- ACRONYMS AND DEFINITIONS
- ACG - American College of Gastroenterology
- AGA - American Gastroenterology Association
- BE - Barrett's esophagus
- EE - Erosive esophagitis
- GERD - Gastroesophageal reflux disease
- H2RA - Histamine-2-receptor antagonists (e.g. Pepcid)
- ODT - Orally disintegrating tablet
- OTC - Over-the-counter
- P = Drugs with pediatric dosing
- PPI - Proton pump inhibitor
- PREVALENCE
- The worldwide prevalence of GERD among adults is approximately 13.3%, and in developed nations, 10 - 20% of people report symptoms of heartburn or regurgitation at least once weekly. In the U.S., GERD is the number one gastrointestinal complaint seen in outpatient clinics. GERD increases with age, with 14% of adults less than 50 years being affected and 17.3% of those over 50 reporting symptoms. [4,5]
- PATHOLOGY
- GERD occurs when stomach acid rises above the gastroesophageal junction and comes in contact with the esophagus. The lower esophageal sphincter protects the esophagus from stomach acid by contracting and closing the junction between the two structures. The sphincter relaxes under the following conditions : (1) to allow passage of food during eating, (2) in response to gastric distension to facilitate the release of gas (belching). GERD can happen if the sphincter does not close properly and/or relaxation is prolonged. Other conditions, including delayed gastric emptying and esophageal body dysfunction, can also contribute to GERD.
- The main symptoms of GERD are heartburn and regurgitation of food or acid [4,5]
- RISK FACTORS
- Obesity and overweight - increases intra-abdominal pressure
- Hiatal hernia
- Tobacco products/smoking
- Family history
- Delayed gastric emptying
- Impaired esophageal peristalsis
- Bariatric surgery - gastric sleeve (sleeve gastrectomy) increases the risk for GERD and gastric bypass (RYGB) is a treatment for GERD (see weight loss procedures for more)
- Intragastric balloon
- Pregnancy - increases intra-abdominal pressure [4,5]
- SYMPTOMS
- Classic symptoms
- Classic symptoms of GERD include the following:
- Heartburn - substernal burning sensation rising from the epigastrium up toward the neck
- Regurgitation - effortless return of gastric contents upward toward the mouth, often accompanied by an acid or bitter taste
- Symptoms may be worse after eating and/or at night when lying down [1]
- Alarm symptoms
- Alarm symptoms may indicate that something more concerning than GERD is causing the patient's complaints
- Alarm symptoms include the following:
- Dysphagia (difficulty swallowing)
- Odynophagia (painful swallowing)
- Weight loss
- Hematemesis
- GI bleeding
- Vomiting
- Anemia [1]
- Extraesophageal symptoms
- A number of symptoms involving the pharynx, larynx, and lungs have been attributed to GERD, and while GERD may play a role in these conditions, other etiologies must be ruled out before GERD is implicated. Examples of extraesophageal GERD symptoms include the following:
- Chronic cough
- Throat-clearing
- Hoarseness
- Globus sensation (sensation of a lump in throat)
- Laryngitis
- Asthma [1]
- BARRETT'S ESOPHAGUS
- Overview
- Barrett's esophagus (BE) is metaplastic change of the distal esophagus, whereby the normal squamous epithelium is replaced by specialized columnar epithelium with goblet cells. Barrett's esophagus is a precursor to esophageal adenocarcinoma, and it is staged in the following manner:
- Non-dysplastic BE - metaplasia without dysplasia; rarely progresses to cancer (0.39%/year); endoscopic surveillance is recommended
- BE with low-grade dysplasia - annual risk for progression to cancer is 1 - 3%; surveillance is recommended and treatment may be appropriate in some patients
- BE with high-grade dysplasia - annual risk for progression to cancer is 5 - 10%; treatment is recommended
- Risk factors for Barrett's esophagus include:
- Chronic GERD
- Male sex
- Age > 50 years
- White race
- Tobacco smoking
- Obesity
- First-degree relative with Barrett's esophagus or esophageal adenocarcinoma [2,3]
- Treatment
- Treatment recommendations from the ACG are available here - ACG 2022 Guidelines on Barrett's Esophagus
- DIAGNOSIS (ACG 2021 RECOMMENDATIONS)
- Patients with classic symptoms (heartburn, regurgitation) and no alarm symptoms
- Prescribe an 8-week trial of empiric PPIs once daily before a meal
- If symptoms resolve, attempt to discontinue PPI after 8 weeks
- If symptoms do not resolve or return after PPI discontinuation, endoscopy is recommended
- Patients with alarm symptoms or multiple risk factors for Barrett's esophagus
- Endoscopy is recommended
- Other
- Barium swallow is not recommended as a diagnostic test for GERD
- In patients for whom the diagnosis of GERD is suspected but not clear, and endoscopy shows no objective evidence of GERD, reflux monitoring off therapy is recommended to establish the diagnosis
- In patients who have chest pain without heartburn and who have had adequate evaluation to exclude heart disease, objective testing for GERD (endoscopy and/or reflux monitoring) is recommended [1]
- TREATMENT (ACG 2021 RECOMMENDATIONS)
- Behavioral therapy
- Weight loss in overweight and obese patients
- Avoiding meals within 2 - 3 hours of bedtime
- Avoidance of tobacco products/smoking
- Avoidance of "trigger foods" such as coffee, chocolate, carbonated beverages, spicy foods, acidic foods such as citrus and tomatoes, and foods with high-fat content
- For patients with nighttime GERD symptoms, elevating the head of the bed
- Acid-suppressing medications
- PPIs are recommended over H2RAs (e.g. Pepcid)
- PPIs should be administered 30 - 60 minutes before a meal rather than at bedtime
- Patients with GERD (without Barrett's esophagus or erosive esophagitis) whose symptoms resolved with PPI therapy should attempt to discontinue their PPI and switch to on-demand therapy
- Patients with GERD who require maintenance PPI therapy should use the lowest effective PPI dose
- Other medications
- Prokinetic agents are not recommended unless there is objective evidence of gastroparesis
- Sucralfate is not recommended except during pregnancy
- Baclofen is not recommended
- Refractory GERD
- Patients with GERD that is refractory to PPI therapy should have further evaluation, which may include endoscopy and/or esophageal pH monitoring
- Switching to another PPI may be tried, but more than one switch is not supported
- Increasing PPI therapy to twice-daily dosing (before breakfast and dinner) has been shown to be effective in some studies and may be tried [1]
- Extraesophageal symptoms
- Patients with extraesophageal GERD symptoms should have a detailed medical history to look for non-GERD etiologies. If a non-GERD etiology seems likely and/or the patient does not have typical GERD symptoms (heartburn, regurgitation), further evaluation for non-GERD causes should be performed.
- For patients with typical (heartburn, regurgitation) and extraesophageal GERD symptoms, an 8 - 12 week trial of twice-daily PPI therapy may be tried before additional testing
- Patients with extraesophageal GERD symptoms who do not have typical GERD symptoms (heartburn, regurgitation) should undergo reflux testing before PPI therapy is tried [1]
- PROTON PUMP INHIBITORS (PPIs)
- Overview
- PPIs are some of the most widely consumed medications in the world, and they have largely replaced H2RAs (e.g. Pepcid) as the preferred treatment for GERD. PPIs work by inhibiting the H+/K+ ATPase enzyme system (also called proton pumps) on the secretory surface of gastric parietal cells. PPIs only bind pumps that are actively secreting acid, so they are best given 30 - 60 minutes before a meal because food stimulates proton pump activity.
| Proton pump inhibitors |
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Dexlansoprazole (Dexilant®)
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Esomeprazole (Nexium®)
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Lansoprazole (Prevacid®)
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Omeprazole (Prilosec®)
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Omeprazole + sodium bicarbonate (Zegerid®)
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Pantoprazole (Protonix®)
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Rabeprazole (Aciphex®)
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- Side effects
- PPIs are generally well tolerated, and in trials, side effect profiles are comparable to placebo, with only diarrhea occurring at an incidence of 2 - 4% more than placebo.
- Drug interactions
- Clopidogrel (Plavix®) - omeprazole and esomeprazole inhibit CYP2C19, and this may prevent the conversion of clopidogrel to its active metabolite, thus reducing its antiplatelet activity. Patients taking clopidogrel who require a PPI should avoid omeprazole and esomeprazole. See clopidogrel and PPIs for more.
- HIV antiretrovirals - PPIs decrease exposure to some antiretrovirals (e.g. rilpivirine atazanavir, nelfinavir) and increase exposure to others (e.g. saquinavir). Patients on HIV antiretrovirals should consult with their healthcare provider for recommendations on taking a PPI. Rilpivirine and nelfinavir should not be taken with a PPI.
- Warfarin - PPIs may increase prothrombin time (PT) and INR in patients receiving warfarin. Monitor PT/INR closely when combining.
- Methotrexate - PPIs may increase exposure to methotrexate, particularly high-dose methotrexate. Monitor patients for toxicity during concomitant therapy and discontinue PPI if necessary.
- Digoxin - PPIs may increase exposure to digoxin. Monitor digoxin levels closely when combining.
- Mycophenolate mofetil - increased gastric pH may decrease the solubility of mycophenolate mofetil (Cellcept®) and prevent its conversion to mycophenolic acid, the active metabolite. Use caution when combining mycophenolate mofetil (Cellcept®) with PPIs. Another mycophenolate product, Myfortic®, contains the active moiety mycophenolic acid and does not appear to be affected by PPIs.
- Drugs dependent on gastric pH for absorption - drugs whose absorption is affected by gastric pH may have reduced exposure when taken with PPIs. Examples include iron salts, erlotinib, dasatinib, nilotinib, ketoconazole, and itraconazole.
- Tacrolimus - dexlansoprazole, omeprazole, esomeprazole, lansoprazole, and rabeprazole may increase tacrolimus exposure, especially in patients who are intermediate or poor metabolizers of CYP2C19. Monitor tacrolimus levels when combining.
- CYP2C19 substrates - omeprazole and esomeprazole are CYP2C19 inhibitors, and they may increase exposure to CYP2C19 substrates.
- CYP3A4 inhibitors and inducers - dexlansoprazole, omeprazole, esomeprazole, and lansoprazole are CYP3A4 sensitive substrates. Concomitant CYP3A4 inducers may decrease exposure, and concomitant CYP3A4 inhibitors may increase exposure.
- CYP2C19 inhibitors and inducers - dexlansoprazole, omeprazole, esomeprazole, and lansoprazole are CYP2C19 sensitive substrates. Concomitant CYP2C19 inducers may decrease exposure, and concomitant CYP2C19 inhibitors may increase exposure.
- False-positive urine THC test
- All PPIs state that there have been reports of false-positive urine THC tests in patients receiving PPIs, particularly pantoprazole. Several small studies that evaluated this phenomenon did not find it to be true. [PMID 31566030, PMID 29126183]
- Long-term effects / Precautions
- A number of observational studies have looked at the association between long-term PPI use and adverse outcomes. These studies have had mixed results, and a causal link cannot be established in most cases. The ACG makes the following statement about the risks of long-term PPI use:
- "PPIs are the most effective medical treatment for GERD. Some medical studies have identified an association between the long-term use of PPIs and the development of numerous adverse conditions including intestinal infections, pneumonia, stomach cancer, osteoporosis-related bone fractures, chronic kidney disease, deficiencies of certain vitamins and minerals, heart attacks, strokes, dementia, and early death. Those studies have flaws, are not considered definitive, and do not establish a cause-and-effect relationship between PPIs and the adverse conditions. High-quality studies have found that PPIs do not significantly increase the risk of any of these conditions except intestinal infections. Nevertheless, we cannot exclude the possibility that PPIs might confer a small increase in the risk of developing these adverse conditions. For the treatment of GERD, gastroenterologists generally agree that the well-established benefits of PPIs far outweigh their theoretical risks."
- Clostridium difficile-associated diarrhea
- Theoretically, reduced gastric acid may enable the survival of ingested C. difficile vegetative forms. Some observational studies have found an association between long-term PPI use and an increased risk of Clostridium difficile-associated diarrhea, while others have not.
- Osteoporosis and bone fractures
- Theoretically, reduced gastric acid secretion may cause calcium malabsorption and increase the risk of osteoporosis-related bone fractures. Some observational studies have found an association between long-term PPI use and bone fractures, while others have not.
- ACG 2021 recommendation
- For patients with GERD on PPIs who have no other risk factors for bone disease, we do not recommend that they raise their intake of calcium or vitamin D or that they have routine monitoring of bone mineral density
- Serious cutaneous reactions
- Rare cases of severe cutaneous reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported in patients receiving PPIs.
- Cutaneous and systemic lupus erythematosus
- Cases of cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients receiving PPIs. Some episodes were new-onset disease, while others were exacerbations of existing disease. The majority of PPI-induced lupus erythematosus cases were cutaneous disease.
- CLE can occur at any time during PPI therapy, and patients of all ages have been affected. SLE can also happen at any time, and it is usually seen in adults (see drug-induced lupus for more).
- Most cases of PPI-induced lupus resolve within 4 - 12 weeks of drug discontinuation
- Vitamin B12 deficiency
- Chronic PPI therapy (> 3 years) may cause malabsorption of vitamin B12 through reduced gastric acid secretion
- ACG 2021 recommendation
- For patients with GERD on PPIs who have no other risk factors for vitamin B12 deficiency, we do not recommend that they raise their intake of vitamin B12 or that they have routine monitoring of serum B12 levels
- Hypomagnesemia
- Chronic PPI therapy (> 3 months, but typically > 1 year) has been associated with rare cases of hypomagnesemia. Hypomagnesemia may lead to hypocalcemia and/or hypokalemia and may exacerbate underlying hypocalcemia. Patients taking loop and thiazide diuretics may be at greater risk, and hypomagnesemia can increase the risk of toxicity (e.g. heart block, arrhythmias) in patients receiving digoxin.
- ACG 2021 recommendation
- There are insufficient data to make a meaningful recommendation regarding the need for monitoring magnesium levels in patients on chronic PPI therapy
- FDA 2011 recommendation
- Healthcare professionals should consider obtaining serum magnesium levels prior to initiation of prescription PPI treatment in patients expected to be on these drugs for long periods of time, as well as patients who take PPIs with medications such as digoxin, diuretics, or drugs that may cause hypomagnesemia. For patients taking digoxin, a heart medicine, this is especially important because low magnesium can increase the likelihood of serious side effects. Healthcare professionals should consider obtaining magnesium levels periodically in these patients. [FDA PPI communication]
- Fundic gland polyps
- Long-term PPI use (> 1 year) is associated with the development of fundic gland polyps. Most polyps are asymptomatic and discovered incidentally on endoscopy.
- Kidney disease
- Cases of acute tubulointerstitial nephritis have been reported in patients receiving PPIs. Some observational studies have found an association between long-term PPI use and chronic kidney disease, while others have not.
- PPI manufacturers do not recommend dose adjustments for people with any degree of renal impairment
- ACG 2021 recommendation
- For patients with GERD on PPIs who have no other risk factors for kidney disease, we do not recommend that they have routine monitoring of serum creatinine levels
- PPIs can be used to treat GERD in patients with renal insufficiency with close monitoring of renal function or consultation with a nephrologist
- Liver disease
- Dexlansoprazole (Dexilant®)
- Child-Pugh A: no dose adjustment necessary
- Child-Pugh B: maximum dose is 30 mg once daily
- Child-Pugh C: not recommended
- Esomeprazole (Nexium®)
- Child-Pugh A/B: no dose adjustment necessary
- Child-Pugh C: exposure is increased. Dose reduction is recommended.
- Lansoprazole (Prevacid®)
- Child-Pugh A/B: no dose adjustment necessary
- Child-Pugh C: maximum dose is 15 mg once daily
- Omeprazole (Prilosec®)
- Liver disease: exposure is increased. Consider dose reduction.
- Pantoprazole (Protonix®)
- Liver disease: no dose adjustment necessary for any degree of liver disease
- Rabeprazole (Aciphex®)
- Child-Pugh A/B: no dose adjustment necessary
- Child-Pugh C: has not been studied. Not recommended.
- DISCONTINUING PPIs (AGA 2022 RECOMMENDATIONS)
- Overview
- In 2022, the AGA published guidelines on who can safely discontinue PPIs and how it should be done. Those recommendations are outlined below.
- Patients who should not discontinue PPIs
- Patients with a history of any of the following:
- Severe erosive esophagitis
- Esophageal ulcer
- Peptic stricture
- Barrett's esophagus
- Eosinophilic esophagitis
- Zollinger-Ellison syndrome
- Idiopathic pulmonary fibrosis
- Patients at high risk for upper GI bleeding. High risk is defined as any of the following:
- History of upper GI bleeding
- Taking multiple antithrombotics (including both anticoagulants and antiplatelets agents)
- Taking aspirin or an NSAID with an additional risk factor for upper GI bleeding (e.g. older than 60 years, severe medical comorbidity, using second NSAID or aspirin, taking an antithrombotic, or taking an oral corticosteroid)
- Patients who can consider discontinuing PPIs
- Patients with no definitive indication for PPI therapy (see above)
- The decision to discontinue PPIs should be based solely on the lack of an indication for PPI use, and not because of concern for PPI-associated adverse events.The presence of a PPI-associated adverse events or a history of a PPI-associated adverse events in a current PPI user is not an independent indication for PPI withdrawal. Similarly, the presence of underlying risk factors for the development of an adverse event associated with PPI use should also not be an independent indication for PPI withdrawal.
- Discontinuation regimens
- Patients who discontinue long-term PPI therapy should be advised that they may develop transient upper gastrointestinal symptoms due to rebound acid hypersecretion
- When deprescribing PPIs, either dose tapering or abrupt discontinuation can be considered. One small study (N=97) found no difference between abrupt discontinuation and a 3-week taper. [PMID 16948806] [6]
- PRICE ($) INFO
Pricing legend
- $ = 0 - $50
- $$ = $51 - $100
- $$$ = $101 - $150
- $$$$ = > $150
- Pricing based on one month of therapy at standard dosing in an adult
- Pricing based on information from GoodRX.com®
- Pricing may vary by region and availability
- BIBLIOGRAPHY
- 1 - PMID 34807007 - ACG Clinical Guideline for the Diagnosis and Management of Gastroesophageal Reflux Disease, Am J Gastroenterol (2022)
- 2 - PMID 34807007 - Diagnosis and Management of Barrett’s Esophagus: An Updated ACG Guideline, Am J Gastroenterol (2022)
- 3 - PMID 35321279 - Barrett's esophagus: Review of natural history and comparative efficacy of endoscopic and surgical therapies, World J Gastrointest Oncol (2022)
- 4 - PMID 33351048 - Gastroesophageal Reflux Disease: A Review, JAMA (2020)
- 5 - PMID 23477993 - Gastro-oesophageal reflux disease, Lancet (2013)
- 6 - PMID 35183361 - AGA Clinical Practice Update on De-Prescribing of Proton Pump Inhibitors: Expert Review, Gastroenterology (2022)