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

Abstract

To determine the evidence for the effectiveness of treatments for acute gout and the prevention of recurrent gout.
Seven electronic databases were searched for randomized controlled trials of treatments for gout from their inception to the end of 2004. 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.
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.
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.

Full text

Rheumatology 2006;45:1422–1431 doi:10.1093/rheumatology/kel071
Advance Access publication 21 April 2006
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 2004. 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.
Barts and The London, Queen Mary, University of London, Institute of Health Sciences, London, UK.
Submitted 16 October 2005; revised version accepted 7 February 2006.
Correspondence to: Shailen Sutaria, Barts and The London, Queen Mary, University of London, Institute of Health Sciences, London, UK.
E-mail: shailen000@yahoo.co.uk
ß The Author 2006. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
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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
10–189). 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 interven-
tions, 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.
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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
Clinical criteria þ
crystals
c
or
hyperuricaemia
Knee (14), ankle (7),
wrists (4), elbow (3),
big toe (2)
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.
4
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
Crystals or
clinical criteria
Not stated 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.
3
Adverse events: 16/30 in indometacin and
15/29 in ketoprofen group.
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)
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.
3
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
Previous history þ
hyperuricaemia
Knee (8), big toe (7),
ankle (4),
wrists (1), thumb (1)
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.
2
Adverse events: 50% of indometacin and 20% of
meclofenamate group.
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)
Crystals or
hyperuricaemia þ
history
Knee (31%), ankle (27%),
big toe (27%),
wrist (12%),
elbow (3%)
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.
3
Lederman [17] 60 Etodolac 600 mg vs
naproxen 1500 mg
Previous history þ
hyperuricaemia
Not stated Two-day pain data presented graphically only.
No statistically significant difference in
any outcome measures.
2
Adverse events:1/29 in etodolac group. None reported in
naproxen group.
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Maccagno et al. [18] 61 Etodolac 600 mg vs
naproxen 1000 mg
Previous history þ
hyperuricaemia
Not stated 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.
3
Adverse events: 3/31 in etodolac and 2/30 in naproxen group.
Schumacher et al. [12] 150 Etoricoxib 120 mg vs
indometacin 150 mg
ACR criteria Great toe (55%),
other (36%),
ankle (32%),
knee (27%)
Difference in pain days 2–5, 0.11 (95% CI 0.14, 0.35). Within
pre-defined bounds for equivalence (0.5–0.5). 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).
5
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).
Shrestha et al. [13] 20 Single dose intramuscular
ketorolac 60 mg vs single
dose oral indometacin.
Followed by indometacin
for both groups
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.
4
Rubin et al. [14] 189 Etoricoxib 120 mg vs
indometacin 150 mg
ACR criteria MTP (56%),
ankle (48%),
other (40%),
Knee (25%),
great toe proximal
IP joint (20%)
Difference in pain days 2–5, 0.08 (95% CI 0.29, 0.13).
Within predefined bounds for equivalence (0.5–0.5).
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).
4
Colchicine vs placebo for acute gout
Ahern et al. [21] 43 Colchicine 1 mg
initially then 0.5 mg
every 2 h vs placebo
Crystals Knee, ankle, wrist,
MTP, MCP, IP
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).
3
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.
Continued.
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TABLE 1. Continued
Study n Intervention compared
a
Diagnostic criteria Joints affected
b
Results Jadad score
Steroids and adrenocorticotrophic hormone(ACTH) for acute gout
Siegel et al. [22] 31 Intramuscular ACTH 40 iu
vs intramuscular
triamcinolone acetonide 60 mg
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.
2
Other treatments for acute gout
Schlesinger et al. [23] 19 Topical ice therapy
for 30 min 4 times
per day vs no topical ice.
Crystals Knee (9), ankle (3),
1st MTP (5),
MCP (2)
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 0.021 Wilcoxon rank sum test. Randomization
was by ‘blindly drawing a folded paper’.
0
Adverse events: not reported.
Prevention of recurrent gout
Gaines and Shulman [24] 14 Colchicine þ placebo
vs colchicine þ
sulphinpyrazone
400–800 mg
Unclear Conference abstract only. Cross over after 12–15 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.
2
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].
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TABLE 2. Excluded studies
Author n Intervention compared Comment
Acute gout
Unavailable treatments for acute gout
Bach [38] 28 Intramuscular phenylbutazone
vs intramuscular diclofenac
In German. Translated abstract indicates no difference in outcome.
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
flurbiprofen P>0.10. Not an intention-to-treat analysis.
Cheng et al. [40] 62 (a) Diclofenac vs rofecoxib
(b) Meloxicam vs rofecoxib
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
danggui-nian-tong-tang
Inadequate randomization, patients intolerant of NSAIDs placed in danggui-nian-tong-tang group.
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
vs intramuscular ketoprofen
In German. English abstract indicates no statistically significant differences between groups.
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.
Axelrod and Preston [52] 76 Intramuscular adrenocorticotropic
hormone vs indometacin
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.
Continued.
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TABLE 2. Continued
Author n Intervention compared Comment
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.
Recurrent gout
Unavailable treatments for the prevention of recurrent gout
Berg [54] 60 Allopurinol vs allopurinol þ
benzbromarone
Subjects did not have gout.
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
benzbromarone
In German. Translation indicates not all subjects had gout.
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
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).
Follow-up/treatment period less than 6 months
Borstad et al. [63] 43 Colchicine þ allopurinol vs
placebo þ allopurinol
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).
Chou and Kuo [41] 20 Allopurinol vs danggui-nian-
tong-tang
Follow-up for 1 month only.
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.
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Acute gout
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 indo-
metacin 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 gastro-
intestinal 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 (http://medicines.
mhra.gov.uk/ourwork/monitorsafequalmed/safetymessages/
ddlcox2170205.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
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 2002–03, 2 423 000 allopurinol prescriptions, at a cost of
£6 848 000, were dispensed in England (http://www.publications.
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 200 000 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 good-
quality observational data showing the relationship between
Articles identified
9854
Full articles obtained
133
Not gout/not RCT
9721
Not gout/not RCT
90
RCTs
43
Acute gout
30
Recurrent gout
13
Included studies
13
Rejected 17
No pain data reported (n=1)
Inadequate randomisation (n=3)
Drug not available (n=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)
FIG. 1. Studies identified.
Intervention for the treatment of acute and prevention of recurrent gout 1429
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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 sulphin-
pyrazone 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. The other authors have declared
no conflicts of interest.
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