Guidelines to Help Reduce the Side-Effects of COX-2 Selective Drugs

Reducing drug side effects of COX-2 non-steroidal anti-inflammatory agents (NSAIDs)


Theodore R. Fields, MD, FACP

Theodore R. Fields, MD, FACP

Attending Physician, Hospital for Special Surgery
Professor of Clinical Medicine, Weill Cornell Medical College

Doctors have long prescribed non-steroidal anti-inflammatory drugs (NSAIDs) to ease the pain and inflammation of arthritis and other types of pain. They achieve their benefits by inhibiting certain inflammation-causing chemicals in the body called prostaglandins (PG). NSAIDs block enzymes in the body, called cyclooxygenase (or COX), that play a role in prostaglandin production. Prostaglandins are mediators of inflammation in the joints. Traditional NSAIDs inhibit both COX-1 and COX-2. However, it has been found that COX-1 plays an important role in protecting the stomach lining; thus, its inhibition can lead to the stomach irritation and ulcers seen when people take most NSAIDs. It appears that for the control of arthritic and other painful symptoms, it is more important for a drug to block COX-2, which is produced in the body in the setting of inflammation.

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 are more specific for COX-2 than others, which relates to different methods of testing the drugs. The most agreed-upon system of classifying the COX specificity of NSAIDs divides the agents into three groups:

  • The traditional group blocks as much, or almost as much, COX-1 as COX-2. (See our review on traditional NSAIDs.)
  • 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 U.S., these are meloxicam (brand named Mobic) and nabumetone (Relafen). In Europe, nimesulide is also classified in this "selective" group.
  • The third category of COX specificity is the "COX-2-specific" group of NSAIDs. This third group includes celecoxib (Celebrex). On 12/17/04, Pfizer reported that a long-term study of celecoxib (looking at its effect on polyps in the colon) showed an increased risk of cardiovascular side-effects, although another similar celecoxib study did not find this increased risk. Celebrex remains available, with indications for osteoarthritis, rheumatoid arthritis, acute pain, menstrual pain, and ankylosing spondylitis (an inflammatory disease involving the spine). Patients who are taking celecoxib should discuss the pros and cons of using this medication in its particular situation, considering how much the medication is helping as well as other medical conditions they may have (or be at risk for).

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" will be used to include the COX-2-selective agent celecoxib (Celebrex). There is not sufficient literature at the moment to allow us to clearly separate the relative safety between these selective and specific drugs, and the choice is often made based on the physician's impression of their relative effectiveness. Overall, the COX-2s appear to be equally effective in controlling inflammation compared to the older, less selective NSAIDs, but they are considerably more expensive. Thus, the COX-2 inhibitors are 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; and those taking other drugs that increase the risk of stomach problems; or those who have other diseases (like heart or lung problems) that appear to increase the risk of ulcers.

For some patients, the risk of ulcer is so high that the physician may choose to give a COX-2 selective or specific agent and also add a medication to protect the stomach (see below). 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 appear to be less likely to irritate the stomach than traditional NSAIDs, it can happen.

  • 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.
  • Although the manufacturers say that these drugs can be taken on an empty stomach, to help reduce irritation of the stomach and prevent an ulcer, take NSAIDs at the end of a full meal, or with antacid.
  • Limit alcohol intake (since alcohol can irritate the stomach).

The FDA placed the following “black box warning” regarding GI symptoms with Celebrex®:

"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."

Allergies

Celecoxibis contra-indicated 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 or valdecoxib, 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 9/30/04 due to questions of increased risk of heart attacks and strokes. Users of as the remaining CXO-2 inhibitor on the market, celecoxib (Celebrex), or COX-2 selective agents, such as meloxicam (Mobic) should be aware that these drugs are not blood thinners. Therefore, some patients whom their physicians feel are at higher than average cardiac risk may need to be given low-dose aspirin to help reduce heart attack risk. Even though adding aspirin to one of these agents may increase risk of ulcer, for a number of patients this risk may be worth taking, in view of the need for heart protection. However, although there is very good evidence that low-dose aspirin helps protect against heart attacks in patients with coronary disease, it is not yet clearly established that this effectiveness still applies in patients taking medications such as Celebrex or Mobic—or any of the NSAID’s (non-steroidal anti-inflammatory agents).

Also, the FDA has required a block box warning about cardiovascular thrombotic events be placed in the package description of all NSAIDs, including COX-2 specific and selective agent, and patients at high risk for cardiovascular disease need to weigh the risks and benefits with their physician before taking any NSAID or COX-2 specific or selective agent. The “black box warning” for Celebrex related to cardiovascular risk reads as follows:

"Cardiovascular Risk:  Celebrex may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs may have a similar risk. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk." 

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.

Dosing

When you are trying on of these drugs for the first time, take the full dose prescribed every day, unless instructed otherwise. It may take as long as 2 weeks to build up to a "blood level" of the drug, and the drug may not help very much until then. If 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 your dose of the NSAID.

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 any COX-2. 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 dose, appears less likely to irritate the stomach than NSAID's, so in many cases it reasonable to take it along with NSAID's- Always read the ingredients listed on the label of over-the-counter products. If acetylsalicylic acid 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, some types of Excedrin, and even Pepto-Bismol contain aspirin.
  • If you are taking medications for high blood pressure, have your pressure checked regularly while on the non-steroidal anti-inflammatory agent. 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

  • If signs of allergy occur, such as rapid breathing, gasping, wheezing, hives, skin rashes, puffy eyelids, and/or rapid heart beat occur.
  • If you develop vision abnormalities.
  • If you develop dizziness, depression, or confusion.
  • If 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 an NSAID).
  • If 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

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