The NSAIDs also are valuable for managing the pain and inflammation of chronic myofascial pain and tem-poromandibular joint disorders. When NSAIDs are prescribed continuously for several weeks or months, however, the risks of gastrointestinal, or GI, ulcerations, bleeding and renal toxicity increase.^4,19 Impaired renal function is associated with chronic exposure to NSAIDs, reportedly requiring hospitalization in 0.5 to 1.0 percent of chronic NSAID users.⁴ A greater risk of toxicity with chronic use of the NSAIDs is reported among geriatric patients.^2,5

The adverse effects seen with chronic NSAID use may occur less frequently with two recently introduced anti-inflammatory analgesic agents, celecoxib (Celebrex, Pharmacia/Pfizer) and rofecoxib (Vioxx, Merck & Co. Inc.). Known as cyclo-oxygenase-2, or COX-2, inhibitors, and also as COX-1–sparing drugs, these newer NSAIDs have been developed to limit the adverse effects seen with chronic NSAID therapy. Therefore, they may provide dental practitioners with an important and valuable alternative therapy for the management of chronic joint pain and, in selected cases, the treatment of acute postoperative pain.

	THE CYCLO-OXYGENASE MECHANISM

TOP ABSTRACT THE CYCLO-OXYGENASE MECHANISM SPECIFIC CYCLO-OXYGENASE-2... ADVERSE REACTIONS AND... CONCLUSIONS AND RECOMMENDATIONS... REFERENCES

 
NSAIDs appear to induce analgesia and to reduce fever and inflammation through a shared biochemical mechanism. All of the agents in this drug class block the production of various mediators of inflammation, including prostaglandins, prostacyclins and thromboxanes.^6,7 The inflammatory process that occurs after tissue injury is mediated, in part, by the breakdown of damaged cell membranes by phospholipase-A₂ into their fatty acid components. One of these fatty acids, arachidonic acid, then is converted into prostaglandins, prostacyclins and thromboxanes by various COX enzymes (Figure). Prostaglandins probably are the most important of these hyperalgesic and inflammatory mediators. By sensitizing nerve ending to bradykinins and histamines, prostaglandins enhance the pain and tenderness of inflammation. Additionally, elevated tissue concentrations of prostaglandins are responsible for initiating the vasodilation seen clinically as erythema and edema. On the other hand, other prostanoids synthesized by COX enzymes, such as prostacyclins and thromboxanes, are responsible for maintaining healthy gastric mucosa, proper renal profusion and normal platelet activation. Inhibition of COX enzymes, therefore, is responsible for both the therapeutic efficacy of NSAIDs and the adverse effects reported for these drugs.^2,6

View larger version (42K): [in this window] [in a new window]   Figure. Nonspecific nonsteroidal anti-inflammatory drugs such as ibuprofen and naproxen inhibit both the cytoprotective cyclo-oxgenases (COX-1) and the inflammatory cyclo-oxygenases (COX-2). Specific COX-2 inhibitors, such as celecoxib and rofecoxib, act preferentially to minimize inflammation, induce analgesia and limit adverse gastrointestinal toxicity.

Aspirin, ibuprofen, naproxen and ketoprofen are nonselective NSAIDs, inhibiting both cytoprotective COX-1 enzymes and inflammatory COX-2 enzymes. Consequently, it is not surprising that prolonged use of these agents is associated with possible damage of the GI tract, causing gastric erosions, ulcers and bleeding.^3,9,10 Drugs that specifically inhibit COX-2 enzymes and leave the cytoprotective COX-1 enzymes intact may provide analgesia, antipyresis and anti-inflammatory activities while avoiding adverse effects on the GI tract and other tissues, as well as on platelets.^11–13

Fewer gastrointestinal ulcers appear with either celecoxib or rofecoxib than with prescription doses of ibuprofen or naproxen.

	SPECIFIC CYCLO-OXYGENASE-2 INHIBITORS

TOP ABSTRACT THE CYCLO-OXYGENASE MECHANISM SPECIFIC CYCLO-OXYGENASE-2... ADVERSE REACTIONS AND... CONCLUSIONS AND RECOMMENDATIONS... REFERENCES

 
Two specific COX-2 inhibitors have received approval by the U.S. Food and Drug Administration for marketing in the United States. The first to enter the market was celecoxib. It became a remarkably popular agent for the management of osteoarthitis and rheumatoid arthritis; in fact, in 1999, it was the 21st most frequently prescribed drug in the United States.¹⁴ The latest addition to this drug class is rofecoxib, which also is indicated for the management of osteoarthritis, as well as for the treatment of primary dysmenorrhea and the management of acute pain in adults. Both rofecoxib and celecoxib have extended metabolic half-lives, allowing the convenience of once- or twice-a-day dosing regimens (Table). These specific COX-2 inhibitors were developed to provide the benefits of NSAIDs while limiting the GI erosions and ulcers reported with nonspecific NSAIDs. Other agents selective to COX-2 inhibition are being developed specifically for chronic management of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis.¹⁵

At a dose of 200 mg, celecoxib provides analgesia greater than placebo, but less than ibupro-fen 400 mg.¹⁶ While celecoxib appears to be as effective as older NSAIDs in treating osteoarthritis and rheumatoid arthritis, further evaluation of its analgesic efficacy is needed to demonstrate its utility in managing acute postoperative pain.

In terms of nondental use, recent evidence has shown that celecoxib, when used as an adjunct to usual clinical care, retards the development of colorectal polyps in patients diagnosed with familial adenomatous polyposis, or FAP, a disorder that often progresses to colorectal cancer. Patients with FAP have had a reduction of the number and mass of polyps when administered celecoxib 400 mg twice a day for six months.¹⁷

Rofecoxib. A study comparing the analgesic efficacy of rofecoxib 50 mg, ibuprofen 400 mg and placebo after third-molar extractions found both ibuprofen and rofecoxib to provide greater pain relief than placebo.¹⁸ Pain relief during the first four hours of the study and maximal analgesic effects were nearly identical for the two active agents. Unlike the shorter-acting (four-six hours) ibuprofen, rofecoxib continued to provide measurable analgesia up to 24 hours after surgery (Table).

Malmstrom and colleagues¹⁶ published a comparative analgesic study of the two currently marketed COX-2 inhibitors. Using the third-molar postextraction model, the researchers compared the analgesic efficacy of rofecoxib 50 mg, celecoxib 200 mg, ibuprofen 400 mg and placebo. The duration of analgesic responses corresponded to each of the drugs’ metabolic half-lives: rofecoxib the longest and ibuprofen the shortest. Rofecoxib 50 mg had a maximal analgesic efficacy equal to that of ibuprofen and superior to those of celecoxib and placebo. Rofecoxib’s analgesic efficacy, long duration of action and apparent lack of inhibition of platelet function suggest that rofecoxib may be useful as a pre-emptive analgesic when postoperative pain is anticipated.^16,19,20

	ADVERSE REACTIONS AND PRECAUTIONS

TOP ABSTRACT THE CYCLO-OXYGENASE MECHANISM SPECIFIC CYCLO-OXYGENASE-2... ADVERSE REACTIONS AND... CONCLUSIONS AND RECOMMENDATIONS... REFERENCES

 
Damage to the GI tract—including erosions, ulcers and bleeding—is a known adverse reaction to the prolonged use of most NSAIDs. The relative risk of ibuprofen administered at a dosage of 1,600 mg per day has been found to be lower than that of other NSAIDs such as diflunisal, aspirin, naproxen and ketoprofen.^3,21 Endoscopic studies have found that higher doses of ibuprofen—2,400 mg per day—are more likely to cause GI damage than are lower doses.^19,20

Fewer GI ulcers appear with either celecoxib or rofecoxib than with prescription doses of ibuprofen or naproxen. A recently published multicenter clinical trial of celecoxib (400 mg twice per day), ibuprofen (800 mg three times per day) and diclofenac (75 mg twice per day) compared GI toxicity after long-term use for osteoarthritis and rheumatoid arthritis.²² Nearly 8,000 adults were enrolled in this prospective study, which lasted up to six months. Compared with ibuprofen and diclofenac, celecoxib induced fewer upper GI symptoms and complications.²² Bombardier and colleagues²³ published a similar large long-term evaluation of rofecoxib. In their study, adult patients who had rheumatoid arthritis received either rofecoxib 50 mg per day or naproxen 500 mg twice per day. The researchers assessed confirmed clinical upper GI events. They found that rofecoxib and naproxen had similar efficacy for treating rheumatoid arthritis, and that confirmed GI events occurred half as often with rofecoxib as with naproxen.²³

Although the GI toxicity of these agents is reduced, reports of abdominal pain, diarrhea and dyspepsia associated with their use still occur. Although these new COX-2 inhibitors appear to be safer than traditional NSAIDs, life-threatening and fatal ulcer complications have been reported with them. Unlike low-dose aspirin, the COX-2 inhibitors are not indicated for chronic prophylaxis to prevent myocardial infarctions. In the recently published long-term toxicity study comparing rofecoxib to naproxen, myocardial infarctions occurred less frequently in patients taking the nonselective COX inhibitor naproxen.²³ Whether this represents a cardioprotective effect of naproxen or a cardiotoxic effect of rofecoxib is not clear. GI ulcer warnings and precautions similar to those required for current NSAIDs still are necessary until further clinical experience with these agents is obtained.²⁴

When given in chronic dosing, COX-2 inhibitors—like other NSAIDs—can produce renal toxicity, including renal insufficiency; sodium retention with hypertension and edema; hyperkalemia; and papillary necrosis. It should be noted that both COX-1 and COX-2 enzyme systems play a role in maintaining kidney function. Because the precise relationship between the COX-1 and COX-2 enzyme isoforms in the kidney has yet to be determined, the same caution should be applied to COX-2 inhibitors as is applied to the nonspecific NSAIDs.²⁵

Drug interactions associated with these COX-2 inhibitors may be due to shifts in their pharmacokinetic or pharmacodynamic responses. While celecoxib is metabolized by the smooth endoplasmic reticulum of liver hepatocytes and gut enterocytes, liver oxidative enzymes play a minor role in rofecoxib metabolism. Both drugs may alter kidney function and subsequently reduce the elimination of lithium and the efficacy of furosemide. Aspirin coadministration with either of these COX-2 inhibitors may increase the risk of developing GI ulcerations. Pharmacokinetic interactions reported for rofecoxib include reduced methotrexate elimination and increased rofecoxib metabolism with rifampin. Celecoxib is more rapidly metabolized when administered with fluconazole.^26,27

Like other NSAIDs, both celecoxib and rofecoxib may decrease the antihypertensive effects of angiotensin-converting enzyme inhibitors. This may be due to the COX mechanisms that play an important role in maintaining normal renal blood flow, especially in hypertensive patients. COX-2 inhibitors are not recommended for use in pregnancy, particularly during the third trimester.²⁸ Patients with a history of aspirin or NSAID allergy or who have aspirin- or NSAID-sensitive asthma should also avoid COX-2 inhibitors.

According to the manufacturer, celecoxib is contraindicated for use by patients reporting sulfonamide allergy.²⁹ Like the antibiotics sulfamethoxazole and sulfisoxazole, celecoxib is a sulfonamide derivative. A meta-analysis of 14 celecoxib trials did not reveal a higher frequency of allergic reactions among patients with a history of sulfonamide hypersensitivity.²⁷ The concern regarding cross-sensitivity between celecoxib and sulfonamide allergy may be only theoretical and, therefore, not clinically relevant.

	CONCLUSIONS AND RECOMMENDATIONS FOR THE DENTAL PRACTITIONER

TOP ABSTRACT THE CYCLO-OXYGENASE MECHANISM SPECIFIC CYCLO-OXYGENASE-2... ADVERSE REACTIONS AND... CONCLUSIONS AND RECOMMENDATIONS... REFERENCES

 
The newly introduced COX-2 inhibitors celecoxib and rofecoxib are NSAIDs that provide some therapeutic advantage over nonselective COX inhibitors by limiting the adverse GI toxicity and platelet inhibition seen with chronic administration of currently available NSAIDs.

The decision to select one of these new COX-2 inhibitors should be based on the following:

– Celecoxib and rofecoxib offer the advantage of once- or twice-per-day dosing regimens.

– Studies to date indicate that the COX-2 inhibitors have little or no effect on platelet aggregation and bleeding parameters.

– Of the currently marketed COX-2 inhibitors, only rofecoxib has demonstrated analgesia comparable with that provided by ibuprofen 400 mg in acute postsurgical dental pain.

– The extremely high price of the COX-2 inhibitors vs. that of over-the-counter NSAIDs, such as ibuprofen, limits routine prescription of them.

The COX-2 inhibitors described in this article provide dentists with a therapeutic alternative to ibuprofen, naproxen and other nonselective NSAIDs. Their primary advantage is limiting adverse GI effects associated with prolonged treatment of chronic pain that is associated with temporomandibular disorders. Future research regarding COX-2 inhibitors should yield even better agents that will maximize the benefits of NSAID therapy and minimize potential adverse reactions.

View larger version (113K): [in this window] [in a new window]   Dr. Moore is a professor of pharmacology, Department of Public Health Dentistry, University of Pittsburgh School of Dental Medicine, 380 Salk Hall, Pittsburgh, Pa. 15261, e-mail "PAM7{at}pitt.edu". Address reprint requests to Dr. Moore.