Prostaglandins are made by two different enzymes, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). The prostaglandins made by the two different enzymes have slightly different effects on the body. COX-2 inhibitors are NSAIDs that selectively block the COX-2 enzyme and not the COX-1 enzyme. Blocking this enzyme impedes the production of prostaglandins by the COX-2 which is more often the cause the pain and swelling of inflammation and other painful conditions. Because they selectively block the COX-2 enzyme and not the COX-1 enzyme, these drugs are uniquely different from traditional NSAIDs which usually block both COX-1 and COX-2 enzymes.

COX-2 inhibitors are used for treating:

• Ankylosing spondylitis
• Juvenile rheumatoid arthritis
• Menstrual cramps (primary dysmenorrhea)
• Acute pain (for example, sports injuries)
• Osteoarthritis
• Rheumatoid arthritis

Celecoxib (Celebrex) is the only COX-2 inhibitor available in the United States. It is available as a generic.

Rofecoxib (Vioxx) and valdecoxib (Bextra) were withdrawn from the market in 2004 and 2005, respectively, because they excessively increased the risk of heart attacks and strokes with long term use.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a class of drugs that reduce inflammation but are different from steroids, another class of drugs that also reduces inflammation. NSAIDs reduce pain, fever, and swelling and are commonly prescribed for inflammation of the joints (arthritis) and other tissues, such as in tendinitis and bursitis. Examples of NSAIDs include:

• aspirin,
• indomethacin (Indocin),
• ibuprofen (Advil, Motrin),
• naproxen (Naprosyn),
• piroxicam (Feldene), and
• nabumetone (Relafen).

NSAIDs are used frequently by millions of individuals for treatment of pain, fever and swelling caused by inflammatory conditions as well as for pain alone. NSAIDs work by blocking the production of prostaglandins, chemical messengers that often are responsible for the pain and swelling of inflammatory conditions.

The side effects of NSAIDs are listed below and are compared and contrasted with those of COX-2 inhibitors.

COX-2 inhibitors impede prostaglandin production. COX-1 is an enzyme which is normally present in a variety of tissues in the body, including sites of inflammation and the stomach. Some of the prostaglandins made by COX-1 protect the inner lining of the stomach. Common NSAIDs such as aspirin block both COX-1 and COX-2 (see below). When the COX-1 enzyme is blocked, inflammation is reduced, but the protection of the lining of the stomach also is lost. This can cause stomach upset as well as ulceration and bleeding from the stomach and even the intestines.

The other cyclooxygenase, COX-2, also produces prostaglandins, but the COX-2 enzyme is located specifically in areas of the body that commonly are involved in inflammation but not in the stomach. When the COX-2 enzyme is blocked, inflammation is reduced; however, since the COX-2 enzyme does not play a role in protecting the stomach or intestine, COX-2 specific NSAIDs do not have the same risk of injuring the stomach or intestines.

Older NSAIDs (for example, aspirin, ibuprofen, naproxen, etc.) all act by blocking the action of both the COX-1 and COX-2 enzymes. COX-2 inhibitors selectively block the COX-2 enzyme and therefore have a lower risk of causing ulcers of the stomach or intestine.

Common side effects of COX-2 inhibitors and NSAIDs may include:

• Insomnia
• Abdominal pain
• Flatulence (gas)
• Headache
• Nausea
• Diarrhea
• Pharyngitis
• Rhinitis
• Sinusitis
• Peripheral edema
• Accidental injury
• Dizziness
• Upper respiratory tract infection
• Rash
• Indigestion (dyspepsia)
• Nausea
• Diarrhea

COX-2 inhibitors may increase the risk of serious, even fatal stomach and intestinal adverse reactions, such as ulcers, bleeding, and perforation of the stomach or intestines but to a lesser extent than other nonselective NSAIDs that block both COX-1 and COX-2. These events can occur at any time during treatment and without warning symptoms.

People allergic to sulfonamides, for example, trimethoprim (Trimpex, Proloprim, Primsol) and sulfamethoxazole (Bactrim), aspirin or other NSAIDs may experience allergic reactions to COX-2 inhibitors and should not take them. Serious allergic reactions have occurred in such patients.

NSAIDs, including COX-2 inhibitors, may increase the risk of heart attacks, stroke, and related conditions. This risk may increase in patients with risk factors for heart disease and related conditions and with longer duration of use; therefore to reduce the risk of heart attacks, stroke, and similar events the lowest effective dose and for the shortest duration of time should be used. NSAIDs should not be used after coronary artery bypass graft (CABG) surgery.

NSAIDs, including COX-2 inhibitors, may cause fluid retention. They should be used cautiously in patients with fluid retention or heart failure.

• Combining COX-2 inhibitors with aspirin or other NSAIDs (for example, ibuprofen, naproxen, etc.) may increase the occurrence of stomach and intestinal ulcers. It may be used with low dose aspirin.
• COX-2 inhibitors increase the concentration of lithium (Eskalith, Lithobid) in the blood and may promote lithium toxicity.
• Persons taking the anticoagulant (blood thinner) warfarin (Coumadin, Jantoven) should have their blood tested when initiating or changing COX-2 treatment, particularly in the first few days, for any changes in the effects of the anticoagulant.
• COX-2 inhibitors, like other NSAIDs, may reduce the blood pressure-lowering effects of drugs that are given to reduce blood pressure. This may occur because prostaglandins play a role in the regulation of blood pressure, including ACE inhibitors and angiotensin II antagonists.
• Persons who drink more than three alcoholic beverages per day may be at increased risk of developing stomach ulcers when taking NSAIDs.