 90 minutes after dosing, often with only modest changes in gastric pH.[14,15] A combination of weak antacid and alginic acid has long been available; the combination produces a foam barrier on top of the gastric pool that is designed to mechanically prevent reflux into the esophagus and neutralize acid. Other antacids are available as swallowable and chewable tablets, liquid suspensions, effervescent solutions, and chewing gum. Chewed tablet antacids and gum are more effective than liquid antacids, even though in vitro acid-neutralizing capacity may be substantially higher with the latter.
There are few well-designed clinical trials with antacids. In small symptomatic GERD studies, antacids were more effective than placebo in relieving heartburn.[17,18] On-demand use of antacids (up to twice daily) was superior to placebo for complete relief of spontaneous heartburn. Alginic acid in combination with low-dose antacid relieved meal-induced heartburn within 15 minutes and was as effective as antacid alone and more effective than placebo for heartburn relief.[21,22]
Overall, antacids provide fast relief of individual heartburn episodes. Their drawback lies in their relatively brief duration of action and inadequacy as heartburn prophylaxis.
H2RAs (cimetidine, ranitidine, famotidine, and nizatidine) bind to histamine-2 receptors on gastric parietal cells to reduce gastric acid secretion. An OTC H2RA dose starts reducing gastric acid concentration within 1-2 hours after dosing, a reduction persisting for many hours. When effects on postprandial gastric acid were compared, antacids neutralized acid within 30 minutes, with duration of effect of 60 minutes. In contrast, OTC H2RA was associated with a later onset (90 minutes) but prolonged duration of action (at least 9 hours). Although H2RAs are notably effective at night, their impact on daytime meal-stimulated acid secretion is much less robust.
Randomized, placebo-controlled H2RA trials at half of their prescription doses have demonstrated prompt and lasting heartburn relief. In 1620 subjects with a >/= 3-month history of heartburn, ranitidine, 25 and 75 mg up to 4 times daily, was more effective than placebo for episodic heartburn relief and reduction of antacid consumption. Low-dose ranitidine relieved heartburn within 30-45 minutes of dosing.
Famotidine and nizatidine are also efficacious for intermittent heartburn. In 565 OTC heartburn sufferers, famotidine, 5 and 10 mg up to twice daily, provided more rapid and more dependable relief than placebo. In 994 subjects, nizatidine, 75 mg up to twice daily, provided sustained adequate relief of more heartburn episodes than placebo.
A French study randomized 1336 heartburn sufferers to on-demand ranitidine, 75 mg, cimetidine, 200 mg, or placebo up to 3 times daily for 15 days. Ranitidine relieved at least 75% of heartburn episodes in 41% of subjects, cimetidine in 38%, and placebo in 28%. Both H2RAs were significantly more effective than placebo.
Thus, all 4 H2RAs are superior to placebo for heartburn relief in various self-treatment paradigms. Comparative studies suggest some differences that could have an impact on OTC H2RA selection (such as higher potency for famotidine and ranitidine vs cimetidine and faster onset of effect on gastric pH with OTC cimetidine and ranitidine vs OTC famotidine).
OTC H2RAs also have been evaluated for heartburn prevention before consumption of provocative meals. In 413 subjects with moderate-to-severe postprandial heartburn, single-dose nizatidine or placebo was administered 30 minutes before a meal. Heartburn was completely prevented in 14.9% of those receiving nizatidine, 75 mg, vs 2.9% of placebo recipients. In 284 subjects receiving a heartburn-provoking meal, ranitidine, 75 mg, was superior to placebo for complete heartburn prevention.
Low-Dose H2RA Plus Antacid
A combination of H2RA plus antacid should provide both antacid speed and H2RA sustained duration. Famotidine, 10 mg, plus calcium carbonate and magnesium hydroxide reduced gastric acidity more than use of H2RA alone and for longer than the antacid alone. Our group, which used integrated gastric and esophageal acidity measurements, demonstrated similar synergy between ranitidine, 75 mg, and calcium carbonate for decreasing both gastric and esophageal acidity. Such acid measures are widely accepted as surrogates for symptom control. Substantiating this concept was our demonstration of better control of heartburn severity for low-dose ranitidine plus calcium carbonate vs placebo.
A commercially available combination of famotidine, 10 mg, plus antacid was recently evaluated. Onset of heartburn relief was faster with the combination than with the H2RA alone or placebo. The combination was associated with a longer duration of action compared with either agent alone or placebo. It might be argued that the fixed combination of H2RA plus antacid would be optimal only for occasional on-demand use and would not be cost-effective for patients who use H2RA therapy mainly or solely for heartburn prophylaxis.
PPIs suppress gastric acid production by blocking parietal cell hydrogen/potassium ion adenosine triphosphatase, known as the proton pump. This is the final common pathway for acid secretion. PPIs affect only active pumps, but not all proton pumps are active at any given time, and 25% of new proton pumps are synthesized daily. As prodrugs, PPIs are generally slow in onset, owing to their requirement for enteric coating to allow small-intestinal absorption, subsequent concentration in parietal-cell canaliculi, and eventual activation in an acidic environment. H2RAs act more swiftly than PPIs: a single dose of ranitidine, 75 mg, increased postprandial gastric pH above 3 and above 4 more rapidly than single doses of omeprazole, 10 and 20 mg. Similarly, pH >/=3 was attained more rapidly with single-dose OTC H2RA plus antacid than with single-dose omeprazole.
The newly available OTC formulation of omeprazole contains the equivalent of the current prescription-strength omeprazole dose. OTC omeprazole is labeled to be taken continuously, one dose daily for 14 days. Since omeprazole cannot be expected to provide symptom relief until multiple doses have been taken, this self-treatment option represents a new OTC paradigm compared with fast-acting antacids or H2RAs.
OTC omeprazole efficacy for intermittent heartburn was evaluated in 2 unpublished randomized controlled studies summarized in the Medical Letter on Drugs and Therapeutics. In both studies, subjects with frequent heartburn received omeprazole magnesium, 20.6 mg (equivalent to omeprazole, 20 mg), or placebo for 14 days. A higher proportion of omeprazole recipients (73% and 70%) became heartburn free compared with placebo recipients (43%). Within 5 days after taking the drug, heartburn incidence was identical in both treated and control subjects.
On-Demand Prescription Therapy With PPIs
Physicians have not yet widely embraced the concept of intermittent or on-demand use of PPIs. However, this concept will probably have increasing appeal due to potential cost reductions of such therapy together with the implied avoidance of PPI dependence that is so tightly associated with chronic PPI therapy.
Studies of on-demand therapy with prescription esomeprazole, lansoprazole, and rabeprazole have evaluated heartburn control in NERD. Standard doses of on-demand lansoprazole and esomeprazole improved heartburn in symptomatic GERD following an initial period of continuous PPI therapy.[39,40] For example, after achieving complete heartburn relief with short-term PPI therapy, 721 patients were randomized to on-demand esomeprazole, 20 or 40 mg, or placebo (maximum 1 dose per day) for 6 months. Compared with placebo, significantly fewer patients discontinued treatment with on-demand esomeprazole. The higher esomeprazole dose provided no additional benefit.
Preliminary reports suggest that on-demand rabeprazole effectively controls heartburn at half the prescription dose.[41,42] In 418 subjects randomized to on-demand rabeprazole, 10 mg, or placebo for 6 months, significantly fewer patients discontinued use of rabeprazole owing to insufficient heartburn control. In another study, on-demand rabeprazole, 10 mg, was comparable to continuous therapy with rabeprazole, 10 mg/d, for symptom relief (75% vs 86%, respectively).
Management Approaches for Intermittent Heartburn
In addition to being fast, antacids last longer than many realize (up to 90 minutes of elevated esophageal pH). Recently an international expert panel supported the use of on-demand antacids as first-line OTC treatment in heartburn. Antacids are likely to be satisfactory for occasional and brief heartburn episodes.
For more frequent or persistent symptoms, OTC H2RA treatment is often highly successful. Although long-term H2RA use can be associated with tachyphylaxis, short-term H2RA use is effective for control of intermittent heartburn. The added advantage of efficacy for heartburn prophylaxis makes H2RAs a popular OTC choice.
PPIs will undoubtedly find their appropriate niche in the OTC arena, but it will not be as dominant as their prescription status. As a class, they are much slower in onset of antisecretory activity than H2RAs. Thus, they may be less effective for intermittent heartburn relief than antacids or H2RAs, but they can still be used on demand in some patients. Rabeprazole, which has particularly rapid (ie, day 1) onset of action, may be especially well suited for on-demand therapy, although data also exist regarding on-demand use of other PPIs (eg, esomeprazole).
When an individual seeks medical care for chronic heartburn or, as is likely, complains of frequent heartburn during a physician visit for another ailment, he or she will probably have used OTC remedies with unsatisfactory results. Healthcare professionals should more rigorously recommend or reinforce lifestyle modifications. In particular, heartburn sufferers should avoid postprandial recumbency for 2-3 hours, elevate the head of the bed at night, and effect dietary changes (smaller meals, avoidance of large quantities of fat).
Physicians must be alert for alarm symptoms and signs (eg, dysphagia, weight loss, and anemia) suggesting serious underlying illness. In the absence of alarm symptoms, further diagnostic evaluation may still be warranted for very chronic symptoms (eg, > 5 years). Otherwise, symptoms other than infrequent and intermittent ones should be addressed with a rational "step-up" approach to therapy. For example, individuals already self-treated with antacids alone might be "escalated" to intermittent H2RA treatment. Prior use of an OTC H2RA with or without antacids could be the basis for recommending more frequent H2RA use, along with compliance with lifestyle modifications. However, most clinicians manage OTC H2RA failures with advancement to PPI therapy. After 1-2 weeks of continuous PPI use, subsequent intermittent or on-demand therapy might suffice for many patients. A history of prior unsuccessful use of an OTC PPI (omeprazole) probably warrants escalation to a new-generation PPI or occasionally to PPI therapy combined with use of a low-dose H2RA at night. In a very few instances, PPI therapy will be needed more than once daily. Optimal timing of PPI dosing should be stressed, ie, 1 hour before a meal.
In most cases, failure of a properly followed PPI regimen suggests that the original diagnosis was in error, since PPI responsiveness is an excellent diagnostic test for acid-mediated disease. Such PPI-resistant patients require more complete assessment, often including endoscopy.
There is no currently accepted role for prokinetic therapy in usual heartburn management. Similarly, there is no primary role for antireflux surgery for patients with intermittent heartburn. Data are insufficient to recommend any of the newer endoscopic antireflux procedures (eg, Stretta, Enteryx, endoscopic plication).
Some heartburn sufferers have no pathological reflux, motility disorder, or structural explanation for their symptoms and are considered to have functional heartburn. This condition might respond to either the 5-hydroxytryptamine-4 agonist tegaserod or low-dose antidepressants.
Prevention of Esophageal Cancer?
Current approaches to intermittent heartburn are appropriate when it is believed that intermittent heartburn does not progress to Barrett's esophagus or esophageal adenocarcinoma. Most experts would espouse that viewpoint despite the paucity of studies of the natural history of symptomatic GERD. Few symptomatic patients appear to develop GERD complications over time.
Does aggressive acid suppression prevent the development of Barrett's esophagus and adenocarcinoma? Recent retrospective analyses have suggested that the incidence of dysplasia and esophageal cancer might be lower in treated patients.[48,49] If these preliminary reports are confirmed, reassessment of the role of aggressive acid-suppressive therapy for symptomatic reflux disease may be warranted. For now, this concept remains an unsubstantiated theory.
Most heartburn sufferers do not have erosive reflux disease and thus require only symptom-driven therapy. OTC remedies that provide fast and durable relief are appropriate options for intermittent heartburn. Antacids dependably produce speedy heartburn relief for many sufferers. OTC H2RAs are an excellent choice based on sustained duration of action and efficacy in preventing postprandial heartburn episodes. H2RAs may be particularly useful for nocturnal symptoms. When OTC treatment is unsatisfactory, clinicians often favor a step-up approach, which may begin with prescription-strength or more frequent H2RAs. PPIs probably should be reserved for use only after less aggressive modalities have been unsuccessful. If PPIs are required, they may be effective when given on demand or intermittently rather than as once-daily continuous therapy.