Can allopurinol (hypoxanthine guanine phosphoribosyltransferase inhibitor) worsen gout?

Can Allopurinol Worsen Gout?

Yes, allopurinol can temporarily worsen gout symptoms by triggering acute gout attacks during the initial phase of treatment, but this effect is transient and proper initiation strategies can minimize this risk. 1, 2

Mechanism of Initial Gout Flares

Allopurinol works by inhibiting xanthine oxidase, which:

• Reduces serum uric acid (SUA) levels
• Causes rapid shifts in urate levels during initiation
• These rapid shifts can mobilize urate crystals from deposits, triggering acute attacks

Early clinical studies reported that approximately 6% of patients experienced increased acute gout attacks when starting allopurinol, though current data suggests this has decreased to less than 1% with modern initiation protocols 1.

Proper Initiation to Minimize Risk

The risk of allopurinol triggering gout flares can be significantly reduced through:

1. Low starting dose approach:

   • Start at 100 mg daily (or 50 mg in CKD stage ≥3) 3
   • Increase by 100 mg increments every 2-4 weeks 2
   • Gradually titrate until target SUA is achieved

2. Mandatory prophylaxis during initiation:

   • Always use anti-inflammatory prophylaxis (colchicine 0.5-1 mg/day) 3
   • Continue prophylaxis for 3-6 months after starting allopurinol 3
   • Adjust colchicine dose in patients with renal impairment

3. Regular monitoring:

   • Check SUA levels every 2-4 weeks during titration 3
   • Target SUA <6 mg/dL (360 μmol/L) for most patients 3
   • Target SUA <5 mg/dL (300 μmol/L) for severe tophaceous gout 3

Research Evidence on Initiation Strategies

Recent studies have challenged the traditional belief that allopurinol must be avoided during acute gout attacks:

• A 2015 randomized clinical trial found no statistically significant difference in days to resolution between patients who started allopurinol during an acute attack (15.4 days) versus those who received placebo (13.4 days) 4

• A 2012 study showed no significant difference in daily pain, recurrent flares, or inflammatory markers when allopurinol was initiated during an acute gout attack compared to delayed initiation 5

Dose Titration Effectiveness

Proper dose titration is critical for both efficacy and safety:

• Up to 97% of patients can achieve target urate levels with appropriate dose titration 6
• Most patients (65%) achieve control after just one 100-mg up-titration 6
• Mean fall in urate levels after a single 100-mg dose increase is approximately 71 μmol/L 6

Safety Considerations

When initiating allopurinol, be aware of these important safety considerations:

• Allopurinol hypersensitivity syndrome (AHS) risk increases with higher starting doses relative to renal function 7
• Starting dose should not exceed 1.5 mg per unit of estimated GFR to reduce AHS risk 7
• Patients with renal impairment require lower starting doses and more careful titration 2, 3
• Consider HLA-B*5801 testing before initiating allopurinol in high-risk populations (Korean patients with CKD stage ≥3, Han Chinese, or Thai descent) 3

Common Pitfalls to Avoid

1. Starting at too high a dose
2. Failing to provide anti-inflammatory prophylaxis during initiation
3. Inadequate dose titration to reach target SUA
4. Premature discontinuation of therapy
5. Insufficient patient education about potential initial flares

Bottom Line

While allopurinol can temporarily worsen gout symptoms during initiation, this effect can be minimized with proper dosing strategies and prophylaxis. The long-term benefits of allopurinol in reducing SUA levels and preventing future gout attacks far outweigh the temporary risk of flares during initiation. Using the "go low, go slow" approach with appropriate prophylaxis is the key to successful allopurinol therapy.