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Current Diagnosis and Treatment of Gastroesophageal Reflux Disease
Subject Review Current Diagnosis and Treatment of Gastroesophageal Reflux Disease KENNETH R. D EVAULT, M.D.,
AND DONALD O. CASTELL,
M.D.
• Objective: To review recent advances in the diagnosis and treatment of gastroesophageal reflux disease (GERD). • Material and Methods: Original English language reports were obtained through a Medline search of the National Library of Medicine up to and including 1993. The reference lists of all original reports and review articles were searched to locate any further material. In the evaluation of therapeutic efficacy, randomized studies were preferentially considered; greatest priority was given to double-blind, placebocontrolled trials. Abstracts, nonrandomized trials, and non-English language publications were considered only when other data were unavailable. • Results: Information obtained from histories and physical examinations suggests that GERD occurs in many patients. Evaluation of mucosal injury with use of either endoscopy or air contrast barium radiography is an important early step in the diagnosis of GERD. Endoscopy obtains tissue for histologie study, especially in Barrett's esophagus. Prolonged esoph-
ageal pH monitoring is the most useful determinant of the presence and amount of reflux of acid. Patients with GERD should be counseled on lifestyle modification and the use of antacids and antirefluxants. Histaminetype 2 receptor antagonists provide symptomatic relief in 32 to 82% of patients with GERD and resolution of verified esophagitis in 0 to 82%. Responses with omeprazole therapy are higher; symptomatic responses were noted in 62 to 94% of patients, and healing of esophagitis occurred in 71 to 96%. Promotility agents and surgical therapy have a role in selected patients. • Conclusion: GERD is a chronic disorder that often necessitates individualized lifelong therapy. Many questions remain to be answered about the costeffectiveness of both diagnostic tests and therapy for GERD. (Mayo Clin Proc 1994; 69:867-876)
In this report, we review the current knowledge about the diagnosis and treatment of gastroesophageal reflux disease (GERD). The term "GERD" is used to include all the symptoms and the mucosal lesions that result from abnormal reflux of gastric contents. Awareness of the prevalence of GERD has increased during the past 18 years since the initial epidemiologie study suggested that approximately 10% of the US population have heartburn daily and that more than a third have intermittent symptoms.1 In addition, long-term consumption of antacids by most people is for symptoms of GERD.2 Most studies have included patients with only typical symptoms of GERD—heartburn and régurgitation. The recognition that clinical manifestations of GERD include various symptoms
(other than heartburn) indicates a prevalence considerably higher than that previously estimated. In up to 50% of patients with noncardiac chest pain,3 78% of patients with chronic hoarseness,4 and 82% of patients with asthma,5 an association with GERD may be noted. In addition to the considerable morbidity related to those conditions, columnar-lined (Barrett's) esophagus in conjunction with its potential for malignant transformation is recognized as a complication of GERD.6·7 The effectiveness of specific antireflux therapy for many of these GERD-related conditions has yet to be established in well-designed placebo-controlled trials. The knowledge that GERD is highly prevalent in our society and that it manifests with many conditions emphatically reinforces the importance of developing a rational approach for appropriate diagnosis and treatment. (Barrett's esophagus and the unusual diagnostic and therapeutic aspects associated with this syndrome will not be thoroughly discussed in this report; however, excellent recent reviews are available.6·7)
From the Division of Gastroenterology and Internal Medicine (K.R.D.), Mayo Clinic Jacksonville, Jacksonville, Florida; and Department of Medicine (D.O.C.), The Graduate Hospital, Philadelphia, Pennsylvania. Address reprint requests to Dr. K. R. De Vault, Division of Gastroenterology, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224. Mayo Clin Proc 1994;69:867-876
b.i.d. = twice a day; GERD = gastroesophageal reflux disease; H,RAs = histaminc type 2 receptor antagonists; LES = lower esophageal sphincter; q.i.d. = four times a day
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MATERIAL AND METHODS Using the National Library of Medicine as a database, we reviewed the English literature and evaluated all appropriate studies. In the evaluation of therapeutic efficacy, randomized studies were preferentially considered, and the greatest priority was given to double-blind, placebo-controlled trials. Information from abstracts and nonrandomized trials was considered only when other data were unavailable. DIAGNOSIS Elicitation of History and Physical Examination.—Establishing that a patient's symptoms are attributable to gastroesophageal reflux can be done in several ways but is best accomplished by initially clarifying the potential contributing factors (Table 1). Often, a thoroughly elicited history will reveal symptoms consistent with both complicated and uncomplicated GERD. Heartburn, a retrostemal burning sensation, and régurgitation that occur within 3 hours after a meal (particularly a large or fatty meal) and are aggravated by recumbency or bending and relieved by taking antacids are the typical symptoms of GERD. Usually, no further diagnostic testing is necessary before initiation of empiric therapy. Because of the large number of patients who have symptoms of GERD, a complete assessment of each may be unnecessary; however, the cost of long-term therapy with no firm diagnosis must also be considered. The advantages of empiric therapy (cost and convenience for both patient and physician) must be weighed against the possible risk of misdiagnosis or inadequate treatment (or both) of severe conditions. To date, no cost-benefit analysis has been reported for patients who receive empiric therapy. In a 3-year follow-up of 100 patients diagnosed with grade 1 or mild esophagitis, only 5% experienced progression to a severe type of esophagitis, 50% had no changes, and 45% experienced spontaneous healing.8 These findings suggest that mild GERD is a relatively benign process. As subsequently discussed, empiric therapy should be limited to those patients in whom it produces symptomatic relief. For a poorly responsive patient in whom the diagnosis is unclear, longterm therapy is probably not cost-effective nor necessarily safe; however, adequate study of this type of patient has not been reported. Evaluation of Mucosal Injury.—After mucosal injury (that is, esophagitis) has been determined, diagnostic options include an air contrast barium esophagogram and upper gastrointestinal endoscopy.9 Single contrast barium studies have low accuracy in the diagnosis of GERD. Some cases of esophagitis and small neoplasms can be demonstrated on double contrast barium studies; however, in up to a third of patients, the esophagogastric junction is not well distended, and abnormalities may be overlooked.10 Both moderate and
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Table 1.—Techniques for Establishing the Diagnosis of GERD* Potential contributing factors Mucosal injury due to GERD Abnormal reflux-induced symptoms Abnormal esophageal pressures
Technique Air contrast barium esophagogram Endoscopy Biopsy Trial of acid-suppressive therapy Bernstein test Ambulatory pH monitoring Esophageal motility study
*GERD = gastroesophageal reflux disease. severe esophagitis are usually accurately detected, particularly when erosions or ulcérations are present; sensitivity for mild esophagitis is less accurate." 14 Whether a reticular mucosal pattern is a specific finding in a columnar-lined esophagus has been debated.15·16 Reflux of barium has questionable clinical significance and, even with use of provocative tests such as the water siphon test, is positive for GERD in only 33% of symptomatic patients.17 Similarly, demonstration of a sliding hiatal hernia has limited diagnostic accuracy for GERD.14 Endoscopy provides direct visualization of the esophageal mucosa and thus high sensitivity and specificity for the detection of mucosal injury.18 Because of specific histologie changes attributable to GERD, an endoscopie biopsy is the most sensitive test for esophagitis.18·19 Nonetheless, many patients with typical symptoms of GERD and abnormal esophageal acid exposure on pH monitoring have no endoscopie or histologie esophagitis.20 Accurate grading of the degree of esophagitis is important both for prognosis and for selection of appropriate therapy. Although response to treatment of esophagitis varies widely, the more severe, high-grade types of the disease respond poorly to standard doses of histamine blockers, as subsequently discussed. Endoscopie verification of high-grade esophagitis should provide support for aggressive initial therapy. Although much debate has surrounded the relative costeffectiveness of a barium esophagogram in comparison with endoscopy for the diagnosis of GERD, the higher sensitivity and specificity of endoscopy (including the opportunity for biopsy) outweigh the price differential. In the case of possible "reflux laryngitis," laryngoscopy is appropriate for evaluating laryngeal mucosal changes.21 Evaluation of Acid Exposure.—Because normal findings on endoscopy or biopsy do not exclude symptomatic GERD, a diagnostic test to verify abnormal reflux often becomes an important component of the evaluation. The
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suggestion that a therapeutic trial with an acid-suppressive drug might provide information is reasonable but may be incorrect. Of importance, this approach does not rule out a placebo effect when results are positive or the use of an inadequate dose when results are negative. Randomized trials showed a symptomatic response in 28% of patients who received placebo and healing of esophagitis in 24% (Tables 2 and 3). The Bernstein test of mucosal sensitivity to acid is fairly reliable for confirming that symptoms are acid related; in patients with severe grades of esophagitis, 80% true positive results are provided.56 A potential problem with the Bernstein test is the lack of positivity in patients with Barrett's esophagus in comparison with those who have esophagitis but not Barrett's esophagus.57 Prolonged ambulatory pH monitoring remains the "gold standard" for detecting excessive reflux or a positive symptom association (or both).58 The reproducibility of ambulatory pH testing is between 84 and 93%.59 Up to 96% sensitivity and specificity were noted with use of prolonged pH monitoring for distinguishing between 45 control subjects and 45 patients with "typical reflux symptoms."60 Nonetheless, because of the finding of normal acid exposure in 23 to 29% of patients with confirmed esophagitis61·62 and the differences in amounts of gastroesophageal reflux recorded with simultaneous monitoring of esophageal pH with two probes,63 the accuracy of this type of testing is questionable. Absolute sensitivity and specificity are difficult to attain because no standards exist for comparison with ambulatory monitoring. In many patients, short periods of pH monitoring may provide adequate information.64 Patients with typical symptoms of GERD and verified esophagitis benefit little from an initial pH study; however, for those patients with atypical symptoms of reflux without esophagitis, pH testing may clarify their syndrome,65 especially those with unexplained chest pain, pulmonary symptoms, or hoarseness.21 An additional use of pH monitoring is for assessing patients who are receiving acid-suppressive therapy but still have symptoms. With use of combined intraesophageal and intragastric pH recording, some such patients will have persistent gastric acidity and abnormal esophageal acid exposure despite aggressive suppression of acid.66 Technically, the degree of esophageal acid exposure can be determined with only esophageal monitoring, but we have found that simultaneous monitoring of gastric pH often proves helpful in formulating treatment plans. A recent report also suggested that severe supine reflux, as measured with intraesophageal pH testing, was a poor prognostic sign and a better descriminator than the grade of esophagitis.67 Finally, evaluating bile or alkaline reflux with ambulatory monitoring remains controversial and is being studied.68 Other Evaluations.—Esophageal motility studies may provide both diagnostic and prognostic information. The
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accurate placement of esophageal pH probes necessitates manometric localization of the lower esophageal sphincter (LES).69·70 Therefore, intubation with a manometric catheter is often necessary and provides an opportunity for a complete measurement. The finding of a high percentage of abnormal esophageal contractions or the presence of a hypotensive LES (or both) not only supports the diagnosis of a severe type of GERD but also implies potential difficulty in accomplishing effective long-term therapy.71·72 The role of peristaltic dysfunction in GERD is unclear; however, in a recent study, approximately 50% of patients with mild to severe esophagitis had some impairment of esophageal peristalsis.73 Transient LES relaxations may be a major mechanism of GERD but can rarely be noted on diagnostic manometric examination.74 For verification of the presence of effective esophageal peristalsis, esophageal manometry is necessary in any patient being considered for an antireflux operation, in whom the goal is to decrease the risk of dysphagia after fundoplication.75 THERAPY Various effective therapies are available for managing GERD.76 Options include lifestyle modifications and systemic medications. Nonpharmacologic and Antacid-Antirefluxant Treatment.—All patients with GERD should receive counseling about adjunctive lifestyle modifications (Table 4).77 No controlled studies have specifically evaluated the effectiveness of postural or dietary maneuvers in the treatment of GERD; however, numerous physiologic studies have indicated that elevation of the head of the bed,78·79 decreased intake of fat,80·81 decrease in smoking,82 and no recumbency for 3 hours postprandially83 will decrease distal esophageal acid exposure. Educating the patient about the nature of GERD and the factors that may precipitate reflux should be considered the cornerstone of appropriate therapy. The use of antacids and antirefluxants such as alginic acid is usually considered part of phase I therapy.84 Antacids work by increasing the pH of the gastric contents, and they have the added advantage of deactivating pepsin. Moreover, antacids may increase LES pressure85 and thereby decrease the amount of material refluxed from the stomach.86 Compounds that contain alginic acid have the additional effect of preventing reflux, particularly when the patient is upright.87 Important aspects of treatment are to educate patients that these over-the-counter medications are appropriate for GERD and to provide an understanding of their mechanism of action and proper use. Although few controlled studies have been done with antacids or alginic acid, their use is supported. Antacids88·89 and alginic acid90 have been shown to be more effective than placebo in providing relief of symptoms, including those induced by a meal
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Table 2.—Randomized Trials of Acid-Suppressive Therapy for GERD* Reference Beharetal, 22 1978 Powell-Jackson et al,23 1978 Wesdorpetal^WS Brown,25 1979 Bright-Asare & El-Bassoussi,26 1980 Fiasse et al,27 1980 Goy et al,28 1983 Wesdorpetal, 29 1983 Fielding & Doyle,30 1984 Hine et al,31 1984 Sherbaniuk et al,32 1984 Johansson et al,33 1986 Kaul et al,34 1986 Koelz et al,351986 Lehtola et al,36 1986 Klinkenberg-Knol et al,37 1987 Sontag et al,381987 Havelund et al,39 1988 Hetzel et al,40 1988 Sandmark et al,4' 1988 Vantrappen et al,421988 Johnson et al,43 1989 Zeitoun et al,44 1989 Bardhan et al,45 1990 Bate et al,46 1990 Farupetal, 47 1990 Lundell et al,481990 Maleev et al,491990
Drugt or control
No. of patients
Cim, 300 q.i.d. Placebo Cim, 400 q.i.d. Placebo Cim, 400 q.i.d. Placebo Cim, 1,000 q.d. Placebo Cim, 300 q.i.d. Placebo Cim, 400 q.i.d. Placebo Ran, 150b.i.d. Placebo Ran, 150b.i.d. Placebo Cim, 400 b.i.d. Ran, 150 b.i.d. Ran, 150 b.i.d. Placebo Ran, 150 b.i.d. Placebo Ran, 150 b.i.d. Placebo Cim, 400 q.i.d. Cim, 400 b.i.d. Ran, 150 b.i.d. Ran, 300 b.i.d. Ran, 150 b.i.d. Placebo Orne, 60 q.d. Ran, 150 b.i.d. Ran, 150 b.i.d. Placebo Orne, 40 q.d. Ran, 150 b.i.d. Orne, 20 q.d. Orne, 40 q.d. Placebo Orne, 20 q.d. Ran, 150 b.i.d. Orne, 40 q.d. Ran, 150 b.i.d. Ran, 150 b.i.d. Ran, 300 q.i.d. Orne, 20 q.d. Ran, 150 b.i.d. Orne, 20 b.i.d. Orne, 20 q.d. Cim, 400 q.i.d. Cim, 400 b.i.d. Antacid, q.i.d. Placebo Orne, 40 q.d. Ran, 300 b.i.d. Cim, 400 b.i.d. Cim, 400 q.i.d.
28 37 15 15 12 12 11 11 20 9 10 11 12 17 19 17 10 9 14 17 36 33 13 13 17 13 52 56 18 18 25 26 119 118 80 82 82 82 82 73 77 26 25 59 63 62 69 45 138 134 29 27 29 51 47 33 32
Duration (wk) 8 6 8 8 8 6 6 6 8 6 6 8 12 12 12 8 6 12 8 8 8 8 8 8 8 8 12 8-12
Healing of esophagitis (%) 45 35 0 0 44φ 0 82 56 0 0 20 27 25 27 37t 12 70 44 33φ 13 17 9 0 0 50 50 70 70 56φ 6 88φ 38 56φ 41 95φ 70 83φ 88φ 9 85φ 50 96φ 52 54 75φ 95φ 66 91 71 35 38 30 21 90φ 47 53 58
Sympton response 70φ 24 42φ 17 90 18 70 56 82 69 50 37 70 78 42φ 9 46φ 19 75 75 47 47 92φ 65 32φ 12 81Φ 81Φ 14 73φ 46 62φ 12 64 84φ 82φ 48 94 66φ 41
90φ 32 57 69
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Table 2.—Continued Reference
Drugt or control
Maxtonetal, 50 1990
Cim, 400 b.i.d. Pyrogastrone, 5 tablets/day Niz, 300 b.i.d. Niz, 300 q.h.s. Placebo Ran, 300 q.i.d. Ran, 150 q.i.d. Placebo Fam, 40 h.s. Fam, 20 b.i.d. Placebo Ome, 20 q.d. Ome, 40 q.d. Placebo Niz, 300 b.i.d. Niz, 150 b.i.d. Placebo
Quiketal, 51 1990 Euleretal, 52 1991 Sabesin et al,53 1991 Sontag et al,54 1992 Cloud et al,55 1992
No. of patients
Duration (wk)
Healing of esophagitis (%)
47
12
66
33 109 109 107 105 100 92 135 137 66 83 87 46 143 139 133
12 8 6 8 6
64 50$ 44 34 70$ 68$ 33 29 34 7 74$ 75$ 14 39$ 41* 26
Symptomatic response (%)
64$ 73$ 39 80$ 82$ 35
*b.i.d. = twice a day; Cim = cimetidine hydrochloride; Fam = famotidine; GERD = gastroesophageal reflux disease; h.s. = at bedtime; Niz = nizatidine; Ome = omeprazole; q.d. = daily; q.h.s. = daily at bedtime; q.i.d. = four times a day; Ran = ranitidine hydrochloride. tDosages are in milligrams. $P<0.01 or greater statistical significance. that causes heartburn.91 In addition, a combination of antacid and alginic acid therapy may be superior to only antacids.8792 Although no studies have specifically evaluated the effectiveness of the combination of antacids and lifestyle modifications, two long-term trials suggest relief of symptoms in approximately 20% of patients.72·93 Acid-Suppressive Treatment.—The four histamine type 2 receptor antagonists (H2RAs) marketed in the United States—cimetidine hydrochloride, ranitidine hydrochloride, famotidine, and nizatidine—have become the mainstay treatment of acid peptic disorders including GERD. Despite such widespread acceptance, controlled studies that have addressed the effectiveness of these agents have yielded variable results. Although these studies are not directly comparable, summaries of symptomatic response and healing of esophagitis are listed in Tables 2 and 3. Duration of treatment and definition of symptomatic response and healing vary, but in general, standard doses of H2RAs provided symptomatic relief in 32 to 82% of patients (mean, 61%). Resolution of endoscopically confirmed esophagitis was demonstrated in 0 to 82% of patients (mean, 48%). Much of the variability in these reports is related to both the range of dosage schedules and the degrees of esophagitis treated; the high healing rates are in subjects with low-grade esophagitis. In some patients in whom a course of routine treatment with H2RAs fails, gastric acid hypersecretors have been noted, a finding that supports the use of high doses of H2RAs.94 High doses of these agents seem to be effective both in the treat-
ment of GERD symptoms and in the healing of esophagitis.43 Because the duration of effective suppression of acid with an orally administered H2RA is less than 6 hours, recent trials have shown more effective control of symptoms and healing with doses given four times daily.43·52 Several recent publications have suggested that omeprazole is the most effective medical therapy for controlling symptoms of GERD and healing esophagitis.37,39"42 Dosages as low as 20 mg daily have been shown to be more effective than either placebo or standard doses of H2RA therapy (Tables 2 and 3). The greater the severity of esophagitis, however, the lower the healing rate; thus, high doses of omeprazole are used in trials outside the United States. Recent evidence has shown that some patients will continue to have secretion of gastric acid and reflux of Table 3.—Summary of Studies* That Evaluated Acid-Suppressive Therapy for GERDt
Agent Placebo H2RA Omeprazole
Symptomatic response No. % 178 of 628 1,318 of 2,159 695 of 834
28 61 83
Healing of esophagitis No. % 174 of 726 844 of 1,760 591 of 754
24 48 78
*See Table 2. tGERD = gastroesophageal reflux disease; H2RA =histamine type 2 receptor antagonist.
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Table 4—Lifestyle Therapy for Patients With GERD* Dietary modification (decrease intake of fat, chocolate, and peppermint) Weight loss Restriction of smoking and intake of alcohol Elevation of head of bed Avoidance of recumbency for 3 hours postprandially Avoidance of potentially adverse medications that may decrease LES pressure (theophylline, anticholinergics, calcium antagonists, and nitrates) Antacid or alginic acid *GERD = gastroesophageal reflux disease; LES = lower esophageal pressure. esophageal acid with dosages of omeprazole as high as 40 mg twice a day (b.i.d.).66'95 During a 4- to 8-week period with omeprazole therapy, symptomatic responses were noted in a mean of 83% of patients (range, 62 to 94%), and healing of esophagitis occurred in 78% (range, 71 to 96). Currently, use of omeprazole presents two major concerns. The first concern relates to its ability to decrease substantially the secretion of gastric acid.96 This decrease is accompanied by the anticipated increase in production of gastrin from the antral-G cells and the sustained increase in serum gastrin, usually to a mild degree (2 to 4 times the basal rate).9798 Whether these changes in serum gastrin cause dangerous trophic effects on human gastric mucosa with long-term use of omeprazole remains to be resolved. To date, no gastric cancer or carcinoid-type tumor has been reported in a patient receiving omeprazole. The second concern of omeprazole therapy relates to the frequently profound diminishment in symptoms of GERD noted with the pronounced suppression of acid. This impressive effect on symptoms, and even healing, is almost always followed by a rapid return of manifestations of GERD after use of omeprazole is discontinued,40 a situation that may be a particular problem in consideration of long-term maintenance therapy (as subsequently discussed). Promotility Drugs.—The primary pathogenesis of GERD is related to defects in esophagogastric motility—LES incompetence, poor esophageal clearance, and delayed gastric emptying.99 Ideal pharmacologie therapy would correct these defects; thus, suppression of normal amounts of gastric acid would be unnecessary. Investigators have shown that metoclopramide hydrochloride (10 mg four times a day [q.i.d.])26 or bethanechol (25 mg q.i.d.)100 produces greater relief of symptoms than does placebo. Nonetheless, an open-label cross-over study that evaluated esophageal acid contact time (pH monitor) and heartburn in 12 patients failed to show any objective or subjective improvement with metoclopramide therapy in comparison with placebo.101 Metoclopramide is usually not
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administered on a regular basis because of its side effects on the central nervous system (drowsiness, irritability, and extrapyramidal influences). Studies have shown that cisapride102·103 and domperidone104 provide symptomatic relief of GERD. The effective symptomatic relief and healing of esophagitis provided by cisapride (10 mg q.i.d.) are comparable to that obtained with cimetidine (400 mg q.i.d.)105 or ranitidine (150 mg b.i.d.).102 Cisapride (10 mg b.i.d.) also offers promise as effective maintenance therapy for GERD.106 Combined therapy with cimetidine and either metoclopramide (10 mg q.i.d.)107 or cisapride (10 mg q.i.d.)103 has been shown to result in improved healing of esophagitis in comparison with only cimetidine. Furthermore, a recent report on cisapride (10 mg q.i.d.) described healing of grade 2 or 3 esophagitis in 8 of 11 patients.108 Therefore, cisapride is comparable to standard doses of H2RA therapy. Surgical Treatment.—Effective antireflux surgical treatment is available. Considerable controversy exists about the long-term effectiveness of fundoplication and whether it is superior to prolonged medical therapy. In two controlled trials of medical versus surgical therapy (fundoplication) for GERD, the latter was considerably more effective. The initial study favored surgical intervention over medical therapy (essentially phase I) for a 36-month period.93 Recently, a comparison of surgical treatment versus H2RA and metoclopramide therapy showed superiority of the surgical approach.109 No similar comparisons are available for omeprazole because of its recent availability and concerns about long-term use. For GERD, fundoplication is a definite option in comparison with long-term therapy; however, longer term assessment of patients after fundoplication (mean, 69 months) has shown disappointing recurrences in heartburn, esophagitis, and decreased LES pressure.110 Perhaps fundoplication should be considered for patients with a mechanically defective cardia, as defined by low LES pressure (less than 6 mm Hg), short overall LES length (less than 2 cm), or short intra-abdominal LES segment (less than 1 cm).1" Maintenance Treatment of GERD.—Because of the growing awareness that a high percentage of patients with GERD require long-term, possibly lifetime, therapy, maintenance treatment is clearly the key issue for such patients. We define effective maintenance as that type of treatment that controls the patient's symptoms satisfactorily and prevents complications, a situation that varies with the nature of the disease in each patient and may require only phase I therapies in 20% of patients,72-93 Patients who have frequent symptomatic relapses despite appropriate therapy with H2RAs or promotility drugs (or both) are a concern. Such patients comprise up to 50% of those being assessed for chronic reflux symptoms.72 A recent abstract suggested that
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Table 5—Treatment Schemes for GERD*
GERD. The preferred approach awaits future well-designed trials. Empiric treatment Treatment of Resistant GERD.—In addition to the meaLifestyle therapy including antacids or alginic acid 6-8 weeks of standard doses of H,RA sures previously discussed, other special considerations are Promotility agent, especially cisapride, may be considered necessary for patients who have persistent symptoms of Initial treatment ofpersistent symptoms, after diagnosis has been GERD or esophagitis (or both). Prolonged ambulatory pH confirmed monitoring (if not already performed) is appropriate at this Continue lifestyle therapy stage to verify the severity and pattern of the reflux and to Increase (double) dose of H2RA clarify the specific symptom association."5 Another approAdd promotility agent priate use of this test is to confirm adequate suppression of Consider omeprazole if evidence of complicated disease acid during treatment.66 The use of dual electrode pH moniTreatment of resistant cases toring (distal esophagus and stomach) may provide a clear Continue lifestyle therapy Double dose of H2RA or higher (consider q.i.d.) appraisal of acid dynamics in such patients and may also Administer omeprazole (up to 80 mg/day) help to detect the presence of duodenogastric reflux, frePerform fundoplication quently inappropriately termed "alkaline" reflux. For paMaintenance therapy tients with resistant GERD, therapeutic considerations inLong-term lifestyle therapy clude increasing the dose and frequency of H2RAs or Standard dose of H,RA or higher combining H,RA with a promotility agent, omeprazole, or Omeprazole (at lowest effective dose) if benefit outweighs risk antireflux surgical intervention. Evidence shows that each Fundoplication of these approaches provides more effective healing of *GERD = gastroesophageal reflux disease; H2RA = histamine type esophagitis than standard doses of H2RAs. A sequential 2 receptor antagonist; q.i.d. = four times a day. treatment approach to GERD is shown in Table 5. The respective costs of the therapies for GERD at a representa10 mg of omeprazole a day maintains remission in 35% of tive pharmacy are presented in Table 6. These cost factors patients and that 20 mg a day increases the remission rate to must be considered in our current medical environment. 59%. '12 We believe that recent studies support the following conclusions about maintenance therapy for GERD. CONCLUSION 1. Many patients will experience symptomatic relapses Advancement in the diagnosis of GERD has been substanand failure of healing of esophagitis with use of standard or tial. Modern endoscopie techniques in conjunction with the even high doses of H,RAs or promotility drugs (or both)."3 appropriate use of ambulatory pH testing should confirm the 2. The concept of maintenance with less than a total dose diagnosis of GERD in most, if not all, patients. Treatment of of H2RA administered once daily is inappropriate.3 this disorder is less clear. Omeprazole therapy fails to con3. Low doses of omeprazole have yet to be shown to be trol symptoms and heal esophagitis in some patients; all effective long-term treatment; however, further investiga- other medical treatments have been shown to be less effections are needed."4 tive than omeprazole. Further developments in promotility Many questions still need to be resolved about effective agents are awaited, as is the development of rational dosing maintenance therapy for GERD. Basically, the choices are schedules of proton pump inhibitors or alternating use of those subsequently discussed for patients with resistant proton pump inhibitors with H,RAs (or both). In addition, the potential role of combining acid-suppressive therapy and promotility agents needs to be clarified. Accurate confirmaTable 6.—Representative Costs of Therapy for GERD* tion of which patients are appropriate candidates for surgical Dosage treatment is needed. The type of thorough investigations that interval Drug Costt (S) have brought us thus far should lead to future resolution of the previously mentioned issues. b.i.d. 70-100 H,RA (standard dose) H,RA (standard dose) H,RA (double dose) Omeprazole (20 mg) Omeprazole ( 10 mg) Cisapride (10 mg)
q.i.d. b.i.d. q.d. b.i.d. q.i.d.
140-200 150-200 110-130 220-260 80-90
*b.i.d. = twice a day; GERD = gastroesophageal reflux disease; H,RA = histamine type 2 receptor antagonist; q.d. = daily; q.i.d. = four times a day. t30-day supply.
REFERENCES 1.
2. 3.
Nebel OT, Fornes MF, Castell DO. Symptomatic gastroesophageal reflux: incidence and precipitating factors. Am J Dig Dis 1976; 21:953-956 Graham DY, Smith JL, Patterson DJ. Why do apparently healthy people use antacid tablets? Am J Gastroenterol 1983;78:257-260 Hewson EG, Sinclair JW, Dalton CB, Richter JE. Twenty-fourhour esophageal pH monitoring: the most useful test for evaluating noncardiac chest pain. Am J Med 1991;90:576-583
874
4.
5.
6. 7. 8. 9. 10.
11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22.
23. 24. 25. 26.
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Wiener GJ, Koufman JA, Wu WC, Cooper JB, Richter JE, Castell DO. Chronic hoarseness secondary to gastroesophageal reflux disease: documentation with 24-h ambulatory pH monitoring. Am J Gastroenterol 1989; 84:1503-1508 Sontag SJ, O'Connell S, Khandelwal S, Miller T, Nemchausky B, Schnell TG, et al. Most asthmatics have gastroesophageal reflux with or without bronchodilator therapy. Gastroenterology 1990; 99:613-620 Katz PO, Castell DO. Barrett's esophagus: today's dilemma. Dis Esophagus 1990;3:55-60 SpechlerSJ. Complications of gastroesophageal reflux disease. In: Castell DO, editor. The Esophagus. Boston: Little, Brown, 1992: 543-556 Roesch W. Erosions of the upper gastrointestinal tract. Clin Gastroenterol 1978 Sep; 7:623-634 Monnier P, Savary M. Contribution of endoscopy to gastrooesophageal reflux disease. Scand J Gastroenterol Suppl 1984; 106:26-44 Chen YM, Ott DJ, Gelfand DW, Munitz HA. Multiphasic examination of the esophagogastric region for strictures, rings, and hiatal hernia: evaluation of the individual techniques. Gastrointest Radiol 1985; 10:311-316 Ott DJ. Barium esophagram. In: Castell DO, Wu WC, Ott DJ, editors. Gastro-esophageal Reflux Disease: Pathogenesis, Diagnosis, Therapy. Mount Kisco (NY): Futura, 1985: 109-128 Ott DJ, Chen YM, Gelfand DW, Munitz HA, Wu WC. Analysis of a multiphasic radiographie examination for detecting reflux esophagitis. Gastrointest Radiol 1986;11:1-6 Ott DJ, Gelfand DW, Lane TG, Wu WC. Radiologie detection and spectrum of appearances of peptic esophageal strictures. J Clin Gastroenterol 1982;4:11-15 Ott DJ, Wu WC, Gelfand DW. Reflux esophagitis revisited: prospective analysis of radiological accuracy. Gastrointest Radiol 1981;6:1-7 Chen YM, Gelfand DW, Ott DJ, Wu WC. Barrett esophagus as an extension of severe esophagitis: analysis of radiologie signs in 29 cases. AJR Am J Roentgenol 1985;145:275-281 Levine MS, Kressel HY, Caroline DF, Laufer I, Herlinger H, Thompson JJ. Barrett esophagus: reticular pattern of the mucosa. Radiology 1983; 147:663-667 Ott DJ, Cowan RJ, Gelfand DW, Wu WC, Chen YM, Munitz HA. The role of diagnostic imaging in evaluating gastroesophageal reflux disease. Postgrad Radiol 1986;6:3-10 Richter JE, Castell DO. Gastroesophageal reflux: pathogenesis, diagnosis, and therapy. Ann Intern Med 1982;97:93-103 Ismail-Beigi F, Horton PF, Pope CE II. Histological consequences of gastroesophageal reflux in man. Gastroenterology 1970; 58:163-174 Pace F, Santalucia F, Bianchi Porro G. Natural history of gastrooesophageal reflux disease without oesophagitis. Gut 1991; 32:845-848 Jacob P, Kahrilas PJ, Herzon G. Proximal esophageal pH-metry in patients with'reflux laryngitis.' Gastroenterology 1991; 100:SOSSIO Behar J, Brand DL, Brown FC, Castell DO, Cohen S, Crossley RJ, et al. Cimetidine in the treatment of symptomatic gastroesophageal reflux: a double blind controlled trial. Gastroenterology 1978; 74:441-448 Powell-Jackson P, Barkley H, Northfield TC. Effect of cimetidine in symptomatic gastro-oesophageal reflux. Lancet 1978; 2:10681069 Wesdorp E, Bartelsman J, Pape K, Dekker W, Tytgat G. Oral cimetidine in reflux esophagitis: a double blind controlled trial. Gastroenterology 1978 ; 74:821 -824 Brown P. Cimetidine in the treatment of reflux oesophagitis. Med JAust 1979;2:96-97 Bright-Asare P, El-Bassoussi M. Cimetidine, metoclopramide, or placebo in the treatment of symptomatic gastroesophageal reflux. J Clin Gastroenterol 1980;2:149-156
27. 28. 29. 30. 31. 32. 33. 34.
35. 36.
37.
38. 39.
40.
41.
42.
43.
44.
45.
46.
Fiasse R, Hanin C, Lepot A, Descamps C, Lamy F, Dive C. Controlled trial of cimetidine in reflux esophagitis. Dig Dis Sci 1980; 25:750-755 Goy JA, Maynard JH, McNaughton WM, O'Shea A. Ranitidine and placebo in the treatment of reflux oesophagitis: a double-blind randomized trial. Med J Aust 1983;2:558-561 Wesdorp IC, Dekker W, Klinkenberg-Knol EC. Treatment of reflux oesophagitis with ranitidine. Gut 1983;24:921-924 Fielding JF, Doyle GD. Comparison between ranitidine and cimetidine in the treatment of reflux oesophagitis. Ir Med J 1984; 77:356-357 Hine KR, Holmes GK, Melikian V, Lucey M, Fairclough PD. Ranitidine in reflux oesophagitis: a double-blind placebo-controlled study. Digestion 1984;29:119-123 Sherbaniuk R, Wensel R, Bailey R, Trautman A, Grace M, Kirdeikis P, et al. Ranitidine in the treatment of symptomatic gastroesophageal reflux disease. J Clin Gastroenterol 1984;6:9-15 Johansson KE, Boeryd B, Johansson K, Tibbling L. Double-blind crossover study of ranitidine and placebo in gastro-oesophageal reflux disease. Scand J Gastroenterol 1986;21:769-778 Kaul B, Petersen H, Erichsen H, Myrvold HE, Grette K, Halvorsen T, et al. Gastroesophageal reflux disease: acute and maintenance treatments with cimetidine. Scand J Gastroenterol 1986; 21:139145 Koelz HR, Birchler R, Bretholz A, Bron B, Capitaine Y, Delmore G, et al. Healing and relapse of reflux esophagitis during treatment with ranitidine. Gastroenterology 1986; 91:1198-1205 Lehtola J, Niemela S, Martikainen J, Krekela I. Ranitidine, 150 mg three times a day, in the treatment of reflux oesophagitis: a placebo-controlled, double-blind study. Scand J Gastroenterol 1986; 21:175-180 Klinkenberg-Knol EC, Jansen JM, Festen HP, Meuwissen SG, Lamers CB. Double-blind multicentre comparison of omeprazole and ranitidine in the treatment of reflux oesophagitis. Lancet 1987; 1:349-351 Sontag S, Robinson M, McCallum RW, Barwick KW, Nardi R. Ranitidine therapy for gastroesophageal reflux disease: results of a large double-blind trial. Arch Intern Med 1987;147:1485-1491 Havelund T, Laursen LS, Skoubo-Kristensen E, Andersen BN, Pedersen SA, Jensen KB, et al. Omeprazole and ranitidine in treatment of reflux oesophagitis: double blind comparative trial. BMJ 1988;296:89-92 Hetzel DJ, Dent J, Reed WD, Narielvala FM, Mackinnon M, McCarthy JH, et al. Healing and relapse of severe peptic esophagitis after treatment with omeprazole. Gastroenterology 1988;95:903-912 Sandmark S, Carlsson R, Fausa O, Lundell L. Omeprazole or ranitidine in the treatment of reflux esophagitis: results of a doubleblind, randomized, Scandinavian multicenter study. Scand J Gastroenterol 1988; 23:625-632 Vantrappen G, Rutgeerts L, Schurmans P, Coenegrachts JL. Omeprazole (40 mg) is superior to ranitidine in the short-term treatment of ulcerative reflux esophagitis. Dig Dis Sci 1988; 33:523-529 Johnson NJ, Boyd EJ, Mills JG, Wood JR. Acute treatment of reflux oesophagitis: a multicenter trial to compare 150 mg ranitidine b.d. with 300 mg ranitidine q.d.s. Aliment Pharmacol Ther 1989;3:259-266 Zeitoun P, Rampai P, Barbier P, Isal JP, Eriksson S, Carlsson R. Omeprazole (20 mg daily) compared to ranitidine (150 mg twice daily) in the treatment of esophagitis caused by reflux: results of a double-blind randomized multicenter trial in France and Belgium. Gastroenterol Clin Biol 1989; 13:457-462 Bardhan KD, Morris P, Thompson M, Dhande DS, Hinchliffe RF, Jones RB, et al. Omeprazole in the treatment of erosive oesophagitis refractory to high dose cimetidine and ranitidine. Gut 1990;31:745-749 Bate CM, Keeling PW, O'Morain C, Wilkinson SP, Foster DN, Mountford RA, et al. Comparison of omeprazole and cimetidine in
Mayo Clin Proc, September 1994, Vol 69
47.
48.
49. 50. 51.
52. 53.
54.
55.
56. 57. 58. 59.
60. 61. 62.
63.
64. 65.
reflux oesophagitis: symptomatic, endoscopie, and histological evaluations. Gut 1990;31:968-972 Farup PG, Weberg R, Berstad A, Wetterhus S, Dahlberg O, Dybdal J, et al. Low-dose antacids versus 400 mg cimetidine twice daily for reflux oesophagitis: a comparative, placebo-controlled, multicentre study. Scand J Gastroenterol 1990;25:315-320 Lundell L, Backman L, Ekstrom P, Enander LH, Fausa O, Lind T, et al. Omeprazole or high-dose rannidine in the treatment of patients with reflux oesophagitis not responding to 'standard doses' of H2-receptor antagonists. Aliment Pharmacol Ther 1990; 4:145' 155 Maleev A, Mendizova A, Popov P, Vlahov V, Dimitrov B, Mihova A, et al. Cisapride and cimetidine in the treatment of erosive esophagitis. Hepatogastroenterology 1990;37:403-407 Maxton DG, Heald J, Whorwell PJ, Haboubi NY. Controlled trial of pyrogastrone and cimetidine in the treatment of reflux oesophagitis. Gut 1990;31:351-354 Quik RF, Cooper MJ, Gleeson M, Hentschel E, Schuetze K, Kingston RD, et al. A comparison of two doses of nizatidine versus placebo in the treatment of reflux oesophagitis. Aliment Pharmacol Ther 1990;4:201-211 Euler AR, Murdock RH, Wilson TH. Ranitidine is effective in healing erosive esophagitis [abstract]. Gastroenterology 1991; 100:A61 Sabesin SM, Berlin RG, Humphries TJ, Bradstreet DC, WaltonBowen KL, Zaidi S, et al. Famotidine relieves symptoms of gastroesophageal reflux disease and heals erosions and ulcérations: results of a multicenter, placebo-controlled, dose-ranging study. Arch Intern Med 1991 ; 151:2394-2400 Sontag SJ, Hirschowitz BI, Holt S, Robinson MG, Behar J, Berenson MM, et al. Two doses of omeprazole versus placebo in symptomatic erosive esophagitis: the US Multicenter Study. Gastroenterology 1992;102:109-118 Cloud ML, Offen WW, Nizatidine Gastroesophageal Reflux Disease Study Group. Nizatidine versus placebo in gastroesophageal reflux disease: a six-week, multicenter, randomized, double-blind comparison. Dig Dis Sci 1992; 37:865-874 Bernstein LM, Baker LA. A clinical test for esophagitis. Gastroenterology 1958;34:760-781 Johnson DA, Winters C, Spurling TJ, Chobanian SJ, Cattau EL Jr. Esophageal acid sensitivity in Barrett's esophagus. J Clin Gastroenterol 1987; 9:23-27 Mattox HE III, Richter JE. Prolonged ambulatory esophageal pH monitoring in the evaluation of gastroesophageal reflux disease. Am J Med 1990;89:345-356 Wiener GJ, Morgan TM, Copper JB, Wu WC, Castell DO, Sinclair JW, et al. Ambulatory 24-hour esophageal pH monitoring: reproducibility and variability of pH parameters. Dig Dis Sci 1988; 33:1127-1133 Fuchs KH, DeMeester TR, Albertucci M. Specificity and sensitivity of objective diagnosis of gastroesophageal reflux disease. Surgery 1987; 102:575-580 Schlesinger PK, Donahue PE, Schmid B, Layden TJ. Limitations of 24-hour intraesophageal pH monitoring in the hospital setting. Gastroenterology 1985; 89:797-804 Vitale GC, Cheadle WG, Sadek S, Michel ME, Cuschieri A. Computerized 24-hour ambulatory esophageal pH monitoring and esophagogastroduodenoscopy in the reflux patient: a comparative study. AnnSurg 1984;200:724-728 Murphy DW, Yuan Y, Castell DO. Does the intraesophageal pH probe accurately detect acid reflux? Simultaneous recording with two pH probes in humans. Dig Dis Sci 1989; 34:649656 Dobhan R, Castell DO. Prolonged intraesophageal pH monitoring with 16-hr overnight recording: comparison with "24-hr" analysis. Dig Dis Sci 1992;37:857-864 Klauser AG, Heinrich C, Schindlbeck NE, Muller-Lissner SA. Is long-term esophageal pH monitoring of clinical value? Am J Gastroenterol 1989; 84:362-366
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66.
67. 68. 69. 70. 71. 72. 73. 74. 75.
76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88.
875
Klinkenberg-Knol EC, Meuwissen SG. Combined gastric and oesophageal 24-hour pH monitoring and oesophageal manometry in patients with reflux disease, resistant to treatment with omeprazole. Aliment Pharmacol Ther 1990; 4:485-495 Schindlbeck NE, Klauser AG, Berghammer G, Londong W, Muller-Lissner SA. Three year follow up of patients with gastrooesophageal reflux disease. Gut 1992;33:1016-1019 Waring JP, LeGrand J, Chinichian A, Sanowski RA. Duodenogastric reflux in patients with Barrett's esophagus. Dig Dis Sci 1990;35:759-762 Klauser AG, Schindlbeck NE, Müller-Lissner SA. Esophageal 24h pH monitoring: is prior manometry necessary for correct positioning of the electrode? Am J Gastroenterol 1990;85:1463-1467 Mattox HE III, Richter JE, Sinclair JW, Price JE, Case LD. Gastroesophageal pH step-up inaccurately locates proximal border of lower esophageal sphincter. Dig Dis Sci 1992;37:1185-1191 Zaninotto G, DeMeester TR, Schwizer W, Johansson KE, Cheng SC. The lower esophageal sphincter in health and disease. Am J Surg 1988; 155:104-111 Lieberman DA. Medical therapy for chronic reflux esophagitis: long-term follow-up. Arch Intern Med 1987;147:1717-1720 Kahrilas PJ, Dodds WJ, Hogan WJ, Kern M, Amdorfer RC, Reece A. Esophageal peristaltic dysfunction in peptic esophagitis. Gastroenterology 1986;91:897-904 Dodds WJ, Dent J, Hogan WJ, Helm JF, Hauser R, Patel GK, et al. Mechanisms of gastroesophageal reflux in patients with reflux esophagitis. N Engl J Med 1982;307:1547-1552 DeMeester TR, Stein HJ. Pre- and postoperative use of ambulatory 24 hour pH monitoring and manometry. In: Richter JE, editor. Ambulatory Esophageal pH Monitoring: Practical Approach and Clinical Applications. New York: Igaku-Shoin, 1991: 179-195 Richter JE. A critical review of current medical therapy for gastroesophageal reflux disease. J Clin Gastroenterol 1986; 8(Suppl l):72-80 Castell DO. Medical therapy for reflux esophagitis: 1986 and beyond. Ann Intern Med 1986;104:112-114 Stanciu C, Bennett JR. Effects of posture on gastro-oesophageal reflux. Digestion 1977;15:104-109 Johnson LF, DeMeester TR. Evaluation of elevation of the head of the bed, bethanechol, and antacid form tablets on gastroesophageal reflux. Dig Dis Sci 1981;26:673-680 Nebel OT, Castell DO. Lower esophageal sphincter pressure changes after food ingestion. Gastroenterology 1972; 63:778783 Becker DJ, Sinclair J, Castell DO, Wu WC. A comparison of high and low fat meals on postprandial esophageal acid exposure. Am J Gastroenterol 1989; 782-786 Waring JP, Eastwood TF, Austin JM, Sanowski RA. The immediate effects of cessation of cigarette smoking on gastroesophageal reflux. Am J Gastroenterol 1989;84:1076-1078 DeMeester TR, Johnson LF, Joseph GJ, Toscano MS, Hall AW, Skinner DB. Patterns of gastroesophageal reflux in health and disease. AnnSurg 1976;184:459-469 Kitchin LI, Castell DO. Rationale and efficacy of conservative therapy for gastroesophageal reflux disease. Arch Intern Med 1991; 151:448-454 Higgs RH, Smyth RD, Castell DO. Gastric alkalinization: effect on lower-esophageal-sphincter pressure and serum gastrin. N Engl JMed 1974;291:486-490 Malmud LS, Fischer RS. Quantitation of gastroesophageal reflux before and after therapy using the gastroesophageal scintiscan. South Med J 1978; 71(Suppl 1):10-15 Castell DO, Dalton CB, Becker D, Sinclair J, Castell JA. Alginic acid decreases postprandial upright gastroesophageal reflux. Dig Dis Sci 1992;37:589-593 Saco LS, Orlando RC, Levinson SL, Bozymski EM, Jones JD, Frakes JT. Double-blind controlled trial of bethanechol and antacid versus placebo and antacid in the treatment of erosive esophagitis. Gastroenterology 1982; 82:1369-1373
876
89. 90.
91. 92. 93. 94. 95. 96. 97. 98.
99. 100. 101. 102. 103.
GASTROESOPHAGEAL REFLUX DISEASE
Graham DY, Patterson DJ. Double-blind comparison of liquid antacid and placebo in the treatment of symptomatic reflux esophagitis. Dig Dis Sci 1983;28:559-563 Buts JP, Barudi C, Otte JB. Double-blind controlled study on the efficacy of sodium alginate (Gaviscon) in reducing gastroesophageal reflux assessed by 24 h continuous pH monitoring in infants and children. EurJPediatr 1987;146:156-158 Lanza FL, Smith V, Page-Castell JA, Castell DO. Effectiveness of foaming antacid in relieving induced heartburn. South Med J 1986; 79:327-330 Stanciu C, Bennett JR. Alginate-antacid in the reduction of gastrooesophageal reflux esophagitis. Lancet 1974;1:109-111 Behar J, Sheahan DG, Biancani P, Spiro H, Storer EH. Medical and surgical management of reflux esophagitis: a 38-month report of a prospective clinical trial. NEnglJMed 1975;293:263-268 Collen MJ, Lewis JH, Benjamin SB. Gastric acid hypersécrétion in refractory gastroesophageal reflux disease. Gastroenterology 1990; 98:654-661 Savarino V, Mela GS, Zentilin P, Celle G. Is gastric acid hypersécrétion the only reason for refractory gastroesophageal reflux disease? [letter]. Gastroenterology 1990;99:1542-1543 Larsson H, Carlsson E, Junggren U, Olbe L, Sjostrand SE, Skanberg I, et al. Inhibition of gastric acid secretion by omeprazole in the dog and rat. Gastroenterology 1983;85:900-907 Festen HP, Thijs JC, Lamers CB, Jansen JM, Pals G, Frants RR, et al. Effect of oral omeprazole on serum gastrin and serum pepsinogen I levels. Gastroenterology 1984;87:1030-1034 Jansen JB, Klinkenberg-Knol EC, Meuwissen SG, De Bruijne JW, Festen HP, Snel P, et al. Effect of long-term treatment with omeprazole on serum gastrin and serum group A and C pepsinogens in patients with reflux esophagitis. Gastroenterology 1990; 99:621-628 Castell DO. Gastroesophageal reflux disease is a motility disorder. Front Gastrointest Res 1992; 20:11 -16 Farrell RL, Roling GT, Castell DO. Cholinergic therapy of chronic heartburn: a controlled trial. Ann Intern Med 1974;80:573-576 Orr WC, Finn A, Wilson T, Russell J. Esophageal acid contact time and heartburn in acute treatment with ranitidine and metoclopramide. Am J Gastroenterol 1990;85:697-700 Janisch HD, Huttemann W, Bouzo MH. Cisapride versus ranitidine in the treatment of reflux esophagitis. Hepatogastroenterology 1988; 35:125-127 Galmiche JP, Brandstatter G, Evreux M, Hentschel E, Kerstan E, Kratochvil P, et al. Combined therapy with cisapride and cimetidine in severe reflux oesophagitis: a double blind controlled trial. Gut 1988;29:675-681
Mayo Clin Proc, September 1994, Vol 69
104.
105. 106. 107. 108. 109.
110.
111. 112.
113.
114.
115.
Brogden RN, Carmine AA, Heel RC, Speight TM, Avery GS. Domperidone: a review of its pharmacological activity, pharmacokinetics and therapeutic efficacy in the symptomatic treatment of chronic dyspepsia and as an antiemetic. Drugs 1982; 24:360400 Galmiche JP, Fraitag B, Filoche B, Evreux M, Vitaux J, Zeitoun P, et al. Double-blind comparison of cisapride and cimetidine in treatment of reflux esophagitis. Dig Dis Sci 1990;35:649-655 Toussaint J, Gossuin A, Deruyttere M, Huble F, Devis G. Healing and prevention of relapse of reflux oesophagitis by cisapride. Gut 1991;32:1280-1285 Lieberman DA, Keefe EB. Treatment of severe reflux esophagitis with cimetidine and metoclopramide. Ann Intern Med 1986; 104:21-26 Lepoutre L, Van der Spek P, Vanderlinden I, Bollen J, Laukens P. Healing of grade-II and III oesophagitis through motility stimulation with cisapride. Digestion 1990;45:109-114 Spechler SJ, Department of Veterans Affairs Gastroesophageal Reflux Disease Study Group. Comparison of medical and surgical therapy for complicated gastroesophageal reflux disease in veterans. NEnglJMed 1992;326:786-792 Brand DL, Eastwood IR, Martin D, Carter WB, Pope CE II. Esophageal symptoms, manometry, and histology before and after antireflux surgery: a long-term follow-up study. Gastroenterology 1979;76:1393-1401 Bonavina L, Evander A, DeMeester TR, Walther B, Cheng SC, Palazzo L, et al. Length of the distal esophageal sphincter and competency of the cardia. AmJSurg 1986;151:25-34 Laursen LS, Bondesen S, Hansen J, Sanchez G, Sebelin E, Havelund T, et al. Omeprazole 10 mg or 20 mg daily for the prevention of relapse in gastroesophageal reflux disease? A double-blind comparative study [abstract]. Gastroenterology 1992; 102:A109 Antonson CW, Robinson MG, Hawkins TM, Mclntosh DL, Campbell DR. High doses of histamine antagonists do not prevent relapses of peptic esophagitis following therapy with a proton pump inhibitor [abstract]. Gastroenterology 1990; 98:A16 Bardhan KD, Daly MJ, Singh S, Morris P, Thompson M, Hinchliffe RFC. Refractory esophagitis: results of maintenance treatment with high-dose H2 receptor antagonists (H2RA) or omeprazole (OM) [abstract]. Gastroenterology 1990;98:A18 Wiener GJ, Richter JE, Copper JB, Wu WC, Castell DO. The symptom index: a clinically important parameter of ambulatory 24-hour esophageal pH monitoring. Am J Gastroenterol 1988; 83:358-361
AND DONALD O. CASTELL,
M.D.
• Objective: To review recent advances in the diagnosis and treatment of gastroesophageal reflux disease (GERD). • Material and Methods: Original English language reports were obtained through a Medline search of the National Library of Medicine up to and including 1993. The reference lists of all original reports and review articles were searched to locate any further material. In the evaluation of therapeutic efficacy, randomized studies were preferentially considered; greatest priority was given to double-blind, placebocontrolled trials. Abstracts, nonrandomized trials, and non-English language publications were considered only when other data were unavailable. • Results: Information obtained from histories and physical examinations suggests that GERD occurs in many patients. Evaluation of mucosal injury with use of either endoscopy or air contrast barium radiography is an important early step in the diagnosis of GERD. Endoscopy obtains tissue for histologie study, especially in Barrett's esophagus. Prolonged esoph-
ageal pH monitoring is the most useful determinant of the presence and amount of reflux of acid. Patients with GERD should be counseled on lifestyle modification and the use of antacids and antirefluxants. Histaminetype 2 receptor antagonists provide symptomatic relief in 32 to 82% of patients with GERD and resolution of verified esophagitis in 0 to 82%. Responses with omeprazole therapy are higher; symptomatic responses were noted in 62 to 94% of patients, and healing of esophagitis occurred in 71 to 96%. Promotility agents and surgical therapy have a role in selected patients. • Conclusion: GERD is a chronic disorder that often necessitates individualized lifelong therapy. Many questions remain to be answered about the costeffectiveness of both diagnostic tests and therapy for GERD. (Mayo Clin Proc 1994; 69:867-876)
In this report, we review the current knowledge about the diagnosis and treatment of gastroesophageal reflux disease (GERD). The term "GERD" is used to include all the symptoms and the mucosal lesions that result from abnormal reflux of gastric contents. Awareness of the prevalence of GERD has increased during the past 18 years since the initial epidemiologie study suggested that approximately 10% of the US population have heartburn daily and that more than a third have intermittent symptoms.1 In addition, long-term consumption of antacids by most people is for symptoms of GERD.2 Most studies have included patients with only typical symptoms of GERD—heartburn and régurgitation. The recognition that clinical manifestations of GERD include various symptoms
(other than heartburn) indicates a prevalence considerably higher than that previously estimated. In up to 50% of patients with noncardiac chest pain,3 78% of patients with chronic hoarseness,4 and 82% of patients with asthma,5 an association with GERD may be noted. In addition to the considerable morbidity related to those conditions, columnar-lined (Barrett's) esophagus in conjunction with its potential for malignant transformation is recognized as a complication of GERD.6·7 The effectiveness of specific antireflux therapy for many of these GERD-related conditions has yet to be established in well-designed placebo-controlled trials. The knowledge that GERD is highly prevalent in our society and that it manifests with many conditions emphatically reinforces the importance of developing a rational approach for appropriate diagnosis and treatment. (Barrett's esophagus and the unusual diagnostic and therapeutic aspects associated with this syndrome will not be thoroughly discussed in this report; however, excellent recent reviews are available.6·7)
From the Division of Gastroenterology and Internal Medicine (K.R.D.), Mayo Clinic Jacksonville, Jacksonville, Florida; and Department of Medicine (D.O.C.), The Graduate Hospital, Philadelphia, Pennsylvania. Address reprint requests to Dr. K. R. De Vault, Division of Gastroenterology, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224. Mayo Clin Proc 1994;69:867-876
b.i.d. = twice a day; GERD = gastroesophageal reflux disease; H,RAs = histaminc type 2 receptor antagonists; LES = lower esophageal sphincter; q.i.d. = four times a day
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MATERIAL AND METHODS Using the National Library of Medicine as a database, we reviewed the English literature and evaluated all appropriate studies. In the evaluation of therapeutic efficacy, randomized studies were preferentially considered, and the greatest priority was given to double-blind, placebo-controlled trials. Information from abstracts and nonrandomized trials was considered only when other data were unavailable. DIAGNOSIS Elicitation of History and Physical Examination.—Establishing that a patient's symptoms are attributable to gastroesophageal reflux can be done in several ways but is best accomplished by initially clarifying the potential contributing factors (Table 1). Often, a thoroughly elicited history will reveal symptoms consistent with both complicated and uncomplicated GERD. Heartburn, a retrostemal burning sensation, and régurgitation that occur within 3 hours after a meal (particularly a large or fatty meal) and are aggravated by recumbency or bending and relieved by taking antacids are the typical symptoms of GERD. Usually, no further diagnostic testing is necessary before initiation of empiric therapy. Because of the large number of patients who have symptoms of GERD, a complete assessment of each may be unnecessary; however, the cost of long-term therapy with no firm diagnosis must also be considered. The advantages of empiric therapy (cost and convenience for both patient and physician) must be weighed against the possible risk of misdiagnosis or inadequate treatment (or both) of severe conditions. To date, no cost-benefit analysis has been reported for patients who receive empiric therapy. In a 3-year follow-up of 100 patients diagnosed with grade 1 or mild esophagitis, only 5% experienced progression to a severe type of esophagitis, 50% had no changes, and 45% experienced spontaneous healing.8 These findings suggest that mild GERD is a relatively benign process. As subsequently discussed, empiric therapy should be limited to those patients in whom it produces symptomatic relief. For a poorly responsive patient in whom the diagnosis is unclear, longterm therapy is probably not cost-effective nor necessarily safe; however, adequate study of this type of patient has not been reported. Evaluation of Mucosal Injury.—After mucosal injury (that is, esophagitis) has been determined, diagnostic options include an air contrast barium esophagogram and upper gastrointestinal endoscopy.9 Single contrast barium studies have low accuracy in the diagnosis of GERD. Some cases of esophagitis and small neoplasms can be demonstrated on double contrast barium studies; however, in up to a third of patients, the esophagogastric junction is not well distended, and abnormalities may be overlooked.10 Both moderate and
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Table 1.—Techniques for Establishing the Diagnosis of GERD* Potential contributing factors Mucosal injury due to GERD Abnormal reflux-induced symptoms Abnormal esophageal pressures
Technique Air contrast barium esophagogram Endoscopy Biopsy Trial of acid-suppressive therapy Bernstein test Ambulatory pH monitoring Esophageal motility study
*GERD = gastroesophageal reflux disease. severe esophagitis are usually accurately detected, particularly when erosions or ulcérations are present; sensitivity for mild esophagitis is less accurate." 14 Whether a reticular mucosal pattern is a specific finding in a columnar-lined esophagus has been debated.15·16 Reflux of barium has questionable clinical significance and, even with use of provocative tests such as the water siphon test, is positive for GERD in only 33% of symptomatic patients.17 Similarly, demonstration of a sliding hiatal hernia has limited diagnostic accuracy for GERD.14 Endoscopy provides direct visualization of the esophageal mucosa and thus high sensitivity and specificity for the detection of mucosal injury.18 Because of specific histologie changes attributable to GERD, an endoscopie biopsy is the most sensitive test for esophagitis.18·19 Nonetheless, many patients with typical symptoms of GERD and abnormal esophageal acid exposure on pH monitoring have no endoscopie or histologie esophagitis.20 Accurate grading of the degree of esophagitis is important both for prognosis and for selection of appropriate therapy. Although response to treatment of esophagitis varies widely, the more severe, high-grade types of the disease respond poorly to standard doses of histamine blockers, as subsequently discussed. Endoscopie verification of high-grade esophagitis should provide support for aggressive initial therapy. Although much debate has surrounded the relative costeffectiveness of a barium esophagogram in comparison with endoscopy for the diagnosis of GERD, the higher sensitivity and specificity of endoscopy (including the opportunity for biopsy) outweigh the price differential. In the case of possible "reflux laryngitis," laryngoscopy is appropriate for evaluating laryngeal mucosal changes.21 Evaluation of Acid Exposure.—Because normal findings on endoscopy or biopsy do not exclude symptomatic GERD, a diagnostic test to verify abnormal reflux often becomes an important component of the evaluation. The
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suggestion that a therapeutic trial with an acid-suppressive drug might provide information is reasonable but may be incorrect. Of importance, this approach does not rule out a placebo effect when results are positive or the use of an inadequate dose when results are negative. Randomized trials showed a symptomatic response in 28% of patients who received placebo and healing of esophagitis in 24% (Tables 2 and 3). The Bernstein test of mucosal sensitivity to acid is fairly reliable for confirming that symptoms are acid related; in patients with severe grades of esophagitis, 80% true positive results are provided.56 A potential problem with the Bernstein test is the lack of positivity in patients with Barrett's esophagus in comparison with those who have esophagitis but not Barrett's esophagus.57 Prolonged ambulatory pH monitoring remains the "gold standard" for detecting excessive reflux or a positive symptom association (or both).58 The reproducibility of ambulatory pH testing is between 84 and 93%.59 Up to 96% sensitivity and specificity were noted with use of prolonged pH monitoring for distinguishing between 45 control subjects and 45 patients with "typical reflux symptoms."60 Nonetheless, because of the finding of normal acid exposure in 23 to 29% of patients with confirmed esophagitis61·62 and the differences in amounts of gastroesophageal reflux recorded with simultaneous monitoring of esophageal pH with two probes,63 the accuracy of this type of testing is questionable. Absolute sensitivity and specificity are difficult to attain because no standards exist for comparison with ambulatory monitoring. In many patients, short periods of pH monitoring may provide adequate information.64 Patients with typical symptoms of GERD and verified esophagitis benefit little from an initial pH study; however, for those patients with atypical symptoms of reflux without esophagitis, pH testing may clarify their syndrome,65 especially those with unexplained chest pain, pulmonary symptoms, or hoarseness.21 An additional use of pH monitoring is for assessing patients who are receiving acid-suppressive therapy but still have symptoms. With use of combined intraesophageal and intragastric pH recording, some such patients will have persistent gastric acidity and abnormal esophageal acid exposure despite aggressive suppression of acid.66 Technically, the degree of esophageal acid exposure can be determined with only esophageal monitoring, but we have found that simultaneous monitoring of gastric pH often proves helpful in formulating treatment plans. A recent report also suggested that severe supine reflux, as measured with intraesophageal pH testing, was a poor prognostic sign and a better descriminator than the grade of esophagitis.67 Finally, evaluating bile or alkaline reflux with ambulatory monitoring remains controversial and is being studied.68 Other Evaluations.—Esophageal motility studies may provide both diagnostic and prognostic information. The
GASTROESOPHAGEAL REFLUX DISEASE
869
accurate placement of esophageal pH probes necessitates manometric localization of the lower esophageal sphincter (LES).69·70 Therefore, intubation with a manometric catheter is often necessary and provides an opportunity for a complete measurement. The finding of a high percentage of abnormal esophageal contractions or the presence of a hypotensive LES (or both) not only supports the diagnosis of a severe type of GERD but also implies potential difficulty in accomplishing effective long-term therapy.71·72 The role of peristaltic dysfunction in GERD is unclear; however, in a recent study, approximately 50% of patients with mild to severe esophagitis had some impairment of esophageal peristalsis.73 Transient LES relaxations may be a major mechanism of GERD but can rarely be noted on diagnostic manometric examination.74 For verification of the presence of effective esophageal peristalsis, esophageal manometry is necessary in any patient being considered for an antireflux operation, in whom the goal is to decrease the risk of dysphagia after fundoplication.75 THERAPY Various effective therapies are available for managing GERD.76 Options include lifestyle modifications and systemic medications. Nonpharmacologic and Antacid-Antirefluxant Treatment.—All patients with GERD should receive counseling about adjunctive lifestyle modifications (Table 4).77 No controlled studies have specifically evaluated the effectiveness of postural or dietary maneuvers in the treatment of GERD; however, numerous physiologic studies have indicated that elevation of the head of the bed,78·79 decreased intake of fat,80·81 decrease in smoking,82 and no recumbency for 3 hours postprandially83 will decrease distal esophageal acid exposure. Educating the patient about the nature of GERD and the factors that may precipitate reflux should be considered the cornerstone of appropriate therapy. The use of antacids and antirefluxants such as alginic acid is usually considered part of phase I therapy.84 Antacids work by increasing the pH of the gastric contents, and they have the added advantage of deactivating pepsin. Moreover, antacids may increase LES pressure85 and thereby decrease the amount of material refluxed from the stomach.86 Compounds that contain alginic acid have the additional effect of preventing reflux, particularly when the patient is upright.87 Important aspects of treatment are to educate patients that these over-the-counter medications are appropriate for GERD and to provide an understanding of their mechanism of action and proper use. Although few controlled studies have been done with antacids or alginic acid, their use is supported. Antacids88·89 and alginic acid90 have been shown to be more effective than placebo in providing relief of symptoms, including those induced by a meal
870
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GASTROESOPHAGEAL REFLUX DISEASE
Table 2.—Randomized Trials of Acid-Suppressive Therapy for GERD* Reference Beharetal, 22 1978 Powell-Jackson et al,23 1978 Wesdorpetal^WS Brown,25 1979 Bright-Asare & El-Bassoussi,26 1980 Fiasse et al,27 1980 Goy et al,28 1983 Wesdorpetal, 29 1983 Fielding & Doyle,30 1984 Hine et al,31 1984 Sherbaniuk et al,32 1984 Johansson et al,33 1986 Kaul et al,34 1986 Koelz et al,351986 Lehtola et al,36 1986 Klinkenberg-Knol et al,37 1987 Sontag et al,381987 Havelund et al,39 1988 Hetzel et al,40 1988 Sandmark et al,4' 1988 Vantrappen et al,421988 Johnson et al,43 1989 Zeitoun et al,44 1989 Bardhan et al,45 1990 Bate et al,46 1990 Farupetal, 47 1990 Lundell et al,481990 Maleev et al,491990
Drugt or control
No. of patients
Cim, 300 q.i.d. Placebo Cim, 400 q.i.d. Placebo Cim, 400 q.i.d. Placebo Cim, 1,000 q.d. Placebo Cim, 300 q.i.d. Placebo Cim, 400 q.i.d. Placebo Ran, 150b.i.d. Placebo Ran, 150b.i.d. Placebo Cim, 400 b.i.d. Ran, 150 b.i.d. Ran, 150 b.i.d. Placebo Ran, 150 b.i.d. Placebo Ran, 150 b.i.d. Placebo Cim, 400 q.i.d. Cim, 400 b.i.d. Ran, 150 b.i.d. Ran, 300 b.i.d. Ran, 150 b.i.d. Placebo Orne, 60 q.d. Ran, 150 b.i.d. Ran, 150 b.i.d. Placebo Orne, 40 q.d. Ran, 150 b.i.d. Orne, 20 q.d. Orne, 40 q.d. Placebo Orne, 20 q.d. Ran, 150 b.i.d. Orne, 40 q.d. Ran, 150 b.i.d. Ran, 150 b.i.d. Ran, 300 q.i.d. Orne, 20 q.d. Ran, 150 b.i.d. Orne, 20 b.i.d. Orne, 20 q.d. Cim, 400 q.i.d. Cim, 400 b.i.d. Antacid, q.i.d. Placebo Orne, 40 q.d. Ran, 300 b.i.d. Cim, 400 b.i.d. Cim, 400 q.i.d.
28 37 15 15 12 12 11 11 20 9 10 11 12 17 19 17 10 9 14 17 36 33 13 13 17 13 52 56 18 18 25 26 119 118 80 82 82 82 82 73 77 26 25 59 63 62 69 45 138 134 29 27 29 51 47 33 32
Duration (wk) 8 6 8 8 8 6 6 6 8 6 6 8 12 12 12 8 6 12 8 8 8 8 8 8 8 8 12 8-12
Healing of esophagitis (%) 45 35 0 0 44φ 0 82 56 0 0 20 27 25 27 37t 12 70 44 33φ 13 17 9 0 0 50 50 70 70 56φ 6 88φ 38 56φ 41 95φ 70 83φ 88φ 9 85φ 50 96φ 52 54 75φ 95φ 66 91 71 35 38 30 21 90φ 47 53 58
Sympton response 70φ 24 42φ 17 90 18 70 56 82 69 50 37 70 78 42φ 9 46φ 19 75 75 47 47 92φ 65 32φ 12 81Φ 81Φ 14 73φ 46 62φ 12 64 84φ 82φ 48 94 66φ 41
90φ 32 57 69
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GASTROESOPHAGEAL REFLUX DISEASE 871
Table 2.—Continued Reference
Drugt or control
Maxtonetal, 50 1990
Cim, 400 b.i.d. Pyrogastrone, 5 tablets/day Niz, 300 b.i.d. Niz, 300 q.h.s. Placebo Ran, 300 q.i.d. Ran, 150 q.i.d. Placebo Fam, 40 h.s. Fam, 20 b.i.d. Placebo Ome, 20 q.d. Ome, 40 q.d. Placebo Niz, 300 b.i.d. Niz, 150 b.i.d. Placebo
Quiketal, 51 1990 Euleretal, 52 1991 Sabesin et al,53 1991 Sontag et al,54 1992 Cloud et al,55 1992
No. of patients
Duration (wk)
Healing of esophagitis (%)
47
12
66
33 109 109 107 105 100 92 135 137 66 83 87 46 143 139 133
12 8 6 8 6
64 50$ 44 34 70$ 68$ 33 29 34 7 74$ 75$ 14 39$ 41* 26
Symptomatic response (%)
64$ 73$ 39 80$ 82$ 35
*b.i.d. = twice a day; Cim = cimetidine hydrochloride; Fam = famotidine; GERD = gastroesophageal reflux disease; h.s. = at bedtime; Niz = nizatidine; Ome = omeprazole; q.d. = daily; q.h.s. = daily at bedtime; q.i.d. = four times a day; Ran = ranitidine hydrochloride. tDosages are in milligrams. $P<0.01 or greater statistical significance. that causes heartburn.91 In addition, a combination of antacid and alginic acid therapy may be superior to only antacids.8792 Although no studies have specifically evaluated the effectiveness of the combination of antacids and lifestyle modifications, two long-term trials suggest relief of symptoms in approximately 20% of patients.72·93 Acid-Suppressive Treatment.—The four histamine type 2 receptor antagonists (H2RAs) marketed in the United States—cimetidine hydrochloride, ranitidine hydrochloride, famotidine, and nizatidine—have become the mainstay treatment of acid peptic disorders including GERD. Despite such widespread acceptance, controlled studies that have addressed the effectiveness of these agents have yielded variable results. Although these studies are not directly comparable, summaries of symptomatic response and healing of esophagitis are listed in Tables 2 and 3. Duration of treatment and definition of symptomatic response and healing vary, but in general, standard doses of H2RAs provided symptomatic relief in 32 to 82% of patients (mean, 61%). Resolution of endoscopically confirmed esophagitis was demonstrated in 0 to 82% of patients (mean, 48%). Much of the variability in these reports is related to both the range of dosage schedules and the degrees of esophagitis treated; the high healing rates are in subjects with low-grade esophagitis. In some patients in whom a course of routine treatment with H2RAs fails, gastric acid hypersecretors have been noted, a finding that supports the use of high doses of H2RAs.94 High doses of these agents seem to be effective both in the treat-
ment of GERD symptoms and in the healing of esophagitis.43 Because the duration of effective suppression of acid with an orally administered H2RA is less than 6 hours, recent trials have shown more effective control of symptoms and healing with doses given four times daily.43·52 Several recent publications have suggested that omeprazole is the most effective medical therapy for controlling symptoms of GERD and healing esophagitis.37,39"42 Dosages as low as 20 mg daily have been shown to be more effective than either placebo or standard doses of H2RA therapy (Tables 2 and 3). The greater the severity of esophagitis, however, the lower the healing rate; thus, high doses of omeprazole are used in trials outside the United States. Recent evidence has shown that some patients will continue to have secretion of gastric acid and reflux of Table 3.—Summary of Studies* That Evaluated Acid-Suppressive Therapy for GERDt
Agent Placebo H2RA Omeprazole
Symptomatic response No. % 178 of 628 1,318 of 2,159 695 of 834
28 61 83
Healing of esophagitis No. % 174 of 726 844 of 1,760 591 of 754
24 48 78
*See Table 2. tGERD = gastroesophageal reflux disease; H2RA =histamine type 2 receptor antagonist.
872
GASTROESOPHAGEAL REFLUX DISEASE
Table 4—Lifestyle Therapy for Patients With GERD* Dietary modification (decrease intake of fat, chocolate, and peppermint) Weight loss Restriction of smoking and intake of alcohol Elevation of head of bed Avoidance of recumbency for 3 hours postprandially Avoidance of potentially adverse medications that may decrease LES pressure (theophylline, anticholinergics, calcium antagonists, and nitrates) Antacid or alginic acid *GERD = gastroesophageal reflux disease; LES = lower esophageal pressure. esophageal acid with dosages of omeprazole as high as 40 mg twice a day (b.i.d.).66'95 During a 4- to 8-week period with omeprazole therapy, symptomatic responses were noted in a mean of 83% of patients (range, 62 to 94%), and healing of esophagitis occurred in 78% (range, 71 to 96). Currently, use of omeprazole presents two major concerns. The first concern relates to its ability to decrease substantially the secretion of gastric acid.96 This decrease is accompanied by the anticipated increase in production of gastrin from the antral-G cells and the sustained increase in serum gastrin, usually to a mild degree (2 to 4 times the basal rate).9798 Whether these changes in serum gastrin cause dangerous trophic effects on human gastric mucosa with long-term use of omeprazole remains to be resolved. To date, no gastric cancer or carcinoid-type tumor has been reported in a patient receiving omeprazole. The second concern of omeprazole therapy relates to the frequently profound diminishment in symptoms of GERD noted with the pronounced suppression of acid. This impressive effect on symptoms, and even healing, is almost always followed by a rapid return of manifestations of GERD after use of omeprazole is discontinued,40 a situation that may be a particular problem in consideration of long-term maintenance therapy (as subsequently discussed). Promotility Drugs.—The primary pathogenesis of GERD is related to defects in esophagogastric motility—LES incompetence, poor esophageal clearance, and delayed gastric emptying.99 Ideal pharmacologie therapy would correct these defects; thus, suppression of normal amounts of gastric acid would be unnecessary. Investigators have shown that metoclopramide hydrochloride (10 mg four times a day [q.i.d.])26 or bethanechol (25 mg q.i.d.)100 produces greater relief of symptoms than does placebo. Nonetheless, an open-label cross-over study that evaluated esophageal acid contact time (pH monitor) and heartburn in 12 patients failed to show any objective or subjective improvement with metoclopramide therapy in comparison with placebo.101 Metoclopramide is usually not
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administered on a regular basis because of its side effects on the central nervous system (drowsiness, irritability, and extrapyramidal influences). Studies have shown that cisapride102·103 and domperidone104 provide symptomatic relief of GERD. The effective symptomatic relief and healing of esophagitis provided by cisapride (10 mg q.i.d.) are comparable to that obtained with cimetidine (400 mg q.i.d.)105 or ranitidine (150 mg b.i.d.).102 Cisapride (10 mg b.i.d.) also offers promise as effective maintenance therapy for GERD.106 Combined therapy with cimetidine and either metoclopramide (10 mg q.i.d.)107 or cisapride (10 mg q.i.d.)103 has been shown to result in improved healing of esophagitis in comparison with only cimetidine. Furthermore, a recent report on cisapride (10 mg q.i.d.) described healing of grade 2 or 3 esophagitis in 8 of 11 patients.108 Therefore, cisapride is comparable to standard doses of H2RA therapy. Surgical Treatment.—Effective antireflux surgical treatment is available. Considerable controversy exists about the long-term effectiveness of fundoplication and whether it is superior to prolonged medical therapy. In two controlled trials of medical versus surgical therapy (fundoplication) for GERD, the latter was considerably more effective. The initial study favored surgical intervention over medical therapy (essentially phase I) for a 36-month period.93 Recently, a comparison of surgical treatment versus H2RA and metoclopramide therapy showed superiority of the surgical approach.109 No similar comparisons are available for omeprazole because of its recent availability and concerns about long-term use. For GERD, fundoplication is a definite option in comparison with long-term therapy; however, longer term assessment of patients after fundoplication (mean, 69 months) has shown disappointing recurrences in heartburn, esophagitis, and decreased LES pressure.110 Perhaps fundoplication should be considered for patients with a mechanically defective cardia, as defined by low LES pressure (less than 6 mm Hg), short overall LES length (less than 2 cm), or short intra-abdominal LES segment (less than 1 cm).1" Maintenance Treatment of GERD.—Because of the growing awareness that a high percentage of patients with GERD require long-term, possibly lifetime, therapy, maintenance treatment is clearly the key issue for such patients. We define effective maintenance as that type of treatment that controls the patient's symptoms satisfactorily and prevents complications, a situation that varies with the nature of the disease in each patient and may require only phase I therapies in 20% of patients,72-93 Patients who have frequent symptomatic relapses despite appropriate therapy with H2RAs or promotility drugs (or both) are a concern. Such patients comprise up to 50% of those being assessed for chronic reflux symptoms.72 A recent abstract suggested that
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873
Table 5—Treatment Schemes for GERD*
GERD. The preferred approach awaits future well-designed trials. Empiric treatment Treatment of Resistant GERD.—In addition to the meaLifestyle therapy including antacids or alginic acid 6-8 weeks of standard doses of H,RA sures previously discussed, other special considerations are Promotility agent, especially cisapride, may be considered necessary for patients who have persistent symptoms of Initial treatment ofpersistent symptoms, after diagnosis has been GERD or esophagitis (or both). Prolonged ambulatory pH confirmed monitoring (if not already performed) is appropriate at this Continue lifestyle therapy stage to verify the severity and pattern of the reflux and to Increase (double) dose of H2RA clarify the specific symptom association."5 Another approAdd promotility agent priate use of this test is to confirm adequate suppression of Consider omeprazole if evidence of complicated disease acid during treatment.66 The use of dual electrode pH moniTreatment of resistant cases toring (distal esophagus and stomach) may provide a clear Continue lifestyle therapy Double dose of H2RA or higher (consider q.i.d.) appraisal of acid dynamics in such patients and may also Administer omeprazole (up to 80 mg/day) help to detect the presence of duodenogastric reflux, frePerform fundoplication quently inappropriately termed "alkaline" reflux. For paMaintenance therapy tients with resistant GERD, therapeutic considerations inLong-term lifestyle therapy clude increasing the dose and frequency of H2RAs or Standard dose of H,RA or higher combining H,RA with a promotility agent, omeprazole, or Omeprazole (at lowest effective dose) if benefit outweighs risk antireflux surgical intervention. Evidence shows that each Fundoplication of these approaches provides more effective healing of *GERD = gastroesophageal reflux disease; H2RA = histamine type esophagitis than standard doses of H2RAs. A sequential 2 receptor antagonist; q.i.d. = four times a day. treatment approach to GERD is shown in Table 5. The respective costs of the therapies for GERD at a representa10 mg of omeprazole a day maintains remission in 35% of tive pharmacy are presented in Table 6. These cost factors patients and that 20 mg a day increases the remission rate to must be considered in our current medical environment. 59%. '12 We believe that recent studies support the following conclusions about maintenance therapy for GERD. CONCLUSION 1. Many patients will experience symptomatic relapses Advancement in the diagnosis of GERD has been substanand failure of healing of esophagitis with use of standard or tial. Modern endoscopie techniques in conjunction with the even high doses of H,RAs or promotility drugs (or both)."3 appropriate use of ambulatory pH testing should confirm the 2. The concept of maintenance with less than a total dose diagnosis of GERD in most, if not all, patients. Treatment of of H2RA administered once daily is inappropriate.3 this disorder is less clear. Omeprazole therapy fails to con3. Low doses of omeprazole have yet to be shown to be trol symptoms and heal esophagitis in some patients; all effective long-term treatment; however, further investiga- other medical treatments have been shown to be less effections are needed."4 tive than omeprazole. Further developments in promotility Many questions still need to be resolved about effective agents are awaited, as is the development of rational dosing maintenance therapy for GERD. Basically, the choices are schedules of proton pump inhibitors or alternating use of those subsequently discussed for patients with resistant proton pump inhibitors with H,RAs (or both). In addition, the potential role of combining acid-suppressive therapy and promotility agents needs to be clarified. Accurate confirmaTable 6.—Representative Costs of Therapy for GERD* tion of which patients are appropriate candidates for surgical Dosage treatment is needed. The type of thorough investigations that interval Drug Costt (S) have brought us thus far should lead to future resolution of the previously mentioned issues. b.i.d. 70-100 H,RA (standard dose) H,RA (standard dose) H,RA (double dose) Omeprazole (20 mg) Omeprazole ( 10 mg) Cisapride (10 mg)
q.i.d. b.i.d. q.d. b.i.d. q.i.d.
140-200 150-200 110-130 220-260 80-90
*b.i.d. = twice a day; GERD = gastroesophageal reflux disease; H,RA = histamine type 2 receptor antagonist; q.d. = daily; q.i.d. = four times a day. t30-day supply.
REFERENCES 1.
2. 3.
Nebel OT, Fornes MF, Castell DO. Symptomatic gastroesophageal reflux: incidence and precipitating factors. Am J Dig Dis 1976; 21:953-956 Graham DY, Smith JL, Patterson DJ. Why do apparently healthy people use antacid tablets? Am J Gastroenterol 1983;78:257-260 Hewson EG, Sinclair JW, Dalton CB, Richter JE. Twenty-fourhour esophageal pH monitoring: the most useful test for evaluating noncardiac chest pain. Am J Med 1991;90:576-583
874
4.
5.
6. 7. 8. 9. 10.
11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22.
23. 24. 25. 26.
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GASTROESOPHAGEAL REFLUX DISEASE
Wiener GJ, Koufman JA, Wu WC, Cooper JB, Richter JE, Castell DO. Chronic hoarseness secondary to gastroesophageal reflux disease: documentation with 24-h ambulatory pH monitoring. Am J Gastroenterol 1989; 84:1503-1508 Sontag SJ, O'Connell S, Khandelwal S, Miller T, Nemchausky B, Schnell TG, et al. Most asthmatics have gastroesophageal reflux with or without bronchodilator therapy. Gastroenterology 1990; 99:613-620 Katz PO, Castell DO. Barrett's esophagus: today's dilemma. Dis Esophagus 1990;3:55-60 SpechlerSJ. Complications of gastroesophageal reflux disease. In: Castell DO, editor. The Esophagus. Boston: Little, Brown, 1992: 543-556 Roesch W. Erosions of the upper gastrointestinal tract. Clin Gastroenterol 1978 Sep; 7:623-634 Monnier P, Savary M. Contribution of endoscopy to gastrooesophageal reflux disease. Scand J Gastroenterol Suppl 1984; 106:26-44 Chen YM, Ott DJ, Gelfand DW, Munitz HA. Multiphasic examination of the esophagogastric region for strictures, rings, and hiatal hernia: evaluation of the individual techniques. Gastrointest Radiol 1985; 10:311-316 Ott DJ. Barium esophagram. In: Castell DO, Wu WC, Ott DJ, editors. Gastro-esophageal Reflux Disease: Pathogenesis, Diagnosis, Therapy. Mount Kisco (NY): Futura, 1985: 109-128 Ott DJ, Chen YM, Gelfand DW, Munitz HA, Wu WC. Analysis of a multiphasic radiographie examination for detecting reflux esophagitis. Gastrointest Radiol 1986;11:1-6 Ott DJ, Gelfand DW, Lane TG, Wu WC. Radiologie detection and spectrum of appearances of peptic esophageal strictures. J Clin Gastroenterol 1982;4:11-15 Ott DJ, Wu WC, Gelfand DW. Reflux esophagitis revisited: prospective analysis of radiological accuracy. Gastrointest Radiol 1981;6:1-7 Chen YM, Gelfand DW, Ott DJ, Wu WC. Barrett esophagus as an extension of severe esophagitis: analysis of radiologie signs in 29 cases. AJR Am J Roentgenol 1985;145:275-281 Levine MS, Kressel HY, Caroline DF, Laufer I, Herlinger H, Thompson JJ. Barrett esophagus: reticular pattern of the mucosa. Radiology 1983; 147:663-667 Ott DJ, Cowan RJ, Gelfand DW, Wu WC, Chen YM, Munitz HA. The role of diagnostic imaging in evaluating gastroesophageal reflux disease. Postgrad Radiol 1986;6:3-10 Richter JE, Castell DO. Gastroesophageal reflux: pathogenesis, diagnosis, and therapy. Ann Intern Med 1982;97:93-103 Ismail-Beigi F, Horton PF, Pope CE II. Histological consequences of gastroesophageal reflux in man. Gastroenterology 1970; 58:163-174 Pace F, Santalucia F, Bianchi Porro G. Natural history of gastrooesophageal reflux disease without oesophagitis. Gut 1991; 32:845-848 Jacob P, Kahrilas PJ, Herzon G. Proximal esophageal pH-metry in patients with'reflux laryngitis.' Gastroenterology 1991; 100:SOSSIO Behar J, Brand DL, Brown FC, Castell DO, Cohen S, Crossley RJ, et al. Cimetidine in the treatment of symptomatic gastroesophageal reflux: a double blind controlled trial. Gastroenterology 1978; 74:441-448 Powell-Jackson P, Barkley H, Northfield TC. Effect of cimetidine in symptomatic gastro-oesophageal reflux. Lancet 1978; 2:10681069 Wesdorp E, Bartelsman J, Pape K, Dekker W, Tytgat G. Oral cimetidine in reflux esophagitis: a double blind controlled trial. Gastroenterology 1978 ; 74:821 -824 Brown P. Cimetidine in the treatment of reflux oesophagitis. Med JAust 1979;2:96-97 Bright-Asare P, El-Bassoussi M. Cimetidine, metoclopramide, or placebo in the treatment of symptomatic gastroesophageal reflux. J Clin Gastroenterol 1980;2:149-156
27. 28. 29. 30. 31. 32. 33. 34.
35. 36.
37.
38. 39.
40.
41.
42.
43.
44.
45.
46.
Fiasse R, Hanin C, Lepot A, Descamps C, Lamy F, Dive C. Controlled trial of cimetidine in reflux esophagitis. Dig Dis Sci 1980; 25:750-755 Goy JA, Maynard JH, McNaughton WM, O'Shea A. Ranitidine and placebo in the treatment of reflux oesophagitis: a double-blind randomized trial. Med J Aust 1983;2:558-561 Wesdorp IC, Dekker W, Klinkenberg-Knol EC. Treatment of reflux oesophagitis with ranitidine. Gut 1983;24:921-924 Fielding JF, Doyle GD. Comparison between ranitidine and cimetidine in the treatment of reflux oesophagitis. Ir Med J 1984; 77:356-357 Hine KR, Holmes GK, Melikian V, Lucey M, Fairclough PD. Ranitidine in reflux oesophagitis: a double-blind placebo-controlled study. Digestion 1984;29:119-123 Sherbaniuk R, Wensel R, Bailey R, Trautman A, Grace M, Kirdeikis P, et al. Ranitidine in the treatment of symptomatic gastroesophageal reflux disease. J Clin Gastroenterol 1984;6:9-15 Johansson KE, Boeryd B, Johansson K, Tibbling L. Double-blind crossover study of ranitidine and placebo in gastro-oesophageal reflux disease. Scand J Gastroenterol 1986;21:769-778 Kaul B, Petersen H, Erichsen H, Myrvold HE, Grette K, Halvorsen T, et al. Gastroesophageal reflux disease: acute and maintenance treatments with cimetidine. Scand J Gastroenterol 1986; 21:139145 Koelz HR, Birchler R, Bretholz A, Bron B, Capitaine Y, Delmore G, et al. Healing and relapse of reflux esophagitis during treatment with ranitidine. Gastroenterology 1986; 91:1198-1205 Lehtola J, Niemela S, Martikainen J, Krekela I. Ranitidine, 150 mg three times a day, in the treatment of reflux oesophagitis: a placebo-controlled, double-blind study. Scand J Gastroenterol 1986; 21:175-180 Klinkenberg-Knol EC, Jansen JM, Festen HP, Meuwissen SG, Lamers CB. Double-blind multicentre comparison of omeprazole and ranitidine in the treatment of reflux oesophagitis. Lancet 1987; 1:349-351 Sontag S, Robinson M, McCallum RW, Barwick KW, Nardi R. Ranitidine therapy for gastroesophageal reflux disease: results of a large double-blind trial. Arch Intern Med 1987;147:1485-1491 Havelund T, Laursen LS, Skoubo-Kristensen E, Andersen BN, Pedersen SA, Jensen KB, et al. Omeprazole and ranitidine in treatment of reflux oesophagitis: double blind comparative trial. BMJ 1988;296:89-92 Hetzel DJ, Dent J, Reed WD, Narielvala FM, Mackinnon M, McCarthy JH, et al. Healing and relapse of severe peptic esophagitis after treatment with omeprazole. Gastroenterology 1988;95:903-912 Sandmark S, Carlsson R, Fausa O, Lundell L. Omeprazole or ranitidine in the treatment of reflux esophagitis: results of a doubleblind, randomized, Scandinavian multicenter study. Scand J Gastroenterol 1988; 23:625-632 Vantrappen G, Rutgeerts L, Schurmans P, Coenegrachts JL. Omeprazole (40 mg) is superior to ranitidine in the short-term treatment of ulcerative reflux esophagitis. Dig Dis Sci 1988; 33:523-529 Johnson NJ, Boyd EJ, Mills JG, Wood JR. Acute treatment of reflux oesophagitis: a multicenter trial to compare 150 mg ranitidine b.d. with 300 mg ranitidine q.d.s. Aliment Pharmacol Ther 1989;3:259-266 Zeitoun P, Rampai P, Barbier P, Isal JP, Eriksson S, Carlsson R. Omeprazole (20 mg daily) compared to ranitidine (150 mg twice daily) in the treatment of esophagitis caused by reflux: results of a double-blind randomized multicenter trial in France and Belgium. Gastroenterol Clin Biol 1989; 13:457-462 Bardhan KD, Morris P, Thompson M, Dhande DS, Hinchliffe RF, Jones RB, et al. Omeprazole in the treatment of erosive oesophagitis refractory to high dose cimetidine and ranitidine. Gut 1990;31:745-749 Bate CM, Keeling PW, O'Morain C, Wilkinson SP, Foster DN, Mountford RA, et al. Comparison of omeprazole and cimetidine in
Mayo Clin Proc, September 1994, Vol 69
47.
48.
49. 50. 51.
52. 53.
54.
55.
56. 57. 58. 59.
60. 61. 62.
63.
64. 65.
reflux oesophagitis: symptomatic, endoscopie, and histological evaluations. Gut 1990;31:968-972 Farup PG, Weberg R, Berstad A, Wetterhus S, Dahlberg O, Dybdal J, et al. Low-dose antacids versus 400 mg cimetidine twice daily for reflux oesophagitis: a comparative, placebo-controlled, multicentre study. Scand J Gastroenterol 1990;25:315-320 Lundell L, Backman L, Ekstrom P, Enander LH, Fausa O, Lind T, et al. Omeprazole or high-dose rannidine in the treatment of patients with reflux oesophagitis not responding to 'standard doses' of H2-receptor antagonists. Aliment Pharmacol Ther 1990; 4:145' 155 Maleev A, Mendizova A, Popov P, Vlahov V, Dimitrov B, Mihova A, et al. Cisapride and cimetidine in the treatment of erosive esophagitis. Hepatogastroenterology 1990;37:403-407 Maxton DG, Heald J, Whorwell PJ, Haboubi NY. Controlled trial of pyrogastrone and cimetidine in the treatment of reflux oesophagitis. Gut 1990;31:351-354 Quik RF, Cooper MJ, Gleeson M, Hentschel E, Schuetze K, Kingston RD, et al. A comparison of two doses of nizatidine versus placebo in the treatment of reflux oesophagitis. Aliment Pharmacol Ther 1990;4:201-211 Euler AR, Murdock RH, Wilson TH. Ranitidine is effective in healing erosive esophagitis [abstract]. Gastroenterology 1991; 100:A61 Sabesin SM, Berlin RG, Humphries TJ, Bradstreet DC, WaltonBowen KL, Zaidi S, et al. Famotidine relieves symptoms of gastroesophageal reflux disease and heals erosions and ulcérations: results of a multicenter, placebo-controlled, dose-ranging study. Arch Intern Med 1991 ; 151:2394-2400 Sontag SJ, Hirschowitz BI, Holt S, Robinson MG, Behar J, Berenson MM, et al. Two doses of omeprazole versus placebo in symptomatic erosive esophagitis: the US Multicenter Study. Gastroenterology 1992;102:109-118 Cloud ML, Offen WW, Nizatidine Gastroesophageal Reflux Disease Study Group. Nizatidine versus placebo in gastroesophageal reflux disease: a six-week, multicenter, randomized, double-blind comparison. Dig Dis Sci 1992; 37:865-874 Bernstein LM, Baker LA. A clinical test for esophagitis. Gastroenterology 1958;34:760-781 Johnson DA, Winters C, Spurling TJ, Chobanian SJ, Cattau EL Jr. Esophageal acid sensitivity in Barrett's esophagus. J Clin Gastroenterol 1987; 9:23-27 Mattox HE III, Richter JE. Prolonged ambulatory esophageal pH monitoring in the evaluation of gastroesophageal reflux disease. Am J Med 1990;89:345-356 Wiener GJ, Morgan TM, Copper JB, Wu WC, Castell DO, Sinclair JW, et al. Ambulatory 24-hour esophageal pH monitoring: reproducibility and variability of pH parameters. Dig Dis Sci 1988; 33:1127-1133 Fuchs KH, DeMeester TR, Albertucci M. Specificity and sensitivity of objective diagnosis of gastroesophageal reflux disease. Surgery 1987; 102:575-580 Schlesinger PK, Donahue PE, Schmid B, Layden TJ. Limitations of 24-hour intraesophageal pH monitoring in the hospital setting. Gastroenterology 1985; 89:797-804 Vitale GC, Cheadle WG, Sadek S, Michel ME, Cuschieri A. Computerized 24-hour ambulatory esophageal pH monitoring and esophagogastroduodenoscopy in the reflux patient: a comparative study. AnnSurg 1984;200:724-728 Murphy DW, Yuan Y, Castell DO. Does the intraesophageal pH probe accurately detect acid reflux? Simultaneous recording with two pH probes in humans. Dig Dis Sci 1989; 34:649656 Dobhan R, Castell DO. Prolonged intraesophageal pH monitoring with 16-hr overnight recording: comparison with "24-hr" analysis. Dig Dis Sci 1992;37:857-864 Klauser AG, Heinrich C, Schindlbeck NE, Muller-Lissner SA. Is long-term esophageal pH monitoring of clinical value? Am J Gastroenterol 1989; 84:362-366
GASTROESOPHAGEAL REFLUX DISEASE
66.
67. 68. 69. 70. 71. 72. 73. 74. 75.
76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88.
875
Klinkenberg-Knol EC, Meuwissen SG. Combined gastric and oesophageal 24-hour pH monitoring and oesophageal manometry in patients with reflux disease, resistant to treatment with omeprazole. Aliment Pharmacol Ther 1990; 4:485-495 Schindlbeck NE, Klauser AG, Berghammer G, Londong W, Muller-Lissner SA. Three year follow up of patients with gastrooesophageal reflux disease. Gut 1992;33:1016-1019 Waring JP, LeGrand J, Chinichian A, Sanowski RA. Duodenogastric reflux in patients with Barrett's esophagus. Dig Dis Sci 1990;35:759-762 Klauser AG, Schindlbeck NE, Müller-Lissner SA. Esophageal 24h pH monitoring: is prior manometry necessary for correct positioning of the electrode? Am J Gastroenterol 1990;85:1463-1467 Mattox HE III, Richter JE, Sinclair JW, Price JE, Case LD. Gastroesophageal pH step-up inaccurately locates proximal border of lower esophageal sphincter. Dig Dis Sci 1992;37:1185-1191 Zaninotto G, DeMeester TR, Schwizer W, Johansson KE, Cheng SC. The lower esophageal sphincter in health and disease. Am J Surg 1988; 155:104-111 Lieberman DA. Medical therapy for chronic reflux esophagitis: long-term follow-up. Arch Intern Med 1987;147:1717-1720 Kahrilas PJ, Dodds WJ, Hogan WJ, Kern M, Amdorfer RC, Reece A. Esophageal peristaltic dysfunction in peptic esophagitis. Gastroenterology 1986;91:897-904 Dodds WJ, Dent J, Hogan WJ, Helm JF, Hauser R, Patel GK, et al. Mechanisms of gastroesophageal reflux in patients with reflux esophagitis. N Engl J Med 1982;307:1547-1552 DeMeester TR, Stein HJ. Pre- and postoperative use of ambulatory 24 hour pH monitoring and manometry. In: Richter JE, editor. Ambulatory Esophageal pH Monitoring: Practical Approach and Clinical Applications. New York: Igaku-Shoin, 1991: 179-195 Richter JE. A critical review of current medical therapy for gastroesophageal reflux disease. J Clin Gastroenterol 1986; 8(Suppl l):72-80 Castell DO. Medical therapy for reflux esophagitis: 1986 and beyond. Ann Intern Med 1986;104:112-114 Stanciu C, Bennett JR. Effects of posture on gastro-oesophageal reflux. Digestion 1977;15:104-109 Johnson LF, DeMeester TR. Evaluation of elevation of the head of the bed, bethanechol, and antacid form tablets on gastroesophageal reflux. Dig Dis Sci 1981;26:673-680 Nebel OT, Castell DO. Lower esophageal sphincter pressure changes after food ingestion. Gastroenterology 1972; 63:778783 Becker DJ, Sinclair J, Castell DO, Wu WC. A comparison of high and low fat meals on postprandial esophageal acid exposure. Am J Gastroenterol 1989; 782-786 Waring JP, Eastwood TF, Austin JM, Sanowski RA. The immediate effects of cessation of cigarette smoking on gastroesophageal reflux. Am J Gastroenterol 1989;84:1076-1078 DeMeester TR, Johnson LF, Joseph GJ, Toscano MS, Hall AW, Skinner DB. Patterns of gastroesophageal reflux in health and disease. AnnSurg 1976;184:459-469 Kitchin LI, Castell DO. Rationale and efficacy of conservative therapy for gastroesophageal reflux disease. Arch Intern Med 1991; 151:448-454 Higgs RH, Smyth RD, Castell DO. Gastric alkalinization: effect on lower-esophageal-sphincter pressure and serum gastrin. N Engl JMed 1974;291:486-490 Malmud LS, Fischer RS. Quantitation of gastroesophageal reflux before and after therapy using the gastroesophageal scintiscan. South Med J 1978; 71(Suppl 1):10-15 Castell DO, Dalton CB, Becker D, Sinclair J, Castell JA. Alginic acid decreases postprandial upright gastroesophageal reflux. Dig Dis Sci 1992;37:589-593 Saco LS, Orlando RC, Levinson SL, Bozymski EM, Jones JD, Frakes JT. Double-blind controlled trial of bethanechol and antacid versus placebo and antacid in the treatment of erosive esophagitis. Gastroenterology 1982; 82:1369-1373
876
89. 90.
91. 92. 93. 94. 95. 96. 97. 98.
99. 100. 101. 102. 103.
GASTROESOPHAGEAL REFLUX DISEASE
Graham DY, Patterson DJ. Double-blind comparison of liquid antacid and placebo in the treatment of symptomatic reflux esophagitis. Dig Dis Sci 1983;28:559-563 Buts JP, Barudi C, Otte JB. Double-blind controlled study on the efficacy of sodium alginate (Gaviscon) in reducing gastroesophageal reflux assessed by 24 h continuous pH monitoring in infants and children. EurJPediatr 1987;146:156-158 Lanza FL, Smith V, Page-Castell JA, Castell DO. Effectiveness of foaming antacid in relieving induced heartburn. South Med J 1986; 79:327-330 Stanciu C, Bennett JR. Alginate-antacid in the reduction of gastrooesophageal reflux esophagitis. Lancet 1974;1:109-111 Behar J, Sheahan DG, Biancani P, Spiro H, Storer EH. Medical and surgical management of reflux esophagitis: a 38-month report of a prospective clinical trial. NEnglJMed 1975;293:263-268 Collen MJ, Lewis JH, Benjamin SB. Gastric acid hypersécrétion in refractory gastroesophageal reflux disease. Gastroenterology 1990; 98:654-661 Savarino V, Mela GS, Zentilin P, Celle G. Is gastric acid hypersécrétion the only reason for refractory gastroesophageal reflux disease? [letter]. Gastroenterology 1990;99:1542-1543 Larsson H, Carlsson E, Junggren U, Olbe L, Sjostrand SE, Skanberg I, et al. Inhibition of gastric acid secretion by omeprazole in the dog and rat. Gastroenterology 1983;85:900-907 Festen HP, Thijs JC, Lamers CB, Jansen JM, Pals G, Frants RR, et al. Effect of oral omeprazole on serum gastrin and serum pepsinogen I levels. Gastroenterology 1984;87:1030-1034 Jansen JB, Klinkenberg-Knol EC, Meuwissen SG, De Bruijne JW, Festen HP, Snel P, et al. Effect of long-term treatment with omeprazole on serum gastrin and serum group A and C pepsinogens in patients with reflux esophagitis. Gastroenterology 1990; 99:621-628 Castell DO. Gastroesophageal reflux disease is a motility disorder. Front Gastrointest Res 1992; 20:11 -16 Farrell RL, Roling GT, Castell DO. Cholinergic therapy of chronic heartburn: a controlled trial. Ann Intern Med 1974;80:573-576 Orr WC, Finn A, Wilson T, Russell J. Esophageal acid contact time and heartburn in acute treatment with ranitidine and metoclopramide. Am J Gastroenterol 1990;85:697-700 Janisch HD, Huttemann W, Bouzo MH. Cisapride versus ranitidine in the treatment of reflux esophagitis. Hepatogastroenterology 1988; 35:125-127 Galmiche JP, Brandstatter G, Evreux M, Hentschel E, Kerstan E, Kratochvil P, et al. Combined therapy with cisapride and cimetidine in severe reflux oesophagitis: a double blind controlled trial. Gut 1988;29:675-681
Mayo Clin Proc, September 1994, Vol 69
104.
105. 106. 107. 108. 109.
110.
111. 112.
113.
114.
115.
Brogden RN, Carmine AA, Heel RC, Speight TM, Avery GS. Domperidone: a review of its pharmacological activity, pharmacokinetics and therapeutic efficacy in the symptomatic treatment of chronic dyspepsia and as an antiemetic. Drugs 1982; 24:360400 Galmiche JP, Fraitag B, Filoche B, Evreux M, Vitaux J, Zeitoun P, et al. Double-blind comparison of cisapride and cimetidine in treatment of reflux esophagitis. Dig Dis Sci 1990;35:649-655 Toussaint J, Gossuin A, Deruyttere M, Huble F, Devis G. Healing and prevention of relapse of reflux oesophagitis by cisapride. Gut 1991;32:1280-1285 Lieberman DA, Keefe EB. Treatment of severe reflux esophagitis with cimetidine and metoclopramide. Ann Intern Med 1986; 104:21-26 Lepoutre L, Van der Spek P, Vanderlinden I, Bollen J, Laukens P. Healing of grade-II and III oesophagitis through motility stimulation with cisapride. Digestion 1990;45:109-114 Spechler SJ, Department of Veterans Affairs Gastroesophageal Reflux Disease Study Group. Comparison of medical and surgical therapy for complicated gastroesophageal reflux disease in veterans. NEnglJMed 1992;326:786-792 Brand DL, Eastwood IR, Martin D, Carter WB, Pope CE II. Esophageal symptoms, manometry, and histology before and after antireflux surgery: a long-term follow-up study. Gastroenterology 1979;76:1393-1401 Bonavina L, Evander A, DeMeester TR, Walther B, Cheng SC, Palazzo L, et al. Length of the distal esophageal sphincter and competency of the cardia. AmJSurg 1986;151:25-34 Laursen LS, Bondesen S, Hansen J, Sanchez G, Sebelin E, Havelund T, et al. Omeprazole 10 mg or 20 mg daily for the prevention of relapse in gastroesophageal reflux disease? A double-blind comparative study [abstract]. Gastroenterology 1992; 102:A109 Antonson CW, Robinson MG, Hawkins TM, Mclntosh DL, Campbell DR. High doses of histamine antagonists do not prevent relapses of peptic esophagitis following therapy with a proton pump inhibitor [abstract]. Gastroenterology 1990; 98:A16 Bardhan KD, Daly MJ, Singh S, Morris P, Thompson M, Hinchliffe RFC. Refractory esophagitis: results of maintenance treatment with high-dose H2 receptor antagonists (H2RA) or omeprazole (OM) [abstract]. Gastroenterology 1990;98:A18 Wiener GJ, Richter JE, Copper JB, Wu WC, Castell DO. The symptom index: a clinically important parameter of ambulatory 24-hour esophageal pH monitoring. Am J Gastroenterol 1988; 83:358-361