Introduction

Gastroesophageal reflux disease (GERD) affects more than 60 million Americans and remains one of the most common gastrointestinal disorders.¹ Most affected individuals experience symptoms of GERD infrequently (less than once a month), but approximately 14% of Americans report GERD symptoms at least once per week, and up to 7% describe daily heartburn or regurgitation. Moreover, the extraesophageal manifestations of GERD, including asthma, chronic cough, and laryngitis, are being recognized with increasing frequency. Over the past 30 years, the management of GERD has evolved to the point at which the use of proton pump inhibitors (PPIs) provides highly effective treatment in even the most severe disease. Effective surgical therapies are available, and several new endoscopic therapies are being actively investigated; the mainstay of GERD treatment, however, remains the use of antisecretory medications, whose effectiveness and safety are well established.

Pathogenesis of Gastroesophageal Reflux Disease

Gastroesophageal reflux disease results from continued exposure of the esophageal mucosa to gastric secretions, particularly acid and pepsin. A number of anatomic and physiologic mechanisms normally prevent reflux from occurring, and derangement in any of these can promote esophageal acid exposure. The most important factors at work in preventing reflux include the lower esophageal sphincter (LES), esophageal clearance mechanisms that limit contact time with noxious substances, and mucosal protective factors intrinsic to the esophageal mucosa.

The LES, a 3- to 4-cm-long region of smooth muscle located at the esophagogastric junction, creates a zone of high pressure separating the esophageal and gastric compartments between swallows. The diaphragmatic crura assist the LES in the maintenance of a tonically closed sphincter. The contribution of hiatus hernia to GERD is well established; the hiatus hernia eliminates the contribution of the crural diaphragm to LES function and thereby promotes gastroesophageal reflux. The severity of reflux disease in patients with hiatal hernia has been positively correlated with the size of the hernia sac.²

The most common cause of gastroesophageal reflux is an excessive exposure of the esophagus to gastric secretions during transient lower esophageal sphincter relaxation (TLESR). These relaxations normally last for approximately 10 to 30 seconds, and occur in response to gastric distention and vagal stimulation. The purpose of TLESRs may be to vent gas from the stomach, and a TLESR is not necessarily associated with gastroesophageal reflux. Patients with GERD, however, have a higher frequency of TLESRs associated with reflux, and, as a consequence, a significantly prolonged duration of esophageal acid exposure.³ The contribution of TLESRs to GERD is greatest for patients with upright (daytime) reflux and nonerosive or mild erosive disease. Patients with more severe grades of esophagitis typically have other factors, such as hiatus hernia or decreased LES pressure, responsible for prolonged acid exposure.⁴

The entry of acid into the esophagus activates clearance mechanisms that limit exposure of the esophageal mucosa to gastric secretions. These include esophageal contractions (secondary peristalsis) that rapidly propel the refluxate into the stomach. Swallowing bicarbonate-rich saliva and secretion of bicarbonate by esophageal glands neutralizes any residual esophageal acid trapped in contact with the mucosa. Patients with either defective esophageal motility or decreased salivary secretion are predisposed to GERD.

Principles of Gastroesophageal Reflux Disease Therapy

Gastroesophageal reflux disease is primarily a disorder of esophageal motility, as most patients with GERD do not secrete abnormal quantities of gastric acid. The treatment of GERD, however, is typically not directed at the underlying pathophysiology but rather at reducing the acid content of the refluxate. If a less acidic fluid contacts the esophageal mucosa, the balance between offensive and defensive forces is shifted toward the side of mucosal protection. An effective therapy for GERD should accomplish three goals. The focus of treatment is control of symptoms, and most patients have complete symptom relief with appropriate medical therapy. An effective therapy should also heal esophageal mucosal damage (erosive esophagitis), which does not necessarily correlate with the presence or severity of symptoms.⁵ Lastly, effective therapy of GERD should prevent the complications of chronic reflux, including esophageal stricture, ulceration, and blood loss. Though intestinal metaplasia (Barrett's esophagus) is commonly regarded as a complication of GERD, there are no prospective endoscopic studies showing de novo development of Barrett's metaplasia in GERD patients who did not have it at initial endoscopy.

Lifestyle Modifications

Although the majority of patients with GERD require pharmacologic therapy, patients should be educated regarding the factors that contribute to gastroesophageal reflux and the nonpharmacologic measures that may improve symptoms (Table 1). Supine reflux is a common cause of nocturnal GERD symptoms, and as gravity plays a significant role in this entity, symptoms may be improved or eliminated by elevating the head of the patient's bed by at least 8 inches. This is best accomplished by the placement of wooden blocks or bricks under the bedposts. The use of a wedge that elevates the patient's head and thorax may also provide benefit but is not widely accepted; the use of multiple pillows elevates only the head and is ineffective in preventing reflux. Patients may find that sleeping with the left side down improves symptoms by augmenting the anatomic barrier to supine reflux. Patients should be advised not to lie down for at least 2 to 3 hours after a meal; this permits gastric emptying and reduces the quantity of gastric secretions available for reflux in to the esophagus. A recent study of patients with nighttime GERD symptoms reported that these practices provide "completely satisfactory" relief in approximately 50% of patients.¹

Table 1: Lifestyle modifications that may improve the symptoms of gastroesophageal reflux disease (GERD)

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Dietary modification may be helpful in improving reflux symptoms, and many patients can identify foods that induce or worsen their symptoms. Patients should be made aware of the most common provocative factors, including fatty foods, citrus fruits, tomato-based foods, coffee (including decaffeinated brands), chocolate, and alcohol. Patients should be advised to evaluate their own diets and eliminate the agents that precipitate symptoms; however, a blanket recommendation to avoid all food that may cause reflux is overly restrictive. Smoking is also associated with a higher frequency of symptomatic GERD, and the possibility of symptom relief may motivate smoking cessation efforts.

Many common antihypertensives, bronchodilators, and psychotropic agents promote gastroesophageal reflux, including calcium-channel blockers, nitrates, oral ₂-agonists, and antidepressants with anticholinergic properties. A careful medication history is essential in evaluating GERD patients, as a simple medication change may greatly reduce symptoms.

Refractory Gastroesophageal Reflux Disease

The term refractory GERD is used to describe patients who continue to have symptoms of gastroesophageal reflux despite conventional PPI therapy. This definition applies to symptoms and does not correlate with pharmacologic refractoriness, that is, failure of the drugs to suppress or abolish acid secretion. The term loosely used suffers from the additional limitation that it is meaningless unless twice-daily dosing with 40 mg of a PPI is specified; 40 mg of esomeprazole cannot be taken as equivalent to 10 or 20 mg of rabeprazole. This should be studied using ambulatory pH monitoring, but in the majority of those with refractory symptoms, inhibition of gastric acid secretion is achieved. True pharmacologic refractoriness is exceptionally rare and poorly studied. As described above, a minority of patients may respond symptomatically to an alternate PPI owing to patient-specific responses to different formulations. Patients who are truly refractory to twice-daily PPIs may have an acid hypersecretory state (e.g., Zollinger-Ellison syndrome) and a fasting serum gastrin level should be obtained after a 2-week period off PPI therapy. It is important that gastrin levels be drawn after a period offPPI therapy, as PPIs may elevate gastrin levels and reduce the specificity of the test. In patients who are diagnosed with gastrinoma, adequate control of acid secretion is often achieved only through the use of higher doses of PPI (up to 240 mg of drug daily).

Most patients with refractory GERD demonstrate appropriate acid suppression on ambulatory pH monitoring. Persistence of symptoms despite acid suppression raises the possibility of "functional heartburn," which may be a subset of patients with symptoms that mimic GERD. Alternatively, patients with persistent GERD symptoms may have an esophageal mucosa that is more sensitive to pH changes so that a less acidic refluxate still induces classic symptoms of reflux. Currently, acid reflux is defined as an esophageal pH <4 on pH monitoring; a pH of 5 or 6, however, remains acidic, and may be the cause of symptoms in a subset of patients with GERD. In such patients, higher doses of PPI may further decrease gastric acidity and relieve symptoms.³⁰

Another possible cause of GERD symptoms despite effective acid suppression is bile acid reflux, in which duodenal contents mix with gastric secretions and come into contact with the esophageal mucosa. Bile acids in the esophagus are considered to be markers for the presence of small–bowel contents of uncertain composition; in the presence of acid, bile acids are protonated and therefore weakly acidic in themselves, perhaps augmenting the noxious effects of acid and pepsin.³¹ If acid suppression is effective, bile acids exist as neutral bile salts, which are less likely to induce mucosal injury. Whether or not bile acids or their salts contribute to refractory or conventional GERD remains uncertain. Refluxate containing bile is commonly found in patients who have undergone gastric surgery (i.e., subtotal gastrectomy with Billroth I or II anastomosis) for prior malignant disease or peptic ulcer. The contribution of such bile acid reflux to GERD, however, remains an area of active research. Tack's group³² recently examined patients with reflux symptoms refractory to daily PPI therapy. Esophageal acid exposure was determined using standard pH monitoring, and duodenogastroesophageal reflux was measured by a spectrophotometric method (Bilitec) that identifies bilirubin in the refluxate by measuring its characteristic light absorption spectrum. Of the 65 patients studied, 38% exhibited only bile acid reflux, with no pathologic acid exposure. Although these patients were not treated with maximal PPI therapy, the results of this trial suggest that reflux of intestinal contents, as indicated by the presence of bile, may indeed play a role in symptomatic GERD. Therapeutic options for such reflux are limited; aluminum hydroxide antacids and liquid sucralfate may bind bile acids, pancreatic enzymes, lysolecithin, or other molecules and offer some relief. Ursodeoxycholic acid is an orally available bile acid that is effective in the treatment of primary biliary cirrhosis and in selected patients with gallstone disease. It displaces more toxic bile acids in the bile salt pool and might decrease the noxious effects of duodenal reflux on the esophagus, but no clinical studies to date have demonstrated the efficacy of this agent in a clinical setting.

Maintenance Therapy

Gastroesophageal reflux disease is a chronic disorder, and the majority of patients relapse after discontinuation of antisecretory therapy. Chiba and colleagues³³ performed a meta-analysis of clinical trials using PPIs and H2RAs in the treatment of GERD with esophagitis; symptoms recurred in approximately 80% of patients within 1 year after the cessation of therapy, with the highest recurrence rates described in patients with grade III to IV esophagitis.³⁴ Long-term therapy for GERD has been shown to be safe and effective, with maintenance omeprazole therapy sustaining remission for up to 11 years in one long-term study, although a number of patients required transient PPI dose increases for short periods of symptomatic recurrence.³⁵ Vigneri and colleagues³⁶ compared the effectiveness of ranitidine, cisapride, omeprazole, ranitidine + cisapride, and omeprazole + cisapride for the maintenance of remission in patients with erosive esophagitis. All patients (n = 175) were initially treated with omeprazole for 4 to 8 weeks, and mucosal healing was documented by endoscopy. Patients were then randomized to one of the five therapy arms. At 12 months, remission was maintained in 80% of patients taking omeprazole, compared with 49% in the ranitidine arm and 54% in the cisapride arm. Omeprazole and cisapride in combination yielded the highest rate of remission (89%), but this was not significantly different from omeprazole alone. It is thus clear that PPIs provide the most effective therapy for the maintenance of remission in patients with reflux esophagitis. Recurrence of maintenance therapy in patients admitted to trials with heartburn—not just the 30% of heartburn patients who have endoscopic esophagitis—has not been adequately studied. In maintenance trials of those admitted with healed esophagitis, those randomized to placebo show 20% to 40% remaining symptom free during 1 to 2 years of follow-up.

"Step Therapy" in the Treatment of Gastroesophageal Reflux Disease

The concept of "step therapy" for GERD includes two approaches to treatment. "Step-up" therapy begins with lifestyle modifications, over-the-counter antacids, and/or low-dose H2RAs. If this is ineffective, the next step should include prescription H2RAs in full dosage (e.g., ranitidine 300 mg or famotidine 20 mg b.i.d.), with a final step up to PPI therapy if symptoms are not fully controlled. By contrast, "step-down" approaches initiate therapy with PPIs to provide the greatest chance of relieving symptoms. Therapy is then stepped down to H2RA therapy to determine whether relief of symptoms can be maintained with less potent acid inhibition. As stated above, it is uncommon for patients to be able to step down to nonpharmacologic therapy. These approaches have been evaluated in a small number of studies. Howden and colleagues³⁷ randomized 593 patients with GERD to one of four treatment groups. Two groups of patients received either continuous ranitidine therapy (150 mg po b.i.d.) or continuous lansoprazole therapy (30 mg po qd). The two step-therapy arms received one of two regimens. One regimen consisted of ranitidine twice a day for 8 weeks followed by a step up to lansoprazole daily for 12 weeks; the other used lansoprazole daily for 8 weeks followed by a step down to ranitidine twice daily for 12 weeks. At the end of 20 weeks, the greatest degree of symptom control was reported in the continuous lansoprazole group.

In contrast, a study of step-down therapy by Inadomi and colleagues³⁸ reported somewhat different results. In this study, 73 patients with GERD symptoms who had failed to respond to therapy with ranitidine 300 mg b.i.d. but who initially responded when stepped up to PPI therapy had their PPI dose decreased and then discontinued over a 4-week period. Patients who had recurrent symptoms off medication were treated with H2RA therapy twice daily with or without a promotility agent. At the end of 1 year, 58% of patients were no longer using PPIs; 27% of patients were off medication entirely, whereas 35% required H2RA therapy and 7% were on prokinetic agents. Younger patients and those with heartburn as a primary symptom were more likely to fail step-down therapy and require maintenance PPI therapy.

Although these studies of step therapy reached different conclusions, and although the Howden et al.³⁷ study did not use ranitidine 300 mg b.i.d., the step-up approach has gained popularity in an era of managed care and cost controls. This not an unreasonable strategy, as many patients with nonerosive GERD or mild erosive esophagitis have adequate symptom relief with H2RA therapy alone. Patients with more severe disease who require a PPI may experience a delay in achieving symptom relief, and this needs to be balanced against the cost savings of any "step therapy" regimen.³⁹

An Approach to the Treatment of Gastroesophageal Reflux Disease

The overwhelming majority of studies evaluating the treatment of GERD have included subjects with either documented erosive esophagitis or severe and frequent episodes of heartburn. Most individuals with GERD, however, have nonerosive disease and experience infrequent symptoms (up to three episodes per week). These patients may not have endoscopic evaluation prior to treatment, as this is typically reserved for patients with (1) long-standing symptoms (>5 years' duration) to exclude the possibility of Barrett's metaplasia; (2) "alarm symptoms," such as dysphagia, weight loss, or signs of gastrointestinal bleeding; or (3) onset of symptoms at an age greater than 45 years. The majority of patients, therefore, are treated on the basis of their symptom complex, rather than on endoscopic findings. Moreover, the presence or absence of esophagitis cannot be accurately predicted from a patient's symptom complex or from the response to therapy.⁵

An approach to patients with symptomatic GERD is outlined in Figure 1. Gastroesophageal reflux is divided into discrete stages based on symptom frequency and severity, as well as the presence of esophageal complications or extraesophageal manifestations of GERD. Stage I GERD is defined as intermittent heartburn (up to three episodes per week) without complicating factors; this level of disease is effectively treated with lifestyle modifications, over-the-counter antacids, and/or nonprescription H2RAs. Stage II disease is characterized by more frequent symptoms (more than three times per week). Full dose therapy with an H2 blocker may be used initially, but PPI therapy is more effective in providing symptom relief and healing esophagitis, which may be present in this group of patients. Patients with stage III GERD have daily symptoms that remit as soon as antisecretory therapy is discontinued. Patients with GERD complications, including strictures and Barrett's esophagus, should be classified as stage III, as should patients with extraesophageal manifestations of GERD, such as asthma, laryngitis, or chest pain. These patients typically require PPI therapy either daily or twice daily to relieve symptoms and prevent complications. This staging system is widely applicable in clinical practice as it is based on presenting symptoms rather than the endoscopic finding of esophagitis; it also promotes graded therapy rather than an inflexible regimen of PPIs.

Figure 1: Approach to antisecretory therapy.

A suggested approach to the use of antisecretory therapy in the treatment of GERD, based on symptoms at presentation.

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Nocturnal Gastroesophageal Reflux Disease Symptoms

Nighttime symptoms are common in patients with GERD, affecting a majority of those who report frequent daytime reflux symptoms. The importance of nighttime reflux has been underestimated, and a recent Gallup study reported significant morbidity related to nocturnal acid reflux. In a sample of 1000 Americans who reported GERD symptoms at least weekly, 79% reported nighttime symptoms of heartburn or regurgitation, and 63% noted that GERD symptoms hampered their quality of sleep. Moreover, 40% reported that their nighttime reflux symptoms and poor sleep had a negative effect on their daytime activities.¹ In this cohort, 71% of patients reported using over-the-counter medications for their nocturnal symptoms, but only 29% considered this approach "completely satisfactory." Forty-one percent of patients in this group reported using prescription medications for their nocturnal GERD, and although 49% of these patients had complete symptom relief with this regimen, a full 51% remained dissatisfied with their symptom control. This study clearly demonstrates that nighttime symptoms of GERD are common and are often difficult to treat with current medical therapy.

Additional concern has been raised over the possibility that nocturnal reflux may be associated with a higher frequency of erosive esophagitis and GERD-related complications.⁴⁰ A retrospective case-control study by Lagergren et al.⁴¹ demonstrated that symptomatic GERD was a significant risk factor for adenocarcinoma of the esophagus, with a relative risk of 7.7 in patients with recurrent symptomatic reflux. Patients with frequent nighttime symptoms had an even greater relative risk (approximately 11). Thus, nocturnal GERD symptoms have an important impact on the clinical sequelae of GERD.

Intermittent Therapy with Proton Pump Inhibitors

Proton pump inhibitor therapy for GERD is typically administered continuously, with either once-daily or twice-daily dosing. Such regimens have been conclusively demonstrated to control symptoms and heal erosive esophagitis. Moreover, as stated earlier, relapse rates after discontinuation of therapy are approximately 75%, confirming the need for maintenance or intermittent therapy. Maintenance PPI therapy has been proven effective in controlling symptoms over a 5- to 10-year period.³⁴ Many patients, however, are rightly hesitant to commit to a lifelong regimen of daily antisecretory therapy. Recent studies have examined the possibility of intermittent therapy with PPIs, also known as "on-demand" therapy, in patients with nonerosive reflux disease or mild esophageal mucosal inflammation. Early studies of "weekend PPI therapy" given three days per week were disappointing, as symptom relief at 1 year was significantly lower with weekend therapy compared with daily dosing (32% vs 89%).⁴⁷ Other studies, using alternate-day dosing regimens, published only in abstract form, have been more promising.

Lind and colleagues⁴⁸ performed a large randomized controlled trial of on-demand therapy in 424 patients with nonerosive GERD. Patients with typical heartburn symptoms were treated for 4 to 8 weeks; those in whom symptoms resolved were randomized to receive omeprazole 20 mg, omeprazole 10 mg, or placebo. These medications were to be taken "on demand," such that if heartburn recurred, patients would use the study drug daily until symptoms resolved. The primary end point of this study was discontinuation of the protocol owing to poorly controlled heartburn. After 6 months, 83% of patients in the on-demand group taking omeprazole 20 mg remained on this regimen. In the lower dose omeprazole group, 69% remained on therapy, while only 56% continued therapy with placebo. The authors concluded that on-demand therapy may be effective in a substantial number of patients. It must be emphasized that this study assessed the effect of PPI therapy given on demand for periods of days to weeks; the use of PPIs on an "as-needed" basis (i.e., a single dose when symptoms occur) has not been proven effective.³⁸ Talley et al.⁴⁹ studied 342 patients with nonerosive GERD, using on-demand esomeprazole. After 6 months, 14% of patients discontinued the study medication owing to inadequate symptom control, compared with 51% receiving placebo. Proton pump inhibitor dosing during relapses in the on-demand esomeprazole group were as follows: 52% were treated for 1 to 3 consecutive days, 22% for 4 to 6 days, and 11% for 7 to 13 days. These two trials demonstrate that on-demand PPI therapy is well tolerated by patients who experience recurrent heartburn after discontinuing GERD therapy. This approach is less costly in terms of medication expenditures, but it remains to be determined whether patients outside of clinical trials will prefer interrupted symptom control to the complete relief obtained with daily maintenance therapy.

A recent review by Bardhan⁵⁰ summarized the data from several randomized controlled trials and uncontrolled studies. He concludes that on-demand or intermittent PPI therapy is acceptable for younger patients with nonerosive or mild erosive GERD that responds rapidly to initial PPI therapy. Daily maintenance PPI therapy is preferred for patients with more severe esophagitis and those with a delayed response to PPI therapy. It should be noted, however, that on-demand therapy as defined in these trials is not in keeping with patients' conception of as-needed therapy. The goal of having rapid-onset long-lasting symptom control with a PPI taken for a single day is unrealistic given the pharmacokinetics of PPIs. In general, at least 4 to 5 days of continuous PPI therapy are required to maximally inhibit gastric acid secretion and ensure symptomatic benefit.³⁹ It is unlikely that a patient using PPIs as needed will have adequate symptom relief unless the PPI is taken for several days at a time.

The Future of Pharmacological Therapy for Gastroesophageal Reflux Disease

Current research is focused both on improving antisecretory medications and in modifying gastrointestinal motility. Novel PPIs are in development, including a competitive inhibitor that reversibly binds near the K⁺ binding site of the H⁺/K⁺-ATPase.²⁸ The clinical effectiveness of these so-called acid pump inhibitors compared with existing PPIs has yet to be determined. More interesting, however, is the ongoing research into non–acid-inhibiting agents that would improve pH restoration or esophageal clearance, enhance gastric accommodation or emptying, or perhaps reverse the disordered neuromuscular function underlying GERD. Baclofen, a GABA_B receptor antagonist, has been reported to reduce the frequency of TLESRs in both healthy volunteers and patients with GERD.^{32, 51, 52} A randomized trial of baclofen therapy has yet to be performed, and will be necessary before GABA_Breceptor antagonists can be added to the armamentarium for the treatment of GERD.

The role of serotonin in the modulation of gastrointestinal motility is the subject of considerable research, and tegaserod, a selective 5HT₄ receptor agonist, has been demonstrated to be effective in irritable bowel syndrome. Serotonin stimulates peristaltic contractions and increases gastric motility, and the use of serotonin agonists has the potential to ameliorate GERD symptoms by promoting gastric emptying and enhancing esophageal acid clearance. Early studies with tegaserod demonstrated a decrease in reflux episodes in treated patients,⁵³ and larger controlled studies with this agent and other 5HT₄ agonists are ongoing.

Other approaches to the treatment of GERD include inhibition of gastrin-mediated acid secretion with cholecystokinin antagonists, inhibition of histamine-mediated acid secretion via histamine-3 receptor blockade, and enhancement of esophageal mucosal protection with agents such as prostaglandin E₂, epidermal growth factor, and transforming growth factor-. These remain in early phases of development and are not currently available for clinical use.

Extraesophageal Manifestations of Gastroesophageal Reflux Disease

Acid reflux is responsible for a number of clinical syndromes outside the esophagus, and these extraesophageal manifestations of GERD have been recognized with increasing frequency (Table 2). As these symptoms may occur without coincident symptoms of heartburn and regurgitation, a high index of suspicion for GERD is required when patients present with any of these features. The association between GERD and pulmonary symptoms is well established. El-Serag and colleagues⁵⁴ studied a cohort of over 100,000 service veterans with erosive esophagitis and demonstrated an increased association with asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis. Conversely, asthmatics have a higher prevalence of GERD symptoms than the general population, with nearly 80% of asthma patients reporting significant heartburn in some studies.^{17, 55} The role of acid reflux in adult-onset asthma in patients without classic GERD symptoms has been evaluated in a study by Harding et al.⁵⁶ Ambulatory 2 pH monitoring was performed in patients with nocturnal asthma symptoms but no clinical evidence of GERD. Abnormal esophageal acid exposure was documented in 62% of this cohort.

Table 2: Extraesophageal Manifestations of gastroesophageal reflux disease (GERD)

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Empiric PPI therapy in presumed GERD-induced asthma has been evaluated several small trials, with conflicting results. Kiljander and colleagues⁵⁷ performed a randomized controlled trial in 52 patients with asthma and abnormal ambulatory pH studies. Omeprazole 40 mg twice daily for 8 weeks was associated with a significant improvement in nocturnal pulmonary symptoms; similar results were reported in an additional uncontrolled trial.⁵⁶ Two other randomized trials, however, with a total of 50 patients reported no improvement in symptoms with PPI therapy.^{58, 59}

Otolaryngeal symptoms, including hoarseness, globus sensation, and excessive throat clearing, may be manifestations of GERD. Koufman⁶⁰ studied 225 patients presenting suspected GERD-induced otolaryngeal symptoms. Abnormal esophageal acid exposure was demonstrated in 62%, with pharyngeal reflux documented in 30%. Classic GERD symptoms were present in only 43% of study patients. Other trials suggest that nearly one third of otolaryngeal symptoms result from unsuspected GERD, and ear, nose, and throat physicians maintain a high index of suspicion for GERD in patients who are referred for hoarseness, chronic cough, or globus sensation.^{61, 62} Empiric PPI therapy in this patient population has been evaluated in several of small trials. El-Serag et al.,⁶³ in a randomized controlled trial comparing lansoprazole 30 mg twice daily to placebo in 22 patients with reflux laryngitis, reported a 50% decrease in symptoms in the treated group, compared with 10% in the placebo group. Noordzij and colleagues,⁶⁴ in a similar study, demonstrated a significant reduction in hoarseness and throat clearing in patients treated with omeprazole 40 mg twice daily for 8 weeks. Thus, for patients with suspected GERD-induced otolaryngeal symptoms, a trial of PPI therapy twice daily for 8 to 12 weeks is reasonable.

Noncardiac chest pain (NCCP) is defined as angina-type chest pain (substernal pressure or heaviness) occurring without demonstrable cardiac disease. It is not uncommon, with a prevalence of 23% reported in one study based in the northern United States.⁶⁵ Although this syndrome is associated with several underlying conditions, including musculoskeletal pain and psychiatric illness, esophageal disorders are the most prevalent inciting factor. Of the esophageal causes of NCCP, GERD is the most common, accounting for 25 & to 60% of cases in several studies.^{66, 67} Other entities such as diffuse esophageal spasm, though often postulated as the cause of chest pain, are much less common. Given the absence of typical reflux symptoms in a subset of patients with NCCP, the diagnosis of GERD is usually established with ambulatory pH monitoring, which is abnormal in up to 60% of patients.^{68, 69} Several studies of PPI therapy in NCCP demonstrate improvement in symptoms with antisecretory therapy.^{70, 71} These observations have led to the use of empiric PPI therapy as a diagnostic test for reflux-induced NCCP. Proton pump inhibitor therapy is administered twice daily (before breakfast and dinner) for 8 to 12 weeks, and patients whose chest pain symptoms resolve are considered to have GERD as a cause of their NCCP. This PPI test has a sensitivity of approximately 80%, but patients who fail to respond to a therapeutic trial should undergo ambulatory pH monitoring to definitively rule out GERD as the etiology of chest pain.⁷⁰

• Esophageal motility > disordersSynopsis Clinical disorders of oral, pharyngeal and esophageal motilityReview Laryngeal and pharyngeal complications of gastroesophageal reflux diseaseGastroesophageal reflux and asthmaGastroesophageal reflux and chronic coughOverview Esophageal motility disordersReview Heartburn and esophageal painEndoscopic evaluation of esophageal motility disordersEsophageal manometryGastroesophageal reflux monitoring: pH and impedancePathophysiology of gastroesophageal reflux diseaseNonerosive reflux diseaseReflux esophagitis and peptic stricturesBarrett's esophagusBarrett's adenocarcinomaHiatus herniaEosinophilic esophagitisEndoscopic therapy for gastroesophageal reflux diseaseSurgical therapy for gastroesophageal reflux diseasePathophysiology of achalasia and diffuse esophageal spasmMedical and endoscopic management of achalasiaSurgical treatment for achalasiaOral, pharyngeal and esophageal motility disorders in systemic diseasesOral, pharyngeal, and esophageal motor disorders in infants and childrenOral, pharyngeal and esophageal motor function in agingPharyngeal and esophageal diverticula, rings, and webs
• Gastroesophageal reflux disease > endoscopic therapyOverview Esophageal motility disordersReview Endoscopic therapy for gastroesophageal reflux diseaseSurgical therapy for gastroesophageal reflux disease
• Gastroesophageal reflux disease > surgical therapyOverview Esophageal motility disordersReview Endoscopic therapy for gastroesophageal reflux diseaseSurgical therapy for gastroesophageal reflux disease
• Gastroesophageal reflux disease > medical managementOverview Esophageal motility disordersReview Endoscopic therapy for gastroesophageal reflux diseaseSurgical therapy for gastroesophageal reflux disease