Effectiveness of interventions for the treatment of acute and prevention of recurrent gout a systematic review

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1 Rheumatology Advance Access published April 21, 2006 Rheumatology 2006; 1 of 10 doi: /rheumatology/kel071 Concise Report Effectiveness of interventions for the treatment of acute and prevention of recurrent gout a systematic review S. Sutaria, R. Katbamna and M. Underwood Objective. To determine the evidence for the effectiveness of treatments for acute gout and the prevention of recurrent gout. Method. Seven electronic databases were searched for randomized controlled trials of treatments for gout from their inception to the end of No language restrictions were applied. All randomized controlled trials of treatments routinely available for the treatment of gout were included. Trials of the prevention of recurrence were included only if patients who had had gout and had at least 6 months of follow-up were studied. Results. We found 13 randomized controlled trials of treatment for acute gout, two of which were placebo controlled. Colchicine was found to be effective in one study; however, the entire colchicine group developed toxicity. The only robust conclusion from studies of non-steroidal anti-inflammatory drugs is that pain relief from indometacin and etoricoxib are equivalent. We found one randomized controlled trial, reported only as a conference abstract, of recurrent gout prevention. Conclusion. The shortage of robust data to inform the management of a common problem such as gout is surprising. All of the drugs used to treat gout can have serious side effects. The incidence of gout is highest in the elderly population. It is in this group, who are at a high risk of serious adverse events, that we are using drugs of known toxicity. The balance of risks and benefits for the drug treatment of gout needs to be reassessed. KEY WORDS: Gout, Treatment, Systematic review. Introduction Gout is a common problem affecting 1% of adult males in developed countries [1]. Recurrent attacks of gout are common. It is the commonest cause of inflammatory joint disease in men aged over 40 yrs; increasing obesity and an ageing population mean that it is becoming more frequent [2, 3]. Gout is essentially a disorder of urate metabolism [4]; however, diet and alcohol intake can affect its incidence [5, 6]. Deposition of urate crystals in hyperuricaemic individuals results in acute gout, characterized by agonizing pain and inflammation of rapid onset, most frequently affecting the first metatarsophalangeal joint, resulting in short-term disability [4]. Aims of the treatment are to relieve the pain and inflammation of the acute attack, and reduce the incidence of recurrent attacks. Internationally, there are considerable variations in management of acute and recurrent gout [7]. The commonest approaches to the treatment of acute gout are non-steroidal anti-inflammatory drugs (NSAIDs) and colchicine. The side effects of these drugs, particularly in the frail, elderly population, who have the highest incidence of acute gout, can be serious. The commonest approach to the prevention of recurrent gout is to use allopurinol, a xanthine oxidase inhibitor. Allopurinol can have serious side effects such as allopurinol hypersensitivity syndrome [8, 9]. We present a systematic review of the randomized controlled trial evidence for the treatment and prevention of recurrent, acute gout. Method Identification of randomized controlled trials We sought to identify all randomized controlled trials of currently available drug treatments, lifestyle and other interventions for the treatment of acute gout and the prevention of recurrent gout. Two of us (S.S. and R.K.), working independently, researched the following electronic databases: Medline, PubMed, Cochrane Controlled Trials Register, ISI Web of Science, Embase, and AMED, from inception to the end of 2004 for all randomized controlled trials of gout treatment using the following search strategy: (gout* or uric* or urate* or hyperuric* or podagra) AND (random* or control* or clinical trial* or placebo* or intervention* or allocat* or blind*). No language or date restrictions were used. Citation tracking from identified trials and reviews identified additional randomized controlled trials. We combined the reference lists using Reference Manager (Version 10.1). Still working independently, the two researchers screened titles and abstracts to identify articles for retrieval; they also independently screened retrieved articles for inclusion. One of us (M.U.) mediated disagreements. We excluded non-randomized studies and studies in which one or more intervention is not routinely available for treating gout. These studies are briefly summarized. Downloaded from at Pennsylvania State University on February 27, 2014 Barts and The London, Queen Mary, University of London, Institute of Health Sciences, London, UK. Submitted 16 October 2005; revised version accepted 7 February Correspondence to: Shailen Sutaria, Barts and The London, Queen Mary, University of London, Institute of Health Sciences, London, UK. shailen000@yahoo.co.uk 1of10 ß The Author Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please journals.permissions@oxfordjournals.org

2 2of10 S. Sutaria et al. Trials of acute gout treatments We included all randomized controlled trials that included subjects with acute gout (however defined) and compared an active intervention with no treatment, placebo or another active intervention. Our primary outcomes of interest were pain at 24 and 48 h or the nearest equivalent. Our secondary outcomes were any other patient-centred outcomes reported by the authors. Additionally, we extracted any reported adverse event data. Trials of prevention of recurrent gout We included all randomized controlled trials of prevention of recurrent gout in subjects with at least one previous attack of acute gout (however defined) who had at least 6 months of treatment and follow-up. Our primary outcome of interest was incidence of recurrent gout and our secondary outcome was difference in serum urate between the intervention and control groups. Additionally, we extracted any reported adverse event data. Quality assessment Study quality was assessed using the Jadad criteria [10]. Each included study was rated on a 0 5 scale (0 ¼ low quality, 5 ¼ high quality). Results Initial searches identified 9854 references. We identified 13 studies of treatment for acute gout and one study of the prevention of recurrent gout that met our entry criteria (Table 1). Excluded studies are summarized in Table 2. A flow diagram of studies is provided in Fig. 1. Treatment of acute gout Methodological quality Most of the research was of poor quality. Only 4/13 included studies were of high quality, a Jadad score of 4/5 or 5/5 [11 14]. The median number of participants per study was 34 (range ). Only two studies had sample size calculations [12, 14]. Typically, the quality of reporting was poor with insufficient detail to understand the analyses. There was no consistent approach to reporting of results. NSAIDs We found one placebo-controlled trial of reasonable quality that compared tenoxicam 30 mg/day with placebo (n ¼ 30). The knee was affected in 14 cases and the great toe in only two cases. After 24 h, 67% of tenoxicam group had 50% reduction in pain compared with 26% of placebo group (P<0.05) [11]. However, at the end of the treatment (4 days), there was no significant difference between the groups. We found nine studies comparing two NSAIDs [12 20]. Two, both of high quality, were equivalence studies comparing etoricoxib and indometacin [12, 14]. Both studies pre-defined equivalence as the limits of the 95% confidence intervals for difference between the two groups for change in pain at days 2 5 to be no more than 0.5 Likert units, based on a four-point Likert scale. Both studies found indometacin and etoricoxib to have an equivalent effect on pain over days 2 5. Both studies reported fewer drug-related adverse events in the etoricoxib group. There were no differences in overall adverse events. The remaining seven studies were of generally poor quality. Only one [18] reported any differences in outcome; these were at one time point and unlikely to be of any clinical importance. Most of these studies were too small to detect any important differences. Colchicine We found one placebo-controlled trial of colchicine 1 mg initially, and then 0.5 mg every 2 h until resolution or toxicity occurred. After 24 h, 41% of the colchicine group and 9% of the placebo group had 50% reduction in pain since baseline (not significant). After 48 h, 73% of the colchicine group and 36% of the placebo group had 50% reduction in pain since baseline (P<0.05). Everyone in the colchicine group developed toxicity (median time to onset 24 h). In only 41% did 50% improvement occur before toxicity. Five of the control group experienced nausea [21]. Steroids and adrenocorticotrophic hormone We found no placebo-controlled trials of steroids or related compounds. We found one poor quality study comparing intramuscular adrenocorticotrophic hormone with intramuscular triamcinolone acetonide [22]. Effect on pain was not reported. There was no difference in time to complete resolution between the two groups. However, this study is probably too small to detect any important differences. Ice There is some evidence from one small study, with poor quality allocation concealment, that local ice provides additional relief when added to systemic treatment [23]. Prevention of recurrent gout We found no randomized controlled trials of lifestyle interventions, such as a low purine diet, weight loss or advice to reduce alcohol intake, in patients with gout that had either the incidence of recurrent gout or changes in serum urate as an outcome. Nor did we find any randomized controlled trials of allopurinol for the prevention of recurrent gout or that reported its long-term effect on serum urate. One small (14 subjects) study, reported only as a conference abstract, suggested that although sulphinpyrazone reduces serum urate it does not affect incidence of recurrent gout [24]. However, this study is probably too small to detect any important differences. Discussion The shortage of robust data for a common problem such as gout is surprising. Current regimens for the treatment and prevention of recurrent gout were developed several decades ago. It is possible that we have overlooked some relevant randomized controlled trials. Firstly, some early studies that have not been indexed would not be identified by our searches. However, extensive citation checking of review articles and included studies did not identify any additional included studies. Secondly, it is possible that there are unpublished randomized controlled trial data that were produced for licencing purposes. We did not have the resources to systematically identify any such studies from multiple manufacturers and regulatory authorities. We are re-assured that this has not introduced substantial bias into our findings because for some drugs, for example allopurinol [25, 26], naproxen [27], diclofenac [28] and etodolac [29], we identified contemporary papers reviewing the early experience of these drugs for gout; none reported relevant randomized studies. Downloaded from at Pennsylvania State University on February 27, 2014

3 TABLE 1. Randomized controlled trials of available gout treatments Study n Intervention compared a Diagnostic criteria Joints affected b Results Jadad score NSAID vs placebo for acute gout de la Torre [11] 30 Tenoxicam 40 mg vs placebo NSAID vs NSAID for acute gout Altman et al. [16] 59 Indometacin 225 mg for one day then 150 mg vs ketoprofen 450 mg for one day then 300 mg Dorfler [19] 10 Indometacin 300 mg (days 1 and 2), 200 mg (day 3), 180 mg (days 4 and 5) vs acemethacin 360 mg (days 1 and 2), 240 mg (day 3), 180 mg (days 4 and 5) Eberl and Dunky [15] 20 Indometacin 200 mg for one day then 150 mg vs meclofenamate 900 mg for one day then 300 mg daily Klumb et al. [20] 34 Indometacin 200 mg (day 1), 150 mg (day 2 4), 100 mg (days 5 7) vs nimesulide 400 mg (day 1), 300 mg (days 2 4), 200 mg (day 5 7) Lederman [17] 60 Etodolac 600 mg vs naproxen 1500 mg Clinical criteria þ crystals c or hyperuricaemia Crystals or clinical criteria Knee (14), ankle (7), wrists (4), elbow (3), big toe (2) Not stated After one day: 50% reduction in spontaneous pain seen in 67% of tenoxicam and 26% of placebo group (P<0.05). After four days: 50% reduction in spontaneous pain seen in 100% of both groups. After one day: 50% reduction in pain on mobilization of affected joint seen in 27% of tenoxicam and 7% of placebo group (P<0.05). After 4 days: 50% reduction in pain on mobilization reported by 87% of tenoxicam and 93% of placebo group (NS). Adverse events: 2/15 in placebo group. None reported in tenoxicam group. Measured on a 0 3 scale (0 ¼ no pain, 3 ¼ severe) mean pain after one day 0.91 for indometacin and 10.8 for ketoprofen. 70% of indometacin and 76% of ketoprofen reported good improvement after one day. No statistically significant difference in outcome measures. Adverse events: 16/30 in indometacin and 15/29 in ketoprofen group. Not stated Not stated Complete pain relief was seen at a mean of 3.75 days in acemethacin group and 1.06 days in indometacin group. No statistical test applied. Adverse events: None reported in acemethacin group, one reported in indometacin group. Previous history þ hyperuricaemia Crystals or hyperuricaemia þ history Previous history þ hyperuricaemia Knee (8), big toe (7), ankle (4), wrists (1), thumb (1) Knee (31%), ankle (27%), big toe (27%), wrist (12%), elbow (3%) Not stated After one day pain improved by 9% in indometacin group and by 16% in meclofenamate group. After two days the improvements were 22 and 33%, respectively. No statistical test applied. Adverse events: 50% of indometacin and 20% of meclofenamate group. Rest pain measured on 0 5 visual scale. At day 3 rest pain 0.75 in nimesulide group and 0.71 in indometacin group. At day 7 rest pain 0 in nimesulide group and 0.13 in indometacin group. No statistically significant difference. Adverse events: 17/34 consultations in indometacin group, 14/39 consultations in nimesulide group. Two-day pain data presented graphically only. No statistically significant difference in any outcome measures. Adverse events:1/29 in etodolac group. None reported in naproxen group Continued. Intervention for the treatment of acute and prevention of recurrent gout 3of10 Downloaded from at Pennsylvania State University on February 27, 2014

4 TABLE 1. Continued Study n Intervention compared a Diagnostic criteria Joints affected b Results Jadad score Maccagno et al. [18] 61 Etodolac 600 mg vs naproxen 1000 mg Schumacher et al. [12] 150 Etoricoxib 120 mg vs indometacin 150 mg Shrestha et al. [13] 20 Single dose intramuscular ketorolac 60 mg vs single dose oral indometacin. Followed by indometacin for both groups Rubin et al. [14] 189 Etoricoxib 120 mg vs indometacin 150 mg Colchicine vs placebo for acute gout Ahern et al. [21] 43 Colchicine 1 mg initially then 0.5 mg every 2 h vs placebo Previous history þ hyperuricaemia Not stated ACR criteria Great toe (55%), other (36%), ankle (32%), knee (27%) Measured on a 1 5 scale (1 ¼ none, 5 ¼ very severe) after two days mean pain was 2.6 in etodolac group and 2.8 in naproxen group (NS). After two days 81% of etodolac group and 53% of naproxen group reported one or more point improvement in patients global assessment, measured on a 1 5 scale (1 ¼ very good 5 ¼ very poor) (no statistical test applied). After four days etodolac is reported to have a statistically significant greater benefit than indometacin on tenderness, range of motion and physician global assessment. Data are presented graphically only. These may be chance findings as a result of multiple comparisons. Adverse events: 3/31 in etodolac and 2/30 in naproxen group. Difference in pain days 2 5, 0.11 (95% CI 0.14, 0.35). Within pre-defined bounds for equivalence ( ). Difference in patients global assessment of response on 0 4 scale (0 ¼ excellent, 4 ¼ poor) over days 2 8 was 0.10 (95% CI 0.22, 0.41). Adverse events: 35/75 of etoricoxib and 45/75 of indometacin groups had adverse clinical experiences (P ¼ 0.141). 17/75 etoricoxib and 35/75 indometacin groups had drug-related adverse clinical experiences (P ¼ 0.003). ACR criteria d Not stated Pain measured on 6-point cartoon pain scale (0 ¼ no pain, 5 ¼ most severe). Pain measured seven times in 24 h. No significant differences at any time point. 24 h data presented graphically only. Adverse events: none in either group. ACR criteria MTP (56%), ankle (48%), other (40%), Knee (25%), great toe proximal IP joint (20%) Crystals Knee, ankle, wrist, MTP, MCP, IP Difference in pain days 2 5, 0.08 (95% CI 0.29, 0.13). Within predefined bounds for equivalence ( ). Difference in patients global assessment of response on 0 4 scale (0 ¼ excellent, 4 ¼ poor) over days 2 8 was 0.11 (95% CI 0.39, 0.17). Adverse events: 45/103 etoricoxib and 49/86 indometacin groups had adverse clinical experiences (P ¼ 0.08). 17/103 etoricoxib and 32/86 indometacin groups had drug-related adverse clinical experiences (P ¼ 0.002). At 24 h: 50% reduction in pain seen in 41% of colchicine group and 9% of placebo group (NS). At 48 h: 50% reduction in pain seen in 73% colchicine group and 36% of placebo group (P<0.05). Adverse events: All (22/22) colchicine group developed diarrhoea and/or vomiting (median time to onset 24 h) in 41% 50% improvement in pain occurred before toxicity. 5/21 of the placebo group experienced nausea of10 S. Sutaria et al. Downloaded from at Pennsylvania State University on February 27, 2014

5 Steroids and adrenocorticotrophic hormone(acth) for acute gout Siegel et al. [22] 31 Intramuscular ACTH 40 iu vs intramuscular triamcinolone acetonide 60 mg Other treatments for acute gout Schlesinger et al. [23] 19 Topical ice therapy for 30 min 4 times per day vs no topical ice. Prevention of recurrent gout Gaines and Shulman [24] 14 Colchicine þ placebo vs colchicine þ sulphinpyrazone mg a All doses are total daily dose unless otherwise stated. b Multiple joints affected in some studies. c Clinical features plus birefringent crystals on joint aspiration. d American College of Rheumatology criteria [37]. Crystals Not stated Pain after one and two days not reported. Mean days to 100% resolution 7.92 in ACTH group and 7.60 in triamcinolone group (P ¼ 0.89). 9/14 of ACTH group and 5/16 of triamcinolone group required one or more additional injection. Two of ACTH group also received triamcinolone because of failure to resolve after third injection. Adverse events: not reported. Crystals Knee (9), ankle (3), 1st MTP (5), MCP (2) Unclear All participants received prednisolone 30 mg for 2 days, 20 mg for 2 days then 10 mg for 2 days plus colchicine 0.6 mg per day. Pain after one and two days not reported. After one week mean reduction in pain, measured on 10cm visual analogue score, 7.75 cm in ice group and 4.42 cm for controls P ¼ Wilcoxon rank sum test. Randomization was by blindly drawing a folded paper. Adverse events: not reported. Conference abstract only. Cross over after months. Serum urate 0.58 mmol/l in colchicine group and 0.35 mmol/l in colchicine þ sulphinpyrazone group. 29 attacks of gout in 170 months of follow-up in colchicine group and 32 attacks of gout in 173 months of follow-up for Colchicine þ sulphinpyrazone group. No statistical tests applied Intervention for the treatment of acute and prevention of recurrent gout 5of10 Downloaded from at Pennsylvania State University on February 27, 2014

6 TABLE 2. Excluded studies Author n Intervention compared Comment Acute gout Unavailable treatments for acute gout Bach [38] 28 Intramuscular phenylbutazone In German. Translated abstract indicates no difference in outcome. vs intramuscular diclofenac Butler et al. [39] 33 Phenylbutazone vs flurbiprofen Pain at one or two days not reported. Median duration of attack 3 days for phenylbutazone and 4 for Cheng et al. [40] 62 (a) Diclofenac vs rofecoxib (b) Meloxicam vs rofecoxib flurbiprofen P>0.10. Not an intention-to-treat analysis. Single blind study, participants aware of allocation. Modified intention-to-treat analysis. Pain after one or two days not reported. Measured on 0 4 scale (0 ¼ none, 4 ¼ extreme) mean improvements in pain after 12 h were 1.6, 1.8 and 1.5 in rofecoxib, diclofenac and meloxicam groups, respectively. No statistical test applied. 84, 57 and 40% of rofecoxib, diclofenac and meloxicam groups, respectively, reported good or excellent response to treatment after 3 days (diclofenac vs rofecoxib not significant, meloxicam vs rofecoxib P ¼ 0.005). Chou and Kuo [41] 20 Indometacin vs Inadequate randomization, patients intolerant of NSAIDs placed in danggui-nian-tong-tang group. danggui-nian-tong-tang Douglas and Thompson [42] 25 Phenylbutazone vs flufenamic acid Pain at one/two days not reported. Mean days to pain relief 3.6 for phenylbutazone and 4.5 for flufenamic acid. No statistical test applied. Ma et al. [43] 40 Tongfengkang vs indometacin þ allopurinol Inadequate randomization. After 10 days 14/20 of Tongfengkang and 15/20 allopurinol þ indometacin groups reported the treatment to be highly effective. Reardon et al. [44] 24 Phenylbutazone vs feprazone Pain at one or two days not reported. Mean time to response 2.3 days for phenylbutazone and 2 days for feprazone. No statistical test applied. Ruotsi and Vainio [45] 18 Indometacin vs proquazone No pain data reported. 8/9 of indometacin and 7/9 proquazone groups reported substantial improvement or complete remission. Follow-up time not stated. No statistical test applied. Siegmeth and Placheta [46] 46 Intramuscular phenylbutazone In German. English abstract indicates no statistically significant differences between groups. vs intramuscular ketoprofen Smyth and Percy [47] 28 Phenylbutazone vs indometacin Reports 31 attacks of gout in 28 subjects. Pain at one or two days not reported. Mean time to complete recovery 5 days in both groups. No statistical test applied. Sturge et al. [48] 41 Phenylbutazone vs naproxen Mean time to end of attack 3.4 days in phenylbutazone group and 2.9 days in naproxen group (NS). Valdes et al. [49] 20 Indometacin vs carprofen In Spanish. English abstract indicates that both groups improved. Outcome similar in both groups. No statistical tests applied. Weiner et al. [50] 30 Phenylbutazone vs fenoprofen Pain at one or two days not reported. Mean reduction in overall severity after one and two days were 31 and 53%, respectively for phenylbutazone and 35 and 59% for fenoprofen. Differences were not statistically significant. Inadequate randomization Alloway et al. [51] 27 Intramuscular triamcinolone acetonide vs oral indometacin Those with contra-indications to indometacin received triamcinolone acetonide. Mean time to resolution for indometacin was 8 days and for triamcinolone it was 7 days. Alternate allocation used, prior to onset of gout attack. Mean time to pain relief for ACTH was 3 h and to indometacin it was 24 h. Axelrod and Preston [52] 76 Intramuscular adrenocorticotropic hormone vs indometacin Lomen et al. [53] 29 Flurbiprofen vs indometacin First two participants at each centre received the same treatment. More than 50% of patients in both groups showed improvement after 24 h. No pain data reported Fraser et al. [18] 93 Indometacin vs azapropazone No pain data reported. 40/46 azapropazone and 35/47 indometacin groups reported treatment suited them. (NS) 10/47 and 8/46 left indometacin and azapropazone groups, respectively because of reported side effects. 6of10 S. Sutaria et al. Downloaded from at Pennsylvania State University on February 27, 2014

7 Recurrent gout Unavailable treatments for the prevention of recurrent gout Berg [54] 60 Allopurinol vs allopurinol þ Subjects did not have gout. benzbromarone Bluhm and Riddle [55] 35 Probenecid vs halfonate Conference abstract only. Liang [56] 74 Benzbromarone vs probenecid In Chinese. Follow-up for 12 weeks. English abstract reports incidence of acute gout 5% in benzbromarone group and 17% in probenecid group (P<0.001). Fraser et al. [57] 93 Allopurinol vs azapropazone 25 attacks of gout in 47 subjects in allopurinol group and 18 attacks in 46 subjects in azapropazone group. Urate results presented graphically only. No significant differences. Frerick et al. [58] 80 Allopurinol vs allopurinol þ In German. Translation indicates not all subjects had gout. benzbromarone Paulus et al. [59] 51 Probenecid vs probenecid þ colchicine Only data from 38 subjects, deemed to be compliant because of a fall in serum urate, were included in the analysis. Mean number of attacks per month was 0.48 in the probenecid group and 0.19 in the probenecid þ colchicine group (P<0.05). Scott et al. [60, 61] Allopurinol vs probenecid Not truly randomized, participants allocated by last digit of hospital number. Follow-up for up to 2 yrs, 9/20 in allopurinol group and 8/17 of probenecid group had no further attacks of gout. Study not truly randomized Gibson et al. [62] 59 Colchicine vs colchicine þ allopurinol Follow-up/treatment period less than 6 months Borstad et al. [63] 43 Colchicine þ allopurinol vs placebo þ allopurinol Three subjects in colchicine þ allopurinol group deemed non-compliant because serum urate did not fall re-allocated to colchicine group for analysis. Over 1 yr, 30% of colchicine group and 19% of colchicine þ allopurinol group had recurrent attacks of gout (NS). Trial of colchicine for first 3 months of allopurinol treatment. Mean number of flares in 3 months: 0.52 in colchicine group, 2.92 in placebo group (P ¼ 0.008), in months 3 6 mean number of flares 0 in the colchicine group and 1.05 in placebo group (P ¼ 0.033). Follow-up for 1 month only. Chou and Kuo [41] 20 Allopurinol vs danggui-niantong-tang Gibson et al. [64] 40 Azapropazone vs Allopurinol þ colchicine Follow-up for 3 months only. 26% of azapropazone group and 52% of allopurinol þ colchicine group had repeat acute attack. Study entrants did not all have gout Ettinger et al. [65] 60 Allopurinol vs placebo Previous attacks of gout were not an entry requirement for patients to be entered into study. Intervention for the treatment of acute and prevention of recurrent gout 7of10 Downloaded from at Pennsylvania State University on February 27, 2014

8 8of10 S. Sutaria et al. Articles identified 9854 Not gout/not RCT 9721 Full articles obtained 133 Not gout/not RCT 90 Acute gout Rejected 17 No pain data reported Inadequate randomisation Drug not available FIG. 1. Studies identified. (n=1) (n=3) (n=13) Acute gout 30 Included studies 13 There is only one small randomized controlled trial to support the use of NSAIDs for the treatment of acute gout. The size, quality and comparisons made in most of the studies comparing different NSAIDs are such that they cannot inform our management. The only robust conclusion that can be drawn from the available randomized data is that the pain-relieving properties of indometacin and etoricoxib are equivalent. However, in the absence of a placebo-controlled trial of either of these drugs for the treatment of gout, we can only speculate on the magnitude of their clinical effect. The high incidence of gastrointestinal and other side effects of the high dose of indometacin used to treat acute gout is well-documented [30]. Etoricoxib has fewer gastrointestinal adverse events, but concerns about cardiovascular adverse events from COX-2 inhibitors mean that this cannot be assumed to be a safer option than indometacin ( mhra.gov.uk/ourwork/monitorsafequalmed/safetymessages/ ddlcox pdf). Likewise, although colchicine appears to be effective in one randomized controlled trial, it has too high an incidence of adverse reactions for routine use [21, 31]. The incidence of gout is highest in the elderly population [32], who may be frail, and it is particularly common in those with cardiovascular disease [33]. It is in this group, who are at high risk of serious adverse events, that we are using drugs of known toxicity in the absence of randomized controlled trials of their effectiveness. There is a need to re-appraise how we treat acute gout. This re-appraisal needs to consider the risks and benefits of the drugs we use to treat a condition that usually improves spontaneously even without treatment [34]. For example, does a treatment with RCTs 43 Recurrent gout 13 Included studies 1 Rejected 10 Gout not primary focus (n=1) Inadequate randomisation (n=1) Follow up <6 months (n=3) Drug not available (n=7) analgesics or oral steroids and ice packs [23] provide an improved balance between risks and benefits compared with routine treatment with non-selective NSAIDs, COX-2 inhibitors or colchicine for most patients with acute gout? Prevention of recurrent gout Allopurinol is the mainstay of recurrent gout prevention. In , allopurinol prescriptions, at a cost of , were dispensed in England ( doh.gov.uk/stats/pca2003.htm). Making a very crude assumption that each person on prophylactic allopurinol has 12 prescriptions per year, then at least people in England are on regular allopurinol. The absence of long-term data on the effect of allopurinol on either incidence of recurrent gout or serum urate is surprising, particularly as it has well-recognized, rare but serious side effects [9, 35]. A number of studies show that it does reduce serum urate, at least in the short term [36] and there is a well-documented relationship between serum urate and the incidence of acute gout [32]. These data, and extensive clinical experience, suggest that allopurinol is effective in preventing recurrent gout. There is a need to re-appraise how we use allopurinol and sulphinpyrazone. For example, what are the risks and benefits of allopurinol/sulphinpyrazone? At what levels of urate and frequency of attacks is it worth considering allopurinol/ sulphinpyrazone? Although there are no randomized controlled trials of dietary changes for the prevention of recurrent gout, there are now goodquality observational data showing the relationship between Downloaded from at Pennsylvania State University on February 27, 2014

9 Intervention for the treatment of acute and prevention of recurrent gout 9of10 diet and alcohol intake, and a first attack of gout [5, 6]. These data suggest that practical lifestyle changes may be an alternative to drug treatment. The role of lifestyle advice for the prevention of recurrent gout also needs to be re-assessed. What is already known on this topic: Gout is a common disorder. Non-steroidal anti-inflammatory drugs or colchicine are common treatments for acute gout. Allopurinol or sulphinpyrazone are commonly used to prevent recurrence. All of the drugs used in the management of gout can have potentially serious side effects. What this study adds: The efficiency of drugs commonly used to treat gout has not been established. The balance of risks and benefits from these drugs is unknown. Current approaches to the treatment of gout need to be re-assessed. Acknowledgements This article is based on dissertations submitted by S.S. and R.K. as part of an intercalated B Med Sci., supported by bursaries from the Research Advisory Board. Translation of de la Torre [11] was originally provided by Clinical Evidence for their review of gout. We are grateful to Yu Mei Chang for translation of Chinese papers and Nancy Schumann for translation of German and Portuguese papers. S.S. and R.K. jointly designed and carried out the study with M.U. s guidance. S.S. wrote the first draft of this article. R.K. and M.U. commented on successive drafts. M.U. had the original idea for this study, supervized all stages of the work and is the guarantor. M.U. has received speaker fees from Pfizer, the manufacturers of valdecoxib and celecoxib, and from Menarini Pharmaceuticals, the manufacturers of ketoprofen and dexketoprofen. M.U. has received fees for speaking from Menarini Pharmaceuticals and from Pfizer. 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