Cox-2 inhibitors are non-steroidal anti-inflammatory drugs (NSAIDs) which selectively inhibit cyclooxygenase-2. The cyclooxygenases are required for the creation of prostaglandins. Prostaglandins act somewhat like hormones in controlling many of the functions of the body, including control of blood pressure and control of the smooth muscle of the respiratory tract and intestines. The traditional NSAIDs inhibit both cyclooxygenase 1 and 2 (Cox-1 and Cox-2). However, while Cox-2 is associated with inflammation and pain, Cox-1 maintains the integrity of the gastric mucosa, mediates normal platelet function, and regulates renal blood flow.
The development of the Cox-2 selective inhibitors was intended to provide drugs that would offer the same pain relieving and anti-inflammatory effects as the traditional NSAIDs without causing the gastric ulcers that have been associated with the older drugs.
Although the non-steroidal anti-inflammatory drugs are considered relatively safe, they are so widely used that their adverse effects are significant. As of 2005, they account for almost one-fourth of all reported adverse drug reactions. Approximately 15% of NSAID users have gastrointestinal tract symptoms such as dyspepsia, heartburn, nausea or vomiting. Each year, 1 to 4% of NSAID users have serious gastrointestinal tract complications such as hemorrhage, with an estimated cost of $15,000 to $20,000 per hospitalization while an estimated 16,500 NSAID-related deaths occur annually among patients with osteoarthritis or rheumatoid arthritis.
In early studies, the Cox-2 inhibitors appeared to be fulfilling their promise. A 1999 study which compared celecoxib (Celebrex) with naproxen (Naprosyn) and placebo reported that the incidence of gastric erosions and ulcers was significantly greater in the naproxen group than in the celecoxib or placebo group. A 1999 report in The American Journal of Orthopedics stated: "Controlled trials have also shown that the incidence of gastroduodenal ulcers and the combined incidence of gastroduodenal ulcers and erosions are significantly lower with celecoxib therapy than with naproxen therapy and are similar to those associated with placebo administration. In a study of platelet function, it was found that a single 650-mg dose of aspirin profoundly diminished platelet function, while therapeutic doses of celecoxib exhibited no such effect. Celecoxib has been shown to be well tolerated, with incidences of adverse events similar to placebo in most instances." However, a French review warned that certain selective Cox-2 inhibitors (i.e. celecoxib, rofecoxib) have not been tested for safety on patients with ulcers or cardiovascular or renal disease.
In 2003, celecoxib was the 28th most prescribed drug in the United States based on number of prescriptions written, while rofecoxib (Vioxx) ranked 36th.
Even so, there were evidences of concern about the potential risks of the Cox-2 inhibitors. While the 1999 review claimed that the drugs had no effect on platelet function, a 2002 paper from the University of Michigan Department of Cardiology warned that the drugs might increase the risk of blood clotting, and a Canadian paper, published about the same time, reported that the efficacy of cycloozygenase inhibitors did not always match that of conventional nonsteroidal anti-inflammatory drugs
On September 30, 2004, the United States Food and Drug Administration announced that Merck and Company was withdrawing rofecoxib from the market, based on evidence from long-term studies showing that the drug had a higher risk of cardiovascular problems than comparable agents.
On April 7, 2005, the Food and Drug Administration asked Pfizer to withdraw valdecoxib (Bextra) from the market. Valdecoxib had been approved for treatment of rheumatoid and osteoarthritis and for primary dysmenorrhea. The FDA recommendation for the discontinuation of valdecoxib was based not on cardiovascular safety, but rather on the relative frequency of rare but very severe skin reactions, including Steven Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). These potentially fatal adverse reactions are seen with many drugs in many different classes, but according to the FDA were observed disproportionately frequently with valdecoxib.
For patients who require NSAIDs but are at risk of ulcers, a number of approaches are available, although few appear to hold up to scientific scrutiny. Although some NSAIDs have made claims of greater gastrointestinal safety, Canada's Therapeutics Initiative failed to find significant advantages to any NSAID, although some do show a limited safety advantage in short term use. Salsalate and ibuprofen were at once the safest and least expensive drugs in the group.
Misoprostol, a prostaglandin, is an effective gastroprotective agent which has reduced the frequency of gastric ulcers from 0.95% to 0.57%. Misoprostol is available by itself or in combination with diclofenac, under the brand name Arthotec. However, misoprostol is an abortifacient and has been associated with birth defects. For this reason, it may be inappropriate for use in women of childbearing potential.
The proton pump inhibitors (esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprozole) appear to be effective at protecting the stomach; however, more studies are needed. The H-2 receptor blockers (cimetidine, famotidine, nizatidine, and ranitidine) have not demonstrated activity in ulcer prevention and are not recommended for this purpose.
The only Cox-2 inhibitor on the market as of April 2005 is celecoxib (Celebrex).
Celecoxib is indicated for treatment of rheumatoid and osteoarthritis, acute pain and the pain associated with primary dysmenorrhea. The drug is also used to reduce the number of polyps in familial adenomatous polyposis (FAP). It is not known whether there is a clinical benefit from a reduction in the number of colorectal polyps in FAP patients or whether the effects of celecoxib treatment will persist after the drug is discontinued. The efficacy and safety of celecoxib treatment in patients with FAP beyond 6 months have not been studied as of April 2005.
Osteoarthritis: 200 mg/day administered as a single dose or as 100 mg twice/day.
Rheumatoid arthritis: 100 to 200 mg twice/day.
Acute pain and primary dysmenorrhea: 400 mg initially, followed by an additional 200 mg dose if needed on the first day. On subsequent days, the recommended dose is 200 mg twice daily as needed.
The following rules have applied to all Cox-2 inhibitors that have been marketed:
- Should not be used by patients who are allergic to sulfonamides
- Should not be used by patients who have shown allergic reactions to other non-steroidal anti-inflammatory agents such as ibuprofen of naproxen.
- Should not be used in patients who have aspirin-associated asthma.
- The use of these drugs is specifically contraindicated in late pregnancy, since they may cause premature closure of the ductus arteriosus.
- The Cox-2 inhibitors have not been studied in patients with advanced kidney disease, and their use is not recommended.
Although the Cox-2 inhibitors cause a lower incidence of ulcers than the non-selective NSAIDs, the frequency of less severe stomach and intestinal side effects is similar. The most common side effects of the Cox-2 inhibitors are: upset stomach, stomach pain, diarrhea, gas or bloating, and sore throat.
There are a large number of other possible effects, which although infrequent may be serious and require prompt medical attention: black and tarry stools, red blood in stools, bloody vomit, vomiting material that looks like coffee grounds, excessive tiredness, unusual bleeding or bruising, itching, lack of energy, loss of appetite, pain in the upper right part of the stomach, yellowing of the skin or eyes, flu-like symptoms, rash, pale skin, unexplained weight gain, swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs, hoarseness, difficulty swallowing, or breathing.
Celecoxib has the potential for a large number of drug interactions. Because it has a large number of possible adverse effects, it may interact with any other drug that causes a similar effect or increases the risk or severity of the problem. For example, since the Cox-2 inhibitors commonly cause stomach upset, there will be an even greater risk of stomach distress when celecoxib is taken with another drug that causes stomach problems. Similarly, since the drug is metabolized by the liver, it will change the normal blood levels of other drugs that are metabolized in a similar manner, which may either increase or decrease the effects of these drugs.
The following is a partial list of drugs that interact with celecoxib:
- Aspirin: Administration of aspirin with Cox-2 inhibitors may result in an increased risk of GI ulceration and complications.
- ACE-inhibitors: Reports suggest that NSAIDs, including the Cox-2 inhibitors, may diminish the antihypertensive effect of ACE-inhibitors. The ACE-inhibitors include benazepril (Lotensin), captopril (Capoten), enalapril (Vasotec), fosinopril (Monopril), lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril (Aceon), quinapril (Accupril), ramipril (Altace), and trandolapril (Mavik).
- Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the sodium removing effect of furosemide (Lasix) and thiazide diuretics in some patients.
- Anticonvulsants (Phenytoin): When these drugs are used together, the levels of Cox-2 inhibitors may be reduced by over 25%. A dose adjustment may be required.
- Warfarin: Cox-2 inhibitors may increase the anticlotting effects of warfarin (Coumadin). Patients taking these drugs together should have their coagulation times closely monitored until the doses can be adjusted.
- Fluconazole and Ketoconazole: These antifungal drugs are metabolized by the same means as the Cox-2 inhibitors and cause very significant increases in the blood levels of celecoxib and valdecoxib. The doses of the Cox-2 inhibitors may have to be reduced.
- Glyburide: Glyburide (Diabeta, Glynase, and Micronase) is used to treat diabetes. Whether there is a drug interaction seems to depend on the dose levels of the drugs, but at some dosages, the Cox-2 inhibitors may increase the blood levels of glyburide, leading to a significant drop in blood sugar levels. If these drugs must be taken together, blood sugar levels should be closely monitored until the doses of the two drugs are fully adjusted.
Cyclooxygenase— An enzyme, found in most tissues, that helps turn some fatty acids into protaglandins.
NSAIDs— A group of drugs that is not formed from a corticosteroid molecule, but which reduces inflammation. Most of these drugs also function as pain relievers and reduce fever as well.
Osteoarthritis— A type of joint deterioration caused by damage to cartilage.
Primary dysmenorrhea— Painful menstruation caused by inflammation, new growths, or anatomic factors.
Proton pump inhibitor— One of a group of drugs that acts to reduce the secretion of stomach acid.
Renal— Relating to the kidneys.
Rheumatoid arthritis— A type of joint deterioration caused by inflammation.
Physicians' Desk Reference 2005. Montvale, NJ: Thomson Healthcare, 2004.
Goldenberg, M. M. "Celecoxib, a selective cyclooxygenase-2 inhibitor for the treatment of rheumatoid arthritis and osteoarthritis." Clinical Therapy 9 (September 21, 1999): 1497-513
Larousse, C., and G. Veyrac. "[Clinical data on COX-1 and COX-2 inhibitors: what possible alerts in pharmacovigilance?]" Therapie. 55, no. 1 (January/February 2000): 21-8 (article in French, English abstract).