Selective cyclo–oxygenase–2 (COX–2) inhibitors are unique types of nonsteroidal anti–inflammatory drugs (NSAIDs) designed to relieve pain from certain conditions as effectively as other pain relievers but without upsetting the stomach. Conditions treated with COX-2 inhibitors include osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis and some types of acute pain.   

Although COX-2 inhibitors are popular, recent research has raised concerns over their safety. Some COX–2 inhibitors have been withdrawn from the market by their manufacturers after being linked to an increased risk of serious side effects including heart attack, stroke and gastrointestinal bleeding. As a result, celecoxib (Celebrex) is the only remaining COX–2 inhibitor available in the United States. However, common side effects generally include mild symptoms (e.g., stomach ache, diarrhea). People with various conditions (e.g., asthma, heart disease, alcoholism, liver disease) should not take COX–2 inhibitors as they increase the risk of serious side effects.

Selective cyclo–oxygenase–2 (COX–2) inhibitors are special types of nonsteroidal anti–inflammatory drugs (NSAIDs). Like all NSAIDs, selective COX–2 inhibitors, also called coxibs, work by blocking the production of prostaglandins, hormone–like substances in the body that are quickly released at the site of an injury or area of pain. The presence of these chemicals registers in the brain as pain. Prostaglandins protect damaged tissues by bathing them in fluids, causing the tissue to swell or inflame. By blocking the production of prostaglandins, NSAIDs reduce the amount of fluid released after an injury and the level of pain experienced.

COX–2 inhibitors differ from traditional NSAIDs by targeting only the pain–signaling prostaglandins. They do not affect cyclo–oxygenase 1 (COX–1), a chemical associated with protecting the stomach lining. Consequently, COX–2 inhibitors may be able to relieve pain without causing stomach problems (e.g., ulcers) often associated with other NSAIDs. Evidence also suggests that some COX–2 inhibitors, like other NSAIDs, may reduce the risk of colon cancer.  

Currently, celecoxib (Celebrex) is the only type of COX–2 inhibitor approved for sale in the United States. According to the U.S. Food and Drug Administration (FDA), it is used for:

• Relieving symptoms of osteoarthritis, rheumatoid arthritis and juvenile rheumatoid arthritis

• Controlling acute pain in adults, such as surgical or dental pain
  
  
• Easing menstrual pain
  
  
• Reducing colorectal polyps in people who have an inherited condition called familial adenomatous polyposis (FAP) that increases the risk of colorectal cancer

In addition, recent research suggests that short-term use of COX-2 inhibitors may be safe to reduce the abdominal pain of  inflammatory bowel disease.

The other two COX–2 inhibitors previously available, valdecoxib (Bextra) and rofecoxib (Vioxx), were each removed from the market by their respective manufacturers. Studies associated these drugs with a greater risk for developing certain serious health problems such as heart attack, stroke and serious skin reactions. Research is being conducted to determine if the benefits of these drugs outweigh the risks of side effects in certain situations, such as treating and preventing cancer. Recent research has suggested that rofecoxib may relieve acute attacks of migraines.

The FDA determined that the benefits of celecoxib outweighed the risks for some patients. It remains on the market with additional warnings on the label about serious risks in patients with certain conditions including heart attack, stroke and gastrointestinal bleeding.

Recent research has produced mixed results on the cardiovascular safety of COX-2 inhibitors compared to some other NSAIDs. For example, a study of more than 650,000 arthritic adults found the probability of heart attack rose 9 percent in those treated with celecoxib, 32 percent in those treated with rofecoxib, 11 percent with ibuprofen, 41 percent with sulindac and 71 percent with indomethacin. As dosages increased, so did the risk. Another study found, in people who have had a heart attack, high-dose diclofenac to be less risky than high-dose COX-2 inhibitors but riskier than low-dose COX-2 inhibitors. Another study found a potential new COX-2 inhibitor, etoricoxib (Arcoxia), had cardiovascular risks comparable to those of diclofenac.

Individuals’ response to COX-2 inhibitors may vary in part because of genetics. Further study to identify who is likely to benefit and who is likely to experience side effects from a medication could increase the safety of COX-2 inhibitors and other drugs.

Recent research indicates that taking COX-2 inhibitors or some other NSAIDs around the time of a vaccination may hinder the vaccine’s effectiveness. Patients scheduled for a flu shot or other vaccination are advised to ask their physician whether they should restrict use of such medications around that time.

Celecoxib (Celebrex) is currently the only kind of selective cyclo–oxygenase 2 (COX–2) inhibitor approved for sale in the United States. Patients may be advised by their physician not to take this drug if they have been diagnosed with any of the following conditions:

• Allergies to other nonsteroidal anti–inflammatory drugs (NSAIDs) such as aspirin, or to sulfonamide antibiotics or other sulfa drugs
  
  
• Asthma
  
  
• Hives
  
  
• Cardiovascular disease, high blood pressure or recent coronary artery bypass surgery
  
  
• Bleeding problems, stomach ulcer or other intestinal problems
  
  
• Anemia (too few red blood cells in the blood)
  
  
• Alcoholism
  
  
• Tobacco use
  
  
• Dehydration or abnormal fluid retention
  
  
• Kidney or liver disease

The only type of selective cyclo–oxygenase-2 (COX–2) inhibitor currently approved for sale in the United States is celecoxib (Celebrex). Despite the potential benefits of using this drug for certain conditions, such as arthritis, serious side effects may occur. Sometimes side effects can happen without any warning, although warning symptoms often occur. A physician should be notified if a patient experiences any of the following:

• Fainting
• Trouble breathing or swallowing
• Rapid heartbeat (tachycardia)
• Swelling of the face, fingers, feet or lower legs
• Intense abdominal pain or nausea
• Black stools
• Vomiting of blood or substance similar in appearance to coffee grounds
• Unusual weight gain
• Rash, hives, blisters or itchiness
• Fever
• Mouth sores
• Drowsiness or fatigue
• Back pain
• Jaundice
• Painful urination (dysuria)

Because celecoxib has been available for only a short time, long-term side effects have only recently begun to be documented and understood.  A physician can assess a patient’s individual risk for certain complications.

In 2004, the COX–2 inhibitor rofecoxib (Vioxx) was voluntarily withdrawn from the market by its manufacturer after studies linked the drug to high blood pressure and increased risk of heart attack and stroke. The U.S. Food and Drug Administration (FDA) found that people who regularly took standard doses of the drug had a 50 percent higher chance of heart attack or sudden cardiac death than patients taking celecoxib.

Another COX–2 inhibitor, valdecoxib (Bextra), was voluntarily withdrawn for sale in the United States by its manufacturer in 2005 because of evidence that the drug may be associated with an increased risk for heart attack, stroke and serious skin reactions. Research is investigating whether the benefits of the drug outweigh these potential risks in some instances, such as treatment and prevention of cancer.

Other COX–2 inhibitors and some traditional nonsteroidal anti–inflammatory drugs (NSAIDs) may also pose similar risks for serious skin reactions. However, the risk of valdecoxib causing these effects appears to be much greater in comparison to the traditional drugs.  

Research has also linked the use of celecoxib and other COX–2 inhibitors to additional serious side effects, including:

• Stomach ache, diarrhea and headache. These are the most common side effects reported by people who take COX–2 inhibitors.
  
  
• Gastrointestinal problems. COX–2 inhibitors in rare cases can cause bleeding in the stomach or intestines. The risk increases if alcohol is consumed daily or in excess. In rare cases, blockage or perforation of the intestines may occur.
  
  
• Kidney or liver problems. Patients taking COX–2 inhibitors rarely experience problems with the kidney or liver. Blood may be monitored routinely by a physician to check for signs of kidney or liver damage in patients who commonly use these drugs.
  
  
• Aseptic meningitis. In rare instances, rofecoxib can cause this nonbacterial form of meningitis. Aseptic meningitis requires hospitalization, but is typically not life threatening in individuals with normal immune systems. Individuals with autoimmune diseases (e.g., lupus) have a higher risk of contracting aseptic meningitis when taking rofecoxib.
  
  
• Anaphylaxis. This is a rare but very serious allergic reaction that may occur in people allergic to aspirin, other NSAIDs or certain antibiotics (e.g., sulfonamides).

The only type of selective cyclo–oxygenase 2 (COX–2) inhibitor approved for sale in the United States is celecoxib (Celebrex). Patients should consult their physician before taking any additional prescriptions, over–the–counter medications, nutritional supplements or herbal medications. Concerns of individuals taking celecoxib include:

• Other nonsteroidal anti–inflammatory drugs (NSAIDs). These may be administered in low doses. However, some NSAIDs (e.g., aspirin, ibuprofen) taken together with celecoxib may increase the risk for serious side effects such as ulcer.
  
  
• ACE inhibitors. A group of drugs that treat high blood pressure. Celecoxib and other COX–2 inhibitors may diminish the effectiveness of ACE inhibitors.
  
  
• Some other antihypertensives, including diuretics and metoprolol (a beta blocker).
  
  
• Antiarrhythmics including amiodarone, mexiletine and propafenone, used to treat irregular heartbeats. Mexiletine can also be used topically to ease chronic nerve pain (neuralgia).
  
  
• Certain antibiotics used to treat nonviral infections, including sulfonamides (sulfa drugs) and metronidazole.
  
  
• Clopidogrel. An antiplatelet used to prevent heart attacks and strokes.
  
  
• Dextromethorphan. An ingredient in some cough medications.
  
  
• Fluconazole. An antifungal used to treat yeast infections.
  
  
• Fluvastatin. A type of cholesterol-controlling statin drug.
  
  
• HIV drugs including atazanavir, efavirenz and ritonavir.
  
  
• Lithium and certain other drugs for depression and mental illness.
  
  
• Ondansetron. Used in preventing nausea and vomiting due to chemotherapy and other procedures.
  
  
• Some opioids (codeine and tramadol).
  
  
• Sulfinpyrazone. Used to treat gout.
  
  
• Tamoxifen. An anti-estrogen used to fight breast cancer.
  
  
• Timolol. Used to treat glaucoma and high blood pressure and to prevent angina, heart attack and migraine.
  
  
• Zafirlukast. An asthma drug.

How cyclo–oxygenase 2 (COX–2) inhibitors affect pregnant women, fetuses and newborns is not completely known. However, heart and blood flow problems in a fetus or newborn may occur if the mother regularly takes COX–2 inhibitors during the third trimester of pregnancy. Experiments on animals with these drugs have produced birth defects in some cases. Pregnant women should not take celecoxib (Celebrex), especially during the final three months, according to the U.S. Food and Drug Administration (FDA).     

Preparing questions in advance can help patients have more meaningful discussions with their physicians regarding their conditions. Patients may wish to ask their doctor the following questions about COX–2 inhibitors:

1. Can a COX-2 inhibitor relieve my condition or my child’s juvenile rheumatoid arthritis?
   
   
2. What are the possible side effects for me or my child?
   
   
3. How likely am I to develop serious side effects from the use of COX–2 inhibitors?
   
   
4. What alternative drugs can I use for my condition besides COX–2 inhibitors?
   
   
5. Are there any new COX–2 inhibitors coming on the market that may work better for me?
   
   
6. How long should I wait before consuming alcohol after taking COX–2 inhibitors?
   
   
7. Should I stop using COX–2 inhibitors if I think I’m pregnant?
   
   
8. I am allergic to sulfa drugs. Can I take COX–2 inhibitors?
   
   
9. Can I take COX-2 inhibitors long-term?
   
   
10. How long do I need to take COX-2 inhibitors before I see improvements?