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Guidelines to Help Reduce the Side Effects of COX-2-Specific Drugs Like Celecoxib (Celebrex)

This discussion focuses primarily on celecoxib (Celebrex), since it is presently the only available COX-2 specific nonsteroidal anti-inflammatory drug (NSAID) in the United States. For a discussion on reducing side effects in other, traditional types of NSAIDs, see Guidelines to Help Reduce the Side Effects of NSAIDs.

NSAIDs as COX-inhibiting agents

Doctors have long prescribed NSAIDs to ease the pain and inflammation of arthritis, as well as for other types of pain. These medications achieve their benefits by inhibiting certain inflammation-causing chemicals in the body called prostaglandins. Prostaglandins are among a group of substance in the body that can promote inflammation in the joints. NSAIDs block a type of enzyme in the body, called cyclooxygenase (or COX), that plays a role in the production of prostaglandin. Traditional NSAIDs inhibit two types of cyclooxygenase, known as COX-1 and COX-2. However, it has been found that COX-1 plays an important role in protecting the stomach lining. For this reason, inhibiting it can lead to the stomach irritation and ulcers that can be seen when people take most NSAIDs. It appears that for the control of arthritic and other painful symptoms, it is more important for a that a drug block COX-2, which is produced in the body when inflammation is present.

Thus, medical scientists have sought to develop newer NSAIDs that are less likely to cause such gastrointestinal (GI) problems. There have been some debates about which drugs more specifically inhibit COX-2 than others. This debate relates to different methods of testing the drugs. The most agreed-upon system of classifying the COX specificity of different NSAIDs divides the agents into three groups:

  1. The traditional group blocks as much, or almost as much, COX-1 as COX-2. (See our review on traditional NSAIDs.)
  2. The second group of drugs are COX-2-selective, that is, are simply more apt to block COX-2 than COX-1. Of the drugs marketed in the United States, these are meloxicam (brand name Mobic) and nabumetone (Relafen). In Europe, nimesulide is also classified in this "selective" group.
  3. The third category of COX-specificity is the "COX-2-specific" group of NSAIDs. In the past, three COX-2-specific NSAIDs were available in the United States, but Vioxx and Bextra have been taken off the market. Celebrex is the only one that remains available, and it is used to treat osteoarthritis, rheumatoid arthritis, acute pain, menstrual pain, and ankylosing spondylitis (an inflammatory disease involving the spine). Patients who are taking celecoxib should discuss with their doctor the pros and cons of using this medication for their particular condition, taking into consideration how much the medication is helping them, but also any other medical conditions they have or may be at risk for.

Potential side effects of COX-2 drugs

The literature on GI side effects with these medications is extensive and still somewhat controversial, but the weight of the evidence still suggests that both the COX-2 selective and COX-2 specific agents have fewer GI side effects than older NSAIDs, as well as fewer of the more serious GI side effects, such as bleeding or perforation of an ulcer.

For the rest of this discussion, the term "COX-2s" refers only to the COX-2-specific agent celecoxib (Celebrex) that is available in the United States. There is not yet sufficient medical literature to allow us to clearly separate the relative safety between these selective and specific drugs. The choice of which drug to use (in those countries where more than one choice is available) is often made based on a particular physician's impression of a drug’s relative effectiveness. In general, when COX-2 specificity is desired for treatment, celecoxib will be most doctors’ first choice due to its higher specificity.

Overall, the COX-2s appear to be equally effective in controlling inflammation compared to the older, less selective NSAIDs. Celecoxib may be considered and is used in patients who are at high risk for stomach irritation, including:

  • the elderly
  • those with a history of NSAID-induced stomach irritation or intolerance
  • those taking other drugs that increase the risk of stomach problems
  • those who have other diseases (like heart or lung problems) that appear to increase the risk of ulcers

As noted below, however, GI problems can still occur with celecoxib, so precautions, such as the use of acid-blocking medications in higher-risk people, may still be needed along with the celecoxib. For other patients, the ulcer risk may simply be too high to recommend using these drugs at all, as in a patient who is actively being treated for a documented ulcer.

If any of the following guidelines are not clear, or if you think it does not apply to you, discuss the issue with your physician.

Gastrointestinal symptoms

Although these drugs (again − in the United States we are referring only to celecoxib) appear to be less likely to irritate the stomach than traditional NSAIDs, such irriation can still occur. Take these general precautions:

  • Stop the drug and call your physician immediately if you have any severe abdominal pain or a black, tarry stool (bowel movement) or any blood in your stool, which are signs of internal bleeding.
  • Take celecoxib at the end of a full meal, or with antacid.
  • Limit alcohol intake (since alcohol can irritate the stomach).

The US Food and Drug Administration (FDA) placed the following black box warning on Celebrex, related to potential GI symptoms:

  • "Gastrointestinal Risk: NSAIDs, including Celebrex, cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal (GI) events."

Note that if your physician has advised you to take aspirin for heart protection, this can increase your risk of ulcer and gastrointestinal bleeding. If you add celecoxib to the aspirin, ask your physician whether you should take a medication along with these to protect against ulcers, such as omeprazole (Prilosec).


Celecoxib is contraindicated (not compatible or recommended) in patients with allergy to sulfa-containing drugs (sulfonamides). Such drugs include the antibiotic trimethoprim-sulfamethoxazole (Bactrim, Septra). If you are thinking of taking celecoxib, make sure that you do not have a history of allergy to such drugs. If you aren't sure if a drug you had a bad reaction to fits in this category, ask your physician. If you are allergic to sulfa-containing drugs, do not take celecoxib.

Heart problems

Rofecoxib (Vioxx), a COX-2 specific agent, was removed from the market on September 30, 2004, due to questions of increased risk of heart attacks and strokes. The black box warning from the FDA about cardiovascular problems with non-specific NSAIDs also appears for Celebrex:

  • "Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in the treatment and may increase with duration of use."

Therefore, the use of Celebrex should be carefully considered in a patient with a history of heart disease, hypertension or stroke. If it is decided to use Celebrex in people with such histories, attempts should be made to lower the dose and shorten the duration of use.

Kidney effects

Celecoxib, like the non-specific NSAIDs, can adversely affect kidney function. For this reason, people with abnormal kidney function should avoid or sharply limit the use of this medication, and if it is used the kidney function should be followed. Even in people with normal kidney function, if celecoxib is used long-term, then the kidney function should be periodically checked.

Skin reactions

Serious skin reactions have occurred in people taking COX-2 inhibitors. These are rare occurrences, but have included potentially life-threatening hypersensitivity reactions. Because many of these reactions were voluntarily reported after the drug was marketed, it is not possible to estimate their frequency or whether they are indeed related to the drug. Severe skin rashes were a major reason for the withdrawal of valdecoxib (Bextra), another COX-2 specific NSAID, from the market, according to the FDA. Therefore, if you experience any rash while you are taking Celebrex, stop taking it immediately and call your doctor.


When you are trying celecoxib for the first time, take the full dose prescribed every day, unless instructed otherwise. It may take as long as two weeks to build up to a "blood level" of the drug, and the drug may not help very much until then. However, there are situations where the pain-killing effect of celecoxib is sufficient and you don’t need to take the full dose every day. Ask your doctor what the goals are for celecoxib in your case, so that you know if you need to take it regularly to build up an “anti-inflammatory drug level.” If the goal was to reach an “anti-inflammatory level” with celecoxib, and you take the drug irregularly, you may never know whether it actually can help you. This could lead to your being switched to a second drug when the first one actually could have helped. Each new drug you take carries a risk of allergic reaction (such as skin rash). Therefore, it's important to find out if a drug can help you before switching to another.

  • Do not exceed the dose of the drug prescribed. The extra benefit is usually small and the increased risk is significant.
  • If you are taking the medicine regularly and miss a dose, take it as soon as possible. However, if it is almost time for your next dose, skip the one you missed and go back to your regular schedule. Do not take a double dose.
  • If your arthritis improves, discuss with your physician the possibility of decreasing or stopping your dose of the celecoxib.

Combining COX-2s and NSAIDs with other drugs

  • Do not mix one COX-2 or NSAID with another. For example, don't take ibuprofen with any other NSAID or with celecoxib. Discuss with your physician whether you should take aspirin with your COX-2 agent – the risk vs benefit is different in individual patients.
  • Acetaminophen, especially in low doses, appears less likely to irritate the stomach than NSAIDs, so in many cases it is reasonable to take it alongside celecoxib if needed. Always read the ingredients listed on the label of over-the-counter products. If acetylsalicylic acid (aspirin) or salicylate is listed, it may be better not to take this with NSAIDs, unless advised by your physician. Keep in mind that Alka-Seltzer, Anacin and some types of Excedrin all contain aspirin.
  • If you are taking medications for high blood pressure, have your pressure checked regularly while on the celecoxib. This is especially important within the first several weeks of starting the drug. In some patients, COX-2 agents can elevate the blood pressure.

When to stop the drug and get immediate medical attention

Cease taking celecoxib if:

  • Signs of allergy occur, such as rapid breathing, gasping, wheezing, hives, skin rashes, puffy eyelids, and/or rapid heartbeat occur.
  • You develop vision abnormalities.
  • You develop dizziness, depression, or confusion.
  • You develop yellowing of the eyes that could indicate liver injury (Note that liver injury is rare and your liver function is checked when you have standard chemistry blood tests, which should be done periodically when you are taking celecoxib).
  • Your urine becomes cloudy or bloody, the amount of urine you pass suddenly decreases, or you develop new ankle swelling, all of which could indicate kidney problems. This is especially important to watch for if your kidney function has been noted, on lab testing, to have been abnormal in the past.

When to call your doctor about changing dosage or medications

Call your doctor if:

  • You develop swelling of the ankles or sudden weight gain after starting one of these drugs due to fluid retention.
  • You develop decreased hearing or ringing in your ears.
  • You are planning to get pregnant, or become pregnant.


Theodore R. Fields, MD, FACP
Attending Physician, Hospital for Special Surgery
Professor of Clinical Medicine, Weill Cornell Medical College

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