The Clinical Management of Gastroesophageal Reflux Disease

Release Date: December 1, 2013

Expiration Date: December 31, 2015

FACULTY:

Golden L. Peters, PharmD, BCPS
Assistant Professor, Pharmacy Practice
St. Louis College of Pharmacy
Clinical Pharmacy Specialist, Ambulatory Care
Veterans Affairs St. Louis Health Care System,
John Cochran Division

P. Benjamin Erwin, PharmD, BCPS
Assistant Professor, Pharmacy Practice
St. Louis College of Pharmacy
Clinical Pharmacy Specialist, Ambulatory Care
Veterans Affairs St. Louis Health Care System,
John Cochran Division

Matthew K. Pitlick, PharmD, BCPS
Assistant Professor, Pharmacy Practice
St. Louis College of Pharmacy
Clinical Pharmacy Specialist, Ambulatory Care
Veterans Affairs St. Louis Health Care System,
John Cochran Division

Shin-Yu Lee, PharmD
Assistant Professor, Pharmacy Practice
St. Louis College of Pharmacy
Clinical Pharmacist, Ambulatory Care
SSM St. Mary's Internal Medicine Clinic
St. Louis, Missouri

FACULTY DISCLOSURE STATEMENTS:

Drs. Peters, Erwin, Pitlick, and Lee have no actual or potential conflicts of interest in relation to this activity.

Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

ACCREDITATION STATEMENT:

Pharmacy
acpePostgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
UAN: 0430-0000-13-033-H01-P
Credits: 2.0 hours (0.20 ceu)
Type of Activity: Knowledge

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Payment of $6.50 required for exam to be graded.

TARGET AUDIENCE:

This accredited activity is targeted to pharmacists. Estimated time to complete this activity is 120 minutes.

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DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients' conditions and possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with recommendations of other authorities.

GOAL:

To provide participants with an overview of the pathophysiology, symptoms, complications, risk factors, diagnosis, and treatment options for gastroesophageal reflux disease (GERD).

OBJECTIVES:

After completing this activity, the participant should be able to:

  1. Define GERD and describe its pathophysiology.
  2. List the risk factors, symptoms, and complications of GERD.
  3. Explain lifestyle modifications for the treatment of GERD.
  4. Differentiate between treatment options for GERD and discuss the role of maintenance therapy for GERD.


ABSTRACT: The management of gastroesophageal reflux disease (GERD) is vital for maintaining patients' quality of life and reducing the risk of complications. Risk factors for GERD include obesity, family history, alcohol consumption, respiratory disease, reflux chest pain, particular medications, and certain foods. Practice guidelines emphasize lifestyle modifications and acid suppression. The three major types of medications utilized for acid suppression are antacids, histamine2-receptor antagonists, and proton pump inhibitors. The drug choice depends upon patient presentation. Goals of treatment include symptom alleviation, prevention of complications, mucosal healing, and reduced disease and symptom frequency. Pharmacists play an important role in identifying appropriate OTC agents for treatment, recognizing alarm symptoms, and advising patients who need more care to immediately seek medical attention.

Gastroesophageal reflux disease (GERD) develops when the reflux of stomach contents causes symptoms that are troublesome.1 It is the most commonly occurring gastrointestinal (GI) diagnosis during outpatient visits.2 Episodic heartburn is not considered under this definition of GERD, since it is not painful or recurrent enough to severely influence quality of life.3

The prevalence of GERD is estimated to range from 10% to 20% in the Western world, with a lesser prevalence in Asia. A recent update revealed that GERD is geographically widespread and that its prevalence is increasing.4 Only East Asia continues to show rates of less than 10%.5 The exact prevalence and incidence are challenging to determine, since patients do not always seek treatment and there is no universal definition for diagnosis.6

There is no significant association between GERD and gender, except during pregnancy and in the development of Barrett's esophagus (BE).4,6,7 BE, which occurs predominantly in adult white males, is more prevalent after age 50 years.4 A major area of concern is the increasing disease burden of esophageal adenocarcinoma, since there has been an upsurge in incidence by a factor of 2 to 6 in the last 20 years.2

Recently, updated practice guidelines for the diagnosis and management of GERD were published in the American Journal of Gastroenterology.4 Lifestyle modifications (LSM) and pharmacotherapy remain the key components of therapy for GERD management.4

Definition

Although there are multiple consensus definitions for GERD, the working definition utilized by current guidelines on the disorder describe GERD as symptoms or complications that result from the reflux of gastric contents into the esophagus or beyond, into the oral cavity or lung.4 Because heartburn is one of the most common and typical symptoms of GERD, it is important to distinguish it from GERD itself, which develops when reflux causes troublesome symptoms and/or complications.3 By this definition, as previously discussed, episodic heartburn would not be considered GERD unless the patient found his or her symptoms to be troublesome or if there were complications. Complications of GERD include esophagitis, esophageal stricture, BE, and adenocarcinoma.

Pathophysiology

The pathophysiology of GERD is a complicated cyclical process, and determining the primary etiology is challenging. One of the prevailing etiologies proposed for GERD is the failure of the lower esophageal sphincter (LES) to maintain adequate pressure (i.e., function to keep gastric contents in the stomach).6 LES relaxation has been associated with certain medications, foods, and spontaneous transient causes.6 Also thought to contribute to reflux are atony of the LES and transient increases in intra-abdominal pressure. Prolonged esophageal clearance has been associated with reflux, especially in patients with impaired peristalsis or reduced salivation.8 Delayed gastric emptying, acidic composition of the refluxate, and poor esophageal mucosal resistance all have been found to contribute to GERD.6 Many of the therapeutic options for GERD target these proposed mechanisms.

Symptoms and Complications

Although heartburn, hypersalivation, and regurgitation are considered the typical reflux symptoms of GERD, many other symptoms have been associated with the disorder. Atypical symptoms such as nausea, bloating, chest pain, and belching may be indicative of GERD; however, because these symptoms may overlap with those of other conditions, other diseases must be ruled out.4 Reflux chest pain, an atypical symptom of GERD, may also be associated with cardiac causes; it is recommended that patients seek medical care to rule out cardiac causes before the symptom can be attributed to GERD.4 Several symptoms, called alarm symptoms, may be associated with GERD and warrant a referral for further diagnostic evaluation to differentiate other diseases as the cause. An esophagogastroduodenoscopy (EGD) may indicate complications of GERD or other GI disorders, such as peptic ulcer disease.6 Alarm symptoms include dysphagia, odynophagia, unintentional weight loss, blood in the stool, and persistent vomiting (TABLE 1).6


tbl1

The complications of GERD, such as esophagitis and BE, are classified as syndromes with esophageal injury. Extraesophageal symptoms—cough, laryngitis, asthma, and dental erosions—also have been associated with reflux.3 Other extraesophageal symptoms, such as sinusitis and recurrent otitis media, have been proposed; however, there is not significant evidence to support a relationship.3

Risk Factors

Knowledge of the many factors that can increase the risk of developing GERD can help the pharmacist make nonpharmacologic recommendations to patients experiencing GERD symptoms. Obesity, smoking, and alcohol consumption increase the risk of GERD. Pregnancy and respiratory diseases also put patients at risk for GERD. Food and medications are some of the most common risk factors for GERD. High-fat foods, chocolate, garlic, peppermint, and caffeine can potentially reduce LES pressure, making it easier for reflux to make its way into the esophagus. Spicy foods, colas, red wine, and tomato-based foods can cause direct irritation to the GI mucosa, which may lead to symptoms of GERD. Medications such as anticholinergics, nitrates, dihydropyridine calcium channel blockers, nonsteroidal antiinflammatory drugs, and tetracycline also are risk factors for GERD (TABLE 2).6


tbl2

Diagnosis

Although several tools and tests are available to aid in the diagnosis of GERD and its potential complications, a noninvasive diagnosis of GERD can be challenging. For patients with typical heartburn and regurgitation symptoms, an empiric trial of a proton pump inhibitor (PPI) is recommended. If the patient responds to therapy, a presumptive diagnosis is made. A patient who presents with significant chest pain must first have cardiac causes ruled out before any additional diagnosis can be made. An EGD should be performed to visualize potential complications in patients who have alarm symptoms of GERD or are at high risk for complications. Males who are overweight, are older than 50 years, and have chronic GERD symptoms are considered to be at high risk. Barium radiograph, esophageal biopsy, and esophageal manometry should not be used to diagnose GERD, although esophageal manometry may be useful for preoperative evaluation in patients who may be candidates for antireflux surgery. Ambulatory esophageal reflux monitoring, which can be done via either telemetry capsule or transnasal catheter, can be useful for symptoms associated with reflux; however, it is recommended only for preoperative evaluation of nonerosive disease, refractory GERD symptoms, and situations in which the diagnosis of GERD is in question.4

Management

Medication therapy for GERD includes antacids, histamine2-receptor antagonists (H2RAs), PPIs, and prokinetic (promotility) agents.9 For patients who are unsuccessful with LSM, the best treatment options include antacids, H2RAs, and PPIs.4 Pharmacologic treatment for GERD is divided into nonprescription-strength and prescription-strength therapy. Antacids, H2RAs, and some PPIs are available as OTC products. Prokinetic agents, H2RAs, and PPIs are available by prescription.

The goals of GERD treatment are to reduce or eliminate symptoms, lessen the frequency and duration of reflux, induce healing of any damaged mucosa, and prevent complications. The approach generally depends upon the patient's current presentation (i.e., frequency of symptoms, complications, and presence of esophagitis). In the past, a step-up approach involving 1) LSM, 2) nonprescription-strength pharmacologic therapy, and 3) prescription-strength pharmacologic therapy was used. Current treatment for GERD should be individually focused.6

Treatment Overview

Acid-suppression therapy with PPIs and H2RAs is the mainstay of GERD treatment. Nonprescription therapy is appropriate for patients with mild-to-intermediate symptoms (<2 episodes/week). Patients presenting with moderate-to-severe symptoms (≥2 episodes/week; severe symptoms impairing quality of life) should be initiated on PPI therapy (TABLE 3).6 PPIs are the drug of choice because they provide the most rapid relief of symptoms and superior healing.10 Stepping down from PPI therapy to H2RA therapy is an acceptable option in patients with nonerosive GERD symptoms. GERD symptoms lasting longer than 2 weeks should be evaluated by the patient's primary care provider (PCP).4,6


tbl3

Combination therapy with acid-suppression and prokinetic agents does not improve GERD symptoms and should not be employed. Adding an H2RA to a PPI regimen to relieve nocturnal symptoms has been found effective; however, the efficacy declines with time owing to tachyphylaxis caused by the H2RA.11 In determining appropriate therapy for GERD, characteristics of several patient populations should be taken into account, including patients presenting with atypical GERD symptoms, pediatric patients, elderly patients, and patients with refractory GERD. These populations may require individualized dosing and treatment schedules and more specific LSM (e.g., dietary adjustments, postural management, parental reassurance [pediatric population]).6

Treatment Options

LSM: Recommendations for LSM should be tailored to the individual patient. It is imperative for the pharmacist to discuss the benefits of LSM with patients experiencing GERD symptoms. Many patients are noncompliant with LSM recommendations, and many who do comply will eventually require acid-suppression therapy (TABLE 4).4,6


tbl4

Antacids: Antacids neutralize gastric fluids to decrease pepsin activity and increase LES pressure. They provide rapid, short-term relief from GERD symptoms, but cannot sustain acid suppression overnight.9 Antacids, which are available OTC, are recommended to patients as a rapid-acting option for the treatment of mild GERD symptoms.9 Antacids are the most beneficial treatment for short-term, occasional, postprandial GERD symptoms; however, they have not been shown to promote healing of erosive esophagitis. They can be utilized in combination with other acid-suppression therapy. Antacids are generally the most cost-effective option for GERD symptoms. Antacids should not be used for more than 2 weeks without PCP involvement.12 Patients requiring chronic use of antacids for GERD symptom relief should be started on prescription-strength acid suppression therapy. TABLE 5 lists the available antacid and alginic acid products and provides dosing information.6,9,13,14


tbl5

The different types of antacids have varying adverse events (AEs). AEs for aluminum-based products include hypophosphatemia, bone demineralization, constipation, and aluminum accumulation; diarrhea is an AE for magnesium products; and AEs for bismuth subsalicylate products include GI upset, tinnitus, and Reye syndrome.15 Antacids interact with multiple medications owing to 1) formation of insoluble complexes with other medications (tetracycline, fluoroquinolones, azithromycin) and 2) alteration of medication absorption by increasing gastric pH (ferrous sulfate, ketoconazole, itraconazole).6

Prokinetic Agents: Prokinetic agents activate cholinergic or dopaminergic receptors to increase LES pressure and gastric peristalsis. This helps treat delayed esophageal clearance in patients with GERD.16 These agents have a slow onset of action and provide short-term relief (4-8 hours).17 Prokinetic agents lack efficacy as acid-suppression therapy and have not been shown to promote healing of esophagitis. Compared with H2RAs and PPIs alone, only modest improvements are achieved by combining prokinetic agents with acid-suppression therapy. Prokinetic agents are useful as an adjunct to acid-suppression therapy in patients with motility defects. Prokinetic agents have undesirable AEs and have limited effectiveness in treating or reducing GERD symptoms.

Metoclopramide, a dopamine antagonist, increases LES pressure and gastric emptying. Although metoclopramide results in symptom improvement in some patients with GERD, there is no clear role for its use in GERD treatment.4 The use of metoclopramide has been limited owing to tachyphylaxis and its AE profile. Metoclopramide can cause extrapyramidal side effects (dystonia, akathisia, tardive dyskinesia), sedation, and irritability.18 This agent should not be used in Parkinson's disease or concomitantly with dopamine antagonists or anticholinergic agents. Metoclopramide (Reglan) is typically dosed at 10 to 15 mg by mouth four times per day.13,14

Cisapride has comparable efficacy to H2RAs in treating mild GERD symptoms. It has caused life-threatening arrhythmias and is no longer available in the United States, except through a limited-access program from the manufacturer. Cisapride (Propulsid) is typically dosed at 10 to 20 mg by mouth four times per day.13,14 Prokinetic agents should not be used to treat GERD without a diagnostic evaluation.4,6

H2RAs: H2RAs competitively inhibit histamine at H2 receptors of gastric parietal cells; this inhibits gastric acid secretion and volume and increases gastric pH. H2RAs that are available both OTC and by prescription include cimetidine, famotidine, nizatidine, and ranitidine (TABLE 6).13,14 Compared with antacids, H2RAs have a slower onset of action, but a longer duration of action. Patients with mild-to-moderate GERD symptoms can be treated effectively with H2RAs in divided doses.10 H2RAs prevent GERD symptoms when taken prior to meals or drinks that are known to cause irritation.15 They are not as effective as PPIs for healing erosive esophagitis.19 Prolonged use of H2RAs is not recommended, owing to the development of tolerance within 1 to 2 weeks.9 These agents should not be used for more than 2 weeks without involvement of a healthcare provider.12


tbl6

The effectiveness of H2RAs in the treatment of GERD is variable. Multiple factors play a role in determining H2RA response, including disease severity, duration of therapy, and regimen. Low doses or standard doses (twice per day) of H2RAs are indicated for mildto-moderate GERD. All H2RAs possess similar efficacy; when selecting an agent, the pharmacokinetics, cost, and safety profile should be considered. In general, H2RAs are well tolerated.6

AEs associated with H2RA therapy include headaches, somnolence, fatigue, diarrhea, constipation, and dizziness. Clinically significant drug interactions occur with cimetidine, which is a moderate inhibitor of CYP1A2, CYP2C19, and CYP3A4. Medications that interact with cimetidine include theophylline, warfarin, phenytoin, nifedipine, and propranolol.6 For all H2RA agents, a decline in renal function may require dosage adjustment or discontinuation of therapy. H2RAs are contraindicated during pregnancy.6,13,14

PPIs: PPIs block gastric acid secretion by inhibiting gastric H+/K+ adenosine triphosphatase in gastric parietal cells. PPIs that are available OTC include omeprazole (20 mg) and lansoprazole (15 mg). Prescriptionstrength PPIs include dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole (TABLE 7).5,13,14 PPIs are the drug of choice for treating GERD symptoms. Their duration of action is longer, but the time to onset is longer compared with prokinetic agents, antacids, and H2RAs. It may take 1 to 4 days to achieve full symptom relief.9,12


tbl7

PPIs are more effective than H2RAs for treating moderate-to-severe GERD symptoms. In patients with erosive esophagitis, PPI therapy has been associated with increased healing rates and reduced relapse rates compared with H2RA therapy.20 In treating nonerosive GERD, PPI therapy was superior to H2RA and prokinetic therapy for symptom relief.21 The drug of choice for symptom relief and healing erosive esophagitis is a PPI taken for 8 weeks. In patients with partial response to PPI therapy, the regimen may be increased to twice daily, or changed to a different PPI. A comparison of PPIs found no major differences between them.

Because PPIs degrade in acidic environments, they are produced as delayed-release capsules or tablets. Lansoprazole, esomeprazole, and omeprazole are available as capsules containing enteric-coated granules that can be mixed in applesauce or orange juice for pediatric patients or patients unable to swallow capsules. Esomeprazole granules can be dispersed in water. Lansoprazole is available as packets for oral suspension and as oral disintegrating tablets. Pantoprazole and rabeprazole should not be cut, crushed, or chewed. Omeprazole also is formulated as delayed-release tablets and in combination with sodium bicarbonate as immediate-release capsules and oral suspension (Zegerid). Zegerid, the first PPI formulated as an immediate-release product, should be taken on an empty stomach at least 1 hour prior to meals.6

Dexlansoprazole, the newest PPI on the market, is a dual delayed-release tablet. The first phase occurs 1 to 2 hours after the dose is taken; the second phase is 4 to 5 hours after the dose is taken. Dexlansoprazole may be taken without regard to meals.6 Delayed-release PPIs should be taken 30 to 60 minutes before meals. PPI therapy should be initiated as once-daily dosing before breakfast. Patients who fail to respond to once-daily dosing can implement personalized regimens, altering dose timing and/or dosing twice daily (in patients with nocturnal symptoms). Patients who do not respond to PPI therapy should be referred to their healthcare provider.4

PPIs are generally well tolerated; however, there are precautions and AEs. Precautions for PPI use include nonresponse, rebound gastritis, atrophic gastritis, Helicobacter pylori or Clostridium difficile infection, and community-acquired pneumonia (CAP).4,9 Literature is conflicting regarding whether PPIs are a risk factor for CAP. There is some evidence that short-term, but not long-term, PPI use can increase the risk of CAP.4 AEs associated with PPI therapy include headache, nausea, insomnia, and dyspepsia (<2% of patients). Other potential AEs include vitamin and mineral deficiencies, hip fractures, osteoporosis, and diarrhea.18 If AEs are present, switching the patient to a different PPI should be considered. PPIs are safe to take during pregnancy when clinically indicated.

PPIs may play a role in the acquisition of C difficile infections during acid suppression, so special care should be exercised in at-risk patients.4 During acid suppression, the patient may have reduced host defenses against ingested spores and bacteria, leading to an increased risk of exposure.22,23

All PPIs decrease absorption of ketoconazole and itraconazole by elevating the gastric pH, thus reducing absorption. All PPIs are metabolized to some extent by CYP2C19 and CYP3A4 enzymes. There has been concern about the concomitant use of clopidogrel with PPIs, specifically omeprazole.24,25 Clopidogrel is a prodrug that is converted via the CYP2C19 and CYP3A4 enzymes. Inhibition of the CYP2C19 enzyme by PPIs has been thought to decrease the effectiveness of clopidogrel, potentially leading to cardiovascular AEs. However, according to current recommendations, patients receiving clopidogrel therapy do not need their PPI therapy changed, since evidence does not support an increased risk of cardiovascular AEs.4

Maintenance Therapy

A large number of patients who have achieved GERD symptom relief will relapse once therapy is discontinued.26 These patients should be considered for long-term maintenance therapy. Maintenance therapy is intended to reduce symptoms and complications, thus improving the patient's quality of life. In most cases, the therapy used to achieve initial relief should not be decreased or changed to a less effective agent. Patients should be educated on LSM and long-term maintenance therapy with standard dosing to prevent relapse.10 H2RAs can be used for maintenance in patients with mild GERD symptoms. PPIs are the drug of choice in patients with moderate-to-severe GERD symptoms.

The long-term use of PPIs at higher doses than is standard is not indicated. Ranitidine 150 mg twice daily is the only FDA-approved H2RA for maintenance therapy. H2RA therapy can be added at bedtime to regimens with PPIs if nocturnal symptoms are present; however, the addition of H2RA therapy has been associated with tachyphylaxis after several weeks. Concerns about hip fractures and osteoporosis should not affect long-term PPI use, unless other risk factors for hip fractures are present.4

Role of the Pharmacist

The pharmacist can provide many services to the patient with GERD. The pharmacist is often one of the first healthcare providers whom a patient contacts about GERD-like symptoms. As the first line of defense, the pharmacist must be able to assess the patient's symptoms, the frequency of symptoms, and any exacerbating issues. The pharmacist should then recommend an OTC product to the patient, discuss prescription medications, or refer the patient to his or her medical provider.27 Exclusion criteria for self-treatment include frequent heartburn (>3 months); heartburn and/or dyspepsia while taking recommended dosages of a nonprescription H2RA or PPI; heartburn that continues after 2 weeks of treatment with a nonprescription H2RA or PPI; worsening or severe symptoms; nocturnal heartburn; pregnancy or nursing; and pediatric patients younger than 2 years (antacids), younger than 12 years (H2RAs), or younger than 18 years (PPIs).27

In addition to recommending medication therapy, the pharmacist can educate the patient in depth about GERD, including conventional symptoms, alarm symptoms, LSM, and specific details about the medication therapy (e.g., time of day to take drug, duration of therapy, AEs, drug interactions, and adherence).

Another key role for the pharmacist is in advising patients and providers regarding discontinuation of inappropriate PPI use. The pharmacist can take the lead in recommending step-down therapy or discontinuing the PPI after 8 weeks of initial treatment of GERD symptoms. The pharmacist should also educate patients and providers about possible long-term AEs with continuous PPI use.

REFERENCES

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  3. Kahrilas PJ, Shaheen NJ, Vaezi MF, et al. American Gastroenterological Association Medical Position Statement on the management of gastroesophageal reflux disease. Gastroenterology. 2008;135:1383-1391.
  4. Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol. 2013;108:308-328.
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  22. Aseeri M, Schroeder T, Kramer J, Zackula R. Gastric acid suppression by proton pump inhibitors as a risk factor for Clostridium difficile-associated diarrhea in hospitalized patients. Am J Gastroenterol. 2008;103:2308-2313.
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