When is allopurinol (xanthine oxidase inhibitor) typically started in patients with gout?

When to Start Allopurinol in Gout

Allopurinol should be initiated in patients with recurrent gout flares (≥2 per year), presence of tophi, radiographic damage from gout, urate arthropathy, renal stones, or serum uric acid >8.0 mg/dL, and can be started during an acute flare rather than waiting for resolution. 1, 2, 3

Strong Indications for Starting Allopurinol

The following conditions warrant definitive initiation of urate-lowering therapy with allopurinol:

• Frequent gout flares: Two or more attacks per year 1, 2, 3
• Tophi: Presence of one or more subcutaneous tophi 1, 2, 3
• Radiographic damage: Any imaging evidence of joint damage attributable to gout 1, 3
• Urate arthropathy: Chronic gouty arthritis 1, 3
• Renal stones: History of uric acid nephrolithiasis 1, 2, 3
• Severe hyperuricemia: Serum uric acid >8.0 mg/dL (>480 μmol/L) 1, 2

Conditional Indications for Starting Allopurinol

The following scenarios support initiating allopurinol, though clinical judgment plays a larger role:

• First gout flare with high-risk features: Chronic kidney disease stage ≥3, serum urate >9 mg/dL, or history of urolithiasis 3
• Young age at onset: Patients <40 years old at first gout diagnosis should be considered for early ULT 2, 3
• Infrequent attacks with comorbidities: Patients with >1 previous flare but <2 per year who have hypertension, ischemic heart disease, heart failure, or renal impairment 1, 2, 3

The EULAR guidelines emphasize discussing ULT with every patient at first gout diagnosis, particularly those with comorbidities, as these conditions increase flare frequency and severity. 1, 2

Timing: Starting During vs. After an Acute Flare

You can start allopurinol during an acute gout flare—you do not need to wait for the flare to resolve. 1, 3

• The 2020 ACR guidelines conditionally recommend initiating ULT during a gout flare rather than delaying until after resolution 1, 3
• Two randomized trials demonstrated that starting allopurinol during an acute attack does not prolong flare duration or worsen severity compared to delayed initiation 1, 4
• Starting during the flare prevents the risk of patients not returning for delayed initiation and capitalizes on patient motivation when symptoms are acute 3

Common pitfall to avoid: The traditional teaching to wait 2 weeks after flare resolution is outdated and may lead to delayed appropriate therapy. 1, 3

However, the supporting evidence used allopurinol doses of 200-300 mg, so these findings may not apply to higher initial doses or more potent urate-lowering strategies. 1

Initial Dosing Strategy

Start allopurinol at a low dose and titrate slowly:

• Normal renal function: Start at 100 mg daily 1, 2
• CKD stage ≥3: Start at ≤50 mg daily 1, 2
• Severe renal impairment: Consider 100 mg every other day or 300 mg twice weekly 5

Dose escalation: Increase by 100 mg increments every 2-4 weeks until serum uric acid target is achieved 1, 2

Maximum doses: Up to 800 mg daily for normal renal function; lower maximums for CKD based on creatinine clearance 2, 5

The low-dose start with gradual titration minimizes the risk of allopurinol hypersensitivity syndrome and reduces flare frequency during initiation. 1, 5 The Patient Panel in the ACR guidelines strongly preferred this safer approach even if it required more visits and blood draws. 1

Mandatory Anti-inflammatory Prophylaxis

You must prescribe concomitant anti-inflammatory prophylaxis when starting allopurinol. 1, 2, 3

• Options: Colchicine (0.5-1 mg/day), low-dose NSAIDs, or prednisone/prednisolone 1, 2, 3
• Duration: Continue for 3-6 months after ULT initiation 1, 2, 3
• Rationale: Prophylaxis reduces the frequency and severity of paradoxical flares that occur as urate mobilizes from tissue deposits 1, 5

Shorter durations (<3 months) are associated with flares upon cessation, so ongoing evaluation and extended prophylaxis may be needed if flares persist. 1

Target Serum Uric Acid Levels

Standard target: Maintain serum uric acid <6 mg/dL (360 μmol/L) lifelong 1, 2, 3

Lower target for severe gout: <5 mg/dL (300 μmol/L) for patients with tophi, chronic arthropathy, or frequent attacks until complete crystal dissolution occurs 1, 2, 3

Avoid long-term very low levels: Do not maintain serum uric acid <3 mg/dL long-term due to potential neuroprotective effects of uric acid 1

Monitor serum uric acid every 2-4 weeks during dose titration to implement the treat-to-target strategy. 2

Special Considerations

Chronic kidney disease: Allopurinol remains the preferred first-line agent even in CKD stage ≥3, though starting doses should be lower and titration more cautious. 1, 2 Patients with CKD may accumulate the active metabolite oxypurinol, potentially achieving greater urate lowering at lower doses. 6

HLA-B*5801 testing: Consider testing before starting allopurinol in patients of Southeast Asian descent (Han Chinese, Korean, Thai) or African American patients due to higher risk of allopurinol hypersensitivity syndrome. 3

Lifelong therapy: Allopurinol should be continued indefinitely, as discontinuation leads to recurrence of gout flares in approximately 87% of patients within 5 years. 2

If already on allopurinol during a flare: Continue the current dose without interruption to maintain steady urate-lowering effects and prevent fluctuations that could trigger additional flares. 3