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Arthritis after Vioxx®

February 2005

By Richard P. Huemer, MD

Reducing Risks of COX-2 Inhibitors

Despite the FDA’s approval of COX-2 inhibitor drugs because of reduced incidences of gastric ulceration, a growing number of studies shows that COX-2 inhibitors still cause numerous upper gastrointestinal problems. Some studies suggest that COX-2 inhibitors are no better than the classic nonsteroidal anti-inflammatory drugs (NSAIDs) that they were supposed to replace.18 NSAIDs suppress both the COX-1 and COX-2 enzymes.

If you are taking a COX-2 inhibitor drug, the first step in reducing risk of heart attack and stroke caused by excess thromboxane A2 is to suppress the COX-1 enzyme.11 Ask your doctor if you can take just 81 mg of aspirin every other day to reduce your risk of developing a life-threatening arterial blood clot. Some studies show the COX-1-inhibiting effects of aspirin last for 48 hours or longer,19 so taking 81 mg of a coated aspirin tablet every other day may suppress enough thromboxane A2 to prevent a heart attack, while not damaging the stomach.

The second step is to guard against the excess accumulation of artery-damaging leukotriene B4. One way to accomplish this is to reduce its mother substrate, arachidonic acid. This can be done by increasing your consumption of foods rich in omega-3 fatty acids, by taking fish oil supplements, and by decreasing your consumption of foods high in omega-6 fatty acids, especially red meat.17 Nutrients that suppress the 5-lipooxygenase enzyme (5-LOX) include a standardized boswellic acid extract20 (trademarked 5-Loxin™) and curcumin.21

Since blocking COX-2 deprives the arteries of beneficial prostacyclin (prostaglandin I2),11 have your blood evaluated at least once a year to identify all risk factors for heart attack and stroke, and take aggressive preventive actions if any parameters are not in the optimal ranges.

If one is to take any drug that may inhibit too much COX-1 (and this includes the COX-2 inhibitors), consuming 1800 mg a day of polyenylphosphatidylcholine provides a considerable degree of protection to the stomach lining.


Although the pharmaceutical and medical communities have embraced COX-2 inhibitor drugs as a safer alternative to nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors are not without gastric side effects. In fact, the COX-2 inhibitors have been associated with adverse upper gastrointestinal side effects, particularly in people with a history of gastrointestinal disorders.47 In those who have inflammatory bowel disease (Crohn’s disease or ulcerative colitis), COX-2 inhibitors have been found to cause gastrointestinal side effects, including relapse of symptoms, requiring cessation of treatment in 25% of patients.48

Is Celebrex® Safe?

To date, the limited studies of the COX-2 inhibitor Celebrex® do not show an increased heart attack or stroke risk from using this drug. One study indicated that Celebrex® is sufficiently different from Vioxx® to not cause cardiovascular problems; however, this difference did not relate to the pathological mechanisms inherent to COX-2 inhibitor drugs, as discussed in the preceding paragraphs.

Celebrex® is a potent COX-2 inhibitor, and those who find relief from arthritis pain by taking it should follow all the precautions outlined in these paragraphs.

The question on the minds of many doctors and patients is, are other drugs in the “coxib” category safe? There are at least six such drugs: celecoxib (Celebrex®), valdecoxib (Bextra®), meloxicam (Mobic®), lumiracoxib (Prexige®), parecoxib (Dynastat®), and etoricoxib (Arcoxia®). Only three of these are available in the US. Recent research indicates that the sulfone component of the Vioxx® molecule, and perhaps that of the etoricoxib molecule, may be related to the occurrence of adverse side effects,22 so non-sulfone coxibs such as Celebrex® may be safer. A look at the underlying mechanisms by which COX-2 inhibitors cause adverse cardiovascular events reveals considerable reasons for concern with any drug in this class.

Pfizer reports that its drug Celebrex® has not been associated with an increased risk of heart attack and stroke in large, long-term studies.23 Bextra®, also from Pfizer, does seem to increase cardiovascular events in people who have undergone a coronary bypass graft.10 Additional studies of both drugs are planned.24,25

With Vioxx® out of the picture, and the safety of other coxib drugs suspect, arthritis sufferers may increasingly rely on other, older drugs. However, many of these older drugs can cause significant gastrointestinal side effects, making them undesirable choices for the long-term management of arthritis. Fortunately, several effective natural remedies for arthritis pain and inflammation are readily available, including fish oil, boswellia, citrus flavonoids, glucosamine, and methylsulfonylmethane. These natural therapies promise to help reduce inflammation and manage arthritis symptoms without the risks associated with commonly used prescription and over-the-counter medications.

Despite the negative publicity about Vioxx®, there is still good reason to inhibit excess cyclooxygenase-2, especially from a cancer-prevention standpoint. Taking the natural approaches suggested in this article to suppress all of the chronic inflammatory inducers would appear to be far safer than resorting to potent drugs that only function by one mechanism.


While Vioxx® (rofecoxib) has been linked with an increased risk of atherothrombotic events, this increased risk has not been observed with another COX-2 inhibitor, Celebrex® (celecoxib).

In a recent human study, investigators examined the effects of COX-2 inhibitors on the oxidation of low-density lipoprotein (LDL), which is associated with the development of heart disease. The researchers found that rofecoxib exhibited pro-oxidant activity as measured by several parameters, including increased oxidized LDL, decreased oxygen radical antioxidant capacity (ORAC), and increased isoprostanes, an inflammatory marker.

By contrast, other selective COX-2 inhibitors and non-selective COX inhibitors were not associated with increased LDL oxidation or decreased plasma ORAC values. X-ray diffraction analysis suggested that sulfone COX-2 inhibitors such as rofecoxib may interact differently with membrane phospholipids, thereby increasing their susceptibility to oxidative modification through a non-enzymatic process. This finding could account for the reported differences in cardiovascular risk associated with different COX-2 inhibitors.22

What Arthritis Is and Is Not

Arthritis is one of our most prevalent chronic health problems, and second only to heart disease as a cause of work disability. More women than men have arthritis. Although arthritis is often seen as an older person’s disease, more than half of those afflicted are under the age of 65.26

Many kinds of arthritis exist—it comprises perhaps 100 different diseases—but the most common forms are osteoarthritis, rheumatoid arthritis, gout, ankylosing spondylitis, juvenile arthritis, lupus, and scleroderma. The most common kind by far is osteoarthritis, which occurs with advancing age and is caused by degeneration of the cartilage “cushions” at the ends of bones, so that bones rub directly against each other. Rheumatoid arthritis afflicts 2.1 million Americans, mostly women, and like lupus and scleroderma, it is thought to be an autoimmune disease caused by the body reacting against its own connective tissue. Gout, which affects mostly men, is caused by the metabolic waste product uric acid crystallizing in one or another of the small joints, causing pain and inflammation.

Arthritis is distinct from other causes of musculoskeletal pain, which can include stiff or spasmed muscles, sprained ligaments and tendons, or vague aches and pains. By definition, arthritis is inflammation affecting the joints, which can occur from any number of causes. The affected joints may be hot, swollen, and painful, but are not always symptomatic. For instance, osteoarthritis of the spine, often seen as changes on an X-ray, may be free of symptoms.


One in three Americans suffers from some form of arthritis, and annual costs related to arthritis are estimated to be more than $82 billion.

Osteoarthritis is the most common among more than 100 rheumatic diseases. Marked by pain, stiffness, and decreased joint motion, osteoarthritis is a significant cause of pain and decreased quality of life. Generally a progressive condition, osteoarthritis is conventionally managed using analgesics and anti-inflammatories. While these therapeutics may relieve discomfort, little evidence exists to suggest that they alter the condition’s underlying pathology. Fortunately, numerous natural agents can help to relieve inflammation, reduce pain, and increase mobility, offering safer options to the millions of Americans whose lives have been limited by arthritis pain.

Anti-Inflammatory Drugs and Nutrients

The mechanisms involved in inflammation are complex. Perhaps the oldest class of arthritis drug is the NSAIDs, which began with the folk remedy, white willow bark. This bark’s active ingredient is salicylic acid. White willow bark’s efficacy inspired a chemist to synthesize acetyl-salicylic acid, which is today known as aspirin. Ibuprofen, indomethacin, naproxen, diclofenac, and others are also members of the NSAID family.

The trouble with most NSAIDs is that they are not very specific, and inhibit both the COX-1 and COX-2 enzymes. Because COX-1 is involved in protecting the stomach lining, its inhibition can cause undesirable side effects, including stomach inflammation or ulcers. Pharmaceutical chemists thought they had something better and safer when the selective COX-2 inhibitors, like Vioxx®, became available.27 It now appears that their optimism was unwarranted.

Several effective inhibitors of inflammation were invented by nature long before there were arthritic people who needed to use them. Today these are being combined into effective formulations that provide safe alternatives to the COX-2 inhibitor drugs.

Omega-3s: Heart-Friendly Fats

One of the most powerful ways to reduce inflammation in the body is to optimize intake of fatty acids. While the intake of certain fats, such as hydrogenated oils from margarine and processed foods, can increase inflammation, other fats promote an anti-inflammatory biochemistry. The metabolism of fatty acids yields prostaglandins that may be either inflammatory or anti-inflammatory.

Strictly speaking, only two fatty acids are nutritionally essential: linoleic acid and alpha-linolenic acid. Our bodies can make all the rest, but with varying degrees of efficiency. A key enzyme called delta-6 desaturase can be impaired because of age, alcohol abuse, B- vitamin deficiency, or diabetes and hyperinsulinism. In that case, relatively less gamma linolenic acid (GLA) and eicosapentaenoic acid (EPA) will be produced, causing a biochemical environment that is more susceptible to inflammation. The delta-6 desaturase enzyme also acts on EPA to transform it to docosahexaenoic acid (DHA), another anti-inflammatory fatty acid.28

GLA is the precursor of DGLA, which becomes the anti-inflammatory prostaglandin 1 (PGE-1).29 Supplemental GLA from sources such as evening primrose oil, black currant oil, and borage oil can be used to help control inflammation.

EPA and DHA reduce levels of joint-destroying inflammatory cytokines, such as tumor necrosis factor-alpha and interleukin-6 (IL-6).30 These omega-3 fatty acids also suppress levels of the inflammatory mediators leukotriene B4 and prostaglandin E2.31 EPA also is metabolized to an anti-inflammatory prostaglandin, PGE-3.30 Excellent dietary sources of DHA and EPA are salmon, other oily cold-water fish, and fish oil. The body can also make EPA from alpha-linolenic acid, a fatty acid found in flaxseed oil.

Modern eating habits promote an imbalance in dietary fatty acids, creating a biochemical environment that is conducive to inflammatory pathologies. The ancestral human diet contained about an equal balance of omega-6 fatty acids (such as arachidonic acid) and omega-3 fatty acids (such as EPA and DHA). A century ago, this dietary ratio of omega-6 fats to omega-3 fats was approximately 4:1, but today it equals or exceeds 20:1, mainly due to increased consumption of omega-6-rich vegetable oils, such as corn oil.32 Supplementing with omega-3 fatty acids is a beneficial strategy for reducing the inflammation inherent in many modern health disorders, including arthritis. An appropriate daily dose of fish oil is 2-3 grams of an EPA-DHA combination. This dosage has been found to relieve painful joints and reduce morning stiffness in patients with rheumatoid arthritis.33