First of all, this study shows that benzbromarone is a very potent antihyperuricemic drug; in this cohort of patients using benzbromarone 100–200 mg/day, more than 90% of the patients have optimal sUr levels. With allopurinol standard dosage 200–300 mg/day, comparable effectiveness cannot be achieved for this group. The average allopurinol dosage (mean 243 mg/day) might be considered relatively low; however, (1) no efficacy data on allopurinol ≥600 mg/day are available in the literature; (2) dosages >300 mg/day are generally not advised because of increased risk of adverse drug reactions ; (3) benzbromarone (mean 138 mg/day) and probenecid (1,000 mg/day) could also be dosed higher.
It must be noted that every patient in this study was previously treated with benzbromarone, thereby introducing the possibility to overestimate the percentage of responders to benzbromarone. Furthermore, a dropout occurred in stage 1 of 38%, which may have influenced the outcome. The relatively high dropout rate was mainly due to the design of the study (cohort) in combination with the sudden need for alternative treatment. On the other hand, we found a mean relative decrease in sUr of 61% for benzbromarone and 36% for allopurinol, which corresponds well with values published in the literature of 54–58% for benzbromarone 80–125 mg/day and 27–44% for allopurinol 300 mg/day in patients not previously treated with benzbromarone [5, 15, 16, 23, 24].
This cohort consisted of more than 90% patients of uric acid underexcretor type. From a pathogenic point of view, it is suggested that allopurinol, as an inhibitor of uric acid production, would be more effective in overproducer-type gout. However, this is not supported by clinical data . Previous findings indicate that even in patients with apparently high uUr, there is a relative underexcretion of urate . Thus, when treatment goals are not achieved with allopurinol in this group of patients, combination with a uricosuric drug (e.g. benzbromarone, probenecid) might be very useful.
Adding probenecid to allopurinol contributed an additional 33% (CI 95%: 28–38%) decrease in sUr on average, resulting in reaching the target sUr for most patients (87% success). Thus, in finding an appropriate alternative therapy for benzbromarone, adding probenecid to allopurinol was proven to be an effective strategy. An interaction between allopurinol and probenecid is described in the literature , resulting in an increased clearance of oxipurinol, the active metabolite of allopurinol. However, our data do not support this finding to be clinically important, as the addition of probenecid to allopurinol decreased sUr with 31% on average.
In stage 1, five patients (10%) stopped allopurinol therapy because of adverse events related to allopurinol. Reported events were rash, pruritus, diarrhoea, nausea and dizziness, which are all well-known side effects of allopurinol. Becker et al.  found a similar rate (12%) of adverse events related to allopurinol.
There are few therapeutic options available to lower sUr to target levels other than the drugs used in this study. The uricosuric drug sulphinpyrazone is not widely used due to its adverse effects profile . Minor additive serum-lowering effects may be achieved by losartan or fenofibrate [27, 28]. The uricostatic febuxostat may be available soon. Recently, it was shown that when using febuxostat 80–120 mg/day, 47–66% of the patients reached sUr levels ≤0.30 mmol/l compared to 13% with allopurinol 300 mg/day . A new promising treatment option for patients with severe tophaceous gout is the development of recombinant uricase [29, 30] and pegylated recombinant uricase. Uricase-based drugs are potentially very effective but also very expensive drugs, so further (pharmacoeconomic) studies on optimizing antihyperuricemic therapy with old (out of patent) drugs, like benzbromarone, are warranted. At this moment, benzbromarone seems to be the most effective antihyperuricemic drug, and from our point of view, availability of benzbromarone in other countries would make treatment of difficult gout more successful .