Allopurinol for chronic gout

  • Major change
  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the efficacy and safety of allopurinol compared with placebo and other urate-lowering therapies for treating chronic gout.

Background

Description of the condition

Gout is the most common inflammatory arthritis in men over the age of 40, and has increasing prevalence amongst postmenopausal women (Chohan 2009). It results from the deposition of monosodium urate (MSU) crystals in and around joints (Schlesinger 2004) and soft tissues. Formation of uric acid crystals requires hyperuricaemia defined as serum urate concentration above its solubility limit (6.8 mg/dl) supersaturating the body fluids (Schumacher 2005).

Gout can evolve from asymptomatic hyperuricaemia to acute gout which is characterized by the rapid onset of severe pain, swelling and redness of the affected joint. The period between attacks when the patient is asymptomatic, is referred to as inter-critical gout. The final stage is chronic gout, characterized by the formation of tophi, which are nodular masses of monosodium urate crystals deposited in the soft tissues of the body which can contribute to joint damage (Klippel 1994). Furthermore, hyperuricaemia can be associated with renal damage secondary to interstitial MSU crystal deposition and the formation of renal stones (Schlesinger 2004).

The treatment of acute gout attacks is aimed at controlling the inflammatory response and alleviating pain, and the drugs commonly used for this are nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, and glucocorticoids (Wortmann 2002).

Description of the intervention

As serum uric acid concentration is the most important determinant for the risk of developing gout (Klippel 1994), treatment is aimed at controlling hyperuricaemia. This prevents gouty attacks and the sequelae of long-standing hyperuricaemia, such as chronic tophaceous gout and uric acid stones (Schlesinger 2004). Maintaining the serum uric acid level below saturating levels at a target < 6 mg/dL (or 0.36 mmol/L) is important in the treatment of chronic gout to reduce or reverse clinical events (Jordan 2007). The urate-lowing drugs available to treat chronic gout are:

  1. uricostatic drugs which reduce urate production such as xanthine oxidase (XO) inhibitors, including allopurinol and febuxostat;

  2. uricosuric drugs including probenecid, benzbromarone, and sulfinpyrazone;

  3. recombinant uricases such as pegloticase and rasburicase;

How the intervention might work

Allopurinol is a uricostatic drug that limits the production of uric acid. It is an isomer of hypoxanthine that inhibits the enzyme xanthine oxidase, thereby preventing the conversion of hypoxanthine to xanthine and xanthine to uric acid. It depletes the pool of phosphoribosylpyrophosphate (PRPP) that drives de novo purine biosynthesis (Wallace 1988). The initial recommended dose of allopurinol is 100 mg daily, which is then adjusted according to plasma or urinary uric acid concentration.

Why it is important to do this review

Allopurinol is one of the most effective and frequently used urate-lowering drugs for gout. However, about 2% of individuals develop hypersensitivity reactions (Dalbeth 2007) and 20% of those are severe, including rash, toxic epidermal necrolysis, hepatitis, interstitial nephritis and death (Wortmann 2002). It is, therefore, clinically relevant to systematically review the efficacy and safety of allopurinol in the treatment of chronic gout.

Objectives

To assess the efficacy and safety of allopurinol compared with placebo and other urate-lowering therapies for treating chronic gout.

Methods

Criteria for considering studies for this review

Types of studies

We will include all randomised or quasi-randomised controlled clinical trials (RCTs or CCTs) comparing allopurinol with another therapy (placebo or other urate-lowering treatment) in adults with chronic gout.

Only trials that are published as full articles or available as a full trial report will be included.

Types of participants

Trials that include adults (age > 18 years) with a diagnosis of chronic gout will be included.

The American College of Rheumatology (ACR) preliminary criteria for the classification of acute arthritis of primary gout remain the most frequently used criteria for chronic gout diagnosis in clinical trials (Wallace 1977). According to these criteria, a patient can be classified as having gout if MSU crystals are identified in a synovial fluid sample or tophus aspirate, or any of six out of 12 following clinical, radiographic and laboratory criteria are fulfilled.

  1. More than one attack of acute arthritis

  2. Maximum inflammation developed within one day

  3. Monoarthritis attack

  4. Redness observed over joints

  5. First metatarsophalangeal joint painful or swollen

  6. Unilateral first metatarsophalangeal joint attack

  7. Unilateral tarsal joint attack

  8. Tophus (proved or suspected)

  9. Hyperuricaemia

  10. Asymmetric swelling within a joint on x-ray film

  11. Subcortical cysts without erosions on x-ray film

  12. Joint culture negative for organism during attack

Trials will be included where adults have either chronic gout based upon the ACR criteria, or author-defined gout.

Types of interventions

All trials that evaluate allopurinol in any dose or dosing interval will be included.

Comparators could be any of the following.

  1. Placebo

  2. No treatment

  3. Another urate lowering therapy including febuxostat, probenecid, benzbromarone, sulfinpyrazone, pegloticase or rasburicase

  4. One regimen of allopurinol versus another

  5. A combination of urate-lowering therapies

Types of outcome measures

OMERACT (Outcome Measures in Rheumatology) is an international network interested in outcome measures across the spectrum of rheumatology intervention studies. At the OMERACT 9 conference, core and discretionary domains for outcome measures in clinical studies of acute and chronic gout were defined (Schumacher 2009). We will include the core domains nominated for chronic gout which include acute gout attacks, serum urate, pain, health-related quality of life (HRQoL), and function.

Main outcomes
  1. Efficacy as assessed by patient-reported reduction in acute gout attack frequency

  2. Safety as assessed by the number of study participant withdrawals due to adverse events

Minor outcomes
  1. Adverse events (AE): total number and type

  2. Serious adverse events (SAE): defined as AEs that are fatal, life-threatening, or require hospitalisation

  3. Joint pain reduction as measured on the visual analogue scale (VAS), numeric rating scale (NRS), or Likert scales

  4. Serum urate normalisation as measured by percentage of participants achieving a target serum urate level (e.g.: < 0.36 mmol (6.1 mg/dL))

  5. Function as assessed by disease-specific instruments (such as the Health assessment questionnaire disability index (HAQ-DI))

  6. Patient global assessment of treatment success as measured by VAS

  7. Health-related quality of life (HRQoL) measures as assessed by generic questionnaires such as Short form-36 (SF-36)

  8. Tophus regression

For the purpose of this review, outcomes will be extracted from all time points and combined into short term (< three months), medium term (three to 12 months) and long term (> 12 months), though this will depend on the feasibility of doing so from the available data. If more than one time point has been reported within the subgroup (e.g. at one week and two week follow-up), we will only extract the later time point.

Outcomes for 'Summary of findings' tables

We will present the following outcomes (at the latest time point) in 'Summary of findings' tables (Schünemann 2011a): participant-reported reduction in acute gout attack frequency, number of study participant withdrawals due to adverse events, serious adverse events, joint pain reduction, serum urate normalisation, function and tophus regression.

Search methods for identification of studies

Electronic searches

The following electronic databases will be searched from inception.

  1. OVID MEDLINE 1948 to present (Appendix 1)

  2. EMBASE 1980 to present (Appendix 2)

  3. The Cochrane Central Register of Controlled Trials (CENTRAL) (Appendix 3)

No language restrictions will be applied.

Searching other resources

Abstracts from the two major international rheumatology scientific meetings - the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) will be searched for the years 2011 and 2012. We will also search the reference lists of included articles for additional trials.

Data collection and analysis

Selection of studies

The results of the search will be independently reviewed by two authors (RS and AK) to identify trials that fulfil the inclusion criteria. We will review titles and abstracts and if more information is required to determine whether a trial meets the inclusion criteria, we will obtain the full text. A record for the reasons for excluding studies will be kept and any disagreement will be resolved by discussion. If no agreement can be met, a third review author (CE) will act as arbiter. Articles in a language other than English will be translated.

Data extraction and management

Data will be independently extracted from the included trials by the two review authors (RS and AK) using the pre-set forms. The collected data will be entered into Revman 5.1 (RevMan 2011).

Two independent reviewers (RS and AK) will extract relevant information from the included trials including study design, characteristics of study population, treatment regimen and duration, outcomes and timing of outcome assessment, using predetermined forms. Differences in data extraction will be resolved by referring back to the original articles and establishing consensus. A third reviewer (CE) will act as arbiter to help resolve differences if necessary.

The raw data (means and standard deviations for continuous outcomes and the number of events for dichotomous outcomes) will be extracted for outcomes of interest.

Assessment of risk of bias in included studies

Two review authors (RS and AK) will independently assess the risk of bias of all included studies. The Cochrane Collaboration's tool for assessing risk of bias will be used (Higgins 2011a). This includes assessing the bias in each of the following domains: random sequence generation, allocation concealment, blinding of participants, personnel and outcome assessors, completeness of outcome data, selective reporting and other sources of bias.

Each of these criteria will be graded as 'high risk' of bias, 'low risk' of bias or 'unclear risk' of bias. Disagreements will be resolved by consensus; if a consensus cannot be reached, a third review author (CE) will act as arbiter.

Measures of treatment effect

The data will be summarized in a meta-analysis only if there is sufficient clinical and statistical homogeneity.

For dichotomous data, the results will be presented as risk ratios (RR) with corresponding 95% confidence intervals (95% CI). A RR > 1.0 will indicate a beneficial effect of allopurinol.

For continuous data, the results will be presented as mean differences (MD) between the intervention and comparator groups with the corresponding 95% CIs.

When different scales are used to measure the same conceptual domain, standardised mean differences (SMD) with corresponding 95% CIs will be calculated instead. For the calculation of SMD, MD is divided by the standard deviation, resulting in a unit-less measure of treatment effect. SMDs larger than zero indicate a beneficial effect of allopurinol. An SMD of 0.2 indicates a small beneficial effect, 0.5 a medium effect and 0.8 a large effect in favour of allopurinol. SMD will be re-expressed as MD by multiplying the SMD by a typical among-person standard deviation using a familiar scale in order to facilitate appraisal by clinicians (Schünemann 2011b).

Unit of analysis issues

We will assess whether each study evaluates the number of people with acute flares or the number of acute flares as a unit of analysis, and we plan to evaluate number of people with acute flares as the preferred outcome.

We will avoid a potential unit of analysis issue by making multiple pair-wise comparisons between all possible pairs of intervention groups for trials with multiple treatment groups, or alternatively, by including only the pair with accepted drug dosages (Higgins 2011c).

Dealing with missing data

If data are missing or incomplete, we will seek further information from the study authors.

In cases where individual data are missing from the reported results and no further information is available from the study authors, we will assume the missing values to have a poor outcome. For dichotomous variables that measure AEs, the withdrawal rate will be calculated using the number of patients who received the treatment as the denominator (worst-case analysis). For dichotomous outcomes that measure benefits, the worst case analysis will be calculated using the number of randomised individuals as the denominator. For continuous variables, we will calculate the MD or the SMD based on the number of patients analysed at the time point. If the number of patients analysed is not available, the number of randomised participants in each group at baseline will be used.

Where possible, missing standard deviations will be calculated from other statistics such as standard errors, CIs or P values, according to methods recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). If standard deviations cannot be calculated, they will be imputed from other studies in the meta-analysis (Higgins 2011c).

Assessment of heterogeneity

We will assess clinical and statistical heterogeneity between studies.

We will initially assess studies for clinical homogeneity with respect to study participants, intervention groups, outcome measures and timing of outcome.

For studies judged as clinically similar, statistical heterogeneity will be assessed using the I2 statistic (Deeks 2011). The following thresholds for the interpretation of I2 will be used: 0% to 40% heterogeneity might not be important, 30% to 60% represents moderate heterogeneity, 50% to 90% represents substantial heterogeneity and > 75% represents considerable heterogeneity. In cases of considerable heterogeneity, we will explore the data further, including subgroup analyses, in an attempt to explain heterogeneity.

Assessment of reporting biases

To assess the potential for reporting bias, we will determine whether the protocol of the trial was published before recruitment of patients began. For trials published after 1 July 2005, we will screen the Clinical Trials Register at the International Clinical Trials Registry Platform of the World Health Organization (http://apps.who.int/trialsearch/). We will evaluate if selective reporting of outcomes is present.

We will compare the fixed-effect estimate against random-effects model to assess the possible presence of small sample bias in the published literature (i.e. in which the intervention effect is more beneficial in smaller studies). In the presence of small sample bias, the random-effects estimate of the intervention is more beneficial than the fixed-effect estimate (Sterne 2011).

Reporting bias will be explored by a funnel plot if 10 or more studies are available (Sterne 2011).

Data synthesis

If studies are considered to be sufficiently homogenous, we will pool data in a meta-analysis using a random-effects model, irrespective of the I2 results.

Subgroup analysis and investigation of heterogeneity

We suspect that responses to treatment may differ according to the participant's age and gender. Elderly patients can present with more associated conditions and possibly a greater chance of adverse effects (Busquets 2011) while reports indicate that gout in women may have different epidemiological and clinical characteristics compared to gout in men (Harrold 2006).

Therefore, we plan the following subgroup analyses if sufficient data are available.

  1. Patient's age (> 65 years or < 65 years)

  2. Gender (men versus women).

Ideally, we would extract the outcome (acute gout attacks) separately for men and women, and the outcome, withdrawals due to adverse events separately by age subgroups from within each trial. We plan to informally compare the magnitudes of effect to assess possible differences in response to treatment by considering the overlap of the confidence intervals of the summary estimates in the two subgroups - non-overlap of the confidence intervals indicates statistical significance. However, we anticipate that the outcomes may not be reported by subgroups within the trials, precluding the planned analyses.

Sensitivity analysis

Where sufficient studies exist, sensitivity analyses are also planned to explore the impact of any bias attributable to inadequate or unclear allocation concealment and outcome assessor blinding.

We will assess the presence of small study bias (i.e., intervention effect is more beneficial in smaller studies) in the meta-analysis by comparing the fixed-effect estimate and the random-effects estimate.

We will investigate the effect of any missing or imputed data by sensitivity analysis.

Presentation of results

The main results will be presented in a 'Summary of findings' table. This table provides key information concerning the quality of evidence, the magnitude of the effect of the interventions examined and the sum of the available data on the outcome as recommended by The Cochrane Collaboration (Schünemann 2011a).

The 'Summary of findings' table includes an overall grading of the evidence related to each of the main outcomes using the GRADE approach (Schünemann 2011b).

In addition to the absolute and relative magnitude of effect provided in the 'Summary of findings' table, for dichotomous outcomes, number needed to treat to benefit (NNTB) or the number needed to harm (NNTH) will be calculated from the control group event rate (unless the population event rate is known) and the RR using the Visual Rx NNT calculator (Cates 2008).

For continuous outcomes, the NNTB and NNTH will be calculated using the Wells calculator software available at the Cochrane Musculoskeletal Group (CMSG) editorial office. The minimally clinically important difference (MCID) for each outcome will be determined for input into the calculator.

In the 'Summary of findings' table, data from the following outcomes will be presented: participant-reported reduction in acute gout attack frequency, number of study participant withdrawals due to adverse events, serious adverse events, joint pain reduction, serum urate normalisation, function and tophus regression.

Acknowledgements

We would like to thank Louise Falzon, former Trial Search Coordinator, Cochrane Musculoskeletal Group, for her help in designing the search strategy.

Appendices

Appendix 1. MEDLINE search strategy

1. exp Gout/

2. gout$.tw.

3. tophus.tw.

4. tophi.tw.

5. tophaceous.tw.

6. or/1-5

7. Allopurinol/

8. Abburic.tw.

9. Abopur.tw.

10. Acepurin.tw.

11. Acifugan.tw.

12. Acyprin.tw.

13. Alfadiman.tw.

14. Algut.tw.

15. Alinol.tw.

16. allo$.tw.

17. Allpargin.tw.

18. Allupol.tw.

19. Allura$.tw.

20. Alluri$.tw.

21. Aloprim.tw.

22. Alopur.tw.

23. Aloral.tw.

24. Alosfar.tw.

25. Alpur$.tw.

26. Aluline.tw.

27. Aluprol.tw.

28. Aluron.tw.

29. Alzoprim.tw.

30. Anurate.tw.

31. Apnol.tw.

32. Apo-Tinole.tw.

33. Apronol.tw.

34. Apulonga.tw.

35. Apurin.tw.

36. Apurol.tw.

37. Arnol.tw.

38. Arsol.tw.

39. Artrex.tw.

40. Arturic.tw.

41. Atisuril.tw.

42. Aurigen.tw.

43. Benoxuric.tw.

44. Be-Uric.tw.

45. Bionol.tw.

46. Biuricowas.tw.

47. Bleminol.tw.

48. Caplenal.tw.

49. Capurate.tw.

50. Cellidrin$.tw.

51. Chinnol.tw.

52. Ciploric.tw.

53. Colpuril.tw.

54. Comburic.tw.

55. Cosuric.tw.

56. Dabroson.tw.

57. Darzune.tw.

58. Desatura.tw.

59. Docallopu.tw.

60. Duovitan.tw.

61. dura AL.tw.

62. Elavil.tw.

63. Embarin.tw.

64. Epidropal.tw.

65. Erloric.tw.

66. Ethipurinol.tw.

67. Etindrax.tw.

68. Facilit.tw.

69. Foligan.tw.

70. Gealgica.tw.

71. Gewapurol.tw.

72. Gichtex.tw.

73. Gotir.tw.

74. Hamarin.tw.

75. Harpagin.tw.

76. Hexanurat.tw.

77. Hycemia.tw.

78. Isoric.tw.

79. Jenapurinol.tw.

80. Labopurinol.tw.

81. Labypurol.tw.

82. Lanolone.tw.

83. Licoric.tw.

84. Llanol.tw.

85. Lonol.tw.

86. Lop?ric.tw.

87. Lopur$.tw.

88. Loricid.tw.

89. Lo-Uric.tw.

90. Lysuron.tw.

91. Marinol.tw.

92. Medoric.tw.

93. Mephanol.tw.

94. Milurit.tw.

95. Nilapur.tw.

96. Novo-Purol.tw.

97. Oloprim.tw.

98. Petrazyc.tw.

99. Ponuric.tw.

100. Prinol.tw.

101. Pritanol.tw.

102. Progout.tw.

103. Pureduct.tw.

104. Puricemia.tw.

105. Puricin.tw.

106. Puricos.tw.

107. Puride.tw.

108. Purigan.tw.

109. Purinase.tw.

110. Purinol.tw.

111. Purispec.tw.

112. Puristen.tw.

113. Puritenk.tw.

114. Pyrazol.tw.

115. Ranpuric.tw.

116. Redurate.tw.

117. Remid.tw.

118. Reucid.tw.

119. Rimapurinol.tw.

120. Rinolic.tw.

121. Sigapurol.tw.

122. Sinoric.tw.

123. Soluric.tw.

124. Stradumel.tw.

125. Suspendol.tw.

126. Synol.tw.

127. Synpurinol.tw.

128. Talol.tw.

129. Tipuric.tw.

130. Trianol.tw.

131. Tylonic.tw.

132. Unizuric.tw.

133. Uredimin.tw.

134. Uribenz.tw.

135. Urica$.tw.

136. Uricemil.tw.

137. Uricina.tw.

138. Uricnol.tw.

139. Urico$.tw.

140. Urifugan.tw.

141. Urikoliz.tw.

142. Urinol.tw.

143. Uriprim.tw.

144. Uripurinol.tw.

145. Uritab.tw.

146. Urobenyl.tw.

147. Urogotan.tw.

148. Uroplus.tw.

149. Urosin.tw.

150. Urozyl-SR.tw.

151. Urtias.tw.

152. Valeric.tw.

153. Xandase.tw.

154. Xanol.tw.

155. Xanthomax.tw.

156. Xanturic.tw.

157. Xanurace.tw.

158. Xuric-A.tw.

159. Z 300.tw.

160. Zilopur.tw.

161. Zurim.tw.

162. Zygout.tw.

163. Zylapour.tw.

164. Zylic.tw.

165. Zylo$.tw.

166. or/7-165

167. 6 and 166

168. randomized controlled trial.pt.

169. controlled clinical trial.pt.

170. randomized.ab.

171. placebo.ab.

172. drug therapy.fs.

173. randomly.ab.

174. trial.ab.

175. groups.ab.

176. or/168-175

177. (animals not (humans and animals)).sh.

178. 176 not 177

179. 167 and 178

Appendix 2. EMBASE search strategy

1. exp gout/

2. gout$.tw.

3. tophus.tw.

4. tophi.tw.

5. tophaceous.tw.

6. or/1-5

7. allopurinol/

8. Abburic.tw.

9. Abopur.tw.

10. Acepurin.tw.

11. Acifugan.tw.

12. Acyprin.tw.

13. Alfadiman.tw.

14. Algut.tw.

15. Alinol.tw.

16. allo$.tw.

17. Allpargin.tw.

18. Allupol.tw.

19. Allura$.tw.

20. Alluri$.tw.

21. Aloprim.tw.

22. Alopur.tw.

23. Aloral.tw.

24. Alosfar.tw.

25. Alpur$.tw.

26. Aluline.tw.

27. Aluprol.tw.

28. Aluron.tw.

29. Alzoprim.tw.

30. Anurate.tw.

31. Apnol.tw.

32. Apo-Tinole.tw.

33. Apronol.tw.

34. Apulonga.tw.

35. Apurin.tw.

36. Apurol.tw.

37. Arnol.tw.

38. Arsol.tw.

39. Artrex.tw.

40. Arturic.tw.

41. Atisuril.tw.

42. Aurigen.tw.

43. Benoxuric.tw.

44. Be-Uric.tw.

45. Bionol.tw.

46. Biuricowas.tw.

47. Bleminol.tw.

48. Caplenal.tw.

49. Capurate.tw.

50. Cellidrin$.tw.

51. Chinnol.tw.

52. Ciploric.tw.

53. Colpuril.tw.

54. Comburic.tw.

55. Cosuric.tw.

56. Dabroson.tw.

57. Darzune.tw.

58. Desatura.tw.

59. Docallopu.tw.

60. Duovitan.tw.

61. dura AL.tw.

62. Elavil.tw.

63. Embarin.tw.

64. Epidropal.tw.

65. Erloric.tw.

66. Ethipurinol.tw.

67. Etindrax.tw.

68. Facilit.tw.

69. Foligan.tw.

70. Gealgica.tw.

71. Gewapurol.tw.

72. Gichtex.tw.

73. Gotir.tw.

74. Hamarin.tw.

75. Harpagin.tw.

76. Hexanurat.tw.

77. Hycemia.tw.

78. Isoric.tw.

79. Jenapurinol.tw.

80. Labopurinol.tw.

81. Labypurol.tw.

82. Lanolone.tw.

83. Licoric.tw.

84. Llanol.tw.

85. Lonol.tw.

86. Lop?ric.tw.

87. Lopur$.tw.

88. Loricid.tw.

89. Lo-Uric.tw.

90. Lysuron.tw.

91. Marinol.tw.

92. Medoric.tw.

93. Mephanol.tw.

94. Milurit.tw.

95. Nilapur.tw.

96. Novo-Purol.tw.

97. Oloprim.tw.

98. Petrazyc.tw.

99. Ponuric.tw.

100. Prinol.tw.

101. Pritanol.tw.

102. Progout.tw.

103. Pureduct.tw.

104. Puricemia.tw.

105. Puricin.tw.

106. Puricos.tw.

107. Puride.tw.

108. Purigan.tw.

109. Purinase.tw.

110. Purinol.tw.

111. Purispec.tw.

112. Puristen.tw.

113. Puritenk.tw.

114. Pyrazol.tw.

115. Ranpuric.tw.

116. Redurate.tw.

117. Remid.tw.

118. Reucid.tw.

119. Rimapurinol.tw.

120. Rinolic.tw.

121. Sigapurol.tw.

122. Sinoric.tw.

123. Soluric.tw.

124. Stradumel.tw.

125. Suspendol.tw.

126. Synol.tw.

127. Synpurinol.tw.

128. Talol.tw.

129. Tipuric.tw.

130. Trianol.tw.

131. Tylonic.tw.

132. Unizuric.tw.

133. Uredimin.tw.

134. Uribenz.tw.

135. Urica$.tw.

136. Uricemil.tw.

137. Uricina.tw.

138. Uricnol.tw.

139. Urico$.tw.

140. Urifugan.tw.

141. Urikoliz.tw.

142. Urinol.tw.

143. Uriprim.tw.

144. Uripurinol.tw.

145. Uritab.tw.

146. Urobenyl.tw.

147. Urogotan.tw.

148. Uroplus.tw.

149. Urosin.tw.

150. Urozyl-SR.tw.

151. Urtias.tw.

152. Valeric.tw.

153. Xandase.tw.

154. Xanol.tw.

155. Xanthomax.tw.

156. Xanturic.tw.

157. Xanurace.tw.

158. Xuric-A.tw.

159. Z 300.tw.

160. Zilopur.tw.

161. Zurim.tw.

162. Zygout.tw.

163. Zylapour.tw.

164. Zylic.tw.

165. Zylo$.tw.

166. or/7-165

167. 6 and 166

168. (random$ or placebo$).ti,ab.

169. ((single$ or double$ or triple$ or treble$) and (blind$ or mask$)).ti,ab.

170. controlled clinical trial$.ti,ab.

171. RETRACTED ARTICLE/

172. or/168-171

173. (animal$ not human$).sh,hw.

174. 172 not 173

175. 167 and 174

 

Appendix 3. The Cochrane Library (Wiley InterScience)

#1             MeSH descriptor Gout explode all trees

#2             gout*:ti,ab

#3             tophus"ti,ab

#4             tophi:ti,ab

#5             tophaceous:ti,ab

#6             #1 or #2 or #3 or #4 or #5

#7             MeSH descriptor Allopurinol, this term only

#8             Abburic:ti,ab

#9             Abopur:ti,ab

#10          Acepurin:ti,ab

#11          Acifugan:ti,ab

#12          Acyprin:ti,ab

#13          Alfadiman:ti,ab

#14          Algut:ti,ab

#15          Alinol:ti,ab

#16          allo*:ti,ab

#17          Allpargin:ti,ab

#18          Allupol:ti,ab

#19          Allura*:ti,ab

#20          Alluri*:ti,ab

#21          Aloprim:ti,ab

#22          Alopur:ti,ab

#23          Aloral:ti,ab

#24          Alosfar:ti,ab

#25          Alpur*:ti,ab

#26          Aluline:ti,ab

#27          Aluprol:ti,ab

#28          Aluron:ti,ab

#29          Alzoprim:ti,ab

#30          Anurate:ti,ab

#31          Apnol:ti,ab

#32          Apo-Tinole:ti,ab

#33          Apronol:ti,ab

#34          Apulonga:ti,ab

#35          Apurin:ti,ab

#36          Apurol:ti,ab

#37          Arnol:ti,ab

#38          Arsol:ti,ab

#39          Artrex:ti,ab

#40          Arturic:ti,ab

#41          Atisuril:ti,ab

#42          Aurigen:ti,ab

#43          Benoxuric:ti,ab

#44          Be-Uric:ti,ab

#45          Bionol:ti,ab

#46          Biuricowas:ti,ab

#47          Bleminol:ti,ab

#48          Caplenal:ti,ab

#49          Capurate:ti,ab

#50          Cellidrin*:ti,ab

#51          Chinnol:ti,ab

#52          Ciploric:ti,ab

#53          Colpuril:ti,ab

#54          Comburic:ti,ab

#55          Cosuric:ti,ab

#56          Dabroson:ti,ab

#57          Darzune:ti,ab

#58          Desatura:ti,ab

#59          Docallopu:it,ab

#60          Duovitan:ti,ab

#61          “dura AL”:ti,ab

#62          Elavil:ti,ab

#63          Embarin:ti,ab

#64          Epidropal:ti,ab

#65          Erloric:ti,ab

#66          Ethipurinol:ti,ab

#67          Etindrax:ti,ab

#68          Facilit:ti,ab

#69          Foligan:ti,ab

#70          Gealgica:ti,ab

#71          Gewapurol:ti,ab

#72          Gichtex:ti,ab

#73          Gotir:ti,ab

#74          Hamarin:ti,ab

#75          Harpagin:ti,ab

#76          Hexanurat:it,ab

#77          Hycemia:ti,ab

#78          Isoric:ti,ab

#79          Jenapurinol:ti,ab

#80          Labopurinol:ti,ab

#81          Labypurol:ti,ab

#82          Lanolone:ti,ab

#83          Licoric:ti,ab

#84          Llanol:ti,ab

#85          Lonol:ti,ab

#86          Lop?ric:ti,ab

#87          Lopur*:ti,ab

#88          Loricid:ti,ab

#89          Lo-Uric:ti,ab

#90          Lysuron:ti,ab

#91          Marinol:ti,ab

#92          Medoric:ti,ab

#93          Mephanol:ti,ab

#94          Milurit:ti,ab

#95          Nilapur:ti,ab

#96          Novo-Purol:ti,ab

#97          Oloprim:ti,ab

#98          Petrazyc:ti,ab

#99          Ponuric:ti,ab

#100       Prinol:ti,ab

#101       Pritanol:ti,ab

#102       Progout:ti,ab

#103       Pureduct:ti,ab

#104       Puricemia:ti,ab

#105       Puricin:ti,ab

#106       Puricos:ti,ab

#107       Puride:ti,ab

#108       Purigan:ti,ab

#109       Purinase:ti,ab

#110       Purinol:ti,ab

#111       Purispec:ti,ab

#112       Puristen:ti,ab

#113       Puritenk:ti,ab

#114       Pyrazol:ti,ab

#115       Ranpuric:ti,ab

#116       Redurate:ti,ab

#117       Remid:ti,ab

#118       Reucid:ti,ab

#119       Rimapurinol:ti,ab

#120       Rinolic:ti,ab

#121       Sigapurol:ti,ab

#122       Sinoric:ti,ab

#123       Soluric:ti,ab

#124       Stradumel:ti,ab

#125       Suspendol:ti,ab

#126       Synol:ti,ab

#127       Synpurinol:ti,ab

#128       Talol:ti,ab

#129       Tipuric:ti,ab

#130       Trianol:ti,ab

#131       Tylonic:ti,ab

#132       Unizuric:ti,ab

#133       Uredimin:ti,ab

#134       Uribenz:ti,ab

#135       Urica*:ti,ab

#136       Uricemil:ti,ab

#137       Uricina:ti,ab

#138       Uricnol:ti,ab

#139       Urico*:ti,ab

#140       Urifugan:ti,ab

#141       Urikoliz:ti,ab

#142       Urinol:ti,ab

#143       Uriprim:ti,ab

#144       Uripurinol:ti,ab

#145       Uritab:ti,ab

#146       Urobenyl:ti,ab

#147       Urogotan:ti,ab

#148       Uroplus:ti,ab

#149       Urosi:ti,ab

#150       Urozyl-SR:ti,ab

#151       Urtias:ti,ab

#152       Valeric:ti,ab

#153       Xandase:ti,ab

#154       Xanol:ti,ab

#155       Xanthomax:ti,ab

#156       Xanturic:ti,ab

#157       Xanurace:ti,ab

#158       Xuric-A:ti,ab

#159       “Z 300”:ti,ab

#160       Zilopur:ti,ab

#161       Zurim:ti,ab

#162       Zygout:ti,ab

#163       Zylapour:ti,ab

#164       Zylic:ti,ab

#165       Zylo*:ti,ab

#166       #7 OR #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or #27 or #28 or #29 or #30 or #31 or #32 or #33 or #34 or #35 or #36 or #37 or #38 or #39 or #40 or #41  or #42 or #43 or #44 or #45 or #46 or #47 or #48 or #49 or #50 or #51 or #52 or #53 or #54 or #55 or #56 or #57 or #58 or #59 or #60 or #61 or #62 or #63 or #64 or #65 or #66 or #67 or #68 or #69 or #70 or #71 or #72 or #73 or #74 or #75 or #76 or #77 or #78 or #79 or #80 or #81 or #82 or #83 or #84 or #85 or #86 or #87 or #88 or #89 or #90 or #91 or #92 or #93 or #94 or #95 or #96 or #97 or #98 or #99 or #100 or #101 or #102 or #103or #104 or #105 or #106 or #107 or #108 or #109 or #110 or #111 or #112 or #113 or #114 or #115 or #116 or #117 or #118 or #119 or #120 or #121 or #122 or #123 or #124 or #125 or #126 or #127 OR #128 OR #129 OR #130 OR #131 OR #132 OR #133 OR #134 OR #135 OR #136 OR #137 OR #138 or #139 OR #140 OR #141 OR #142 OR #143 OR #144 OR #145 OR #146 OR #147 OR #148 OR #149 OR #150 OR #151 OR #152 OR #153 OR #154 OR #155 OR #156 OR #157 OR #158 OR #159 OR #160 OR #161 OR #162 OR #163 OR #164 OR #165

#167       #6 AND #166

What's new

DateEventDescription
14 November 2012New citation required and major changesNew authors took over the protocol, and updated methods in line with current Cochrane Collaboration guidance.
3 September 2008AmendedConverted to new review format

Contributions of authors

RS drafted the protocol and all authors provided comments on drafts of the protocol.

Declarations of interest

None known

Sources of support

Internal sources

  • Complete this section- institution of each author , Not specified.

  • University Hospital Southampton NHS Foundation Trust, UK.

    In-kind support

  • Department of Epidemiology and Preventitive Medicine, School of Public Health and Preventitive Medicine, Monash University, Australia.

    In-kind support

  • Division of Rheumatology, University of British Columbia, Vancouver,, Canada.

    In-kind support

  • Institute for Work & Health, Toronto, Canada.

    In-kind support

External sources

  • No sources of support supplied

Ancillary