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Acute Gout

Time to consider an additional weapon

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Gouty arthritis is a common condition that touches the lives of more than 1% of adults in the United States.1 Common risk factors for gout are age, male gender, diet rich in purines (red meat, seafood, etc.), alcohol intake, obesity, medications, poor renal function and most importantly, increased serum urate levels.1

Increased concentration of urate in the serum leads to the risk of oversaturation. Serum urate levels of more than 6.8 mg/dL are considered oversaturated.2 At levels beyond this threshold, monosodium urate crystals begin to precipitate and deposit into the synovial fluid of joints.2 Phagotization of these crystals by neutrophils leads to an inflammatory process that includes the release of cytokines, interleukins, tumor necrosis factor and the recruitment of more neutrophils.3 This pro-inflammatory cascade is a major target of acute therapy for gout patients.

The current standard of care for acute gouty athropathy is immediate management with nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) such as naproxen, indomethacin or ibuprofen because of their anti-inflammatory and pain-relieving properties.4 Colchicine (Colcrys) is another anti-inflammatory option that works by binding tubulin and disaggregating leukocytes to reduce the inflammatory process.5 For patients who cannot take NSAIDs or colchicine, or who have experienced minimal improvement with these regimens, corticosteroids are another option. These drugs can be injected into the affected joint or taken orally. Corticosteroids reduce inflammation, but to prevent a potential rebound flare of gout, oral forms must be tapered.6

Based on the data presented in this article, it may be time to consider adjusting the standard approach to include cyclooxygenase-2 (COX-2) selective NSAIDs as well, due to a favorable side effect profile and comparable efficacy.

Nonselective NSAIDs

Nonselective NSAIDs inhibit both cyclooxygenase-1 and cyclooxygenase-2 enzymes. Cyclooxygenase is an enzyme that contributes to the formation of prostaglandins, which are in part responsible for inflammation, pain and recruitment of neutrophils.

COX-1 is known as a "housekeeping" enzyme. It is widely expressed in most tissue and is important to help cells continue their "normal" processes (e.g., vascular homeostasis, platelet aggregation, gastric mucosa integrity, etc.). COX-2 is mostly present in response to inflammation and is activated by factors such as interleukin-1 and growth factors, which increase prostaglandin synthesis.7

By inhibiting both COX-1 and COX-2 enzymes, nonselective NSAIDs such as naproxen (500 mg twice daily), indomethacin (50 mg three times daily) and diclofenac (Voltaren, 50 mg three times daily) reduce the pain and inflammation of gout that is mediated by the COX-2 enzyme. But they also cause certain adverse effects produced mainly by inhibiting the COX-1 enzyme.

Some of these side effects are well known: gastrointestinal toxicity, renal and hepatic insufficiency, increased bleeding time, etc. Many side effects of NSAIDs are specifically related to inhibition of the COX-1 enzyme, although COX-2 inhibition is attributed to certain side effects as well. Inhibition of prostaglandins that the COX-1 enzymes helps to mediate leads to loss of gastric mucosa integrity, platelet aggregation and regulation of renal blood circulation. This leads to compromised gastric mucosa, ulcers, prolonged bleeding time, and renal problems.8

Nonselective COX inhibitors have long been the standard of care for gout and have produced the best outcomes when used within 48 hours of the initial attack. Treatment can be continued until the resolution of symptoms. An additional 2 to 3 days of treatment will help improve the patient's prognosis.9

Because of their efficacy in reducing the inflammatory process and diminishing pain, nonselective COX inhibitors are a major force in the fight against acute gout pain. So can we have the good without the bad? Can pain and inflammation be reduced while common side effects are minimized?

Selective NSAIDs

COX-2 inhibitors specifically inhibit the cyclooxygenase-2 enzyme to prevent the inflammatory process. This enzyme is also inhibited by glucocorticoids, which explains their anti-inflammatory effect. The drugs in this class include celecoxib (Celebrex), valdecoxib (Bextra) and rofecoxib (Vioxx; this drug was recently pulled from the U.S. market). Etoricoxib (Arcoxia) is a COX-2 inhibitor that has been approved in more than 50 countries but has not received FDA approval for use in the United States.10,11 Refecoxib was removed from the market due to its potential for cardiovascular complications, and although this risk is present for the COX-2 inhibitor class as a whole, the risk is likely small in patients with low cardiovascular risk.12

In fact, some studies even question the validity of this concern about cardiovascular effects. A 2002 study that reviewed 55,396 prescriptions of traditional and selective COX inhibitors suggested that COX-2 inhibitors were prescribed preferentially to patients who were at increased baseline risk for CV events compared with patients who took nonspecific NSAIDs.13 One major advantage to the selective COX-2 inhibitors is the avoidance of some of the major adverse effects of traditional NSAIDs, including lack of effect on platelets, reduced risk of bleeding and reduction in gastroduodenal toxicity.

Consider a randomized, placebo-controlled, double-blind trial in which 688 patients with rheumatoid arthritis randomly received naproxen, celecoxib or placebo. After 12 weeks, both celecoxib and naproxen improved signs and symptoms compared to placebo, but celecoxib had a rate of gastroduodenal ulcers similar to placebo (4%). Patients who received naproxen had a much higher rate of ulcers (26%).14 Some clear potential advantages are associated with the selective COX inhibitors, but so far little push has been made to increase availability of these drugs to patients with gouty arthritis.

It may be time to consider bolstering the repertoire of medications for gouty arthritis patients to include selective COX-2 inhibitors, especially for patients who cannot tolerate traditional NSAIDs and are not at an increased cardiovascular risk. Multiple attributes of etoricoxib (Arcoxia), for example, stack up evenly or sometimes better than traditional NSAIDs and show that it should receive consideration as a possible therapy.15-19

One aspect would be efficacy. Two separate studies documented comparable or even slightly improved efficacy and pain relief for etoricoxib over indomethacin.15,16 A second important feature of the therapies is cost. A 2004 study of the economic evaluation of etoricoxib and other traditional NSAIDs showed that etoricoxib was a cost-effective alternative to other current therapeutic approaches with traditional NSAIDs. This study evaluated the cost of the drugs as well as the entire therapeutic approach involving the different drug treatments (e.g., including the cost of PPIs to control the side effects of nonselective NSAIDs).17

A third consideration to the therapies would be dosages. For etoricoxib, the recommended dose is 60 mg to 120 mg once daily. Indomethacin dosing is 25 mg to 50 mg three times daily with a maximum dose of 200 mg/day. Naproxen is dosed 250 mg by mouth every 8 hours.18 The advantage of etoricoxib is the once-daily dosing that would likely facilitate patient adherence and therefore increase the efficacy of the treatment. Etoricoxib, as well as the other selective COX-2 inhibitors, do present certain risks and should be avoided in patients who have pre-existing cardiovascular disease. They also cause minor side effects similar to nonselective NSAIDs, such as cough, swelling, headache, etc.

If option A and option B were two therapeutic options and clinicians were told that option A had a better side effect profile, similar (if not better) efficacy for the condition, and had similar (if not better) economic impact on both the patient and on the industry, it would seem like an obvious choice to consider option A. Option A for acute gouty arthritis is here, and it is the selective COX-2 inhibitors. It is time to begin incorporating this therapy into management. Our goal as clinicians should be to provide the best care available and it is time to consider rethinking our approach to gout in order to provide the best care.

 References

1. Saag KG, Choi H. Epidemiology, risk factors, and lifestyle modifications for gout. Arthritis Res Ther. 2006;8(Suppl 1):S2.

2. Schumacher HR Jr. The pathogenesis of gout. Cleve Clin J Med. 2008;75(Suppl 5):S2-S4.

3. Monach P, Becker M. Pathophysiology of gouty arthritis. UpToDate. http://www.uptodate.com/contents/pathophysiology-of-gouty-arthritis

4. Kurakula PC, Keenan RT. Diagnosis and management of gout: an update. J Musculoskel Med [online]. 2010;27(10).

5. Brody TM, et al. Drugs to Control Pain. In: Brody's Human Pharmacology, Molecular to Clinical. Philadelphia: Mosby; 2010: 391-409.

6. Becker MA. Patient Information: Gout (beyond the basics). http://www.uptodate.com/contents/gout-beyond-the-basics

7. Solomon DH. NSAIDs: Mechanism of Action. UpToDate. http://www.uptodate.com/contents/nsaids-mechanism-of-action

8. Süleyman H, et al. Anti-inflammatory and side effects of cyclooxygenase inhibitors. Pharmacol Rep. 2007;59(3):247-258.

9. Becker MA. Treatment of acute gout. UpToDate Marketing Professional. http://www.uptodate.com/contents/treatment-of-acute-gout

10. Solomon DH. Overview of Selective COX-2 Inhibitors. UpToDate. http://www.uptodate.com/contents/overview-of-selective-cox-2-inhibitors?detectedLanguage=en&source=search_result&search=Overview+of+selective+COX-2+inhibitors&selectedTitle=1~150&provider=noProvider

11. Brooks P, Kubler P. Etoricoxib for arthritis and pain management. Ther Clin Risk Manag. 2006;2(1):45-57.

13. Solomon, Daniel H. COX-2 selective inhibitors: adverse cardiovascular effects. UpToDate. http://www.uptodate.com/contents/cox-2-selective-inhibitors-adverse-cardiovascular-effects?source=see_link

14. Zhao SZ, et al. Comparison of the baseline cardiovascular risk profile among hypertensive patients prescribed COX-2-specific inhibitors or nonspecific NSAIDs: data from real-life practice. Am J Manag Care. 2002;8(15 Suppl):S392-S400.

15. Simon LS, et al. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial. JAMA. 1999;282(20):1921-1928.

16. Schumacher HR, et al. Randomised double blind trial of etoricoxib and indometacin in treatment of acute gouty arthritis. BMJ. 2002;324(7352):1488-1492.

17. Rubin BR, et al. Efficacy and safety profile of treatment with etoricoxib 120 mg once daily compared with indomethacin 50 mg three times daily in acute gout: a randomized controlled trial. Arthritis Rheum. 2004;50(2):598-606.

18. Moore A, et al. Economic evaluation of etoricoxib versus non-selective NSAIDs in the treatment of osteoarthritis and rheumatoid arthritis patients in the UK. Pharmacoeconomics. 2004;22(10):643-660.

19. Naproxen. http://www.medindia.net/doctors/drug_information/naproxen.htm

Andrew Porter is a student in the physician assistant program at Georgia Regents University in Augusta, Ga. Bonnie Dadig is the director and an associate professor for the program. The authors have completed disclosure statements and report no relationships related to this article.






     

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