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Medical management of gastroesophageal reflux disease in adults

Medical management of gastroesophageal reflux disease in adults
Author:
Peter J Kahrilas, MD
Section Editor:
Nicholas J Talley, MD, PhD
Deputy Editor:
Shilpa Grover, MD, MPH, AGAF
Literature review current through: Feb 2022. | This topic last updated: Nov 29, 2021.

INTRODUCTION — The passage of gastric contents into the esophagus (gastroesophageal reflux) is a normal physiologic process. Most episodes are brief and do not cause symptoms, esophageal injury, or other complications. Gastroesophageal reflux becomes a disease when it either causes macroscopic damage to the esophagus or causes symptoms.

This topic will review the initial management of gastroesophageal reflux disease (GERD) and management of patients with recurrent GERD when treatment is discontinued. Our recommendations are largely consistent with the American Gastroenterological Association and the American College of Gastroenterology guidelines [1,2]. The evaluation and management of refractory GERD and the role of surgery and endoscopic therapy in patients with GERD are discussed separately. (See "Approach to refractory gastroesophageal reflux disease in adults" and "Surgical management of gastroesophageal reflux in adults" and "Radiofrequency treatment for gastroesophageal reflux disease".)

PRETREATMENT EVALUATION

Assessment of clinical severity — The frequency and severity of symptoms can guide the management of GERD. Symptoms are considered mild or moderate/severe based on whether they impair quality of life. Symptoms may be intermittent (less than two episodes per week) or frequent (two or more episodes per week). (See "Clinical manifestations and diagnosis of gastroesophageal reflux in adults", section on 'Clinical features'.)

Are there indications for upper endoscopy? — Upper endoscopy is not required in the presence of typical GERD symptoms of heartburn or regurgitation [2]. We recommend an upper endoscopy if the diagnosis of GERD is unclear and to evaluate alarm features or abnormal imaging if not performed within the last three months. Upper endoscopy should also be performed to screen for Barrett’s esophagus in patients with risk factors. Patients with GERD should receive empiric acid suppressive therapy, even if additional evaluation with an upper endoscopy is indicated. (See "Clinical manifestations and diagnosis of gastroesophageal reflux in adults", section on 'Evaluation in selected patients'.) (Related Pathway(s): Gastroesophageal reflux disease: Identification of adults who require upper endoscopy.)

INITIAL MANAGEMENT

Overall approach — Our management approach to patients with gastroesophageal reflux disease (GERD) is based on the frequency and severity of symptoms and the presence of erosive esophagitis or Barrett’s esophagus on upper endoscopy, if previously performed (algorithm 1). (See 'Pretreatment evaluation' above and "Clinical manifestations and diagnosis of gastroesophageal reflux in adults", section on 'Endoscopic findings'.)

In patients with mild and intermittent symptoms (fewer than two episodes per week) and no evidence of erosive esophagitis, we suggest step-up therapy for GERD. The step-up approach involves incrementally increasing the potency of therapy until symptom control is achieved. In patients who are naïve to treatment, we initially recommend lifestyle and dietary modification and, as needed, low-dose histamine 2 receptor antagonists (H2RAs) (table 1). We suggest concomitant antacids and/or sodium alginate as needed if symptoms occur less than once a week. For patients with continued symptoms despite these measures, we increase the dose of H2RAs to standard dose, twice daily for a minimum of two weeks. Further increases in the dose of H2RA, prolonging the course of treatment, or switching to another H2RA is unlikely to control symptoms [3,4]. Therefore, if symptoms of GERD persist, we discontinue H2RAs and initiate once-daily proton pump inhibitors (PPIs) at a low dose and then increase to standard doses if required (table 1). We make incremental changes in therapy at four to eight-week intervals. Once symptoms are controlled, treatment should be continued for at least eight weeks.

In patients with erosive esophagitis, frequent symptoms (two or more episodes per week), and/or severe symptoms that impair quality of life, we use step-down therapy in order to optimize symptom relief. The step-down approach starts with potent antisecretory agents and then involves incrementally, decreasing the potency of therapy until breakthrough symptoms define the treatment necessary for symptom control. We begin with standard-dose PPI once daily for eight weeks in addition to lifestyle and dietary modification (table 1). We subsequently decrease acid suppression to low-dose PPIs and then to H2RAs if patients have mild or intermittent symptoms. We discontinue acid suppression in all asymptomatic patients with the exception of patients with severe erosive esophagitis or Barrett's esophagus, in whom we suggest maintenance PPI therapy. (See 'Duration of acid suppression' below.)

Patients with GERD may be managed with a step-up or step-down approach to therapy. While the optimal strategy is controversial, both have advantages [5-7]. The step-up approach minimizes the use of PPIs and their associated costs and side effects, whereas step-down therapy provides faster symptom relief. (See "Proton pump inhibitors: Overview of use and adverse effects in the treatment of acid related disorders", section on 'Adverse effects'.)

Mild and intermittent symptoms

Lifestyle and dietary modification — Although several lifestyle and dietary modifications have been used in clinical practice, a systematic review of 16 randomized trials that evaluated the impact of these measures on GERD concluded that only weight loss and elevation of the head end of the bed improved esophageal pH-metry and/or GERD symptoms [8-13].

We suggest the following lifestyle and dietary measures [14,15]:

Weight loss for patients with GERD who are overweight or have had recent weight gain.

Elevation of the head of the bed in individuals with nocturnal or laryngeal symptoms (eg, cough, hoarseness, throat clearing). This can be achieved either by putting six- to eight-inch blocks under the legs at the head of the bed or a Styrofoam wedge under the mattress. We also suggest a corollary to this recommendation: refraining from assuming a supine position after meals and avoidance of meals two to three hours before bedtime [2]. (See "Clinical manifestations and diagnosis of gastroesophageal reflux in adults", section on 'Clinical features'.)

We suggest selective elimination of dietary triggers (caffeine, chocolate, spicy foods, food with high fat content, carbonated beverages, and peppermint) in patients who note correlation with GERD symptoms and an improvement in symptoms with elimination. In a prospective study of 48,308 women, intake of coffee, tea, and soda, but not milk, water, or juice were associated with a modest and dose-dependent increase in risk of GERD symptoms (HR 1.34, 1.26 and 1.29) [16]. Substitution of two servings per day of coffee, tea, or soda with water was associated with a small reduction in GERD symptoms (HR, 0.96; tea HR, 0.96; and soda HR, 0.92, respectively).

Other measures that have a physiologic basis but have not consistently been demonstrated to improve reflux symptoms include [8,15,17,18]:

Avoidance of tight-fitting garments to prevent increasing intragastric pressure and the gastroesophageal pressure gradient. (See "Pathophysiology of reflux esophagitis", section on 'Gastroesophageal junction incompetence'.)

Promotion of salivation through oral lozenges/chewing gum to neutralize refluxed acid and increase the rate of esophageal acid clearance.

Avoidance of tobacco and alcohol, as both reduce lower esophageal sphincter pressure and smoking also diminishes salivation.

Abdominal breathing exercises to strengthen the antireflux barrier of the lower esophageal sphincter.

In a prospective study of 42,955 females, the risk for GERD symptoms was significantly lower for those with five antireflux lifestyle factors as compared with females without adherence to antireflux lifestyle factors (HR 0.50; 95% CI 0.42-0.59) [19]. These measures included eating a diet rich in whole grains, vegetables, and fruits; maintaining a healthy body weight; not smoking; exercising for 30 minutes per day; and drinking no more than two cups of soda, coffee, or tea per day. Up to 40 percent of weekly GERD symptoms could be prevented through five dietary and lifestyle factors. The decreased risk of GERD symptoms associated with these measures was observed even among regular users of PPIs and H2RAs.

Antacids — As antacids do not prevent GERD, their role is limited to intermittent (on-demand) use for relief of mild GERD symptoms that occur less than once a week [4]. Antacids usually contain a combination of magnesium trisilicate, aluminum hydroxide, or calcium carbonate, which neutralize gastric pH, thereby decreasing the exposure of the esophageal mucosa to gastric acid during episodes of reflux. Antacids begin to provide relief of heartburn within five minutes, but have a short duration of effect of 30 to 60 minutes. The side effects of antacids are discussed separately. (See "Antiulcer medications: Mechanism of action, pharmacology, and side effects", section on 'Adverse effects'.)

Surface agents and alginates — Sucralfate (aluminum sucrose sulfate), a surface agent, adheres to the mucosal surface, promotes healing, and protects from peptic injury by mechanisms that are incompletely understood. However, given the short duration of action and limited efficacy as compared with PPIs, the use of sucralfate is limited to the management of GERD in pregnancy [2,20]. (See 'Pregnancy and lactation' below.)

Sodium alginate is a polysaccharide derived from seaweed that forms a viscous gum that floats within the stomach and neutralizes the postprandial acid pocket in the proximal stomach [21]. Studies evaluating the efficacy of alginates on GERD symptoms and esophageal acid exposure suggest this may be beneficial, especially for post-prandial symptoms in individuals with relatively mild reflux disease [22-25]. They are also used as add on therapy in patients with refractory GERD. (See "Approach to refractory gastroesophageal reflux disease in adults", section on 'Residual acid reflux'.)

Histamine 2 receptor antagonist — Histamine 2 receptor antagonists (H2RAs) decrease the secretion of acid by inhibiting the histamine 2 receptor on the gastric parietal cell. However, the development of tachyphylaxis within two to six weeks of initiation of H2RAs limits their use in the management of GERD [26]. (See 'Mild and intermittent symptoms' above.)

In contrast to antacids, H2RAs have a slower onset of action, reaching peak concentrations 2.5 hours after dosing, but a significantly longer duration of action of 4 to 10 hours [27]. H2RAs are also more effective in decreasing the frequency and severity of heartburn symptoms as compared with antacids and placebo.

However, H2RAs have limited efficacy in patients with erosive esophagitis. While mucosal healing rates in patients with mild erosive esophagitis are 10 to 24 percent higher with H2RA therapy as compared with placebo, H2RAs are ineffective in patients with severe esophagitis [28-30].

Severe or frequent symptoms or erosive esophagitis — We use step-down therapy in patients with erosive esophagitis, frequent symptoms (two or more episodes per week), and/or severe symptoms that impair quality of life in order to optimize symptom relief. We begin with standard-dose PPI once daily for eight weeks in addition to lifestyle and dietary modification (table 1). (See 'Lifestyle and dietary modification' above.)

Proton pump inhibitors — PPIs should be used in patients who fail twice-daily H2RA therapy and in patients with erosive esophagitis and/or frequent (two or more episodes per week) or severe symptoms of GERD that impair quality of life. (See 'Mild and intermittent symptoms' above and "Clinical manifestations and diagnosis of gastroesophageal reflux in adults", section on 'Endoscopic findings'.)

PPIs are the most potent inhibitors of gastric acid secretion by irreversibly binding to and inhibiting the hydrogen-potassium (H-K) ATPase pump. PPIs are most effective when taken 30 to 60 minutes before the first meal of the day because the amount of H-K-ATPase present in the parietal cell is greatest after a prolonged fast. PPIs should be administered daily rather than on-demand because continuous therapy provided better symptom control, quality of life, and higher endoscopic remission rates [31,32]. (See "Proton pump inhibitors: Overview of use and adverse effects in the treatment of acid related disorders", section on 'Dose and timing of administration'.)

PPIs at standard doses for eight weeks relieve symptoms of GERD and heal esophagitis in up to 86 percent of patients with erosive esophagitis [27,33]. There are no major differences in efficacy among PPIs and no consistent increase in symptom resolution or esophagitis healing rates between different doses or dosing regimens of PPI therapy [31]. (See "Proton pump inhibitors: Overview of use and adverse effects in the treatment of acid related disorders", section on 'Pharmacology'.)

As compared with H2RAs, PPIs provide faster symptom relief and are more effective in relieving symptoms of GERD [34-36]. In a meta-analysis of 34 trials that included 1314 individuals, PPIs were significantly more effective than H2RAs in relieving heartburn in patients treated empirically for GERD and in patients with nonerosive reflux disease on upper endoscopy (relative risk [RR] 0.66 and 0.78, respectively) [36]. PPIs are also more effective than H2RAs in healing erosive esophagitis, regardless of the severity of esophagitis and the dose and duration of treatment [28,37,38].

Limitations of PPIs include a higher cost as compared with H2RAs, and potential side effects. The side effects associated with PPIs are discussed separately. (See "Proton pump inhibitors: Overview of use and adverse effects in the treatment of acid related disorders", section on 'Adverse effects'.)

Repeat endoscopy for severe erosive esophagitis — Patients with severe erosive esophagitis (Los Angeles classification Grade C and D) on initial endoscopy should undergo a follow-up endoscopy after a two-month course of PPI therapy to assess healing and rule out Barrett's esophagus. Repeat endoscopy after this follow-up examination is not indicated in the absence of Barrett's esophagus unless patients have bleeding, dysphagia, or a significant change in symptoms while on effective therapy for GERD. (See "Clinical manifestations and diagnosis of gastroesophageal reflux in adults", section on 'Endoscopic findings' and "Barrett's esophagus: Surveillance and management", section on 'Surveillance'.)

SUBSEQUENT MANAGEMENT

PPI refractory symptoms — Patients who fail to respond to once-daily proton pump inhibitor (PPI) therapy are considered to have refractory reflux-like symptoms. We perform a diagnostic endoscopy along with an ambulatory esophageal pH-metry study, ideally after PPIs are stopped for at least two weeks, in patients whose reflux-like symptoms do not respond adequately to an eight-week empiric trial of PPIs [2,39]. This helps phenotype them as refractory GERD, reflux hypersensitivity, or functional heartburn [40]. The management of patients with refractory GERD is discussed separately. (See "Approach to refractory gastroesophageal reflux disease in adults", section on 'Initial assessment'.)

Duration of acid suppression

Patients with erosive esophagitis or Barrett's esophagus — Patients with erosive esophagitis or Barrett's esophagus require maintenance acid suppression with a PPI at standard dose as they are likely to have recurrent symptoms and complications if acid suppression is decreased or discontinued [31,41-44]. The rationale for continuing PPI therapy in patients with Barrett's esophagus is discussed separately. (See "Barrett's esophagus: Surveillance and management", section on 'Management of acid reflux'.)

Patients without erosive esophagitis and Barrett's esophagus — PPIs should be prescribed at the lowest dose and for the shortest duration appropriate to the condition being treated [2,41]. In patients whose classic GERD symptoms respond to an eight-week empiric trial of PPIs, an attempt should be made to discontinue treatment. In patients on PPIs for longer than six months, we taper the PPI dose before discontinuing it and use H2RAs for mild or intermittent symptoms. We discontinue acid suppression completely in asymptomatic patients. (See "Proton pump inhibitors: Overview of use and adverse effects in the treatment of acid related disorders", section on 'Discontinuing PPIs'.)

Recurrent symptoms — Approximately two-thirds of patients with nonerosive reflux disease relapse when acid suppression is discontinued. Patients with recurrent symptoms should be managed with acid suppressive therapy with the medication and dose used to previously control symptoms [42,45,46]. If necessary for symptom control, therapy may be stepped up to medications of increasing potency as with initial therapy (algorithm 1 and table 1).

In patients with recurrent symptoms ≥3 months after discontinuing acid suppression, we use repeated eight-week courses of acid suppressive therapy.

In patients with recurrent symptoms <3 months of discontinuing acid suppression who have not previously undergone an upper endoscopy, we perform an upper endoscopy to rule out other etiologies and complications of GERD. Patients with recurrent symptoms within three months of discontinuing acid suppression require long-term maintenance therapy with a PPI for acid suppression. However, PPI therapy should be used at the lowest effective dose necessary to control GERD symptoms.

The role of surgery and endoscopic therapy in patients with GERD who cannot tolerate long-term PPIs or want to discontinue therapy due to concerns about long-term side effects are discussed separately. (See "Proton pump inhibitors: Overview of use and adverse effects in the treatment of acid related disorders", section on 'Adverse effects' and "Surgical management of gastroesophageal reflux in adults", section on 'Indications for operation' and "Radiofrequency treatment for gastroesophageal reflux disease".)

Indications for referral — Referral to a subspecialist is warranted for patients who fail to respond to once daily PPI therapy (refractory GERD), and patients who cannot tolerate long-term PPIs or want to discontinue therapy. (See "Approach to refractory gastroesophageal reflux disease in adults" and "Surgical management of gastroesophageal reflux in adults" and "Radiofrequency treatment for gastroesophageal reflux disease".)

No role for empiric eradication of H. pylori — It is uncertain whether chronic acid suppression with PPIs increases the risk for atrophic gastritis in patients with H. pylori. Therefore, routine screening for H. pylori infection and empiric eradication of H. pylori are not recommended in patients with GERD [14].

However, if H. pylori is diagnosed in the setting of GERD, eradication of H. pylori has been associated with an improvement of symptoms in patients with antral-predominant gastritis. The treatment of H. pylori in the setting of GERD is discussed separately. (See "Helicobacter pylori and gastroesophageal reflux disease".)

PREGNANCY AND LACTATION — Initial management of gastroesophageal reflux disease (GERD) in pregnancy consists of lifestyle and dietary modification (eg, elevation of the head end of the bed, avoidance of dietary triggers). In patients with persistent symptoms, pharmacologic therapy should begin with antacids followed by sucralfate. In patients who fail to respond, similar to nonpregnant patients, histamine 2 receptor antagonists (H2RAs) and then proton pump inhibitors (PPIs) should be used to control symptoms (table 1). (See 'Mild and intermittent symptoms' above.)

Most antacids are considered safe in pregnancy and are compatible with breastfeeding [47]. However, antacids containing sodium bicarbonate and magnesium trisilicate should be avoided in pregnancy [48]. (See 'Antacids' above.)

Sucralfate is likely safe during pregnancy and lactation because it is poorly absorbed [49]. In patients who continue to have symptoms of GERD despite antacids, we suggest sucralfate (1 g orally three times daily) [50]. In patients with continued GERD symptoms on sucralfate, we use H2RAs [51]. (See 'Surface agents and alginates' above.)

Experience with PPIs is more limited compared with H2RAs, but suggests that PPIs are probably safe in pregnancy [52,53]. Limited data are available on the secretion of PPIs in breast milk. Omeprazole and pantoprazole are secreted in low concentrations in breast milk [54,55]. However, most of this is likely destroyed by gastric acid in the infant's stomach [56]. In pregnant patients with GERD symptoms despite H2RAs, we suggest the use of omeprazole, lansoprazole, or pantoprazole rather than other PPIs, as they have been more widely used in pregnancy. The safety of PPIs in pregnancy has been evaluated in several studies. A meta-analysis of seven observational studies found no significant difference in the risk for major congenital birth defects, spontaneous abortions, or preterm delivery among 1530 women exposed to PPIs during pregnancy as compared with 133,410 who were not exposed to PPIs [52]. A subsequent observational study that evaluated PPI exposure in early pregnancy also found no increase in the risk of major birth defects in 3651 infants exposed to PPIs during the first trimester, as compared with 837,317 infants who had not been exposed [53]. (See 'Proton pump inhibitors' above.)

Upper endoscopy should be performed during pregnancy only if there is a strong indication (eg, significant gastrointestinal bleeding). When possible, endoscopy should be postponed until the second trimester [57]. Obstetrical staff should be closely involved and the degree of maternal and fetal monitoring should be individualized. Recommendations for procedural sedation for endoscopy in pregnant and nursing women are discussed separately. (See "Gastrointestinal endoscopy in adults: Procedural sedation administered by endoscopists", section on 'Special populations'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Gastroesophageal reflux in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Acid reflux and gastroesophageal reflux disease in adults (The Basics)" and "Patient education: H. pylori infection (The Basics)" and "Patient education: Acid reflux (gastroesophageal reflux disease) during pregnancy (The Basics)")

Beyond the Basics topics (see "Patient education: Gastroesophageal reflux disease in adults (Beyond the Basics)" and "Patient education: Helicobacter pylori infection and treatment (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

The optimal approach to the management of gastroesophageal reflux disease (GERD) is controversial. Our management approach to patients with GERD is based on the frequency and severity of symptoms and the presence of erosive esophagitis or Barrett’s esophagus on upper endoscopy, if previously performed (algorithm 1). (See 'Pretreatment evaluation' above and "Clinical manifestations and diagnosis of gastroesophageal reflux in adults", section on 'Indications'.)

We suggest lifestyle and dietary modification in all patients with GERD (Grade 2C). (See 'Lifestyle and dietary modification' above.)

In patients with mild and intermittent (less than two episodes per week) symptoms of GERD who are naïve to treatment and no evidence of erosive esophagitis or Barrett’s esophagus, we suggest as needed low-dose histamine 2 receptor antagonists (H2RAs) (table 1) (Grade 2B). Concomitant antacids, and/or sodium alginate can be used if symptoms occur less than once a week. In patients with continued symptoms, we increase the dose of H2RAs to standard dose, twice daily for a minimum of two weeks. (See 'Antacids' above and 'Overall approach' above.)

If symptoms of GERD persist, we discontinue H2RAs and initiate once-daily proton pump inhibitors (PPIs) at a low dose (Grade 2B) and then increase to standard doses if required for symptom control (table 1). Once symptoms are controlled, therapy should be continued for at least eight weeks. (See 'Histamine 2 receptor antagonist' above and 'Overall approach' above.)

In patients with erosive esophagitis, we recommend initial acid suppressive therapy with standard-dose PPI once daily (table 1) (Grade 1A). (See 'Overall approach' above and 'Proton pump inhibitors' above.)

In patients with frequent (two or more episodes per week), severe symptoms that impair quality of life or Barrett’s esophagus, we suggest initial therapy with standard-dose PPI once daily (Grade 2B). (See 'Overall approach' above and 'Proton pump inhibitors' above.)

Referral to a subspecialist is warranted for patients who fail to respond to once-daily PPI therapy and patients who cannot tolerate long-term PPIs or want to discontinue therapy. (See 'PPI refractory symptoms' above.)

We discontinue acid suppression in all patients with GERD whose symptoms resolve completely with treatment, with the exception of those with erosive esophagitis on upper endoscopy and Barrett's esophagus. (See 'Duration of acid suppression' above.)

In patients with recurrent symptoms within three months of discontinuing acid suppression, we continue long-term maintenance therapy with a PPI. However, if symptoms occur after three or more months, we use repeated eight week courses of previously effective acid suppressive therapy (algorithm 1) (see 'Recurrent symptoms' above).

Management of GERD in pregnancy includes lifestyle and dietary modification followed by pharmacologic therapy with antacids and sucralfate. Antacids containing sodium bicarbonate and magnesium trisilicate should be avoided in pregnancy. In patients who fail to respond, similar to nonpregnant patients, H2RAs and then PPIs are used to control symptoms. (See 'Pregnancy and lactation' above and 'Mild and intermittent symptoms' above.)

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Topic 2258 Version 50.0

References

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2 : ACG Clinical Guideline for the Diagnosis and Management of Gastroesophageal Reflux Disease.

3 : High- versus standard-dose ranitidine for control of heartburn in poorly responsive acid reflux disease: a prospective, controlled trial.

4 : The medical management of reflux esophagitis. Role of antacids and acid inhibition.

5 : Step-down management of gastroesophageal reflux disease.

6 : Step-down from multiple- to single-dose proton pump inhibitors (PPIs): a prospective study of patients with heartburn or acid regurgitation completely relieved with PPIs.

7 : Proton pump inhibitor step-down therapy for GERD: a multi-center study in Japan.

8 : Are lifestyle measures effective in patients with gastroesophageal reflux disease? An evidence-based approach.

9 : Nonlinear relationship between body mass index and esophageal acid exposure in the extraesophageal manifestations of reflux.

10 : Relationship between upper gastrointestinal symptoms and changes in body weight in a population-based cohort.

11 : Gastroesophageal reflux in obese patients is not reduced by weight reduction.

12 : Body-mass index and symptoms of gastroesophageal reflux in women.

13 : Weight loss and reduction in gastroesophageal reflux. A prospective population-based cohort study: the HUNT study.

14 : Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease.

15 : Lifestyle Intervention in Gastroesophageal Reflux Disease.

16 : Association Between Beverage Intake and Incidence of Gastroesophageal Reflux Symptoms.

17 : Positive effect of abdominal breathing exercise on gastroesophageal reflux disease: a randomized, controlled study.

18 : Tobacco smoking cessation and improved gastroesophageal reflux: a prospective population-based cohort study: the HUNT study.

19 : Association of Diet and Lifestyle With the Risk of Gastroesophageal Reflux Disease Symptoms in US Women.

20 : Sucralfate gel versus placebo in patients with non-erosive gastro-oesophageal reflux disease.

21 : An alginate-antacid formulation localizes to the acid pocket to reduce acid reflux in patients with gastroesophageal reflux disease.

22 : Randomized, multicentre comparison of sodium alginate and cisapride in the symptomatic treatment of uncomplicated gastro-oesophageal reflux.

23 : Post-prandial reflux suppression by a raft-forming alginate (Gaviscon Advance) compared to a simple antacid documented by magnetic resonance imaging and pH-impedance monitoring: mechanistic assessment in healthy volunteers and randomised, controlled, double-blind study in reflux patients.

24 : Randomised clinical trial: sodium alginate oral suspension is non-inferior to omeprazole in the treatment of patients with non-erosive gastroesophageal disease.

25 : Randomised clinical trial: relief of upper gastrointestinal symptoms by an acid pocket-targeting alginate-antacid (Gaviscon Double Action) - a double-blind, placebo-controlled, pilot study in gastro-oesophageal reflux disease.

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32 : Esomeprazole 20 mg on-demand is more acceptable to patients than continuous lansoprazole 15 mg in the long-term maintenance of endoscopy-negative gastro-oesophageal reflux patients: the COMMAND Study.

33 : Acid suppression for reflux disease: "off-the-peg" or a tailored approach?

34 : Speed of healing and symptom relief in grade II to IV gastroesophageal reflux disease: a meta-analysis.

35 : Response of regurgitation to proton pump inhibitor therapy in clinical trials of gastroesophageal reflux disease.

36 : Short-term treatment with proton pump inhibitors, H2-receptor antagonists and prokinetics for gastro-oesophageal reflux disease-like symptoms and endoscopy negative reflux disease.

37 : Proton pump inhibitors in acute healing and maintenance of erosive or worse esophagitis: a systematic overview.

38 : Head-to-head comparison of H2-receptor antagonists and proton pump inhibitors in the treatment of erosive esophagitis: a meta-analysis.

39 : Ambulatory Reflux Monitoring Guides Proton Pump Inhibitor Discontinuation in Patients With Gastroesophageal Reflux Symptoms: A Clinical Trial.

40 : Advances in the diagnosis and management of gastroesophageal reflux disease.

41 : Lansoprazole for long-term maintenance therapy of erosive esophagitis: double-blind comparison with ranitidine.

42 : A comparison of five maintenance therapies for reflux esophagitis.

43 : Three year follow up of patients with gastrooesophageal reflux disease.

44 : Three year follow up of patients with gastrooesophageal reflux disease.

45 : Omeprazole v ranitidine for prevention of relapse in reflux oesophagitis. A controlled double blind trial of their efficacy and safety.

46 : Effective maintenance treatment of reflux esophagitis with low-dose lansoprazole. A randomized, double-blind, placebo-controlled trial.

47 : Comparison of cimetidine (Tagamet) with antacid for safety and effectiveness in reducing gastric acidity before elective cesarean section.

48 : The effects of chronic gastrointestinal medication on the fetus and neonate.

49 : The effects of chronic gastrointestinal medication on the fetus and neonate.

50 : Sucralfate in the treatment of gravidic pyrosis

51 : Double-blind, placebo-controlled study of ranitidine for gastroesophageal reflux symptoms during pregnancy.

52 : The safety of proton pump inhibitors (PPIs) in pregnancy: a meta-analysis.

53 : Use of proton-pump inhibitors in early pregnancy and the risk of birth defects.

54 : Omeprazole for refractory gastroesophageal reflux disease during pregnancy and lactation.

55 : Excretion of pantoprazole in human breast.

56 : Excretion of pantoprazole in human breast.

57 : Guidelines for endoscopy in pregnant and lactating women.