Nonsteroidal Antiinflammatory Drugs (NSAIDs) and the Risk for Stomach Ulcers and Bleeding
Rosemary R. Berardi, Pharm.D., FCCP, FASHP, FAPHA
Professor of Pharmacy, University of Michigan College of Pharmacy
Background
Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used medications in the United States. Some NSAIDs (e.g., indomethacin, tolmetin, piroxicam, sulindac, flurbiprofen) are available only by prescription and must be prescribed by your health care provider, while others (e.g., ibuprofenâ, naproxen) are also available over-the-counter (OTC) in lower daily dosages intended for self-treatment (see Table 1). Each year, about 111 million prescriptions for NSAIDs are filled in the U.S. and millions of dollars are spent on OTC NSAIDs.1 The widespread use of NSAIDs is a major concern, especially in older adults, because of side effects such as stomach ulcers and bleeding.
What medications are considered to be NSAIDs and how do they differ?
NSAIDs are used primarily to treat arthritis and other painful conditions. The term "NSAID" usually describes traditional NSAIDs, aspirin and newer NSAIDs known as cyclooxygenase-2 (COX-2) inhibitors (see Table 1).
· Traditional NSAIDs - Traditional NSAIDs have been used for years to relieve inflammation associated with arthritis and other types of pain, e.g., tendonitis, menstrual pain, and headache. Although very effective pain relievers, some patients are at risk of developing stomach ulcers with continued use and a smaller number may develop ulcer complications such as bleeding.
· Aspirin - Aspirin is also a NSAID, but it differs from traditional NSAIDs because of its chemical structure. Aspirin also increases the risk for stomach ulcers and bleeding when usual dosages are used continuously to relieve pain and to a lesser extent when daily low aspirin dosages (81 mg/day) are used to decrease the risk of a heart attack (myocardial infarction). Although aspirin tablets may be enteric-coated, or buffered, the risk of ulcers and bleeding remains.
· Newer NSAIDs (COX-2 Inhibitors) - The COX-2 inhibitors belong to a newer class of NSAIDS that may be somewhat less likely to cause ulcers and bleeding when taken continuously. Initially celecoxib (Celebrex®) was thought to be a COX-2 inhibitor, but today the Food and Drug Administration (FDA) requires the same warnings and labeling related to stomach ulcers and bleeding for celecoxib as those required for the traditional NSAIDs. Although many individuals still refer to celecoxib as a COX-2 inhibitor, there is insufficient evidence to support this claim. Two previously available COX-2 inhibitors, rofecoxib (Vioxx®) and valdecoxib (Bextra®), were associated with fewer ulcers and bleeding than the traditional NSAIDs, but they were withdrawn from the US market because of an increased risk of cardiovascular problems (e.g., heart attack, stroke), especially in patients who had underlying heart disease. The risk of cardiovascular adverse effects with celecoxib and other traditional NSAIDs is not as clear. Therefore, celecoxib and other NSAIDS should only be used in the lowest possible dose for the shortest period of time and only when there is no appropriate alternative. If you have concerns, you should discuss them with your health care provider.
What are the most common side effects associated with NSAID use?
The most common side effects include heartburn, acid indigestion, upset stomach, nausea, and abdominal pain. Although these side effects may be troublesome, they usually do not indicate that you have a stomach ulcer. About 15-30 percent of patients who take traditional NSAIDs on a continuing basis are likely to develop a stomach ulcer, which occasionally leads to serious complications, the most common of which is ulcer-related bleeding.1,2 NSAIDs can also cause other side effects including an increase in blood pressure, fluid retention (e.g., ankle swelling) worsening heart failure, and decreased kidney function.
Who is at greatest risk of developing a stomach ulcer or bleeding when taking a NSAID?
When taken as directed by a healthcare provider or according to the OTC label, NSAIDs are safe for most people. Some of the most important factors that increase the risk for stomach ulcers and bleeding are listed below. A combination of risk factors further increases ulcer risk.
· Age - Adults over 60 years of age
· Past Ulcer or Ulcer Complication - Individuals who have had a prior ulcer or ulcer-related complication such as bleeding
· Medications - Individuals taking NSAIDs along with certain medications such as prednisone, blood thinners (e.g., warfarin or clopidogrel), bisphosphonates (e.g., alendronate), and certain antidepressants (e.g., sertraline)
· Aspirin - Including low-dose (81 mg), enteric-coated (e.g., Ecotrinâ) and buffered products (e.g. Bufferinâ).
· High-Dose NSAIDs - Taking a high-dose (higher than what is directed) NSAID or taking more than one NSAID (e.g., prescription NSAID plus OTC NSAID or NSAID plus aspirin). Remember that OTC NSAIDS may have different trade names (e.g., Advil®, Aleve®) include registered trade marks or different generic names (e.g., ibuprofen, naproxen) but all have similar uses and side effects. Combining different OTC NSAID products may increase your chance of developing an ulcer
· Alcohol – It varies from person to person, but especially when alcohol is consumed daily.
How do I know if I have an ulcer or if I am bleeding from taking a NSAID?
Ulcers are usually related to the regular use of NSAIDs and occur most often in patients at increased risk (see above). Although NSAID-related side effects such as heartburn and upset stomach may be troublesome, they are usually not indicative of an ulcer. Some patients develop an NSAID-related ulcer without any symptoms, while others have typical ulcer symptoms such as stomach pain (e.g., burning, gnawing pain between the bottom of the breastbone and the navel) and pain that sometimes awakens people from sleep. When bleeding occurs from the stomach where most NSAID-induced ulcers occur, you may vomit bright red blood or material that looks like coffee grounds and pass black, tarry-looking stools. Feeling tired or short of breath may be a sign of blood loss. You should seek medical attention if you experience these or any other unusual signs or symptoms.
Is there anything I can take that decreases the chance of getting an NSAID-related ulcer or bleeding?
Several options are available for patients who must take NSAIDs regularly and are at increased risk of developing an ulcer.
· Proton Pump Inhibitors - The proton pump inhibitors (PPIs), lansoprazole (Prevacid®), omeprazole (Prilosec®), esomeprazole (Nexium®), pantoprazole (Protonix®), and rabeprazole (Aciphex®) are prescription drugs and are very effective in reducing the risk of NSAID-related stomach ulcers. Prilosec OTC®, which is available OTC for self-treatment of frequent heartburn (heartburn two or more days a week), should only be used to prevent NSAID-related ulcers if it is recommended by your healthcare provider. The PPIs reduce the release of acid in the stomach where ulcers are likely to form. PPIs are usually taken once daily in the morning about 30-60 minutes before breakfast. Their short-term side effects are infrequent and include headache and diarrhea. When taken long-term and in higher dosages they have been associated with an increased risk of hip fracture in older individuals3, intestinal infections4 and pneumonia5. However, there is insufficient information to indicate that PPIs actually cause these problems. For additional information regarding safety issues when taking PPIs long-term, please see the National Heartburn Alliance’s Web site and the informational page, “Debunking the Myth: Safety Issues with Proton Pump Inhibitors.” Like all medications, PPIs should only be used when necessary in the lowest possible dose and when their benefits outweigh the potential risks associated with their use. If you have any questions or concerns you should contact your healthcare provider.
· Misoprostol - Another option for reducing the risk of an NSAID-related ulcer is misoprostol (Cytotec®). Misoprostol replenishes the stomach prostaglandins and protects the stomach lining from damage. Although effective, misoprostol is used less often than the PPIs because of troublesome side effects such as abdominal cramping and diarrhea and because it must be taken more than once daily. Misoprostol must not be used in women who are pregnant. A negative pregnancy test is required if the drug is to be used in women of childbearing age.
· H2-receptor antagonists - The H2RAS, famotidine (Pepcid®, Pepcid AC®, Pepcid AC Max®), ranitidine (Zantac®, Zantac 75®, Zantac 150®), cimetidine (Tagamet®, Tagamet HB®), and nizatidine (Axid®, Axid AR®) are available OTC and on prescription. These H2RAs provide excellent relief of NSAID symptoms such as heartburn and acid indigestion and last much longer than antacids. However, the H2RAs are not very effective for reducing the risk of a stomach ulcer or bleeding. Tagametâ is best avoided because of its high potential to interact adversely with several other drugs.
· Antacids - Antacids relieve NSAID-related heartburn and acid indigestion quickly, but relief only lasts about 30 minutes on an empty stomach. Antacids are intended primarily for prompt relief of mild, infrequent heartburn and acid indigestion. Antacids do not reduce the risk of a stomach ulcer or bleeding.
What are key points I should remember about NSAIDs and the risk for stomach ulcers and bleeding?
· Follow the label directions on OTC NSAIDs and do not take more than the recommended dose or continue treatment for longer than the recommended duration. If you are not receiving adequate pain relief using one OTC NSAID, or from your prescription NSAID, contact your healthcare provider for advice.
· If an NSAID causes ulcer-like pain, worsens heartburn, or if you observe signs or symptoms associated with ulcer bleeding, stop the medication and consult your healthcare professional.
· Patients at increased risk of NSAID-related ulcers and bleeding should receive effective prophylactic therapy. Only the PPIs and misoprostol have been shown to reduce the risk of NSAID-related ulcers in high-risk patients, but side effects often limit the use of misoprostol. Although the H2RAs relieve NSAID-related indigestion, they are not very effective in preventing ulcers and bleeding. Antacids provide quick relief of NSAID-related indigestion, but relief is not long-lasting and antacids do not reduce NSAID-related ulcer risk.
References:
1Laine L. Approaches to nonsteroidal anti-inflammatory drug use in the high-risk patient. Gastroenterology 2001;120:594–606.
2Cryer B. NSAID-associated deaths: the rise and fall of NSAID-associated GI mortality. Am J Gastroenterol 2005;100:1694-95.
3Yang YX, Lewis JD, Epstein S, et al. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA 2006;296:2947-53.
4Lowe DO, Mamdani MM, Kopp A, et al. Proton pump inhibitors and hospitalization for Clostridium difficile-associated disease: a population-based study. Clin Inf Dis 2006;43:1272-76.
5LaHeij RJF, Sturkenboom MCJM, Hassings RJ, et al. Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs. JAMA 2004;292:1955-60.
Other References
Berardi RR. Peptic ulcer disease and NSAIDs: update on risk, risk reduction strategies, and treatment. The Rx Consultant, 2007;18:1-8.
Garcia Rodriguez LA, Barreales Tolosa L. Risk of upper gastrointestinal complications among users of traditional NSAIDs and COXIBs in the general population. Gastroenterology 2007;132:498-506.
Naesdal J, Brown K. NSAID-associated adverse effects and acid control aids to prevent
them: a review of current treatment options. Drug Safety 2006;29:119-32.
Tata LJ, Fortun PJ, Hubbard RB, et al. Does concurrent prescription of selective serotonin reuptake inhibitors and non-steroidal anti-inflammatory drugs substantially increase the risk of upper gastrointestinal bleeding? Aliment Pharmacol Ther 2005;22:175-81.
Thomas J, Straus WL, Bloom BS. Over-the-counter nonsteroidal anti-inflammatory drugs and risk of gastrointestinal symptoms. Am J Gastroenterol 2002;97:2215-19.
White WB. Cardiovascular effects of the cyclooxygenase inhibitors. Hypertension 2007;49:408-18.
Table 1. Nonsteroidal Antiinflammatory Drugs (NSAIDs)
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Traditional NSAIDs
Ibuprofen (Motrin®, Advil®, available generically and OTC)
Naproxen (Naprosyn®, Aleve®, available generically and OTC)
Nabumetone (Relafen®, generic)
Piroxicam (Feldene®, generic)
Sulindac (Clinoril®, generic)
Diclofenac (Voltaren®, generic)
Etodolac (Lodine®, generic)
Tolmetin (Tolectin®, generic)
Aspirin - regular strength (325 mg), baby aspirin (81 mg)
Newer NSAIDs (Cox-2 inhibitors)
Celecoxib (Celebrex®)
Rofecoxib (Vioxx®) - withdrawn from the US market due to safety issues.
Valdecoxib (Bextra®) - withdrawn from the US market due to safety issues.
