Results

One hundred and twenty consecutive patients with primary gout (118 men, two women) were included in the analysis. Their mean (SD) age was 52.7 (12.4) years (median 55) and disease duration was 13.4 (8.1) years (median 12). Allopurinol had been administered for a mean of 3.3 (4.5) years (median 1.2) in daily doses ranging from 100 mg to 450 mg (table 1). Concomitant diseases were: hypertension in 33 (54%), hyperlipidaemia in 25 (43%), and diabetes mellitus in 10 (16%). Renal failure, as defined by a creatinine clearance rate of 50 ml/min or less, was diagnosed in 30 patients (44%).

Only five patients (4%, all men) from the whole group developed allopurinol related adverse reactions (table 2). Four patients had minor reactions within 5–32 months of starting treatment, consisting of a skin rash in two cases (both in group A), mild cutaneous vasculitis in one (group B), and fixed pigmented drug eruption in one case (group B). The only serious adverse event was AHS which was diagnosed within 2 weeks of starting allopurinol treatment in a 36 year old man in group A with a 16 year history of tophaceous gout and a normal creatinine clearance rate (reported elsewhere).12In all patients, including the latter after drug desensitisation, allopurinol re-challenge with escalating doses did not result in any adverse reactions. Thus, three adverse reactions, including one serious event, occurred in group A and two in group B (5.8% versus 3.0%, p=NS).

Most variables were further analysed by group. Group A comprised 52 patients (all men) and group B consisted of 68 patients (66 men and two women). The mean age and duration of disease in group A was significantly lower than in group B (48.3 (10.9) yearsv 56.2 (12.1) years, p=0.002; and 11.7 (6.4) years v 15 (9.0) years, p=0.05). Serum uric acid levels did not differ between groups during the follow up period (group A: 400 (314) μmol/l (median 390); group B: 390 (172) μmol/l (median 360), p=NS). The mean duration of treatment with allopurinol was similar at the time of the analysis (2.3 (3.3) years in group A, 3.7 (4.8) years in group B). No patient in group A but 30 in group B (44%) had renal failure. The prevalence of hyperlipidaemia, hypertension, and diabetes mellitus in the two groups was similar (table 1), although there were several differences in laboratory test results between the two groups. Thirty four patients in group A (65%) and 49 in group B (72%) received additional treatment, mainly antihypertensive drugs (angiotensin converting enzyme inhibitors or calcium blockers) and non-steroidal anti-inflammatory drugs, but none received diuretics, ampicillin, or azathioprine.

Discussion

The results of this study show that, although more than half the patients were treated with allopurinol in doses higher than those corresponding to their creatinine clearance rate, the frequency of adverse events was very low and similar to that found in patients given doses adjusted to the creatinine clearance rate.2 ,8 This finding may be relevant when treating populations with gout in which there is a high prevalence of renal failure. Differences from previous reports may be related to race, age, concomitant medications and morbidity, and also to study design. Most previous reports have described individual cases or series of patients with adverse events related to allopurinol but, interestingly, only a minority had gout1-7 and patients receiving allopurinol who did not develop adverse events were not included. There is only one study reporting allopurinol associated adverse reactions in hospitalised patients with comorbid conditions and receiving multiple treatments.5

The proposal by Hande et al 7was based on six of their patients and 72 cases with severe allopurinol toxicity reported in the literature. Only 44% of these patients had a clear indication for allopurinol; 81% in whom data were available had renal failure before starting allopurinol; 49% were receiving concomitant diuretic treatment; and serious adverse events associated with allopurinol appeared within 3 weeks of treatment. Handeet al 7 showed that the renal clearance of oxypurinol was directly proportional to the creatinine clearance rate and attributed the appearance of severe toxicity to this finding. They therefore proposed guidelines to dose adjustment and these are widely recommended.8 ,11

Although the retrospective nature of our study limits its scope, our findings challenge the role of the prolonged half life and raised serum concentrations of oxypurinol in the pathogenesis of serious adverse reactions. This issue should be further investigated and tested against a number of other factors implicated in the pathogenesis of serious toxicity.7 ,13

Whether physicians follow any guideline for adjusting the dose of allopurinol according to the creatinine clearance rate is unknown. In the 1980s more than five million patient years of treatment were accumulated and 240 million doses of allopurinol were prescribed or 70 tonnes ingested each year for a variety of conditions.2 We believe that a significant proportion of patients with a low creatinine clearance rate seen in general practice receive non-adjusted doses of allopurinol, but severe toxicity is rare. In contrast, minor adverse reactions to allopurinol probably occur in 1.8–2.0% of patients receiving the drug.2 ,5 ,14 The cause of severe toxicity to allopurinol, including AHS, is unknown. Hypersensitivity, genetic predisposition, and a number of factors such as age, concomitant diseases, and medications like ampicillin and diuretics are likely to play a role in its pathogenesis.2 ,14 ,15

One recent report16 suggests that benzobromarone could be effective as a urate lowering drug in patients with gout, decreasing excretion of uric acid, and renal impairment but, unfortunately, it is not yet available in all countries.

In conclusion, from the results of our study we suggest the following recommendations for allopurinol treatment: (1) Verify that there is a clear indication for allopurinol treatment. (2) Start allopurinol in doses according to the creatinine clearance rate. (3) Check for concomitant diseases or treatment associated with serious adverse events in patients requiring higher doses of allopurinol. (4) In patients for whom no other urate lowering drug is available, the dose of allopurinol should be increased with caution.