The presence or absence of H. pylori infection is the critical determinant of ulcer treatment. Beyond eradication of H. pylori, symptom relief and promotion of ulcer healing are the main treatment objectives for uncomplicated peptic ulcers. Complications such as uncontrolled or recurrent bleeding, perforation, and obstruction may require surgery (Lee 2013; Ramakrishnan 2007; DiMarino 2016a).
The 2017 clinical guideline from the American College of Gastroenterology for the treatment of H. pylori recommends as first-line treatment either a combination of three antibiotics and a proton pump inhibitor (PPI) medication or “bismuth quadruple therapy” which uses a bismuth preparation, two antibiotics, and a PPI. Multiple variations of treatment based on these or similar combinations of drugs may also be considered. All recommended treatments are of 10‒14 days duration (Chey 2017).
Antibiotics. Eradication of H. pylori by antibiotics is the mainstay of treatment for peptic ulcers associated with H. pylori, and results in a 70‒90% cure rate (UMMC 2012; Lee 2013). Recommended first-line treatment combinations include clarithromycin (Biaxin), a nitroimidazole such as metronidazole (Flagyl), and amoxicillin; or tetracycline and a nitroimidazole (Chey 2017).
Clarithromycin resistance plays an important role in the variable estimates of cure rates for H. pylori and peptic ulcer. This is a growing problem in the United States and Canada. Resistance to metronidazole and levofloxacin (Levaquin) has also been documented (Chey 2017).
Proton pump inhibitors (PPIs). PPIs are drugs that block the secretion of stomach acid, allowing ulcers to heal and often relieving pain (DiMarino 2016b). PPIs also enhance the efficacy of antibiotics in H. pylori eradication (Lee 2013). PPIs used for this purpose include omeprazole (Prilosec), lansoprazole (Prevacid), esomeprazole (Nexium), and rabeprazole (AcipHex) (UMMC 2012).
H. pylori eradication regimens are generally brief, lasting 10‒14 days. However, when used long-term, PPIs are associated with a wide range of serious side effects including kidney and cardiovascular disease (see “Potential Risks of Long-term Proton Pump Inhibitor (PPI) Use”).
- Bismuth. Bismuth-containing medications (eg, Pepto-Bismol, Kaopectate) reduce gastrointestinal acidity and improve the efficacy of standard antimicrobial therapy against H. pylori. Bismuth rarely causes systemic side effects, but can result in black and tarry stools (UMMC 2012; Lee 2013).
Salvage therapy is sometimes used when initial therapy fails; this strategy uses different antibiotics than those that previously failed. Bismuth quadruple therapy or regimens containing levofloxacin are preferred salvage regimens (Chey 2017).
In addition to antibiotic resistance, poor compliance is an obstacle to effective treatment. Triple and quadruple therapies are complicated, expensive, and cause side effects (mostly digestive) in about 30% of patients (UMMC 2015; Safavi 2016).
In most patients, drug therapy relieves ulcer symptoms, but in some cases, symptoms persist despite effective clearing of H. pylori. Long-term management of dyspepsia with acid-suppression or other treatments may be helpful in these cases (Lee 2013).
H. pylori- Negative
For patients with peptic ulcers who test negative for H. pylori, NSAID use should be discontinued if possible. Antacids and medications that reduce acid secretion including PPIs are used in these situations (Lee 2013; Ferri 2016):
Antacids. Antacids neutralize stomach acid. Antacids containing bismuth subsalicylate (eg, Pepto-Bismol, Kaopectate), calcium carbonate (eg, Tums), and a combination of aluminum hydroxide and magnesium hydroxide (Maalox, Mylanta) are available over the counter. These drugs usually cause only mild side effects, including diarrhea or constipation (IFFGD 2015; NCBI 2007).
H2 receptor antagonists. H2 receptor antagonists block the acid-stimulating action of histamine in the stomach. Examples include cimetidine (Tagamet), famotidine (Pepcid AC), and ranitidine (Zantac). They are available over the counter, but a prescription is required for higher doses. Serious side effects caused by H2 receptor antagonists are rare but more common in older patients (DiMarino 2016b; UMMC 2012; NLM 2017b). H2 receptor antagonists can reduce vitamin B12 absorption, so B12 status should be monitored in long-term users, and B12 supplementation should be initiated if a B12 deficiency is detected (Force 1992).
Mucosal protective agents. Misoprostol (Cytotec) and sucralfate (Carafate) are used to help protect the stomach lining against the damaging effects of NSAIDs in patients who must continue to take them. Misoprostol stimulates prostaglandin production, and can prevent NSAID-related ulcer, but does not heal existing ulcers. Misoprostol also inhibits stomach acid and pepsin production (CIHR 2017). Misoprostol causes diarrhea and other gastrointestinal side effects relatively frequently, and is contraindicated in pregnant women because it can cause miscarriages and birth defects (Lee 2013; Ferri 2016; UMMC 2012). Sucralfate forms a chemical barrier at ulcerated sites to protect against further damage. Sucralfate occasionally causes constipation but has few side effects, though it does interfere with a number of different medications (Gold Standard 2013; UMMC 2012).
Maintenance therapy is recommended for patients who experience recurrent ulcers. Maintenance therapy generally involves long-term use of antacids, H2 receptor antagonists, mucosal protectants, or PPIs. Although PPIs are usually considered the most effective maintenance treatment (Ferri 2016), long-term PPI use is associated with an array of grave health consequences and an increased risk of death (Maggio, Corsonello 2013; Shih 2014; Klepser 2013).
Potential Risks of Long-term Proton Pump Inhibitor (PPI) Use
Although proton-pump inhibitor (PPI) drugs are widely used, they are associated with a number of potentially serious outcomes. Moreover, many people may use PPIs for longer than the directed usage, which may exacerbate side-effect risk. Over-the-counter PPIs should not be used for more than three 14-day treatment periods each year (FDA 2016b), and prescription PPIs should be used as directed, usually no more than eight weeks (JAGS 2015).
Long-term use of PPIs—more than four to eight weeks—may lead to physiological deficiencies of important micronutrients such as calcium, magnesium, and vitamin B12. These deficiencies increase the risk of a host of conditions such as musculoskeletal and neurological abnormalities, heart rhythm irregularities, and increased risk of cardiovascular disease and diabetes (Atkinson 2015; Yang 2012; Linder 2016).
Other observational associations with PPI use include:
Risk of death. Several studies have found that PPI use is associated with increased risk of death from any cause (Maggio, Corsonello, Ceda 2013; Teramura-Gronblad 2012). In one study that enrolled 491 patients with an average age of 80 years, PPI use was independently associated with a 51% increased risk of dying during a one-year period; those on high-dose PPI therapy (20‒40 mg daily) had an almost 2.6-fold increased risk of dying within one year (Maggio, Corsonello, Ceda 2013).
Heart attack. PPI use has been associated with heart attacks in several studies, though a causal relationship between PPI use and heart attack has not been established (Fusaro 2013; Shah 2015). One study of over 126,000 PPI users and an equal number of nonusers found PPI use was linked to a 58% increased risk of heart attack over a 4-month period (Shih 2014; Fusaro 2013; Shah 2015).
Kidney disease. PPI use has been associated with kidney damage and chronic kidney disease (Antoniou 2015; Lazarus 2016). One study in over 184,000 individuals found that those with kidney disease were twice as likely to have used a PPI (Klepser 2013).
Pneumonia. PPI use appears to increase the risk of community-acquired pneumonia (Giuliano 2012). PPIs may increase pneumonia risk by several mechanisms: 1) inhalation of pathogens from the digestive tract that would normally be killed in more acidic conditions; 2) changes in the normal bacterial population of the airways due to acid reduction in the respiratory tract; and 3) PPIs directly impair immune cell function (Ho 2015; Lambert 2015).
Clostridium difficile infection. Clostridium difficile is a bacterium that can cause potentially severe intestinal infections (NLM 2017a). PPI users who also take antibiotics have a particularly pronounced risk of C. difficile infection (Kwok 2012; Janarthanan 2012). The Food and Drug Administration (FDA) has issued a warning to patients taking PPIs that they should contact their healthcare provider immediately if they develop diarrhea that does not improve (FDA 2016a).
Fractures and osteoporosis. Several studies have correlated long-term use of PPIs with increased risk of fractures, including fractures of the hip, spine, and wrist (Gray 2010; Lau 2012). Impairment of calcium absorption is one factor that may contribute to the increased fracture risk observed with prolonged PPI use (Fournier 2009).
Disturbance of gastrointestinal flora. PPIs alter the populations of microorganisms that inhabit the gastrointestinal tract. This can lead to small intestinal bacterial overgrowth, which may increase susceptibility to NSAID-induced injury to the small intestinal mucosa (Fujimori 2015; Lombardo 2010). Alterations in gut microbial composition are also implicated in an observed link between PPI use and celiac disease, though more research is needed to firmly establish the influence of PPI use on celiac risk (Freedberg 2014).
Development of hypersensitivities. Gastric acid normally breaks down potentially immunogenic proteins in food, but acid suppressive therapy may hinder this process, causing reactive particles to pass into the intestine and trigger an immune response (Trikha 2013). Studies have demonstrated an increased incidence of hypersensitivity reactions to both foods and drugs in PPI users. In hospitalized patients, those taking PPIs were nearly 4 times as likely to develop drug hypersensitivity reactions (Trikha 2013; Ramirez 2013). More rigorous prospective research is needed to establish the degree of causality in this relationship.
People who use PPIs for more than eight weeks should consult with a qualified healthcare provider to discuss risks and benefits. In some cases, long-term risks may outweigh potential benefits and therapy should be discontinued or adjusted—each case is unique and healthcare providers should take the patient’s complete health history into consideration.