Yes, Jim Meeks, PA-C, says Cox-II inhibitors can be effective with appropriate patient selection. No, Blaine P. Carmichael, MPAS, PA-C, notes that various studies have shown elevated risks of cardiovascular and renal side effects with these drugs.

Yes, Cox-II inhibitors can be effective with appropriate patient selection. While the studies have been mixed in regard to cardiovascular risks with celecoxib, the only currently available Cox-II medication, this author says the Cox-II class of drug does have a place within the treatment armamentarium for arthritic conditions.
By Jim Meeks, PA-C

Approximately 46 million Americans have either arthritic or rheumatic conditions. Nineteen million adults are limited in their daily activity due to arthritis, the leading cause of disability in the United States.1 Recent estimates from the Centers for Disease Control and Prevention (CDC) project that nearly 67 million people in the United States will have diagnosed arthritis in 2030. Conditions and diseases associated with arthritis include over 100 maladies with osteoarthritis (OA), gout, rheumatoid arthritis (RA) and fibromyalgia being the most common.¹

With this projected increase in patients with arthritis over the next couple of decades, clinicians can certainly expect to see more and more patients presenting with associated symptoms of joint pain, stiffness and many other concerns associated with musculoskeletal conditions related to aging.

Increased pain due to arthritis can get to a point where people resort to virtually anything to relieve the pain. Self-medicating or self-treating patients are a major concern for clinicians as we have no assurance that our patients will follow our advice or refrain from supplementing our treatment with their own remedies. What about our patients who are taking aspirin for cardiovascular protection? How do we manage their inflammatory symptoms?

Gastrointestinal (GI) side effects from the use of over-the-counter (OTC) pain medications have been a concern for years. When I was a PA student, I remember being taught the importance of considering all potential effects of any drugs we prescribe. All drugs have the potential for untoward effects. It is up to us as providers to educate the patient about those risks and the expected benefit of the therapy. We also need to know which drugs, if any, a patient may be using to self-treat at home.

A Closer Look At The Evolution Of NSAIDs
Aspirin was introduced at the beginning of the 20th century and continues to be used today for many of the same reasons it was originally intended. Researchers discovered cardiovascular benefits with aspirin early on and these findings have been verified in a Physician’s Health Study (PHS).² In 2002, the PHS discovered that daily, low dose aspirin reduced the risk of a first myocardial infarction by 44 percent. The second phase of this study is still testing the effects of vitamin E, vitamin C and a multivitamin.

Since the introduction of aspirin, a number of other drugs for pain treatment have found their way into the public’s medicine cabinet. Many of these drugs are nonsteroidal antinflammatory drugs (NSAIDs), which all have benefits and side effects.

The Food and Drug Administration (FDA) Center For Drug Evaluation and Research published memorandums in 2002 that outlined the results of studies on aspirin-containing products and nonsteroidal antiinflammatory drugs (NSAIDs), and gastrointestinal (GI) effects. Looking at adverse events reported to the FDA between Jan 1, 1998 and Dec 31, 2001, these studies identified two significant factors that contributed to adverse GI events. These factors were concomitant use of medications and advanced age.³

When cyclooxygenase-2 (Cox-II) drugs were introduced, they were promoted for their antiinflammatory benefits, which were generally equal to that of the other NSAIDs but were much easier on the GI tract. Cox-II inhibitors quickly gained popularity with providers and patients. The emergence of Cox-II inhibitors was welcome as many patients were able to achieve pain relief without the stomach distress associated with other NSAIDs.

However, during a number of studies of Cox-II drugs, questions were raised about the safety of these drugs in relation to cardiovascular (CV) events. When some of these drugs were associated with increased cardiovascular risk, rofecoxib (Vioxx) and valdecoxib (Bextra) were withdrawn from the market in 2004 and 2005 respectively.

What The Studies Have Revealed About Cox-II Drugs
The National Cancer Institute’s Adenoma Prevention with Celecoxib (APC) trial reported a two- to threefold increase in the risk of CV events compared to placebo.⁴ However, a similar study, the Prevention of Spontaneous Adenomatous Polyps (PreSAP) trial, did not demonstrate similar CV events with celecoxib.⁵ Additionally, the ADAPT trial and the Celebrex Long-Term Arthritis Safety Study (CLASS) did not show an increased risk for CV events.^6,7

Other Cox-II drugs had similar outcomes with demonstrated trends for increased CV events in some studies and no increase in others. It appeared that the risks were often related to the dose taken and the timing of administration. These studies included the Adenomatous Polyp Prevention on Vioxx (APPROVe) trial and the Vioxx GI Outcomes Research (VIGOR) trial; two short-term studies of valdecoxib in patients after coronary artery bypass graft surgeries showing an increased risk of CV events; and a final short-term valdecoxib study, involving patients who had general surgical (non-vascular) procedures, which did not show an increased risk of CV events with valdecoxib.^7-10 The valdecoxib studies were not named in the FDA memorandum.¹¹

In a December 2004 Public Health Advisory, the FDA’s Center for Drug Evaluation and Research advised health care providers to use caution when prescribing “nonsteroidal antiinflammatory drug products, including those known as Cox-2 selective agents.”¹² This advisory reported that NSAIDs and Cox-II drugs might be associated with increased CV risks compared to placebo. It further advised that providers should weigh the benefit to risk concerns for each patient.¹² This is the same concept I was taught as a PA student in my memorable pharmacology classes so long ago.

To further confuse the issue, subsequent published reports have found an actual decrease in the risk of serious coronary artery disease and point to findings of “beneficial effects of celecoxib on endothelial function and coronary artery blood flow.”¹³

Recently published studies continue to expound upon the issue of COX-II inhibitor safety. Singh and co-workers discuss the apparent superiority of celecoxib over non-selective NSAIDs in patients with OA.¹⁴ In a recent meta-analysis of randomized clinical trials, White et al., found that celecoxib treatment does not increase CV events.¹⁵ These articles make fascinating reading as we try to sort out what is best for our patients.

When we consider the patient sitting in front of us, not only do we have to decide what is best for him or her, we have to consider what risk we may add to the situation by prescribing or even recommending any therapies. Part of our consideration needs to include a discussion with the patient about his or her use of OTC drugs and any other remedies.

For example, I know a patient who takes a number of aspirin tablets every night. He says it is the only thing that helps him get up in the morning. Otherwise, he would be too sore to crawl out of bed. Would he be better off taking a Cox-II drug? What if he only took one aspirin at night for its CV benefits?

An article last summer in Rheumatology discusses this very issue. The authors concluded that patients taking celecoxib and aspirin concurrently were less likely to be hospitalized for GI problems than those taking NSAIDs and aspirin.¹⁶ When it comes to treating arthritis patients who need to take aspirin for its CV protection, clinicians can consider celecoxib as a treatment option for their arthritis.
One further consideration is the recent approval of celecoxib for the treatment of juvenile rheumatoid arthritis (JRA) in patients two years of age or older.¹⁷ A 24-week study involving 242 patients between the ages of 2 and 17 found that celecoxib was effective in treating JRA. According to the FDA release, the most common side effects were cough, cold, upper respiratory tract infection, abdominal pain, headache, fever, nausea and vomiting.¹⁷

Key Considerations In Prescribing Cox-II Inhibitors
Our goal as healthcare providers is to treat the whole patient. No one prescription or treatment program will be effective in every patient. If our patients continue to be in pain despite our efforts to help, they will search for remedies from other sources. Accordingly, we are obligated to know what our patients are taking in addition to what we are prescribing or recommending. The aforementioned FDA Public Health Advisory from 2004 advised that use of OTC NSAIDs for more than 10 days should be discussed with a healthcare provider.¹² I suspect that many of our patients significantly exceed that 10-day recommendation.

Having a number of options for treatment is essential to the good practice of medicine. The Cox-II inhibitor should be among the options in our treatment armamentarium. If our patients with arthritis are taking aspirin for CV protection, the Cox-II option is superior to the NSAID and aspirin option for GI protection.

There are several factors clinicians should weigh when considering a Cox-II inhibitor.
• Clinicians should obtain a complete drug history, which includes prescription medications, OTC drugs and supplements, and even herbal preparations.
• When obtaining a complete and current medical history, clinicians should determine if there is any history of coronary artery or vascular diseases, gastrointestinal diseases and any other potential problems. Intolerance of a previous Cox-II medication should raise a red flag.
• Clinicians should thoroughly discuss the patient’s expectations regarding treatment and quality of life issues. This discussion should address potential side effects of any treatments one recommends.
• Clinicians should evaluate cost versus benefit versus risk honestly for the given patient.
• Clinicians should reassess the effectiveness of treatment frequently. Ensuring close follow up with every patient allows us the opportunity to modify therapy or even stop it if any concerns develop.

In Conclusion
The Cox-II class of drug is an effective treatment for many musculoskeletal problems. As with any medication we may prescribe, there are inherent risks for unwanted side effects. Every patient is unique and our ability to predict which patients will respond favorably versus those that may not is limited.

Current research shows both potential problems and benefits of these medications. Ongoing research will continue to evaluate those aspects. In the interim, the Cox-II class of drug can be effective when one ensures appropriate patient selection. As clinicians, we need to educate our patients on the available treatment options, their benefits and their risks. It is important to remember that no prescription we write — or OTC medications for that matter — is without risk.

References
1. www.cdc.gov/arthritis/
2. http://phs.bwh.harvard.edu/phs1.htm
3. U.S. Food and Drug Administration Nonprescription Drugs Advisory Committee September 19, 2002. Briefing Information NSAID – GI Bleed (PDF) April 17, 2002 and Aspirin – GI Bleed (PDF) July 15, 2002. http://www.fda.gov/ohrms/dockets/ac/02/briefing/3882b1_03_E-NSAID%20GI%20Bleed.pdf
4. Solomon SD, McMurray JJV, Pfeffer MA, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectoral adenoma prevention. N Engl J Med 2005; 352:1071-1080.
5. Arber N, Eagle CJ, Spicak J, et al. Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med 2006; 355:885-895.
6. ADAPT Research Group (2006). Cardiovascular and cerebrovascular events in the randomized, controlled Alzheimer’s disease anti-inflammatory prevention trial (ADAPT). PLoS Clin Trials 1(7):e33.
7. Silverstein FE, Faich G, Goldstein JL, et al. Celecoxib long-term arthritis safety study. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. JAMA 2000;284:1247-1255.
8. Baron JA, Sandler RS, Bresalier RS, et al. A randomized trial for rofecoxib for the chemoprevention of colorectal adenomas. Gastroenterology 2006; 131(6):1674-1682.
9. Bombardier C, Laine L, Reicin A, et al, for the VIGOR study group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000; 343:1520-1528.
10. Whelton A, Nussmeier NA, Martineau RJ, et al. Safety of parecoxib and valdecoxib in the treatment of postoperative pain following coronary artery bypass graft surgery or major general surgery. Presented at American College of Cardiology Annual Scientific Session 2005; March 6-9, 2005; Orlando, Fla. Late breaking clinical trials I.
11. Jenkins JK, Seligman PJ. FDA memorandum: Analysis and recommendations for agency action regarding non-steroidal anti-inflammatory drugs and cardiovascular risk. April 6, 2005.
12. Public Health Advisory. U.S. Food and Drug Administration Center for Drug Evaluation and Research, December 23, 2004. http://www.fda.gov/cder/drug/advisory/nsaids.htm
13. Graham DJ, Campen D, Hui R, et al. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet 2005; 365 (9458): 475-481.
14. Singh G, Fort JG, Goldstein JL, et al. Celecoxib versus naproxen and dicofenac in osteoarthritis patients: SUCCESS-I Study. Amer Journal of Med 2006;119(3):255-266.
15. White WB, West CR, Borer JS, et al. Risk of cardiovascular events in patients receiving celecoxib: a meta-analysis of randomized clinical trials. Amer Journal of Cardiology 2007;99(1):91-98.
16. Rahme E, Bardou M, Dasgupta K, et al. Hospitalization for gastrointestinal bleeding associated with non-steroidal anti-inflammatory drugs among elderly patients using low-dose aspirin: a retrospective cohort study. Rheumatology 2007;46(2):265-272.
17. http://www.fda.gov/cder/drug/infopage/COX2/default.htm


No, various studies have shown elevated risks of cardiovascular and renal side effects with the use of Cox-II inhibitors. This author says clinicians should emphasize other modalities for managing arthritis pain and limit the use of Cox-II drugs for the treatment of acute pain in otherwise healthy people.
By Blaine P. Carmichael, MPAS, PA-C

In treating our patients, decision-making has always centered around the idea of balancing potential benefits against potential risks. Cyclooxygenase-II (Cox-II) selective agents were developed and prescribed with the best intentions, namely to help relieve patient suffering, pain and disability. However, with the discovery that many patients treated with Cox-II inhibitors are at increased risk for myocardial infarction or stroke, this difficult balancing act has increasingly become the focus of media attention.

Knowing what we now know, physician assistants, nurse practitioners and other clinicians should begin by assessing each patient’s risk factors for cardiovascular (CV) events and consider placing the patient on aspirin prophylaxis before prescribing NSAIDs for chronic pain relief. User-friendly tools are available on the Internet (http://hin.nhlbi.nih.gov/atpiii/calculator.asp?usertype=prof) to assess CV risk and indications for aspirin.¹ For arthritis patients with an increased risk of myocardial infarction and stroke, none of the Cox-II-selective agents are the best pain treatment for two important reasons.

Long-term CV safety data for the available Cox-II-selective agents in at-risk patients are currently lacking.^2,3
Secondly, it is an underappreciated fact that the GI risk-reducing effect of Cox-II agents is greatly reduced with concomitant aspirin use.^4-6 One national survey reported that more than 50 percent of chronic Cox-II users over the age of 55 took regular aspirin therapy, potentially negating the safety advantage of coxibs in these patients.⁷

Despite their dangers, Cox-I inhibitor nonsteroidal antiinflammatory drugs (NSAIDs) are widely used and are the generally accepted agents of choice in the treatment of osteoarthritis (OA) for patients who do not respond to acetaminophen (Tylenol, Johnson and Johnson). The most commonly prescribed NSAIDs in the United States and Canada include diclofenac sodium, a combination of diclofenac and misoprostol, ibuprofen and naproxen.⁸

Current concerns about the greater risk of gastrointestinal (GI) toxicity have lead us to reevaluate the role of NSAIDs in the treatment of the pain of chronic arthritis. Risk factors for GI toxicity of Cox-I inhibitors include: age of 65 or older; a history of peptic ulcer or upper GI bleeding; concomitant use of oral corticosteroids and anticoagulants; and comorbid cardiac and/or renal disease. For patients with GI risk factors, coprescription of a gastroprotective agent is indicated.

Since the introduction of the Cox-II inhibitors, I initially prescribe acetaminophen for patients who require chronic analgesia and who are at risk for GI adverse events with NSAIDs. If they do not respond, I consider a Cox-II inhibitor. The Cox-II inhibitor celecoxib selectively inhibits Cox-II with little effect on Cox-I.
However, keep in mind that coxibs are not free of adverse side effects. Researchers have reported dyspepsia with coxib use but at a lower frequency than with NSAIDs.^9,10

A Closer Look At Possible Links Between Pain Relievers And Increased Hypertension
In one recent study, researchers reported that men taking pain medication regularly have an increased risk of high blood pressure.¹¹ Researchers followed a total of 16,031 male health professionals (an average age of 64.6) without a history of high blood pressure. They asked the study participants in 2000 and again in 2002 about whether and how often they used three types of pain relievers: acetaminophen, NSAIDs (including coxibs) and aspirin. Researchers also asked the study participants to report if their health care provider had diagnosed them with hypertension.

According to the study, 1,968 had developed hypertension at the four-year follow-up. In comparison to men who did not take analgesics, those who took acetaminophen six or seven days a week had a 34 percent higher risk of hypertension. Those who took NSAIDs six or seven days a week had a 38 percent higher risk and those who took aspirin six or seven days a week had a 26 percent increase in risk.¹¹

Researchers also evaluated the total number of pills (regardless of type) that men took each week for pain relief. In comparison to men who took no pills, those who took 15 or more pills each week had a 48 percent higher risk of hypertension. The inference is that all three types of analgesics may reduce the effects of the renin-angiotensin-aldosterone system and prostaglandin synthesis of enzymes that dilate the capillary bed. The study authors suggest this inhibition results in increasing blood pressure. Acetaminophen may also impair cell functioning through oxidative stress or reduce the proper functioning of vascular endothelium.

“These data add further support to the hypothesis that non-narcotic analgesics independently elevate the risk of hypertension,” the authors note in the study. “Given their common consumption and the high prevalence of hypertension, our results may have substantial public health implications and suggest that these agents be used with greater caution. The contribution of non-narcotic analgesics to the hypertension disease burden merits further study.”¹¹ (Two large studies have also recently suggested that analgesics may be associated with an increased risk of hypertension in women as well.)^12,13

Nongastrointestinal side effects and safety issues are an important consideration in the therapeutic management of chronic OA and rheumatoid arthritis (RA) pain, particularly in light of the overall evaluation of the cost-effectiveness of treatment. Clear evidence suggests that Cox-II–selective inhibitors share the same effects of nonselective NSAIDs on blood pressure and renal function when they are given in similar efficacious doses.¹⁴

The possibility of an increased risk for CV events associated with Cox-II–selective inhibitors in comparison to traditional NSAID therapy has been suggested, as in the above comments, although the results remain controversial.¹⁵

What About The Effect Of Cox-II Inhibitors On Renal Function?
Cox-II–selective inhibitors can exert a deleterious effect on renal function.¹⁶ The fact that both nonselective NSAIDs and the Cox-II selective inhibitors have an unfavorable effect on renal function in high-risk patients suggests that Cox-II derived products (15-epi-lipoxins and resolvins) are needed to support normal renal function.

The conventional thinking is that the negative effects of these drugs on renal function are also related to their suppression of prostaglandin synthesis. Nonsteroidal antiinflammatory drugs can decrease sodium and potassium excretion, renal perfusion and impair renal function sufficiently to cause acute renal failure in at-risk patients.

While fluid retention causing edema and exacerbation of hypertension can occur in patients for other reasons, clinicians can easily identify — via basic chemistry and office urinalysis — those with an increased risk for these adverse renal effects. Accordingly, these tests can facilitate appropriate precautionary measures.¹⁷

When it comes to patients who are at high risk of negative renal effects, clinicians should either avoid coxibs and NSAIDs or use them in the lowest possible dose with careful monitoring of blood pressure and renal function. Other studies have noted that Cox-II inhibitors altered urinary prostaglandin excretion, glomerular filtration rate and sodium retention in a similar manner to nonselective NSAIDs.¹⁸

A retrospective analysis of patients in a large managed care population evaluated the clinical impact of Cox-II selective inhibitors on new onset hypertension in patients who received at least one prescription for rofecoxib or celecoxib but no concurrent therapy with any other NSAID during an 18-month period. The rates of new onset hypertension were similar for patients who received rofecoxib (3.83%) and celecoxib (3.43%), and included the incidence of hypertension not attributable to Cox-II selective inhibitor use.¹⁹

What You Should Know About The Cardiovascular Effects
Data from the Vioxx Gastrointestinal Outcomes Research (VIGOR) trial indicated an increased risk of confirmed CV thrombotic events in patients taking rofecoxib 50 mg qd for RA in comparison to patients taking naproxen 500 mg bid.²⁰ This excess risk was largely but not completely limited to nonfatal myocardial infarction (MI).

This unexpected observation led to a hypothesis-generating analysis by Mukherjee et al., that Cox-II selective inhibitors were associated with an increased risk of CV thrombotic events.¹⁵ This claim, however, was based on invalid comparisons of different studies rather than robust scientific observations. Any possible prothrombotic effect of Cox-II selective inhibitors may be due to their ability to inhibit vascular prostacyclin synthesis in the absence of an inhibitory effect on prothrombotic Cox-I mediated platelet aggregation and thromboxane production.²¹

The American Pain Society, the American College of Rheumatology (ACR) and the International Consensus Conference have all recommended more judicious use of Cox-II selective inhibitors in appropriate patients.^22-24 This should lead to a decrease in mortality, morbidity and healthcare utilization and costs associated with the serious upper GI complications of nonselective NSAIDs. However, there is a great deal of public controversy regarding the use of Cox-II inhibitors as evidenced by recent testimony before the Food and Drug Administration (FDA).²⁵

Coxibs are also indicated for the prevention of colorectal adenomas in patients with familial polyposis. There have been several studies designed to detect cardiovascular risk in this setting. The clinical bottom line is that aspirin and coxibs increase the risk of CV events in patients at risk of colorectal adenomas. The absolute increased risk is about 0.5 percent per year of treatment.^26-28

Other Pertinent Considerations
Controlling pain with NSAIDs and other analgesics does not prevent the permanent damage that occurs in the rheumatic inflammatory arthritities. However, using disease-modifying antirheumatic drugs (DMARDs), including the biologics, does in most cases. Without DMARD treatment, joint inflammation irreversibly erodes joints.

Clinicians should initiate DMARDs early as they take a long time to show results. For example, hydroxychloroquine (Plaquenil, Sanofi-Aventis) and sulfasalazine (Azulfidine, Pfizer) may take up to three or four months before one notices effects. Nonsteroidal antiinflammatory drugs can be useful in selected patients to help control pain and inflammation while they are getting started with DMARD therapy.

While clinicians most commonly use DMARDs to treat RA, they are also useful for juvenile RA, ankylosing spondylitis, psoriatic arthritis and lupus. However, given that DMARDs suppress the immune system, the clinicians involved in the care of these patients must be alert to the increased risk of infection.²⁹

Final Notes
What else can we do for patients with the chronic pain of arthritis? There are a number of safe and effective non-NSAID treatments for arthritis pain. These options include:
• sensible supervised weight loss;
• physical therapy and occupational therapy modalities, and assistive Aid to Daily Living devices;
• canes and supportive splinting for knee and hip arthritis; and
• non-NSAID analgesics.

In conclusion, it is best to reserve all NSAIDs, including Cox-II inhibitors, for use in acute pain among otherwise healthy people whenever possible.

References
1. National Cholesterol Education Program. Risk Assessment Tool for Estimating 10-year Risk of Developing Hard CHD. Available at: http://hin.nhlbi.nih.gov/atpiii/calculator.asp?usertype=prof. Accessed April 24, 2007.
2. Topol EJ. Failing the public health – rofecoxib, Merck, and the FDA. N Engl J Med 2004;351(17):1707-1709.
3. Fitzgerald GA. Coxibs and cardiovascular disease. N Engl J Med 2004;351(17):1709-1711.
4. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis. The CLASS study: A randomized controlled trial. JAMA 2000;284:1247-1255.
5. Schnitzer TJ, Burmester GR, Mysler, et al. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: randomised controlled trial. Lancet 2004;364(9435):665-674.
6. Laine L, Maller ES, Yu C, Quan H, Simon T. Ulcer formation with low-dose enteric-coated aspirin and the effect of COX-2 selective inhibition: a double-blind trial. Gastroenterology 2004;127(2):395-402.
7. Cox ER, Frisse M, Behm A, Fairman KA. Over-the-counter pain reliever and aspirin use within a sample of long-term cyclooxygenase 2 users. Arch Intern Med 2004;164(11):1243-1246.
8. Bloom BS. Direct medical costs of disease and gastrointestinal side effects during treatment of arthritis. Am J Med 1988;88(suppl 2A):20-24.
9. Watson DJ, Harper SE, Zhao PL, et al. Gastrointestinal tolerability of the selective cyclooxygenase-2 (COX-2) inhibitor rofecoxib compared with non-selective COX1/COX-2 inhibitors in osteoarthritis. Arch Intern Med 2000;160:2998-3003.
10. Komhoff M, Grone H-J, Klein T. Localisation of cyclooxygenase-1 and -2 in adult and fetal human kidney: implications of renal function. Am J Physiol 1997;272:460-468.
11. Forman JP, Rimm EB, Curhan GC. Frequency of analgesic use and risk of hypertension among men. Arch Intern Med 2007;167:394-399.
12. Forman JP, Stampfer MJ, Curhan GC. Non-narcotic analgesic dose and risk of incident hypertension in US women. Hypertension 2005;46(3):500-507.
13. Curhan GC, Willett WC, Rosner B, Stampfer MJ. Frequency of analgesic use and risk of hypertension in younger women. Arch Intern Med 2002; 162:2204-2208.
14. Simon LS, Smolen JS, Abramson SB, et al. Controversies in COX-2 selective inhibition. J Rheumatol 2002;29:1501-1510.
15. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 2001;286:954-959.
16. Eras J, Perazella MA. NSAIDs and the kidney revisited: are selective cyclooxygenase-2 inhibitors safe? Am J Med Sci 2001;321:181-190.
17. Brater DC. Effects of nonsteroidal anti-inflammatory drugs on renal function: focus on cyclooxygenase-2-selective inhibition. Am J Med 1999;107:65S-70S; discussion 70S-71S.
18. Brater DC, Harris C, Redfern JS, Gertz BJ. Renal effects of COX-2-selective inhibitors. Am J Nephrol 2001;21:1-15.
19. Straus WL, Barlas S, Stever G, Brater D. A comparison of the clinical impact of rofecoxib vs. celecoxib on new onset hypertension [abstract]. Arthritis Rheum 2001;44(suppl 9):S317. A1589.
20. Bombardier C, Laine L, Reicin A, et al.
Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 2000;343:1520-1528.
21. FitzGerald GA. Cardiovascular pharmacology of nonselective nonsteroidal anti-inflammatory drugs and coxibs: clinical considerations. Am J Cardiol 2002;89(6A):26D-32D.
22. American Pain Society. Guideline on the Management of Pain in Osteoarthritis, Rheumatoid Arthritis, and Juvenile Chronic Arthritis. Glenview, IL: American Pain Society; 2002.
23. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Recommendations for the medical management of osteoarthritis of the hip and knee. Arthritis Rheum 2000;43:1905-1915.
24. Simon LS, Smolen JS, Abramson SB, et al. Controversies in COX-2 selective inhibition. J Rheumatol 2002;29:1501-1510.
25. http://www.citizen.org/publications/release.cfm?
ID=7362#-ftnref1. (Last accessed April 24, 2007).
26. Baron JA, et al. A randomized trial of aspirin to prevent colorectal adenomas. N Engl J Med 2003;348:891-899.
27. Bresalier RS, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005; 352:1092-1102.
28. Solomon SS, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Eng J Med 2005; 352:1071-1080.
29. Disease-modifying antirheumatic drugs. The Arthritis Foundation. (http://www.arthritis.org/conditions/DrugGuide/about_dmards.asp).