Is there any literature to support the use of a proton pump inhibitor (PPI) plus a histamine-2-receptor antagonist (H2RA) for gastroesophageal reflux disease (GERD)?
Introduction
Pharmacologic therapy for the medical management of gastroesophageal reflux disease (GERD) consists of medications that neutralize or reduce gastric acid. 1-3 Agents may include antacids, histamine-H2-receptor antagonists (H2RAs), and proton pump inhibitors (PPIs). Typically, these agents are initiated in a stepwise fashion, with the lowest effective dose recommended to minimize any adverse events or risks. It has been postulated that due to differing mechanisms and sites of actions, more than one agent used concomitantly may be beneficial in the treatment of GERD. The purpose of this article is to provide evidence on if or when it may be appropriate to use an H2RA and PPI together in the treatment of GERD.
Background
Gastroesophageal reflux disease is a chronic gastrointestinal disorder that is characterized by the regurgitation of gastric contents into the esophagus resulting in troublesome symptoms and/or complications. 1-3 It is one of the most diagnosed digestive disorders in the United States, with an estimated prevalence of up to 20% of individuals. 3,4 Gastroesophageal reflux is a normal physiologic process. 1-3 It becomes problematic and may warrant a diagnosis of GERD when symptoms impact quality of life or complications occur due to gastric reflux. These troublesome symptoms are thought to be caused by a poorly functioning esophagogastric junction, a sphincter made up of the lower esophageal sphincter (LES) and surrounding crural diaphragm that acts as a barrier to reflux when functioning appropriately, along with impaired clearance of refluxed gastric juice and loss of esophageal mucosal integrity.
Heartburn and regurgitation are the typical symptoms associated with GERD. 1-3 Other symptoms that are less common may include chest pain or difficulty swallowing. Extraesophageal syndromes may occur in association with GERD if left untreated, such as chronic cough, laryngitis, and dental erosions. Other complications of unchecked GERD may be related to chronic esophagitis. Lifestyle modifications are generally recommended in addition to pharmacologic therapy for GERD. These modifications are generally related to avoidance of foods that may reduce LES pressure, making reflux more likely, such as alcohol, spearmint, and fatty foods, or avoidance of acidic foods such as tomato-based foods and citrus fruits. Additionally, patients who are overweight are encouraged to lose weight if they have GERD, as there is a strong relationship between body mass index and GERD symptoms.
Pharmacologic therapy for GERD
Pharmacologic therapy in the medical management of GERD consists of medications that neutralize or reduce gastric acid. 1-3 Agents may include antacids, H2RAs, and PPIs. Table 1 describes certain characteristics of the PPI and H2RA agents that are approved for the treatment of GERD in the United States.
Proton Pump Inhibitors
Proton pump inhibitors are the most potent inhibitors of gastric acid secretion, by irreversibly binding to the hydrogen-potassium ATPase pumps that results in the long-lasting and specific inhibition of gastric acid secretion. 5,6 Although similar in structure and mechanism of action, PPIs differ in their pharmacokinetic properties, bioavailability, and route of excretion; however, clinical relevance of these differences has not been established. These drugs are most effective when the parietal cell is stimulated to secrete acid after a meal, which has important implications for appropriate timing of administration. Ideally, PPIs should be administered 30 to 60 minutes prior to the first meal of the day because the amount of hydrogen-potassium-ATPase present in parietal cells is greatest after fasting. Most individuals only require once daily dosing to sufficiently inhibit acid secretion and efficacy is similar among all PPIs. These agents should be taken daily for 4 to 8 weeks to optimally inhibit proton pumps and lead to “complete” symptom relief, as not all parietal cells are active simultaneously. This means that an “as-needed” dosing strategy will not reliably provide adequate acid inhibition or consistent clinical response.
In general, PPIs are well tolerated, if taken appropriately. 5,6 The most common adverse reactions include diarrhea, abdominal pain, nausea, constipation, and flatulence. All PPIs are contraindicated with use of rilpivirine-containing products. Additionally, PPIs can reduce the absorption of other drugs that depend on gastric pH for absorption. These agents are metabolized by hepatic cytochrome-P enzymes and may interfere with elimination of other hepatically metabolized drugs. Chronic treatment may lead to decreases in absorption of vitamins, such as vitamin B12 and may be associated with an increased risk of Clostridium difficile-associated diarrhea. Use of the lowest effective dose for the shortest effective duration is recommended, but treatment should be reassessed regularly and individualized based on patient needs and risk factors. 1
Histamine-H2-Receptor Antagonists
Histamine-H2-receptor antagonists, otherwise known as histamine blockers, inhibit gastric acid secretion by reversibly blocking histamine 2 receptors on parietal cells. 5,6 Unlike PPIs, H2RAs can be taken on an as-needed basis due to their quick onset of action. However, efficacy is variable and frequently lower than desired by patients and providers, as they are less potent than PPIs. These agents can be taken without regard to meals. Tolerance to acid suppression effects has been demonstrated with H2RAS within 3 days of treatment initiation. This tolerance may be resistant to increased doses of the medications in some individuals.
H2RAs are typically well tolerated, with adverse events being rare. 5,6 Most common adverse events include headache, fatigue, dizziness, and constipation. Cimetidine is eliminated by a combination of hepatic and renal metabolism and may cause significant drug interactions for drugs with similar routes of metabolism, so should be avoided if interactions are likely. Ranitidine, a previously commonly used H2RA agent, has been withdrawn from the United States market by the U.S. Food and Drug Administration due to contamination with nitrosodimethylamine (NDMA), a probable human carcinogen. 7
1 Updated Heading link
| Table 1. PPIs and H2RAs approved for GERD. 8-19 | ||
|---|---|---|
| Drug name | How supplied | Comments |
| PPIs |
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| Dexlansoprazole (Dexilant) | Delayed-release capsules for oral use: 30 mg; 60 mg | Not indicated in pediatric patients younger than 12 years of age Not recommended in patients with severe hepatic impairment Swallow whole, do not chew Capsules can be opened and administered with applesauce for patients with trouble swallowing capsules or administered with water via oral syringe or NG tube |
| Esomeprazole (Nexium) | Delayed-release capsules for oral use: 20 mg; 40 mg Delayed-release oral suspension: 2.5 mg; 5 mg; 10 mg; 20 mg; 40 mg | A maximum dose of 20 mg once daily is recommended in patients with severe liver impairment (Child-Pugh Class C) Swallow capsules whole, do not chew Capsules can be opened, and contents mixed with applesauce for patients who cannot swallow capsules Opened capsules can be administered through NG tube and oral suspension can be administered through NG or gastric tube |
| Lansoprazole (Prevacid) | Delayed-release capsules for oral use: 15 mg; 30 mg Delayed-release ODT: 15 mg; 30 mg | Recommended maximum dosage of 15 mg once daily in patients with severe liver impairment (Child-Pugh Class C) Swallow capsules whole, do not chew; do not break or cut ODT For patients who have difficulty swallowing capsules, capsules can be opened and administered orally or via NG tube in soft foods or liquids; ODT can be administered with water via oral syringe or NG tube |
| Omeprazole (Prilosec) | Delayed-release capsules for oral use: 10 mg; 20 mg; 40 mg Delayed-release ODT: 20 mg Delayed-release tablet for oral use: 20 mg Delayed-release granules for oral suspension: 2.5 mg; 10 mg | Recommended maximum dosage of 10 mg once daily for patients with hepatic impairment (Child-Pugh Class A, B, or C) and Asian patients Tablets should not be chewed or crushed into food; granules should also not be chewed or crushed For patients who have difficulty swallowing capsules, capsules can be opened, and granules sprinkled on applesauce or yogurt, given with fruit juices, or swallowed with water; granules can be given via NG tube with juice |
| Pantoprazole (Protonix) | Delayed-release tablets for oral use: 20 mg; 40 mg Delayed-release suspension for oral use: 40 mg Powder or solution for IV injection: 40 mg | No dosage adjustment is required for patients with hepatic impairment Swallow tablets whole, do not crush or chew |
| Rabeprazole (Aciphex) | Delayed-release tablets for oral use: 20 mg Delayed-release capsules for oral use: 5 mg; 10 mg | No dosage adjustment is required for patients with hepatic impairment Swallow tablets and capsules whole, do not crush or chew Pediatric patients ages 1 to 11 years should only receive the delayed-release sprinkle capsules |
| H2RAsa |
||
| Cimetidine | Tablet for oral use: 200 mg; 300 mg; 400 mg; 800 mg Solution for oral use: 300 mg/5 mL; 400 mg/6.67 mL | Consider a decreased dosage for patients with severe hepatic disease (Child-Pugh Class C) Reduce usual daily dose by 50% (maximum 300 mg every 12 hours) in adults with CrCl <30 mL/min |
| Famotidine (Pepcid) | Tablet for oral use: 10 mg; 20 mg; 40 mg Powder for suspension for oral use: 40 mg/5 mL Solution for injection: 10 mg/mL; 20 mg/50 mL | No dosage adjustments are required in patients with hepatic impairment In general, for adults with GFR: >50 mL/min, administer 50% to 75% of normal dose 10 to 50 mL/min, administer 10% to 50% of normal dose <10 mL/min, administer 10% of normal doseb In general, for pediatric patients with GFR: 30 to 50 mL/min/1.73 m2, give 0.5 mg/kg/dose every 24 hours 10 to 29 mL/min/1.73 m2, give 0.25 mg/kg/dose every 24 hours <10 mL/min/1.73 m2, give 0.125 mg/kg/dose every 24 hoursb |
| Nizatidine | Capsule for oral use: 150 mg; 300 mg | No specific dosage adjustments for hepatic impairment are recommended In adults with CrCl 20 to 50 mL/min, decrease the dose to 150 mg once daily for active GERD and 150 mg every other day for maintenance therapy In adults with CrCl <20 mL/min, decrease the dose to 150 mg every other day for active GERD and 150 mg once every 3 days for maintenance therapy Specific dosage adjustments for pediatric patients with renal impairment are not available |
| aAs of April 2020, all prescription (including oral and injectable) and OTC ranitidine formulations have been withdrawn from the United States market7bDosage adjustments may differ based on formulation; refer to prescribing information for appropriate dosing in renal impairment Abbreviations: CrCl=creatinine clearance; ERD=gastroesophageal reflux disease; GFR=glomerular filtration rate; H2RA=histamine-H2-receptor antagonist; IV=intravenous; NG=nasogastric; ODT=orally disintegrating tablets; OTC=over the counter; PPI=proton pump inhibitor |
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Guidelines
The American College of Gastroenterology (ACG) released a guideline in 2022 for the diagnosis and management of GERD. 1 Treatment with PPIs over treatment with H2RAs is strongly recommended. Additionally, the routine addition of any medical therapy, including H2RAs, to PPI non-responders is not recommended, as data are lacking on any benefit of coadministration. However, there has been data on the use of these agents together in the setting of nighttime acid breakthrough when patients continue to have persistent symptoms at bedtime. Based on this, the short-term addition of an as-needed H2RA agent at bedtime may be beneficial for nighttime acid control in patients with nocturnal symptoms or patients with objective evidence of nocturnal acid reflux on pH monitoring despite adequate PPI treatment.
Additional literature
Very little recent data exists examining the concomitant use of H2RA and PPI therapy in GERD. Some data demonstrating a benefit of concomitant PPI and H2RA use has been in the setting of nighttime acid control in patients with nocturnal symptoms or patients with objective evidence of nocturnal acid reflux on pH monitoring despite adequate PPI treatment. Most of the evidence supporting use in this context comes from observational studies and case reports from the late 1990s through early 2000s. A small cross-over design study (N=12) demonstrated that the addition of ranitidine 150 mg or 300 mg at bedtime to omeprazole 20 mg twice daily over the course of 7 days significantly reduced the percentage of time patients with nocturnal acid reflux had intragastric pH <4. 20 A later trial investigating the impact of famotidine and lansoprazole combination on nocturnal acid breakthrough found similarly lowered pH in participants on dual therapy after 24 hours. 21 A 2002 study by Fackler and colleagues was the first prospective study to investigate long-term effects of H2RA therapy added to PPI therapy on nocturnal gastric acid breakthrough. 22 Investigators found that individuals taking both an H2RA and PPI experienced a reduction in nighttime acid symptoms only during the first week an H2RA was introduced to PPI therapy. After 1 week of dual therapy, there was no difference in acid suppression between those taking a PPI and H2RA or those taking a PPI alone. Based on historical data, there may be a place in therapy for short-term combination of H2RA and PPI therapy in patients with nocturnal acid breakthrough. Table 2 summarizes identified literature on dual therapy published within the past 15 years. The trials identified are limited by their small sample sizes and short follow-up times.
| Table 2. Studies examining concomitant H2RA and PPI therapy, published between 2007 and 2022. 23,24 | ||||
|---|---|---|---|---|
| Design/duration | Subjects | Interventions | Results | Conclusions |
| Mainie 200823 Duration: 20 hours + SD (not described) | 100 adults with refractory reflux symptoms despite twice daily PPI therapy for at least 1 month | PPI twice daily PPI twice daily plus H2RA nightly | Nocturnal acid breakthrough symptoms were noted in 64% of patients taking a PPI twice daily compared to only 17% of patients on a PPI + H2RA after monitoring (p<0.001) Percentage of time intragastric pH <4 was significantly higher (p<0.01) in patients on PPI twice daily compared with patients on PPI + H2RA during upright, recumbent, and entire periods | Addition of a bedtime H2RA reduces percentage of time intragastric pH<4 |
| Abdul-Hussein 201524 DB three-way crossover RCT Duration: 7 days | 21 healthy adults with no history of upper GI disorders | H2RA (ranitidine 300 mg) plus placebo PPI (omeprazole 40 mg) plus placebo H2RA plus PPI (ranitidine 300 mg plus omeprazole 40 mg) | H2RA plus PPI resulted in significantly longer time that gastric pH >4 (median, 410.5 min; IQR, 298.5 to 454.25 min) compared to PPI alone (median, 356.7; IQR, 254.9 to 419.2 min; p=0.023) or H2RA alone (median, 134.1 min; IQR, 99.9 to 302.5 min; p<0.0001) Median gastric pH was higher when PPI and H2RA were given in combination (pH, 5.92; IQR, 4.75 to 6.46) vs PPI alone (pH, 4.88; IQR, 4.27 to 6.11; p=0.001) or H2RA alone (pH, 2.31; IQR, 2.04 to 5.27; p=0.0003) Percentage of time gastric pH was >4 was higher when PPI and H2RA were given together (median, 82.52%) than either PPI alone (74.31%; p=0.027) or H2RA alone (27.94%; p=0.0002) | Concomitant administration of PPI and H2RA resulted in improved gastric acid control |
| Abbreviations: DB=double-blind; GI=gastrointestinal; H2RA=histamine-H2-receptor antagonist; IQR=interquartile range; PPI=proton pump inhibitor; RCT=randomized controlled trial; SD=standard deviation. |
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Conclusions
In general, long-term combination therapy with H2RAs and PPIs does not offer additional benefit for the management of GERD. It may be an appropriate short-term option to add a nighttime H2RA for patients on adequate PPI treatment with remaining nocturnal symptoms or nocturnal acid reflux. Very little research has been conducted on concomitant use of H2RA and PPI agents in the past 15 years, indicating there will likely be no change to guideline recommendations on this combination. To minimize potential adverse reactions, patients on acid-lowering therapies should be consistently re-evaluated and medications should be discontinued if the patient no longer has symptoms or has no indication for continued use. Additionally, the lowest effective dose of PPIs should be used when therapy is indicated.
References
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- Kahrilas PJ, Hirano I. Diseases of the Esophagus. In: Loscalzo J, Fauci A, Kasper D, Hauser S, Longo D, Jameson JL, eds. Harrison’s Principles of Internal Medicine. 21 ed: McGraw Hill; 2022. Accessed July 20, 2022. https://accessmedicine-mhmedical-com.proxy.cc.uic.edu/content.aspx?sectionid=265427279&bookid=3095&Resultclick=2
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- Sweis R, Fox M. The global burden of gastro-oesophageal reflux disease: more than just heartburn and regurgitation. Lancet Gastroenterol Hepatol. 2020;5(6):519-521. doi:10.1016/s2468-1253(20)30002-9
- May D, Thiman ML, Rao SS. Gastroesophageal Reflux Disease. In: DiPiro JT, Yee GC, Posey LM, Haines ST, Nolin TD, Ellingrod V, eds. Pharmacotherapy: A Pathophysiologic Approach. 11 ed: McGraw Hill; 2020. Accessed July 20, 2022. https://accesspharmacy-mhmedical-com.proxy.cc.uic.edu/content.aspx?sectionid=219309078&bookid=2577&Resultclick=2#1182435997
- Pharmacotherapy of Gastric Acidity, Peptic Ulcers, and Gastroesophageal Reflux Disease. In: Hilal-Dandan R, Brunton LL, eds. Goodman and Gilman’s Manual of Pharmacology and Therapeutics. 2 ed: McGraw Hill; 2014. Accessed July 20, 2022. https://accesspharmacy-mhmedical-com.proxy.cc.uic.edu/content.aspx?sectionid=124495007&bookid=1810#1127552635
- FDA News Release: FDA requests removal of all ranitidine products (Zantac) from the market. U.S. Food and Drug Administration. April 1, 2020. Accessed July 20, 2022. https://www.fda.gov/news-events/press-announcements/fda-requests-removal-all-ranitidine-products-zantac-market
- Dexilant (dexlansoprazole). Package insert. Takeda Pharmaceuticals America, Inc.; 2022.
- Nexium (esomeprazole). Package insert. AstraZeneca Pharmaceuticals LP; 2022.
- Prevacid (lansoprazole). Package insert. Takeda Pharmaceuticals America, Inc.; 2022.
- Prilosec (omeprazole). Package insert. Covis Pharma US, Inc.; 2022.
- Protonix (pantoprazole) tablets. Package insert. Wyeth Pharmaceuticals LLC; 2022.
- Protonix (pantoprazole) for injection. Package insert. Wyeth Pharmaceuticals LLC; 2022.
- Rabeprazole. Package insert. Amneal Pharmaceuticals LLC; 2022.
- Cimetidine. Package insert. Mylan Pharmaceuticals Inc.; 2019.
- Famotidine for injection. Package insert. Fresenius Kabi USA, LLC; 2021.
- Famotidine tablet. Package insert. Amerisource Bergen; 2019.
- Nizatidine. Package insert. Actavis Pharma, Inc.; 2016.
- Clinical Pharmacology database. Elsevier Inc. 2022. Accessed July 20, 2022. https://www.clinicalkey.com/pharmacology/login
- Peghini PL, Katz PO, Castell DO. Ranitidine controls nocturnal gastric acid breakthrough on omeprazole: a controlled study in normal subjects. Gastroenterology. 1998;115(6):1335-1339. doi:10.1016/s0016-5085(98)70010-1
- Katsube T, Adachi K, Kawamura A, et al. Helicobacter pylori infection influences nocturnal gastric acid breakthrough. Aliment Pharmacol Ther. 2000;14(8):1049-1056. doi:10.1046/j.1365-2036.2000.00799.x
- Fackler WK, Ours TM, Vaezi MF, Richter JE. Long-term effect of H2RA therapy on nocturnal gastric acid breakthrough. Gastroenterology. 2002;122(3):625-632. doi:10.1053/gast.2002.31876
- Mainie I, Tutuian R, Castell DO. Addition of a H2 receptor antagonist to PPI improves acid control and decreases nocturnal acid breakthrough. J Clin Gastroenterol. 2008;42(6):676-679. doi:10.1097/MCG.0b013e31814a4e5c
- Abdul-Hussein M, Freeman J, Castell D. Concomitant Administration of a Histamine2 Receptor Antagonist and Proton Pump Inhibitor Enhances Gastric Acid Suppression. Pharmacotherapy. 2015;35(12):1124-1129. doi:10.1002/phar.1665
Prepared by:
Rachel Brunner, PharmD
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy
August 2022
The information presented is current as of July 12, 2022. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.