In an adult with gout, which should be used as first‑line urate‑lowering therapy—allopurinol or probenecid—and what are the appropriate dosing, contraindications, and renal function considerations for each?

Allopurinol vs Probenecid for Gout: First-Line Urate-Lowering Therapy

Allopurinol is the strongly recommended first-line urate-lowering therapy for all patients with gout, including those with chronic kidney disease stage ≥3, whereas probenecid is reserved for patients who cannot tolerate xanthine oxidase inhibitors or have moderate-to-severe CKD where allopurinol/febuxostat are strongly preferred. 1

First-Line Agent Selection

• Allopurinol is strongly recommended over all other urate-lowering therapies as the preferred first-line agent for all patients with gout, based on moderate-quality evidence from the 2020 American College of Rheumatology guidelines. 1

• Xanthine oxidase inhibitors (allopurinol or febuxostat) are strongly recommended over probenecid for patients with moderate-to-severe chronic kidney disease (stage ≥3). 1

• The preference for allopurinol is based on its extensive safety profile, lower cost, and broader applicability across different patient populations compared to probenecid. 1

Allopurinol Dosing Protocol

Initial Dosing Strategy

• Start allopurinol at ≤100 mg/day (and lower doses of ≤50 mg/day in patients with CKD stage ≥3) with subsequent dose titration every 2–4 weeks. 1

• This "start low, go slow" approach is strongly recommended to reduce the risk of allopurinol hypersensitivity syndrome and gout flares during initiation. 1

Dose Titration to Target

• Titrate allopurinol upward by 100 mg increments every 2–4 weeks until serum urate falls below 6 mg/dL (or <5 mg/dL in patients with tophi or chronic arthropathy). 1

• Most patients require 300–600 mg daily, and doses up to 800 mg/day are FDA-approved and may be necessary in severe hyperuricemia. 2, 3

• Do not limit allopurinol to 300 mg/day based solely on renal function—dose escalation can be performed safely even in CKD with appropriate monitoring. 3

Mandatory Prophylaxis

• Initiate colchicine prophylaxis (0.6 mg once or twice daily) concurrently with allopurinol and continue for at least 6 months, or for 3 months after achieving target serum urate if no tophi are present. 1

• This prophylaxis is strongly recommended to prevent acute gout flares triggered by urate mobilization during therapy initiation. 1

Probenecid Dosing and Indications

When to Consider Probenecid

• Probenecid is appropriate only when xanthine oxidase inhibitors are ineffective, not tolerated, or contraindicated—it is not a first-line agent. 4

• Probenecid may be added to allopurinol in refractory cases where maximum-dose allopurinol fails to achieve target serum urate. 5

Dosing Protocol

• Start probenecid at 500 mg once or twice daily with subsequent dose titration upward as needed. 1

• The combination of allopurinol plus probenecid produces a significantly greater hypouricemic effect than allopurinol alone, despite reducing plasma oxypurinol concentrations by 26%. 5

Efficacy Limitations

• Probenecid monotherapy achieves target serum urate (<6 mg/dL) in only 33% of patients in clinical practice, demonstrating moderate efficacy. 4

• When combined with allopurinol, probenecid achieves target in 37% of patients—still substantially lower than allopurinol dose escalation alone. 4

Renal Function Considerations

Allopurinol in CKD

• Allopurinol can be safely dose-escalated in CKD when started at lower initial doses (≤50–100 mg/day) and titrated slowly. 1, 3

• The outdated practice of capping allopurinol at 300 mg/day based on creatinine clearance is not evidence-based and suboptimally controls hyperuricemia. 2

• Patients with CKD may require doses above 300 mg/day to achieve target serum urate, and this can be accomplished safely with gradual titration. 1, 3

Probenecid in CKD

• Probenecid is strongly recommended against in moderate-to-severe CKD (stage ≥3) in favor of xanthine oxidase inhibitors. 1

• However, clinical data show that probenecid may be used in CKD with similar adverse event rates (13% in eGFR <50 mL/min vs 19% in eGFR ≥50 mL/min). 4

• The additional hypouricemic effect of probenecid appears lower in patients with renal impairment. 5

Contraindications and Safety

Allopurinol Contraindications

• Absolute contraindication: Known severe allopurinol hypersensitivity syndrome (AHS), which occurs rarely but can be life-threatening with mortality rates of 25–30%. 1

• Relative caution: Patients with HLA-B*58:01 allele (particularly in Korean and Han Chinese populations) have markedly increased risk of AHS and should be screened before initiation. 1

Probenecid Contraindications

• Absolute contraindications: History of nephrolithiasis or uric acid kidney stones, as probenecid increases urinary uric acid excretion. 1

• Strong recommendation against use: Moderate-to-severe CKD (stage ≥3), where xanthine oxidase inhibitors are strongly preferred. 1

Clinical Algorithm for Selection

1. For all patients with gout requiring urate-lowering therapy: Start allopurinol ≤100 mg/day (≤50 mg/day if CKD stage ≥3) with colchicine prophylaxis. 1

2. If allopurinol is not tolerated or contraindicated: Consider febuxostat as second-line xanthine oxidase inhibitor. 1

3. If both xanthine oxidase inhibitors fail or are contraindicated: Consider probenecid 500 mg once or twice daily, but only if eGFR ≥50 mL/min and no history of kidney stones. 1, 4

4. For refractory hyperuricemia on maximum-dose allopurinol: Add probenecid to allopurinol rather than switching agents. 5

5. Titrate to target serum urate <6 mg/dL (or <5 mg/dL if tophi present) and maintain prophylaxis for 3–6 months after achieving target. 1

Common Pitfalls to Avoid

• Do not cap allopurinol at 300 mg/day based solely on renal function—this outdated practice fails to adequately control hyperuricemia in most patients. 2

• Do not use probenecid as first-line therapy—it is less effective than allopurinol and contraindicated in CKD stage ≥3. 1

• Do not initiate urate-lowering therapy without concurrent prophylaxis—this markedly increases the risk of acute gout flares. 1

• Do not discontinue allopurinol during an acute gout flare if the patient is already on it—continue the urate-lowering therapy and treat the flare separately. 6

• Do not start allopurinol at high doses (≥300 mg/day)—this significantly increases the risk of hypersensitivity reactions and acute flares. 1