What is the difference between other non-steroidal antiinflammatory drugs (NSAIDs) and selective COX-2 inhibitors? Which patients benefit from them?

Let's first review how NSAIDs relieve pain. When tissue damage occurs, inflammatory mediators, such as bradykinin and prosta-glandins, are released at the site of injury. This activates nociceptors, which transmit pain. An enzyme called cyclooxygenase (COX) breaks down arachidonic acid to produce prostaglandins. NSAIDs relieve pain by blocking the action of COX and interfering with the production of prostaglandins, thus earning them the name "COX inhibitors" or "COX blockers."

There are two forms of cyclooxygenase: COX-1 and COX-2. COX-1 isoenzymes are involved in the production of prostaglandins that preserve platelet function and protect gastric mucosa. COX-2 isoenzymes are involved in the production of prostaglandins that cause pain. Conventional NSAIDs block both COX-1 and COX-2, producing pain relief and causing bleeding and GI disturbances ranging from dyspepsia to perforation. Because selective COX-2 inhibitors block only COX-2, they don't cause the side effects associated with blocking COX-1.

INDICATIONS AND DOSING

The indications and dosing regimens differ for the two COX-2 inhibitors approved for use in the United States, celecoxib and rofecoxib. It's recommended that 200 mg of celecoxib be taken daily in one or two doses for osteoarthritis and 100 mg to 200 mg be taken twice daily for rheumatoid arthritis. The maximal recommended dose of rofecoxib for osteoarthritis pain is 25 mg taken once daily. For acute pain, such as surgery or dysmenorrhea, 50 mg per day of rofecoxib may be taken for five days. Both are available in capsules, and rofecoxib is also available in suspension form. As with other NSAIDs, both may be used for pain relief alone, not just as antiinflammatory drugs.

Onset of analgesia is 30 minutes for rofecoxib and one hour for celecoxib. Peak analgesic effect is approximately three hours for both, however, rofecoxib has a higher peak effect. 1 Although in one study both drugs were shown to produce comparable analgesic effects in the first four hours after surgery, rofecoxib demonstrated an extended analgesic effect that lasted for 24 hours. 2 The two COX-2 inhibitors have a longer half-life (11 to 17 hours) than most conventional NSAIDs (two to 12 hours) and an analgesic ceiling effect (increases in dose don't produce increases in pain relief). 3 Steady state is reached within five days of regular dosing of the drugs.

SAFETY

The incidence of serious GI ulcer complications from NSAIDs is 2% to 4% in patients who take them for one year. 4 Although GI disturbances can occur, COX-2 inhibitors are thought to be safer than conventional NSAIDs. 3,5 An analysis of more than 5,000 patients with osteoarthritis who received rofecoxib or an NSAID (ibuprofen, diclofenac, or nabumetone) over a 12-month period revealed a significantly lower incidence of GI toxic effects with rofecoxib (1.3%) compared with the NSAIDs (1.8%). 5

Comparable results were found in a 12-week study of 1,149 patients with rheumatoid arthritis that compared celecoxib to the NSAID naproxen. 6 Overall incidences of GI tract adverse effects were 19% for placebo; 28%, 25%, and 26% for celecoxib 100 mg, 200 mg, and 400 mg twice daily, respectively; and 31% for naproxen 500 mg twice daily. At all three doses, celecoxib was as effective, but no more so, than naproxen in reducing patients' arthritis symptoms.

In a placebo-controlled study, rofecoxib 50 mg and celecoxib 200 mg were compared to ibuprofen 400 mg. 1 Patients (N = 272) were randomized to receive a single dose of one of the drugs or a placebo after the removal of two or more third molars. Results revealed that the analgesic effect of rofecoxib 50 mg was superior to celecoxib 200 mg and comparable to ibuprofen 400 mg. Pain relief lasted for more than 24 hours with rofecoxib, for nine hours with ibuprofen, and for five hours with celecoxib. It is important to note that the results of this study are compromised, because patients who received celecoxib were given the recommended osteoarthritis dose, whereas those who received rofecoxib were given twice the recommended osteoarthritis dose. 3

Although COX-2 inhibitors have not been shown to produce better analgesia than NSAIDs, some patient populations may benefit from the improved adverse effect profile. For example, consider using a selective COX-2 inhibitor for pain control in people who have experienced adverse effects from conventional NSAID use and in those, such as the elderly and patients with rheumatoid arthritis or osteoarthritis, who are at high risk for adverse effects and death associated with NSAID use. 4,7 COX-2 inhibitors also should be considered for patients with cancer, HIV, or AIDS, because the antipyretic properties of NSAIDs can mask opportunistic infections. They may even cause lethal complications in patients who are neutropenic, thrombocytopenic, or otherwise immunocompromised. 4

A MULTIMODAL APPROACH

One of the best uses of the COX-2 inhibitors may be as part of a multimodal approach to managing pain. A multimodal approach combines analgesics and is based on the logic that two or more drugs attack multiple underlying pain mechanisms. Appropriate combinations of analgesics can produce additive pain relief and allow smaller doses of each drug, thereby reducing the side effects from any one analgesic. 8 For example, in patients who are at risk for bleeding or GI distress, combine a COX-2 inhibitor with acetaminophen, or add a COX-2 inhibitor to opioid analgesic therapy for results better than those of acetaminophen or opioid alone.

Individuals who are allergic to aspirin or other NSAIDs should not take a COX-2 inhibitor, and those who are allergic to sulfa drugs should not take celecoxib. COX-2 inhibitors have not been studied for use in children under age 18. Be sure patients are well hydrated to prevent renal toxicity. Taking aspirin with a COX-2 inhibitor does not provide any benefit, and it increases the risk of GI bleeding. 9

The Food and Drug Admini-stration is currently evaluating reported cases of thrombotic events, including myocardial infarction, cerebrovascular events, pulmonary embolism, and deep venous thrombosis, possibly associated with COX-2 inhibitors. In general, patients were elderly with underlying disease, taking concomitant medications, or had experienced acute concurrent adverse reactions.

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