Background - what is chronic gout and what are uricosuric medications?
Chronic gout is a type of inflammatory arthritis caused by high levels of uric acid in the blood leading to crystal formation in the joints and repeated attacks of acute gout. Treatment of chronic gout can make acute gout attacks less likely.
Uricosuric medications work to lower blood uric acid levels by increasing the amount of uric acid that is eliminated via the kidneys.
This summary of a Cochrane review presents what we know from research about the effect of uricosuric medications for treating chronic gout. After searching for all relevant studies to May 2013, we found five studies. Most participants in these studies were male (81% to 100%), aged between 50 and 70 years and did not have significant kidney or liver disease. Two trials compared benzbromarone with allopurinol, two trials compared benzbromarone with probenecid and one trial compared allopurinol with probenecid. We found no studies comparing uricosuric medications with placebo, or with newer urate-lowering therapies such as febuxostat or pegloticase. We restricted reporting of results here to benzbromarone versus allopurinol, as allopurinol is a commonly used first-line treatment for gout.
Key results - what happens to people with chronic gout who take uricosuric medications
Benzbromarone compared with allopurinol:
Acute gout attacks:
- 4 fewer people out of 100 had acute gout attacks after four months' treatment with allopurinol compared with benzbromarone.
- 4 people out of 100 on benzbromarone had acute gout attacks.
- 0 people out of 100 on allopurinol had acute gout attacks.
Proportion achieving normal serum urate:
- 17 more people out of 100 achieved a normal serum urate level after for months on benzbromarone compared with allopurinol.
- 76 people out of 100 on benzbromarone achieved a normal serum urate level after four months.
- 60 people out of 100 on allopurinol achieved a normal serum urate level after four months.
Withdrawal due to side effects:
- 1 more person out of 100 stopped benzbromarone due to side effects compared with allopurinol.
- 8 people out of 100 stopped benzbromarone due to side effects.
- 6 people out of 100 stopped allopurinol due to side effects.
The trials did not report pain, function and tophus regression.
Quality of the evidence
Low-quality evidence indicated that there was no important difference in acute gout attacks, or in the number of people who had to stop the medication due to a side effect between benzbromarone and allopurinol. Moderate-quality evidence from two studies showed that both medications reduced uric acid levels to a similar degree. Benzbromarone was no more likely than probenecid to result in acute gout attacks, but may result in fewer withdrawals due to side effects (low-quality evidence), and is probably more likely to reduce uric acid levels to a normal level (moderate-quality evidence). The trials did not measure pain, function and tophus regression.
Low-quality evidence from a single study indicated that probenecid was no more likely to result in acute gout attacks than allopurinol. Further research is highly likely to impact on this estimate. This study did not measure proportion of people achieving a normal serum urate level, pain reduction, function, tophus regression or the number of people stopping the medication due to side effects.
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimates.
We found no studies that looked at sulphinpyrazone in treating chronic gout. We do not have information about the effects of uricosuric medications in particular groups of patients such as people with impaired kidney function or with different levels of uric acid. Possible side effects of uricosuric medications may include rash, stomach upset, flushing, dizziness, headache or acute gout attacks. Rare complications may include liver failure, kidney stones, anaemia or allergic reaction.
There was moderate-quality evidence that there is probably no important difference between benzbromarone and allopurinol at achieving serum urate normalisation, but that benzbromarone is probably more successful than probenecid at achieving serum urate normalisation in people with gout. There is some uncertainty around the effect estimates, based on low-quality evidence from only one or two trials, on the number of acute gout attacks, the number of withdrawals due to adverse events or the total number of participants experiencing adverse events when comparing benzbromarone with allopurinol. However, when compared with probenecid, benzbromarone resulted in fewer withdrawals due to adverse events and fewer participants experiencing adverse events. Low-quality evidence from one small study indicated uncertain effects in the incidence of acute gout attacks when comparing probenecid with allopurinol therapy. We downgraded the evidence because of a possible risk of performance and other biases and imprecision.
Uricosuric agents have long been used in the treatment of gout but there is little evidence regarding their benefit and safety in this condition.
To assess the benefits and harms of uricosuric medications in the treatment of chronic gout.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 4, 2013), Ovid MEDLINE and Ovid EMBASE for studies to the 13 May 2013. We also searched the World Health Organization Clinical Trials Registry, ClinicalTrials.gov and the 2011 to 2012 American College of Rheumatology and European League against Rheumatism abstracts. WE considered black box warnings and searched drug safety databases to identify and describe rare adverse events.
We considered all randomised controlled trials (RCTs) or quasi-randomised controlled trials (controlled clinical trials (CCTs)) that compared uricosuric medications (benzbromarone, probenecid or sulphinpyrazone) alone or in combination with another therapy (placebo or other active uric acid-lowering medication, or non-pharmacological treatment) in adults with chronic gout for inclusion.
Two review authors independently selected the studies for inclusion, extracted data and performed a risk of bias assessment. Main outcomes were frequency of acute gout attacks, serum urate normalisation, study participant withdrawal due to adverse events, total adverse events, pain reduction, function and tophus regression.
The search identified four RCTs and one CCT that evaluated the benefit and safety of uricosurics for gout. One study (65 participants) compared benzbromarone with allopurinol for a duration of four months; one compared benzbromarone with allopurinol (36 participants) for a duration of nine to 24 months; one study (62 participants) compared benzbromarone with probenecid for two months and one study (74 participants) compared benzbromarone with probenecid. One study (37 participants) compared allopurinol with probenecid. No study was completely free from bias.
Low-quality evidence from one study (55 participants) comparing benzbromarone with allopurinol indicated uncertain effects in terms of frequency of acute gout attacks (4% with benzbromarone versus 0% with allopurinol; risk ratio (RR) 3.58, 95% confidence interval (CI) 0.15 to 84.13), while moderate-quality evidence from two studies (101 participants; treated for four to nine months) indicated similar proportions of participants achieving serum urate normalisation (73.9% with benzbromarone versus 60% with allopurinol; pooled RR 1.27, 95% CI 0.90 to 1.79). Low-quality evidence indicated uncertain differences in withdrawals due to adverse events (7.1% with benzbromarone versus 6.1% with allopurinol; pooled RR 1.25, 95% CI 0.28 to 5.62), and total adverse events (20% with benzbromarone versus 6.7% with allopurinol; RR 3.00, 95% CI 0.64 to 14.16). The study did not measure pain reduction, function and tophus regression.
When comparing benzbromarone with probenecid, there was moderate-quality evidence based on one study (62 participants) that participants taking benzbromarone were more likely to achieve serum urate normalisation after two months (81.5% with benzbromarone versus 57.1% with probenecid; RR 1.43, 95% CI 1.02 to 2.00). This indicated that when compared with probenecid, five participants needed to be treated with benzbromarone in order to have one additional person achieve serum urate normalisation (number needed to treat for an additional beneficial outcome (NNTB) 5). However, the second study reported no difference in the absolute decrease in serum urate between these groups after 12 weeks. Low-quality evidence from two studies (129 participants) indicated uncertain differences between treatments in the frequency of acute gout attacks (6.3% with benzbromarone versus 10.6% with probenecid; pooled RR 0.73, 95% CI 0.09 to 5.83); fewer withdrawals due to adverse events with benzbromarone (2% with benzbromarone versus 17% with probenecid; pooled RR 0.15, 95% CI 0.03 to 0.79, NNTB 7) and fewer total adverse events (21% with benzbromarone versus 47% with probenecid; pooled RR 0.43, 95% CI 0.25 to 0.74; NNTB 4). The studies did not measure pain reduction, function and tophus regression.
Low-quality evidence based on one small CCT (37 participants) indicated uncertainty around the difference in the incidence of acute gout attacks between probenecid and allopurinol after 18 to 20 months' treatment (53% with probenecid versus 55% with allopurinol; RR 0.96, 95% CI 0.53 to 1.75). The study did not measure or report the proportion achieving serum urate normalisation, pain reduction, function, tophus regression, withdrawal due to adverse events and total adverse events.