The Diagnosis and Treatment of Gout

Robert G. Smith, DPM, MSc, RPh, CPed


US Pharmacist. 2009;34(5):40-47. 

In This Article

Treatment of Gout

Key elements necessary to improve clinical outcomes in gout management include enhancing health professional and patient education as well as exploring novel urate-lowering agents. One of the most valuable health care professionals when assisting clinicians in the treatment of gout is the pharmacist. Pharmacists can appreciate that the optimal treatment for gout requires both adjunctive nonpharmacologic as well as pharmacologic interventional therapies ( Table 1 ). A practicing pharmacist is directed to read the Becker and Chohan editorial, which suggests that successful gout management is possible by embracing the 12 evidence-based recommendations from the European League Against Rheumatism (EULAR) ( Table 2 ).[25,26] Treatment and prevention of acute gout flares, as well as the management of hyperuricemia and gout, can best be appreciated by patients with a brief narrative and be accentuated graphically through easy-to-read tables that the pharmacist may access quickly when a question arises.

A treatment regimen must be individually tailored to each patient. The treatment of gout has three main components: therapy of the acute attack, prophylaxis against gout flares, and management of hyperuricemia.[8] Several aspects must be independently considered when planning to treat a patient with gout. Given that gout is a reversible urate crystal deposit disease, the main objective is to eliminate the urate crystals from the joints and other structures.[27] Li-Yu et al determined through a 10-year prospective investigation that serum urate levels should be reduced to below 6.0 mg/dL in order to eliminate crystals.[28]

Pharmacotherapy for Acute Gout Attacks

Medications used to treat an acute gout attack include nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, and corticosteroids. A combination of these may also be necessary. A summary of the pharmacologic agents used to treat acute gout is shown in Table 3 .[6,7,8,25,26,27] These medications have no effect on the serum uric acid level. The classic antidote for gouty arthritis is colchicine. The most common associated adverse drug event reported with colchicine use is diarrhea.[6] However, even low-dose colchicine may be associated with severe adverse effects and toxicity such as myopathy and myelosuppression.[6,8,27] Monitoring of serum troponin levels during an acute colchicine overdose may help avoid vascular collapse.[29]

Guidelines indicate that fast-acting oral NSAIDs should be used during acute attacks if there are no contraindications.[6,7,8,26] Since there are no significant clinical differences among NSAIDs, the choice of agent should be based on the agent;s side-effect profile, it;s cost, and patient;s ability to adhere to the prescribed agent.[6,8,25,27] Suppressive therapy to prevent flares usually involves colchicine or NSAIDs.[8] An important factor in choosing therapeutic agents for an acute attack is the presence of comorbidities. The most common therapy for acute gout in the setting of acute or chronic renal or hepatic failure is corticosteroids.[8] If NSAIDs and colchicine are contraindicated because of patient comorbidities, intra-articular aspiration and injection of a corticosteroid is an effective treatment of an acute attack of gout once the possibility of a septic joint has been eliminated.[6]

Urate-Lowering Therapy

The therapeutic goal of urate-lowering therapy is to promote dissolution of the urate crystals and to prevent crystal formation.[6,28] In addition, urate-lowering therapy is used to prevent disease progression, reduce the frequency of acute attacks, and maintain and improve quality of life. Treatments for chronic gout are aimed at reducing serum urate levels to less than 6.0 mg/dL in order to dissolve existing crystals and prevent formation of new ones.[8] Dore recommends that patients who overproduce urate should be treated with allopurinol, as this drug has the advantage of being effective for both overproducers and underexcretors.[6] Patients who underexcrete urate despite near-normal creatinine clearance levels should be treated with uricosurics. Urate-lowering therapy should be lifelong. If an acute flare occurs when urate-lowering therapy is initiated, therapy should not be discontinued, because doing so will result in fluctuating urate levels.[30] Initiating urate-lowering therapy can mobilize urate deposits, which may precipitate an attack because of rapid serum uric acid lowering.[7] The practice of using concomitant gastroprotectant NSAID and colchicine prophylaxis with the initialization of urate-lowering therapy has been suggested.[7,25]

Pharmacists can be a tremendous resource by informing the clinician about potential drug interactions and side effects of urate-lowering agents to maximize therapeutic outcomes. Finally, pharmacists must remember that treatment of asymptomatic hyperuricemia is not recommended.[7]

Since 1965, one traditional approach to the treatment of gout has been the drug allopurinol, an isomer of hypoxanthine. Allopurinol is a substrate for xanthine oxidase. The product binds so tightly that the enzyme is now unable to be oxidized in its normal substrate. Uric acid production is diminished, and xanthine and hypoxanthine levels in the blood rise. These are more soluble than urate and are less likely to deposit as crystals in the joints. The allopurinol dose must be adjusted in patients with renal impairment.[6] Allopurinol is often started at 100 mg per day, and the daily dosage is increased in 100 mg increments every 2 to 4 weeks.[8,25,26] The usual dosage range for allopurinol is 200 to 300 mg/day for mild gout and 400 to 600 mg/day for cases of moderate and severe gout. Up to 5% of patients are unable to tolerate allopurinol due to adverse effects such as rash, nausea, and bone marrow suppression.[31] If a severe rash occurs, the pharmacist should advise discontinuation of allopurinol. Allopurinol has fewer drug interactions than uricosuric agents.[6] Despite allopurinol's limitations, it is used extensively for most gouty patients and is considered safe and effective.[27]

Emerging Therapies

Uricosurics are considered second-line therapy for patients who are intolerant to allopurinol. Of all the older urate-lowering drugs, probenecid or sulfinpyrazone may be used in patients refractory to allopurinol therapy.[27] In the U.S., probenecid is the only potent uricosuric agent available.[8] Probenecid is most useful in patients with mild gout and normal renal function. Its mechanism of action is inhibition of the uric acid transporter (URAT1) involved in the reabsorption of uric acid.[8] Uricosuric therapy is contraindicated in patients with a history of nephrolithiasis and is not effective in patients with a creatinine clearance of less than 50 mL/min. Finally, both losartan and fenofibrate have slight uricosuric properties and may be useful as adjunctive therapy in gout patients with comorbidities of hypertension and hyperlipidemia.[6,32]

Febuxostat is a potent, new selective xanthine oxidase inhibitor that received FDA approval in February 2009 for the management of hyperuricemia in patients with gout.[8,33,34] This agent is not a purine analog and has a mechanism similar to that of allopurinol. The recommended starting dose of febuxostat is 40 mg once a day. For patients who do not achieve a serum uric acid less than 6 mg/dL after 2 weeks with 40 mg, increasing the dose to 80 mg is recommended.[34] Febuxostat has demonstrated efficacy superior to allopurinol.[27,34] It is primarily metabolized by the liver and may be an alternative agent for patients with renal insufficiency. The adverse-effect profile for febuxostat includes elevation in liver enzymes, rash, diarrhea, and headache.[8] The manufacturer has reported that febuxostat has a higher rate of risk of cardiovascular thromboembolic events compared to allopurinol.[34] Finally, febuxostat is contraindicated in patients treated with azathioprine, mercaptopurine, or theophylline.[34]

Uric acid oxidase, also known as uricase, is an enzyme that catalyzes the conversion of uric acid to allantoin and is present in all mammals except humans and higher primates.[27] There is interest in using uricase therapies to lower serum uric acid. Rasburicase, a recombinant uricase IV product indicated for tumor lysis syndrome, might be successfully used in unusually severe cases of gout.[35] Rasburicase has a black box warning for anaphylaxis, hemolysis, and methemoglobin. Pegloticase (pegylated recombinant porcine uricase) has also shown urate-lowering efficacy.[14,36] Adding polyethylene glycol (PEG) prolongs the half-life of uricase and decreases the antigenicity. Intravenous administration of PEG-uricase has been investigated for the potential treatment of severe tophaceous gout in patients who are hypersensitive to allopurinol.[37]

Pharmacists should appreciate the relative contraindications to both NSAIDs and corticosteroids as symptomatic therapies. Therefore, attention has been directed to the recent advances in the understanding of gouty inflammation and the proinflammatory role of several cytokines in the pathophysiology of acute gout.[25,38] Early small clinical trials have identified interleukin-1B as the most prominent in acute gout. The practice of inhibiting interleukin-1 may be efficient and safe in terminating the symptoms of acute gouty arthritis.[25]