Allopurinol for chronic gout

Evidence Summaries

Level of Evidence = B

Allopurinol appears to lower serum urate levels more effectively than placebo in subjects with gout.

The quality of evidence is downgraded by imprecise results (few patients and outcome events).

A Cochrane review 1 included 11 studies with a total of 4,531 subjects. The included studies compared allopurinol (various doses) with placebo (2 studies); febuxostat (4 studies); benzbromarone (2 studies); colchicine (1 study); probenecid (1 study); continuous versus intermittent allopurinol (1 study), and different doses of allopurinol (1 study).

Efficacy data from the 2 studies that compared allopurinol with placebo could not be pooled due to lack of clinical homogeneity with differences in study design. Safety data from these 2 studies was pooled. One study (n=1,072) compared a dose of up to 300 mg of allopurinol (dependent on renal function) with placebo, and found no difference in the proportion of participants requiring treatment for gout flares in the first 8 weeks (during the period of co-administration of naproxen 250 mg twice daily or colchicine 0.6 mg daily): 61/268 (23%) in allopurinol group versus 27/134 (20%) in placebo group; RR 1.13, 95% CI 0.76 to 1.69. The authors also reported no between-group difference in gout flares between weeks 8 and 28 although these data were not provided. Participants in the allopurinol group were more likely to achieve a target serum urate level less than 6.0 mg/dL (357 µmol/L): 103/263 in allopurinol group versus 1/127 in placebo group; RR 49.25, 95% CI 6.95 to 349.02. For the subgroup with impaired renal function, none of the participants in the allopurinol 100 mg daily group (1/10) or placebo group (0/5) achieved this target.

The second study (n=57) compared the initiation of allopurinol 300 mg during an acute attack of gout versus placebo for 10 days. After 10 days, participants in the placebo arm were also started on allopurinol 300 mg daily. There was no between-group difference in the rate of new or recurrent gout attacks between days 1 and 30 when allopurinol was compared with 10 days of placebo and then allopurinol: 2/26 (7.7%) in allopurinol group versus 3/25 (12%) in placebo group; RR 0.64, 95% CI 0.12 to 3.52. Both treatment groups also received colchicine for 90 days and indomethacin for 10 days from study commencement. Serum urate levels decreased rapidly in the allopurinol group, reaching less than 6.5 mg/dL (387 µmol/L) by day 10: 25/26 in allopurinol group versus 0/25 in placebo group; RR 49.11, 95% CI 3.15 to 765.58; NNTB was 1, 95% CI 1.04 to 1.35. There was no between-group differences with respect to pain reduction to day 10.

Neither study provided data for function, participant global assessment of treatment success or quality of life. Pooled analysis showed no difference in the number of participants who withdrew due to adverse events (AEs), or in serious adverse events (SAE), see table T1.


Table 1. Allopurinol compared with placebo for chronic gout
Outcome Follow-up Relative effect (95% CI) Assumed risk - Placebo Corresponding risk - Allopurinol (95% CI) Participants (studies)
Withdrawal due to adverse events 0–28 weeks RR 1.36 (0.61 to 3.08) 44 per 1000 60 per 1000 (26 to 136) 453 (2 studies)
Serious adverse events 0–28 weeks RR 1.93 (0.48 to 7.80) 13 per 1000 24 per 1000 (6 to 98) 453 (2 studies)
There was no difference in the incidence of acute gout attacks with allopurinol up to 300 mg daily versus febuxostat 80 mg daily over 8 to 24 weeks (table T2). More participants achieved target serum urate level with febuxostat 80 mg daily versus allopurinol 300 mg daily (NNTB with febuxostat 4). Two studies reported no difference in tophus regression between allopurinol and febuxostat over a 28- to 52-week period. The studies did not report pain reduction or function. There was no difference in the number of withdrawals due to AE or SAE.


Table 2. Allopurinol 100-300 mg daily compared with febuxostat 80 mg daily for chronic gout
Outcome Follow-up Relative effect (95% CI) Assumed risk - Febuxostat Corresponding risk - Allopurinol (95% CI) Participants (studies)
Acute gout attacks up to 24 weeks RR 0.89 (0.71 to 1.1) 233 per 1000 207 per 1000 (165 to 256) 1,136 (3 studies)
Proportion achieving target serum urate 24–52 weeks RR 0.56 (0.48 to 0.65) 697 per 1000 383 per 1000 (335 to 439) 2,618 (4 studies)
Withdrawal due to adverse effects 24–52 weeks RR 0.89 (0.62 to 1.26) 77 per 1000 68 per 1000 (48 to 97) 2,555 (3 studies)
Serious adverse effects 24–52 weeks RR 1.13 (0.71 to 1.82) 39 per 1000 44 per 1000 (28 to 71) 2,556 (3 studies)
There was no difference in the incidence of acute gout attacks with allopurinol up to 600 mg daily compared with benzbromarone up to 200 mg daily over a four-month period (0/30 with allopurinol versus 1/25 with benzbromarone; RR 0.28, 95% CI 0.01 to 6.58; 1 study, n=65). There was no difference in the proportion of participants achieving a target serum urate level with allopurinol versus benzbromarone (58% with allopurinol versus 74% with benzbromarone; RR 0.79, 95% CI 0.56 to 1.11; 2 studies, n=102). There was no difference in the number of participants who withdrew due to AE with allopurinol versus benzbromarone over a four- to nine-month period (6% with allopurinol versus 7% with benzbromarone; RR 0.80, 95% CI 0.18 to 3.58; 2 studies, n=91). There were no SAEs. The studies did not report tophi regression, pain and function.

A further safety assessment on allopurinol was performed by searching the safety registries. The FDA reported the incidence of adverse reactions was less than 1%, and that the most common adverse reaction to allopurinol is skin rash, recommending treatment be discontinued immediately if a rash develops. In some cases, a skin rash may be followed by more severe hypersensitivity reactions such as exfoliative, urticarial and purpuric lesions as well as Stevens-Johnson syndrome (erythema multiforme exudativum) or generalised vasculitis or both.

References

1. Seth R, Kydd AS, Buchbinder R et al. Allopurinol for chronic gout. Cochrane Database Syst Rev 2014;(10):CD006077.  [PMID:25314636]


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