Comparing the COX-2 Inhibitors with Traditional NSAIDs

These promising new drugs, which selectively inhibit the enzyme cyclooxygenase (COX) 2, are as effective as the nonselective COX inhibitors but cause fewer adverse gastrointestinal effects.

By Roland Staud, MD

Approximately 17 million Americans take nonsteroidal antiinflammatory drugs (NSAIDs) daily for treatment of pain or inflammation. These drugs (see table, below) are nonselective inhibitors of the enzymes cyclooxygenase (COX) 1 and 2, which convert arachidonic acid to prostaglandins. Unfortunately, they are also associated with serious adverse gastrointestinal effects, such as gastritis, dyspepsia, gastroduodenal ulcers, perforations, and bleeding. Endoscopic studies have shown that within one week of starting NSAID therapy more than 30% of patients will have gastric erosions or ulcers, and within one year approximately 3% will have significant gastrointestinal bleeding. As many as 15,000 deaths each year have been attributed to NSAID use in the United States.

The stimulus for development of selective COX-2 inhibitors was clinical evidence indicating that most of the adverse effects associated with NSAIDs are related to inhibition of COX-1, and that only COX-2 enzymes produce prostaglandins that mediate fever, inflammation, and pain. Two of these new drugs-celecoxib and rofecoxib-were introduced in 1999 in the biggest drug launch ever. To date, more than 6.6 million prescriptions have been filled. A third drug, meloxicam, which was recently introduced in the United States, has a high affinity for COX-2 but also inhibits COX-1 at therapeutic doses.

Early analysis of postmarketing data on celecoxib and rofecoxib revealed that the drugs produced a significant decrease in the incidence of serious adverse gastrointestinal effects, a result that had also been noted during phase III clinical studies. This low incidence of gastrointestinal effects is the major advantage these drugs have over traditional NSAIDs. Their biggest drawback is their high cost-approximately $2000/year. In some cases, however, the expense may be justified in light of the morbidity and mortality associated with NSAIDs.  Currently approved indications for COX-2 inhibitors include acute pain (rofecoxib) and signs and symptoms of osteoarthritis (rofecoxib and celecoxib) or rheumatoid arthritis (celecoxib). Other important indications may emerge from ongoing clinical studies of the effects of these drugs on Alzheimer's dementia and tumor growth.

This article will discuss the mechanism of action of COX-2 inhibitors and the role of COX-2 in the development of various symptoms and conditions. It will also review the results of clinical studies on the efficacy of these new drugs, their approved indications, and adverse effects.

MECHANISM OF ACTION OF COX INHIBITORS

Although traditional NSAIDs and the new COX-2 inhibitors are chemically different compounds, they share many of the therapeutic benefits of aspirin. Sir John Vane, who received the Nobel Prize in 1971 for his research on aspirin, was the first to demonstrate that the drug's effects depend on the inhibition of the COX pathway (see figure, below). Cyclooxygenase converts arachidonic acid derived from cell membranes to prostaglandins, which have important signaling and "housekeeping" functions, particularly in platelets, the gastrointestinal tract, lungs, and kidneys.

Tracking the Cyclooxygenase Pathway

 

Initially, COX was considered a stably expressed enzyme, and the rate-limiting step in prostaglandin biosynthesis was thought to be the availability of arachidonic acid substrate. More recently, however, it was found that production of COX enzymes varies greatly and can be stimulated or inhibited by chemical compounds. In vivo experiments involving synovial tissues from animals with experimental inflammatory arthritis, as well as from patients with rheumatoid arthritis, showed increased levels of COX in affected joints.

These findings led to the discovery of the two different types of COX present in animals and humans. One is the constitutively expressed isoform COX-1, which has important maintenance functions; the other is the inducible isoform COX-2. COX-1, for example, was found to be necessary for platelet function and maintaining an intact gastric mucosa, but it does not seem to play an important role in pain and inflammation. In contrast, the selective blockade of COX-1 in rodents with adjuvant arthritis does not result in significant changes in joint swelling and pain. Selective COX-2 inhibitors in this arthritis model, however, provided all the antiinflammatory action usually seen with traditional NSAIDs. Subsequently, it was revealed that all traditional NSAIDs affect the action of both COX-1 and COX-2 but produce most of their therapeutic effects by blocking COX-2.

More recent studies have shown that COX-2, like COX-1, is also responsible for normal physiologic functions. For example, COX-2 seems to be involved in reproductive functions and may be involved with the timing of ovulation. COX-2 also appears to play an important role in renal function, as suggested by the dependent edema-caused by decreased urinary sodium excretion-that occasionally occurs when a COX-2 inhibitor is taken. Moreover, because these drugs can decrease prostaglandin production in blood vessels, they may lead to unopposed thromboxane activity in platelets. This finding has raised concerns about increased clotting susceptibility in patients who are taking selective COX-2 inhibitors.

CLINICAL ROLE OF COX-2

COX-2 plays a significant role in the development of various symptoms and conditions, including fever, inflammation, and pain. Its role in other conditions, such as cancer and Alzheimer's dementia, also is being investigated.

Fever and pain. In peripheral tissues, prostaglandins work synergistically with several mediators of inflammation and pain, including bradykinin and histamine. Nonselective COX inhibitors decrease prostaglandin production in inflamed tissues. However, in rodent experiments only selective COX-2 inhibitors have been found to prevent fever, hyperalgesia, and inflammation. In the central nervous system, COX-2 inhibitors decrease the expression of prostaglandins, which play an important role in fever as well as in pain.

Arthritis. Both COX-1 and COX-2 have been found in synovial tissues of patients with arthritis. COX-1 is stably expressed in the synovium and unchanged by inflammatory conditions. In contrast, COX-2 expression is increased in the joint lining and synovial monocytes of patients with inflammatory arthritis.

Gastrointestinal inflammation and ulcers. Significant COX-2 up-regulation occurs after tissue injury, reflecting its physiologic role in tissue repair. In the gastrointestinal tract especially, COX-2 expression is notably increased in response to acute and chronic injury. Although the significance of COX-2 in maintaining a normal gastrointestinal mucosa is still controversial, animal studies have shown that selective COX-2 inhibition delays healing of inflammation and ulcers. It may be that COX-1 plays a bigger role in maintaining normal gastroduodenal mucosa, whereas COX-2 is more significant in healing damaged gastrointestinal mucosa. This particular role of COX-2 will need to be addressed in future clinical studies.

Cancer. A growing body of evidence indicates that prostaglandins play an important role in the development of colon cancer. In rodent models of colon cancer, NSAID treatment resulted in significant inhibition of tumor growth. In clinical trials of patients with rheumatoid arthritis, a 50% decrease in colorectal cancer risk was found in those taking aspirin or an NSAID on a regular basis. Further, NSAID use can lead to regression of precancerous colon polyps in patients with familial adenomatous polyposis.

One possible explanation for these dramatic results is the COX-2 up-regulation that has been observed to occur in adenomas of the colon in animals and humans. Further support for the role of prostaglandins in colon cancer is that selective COX-2 inhibition has been shown to significantly decrease colon cancer in animals, suggesting that increased expression of COX-2 in the colon mucosa promotes cell changes leading to abnormal growth.

Alzheimer's dementia. Convincing evidence has emerged indicating that COX-2 expression contributes to the development of Alzheimer's dementia, primarily as a result of neuronal inflammation and programmed cell death. COX-2 inhibitor therapy may therefore delay or even halt progression of this devastating disease.

EFFICACY OF COX-2 INHIBITORS

Several clinical trials have investigated the efficacy of selective COX-2 inhibitors in the treatment of pain and inflammation, testing the hypothesis that these drugs are as effective as traditional NSAIDs but result in fewer adverse effects and thus are better tolerated by patients.

Clinical trials with celecoxib or rofecoxib have confirmed that their clinical efficacy is equal to that of nonselective NSAIDs. For example, at dosages of 100 to 200 mg twice daily in patients with osteoarthritis and 200 to 400 mg twice daily in patients with rheumatoid arthrthritis, celecoxib was as effective as diclofenac (50 mg twice daily). Similarly, at dosages of 50 mg once daily in patients with dental pain and 25 mg once daily in patients with osteoarthritis of the knee, the efficacy of rofecoxib was comparable to that of ibuprofen (200 to 400 mg three times a day). Meloxicam (7.5 or 15.0 mg once daily), the recently introduced NSAID with partial COX-2 selectivity, was as effective as piroxicam (20 mg once daily) in patients with osteoarthritis.

Results of studies involving celecoxib or rofecoxib suggest that the safety of these drugs with regard to gastrointestinal effects is much improved over that of traditional NSAIDs. A six-month study of patients with rheumatoid arthritis demonstrated that the occurrence of ulcers and erosions was markedly lower among patients receiving celecoxib than among those receiving diclofenac. The incidence of significant ulcers-more than 3 mm in diameter-among the diclofenac group and celecoxib group was 15% and 4%, respectively. In a six-month study of patients with osteoarthritis who received rofecoxib (25 or 50 mg once daily) or ibuprofen (800 mg three times a day), the incidence of gastroduodenal ulcers was 54% in the ibuprofen group but only 9% in the rofecoxib group, a rate comparable to that in the placebo group.

The gastrointestinal safety of meloxicam was evaluated in the Meloxicam Large-scale International Study Safety Assessment (MELISSA) trial (British Journal of Rheumatology, vol. 37, p. 937, 1998) and the Safety and Efficacy Large-scale Evaluation of COX-inhibiting Therapies (SELECT) trial (British Journal of Rheumatology, vol. 37, p. 946, 1998), which studied large numbers of patients with osteoarthritis. Although not considered a selective COX-2 inhibitor, meloxicam exhibited an adverse gastrointestinal effect profile that was better than that of either diclofenac or piroxicam.

The findings of these clinical trials reveal that the incidence of adverse gastrointestinal effects is significantly reduced among patients taking selective COX-2 inhibitors. It is possible, however, that the drugs may be associated with an increased risk of complications in patients with active or healing gastrointestinal ulcers, as COX-2 had been found in ulcer margins. Therefore, treatment of gastrointestinal ulcers should be initiated before selective COX-2 inhibitor therapy is administered.

INDICATIONS FOR COX-2 INHIBITORS

Based on the results of the clinical trials that have been conducted to date, selective COX-2 inhibitor therapy has been approved for osteoarthritis, rheumatoid arthritis, and several other disorders.

Treatment of osteoarthritis frequently must include pain control in addition to exercise and physical therapy. Both rofecoxib and celecoxib have been approved for treatment of this common form of arthritis. These drugs should be strongly considered for patients with osteoarthritis who are at risk for such gastrointestinal complications as ulcers, bleeding, or perforation. Patients with a history of gastroduodenal ulcers and those taking glucocorticoids are at particularly high risk for those disorders, which often occur with traditional NSAID therapy. Patients with serious concomitant conditions and those who are older than 60 years of age are also at high risk for such disorders. Low doses of celecoxib (200 mg once daily or 100 mg twice daily) and rofecoxib (12.5 mg or 25.0 mg once daily) have been found to be as efficacious as ibuprofen, diclofenac, nabumetone, or naproxen.

Celecoxib (200 mg twice daily) has been studied for periods as long as 24 weeks in more than 2000 patients with rheumatoid arthritis and was as effective as naproxen (500 mg twice daily) for relief of joint tenderness and swelling. Although rofecoxib has not been approved by the Food and Drug Administration (FDA) specifically for treatment of rheumatoid arthritis, it can be considered as an alternative to celecoxib. Rofecoxib has been noted to increase plasma levels of methotrexate and warfarin, however, so it should be used with caution in patients taking these drugs.

Rofecoxib (50 mg once daily, as needed) has also been approved for the treatment of acute pain and dysmenorrhea. This year, after a six-month study demonstrated a substantially reduced incidence of colon polyps among patients with familial polyposis, the FDA approved celecoxib (400 mg twice daily) for the treatment of that disorder. Because COX-2 inhibitors do not affect platelet function, they can be safely administered to patients undergoing anticoagulation therapy.

ADVERSE EFFECTS TO WATCH FOR

The most common adverse effects of selective COX-2 inhibitors include abdominal pain, diarrhea, and dyspepsia. Rarely, the drugs may affect renal function. Although a trial of rofecoxib in patients with osteoarthritis found no evidence of significant blood pressure or serum creatinine changes in any patient group, some concern remains that selective COX-2 inhibitors may reduce sodium excretion. Therefore, COX-2 inhibitors should be prescribed with caution for patients with renal disease.

Rofecoxib has been found to interfere with the elimination of several drugs, including methotrexate and warfarin, necessitating more frequent laboratory monitoring of patients undergoing such treatment.

Patients with heart disease may benefit from also taking aspirin when COX-2 inhibitors are prescribed, primarily because the latter block endothelial prostacyclin production without affecting platelet thromboxane A. Although several clinical trials comparing patients receiving COX-2 inhibitors with those taking NSAIDs found no difference in the incidence of cardiovascular thromboembolic events, the studies had not been designed to address this important issue. In addition, it should be pointed out that adding aspirin to COX-2 inhibitor therapy may alter the latter's otherwise favorable risk profile.

COX-2 inhibitor therapy is contraindicated for patients with known NSAID allergies. Because celecoxib contains a sulfonamide moiety, the drug also should not be administered to patients who are allergic to that compound.

WIDER RANGE OF OPTIONS

The development of selective COX-2 inhibitors provides physicians with a wider range of therapeutic options for treatment of pain or inflammation. Clinical studies have clearly shown COX-2 inhibitors to be as clinically effective as traditional NSAIDs and to have a better adverse effect profile (see table, below). Although NSAIDs will likely remain the drugs of choice for short-term therapy, COX-2 inhibitors have demonstrated superior safety with prolonged therapy. If the results of further long-term studies of these drugs confirm a significant reduction in NSAID-associated morbidity and mortality, the high cost of this important new class of antiinflammatory agent may be justified.

 

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