Daniel H Solomon, MD, MPH
Daniel E Furst, MD
Paul L Romain, MD
NONSTEROIDAL ANTIINFLAMMATORY DRUG OVERVIEW — Nonsteroidal anti-inflammatory drugs (NSAIDs) are medications used to relieve pain and reduce inflammation. They are one of the most commonly used medications in adults. A variety of NSAIDs are available, including at least 20 in the United States and more elsewhere.
Because of the wide availability of NSAIDs, it is important to be aware of their proper use, dose, and potential side effects.
CHOOSING A NONSTEROIDAL ANTIINFLAMMATORY DRUG — Because of the large number of NSAIDS that are available, it can be difficult to know which one is best. In addition, a person’s response to a particular NSAID is hard to predict. If two people take an identical drug and dose, their individual response may be considerably different. It is sometimes necessary to try one drug for a few weeks, and then try a different one to find the optimal combination of these factors.
A healthcare provider is the most qualified person to help choose an NSAID, although you can assist in the decision-making process.
HOW NONSTEROIDAL ANTIINFLAMMATORY DRUGS WORK — NSAIDs work to reduce pain and inflammation by inhibiting enzymes, called cyclooxygenases, which participate in the production of prostaglandins. By inhibiting cyclooxygenase, NSAIDs help to prevent and/or reduce pain and inflammation. Cyclooxygenase enzyme inhibition is also responsible for many of the side effects of NSAIDs.
TYPES OF NONSTEROIDAL ANTIINFLAMMATORY DRUGS — There are two main types of NSAIDs, nonselective and selective. The terms nonselective and selective refer to different NSAIDs’ ability to inhibit specific types of cyclooxygenase (COX) enzymes.
- Nonselective NSAIDs — Nonselective NSAIDs inhibit both COX-1 and COX-2 enzymes to a significant degree.
- Selective NSAIDs — Selective NSAIDs inhibit COX enzymes found at sites of inflammation (COX-2) more than the type that is normally found in the stomach, blood platelets, and blood vessels (COX-1).
Nonselective NSAIDs — Nonselective NSAIDs include drugs commonly available without prescription, such as aspirin, ibuprofen (Advil®, Motrin®, Nuprin®), and naproxen (Aleve®), as well as many prescription-strength NSAIDs.
Selective NSAIDs — Selective NSAIDs (also called COX-2 inhibitors) are as effective in relieving pain and inflammation as nonselective NSAIDs and are less likely to cause gastrointestinal injury. Celecoxib (Celebrex®) is the only selective NSAID currently available in the United States.
Selective NSAIDs are sometimes recommended for people who have had a peptic ulcer, gastrointestinal bleeding, or gastrointestinal upset when taking nonselective NSAIDs. Selective NSAIDs have less potential to cause ulcers or gastrointestinal bleeding, but they do not prevent ulcers that develop for other reasons.
Precautions with selective NSAIDs — Rofecoxib (Vioxx®) and valdecoxib (Bextra®) were taken off the market in 2004 when it was discovered that people who took these medications had a slightly increased risk of heart attack and stroke.
People with known coronary artery disease (eg, past history of heart attack, angina (chest pain due to narrowed heart arteries), history of a stroke, or narrowed arteries to the brain) and people who are at a higher than average risk for these conditions should avoid using COX-2 inhibitors and some nonselective NSAIDs until more information is available, and should consult their clinician before any such use.
NSAIDs are generally not recommended for people with kidney disease, heart failure, cirrhosis, or people who take diuretics. Some patients who are allergic to aspirin may be able to take selective NSAIDs safely, although this should be discussed in advance with a healthcare provider.
Dose of NSAIDs — Lower doses of NSAIDs, as recommended for use with nonprescription NSAIDs, are adequate to relieve pain in most people. To fully treat inflammation, a higher dose of the NSAID must be taken on a regular basis for several weeks before the full antiinflammatory benefit is realized.
If the initial dose of NSAIDs does not improve symptoms, a clinician may recommend increasing the dose gradually or switching to another NSAID. People taking one NSAID should not take a second NSAID at the same time.
NONSTEROIDAL ANTIINFLAMMATORY DRUG SIDE EFFECTS — Most people tolerate NSAIDs without any difficulty. However, side effects can occur. The most common side effects include the following:
- Gastrointestinal system — Short term use of NSAIDs can cause stomach upset (dyspepsia). Long term use of NSAIDs, especially at high doses, can lead to peptic ulcer disease and bleeding from the stomach. (See ‘Ulcer disease’ below.)
- Liver toxicity — Long term use of NSAIDs, especially at high doses, can harm the liver. Monitoring the liver function with blood tests may be recommended in some cases.
- Kidney toxicity — Use of NSAIDs, even for a short period of time, can harm the kidneys. This is especially true in people with underlying kidney disease. The blood pressure and kidney function should be monitored at least once per year, but may need to be checked more often, depending on a person’s medical conditions. (See ‘Kidney disease’ below.)
- Ringing in the ears — Ringing in the ears (tinnitus) is common in people who take high doses of aspirin, although it can also occur in people who take other NSAIDs. The ringing usually resolves when the dose is decreased.
MEDICAL CONDITIONS AND NONSTEROIDAL ANTIINFLAMMATORY DRUGS — People with some medical problems and those taking various medications are at increased risk of complications related to NSAIDs. Potential complications of NSAIDs include the following:
Cardiovascular disease — Anyone who is at risk for or has cardiovascular disease (coronary artery disease) may have a further increase in risk of heart attacks when taking an NSAID. This includes people who have experienced a heart attack, angina (chest pain due to narrowed arteries in the heart), a stroke, or narrowed arteries to the brain. As a result, people who have or who are at risk for coronary artery disease are generally advised to avoid NSAIDs, or if that is not possible, to take the lowest possible dose of NSAID for the shortest possible time.
The recommendation to avoid or limit the use of NSAIDs does NOT apply to people who have been advised to take low-dose aspirin to treat or prevent coronary artery disease. Aspirin is an NSAID, but is often recommended in low doses to people with coronary artery disease to reduce the risks of developing a blood clot. (See “Patient information: Aspirin and cardiovascular disease”.)
Ulcer disease — Those who have had a stomach or intestinal ulcer are at an increased risk of another ulcer while taking an NSAID. People being treated for ulcers should consult their healthcare provider about the safety of taking NSAIDs or drugs containing aspirin. People over 65 years of age have an increased risk of developing ulcers when taking NSAIDs. (See “Patient information: Peptic ulcer disease”.)
Reducing ulcer risk — The risk of developing ulcers can be reduced by taking an anti-ulcer medication in addition to an NSAID. Anti-ulcer agents that reduce gastrointestinal damage from NSAIDs include:
- Inhibitor of stomach acid production — High doses of antacid histamine blockers, such as famotidine (Pepcid®), and ordinary doses of the acid production inhibitors, such as omeprazole (Prilosec®) or lansoprazole (Prevacid®), can reduce the risk of developing an ulcer (related to use of an NSAID).
- Misoprostol — Misoprostol (Cytotec®) protects the gastrointestinal tract from the effects of NSAIDs and can reduce the risk of gastrointestinal bleeding. Common side effects of misoprostol include diarrhea, abdominal pain, and intestinal cramping.
Bleeding — People who have had bleeding from the stomach, upper intestine, or esophagus have an increased risk of recurrent bleeding when taking NSAIDs.
People with platelet disorders, such as von Willebrand disease, abnormal platelet function from uremia, and those with a low platelet count (thrombocytopenia) are advised to avoid NSAIDs.
Before surgery — Most clinicians recommend stopping all NSAIDs approximately one week before elective surgery to decrease the risk of excessive bleeding. This usually includes aspirin, ibuprofen, naproxen, and most prescription NSAIDs. Specific instructions regarding NSAIDs and surgery should be discussed with the surgeon and with the clinician who prescribed the NSAID.
Interaction with other medications
- Warfarin and heparin — People using anticoagulant medications such as warfarin (Coumadin®) or heparin should generally not take NSAIDs or aspirin because of an increased risk of bleeding when both classes of drugs are used. (See “Patient information: Warfarin (Coumadin®)”.)
Celecoxib may be safe in such instances but should be used with caution and under the guidance of a physician.
- Aspirin — NSAIDs appear to be safe when taken with low-dose aspirin (81 mg). To preserve the benefit of low-dose aspirin for the heart, aspirin should be taken at least two hours before the NSAID. (See “Patient information: Aspirin and cardiovascular disease”.)
- Phenytoin — Taking an NSAID and phenytoin (Dilantin®, Phenytek®) can increase the phenytoin level. As a result, people who take phenytoin should have a blood test to monitor the phenytoin level when starting or increasing the dose of an NSAID.
- Cyclosporine — People who take cyclosporine (eg, to prevent rejection after an organ transplant or for a rheumatic disease, such as rheumatoid arthritis) should take particular care when taking an NSAID. There is a theoretical risk of kidney damage when cyclosporine and NSAIDs are taken together. To monitor for this complication, blood testing may be recommended.
- People taking one NSAID should not take a second NSAID at the same time because of the increased risk of side effects.
Fluid retention — People with medical conditions that require diuretics, including heart failure, liver disease, and kidney damage, are at increased risk of developing kidney damage while taking nonselective NSAIDs (eg, ibuprofen) as well as selective NSAIDs (eg, celecoxib (Celebrex®)).
Kidney disease — NSAIDs can worsen kidney function in people whose kidneys are not functioning normally. Most people with chronic kidney disease are advised to avoid all types of NSAIDs. (See “Patient information: Chronic kidney disease”.)
Aspirin allergy — People who have had hives (urticaria) or other symptoms of an allergy to aspirin should generally avoid NSAIDs, unless they have specifically discussed their reaction with a healthcare provider. People with certain types of reactions to one NSAID may be able to take another type safely. It may be necessary to consult with an allergy specialist, who has experience with allergic reactions to NSAIDS. (See “Patient information: Hives (urticaria)”.)
Aspirin and other NSAIDs may also cause worsening of asthma and related symptoms in some people with these conditions. This is not a true allergy, but can be a significant problem for some people, who may need to avoid these medications if this occurs.
Celecoxib may be a safe alternative to aspirin in such people but should be used with caution under the supervision of a physician.
Pregnancy and breastfeeding — NSAIDS are not generally recommended for pregnant women during the third trimester due to an increased risk of complications in the newborn. NSAIDs are safe for use during breastfeeding. (See “Patient information: Maternal health and nutrition during breastfeeding”.)
NONSTEROIDAL ANTIINFLAMMATORY DRUG OVERDOSE — Accidentally or intentionally taking a larger than recommended dose of an NSAID does not usually cause serious complications. However, taking large doses of other pain medications may have more serious consequences. For example, overdose with salicylates (eg, aspirin) or acetaminophen (eg, Tylenol®) can be harmful or even fatal.
People who accidentally or intentionally take an overdose of any medication should contact their healthcare provider or the Poison Control Hotline (in the United States, 1-800-222-1222). If the person is not breathing or is not conscious, emergency medical attention is needed; this is available in most areas of the United States by calling 911.
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem.
This article will be updated as needed every four months on our Web site (www.uptodate.com/patients).
Related topics for patients, as well as selected articles written for healthcare professionals, are also available. Some of the most relevant are listed below.
Patient Level Information:
Patient information: Aspirin and cardiovascular disease
Patient information: Peptic ulcer disease
Patient information: Warfarin (Coumadin®)
Patient information: Chronic kidney disease
Patient information: Hives (urticaria)
Patient information: Maternal health and nutrition during breastfeeding
Professional Level Information:
COX-2 inhibitors and gastroduodenal toxicity — major clinical trials
COX-2 selective inhibitors: Adverse cardiovascular effects
Nonselective NSAIDs: Adverse cardiovascular effects
Nonselective NSAIDs: Overview of adverse effects
NSAIDs (including aspirin): Pathogenesis of gastroduodenal toxicity
NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity
NSAIDs (including aspirin): Role in prevention of colorectal cancer
NSAIDs (including aspirin): Secondary prevention of gastroduodenal toxicity
NSAIDs (including aspirin): Treatment of gastroduodenal toxicity
NSAIDs and acetaminophen: Effects on blood pressure and hypertension
NSAIDs: Acute kidney injury (acute renal failure) and nephrotic syndrome
NSAIDs: Adverse effects on the distal small bowel and colon
NSAIDs: Electrolyte complications
NSAIDs: Mechanism of action
NSAIDs: Therapeutic use and variability of response in adults
Overview of selective COX-2 inhibitors
The following organizations also provide reliable health information.
- National Library of Medicine
- American Academy of Orthopaedic Surgeons
- United States Food and Drug Administration
- Brooks PM, Day RO. Nonsteroidal antiinflammatory drugs–differences and similarities. N Engl J Med 1991; 324:1716.
- Walker JS, Sheather-Reid RB, Carmody JJ, et al. Nonsteroidal antiinflammatory drugs in rheumatoid arthritis and osteoarthritis: support for the concept of “responders” and “nonresponders”. Arthritis Rheum 1997; 40:1944.
- Ray WA, Stein CM, Daugherty JR, et al. COX-2 selective non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease. Lancet 2002; 360:1071.
- Solomon DH, Schneeweiss S, Glynn RJ, et al. Relationship between selective cyclooxygenase-2 inhibitors and acute myocardial infarction in older adults. Circulation 2004; 109:2068.