Comparison of GOUT therapies

Gout risk factors include high blood pressure, obesity/metabolic syndrome, kidney disease, diabetes, and some medications (e.g., hydrochlorothiazide..

Overview

Gout is one of the most common forms of arthritis. It occurs more often in men. During a gout attack, high uric acid levels lead to the formation of uric acid crystals in joints (usually knees, ankles, and feet; can affect elbows, wrists, and fingers). Symptoms can include pain, redness, joint swelling and limited range of motion, and fever.

Gout risk factors include high blood pressure, obesity/metabolic syndrome, kidney disease, diabetes, and some medications (e.g., hydrochlorothiazide, cyclosporine). Many vitamins, and supplements (e.g., vitamin C, milk thistle) are being evaluated or touted to reduce uric acid levels. However, it is NOT clear yet if these improve or prevent gout attacks.

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Management

Anti-inflammatory medications (NSAIDs, steroids) are usually needed to treat acute gout flares. However, in addition to staying well hydrated, the following can also be done to help relieve pain and swelling:

Ice and elevate the affected joint.
Rest, stay off the affected joint as much as possible.
Relax, stress can aggravate gout.

Table (1). Pharmacological points about anti-inflammatory medications used for gout
Topic	NSAIDs	Corticosteroids	Colchicine
Place in therapy	First-line	First-line or alternative to NSAIDs or colchicine	First-line or alternative to NSAIDs Must be taken at first sign of gout symptoms (within 36 hours).
Typical dosing	Normal dose: full-dose NSAID until the attack is resolved (ibuprofen 400 to 800 mg PO three to four times a day). No specific NSAID is preferred. Celecoxib (Celebrex 800 mg PO once followed by 400 mg on day one, then 400 mg twice daily for one week) may be used No comment on the use of IM or topical NSAIDs.	Normal doses: Oral prednisone or prednisolone 0.5 mg/kg/day PO for five to ten days, then stopped, 30 to 40 mg PO daily for five days. Intra-articular or IM steroid doses (e.g. single-dose intra-articular triamcinolone 2.5 to 5 mg for smaller joints or 5 to 15 mg for larger joints; IM triamcinolone 40 to 80 mg/day).	Normal dose: 1.2 mg PO × one dose, followed by a single dose of 0.6 mg PO one hour later.
Adverse effects	NSAIDs are associated with the following types of adverse effects: GI tract, CV, renal and hepatic.	Short-term steroid use is not typically associated with significant adverse effects. Patients may experience injection site pain with IM or intra-articular steroids.	GI (diarrhea, nausea, vomiting, abdominal pain) Hematologic (thrombocytopenia, leukopenia, agranulocytosis) Muscle pain or weakness, and possible rhabdomyolysis
Other considerations	Can consider combination therapy with an NSAID plus either colchicine or an intra-articular steroid for severe attacks (e.g. severe pain, multiple small joints involved, ineffective monotherapy). Avoid systemic steroids plus NSAIDs due to potential synergistic GI toxicity.	Can consider combination therapy using an oral steroid with either colchicine or a single dose of an injectable steroid OR using an intra-articular steroid with an NSAID or colchicine for severe attacks (e.g. severe pain, multiple small joints involved, ineffective monotherapy). Avoid systemic steroids plus NSAIDs due to potential synergistic GI toxicity. For patients who are unable to take anything by mouth, injectable steroids (IM, IV, or intra-articular) are recommended. Limit intra-articular steroid injections into individual joints to three or four injections per year.

Urate lowering therapy

Start uric acid lowering therapy in patients with ≥ 1 subcutaneous tophi (crystalline uric acid deposits), radiographic damage from gout (e.g. bone erosions), or ≥ 2 gout flares/year. Can consider starting uric acid lowering therapy after one gout flare, especially in patients with CKD stage ≥ 3, uric acid level > 9 mg/dL (535 μmol/L), or kidney stones. It’s not necessary to delay starting or to stop existing uric acid lowering therapy during an acute flare. Some may delay initiation for one to two weeks after an acute flare, especially if not co-prescribing anti-inflammatory prophylaxis.

Start anti-inflammatory prophylaxis when starting or just before starting uric acid lowering therapy to help prevent an acute gout flare (e.g., colchicine 0.6 mg once or twice daily, naproxen 250 mg twice daily, prednisone or prednisolone ≤ 10 mg/day) for three to six months. If switching between uric acid lowering medications with different mechanisms of action, cross-titrate over several weeks, or continue both medications until urate levels and gout symptoms have been controlled for several months. Generally, aim for uric acid level < 6 mg/dL (360 μmol/L). Reserve alkalinization of the urine with potassium citrate for patients who experience uric acid kidney stones. In patients with an indication for an ARB, can give preference to losartan (Cozzar) for its uric acid lowering effects.

Table (2). Urate lowering medications
Topic	Allopurinol	Febuxostat	Probenecid
Mechanism of action and place in therapy	Xanthine oxidase inhibitor: inhibits uric acid production. First-line	Xanthine oxidase inhibitor: inhibits uric acid production. Due to higher risk of CV death, ONLY use in patients who don’t respond to allopurinol, who have severe adverse effects with allopurinol, or in patients for whom allopurinol is not appropriate. Discuss the CV risk with patients as part of shared decision making. NOT recommended in patients with ischemic heart disease or congestive heart failure.	Uricosuric: increases urinary elimination of uric acid thereby decreasing uric acid levels. First-line alternative for patients who fail, have contraindications to, or are unable to tolerate allopurinol and febuxostat. Avoid monotherapy use in patients with a history of nephrolithiasis (kidney stones). Avoid in patients known to be overproducers of uric acid.
Dosing	Normal dose: start ≤ 100 mg/day (50 mg/day in patients with a CrCl ≤ 30 mL/min). Increase dose every few weeks (no sooner than weekly) based on serum uric acid level, to control symptoms and with a goal uric acid level ≤ 6 mg/dL. Give in divided doses for doses > 300 mg/day. Avoid doses > 800 mg/day in patients with normal renal function. Max dose of 200 mg/day in patients with CrCl between 10 and 20 mL/min. However, it may be necessary to use > 300 mg/day in this patients with close monitoring.	Normal dose: 40 mg once daily for two weeks, increase to 80 mg once daily if uric acid is not < 6 mg/dL. Can start with 80 mg once daily per Canadian labeling. Limit dose to 40 mg/day in patients with CrCl 15 mL/min to 29 mL/min. Use in patients with CrCl less than 30 mL/min is NOT recommended.	Normal dose: 250 mg twice daily (or 500 mg once daily) for one week, then 500 mg twice daily. Dose can be increased in 500 mg/day increments monthly to a maximum daily dose of 2,000 mg. Avoid use in patients with CrCl < 50 mL/min. due to lack of safety and efficacy data. Efficacy may be limited if CrCl <6 0 mL/min.
Adverse effects and patient education	Rare hypersensitivity syndrome (< 1% of patients; usually within two months of starting therapy or dose increase). Can include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). Consider HLA-B*5801 testing before starting allopurinol in patients at high risk (e.g. Han Chinese, Thai, Korean, African American). Rare increased LFTs. Advise patients, especially those with CKD, to monitor for hypersensitivity reactions.	Increased LFTs and liver failure. Check LFTs at baseline, after two and four months of therapy, and then periodically (check at baseline and periodically. Check LFTs in patients reporting symptoms of liver injury (e.g. anorexia, dark urine, abdominal pain, jaundice). Advise patients to monitor for signs and symptoms of CV events (e.g. heart attack, stroke, and heart failure). Can consider changing to another medication if patients experience a CV event while taking febuxostat.	GI (nausea, vomiting, decreased appetite) Advise patients to take with food to minimize GI adverse effects.
Other considerations	Allopurinol 300 mg usually lowers uric acid by about 2 to 3.5 mg/dL (120 to 210 μmol/L). Limited data in patients on dialysis: Some recommend 300 mg after each dialysis session (this dose reduced urate levels by < 50%).	Febuxostat 80 mg usually lowers uric acid by about 4.5 mg/dL (270 μmol/L). Post-marketing signal of an increased risk of CV events in patients taking febuxostat compared to allopurinol.	Advantages: Long history of use Less expensive than febuxostat Disadvantages: Risk of kidney stones. Drug-drug interactions (e.g. NSAIDs, benzodiazepines, antivirals) Twice-daily dosing Can be combined with allopurinol or febuxostat in patients unable to reach uric acid goals.

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References

Khanna D, Fitzgerald JD, Khanna PP, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken). 2012;64(10):1431-1446.
Clinical Pharmacology powered by ClinicalKey. Tampa (FL): Elsevier. 2020. http://www.clinicalkey.com.
Rothschild B, 'Gout and Pseudogout Treatment & Management: Approach Considerations, Treatment of Acute Attacks, Treatment Of Chronic Gout' (medscape.com, 2020). https://emedicine.medscape.com/article/329958-treatment.