When Is Stomach Protection Necessary for People Taking NSAIDs?
Introduction
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in acute conditions for their analgesic and antipyretic effects. NSAIDs are also frequently prescribed to relieve pain in chronic inflammatory conditions, including rheumatic and musculoskeletal diseases, while low-dose acetylsalicylic acid is used to prevent cardiovascular complications. Approximately 30 million people worldwide take NSAIDs every day, and about 40% of them are over 60 years of age (1, 2).
The main factor limiting the use of these drugs is the gastrointestinal (GI) damage they may cause, including ulcers, bleeding from the upper GI tract, perforation, and dyspeptic symptoms. Endoscopic examinations show that up to 40% of patients taking NSAIDs long term have asymptomatic ulcers (1, 3, 4). Bleeding from the upper GI tract and perforation occur in approximately 1.5% of such patients annually (5, 6), while dyspeptic symptoms affect up to 60% of patients taking NSAIDs. The mortality rate among patients hospitalized because of NSAID-induced bleeding is 5–10% (7).
Histamine H2-receptor antagonists used at standard doses are ineffective in preventing NSAID-induced ulcers, although they may reduce symptoms of upper GI tract injury caused by NSAID use. Proton pump inhibitors (PPIs), prescribed once daily, reduce the incidence of NSAID-induced ulcers and their complications and also alleviate symptoms of upper GI tract damage. When selective cyclooxygenase-2 (COX-2) inhibitors are added to acetylsalicylic acid therapy, the risk of GI injury increases to a level comparable to that associated with nonselective NSAIDs. The combination of acetylsalicylic acid and nonselective NSAIDs increases this risk even further. Patients taking low-dose acetylsalicylic acid who also have risk factors for GI complications, such as concomitant NSAID use, should be prescribed PPIs.
Factors Increasing the Risk of GI Damage
Not all patients taking NSAIDs are equally susceptible to GI damage. Because it is difficult to predict such damage on the basis of symptoms alone, it is important to identify patients at increased risk.
Factors that further increase this risk include a previous GI ulcer or bleeding, older age (>65 years), long-term use of high NSAID doses, concomitant use of several NSAIDs, concurrent corticosteroid or anticoagulant therapy, and severe comorbidities such as cardiovascular disease, renal or hepatic dysfunction, diabetes, and hypertension (1, 8).
The role of Helicobacter pylori infection in the development of NSAID-related ulcers remains incompletely understood. Various hypotheses have been proposed, but current evidence indicates that H. pylori infection and NSAID use are independent risk factors that mutually increase the likelihood of GI ulcer formation (Table 1) (9–12).
Studies also show that H. pylori infection increases the risk of gastroduodenal ulcers and their complications in patients taking NSAIDs. Eradication of H. pylori reduces the risk of gastroduodenal ulcer development in patients starting NSAID therapy for the first time (13).
In high-risk patients receiving NSAIDs, H. pylori eradication alone is insufficient to prevent recurrent GI bleeding. However, eradication may be more beneficial in patients taking low-dose acetylsalicylic acid or COX-2 inhibitors (14–16).
NSAID-Induced Gastropathy
Endoscopically detected lesions of the stomach and duodenum caused by NSAIDs, referred to as NSAID-induced gastropathy, may present as mucosal erythema, diffuse or focal erosions, or ulcers.
Erosions and subepithelial hemorrhages are lesions that do not extend beyond the mucosa. An ulcer is a defect that penetrates through the muscular layer of the mucosa, the muscularis mucosae, into the submucosa or deeper, potentially reaching larger blood vessels (24).
For this reason, ulcers may cause significant bleeding when vessels beneath the mucosa are damaged. Approximately 3% of cases of hemorrhagic or erosive gastropathy result in severe bleeding. However, such bleeding is generally not life-threatening and rarely requires extensive blood transfusion unless the patient has significant coagulation abnormalities (25).
It has been observed that gastric ulcers occur twice as often as duodenal ulcers in patients taking NSAIDs, although the risk of bleeding is similar for both types (26).
Prevention of NSAID-Induced Gastropathy
There are several approaches that may theoretically reduce the risk of ulcer formation and related complications (Table 2).
Table 1. Risk Factors for NSAID-Induced Gastrointestinal Injury
| Risk factor |
|---|
| History of peptic ulcer complications |
| History of uncomplicated peptic ulcer disease |
| Age >65 years (high risk if >75 years) |
| Concomitant NSAID use with: |
| • low-dose acetylsalicylic acid |
| • anticoagulants (e.g., warfarin) |
| • corticosteroids |
| • two or more NSAIDs |
| NSAID type: |
| • lower-risk agents – diclofenac, ibuprofen (<1,200 mg/day) |
| • higher-risk agents – piroxicam, ketoprofen, ketorolac |
| High NSAID doses (risk is dose-dependent) |
| Helicobacter pylori infection |
| Smoking and alcohol consumption |
| History of dyspepsia |
Table 2. Treatment and Prevention of NSAID-Induced Gastropathy
Prevention of NSAID-Induced Gastropathy
- Use non-NSAID analgesics instead of NSAIDs whenever possible.
- Prescribe the lowest effective NSAID dose.
- Use the lowest effective corticosteroid dose when corticosteroids are required instead of NSAIDs.
- Identify patients with risk factors (Table 1) and consider preventive therapy with proton pump inhibitors (PPIs).
Treatment of NSAID-Induced Gastropathy
- If possible, discontinue NSAID therapy. Any standard ulcer treatment regimen is appropriate.
- If NSAID therapy cannot be discontinued, proton pump inhibitors (e.g., pantoprazole) are the most effective treatment option.
Prevention of NSAID-Induced Gastropathy
Patients taking NSAIDs who are at high risk of GI injury should receive prophylactic gastroprotective therapy (1, 8). Long-term treatment with the prostaglandin analogue misoprostol has been shown to provide effective gastroprotection (5, 27–32). However, many patients are unwilling to continue treatment because of its adverse effects, particularly diarrhea and abdominal pain. Histamine H2-receptor antagonists provide moderate protection against duodenal ulcers but have little effect in preventing gastric ulcers, which are more common in patients taking NSAIDs (32–37).
Proton pump inhibitors (PPIs) are effective and well-tolerated agents that protect against both gastric and duodenal ulcers associated with NSAID therapy. PPIs suppress gastric acid secretion by inhibiting the proton pumps (H+,K+-ATPase) in stimulated gastric parietal cells (38). Studies have shown that even low-dose acetylsalicylic acid can cause significant gastric mucosal injury within a short period. However, when combined with a PPI, such as pantoprazole, this damage can largely be prevented (39). This gastroprotective effect is considered clinically important for reducing the risk of NSAID-induced GI injury, particularly during long-term therapy.
PPI Administration for Primary Prevention of GI Injury
The efficacy of pantoprazole in preventing NSAID-induced ulcers has been demonstrated in clinical trials (42).
The benefits of Helicobacter pylori eradication in patients receiving NSAIDs remain controversial. One study (44) found that among elderly patients infected with H. pylori who were taking NSAIDs, treatment with pantoprazole 40 mg/day for one month was more effective in preventing severe GI injury than H. pylori eradication therapy consisting of pantoprazole, amoxicillin, and clarithromycin.
Peptic gastric ulcers or severe erosive gastritis developed in 28.5% of patients who received H. pylori eradication therapy compared with only 8.8% of patients treated with pantoprazole 40 mg/day (p<0.05).
Secondary Prevention
Patients with healed NSAID-induced ulcers remain at high risk of recurrent GI injury. They are particularly susceptible to serious complications, including bleeding and perforation. Therefore, patients who require continued NSAID therapy should receive gastroprotective treatment.
PPIs are particularly suitable in this setting, as they have been shown to be more effective than ranitidine or placebo in preventing recurrent ulcers in patients receiving long-term NSAID therapy (45).
Pantoprazole (e.g., Nolpaza) effectively reduces the recurrence of NSAID-associated ulcers. In a comparative study (46), remission after 12 months was highest among patients treated with pantoprazole (66%), compared with omeprazole (55%, p=0.07) and misoprostol (44%, p=0.02) in patients taking NSAIDs with previously healed gastric ulcers.
Furthermore, patients treated with pantoprazole experienced fewer adverse effects than those receiving misoprostol.
Another study (17) included 489 patients receiving NSAIDs who had healed gastric or duodenal ulcers or multiple erosions. Participants were randomly assigned to receive pantoprazole 20 mg/day, omeprazole 20 mg/day, or ranitidine 300 mg/day.
After six months of treatment, patients receiving pantoprazole had significantly fewer recurrent ulcers and episodes of GI bleeding than those treated with omeprazole or ranitidine (p<0.05).
PPI Therapy for NSAID-Induced Ulcers
Current guidelines for the management of NSAID-induced ulcers recommend discontinuing NSAID therapy whenever possible and initiating any approved treatment regimen for peptic ulcer disease (1, 8). Proton pump inhibitors (PPIs) are among the recommended treatment options and are effective not only when NSAIDs can be discontinued but also when continued NSAID therapy is necessary. PPIs have been shown to promote ulcer healing and reduce the risk of ulcer recurrence in these patients.
Pantoprazole has demonstrated high efficacy in the treatment of ulcers in patients who require ongoing NSAID therapy. A comparative study involving 120 Helicobacter pylori-negative patients with NSAID-induced ulcers evaluated the efficacy of pantoprazole, omeprazole, and misoprostol (46). Participants were randomly assigned to receive pantoprazole 40 mg/day, omeprazole 20 mg/day, or misoprostol 800 μg/day. Ulcers healed more rapidly in patients receiving pantoprazole than in the other treatment groups, although after eight weeks all patients had achieved ulcer healing.
Should PPIs Be Prescribed to Elderly Patients Receiving Short-Term NSAID Therapy?
Peptic ulcers may develop during both short-term and long-term NSAID therapy, particularly in older adults. One study demonstrated that more than 50% of NSAID-induced gastric and duodenal lesions in elderly patients occurred after no more than 30 days of NSAID use before endoscopic examination.
The study included 676 elderly individuals taking NSAIDs or acetylsalicylic acid and 2,435 individuals not receiving these medications (18). All participants underwent upper gastrointestinal endoscopy. Information regarding NSAID, acetylsalicylic acid, and antisecretory drug use, including H2-receptor antagonists and PPIs, was collected by questionnaire. Gastric or duodenal ulcers and H. pylori infection were diagnosed by endoscopy and histological examination of gastric biopsy specimens.
The results showed that 47.3% of patients had used NSAIDs for a short period, whereas 52.7% had received long-term therapy. After adjustment for age, sex, H. pylori infection, and antisecretory drug use, the risk of peptic ulcer disease was higher among short-term NSAID users than among long-term users.
For short-term NSAID use, the relative risk (RR) of gastric ulcer was 4.47 (95% CI 3.19–6.26), and the RR of duodenal ulcer was 2.39 (95% CI 1.73–3.31). In comparison, among long-term NSAID users, the RR was 2.80 (95% CI 1.97–3.99) for gastric ulcers and 1.68 (95% CI 1.22–2.33) for duodenal ulcers.
PPI therapy was associated with a reduced risk of peptic ulcer disease in both short-term users (RR 0.70; 95% CI 0.24–2.04) and long-term users (RR 0.32; 95% CI 0.15–0.67) of NSAIDs or acetylsalicylic acid.
In contrast, prophylactic treatment with H2-receptor antagonists was associated with a substantially higher risk of peptic ulcer disease among both short-term NSAID users (RR 10.9; 95% CI 3.87–30.9) and long-term users (RR 6.26; 95% CI 2.56–15.3) compared with patients not receiving these medications.
PPI therapy reduced the absolute risk of peptic ulcer disease by 36.6% among short-term NSAID or acetylsalicylic acid users and by 34.6% among long-term users.
These findings suggest that elderly symptomatic patients requiring even short-term treatment with NSAIDs or acetylsalicylic acid should also receive PPI therapy.
Another study (44) clearly demonstrated the protective effect of short-term pantoprazole treatment in elderly patients at high risk of GI complications. This finding is clinically important because most NSAID-related upper gastrointestinal injuries in older adults occur during short-term treatment for musculoskeletal pain. The study also confirmed that pantoprazole is not only effective but also well tolerated in elderly patients.
Tolerability and Safety of Pantoprazole
PPIs are generally well tolerated and have an excellent safety profile (19). This has been consistently demonstrated in both short-term and long-term clinical studies. According to some reports, adverse events occur in only 0.77% of patients treated with pantoprazole. The most commonly reported adverse effects include diarrhea, headache, dizziness, pruritus, and skin rash. These reactions are usually mild to moderate in severity and rarely require discontinuation of treatment.
PPIs are metabolized in the liver via the cytochrome P450 (CYP450) enzyme system. Although all PPIs undergo the same initial metabolic pathway, differences in subsequent metabolism result in pantoprazole (e.g., Nolpaza®) having significantly fewer interactions with the CYP450 system than other PPIs (20).
Pharmacokinetic studies have demonstrated no clinically significant drug interactions between pantoprazole and other commonly prescribed medications mediated through the CYP450 system (21). Clinical studies have confirmed that pantoprazole can be safely co-administered with diclofenac, piroxicam, and naproxen (22, 23, 40).
In contrast, omeprazole has been shown to interact significantly with several medications, including diazepam, carbamazepine, warfarin, and phenytoin (21, 41).
The risk of clinically relevant drug interactions is particularly high in elderly patients and in those receiving multiple medications. Because most patients requiring NSAID therapy are older adults with multiple comorbidities, pantoprazole is especially well suited for the prevention and treatment of NSAID-associated gastrointestinal injury.
Studies have also demonstrated that the pharmacokinetics of pantoprazole remain unchanged in healthy older adults as well as in patients with renal insufficiency. Therefore, dose adjustment is not required in either of these populations (43).
