Colchicine for acute gout.

Colchicine for acute gout (Review) van Echteld I, Wechalekar MD, Schlesinger N, Buchbinder R, Aletaha D

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2014, Issue 8 http://www.thecochranelibrary.com

Colchicine for acute gout (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

TABLE OF CONTENTS HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.1. Comparison 1 High-dose colchicine versus placebo, Outcome 1 Proportion with 50% or greater decrease in pain score from baseline. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.2. Comparison 1 High-dose colchicine versus placebo, Outcome 2 Proportion with 50% or greater decrease in clinical score from baseline. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.3. Comparison 1 High-dose colchicine versus placebo, Outcome 3 All adverse events. . . . . . . . Analysis 1.4. Comparison 1 High-dose colchicine versus placebo, Outcome 4 Gastrointestinal adverse events (diarrhoea, vomiting or nausea). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 2.1. Comparison 2 Low-dose colchicine versus placebo, Outcome 1 Proportion with 50% or greater decrease in pain score from baseline. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 2.2. Comparison 2 Low-dose colchicine versus placebo, Outcome 2 All adverse events. . . . . . . . . Analysis 2.3. Comparison 2 Low-dose colchicine versus placebo, Outcome 3 Gastrointestinal adverse events (diarrhoea, vomiting or nausea). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 3.1. Comparison 3 High-dose versus low-dose colchicine, Outcome 1 Proportion with 50% or greater decrease in pain score from baseline. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 3.2. Comparison 3 High-dose versus low-dose colchicine, Outcome 2 All adverse events. . . . . . . . Analysis 3.3. Comparison 3 High-dose versus low-dose colchicine, Outcome 3 Gastrointestinal adverse events (diarrhoea, vomiting or nausea). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


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[Intervention Review]

Colchicine for acute gout Irene van Echteld1 , Mihir D Wechalekar2 , Naomi Schlesinger3 , Rachelle Buchbinder4 , Daniel Aletaha5 1 Department

of Rheumatology, St Elisabeth Hospital, Tilburg, Netherlands. 2 Rheumatology Unit, Repatriation General Hospital, Daw Park, Australia. 3 Division of Rheumatology, UMDNJ - Robert Wood Johnson Medical School, New Brunswick, NJ, USA. 4 Monash Department of Clinical Epidemiology, Cabrini Hospital, Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Malvern, Australia. 5 Division of Rheumatology, Department of Internal Medicine 3, Medical University Vienna, Vienna, Austria Contact address: Irene van Echteld, Department of Rheumatology, St Elisabeth Hospital, Hilvarenbeekseweg 60, Tilburg, 5022GC, Netherlands. [email protected].

Editorial group: Cochrane Musculoskeletal Group. Publication status and date: New search for studies and content updated (conclusions changed), published in Issue 8, 2014. Review content assessed as up-to-date: 8 April 2014. Citation: van Echteld I, Wechalekar MD, Schlesinger N, Buchbinder R, Aletaha D. Colchicine for acute gout. Cochrane Database of Systematic Reviews 2014, Issue 8. Art. No.: CD006190. DOI: 10.1002/14651858.CD006190.pub2. Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT Background This is an update of a Cochrane review first published in 2006. Gout is one of the most common rheumatic diseases worldwide. Despite the use of colchicine as one of the first-line therapies for the treatment of acute gout, evidence for its benefits and harms is relatively limited. Objectives To evaluate the benefits and harms of colchicine for the treatment of acute gout. Search methods We searched the following electronic databases from inception to April 2014: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE. We did not impose any date or language restrictions in the search. We also handsearched conference proceedings of the American College of Rheumatology and the European League against Rheumatism (2010 until 2013) and reference lists of identified studies. We searched the clinical trials register clinicaltrials.gov and the WHO trials register. Selection criteria We considered published randomised controlled trials (RCTs) and controlled clinical trials (CCTs) evaluating colchicine therapy compared with another therapy (active or placebo) in acute gout. The primary benefit outcome of interest was pain, defined as a proportion with 50% or greater decrease in pain, and the primary harm outcome was study participants withdrawal due to adverse events. Data collection and analysis Two authors independently screened search results for relevant studies, extracted data into a standardised form and assessed the risk of bias of included studies. We pooled data if deemed to be sufficiently clinically homogeneous. We assessed the quality of the body of evidence for each outcome using the GRADE approach. Colchicine for acute gout (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Main results Two RCTs (124 participants) were included in this updated review, including one new RCT. We considered one trial to be at low risk of bias, while we considered the newly included trial to be at unclear risk of bias. Both trials included a placebo and a high-dose colchicine arm, although the colchicine regimens varied. In one trial 0.5 mg colchicine was given every two hours until there was either complete relief of symptoms or toxicity and the total doses were not specified. In the other trial a total of 4.8 mg colchicine was given over six hours. The newly identified trial also included a low-dose colchicine arm (total 1.8 mg over one hour). Based upon pooled data from two trials (124 participants), there is low-quality evidence that a greater proportion of people receiving high-dose colchicine experience a 50% or greater decrease in pain from baseline up to 32 to 36 hours compared with placebo (35/74 in the high-dose colchicine group versus 12/50 in the placebo group (risk ratio (RR) 2.16, 95% confidence interval (CI) 1.28 to 3.65), with a number needed to treat to benefit (NNTB) of 4 (95% CI 3 to 12). However, the total number of adverse events (diarrhoea, vomiting or nausea) is greater in those who receive high-dose colchicine versus placebo (62/74 in the high-dose colchicine group versus 11/50 in the placebo group (RR 3.81, 95% CI 2.28 to 6.38), with a number needed to treat to harm (NNTH) of 2 (95% CI 2 to 5). Only one trial included reduction of inflammation as part of a composite measure comprising pain, tenderness, swelling and erythema, each graded on a four-point scale (none 0 to severe 3) to derive a maximum score for any one joint of 12. They reported the proportion of people who achieved a 50% reduction in this composite score. Based upon one trial (43 participants), there was low-quality evidence that more people in the high-dose colchicine group had a 50% or greater decrease in composite score from baseline up to 32 to 36 hours than people in the placebo group (11/22 in the high-dose colchicine group versus 1/21 in the placebo group (RR 10.50, 95% CI 1.48 to 74.38) and 45% absolute difference). Based upon data from one trial (103 participants), there was low-quality evidence that low-dose colchicine is more efficacious than placebo with respect to the proportion of people who achieve a 50% or greater decrease in pain from baseline to 32 to 36 hours (lowdose colchicine 31/74 versus placebo 5/29 (RR 2.43, 95% CI 1.05 to 5.64)), with a NNTB of 5 (95% CI 2 to 20). There are no additional harms in terms of adverse events (diarrhoea, nausea or vomiting) with low-dose colchicine compared to placebo (19/74 and 6/29 respectively (RR 1.24, 95% CI 0.55 to 2.79)). Based upon data from one trial (126 participants), there is low-quality evidence that there are no additional benefits in terms of the proportion of people achieving 50% or greater decrease in pain from baseline up to 32 to 36 hours with high-dose colchicine compared to low-dose (19/52 and 31/74 respectively (RR 0.87, 95% CI 0.56 to 1.36). However, there were statistically significantly more adverse events in those who received high-dose colchicine (40/52 versus 19/74 in the low-dose group (RR 3.00, 95% CI 1.98 to 4.54)), with a NNTH of 2 (95% CI 2 to 3). No trials reported function of the target joint, patient-reported global assessment of treatment success, health-related quality of life or withdrawals due to adverse events. We identified no studies comparing colchicine to non-steroidal anti-inflammatory drugs (NSAIDs) or other active treatments such as glucocorticoids (by any route). Authors’ conclusions Based upon only two published trials, there is low-quality evidence that low-dose colchicine is likely to be an effective treatment for acute gout. We downgraded the evidence because of a possible risk of selection and reporting biases and imprecision. Both high and low-dose colchicine improve pain when compared to placebo. While there is some uncertainty around the effect estimates, compared with placebo, high-dose but not low-dose colchicine appears to result in a statistically significantly greater number of adverse events. Therefore low-dose colchicine may be the preferred treatment option. There are no trials about the effect of colchicine in populations with comorbidities or in comparison with other commonly used treatments, such as NSAIDs and glucocorticoids.

PLAIN LANGUAGE SUMMARY Colchicine for treating acute gout attacks We reviewed the evidence about the benefits and harms of colchicine in acute gout up to April 2014 and identified two trials. One trial included 43 participants and compared high-dose colchicine (1 mg of colchicine followed by 0.5 mg every two hours until the attack resolved or participants had side effects (total dose unspecified)) to placebo. The second study included 184 participants and compared high-dose (total 4.8 mg over six hours) to low-dose colchicine (total 1.8 mg over one hour) and high or low-dose colchicine to placebo. What is gout and what is colchicine? Colchicine for acute gout (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Gout is a very common cause of inflammatory arthritis (pain, redness, warmth and swelling of affected joints) and is caused by urate crystals forming either within or around joints. Uric acid is a normal waste product that is usually excreted with urine. However, in the case of gout, there is either excessive production of uric acid, or the body is not able to excrete it quickly enough, or a combination of both. An attack of gout usually occurs rapidly and usually resolves within 7 to 10 days. Colchicine is a drug that is used mainly in gout to treat an acute attack or to prevent an attack while starting uric acid-lowering therapy. Best estimate of what happens to people with gout who use high-dose colchicine compared to a fake medication (placebo) after 32 to 36 hours: Pain: - 52 people out of 100 who used high-dose colchicine rated their pain 50% lower compared to 24 people out of 100 who used placebo (28% absolute difference). Side effects: - 84 people out of 100 who used high-dose colchicine had side effects (such as diarrhoea, vomiting or nausea) compared to 22 people out of 100 who used placebo (62% absolute difference). Inflammation (redness and swelling of the joint): - 50 people out of 100 who used high-dose colchicine rated their inflammation 50% lower compared to 5 people out of 100 who used a placebo (45% absolute difference). Best estimate of what happens to people with gout who use low-dose colchicine compared to a fake medication (placebo) after 32 to 36 hours: Pain: - 42 people out of 100 who used low-dose colchicine rated their pain 50% lower compared to 17 people out of 100 who used placebo (25% absolute difference). Side effects: - 26 people out of 100 who used low-dose colchicine had side effects (such as diarrhoea, vomiting or nausea) compared to 20 people out of 100 who used placebo (6% absolute difference). Best estimate of what happens to people with gout who use high-dose colchicine compared to low-dose colchicine after 32 to 36 hours: Pain: - 37 people out of 100 who used high-dose colchicine rated their pain 50% lower compared to 42 people out of 100 used low-dose colchicine (this may have happened by chance). Side effects: - 77 people out of 100 who used high-dose colchicine had side effects (such as diarrhoea, vomiting or nausea) compared to 26 people out of 100 who used low-dose colchicine (51% absolute difference). We do not know how many people dropped out of the studies due to side effects, or whether they had any changes in inflammation (joint swelling/erythema/ tenderness), function of the target joint, patient global assessment or health-related quality of life, because this was not reported in the studies that compared low-dose to placebo or high-dose to low-dose colchicine. Quality of the evidence This review shows that in people with acute gout: - There is low-quality evidence that treatment of acute gout with high-dose colchicine may reduce pain, swelling, redness and tenderness. - There is low-quality evidence that high-dose colchicine may have little or no difference in decreasing pain compared to low-dose colchicine. - There is low-quality evidence that low-dose colchicine has fewer side effects such as nausea, vomiting and diarrhoea than high-dose colchicine. Colchicine for acute gout (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.


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S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]

High-dose colchicine versus placebo for acute gout Patient or population: patients with acute gout Settings: hospital and outpatient Intervention: high-dose colchicine versus placebo Outcomes

Illustrative comparative risks* (95% CI)

Assumed risk

Corresponding risk

Control (Placebo)

High-dose colchicine

Relative effect (95% CI)

No of participants (studies)

Quality of the evidence (GRADE)

Comments

Proportion with 50% or 240 per 1000 greater decrease in pain score from baseline - 32 to 36 hours

518 per 1000 (307 to 876)

RR 2.16 (1.28 to 3.65)

124 (2 studies)

⊕⊕

low1,2

Absolute risk difference: 28% (8% to 46%) more people receiving colchicine achieved the endpoint Relative per cent change: 116% (28% to 265%) NNTB: 4 (3 to 12)3

Withdrawals due to ad- See comment verse events - not reported

See comment

Not estimable

-

See comment

Not reported clearly if participants stopped treatment when they had an adverse event

Proportion with 50% or 48 per 1000 greater decrease in inflammation score from baseline - 32 to 36 hours

504 per 1000 (278 to 1000)

RR 10.50 (1.48 to 74.38) 43 (1 study)

⊕⊕

low2

Absolute risk difference: 45% (22% to 68%) more people receiving colchicine achieved endpoint Relative per cent change: 950% (48% to 7338%) NNTB: 3 (2 to 19)3

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Function - not measured See comment

See comment

Not estimable

-

See comment

Not measured

Participant global as- See comment sessment - not measured

See comment

Not estimable

-

See comment

Not measured

Quality of life - not mea- See comment sured

See comment

Not estimable

-

See comment

Not measured

Total adverse events 220 per 1000 (diarrhoea, vomiting or nausea)

838 per 1000 (502 to 1000)

RR 3.81 (2.28 to 6.38)

124 (2 studies)

⊕⊕⊕ low1,2

Absolute risk difference: 62% (46 to 86) more events with colchicine Relative per cent change: 281% (128% to 538%) more events with placebo NNTH: 2 (2 to 5)3

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; NNTB: number needed to treat to benefit; NNTH: number needed to treat to harm; RR: risk ratio GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1

There was a risk of selection bias due to unclear reporting of the method of randomisation, and a risk of reporting bias in one trial. The total number of participants is small and the total number of events is small. 3 NOTE: number needed to treat to benefit or harm (NNTB or NNTH) = n/a when result is not statistically significant. NNT for dichotomous outcomes calculated using Cates NNT calculator (http://www.nntonline.net/visualrx/). 2

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BACKGROUND

Description of the condition Gout is a disease in which monosodium urate crystals form deposits in and around the joints, which may result in painful, swollen and tender joints or soft tissues and/or tophi. The onset of acute gout is often sudden and dramatic, often beginning at night, and characterised by severe pain (Schumacher 2005). Uric acid is a normal waste product that is usually excreted from the body. However, in the case of gout, there is either excessive production of uric acid (in a minority of people with gout) or the body is not able to excrete it quickly enough (in most people with gout), or both. This results in the formation of monosodium urate crystals. The lower extremity joints, particularly the first metatarsophalangeal joint, are most commonly affected. Other joints that can be affected include the ankle, knee, foot, hand, wrist and elbow. Usually, only one joint is affected (monoarthritis), but oligoarticular or polyarticular acute gout may also occur and is more prevalent in male hypertensive patients and in postmenopausal women (Kasper 2005). Gout is the most common form of inflammatory joint disease in men greater than 40 years of age, and its prevalence varies widely, since both genetic and environmental factors contribute to its incidence (Schumacher 2005). The highest prevalence is among elderly men, with rates as high as seven per cent in men over the age of 65 years (Mikuls 2005). Risk factors traditionally associated with gout include obesity, alcohol consumption, renal dysfunction, diuretic use and hyperuricaemia (Wortmann 2002). Gout is traditionally perceived as a disease afflicting men, while women represent only 5% to 17% of all patients with the disease. Premenopausal gout is rare and seen mostly in women with strong family histories of the disorder (Kasper 2005). Menopause increases the risk of gout among women, whereas postmenopausal hormone therapy modestly reduces gout risk (Hak 2010). Some patients recover from an acute gout attack without intervention within seven days, but the clinically significant pain associated with acute gout attacks creates a need for agents that accelerate the rate of improvement (Bellamy 1987). Resting the afflicted joint for one to two days may aid in the resolution of an attack, and less medication may be needed to bring about the resolution (Agudelo 1972; Schumacher 2005). Ice therapy has been suggested to reduce the pain associated with acute attacks - cold application may be a useful adjunct to the pharmacological treatment of acute gout (Moi 2013; Schlesinger 2002). Heat application to an inflamed joint may exacerbate inflammation and is not recommended (Dorwart 1974). Avoidance of triggers important in the development of gout by asymptomatic hyperuricaemic patients may reduce the frequency of attacks. Avoiding diuretics, weight gain and alcohol may lead to a decrease in the frequency of acute gout attacks (Tugwell 2004). Dietary interventions, such as limitation of carbohydrate intake, an increased

proportional intake of protein and the use of unsaturated fat, may also limit the frequency of acute gout attacks (Tugwell 2004). Pharmacological treatments that are commonly used in the treatment of acute gouty flares include oral non-steroidal anti-inflammatory drugs (NSAIDs), colchicine, oral glucocorticoids and injection of glucocorticoids into the affected joint (Arnold 1988; Janssens 2008a; Janssens 2008b; Schlesinger 2004; Wallace 1998; Wechalekar 2013). The use of adrenocorticotropic hormone may also aid in the resolution of acute gout attacks (Schlesinger 2001). In this review we focus on the evidence for colchicine in the treatment of acute gout.

Description of the intervention In gout, monosodium urate crystals are phagocytosed and additional leucocytes are attracted to the site of inflammation. Colchicine is the main alkaloid of the poisonous autumn crocus plant and has been used to treat acute gout for over 2000 years (Schlesinger 2004). Colchicine is available in oral and intravenous form. The absorption of oral colchicine is rapid but can be highly variable. Relief of pain usually occurs 24 hours after colchicine is given orally (Schlesinger 2004). Serious systemic reactions, including bone marrow suppression, renal failure, alopecia, disseminated intravascular coagulation, hepatic necrosis, diarrhoea, seizures and death, have all been associated with intravenous colchicine (Wallace 1998). The most important side effects of oral colchicine are nausea, vomiting and diarrhoea and these may be particularly difficult to endure when patients are in pain and incapacitated by acute gouty arthritis (Morris 2003). The recommended dosage of oral colchicine has been debated in the literature, and the optimal dose is not well defined (Cox 2004; Morris 2003; Sivagnanam 2004). Both the European League against Rheumatism (EULAR) recommendation (Zhang 2006) and a more recent recommendation (Hamburger 2011), advise the use of a low-dose colchicine regimen because of the toxicity of higher doses, but neither specify what the low-dose regimen entails. Colchicine tablets come in different strengths depending upon country of use. For example, in Australia the tablets are 0.5 mg (also expressed as 500 micrograms) and the Australian Rheumatology Association patient information leaflet for colchicine (last updated November 2012) recommends one or two tablets initially (0.5 mg to 1 mg), followed by one tablet (0.5 mg) one hour later and waiting 12 hours before taking the next tablet (Australian Rheumatology Association 2012). Thereafter one or two tablets can be taken daily for a couple of days to completely settle the attack. In Austria, the tablets are 0.372 mg. The dosing regimen is two tablets (0.744 mg) every two to three hours until either a maximum dose of 6 mg (i.e. 15 to 16 tablets), symptoms resolve or side effects occur. After a minimum of two to three days the course can be repeated if needed.


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How the intervention might work

Types of participants

The exact mechanism by which colchicine relieves the pain of an acute gouty attack is not presently known. The major pharmacological action of colchicine is its ability to bind to tubulin dimers (Schlesinger 2004). It prevents the polymerisation of microtubules by binding their protein subunits and preventing conglomeration - disrupting membrane-dependent functions such as chemotaxis and phagocytosis (Schumacher 1993). Colchicine is also suspected to interfere with leukocyte function, preventing diapedesis, mobilisation, lysosomal degranulation and chemotaxis (Schlesinger 2004).

Adult patients (aged 18 years or older) with a diagnosis of acute gout (author defined or presence of monosodium crystals in joint aspirate, or patients fulfilling the American College of Rheumatology (Wallace 1977) or the Rome (1963) or New York (1966) criteria for gout (O’Sullivan 1972)). We excluded populations that included a mix of people with acute gout and other musculoskeletal pain unless results for the acute gout population could be separated out from the analysis.

Why it is important to do this review The natural course of untreated gouty arthritis attacks can last from several hours to several weeks (Schlesinger 2004). Although rest of the affected joint and cold therapy may provide some relief of symptoms, non-pharmacological measures often fall short (Agudelo 1972; Moi 2013; Schlesinger 2002). Therefore it is important to understand the benefits and harms of pharmacological agents. Colchicine is commonly used to treat patients with mono- or oligo-articular acute gout but has potential side effects. In addition, people with gout may have clinically significant comorbidities that may influence the choice of therapy. While rheumatologic guidelines recommend use of low-dose oral colchicine for the treatment of people with acute gout, the specific dosage has not been specified. Therefore there is a need to determine the benefits and harms of high and low-dose colchicine in a systematic review and identify the optimum dosing regimen.

OBJECTIVES To evaluate the benefits and harms of colchicine for the treatment of acute gout.

METHODS

Criteria for considering studies for this review

Types of interventions All trials that evaluated the benefits or harms (or both) of colchicine administered by any route and at any dose were considered for inclusion. Comparators could be: 1. placebo; 2. no treatment; 3. paracetamol; 4. NSAIDs (via any route); 5. glucocorticoids (via any route); 6. interleukin-1 (IL-1) inhibitors; 7. non-pharmacological treatment; 8. one dose of colchicine versus another; 9. combination therapy (any of the above combinations). Types of outcome measures There is considerable variation in the outcome measures reported in clinical trials of interventions for acute gout. For the purpose of this review, we aimed to include outcome measures that are considered to be of greatest importance to patients with acute gout and the clinicians who care for them. OMERACT (Outcome Measures in Rheumatology Clinical Trials) has proposed outcome measures to be used in evaluation of resolution of acute attacks (Grainger 2009; Schumacher 2005). Intense pain is the hallmark of an acute gout attack and hence pain has been proposed as an OMERACT outcome measure; it also has been a consistent outcome measure in clinical trials involving acute gout attacks, although the instruments and time intervals used to measure pain vary (Grainger 2009). The other proposed OMERACT outcome measures include joint swelling and tenderness, patient global assessment and safety (Grainger 2009; Schumacher 2005). Major outcomes

Types of studies All published randomised controlled trials and controlled clinical trials (RCTs or CCTs) investigating the benefits and harms of colchicine in patients with acute gout were eligible for inclusion. We only considered trials that were published as full articles or were available as a full trial report for inclusion.

1. Benefits: defined as the proportion of participants with 50% or greater decrease in pain 2. Harms: defined as study participant withdrawal due to adverse events (AE) 3. Reduction of inflammation (joint swelling/erythema/ tenderness)


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4. Function of target joint (movement) 5. Patient global assessment of treatment success 6. Health-related quality of life (HRQoL) 7. Total number of adverse events (AE), serious adverse events (SAE) and type of adverse events We considered inclusion of all endpoints as measured in the included trials and combined data into short (up to two weeks), medium (two to six weeks) and long-term (more than six weeks), but only short-term data were available.

Search methods for identification of studies

assessment, co-interventions, adverse effects and loss to followup of included studies, using a standardised data extraction form. We resolved differences in data extraction by referring back to the original articles and establishing consensus. We consulted a third author (RB) to help resolve differences if necessary. Only outcomes specified in the protocol were included in the review. We entered continuous data (e.g. visual analogue scales of pain, patient global assessment) as means and standard deviations (SD), and dichotomous outcomes (e.g. response, improvement) as number of events. When raw data were not provided, we extracted data from figures and calculated standard deviations from confidence interval estimates. Assessment of risk of bias in included studies

Electronic searches We performed searching as outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011d). We searched the following electronic databases from their inception: 1. Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 3) to 8 April 2014 (Appendix 1); 2. OVID MEDLINE 1948 to 8 April 2014 (Appendix 2); 3. EMBASE 1980 to 8 April 2014 (Appendix 3). We applied no language restrictions. Searching other resources We searched abstracts from the two major international rheumatology scientific meetings, the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR), for the years 2010 to 2013. We inspected the reference lists of included articles for additional trials. We searched the clinical trials register clinicaltrials.gov and the World Health Organization (WHO) trials register for relevant trials.

Data collection and analysis Selection of studies Two review authors (IvE, MW) independently assessed each title and abstract for suitability for inclusion in the review according to the predetermined selection criteria. The review authors were not blinded to authors or institutions. In cases of doubt, we retrieved and read all articles. We discussed disagreements about the eligibility of the articles between review authors in a consensus meeting.

Two review authors (IvE, MW) independently assessed the risk of bias of each included study with regard to the following items: random sequence generation; allocation concealment; blinding of participants, care provider and outcome assessor for each outcome measure (see Types of outcome measures); incomplete outcome data; selective outcome reporting; and other potential sources of bias (baseline imbalance and inappropriate administration of a cointervention), conforming to the methods recommended by The Cochrane Collaboration (Higgins 2011a). To determine the risk of bias of a study, we evaluated the presence of sufficient information and the likelihood of potential bias for each criterion. We rated each criterion as low risk of bias, high risk of bias or unclear risk of bias (either lacking information or uncertainty over the potential for bias). In a consensus meeting of review authors we discussed and resolved any disagreements. Measures of treatment effect In order to assess benefits, if available, we extracted raw data for outcomes of interest as well as number of participants. If reported data needed to be converted or imputed, we recorded this in the notes section of the table Characteristics of included studies. We plotted the results of each trial as risk ratios (RRs) with corresponding 95% confidence intervals (CIs) for dichotomous outcomes and as mean differences (MDs) between the intervention and comparator group, with corresponding 95% CIs for continuous data. The mean difference between treated group and control group is weighted by the inverse variance in the pooled treatment estimate. However, if different scales were used to measure the same conceptual outcome (e.g. functional status or pain), we calculated standardised mean differences (SMD) instead, with corresponding 95% confidence intervals. We calculated SMDs by dividing the MD by the standard deviation, resulting in a unitless measure of treatment effect (Deeks 2011).

Data extraction and management Two review authors (IvE, MW) independently extracted data regarding study design, study duration, characteristics of study population, interventions, outcome measures and timing of outcome

Unit of analysis issues In the event that we identified cross-over trials in which the reporting of continuous outcome data precluded paired analysis, we did


9

not plan to include these data in a meta-analysis, in order to avoid unit of analysis error. Where carry-over effects were thought to exist, and where sufficient data existed, we planned to only include data regarding the first period in the analysis (Higgins 2011b). However, we identified no cross-over trials. For studies containing more than two intervention groups, to make multiple pair-wise comparisons between all possible pairs of intervention groups possible, if data were available we planned to include the same group of participants only once in the same meta-analysis. Dealing with missing data In cases where individuals were missing from the reported results, we assumed the missing values to have a poor outcome. For dichotomous outcomes (e.g. number of withdrawals due to adverse events), we calculated the withdrawal rate using the number of patients randomised in the group as the denominator (worst case scenario). For continuous outcomes (e.g. mean change in pain score), we calculated the MD or SMD based on the number of patients analysed at that time point. If the number of patients analysed was not presented for each time point, we used the number of randomised patients in each group at baseline. Where possible, we computed missing SDs from other statistics such as standard errors (SEs), CIs or P values, according to the methods recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011c). If we could not calculate SDs, we imputed them, for example from other studies in the meta-analysis. Assessment of heterogeneity Prior to meta-analysis we assessed studies for clinical homogeneity with respect to type of therapy, control group and the outcomes. For any studies judged as clinically homogeneous, we assessed statistical heterogeneity using I2 statistics (Deeks 2011), using the following as a rough guide for interpretation: 0% to 40% might not be important; 30% to 60% may represent moderate heterogeneity; 50% to 90% may represent substantial heterogeneity; and 75% to 100% may represent considerable heterogeneity. In cases of considerable heterogeneity (defined as I2 > 75%), we planned to explore the data further, including subgroup analyses, in an attempt to explain the heterogeneity. Assessment of reporting biases We planned an assessment of reporting bias through the screening of the International Clinical Trials Registry Platform of the World Health Organization (http://apps.who.int/trialssearch; De Angelis 2004), to determine whether the protocols for included RCTs were published before recruitment of participants into the study had started. We planned to evaluate whether selective reporting of outcomes was present (outcome reporting bias).

We planned to compare the fixed-effect estimate against the random-effects model. In the event of the possible presence of small sample bias in the published literature (i.e. in which the intervention effect is more beneficial in smaller studies), the random-effects estimate of the intervention is more beneficial than the fixedeffect estimate (Sterne 2011). We planned to further explore the potential for reporting bias by funnel plots if more than 10 studies were included. Data synthesis Where studies were sufficiently homogeneous that it remained clinically meaningful for them to be pooled, we performed metaanalysis using a random-effects model, regardless of the I2 results. We performed analyses using Review Manager 5.1 (RevMan 2014), and produced forest plots for all analyses. Subgroup analysis and investigation of heterogeneity We planned to perform a subgroup analysis if data were available comparing treatment response for those with or without comorbidities. If data were available in the trials, we planned to extract data on subgroups and present data with subgroup totals. We planned to compare the magnitudes of the effects informally between the subgroups by means of assessing the overlap of the confidence intervals of the effect estimate. Non-overlap of the confidence intervals indicates statistically significant responses between the subgroups. There were insufficient data for this subgroup analysis. Sensitivity analysis We had planned sensitivity analyses for studies with regard to allocation concealment, blinding of outcome assessor and loss to follow-up, comparing studies with limitations (low risk of bias versus high risk of bias or unclear risk of bias), however there were insufficient data to perform sensitivity analyses. ’Summary of findings’ table The main results of the review are presented in a ’Summary of findings’ table, which includes an overall grading of the evidence using the GRADE approach (GRADEpro) as described in the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2011). We produced a summary of the available data for the main outcomes (proportion who reported an improvement in pain by 50% or more, reduction in inflammation, function of target joint, patient global assessment, quality of life, total number of withdrawals due to adverse effects and total adverse events). Grading of the evidence involves consideration of within-study risk of bias, indirectness of evidence, heterogeneity, imprecision of effect estimates and risk of publication bias. However, other factors can affect the quality of evidence, for example it can be increased by a large magnitude of effect, plausible confounding and dose-


10

response gradients. Using this system, we planned to grade the quality of the body of evidence as ’high’, ’moderate’, ’low’ or ’very low’ (Atkins 2004). In addition to the absolute and relative magnitude of effect provided in the ’Summary of findings’ table, for dichotomous outcomes, we calculated the number needed to treat to benefit (NNTB) or the number needed to treat to harm (NNTH) from the control group event rate and the RR using the Visual Rx NNT calculator (Cates 2008). For continuous outcomes, we calculated the NNTB or NNTH using the Wells calculator software available at the Cochrane Musculoskeletal Group (CMSG) editorial office. We determined the minimal clinically important difference (MCID) for each outcome for input into the calculator.

RESULTS

Description of studies Results of the search The search strategy yielded a total of 1035 articles from the databases (Figure 1). After de-duplication and title and abstract screening, we retrieved three studies for full assessment (Ahern 1987; Schlesinger 2002; Terkeltaub 2010). We identified two meeting abstracts from conference proceedings. Both appear to be secondary analyses of Terkeltaub 2010. As these data have not yet been published, they were not included in this review.


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Figure 1. Study flow diagram.


12

Included studies Two RCTs fulfilled our inclusion criteria (see Characteristics of included studies table) (Ahern 1987; Terkeltaub 2010). One trial was conducted in Australia, included 43 participants (40 men, three women) and compared high-dose colchicine (1 mg oral colchicine then 0.5 mg every two hours until there was either relief of pain or side effects from the drug) (n = 22) with placebo (n = 21), for acute gout attacks (Ahern 1987). The mean (SD) total dose of colchicine given was not specified. All patients had the diagnosis of acute gout confirmed by joint aspiration and demonstration of negatively birefringent needle-shaped monosodium urate crystals under polarised light microscopy. No NSAIDs were allowed for 48 hours before or during the study. Participants were assessed every six hours for 48 hours. Pain was measured on a 100-point visual analogue scale and results were reported as proportion with 50% or greater improvement in pain from baseline at 12, 24, 36 and 48 hours, while mean pain scores at six-hourly intervals to 48 hours were shown graphically only. A compound clinical score comprised of pain, tenderness, redness and swelling (on a four-point scale, 0 to 3 score recorded for each symptom, maximum compound score of 12) was also recorded and presented as proportion with 50% or greater improvement in clinical score from baseline at 12, 24, 36 and 48 hours. The second trial, conducted in 54 centres in the USA, involved a total of 575 participants randomised to one of three treatment groups: low-dose colchicine (total 1.8 mg over one hour), highdose colchicine (total 4.8 mg over six hours) or placebo (Terkeltaub 2010). Participants were included if they had a diagnosis of acute gout according to the ACR preliminary classification criteria. All randomised participants were provided with study medication and instructed to call the Gout Flare Call Center if they developed a gout flare. A gout flare was confirmed if the onset was within the prior 12 hours, four cardinal signs of inflammation were present, joint pain was assessed at 4 or more on a 0 to 10 numeric rating scale, and if there had been no use of prohibited medication or change in medical history since randomisation. One hundred and eighty-five participants had a qualifying flare (74/192 randomised to low-dose colchicine, 52/193 randomised to high-dose colchicine and 59/190 randomised to the placebo group) and 390/ 575 participants did not have a flare or had a ’non qualifying flare’ and were not included in the analysis. Rescue medication (including NSAIDs) was permitted if intolerable pain continued after taking at least one dose of the study drug. Uric acid-lowering therapy was permitted during the study period, and was not to be discontinued at the onset of the attack. Data were collected by a standardised diary to track symptoms, pain, adverse events and rescue medication use. Pain was measured on an 11-point Likert scale (0 no pain to 10 worst possible pain) at

baseline, then hourly for the first eight hours and every eight hours thereafter until 72 hours following the initial dose or symptom resolution. In addition, participants were assessed in the clinic as soon as possible following the onset of the attack, with the target for the first post attack visit being within 48 hours. After attack onset there were up to three more planned visits, the last being seven days after attack onset. At the clinic any adverse events were graded as mild, moderate or severe based on the study physicians’ clinical judgement. The primary outcome of this trial was the proportion of participants who responded to treatment, defined as having a reduction in pain of 50% or more from baseline within 24 hours of the first study dose. Alternate definitions of response included 1) treatment response based on the target joint pain score 32 hours after the first dose, 2) treatment response based on at least a two-unit reduction in the target joint pain score 24 hours after the first dose, and 3) treatment response based on at least a two-unit reduction in the target joint pain score 32 hours after the first dose. Excluded studies We excluded one study after detailed review (Schlesinger 2002). The excluded study was a RCT of local ice therapy in which both groups were treated with similar doses of prednisolone and colchicine (see the Characteristics of excluded studies table).

Risk of bias in included studies See also Characteristics of included studies table. We judged Ahern 1987 to be at an overall low risk of bias. This trial performed randomisation by a computer-generated random sequence held remotely; study personnel, outcome assessors and participants were all blinded and unaware of treatment allocation (personal communication from author). A matching placebo was used in conjunction with the study drug. No participants were lost to follow-up. Sample size calculation was performed but not provided (personal communication from author). There did not appear to be selective reporting of outcomes although it was not clear if the criterion of improvement (50% reduction from baseline score) was pre-specified. This trial predated compulsory registration. We considered other potential sources of bias, such as baseline imbalance and inappropriate administration of a co-intervention. We judged Terkeltaub 2010 to be at an overall unclear risk of bias. It was described as randomised but no further details on how randomisation was done were provided. Patients and study personnel at each site were blinded to treatment but the allocation concealment was not described (Terkeltaub 2010). For benefits, only the responders’ analysis was presented. The numbers of participants randomised to each group was equal but the number of


13

participants in each group who had an acute attack of gout and therefore received treatment and had outcome data was not equal. In addition, the numbers of participants by group treated at each site was not specified, but it is stated that some sites did not have patients in all treatment groups. Trial recruitment began in April 2007 and the study was registered in July 2007. Not all outcomes that were reported to have been measured were reported. We considered other potential sources of bias, such as baseline imbalance and inappropriate administration of a co-intervention. A ’Risk of bias’ graph and a ’Risk of bias’ summary can be seen in Figure 2 and Figure 3 respectively. Figure 2. ’Risk of bias’ graph: review authors’ judgements about each risk of bias item presented as percentages across all included studies.


14

Figure 3. ’Risk of bias’ summary: review authors’ judgements about each risk of bias item for each included study.

Effects of interventions See: Summary of findings for the main comparison High-dose colchicine versus placebo for acute gout; Summary of findings 2 Low-dose colchicine versus placebo for acute gout; Summary of findings 3 High-dose versus low-dose colchicine for acute gout We performed three comparisons: high-dose colchicine versus placebo, low-dose colchicine versus placebo and high versus lowdose colchicine. High-dose colchicine versus placebo

Benefits

Data from the two trials (124 participants) could be pooled (Summary of findings for the main comparison). Compared to placebo, a statistically significantly greater proportion of participants responded to treatment, defined as a 50% or greater reduction in pain from baseline, with high-dose colchicine at 24 hours and 32 to 36 hours (26/74 in the high-dose colchicine group versus 6/50 in the placebo group (risk ratio (RR) 2.88, 95% confidence interval (CI) 1.28 to 6.48); and 35/74 in the high-dose colchicine group versus 12/50 in the placebo group (RR 2.16, 95% CI 1.28 to 3.65); number needed to treat to benefit (NNTB) 4 (95% CI


15

3 to 12), respectively) (Analysis 1.1). Data from one trial (43 participants) also showed that the proportion of responders with respect to reduction of inflammation also favoured the high-dose colchicine group at 24 hours (5/22 in the high-dose colchicine group versus 0/21 in the placebo group (RR 10.52, 95% CI 0.62 to 179.29)); and at 36 hours (11/22 in the high-dose colchicine group versus 1/21 in the placebo group (RR 10.50, 95% CI 1.48 to 74.38)) (Analysis 1.2). Neither trial measured function of the target joint, patient global assessment of treatment response or health-related quality of life.

Adverse events

Neither trial reported study participant withdrawal due to serious adverse events (SAE), or withdrawals due to adverse events. In one trial, treatment was continued until complete response or toxicity (Ahern 1987). All 22 participants in the high-dose colchicine group in this trial developed diarrhoea or vomiting, or both (Ahern 1987). Median time of onset was at 24 hours (range 12 to 36 hours) or after a mean dose of 6.7 mg of colchicine. These adverse events occurred before treatment response (defined as 50% or greater reduction in pain from baseline) in 12/22 (55%), after response in 9/22 (41%) and concurrent with response in 1/22. Five participants (24%) in the placebo group developed nausea but none developed diarrhoea or vomiting, or both. Terkeltaub 2010 reported that statistically significantly more people in the high-dose colchicine group had adverse events (40/52) compared with the placebo group (8/29) (RR 2.79, 95% CI 1.52 to 5.12) (Analysis 1.3). Although the risk of adverse events was likely to have been inflated in the Ahern 1987 trial, we pooled data from the two trials for gastrointestinal adverse events (diarrhoea, vomiting or nausea). Compared to placebo, there was a statistically significant greater risk of developing gastrointestinal side effects with high-dose colchicine (62/74 in the high-dose colchicine group versus 11/50 in the placebo group (RR 3.81, 95% CI 2.28 to 6.38); NNTH 2 (95% CI 2 to 5)) (Analysis 1.4).

(RR 2.43, 95% CI 1.05 to 5.64), NNTB 5 (2 to 20), respectively) (Analysis 2.1) (Summary of findings 2). This trial did not measure reduction of inflammation, function of the target joint, patient global assessment of treatment response or health-related quality of life.

Adverse events

Data from one trial, involving 103 participants, indicated that the total number of adverse events was not statistically significantly different among those who received low-dose colchicine (27/74) or placebo (8/29) (RR 1.32, 95% CI 0.68 to 2.56) (Analysis 2.2). Gastrointestinal side effects (diarrhoea, vomiting or nausea) in the low-dose colchicine group were not statistically significantly more frequent than in the placebo group (19/74 with low-dose colchicine versus 6/29 with placebo (RR 1.24, 95% CI 0.55 to 2.79)) (Analysis 2.3). This trial did not measure study participant withdrawal due to serious adverse events (SAE). High-dose versus low-dose colchicine

Benefits

Data from one trial, involving 126 participants, found that there was no statistically significant difference between high and lowdose colchicine with respect to the proportion of participants who reported a reduction in pain of 50% or more from baseline at 24 hours and 32 hours (17/52 in the high-dose colchicine group versus 28/74 in the low-dose colchicine group (RR 0.86, 95% CI 0.53 to 1.41), and 19/52 in the high-dose colchicine group versus 31/74 in the low-dose colchicine group (RR 0.87, 95% CI 0.56 to 1.36), respectively) (Analysis 3.1) (Summary of findings 3). This trial did not measure reduction of inflammation, function of the target joint, patient global assessment of treatment response or health-related quality of life.

Adverse events

Low-dose colchicine versus placebo

Benefits

Data from one trial, involving 103 participants, found that a statistically significant greater proportion of participants reported a reduction in pain of 50% or more from baseline at 24 hours and 32 hours with low-dose colchicine than with placebo (28/74 versus 4/29 (RR 2.74, 95% CI 1.05 to 7.13); and 31/74 versus 5/29

Data from one trial, involving 126 participants, indicated that the total number of adverse events was statistically significantly greater among those who received high-dose colchicine compared with those who received low-dose colchicine (40/52 versus 27/74 (RR 2.11, 95% CI 1.51 to 2.95)) (Analysis 3.2). Compared with lowdose colchicine, there was also a higher risk of gastrointestinal side effects (diarrhoea, vomiting or nausea) with high-dose colchicine (40/52 versus 19/74 (RR 3.00, 95% CI 1.98 to 4.54)) (Analysis 3.3). This trial did not measure study participant withdrawal due to serious adverse events (SAE).


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A D D I T I O N A L S U M M A R Y O F F I N D I N G S [Explanation]

Low-dose colchicine versus placebo for acute gout Patient or population: patients with acute gout Settings: outpatient Intervention: low-dose colchicine versus placebo Outcomes


Assumed risk

Corresponding risk

Control (placebo)

Low-dose colchicine




Comments


418 per 1000 (181 to 970)

RR 2.43 (1.05 to 5.64)

103 (1 study)

⊕⊕

low1,2

Absolute risk difference: 25% more people achieved endpoint with colchicine (7% to 42% more); Relative per cent change: 143% (5% to 464%) NNTB 5 (2 to 20)2


See comment

Not estimable

-

See comment


Proportion with 50% or See comment greater decrease in inflammation score from baseline - 32 to 36 hours - not measured

See comment

Not estimable

-

See comment

Not measured


See comment

Not estimable

-

See comment

Not measured

17



See comment

Not estimable

-

See comment

Not measured


See comment

Not estimable

-

See comment

Not measured


257 per 1000 (114 to 578)

RR 1.24 (0.55 to 2.79)

103 (1 study)

⊕⊕

low1,2

Absolute risk difference: 6% more events with colchicine (13% fewer to 23% more) Relative per cent change: 24% more events (45% fewer to 179% more) NNTH n/a3

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; NNTB: number needed to treat to benefit; NNTH: number needed to treat to harm; RR: risk ratio GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 There

was a risk of selection bias due to unclear reporting of the method of randomisation, and a risk of reporting bias. event rate and 95% CI includes no effect, or appreciable benefit. 3 NOTE: number needed to treat to benefit or harm (NNTB or NNTH) = n/a when result is not statistically significant. NNT for dichotomous outcomes calculated using Cates NNT calculator (http://www.nntonline.net/visualrx/) 2 Low

18


High-dose versus low-dose colchicine for acute gout Patient or population: patients with acute gout Settings: outpatient Intervention: high-dose versus low-dose colchicine Outcomes


Assumed risk Control colchicine)




Comments

Corresponding risk (low-dose High-dose colchicine


365 per 1000 (235 to 570)

RR 0.87 (0.56 to 1.36)

126 (1 study)

⊕⊕

low1,2

Absolute risk difference: 5% fewer events with high-dose (23% fewer to 12% more) Relative per cent change: 13% fewer (44% fewer to 136% more) NNTB n/a3


See comment

Not estimable

-

See comment


Proportion with 50% or See comment greater decrease in inflammation score from baseline - 32 to 36 hours - not measured

See comment

Not estimable

-

See comment

Not reported


See comment

Not estimable

-

See comment

Not measured

19



See comment

Not estimable

-

See comment

Not measured


See comment

Not estimable

-

See comment

Not measured


771 per 1000 (509 to 1000)

RR 3.00 (1.98 to 4.54)

126 (1 study)

⊕⊕

low1,2

Absolute risk difference: 51% more events with high-dose (36% to 66%) Relative per cent change: 200% more (98% to 354%) NNTH 2 (2 to 3)3

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; NNTB: number needed to treat to benefit; NNTH: number needed to treat to harm; RR: risk ratio GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 There

was a risk of selection bias due to unclear reporting of the method of randomisation, and a risk of reporting bias. event rate and 95% CI includes no effect, or appreciable benefit. 3 NOTE: number needed to treat to benefit or harm (NNTB or NNTH) = n/a when result is not statistically significant. NNT for dichotomous outcomes calculated using Cates NNT calculator (http://www.nntonline.net/visualrx/). 2 Low

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DISCUSSION

Summary of main results

High-dose colchicine versus placebo Compared with placebo, there is low-quality evidence that highdose colchicine results in statistically significant benefits at 36 hours, but is associated with statistically significant adverse events (Summary of findings for the main comparison). We downgraded the evidence because of a potential risk of bias, and the small number of trial participants and the low event rates indicating imprecision. Both high and low-dose colchicine improve pain when compared to placebo. While there is some uncertainty around the effect estimates, there was a statistically significant difference favouring high-dose colchicine with respect to the proportion of people whose pain reduces by 50% or more from baseline. However, there was also a statistically significant difference favouring the placebo group with respect to total numbers of people with gastrointestinal adverse events (diarrhoea, vomiting or nausea), with more people receiving high-dose colchicine developing a gastrointestinal adverse event. There was also a statistically significant difference favouring high-dose colchicine with respect to improvement in inflammation based upon a composite clinical score, with more people receiving high-dose colchicine achieving this endpoint. No trials measured withdrawals due to adverse events, function, patient global assessment of treatment response or health-related quality of life.

Low-dose colchicine versus placebo Compared with placebo, there is low-quality evidence that lowdose colchicine results in benefits at 36 hours, with a comparable safety profile. While there is some uncertainty around the effect estimates, there was a statistically significant difference favouring low-dose colchicine with respect to the proportion of people whose pain reduces by 50% or more from baseline, with more people receiving low-dose colchicine achieving this endpoint. However, there was no statistically significant difference between the placebo and the low-dose colchicine group with respect to the total numbers of people with gastrointestinal events (diarrhoea, vomiting or nausea). We downgraded the evidence because of a potential risk of bias, and the small number of trial participants and the low event rates indicating imprecision. No trials measured withdrawals due to adverse events, reduction of inflammation, function, patient global assessment of treatment response or health-related quality of life.

High-dose versus low-dose colchicine Compared with low-dose colchicine, there is low-quality evidence that high-dose colchicine results in similar benefits at 36 hours, but is associated with more adverse events. While there is some uncertainty around the effect estimates, there was no statistically significant difference between the low-dose colchicine group and the high-dose colchicine group with respect to the proportion of people whose pain reduces by 50% or more from baseline. However, there was a statistically significant difference favouring the low-dose colchicine group with respect to the total numbers of people with gastrointestinal events (diarrhoea, vomiting or nausea), with more people receiving high-dose colchicine developing a gastrointestinal adverse event. We downgraded the evidence because of a potential risk of bias, and the small number of trial participants and the low event rates indicating imprecision. No trials measured withdrawals due to adverse events, reduction of inflammation, function, patient global assessment of treatment response or health-related quality of life. There were no trials that compared colchicine to other interventions known to be effective in the treatment of acute gout, such as non-steroidal anti-inflammatory drugs (NSAIDs) or glucocorticoids.

Overall completeness and applicability of evidence There are several treatment options for acute gout. When it comes to the use of colchicine, the overall balance of benefits and harms is key. We identified only two trials investigating the benefits and harms of colchicine here. Both trials compared highdose colchicine to placebo while one trial also included a lowdose colchicine comparator arm. The data suggest that low-dose colchicine is as effective as higher doses of colchicine but that the risk of adverse events is lower, without any difference from placebo. Colchicine and its metabolites are excreted through the urinary and biliary tracts, and the presence of renal or liver disease increases the time needed for clearance of colchicine two- to three-fold (Ben-Chetrit 1998). This suggests that patients with either liver or renal disease may need to be closely monitored even while on low doses of colchicine. Neither trial included in this review provided baseline participant hepatic or renal function data, however, one trial did report that the risk of experiencing gastrointestinal events was similar when demographic characteristics, concomitant allopurinol use or estimated creatinine clearance was compared (Terkeltaub 2010). The small number of included studies and study participants means that uncommon but potentially serious adverse events may not have been detected. There have been reports of bone marrow and neuromuscular toxicity with the use of low-dose colchicine (0.5 mg twice a day) (Kuncl 1987). We found no trials of colchicine compared with other interventions, including NSAIDs and oral or intraarticular gluco-


21

corticoids. However the British National Formulary states that “colchicine is probably at least as effective as NSAIDs in treating acute attacks of gout, although no randomised controlled trials have been completed to date” (BNF 2006). In addition, the EULAR guideline (Zhang 2006) and a more recent review by Hamburger et al (Hamburger 2011) stated that NSAIDs were equally effective for addressing the signs and symptoms of an acute gout attack, however we are unaware of any head-to-head randomised controlled trials that have examined the comparative benefits and harms of colchicine in comparison to NSAIDs. Colchicine can be administered intravenously to treat attacks of acute gout. However, overdose is a serious risk, and misuse can result in toxicity, severe organ damage or death. Although no randomised controlled trials have been conducted to evaluate the benefits and harms of intravenous colchicine, most practitioners discourage its use because of the possibility of these serious and sometimes life-threatening side effects (Schlesinger 2004). Colchicine is metabolised by cytochrome P450 3A4 (CYP3A4) and is also a substrate for the P-glycoprotein transporter and serious (including fatal) colchicine toxicity has been reported in patients taking standard therapeutic doses of colchicine and concomitantly prescribed medications that inhibit CYP3A4 or Pglycoprotein (these include clarithromycin, erythromycin, ketoconazole, ritonavir, verapamil and diltiazem, among others). The US Food and Drug Administration (FDA) recommends that these drugs not be used in patients taking colchicine (particularly when there is co-existing renal of hepatic impairment) and, relatively recently, a dose reduction algorithm to predict and prevent colchicine toxicity in the presence of these drugs has been proposed (Terkeltaub 2010). In both included trials low-dose colchicine consisted of a total of 1.8 mg given over one hour. Current clinical practice varies and lower doses are often employed, however no trials have been performed examining lower doses.

Agreements and disagreements with other studies or reviews

Quality of the evidence

Implications for research

The overall quality of the evidence for the benefits and harms of colchicine for acute gout is low. Data were only available for pain, reduction of inflammation and adverse events, and there was the potential for selection bias and the risk of selective reporting in one trial and a small number of participants and events in both trials.

Randomised controlled trials comparing colchicine (at different doses and also the clinical dose most often used of 0.6 mg twice a day) to placebo and to the relevant alternative treatment options in acute gout (NSAIDs and glucocorticoids) would clearly benefit clinical decision-making. Such trials should ideally be pragmatic in the way that they include gout patients with all their typical comorbidities.

Potential biases in the review process We believe that our broad search strategy and database search identified all relevant studies, and minimised the likelihood of having missed any relevant trials. Two review authors independently assessed the trials for inclusion in the review and their risk of bias.

We did not identify any previous systematic reviews of colchicine for the treatment of acute gout.

AUTHORS’ CONCLUSIONS Implications for practice Based upon only two published trials, one with a low risk of bias and one with an unclear risk of bias, there is low-quality evidence that low-dose colchicine is likely to be an effective treatment for acute gout. We downgraded the evidence because of a potential risk of selection and reporting biases, and the small number of trial participants and the low event rates indicating imprecision. Both high and low-dose colchicine improve pain when compared to placebo. While there is some uncertainty around the effect estimates, compared with placebo, high-dose but not low-dose colchicine appears to result in a statistically significantly greater number of adverse events. Therefore low-dose colchicine may be the preferred treatment option. However, in this trial low-dose is 1.8 mg colchicine in one hour, while in clinical practice we most often use 0.6 mg twice a day. From a clinical perspective the position of colchicine in the context of other therapeutic options for treatment of acute gout remains unclear. In the absence of comparative data, a patient’s risk profile and comorbidities will likely influence the choice of colchicine, non-steroidal anti-inflammatory drugs (NSAIDs) or glucocorticoids in clinical practice. In some circumstances colchicine may be preferred because of the possibility of dose titration, particularly in patients at risk of side effects, but in general the relative lack of experience in the use of colchicine in clinical practice compared to other treatment modalities, such as NSAIDs and glucocorticoids, will often guide the clinician to chose one of the latter.

Planned trials should include participants with a range of gout manifestations (e.g. tophi, nephrolithiasis), comorbidities that influence pharmacotherapy choice for gout treatment (e.g. renal impairment, cardiovascular disease) and assess the outcomes recommended by OMERACT for studies of chronic gout, including reduction in gout attack frequency, joint pain, serum urate concentration, tophus burden, physical function and quality of life


22

(Singh 2011). The CONSORT statement should also be used as a guide for both designing and reporting trials (Boutron 2008).

Trial reporting should include the method of randomisation and treatment allocation concealment, blinding of study participants, study personnel and outcome assessment, follow-up of all participants who entered the trial and complete reporting of outcomes. Sample sizes should be reported and have adequate power to answer the research question; ideally trials should assess both the benefits and risks of lifestyle interventions. To enable comparison and pooling of the results of randomised controlled trials, we suggest

that future trials report means with standard deviations for continuous measures or number of events and total numbers analysed for dichotomous measures, and use standardised measurement tools for reporting relevant outcomes.

ACKNOWLEDGEMENTS Thanks to Louise Falzon for developing the search strategy and thanks to Renea Johnston for help with the ’Summary of findings’ tables.

REFERENCES

References to studies included in this review Ahern 1987 {published data only} Ahern MJ, Reid C, Gordon TP. Does colchicine work? Results of the first controlled study in gout. Australian and New Zealand Journal of Medicine 1987;17:301–4. Terkeltaub 2010 {published data only} Furst D, Maranian E, Davis P, Wason MW, Khanna S, Terkeltaub D. Chronologic age, renal function, and comorbid conditions (physiologic age) of patients with gout did not increase likelihood of adverse events (AEs): AGREE study post hoc analyses. Arthritis and Rheumatism 2009;62 (Suppl 10):147. Terkeltaub R, Furst D, Bennett E, Kook K, Crockett K, Davis RS, et al.Colchicine efficacy assessed by time to 50 reduction of pain is comparable in low dose and high dose regimens: secondary analyses of the agree trial. Arthritis and Rheumatism 2010;60(Suppl 10):1103. ∗ Terkeltaub RA, Furst DE, Bennett K, Kook KA, Crockett RS, Davis MW. High versus low dosing of oral colchicine for early acute gout flare: twenty-four-hour outcome of the first multicenter, randomised, double-blind, placebocontrolled, parallel-group, dose-comparison colchicine study. Arthritis and Rheumatism 2010;62:1060–8.

References to studies excluded from this review Schlesinger 2002 {published data only} Schlesinger N, Baker DG, Beutler AM, Hoffman BI, Schumacher Hr, Jr. Local ice therapy during bouts of acute gouty arthritis. Journal of Rheumatology 2002;29(2):331–4.

gouty arthritis treated with non-steroidal-anti-inflammatory drugs. British Journal of Clinical Pharmacology 1988;26: 488–9. Atkins 2004 Atkins D, Best D, Briss PA, Eccles M, Palck-Ytter Y, Flottorp S, et al.GRADE Working Group. Grading quality of evidence and strength of recommendations. BMJ 2004; 328(7454):1490–4. Australian Rheumatology Association 2012 Australian Rheumatology Association. Patient information on colchicine (last updated November 2012). http:// www.rheumatology.org.au (accessed 3 December 2013). Bellamy 1987 Bellamy N, Downie WW, Buchanan WW. Observations on spontaneous improvement in patients with podagra: implications for therapeutic trials of non-steroidal antiinflammatory drugs. British Journal of Clinical Pharmacology 1987;24(1):33–6. Ben-Chetrit 1998 Ben-Chetrit E, Levy M. Colchicine: 1998 update. Seminars in Arthritis and Rheumatism 1998;28:48–59. BNF 2006 British National Formulary. http://bnf.org/bnf/bnf/current/ search.htm?n=50&q=colchicine+gout (accessed 10 August 2006).

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Boutron 2008 Boutron I, Moher D, Altman DG, Schulz K, Ravaud P, CONSORT Group. Methods and processes of the CONSORT Group: example of an extension for trials assessing nonpharmacologic treatments. Annals of Internal Medicine 2008;148:295–309.

Agudelo 1972 Agudelo CA, Schumacher HR Jr, Phelps P. Effect of exercise on urate crystal-induced inflammation in canine joints. Arthritis and Rheumatism 1972;15:609–16.

Cates 2008 Dr. Chris Cates’ EBM website. URL: http:// www.nntoline.net. Visual Rx Version 3. Dr. Chris Cates’ EBM website. URL: http://www.nntoline.net, 2008.

Arnold 1988 Arnold MH, Preston SJ, Buchanan WW. Comparison of the natural history of untreated acute gouty arthritis vs acute

Cox 2004 Cox AR. Colchicine in acute gout: optimal dose of colchicine is still elusive. BMJ 2004;328(7434):288.


23

De Angelis 2004 De Angelis CD, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, et al.Clinical Trial Registration: a statement from the International Committee of Medical Journal Editors. JAMA 2004;292(11):1363–4. Deeks 2011 Deeks JJ, Higgins JPT, Altman DG. Chapter 9: Analysing data and undertaking meta-analyses. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.

5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org. Janssens 2008a Janssens HJ, Janssen M, Van de Lisdonk EH, Van Riel PL, Van Weel C. Use of oral prednisolone or naproxen for the treatment of gout arthritis: a double-blind, randomised equivalence trial. Lancet 2008;371:1854–60. Janssens 2008b Janssens HJ, Lucassen PL, Van de Laar FA, Janssen M, Van de Lisdonk EH. Systemic corticosteroids for acute gout. Cochrane Database of Systematic Reviews 2008, Issue 2. [DOI: 10.1002/14651858.CD005521.pub2]

Dorwart 1974 Dorwart BB, Hansell JR, Schumacher HR Jr. Effects of cold and heat on urate-induced synovitis in the dog. Arthritis and Rheumatism 1974;17(5):563–71.

Kasper 2005 Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson DL, et al.Harrison’s Principles of Internal Medicine. 16th Edition. McGraw-Hill Professional, 2005.

Grainger 2009 Grainger R, Taylor WJ, Dalbeth N, Perez-Ruiz F, Singh JA, Waltrip RW, et al.Progress in measurement instruments for acute and chronic gout studies. Journal of Rheumatology 2009;36(10):2346–55.

Kuncl 1987 Kuncl R, Duncan G, Watson D, Alderson K, Rogawski MA, Peper M. Colchicine myopathy and neuropathy. New England Journal of Medicine 1987;316(25):1562–8.

Hak 2010 Hak AE, Curhan GC, Grodstein F, Choi HK. Menopause, postmenopausal hormone use and risk of incident gout. Annals of the Rheumatic Diseases 2010;69(7):1305–9. Hamburger 2011 Hamburger M, Baraf HS, Adamson TC, Basile J, Bass L, Cole B, et al.2011 recommendations for the diagnosis and management of gout and hyperuricemia. Physician and Sportsmedicine 2011;39(4):98–123.

Mikuls 2005 Mikuls TR, Farrar JT, Fernandes S, Schumacher HR Jr, Saag KG. Gout epidemiology: results from the UK General Practice Research Database, 1990-1999. Annals of the Rheumatic Diseases 2005;64:267–72. Moi 2013 Moi JHY, Sriranganathan MK, Edwards CJ, Buchbinder R. Lifestyle interventions for chronic gout. Cochrane Database of Systematic Reviews 2013, Issue 5. [DOI: 10.1002/ 14651858.CD010039.pub2]

Higgins 2011a Higgins JPT, Altman DG, Sterne JAC. Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.

Morris 2003 Morris I, Varughese G, Mattingly P. Colchicine in acute gout. BMJ 2003;327(7426):1275–6.

Higgins 2011b Higgins JPT, Deeks JJ, Altman DG. Chapter 16: Special topics in statistics. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.

RevMan 2014 The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager. 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.

Higgins 2011c Higgins JPT, Deeks JJ. Chapter 7: Selecting studies and collecting data. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org. Higgins 2011d Lefebvre C, Manheimer E, Glanville J. Chapter 6: Searching for studies. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version

O’Sullivan 1972 O’Sullivan JB. Gout in a New England Town. A prevalence study in Sudbury, Massachusetts. Annals of the Rheumatic Diseases 1972;31(3):166–9.

Schlesinger 2001 Schlesinger N, Schumacher Jr HR. Gout: can management be improved?. Current Opinion in Rheumatology 2001;13 (3):240–4. Schlesinger 2004 Schlesinger N. Management of acute and chronic gouty arthritis: present state-of-the-art. Drugs 2004;64(21): 2399–416. Schumacher 1993 Schumacher H, Klippel J, Koopman W, et al.Primer on the Rheumatic Diseases. Tenth. Arthritis Foundation, 1993. Schumacher 2005 Schumacher HR, Edwards LN, Perez-Ruiz F, Becker M, Chen LX, Furst DE. Outcome measures for acute and


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chronic gout. Journal of Rheumatology 2005;32(12): 2452–5. Schünemann 2011 Schünemann HJ, Oxman AD, Higgins JPT, Vist GE, Glasziou P, Guyatt GH. Chapter 11: Presenting results and ’Summary of findings’ tables. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org. Singh 2011 Singh JA, Taylor WJ, Simon LS, Khanna PP, Stamp LK, McQueen FM, et al.Patient-reported outcomes in chronic gout: a report from OMERACT 10. Journal of Rheumatology 2011;38:1452–7. Sivagnanam 2004 Sivagnanam G. Colchicine in acute gout: low dose colchicine was started after usual dose. BMJ 2004;328 (7434):288–9. Sterne 2011 Sterne JAC, Egger M, Moher D. Chapter 10: Addressing reporting biases. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org. Tugwell 2004 Tugwell P, Shea B, Boers M, Brooks P, Simon LS, Strand V, et al.Evidence-Based Rheumatology. BMJ Books, 2004.

Wallace 1977 Wallace SL, Robinson H, Masi AT, Decker JL, McCarty DJ, Yu T-F. Preliminary criteria for the classification of the acute arthritis of primary gout. Arthritis and Rheumatism 1977;20:895–900. Wallace 1998 Wallace SL, Singer JZ. Therapy in gout. Rheumatic Diseases Clinics of North America 1988;14:441–57. Wechalekar 2013 Wechalekar MD, Vinik O, Schlesinger N, Buchbinder R. Intra-articular glucocorticoids for acute gout. Cochrane Database of Systematic Reviews 2013, Issue 4. [DOI: 10.1002/14651858.CD009920.pub2] Wortmann 2002 Wortmann RL. Gout and hyperuricemia. Current Opinion in Rheumatology 2002;14:281–6. Zhang 2006 Zhang W, Doherty M, Bardin T, Pascual E, Barskova V, Conaghan P, et al.EULAR evidence based recommendations for gout. Part II: Management. Report of a task force of the EULAR standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Annals of the Rheumatic Diseases 2006;65(10):1312–24.

References to other published versions of this review Schlesinger 2006 Schlesinger N, Schumacher R, Catton M, Maxwell L. Colchicine for acute gout. Cochrane Database of Systematic Reviews 2006, Issue 4. [DOI: 10.1002/ 14651858.CD006190] ∗ Indicates the major publication for the study


25

CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID] Ahern 1987 Methods

Design: randomised, double-blind, parallel-group trial of 48 hours duration Blinding: participants and outcome assessor was blinded to treatment Sample size: not described in the published report Analysis: not described whether intention-to-treat or per protocol analysis Withdrawals: 2 participants withdrew but their treatment groups were not specified

Participants

43 participants (22 in colchicine and 21 in placebo group) (another 2 participants were excluded due to their inability to understand visual analogue scales) Mean age (SD): 69 (8) years (colchicine group), 70 (8) years (placebo group) Gender: 40/43 (93%) were men Mean (SD) duration of symptoms: 38 (51) hours (colchicine group), 38 (29) hours (placebo group) Number of affected joints: all participants had a single joint involved except for 1 participant in the placebo group who had 2 affected joints. Distribution of involved joints appeared balanced between groups (knee, ankle or wrist: 8 colchicine group and 6 placebo group; MTP, MCP or PIP joint: 14 colchicine group and 16 placebo group) Inclusion criteria: acute gout, confirmed by identification of monosodium urate crystals in synovial fluid Exclusion criteria: not described

Interventions

Group 1: oral colchicine 1 mg followed by 0.5 mg every 2 hours until complete response (number of doses and total dose not specified) or toxicity (nausea, vomiting or diarrhoea) occurred Group 2: matching placebo given in the same way No NSAIDs or analgesics were allowed 48 hours before study entry or during the trial

Outcomes

Outcomes evaluated every 6 hours for 48 hours by a single assessor Primary outcome 1. Number of responders, defined as number who had a 50% decrease in pain from baseline: pain was measured on a visual analogue scale (type of visual analogue scale not described) Secondary outcomes 2. Number of responders, defined as number who had a 50% decrease in the compounded clinical score comprising pain, tenderness on palpation, swelling and redness, each graded on a 4-point scale (none 0, mild 1, moderate 2, severe 3) (range 0 to 12 for each affected joint) 3. Adverse events

Notes

The number of doses and total dose of colchicine was not specified The mean (95% CI) for each pain measure at each time point in each group was reported graphically only. Responder data were reported at 12, 24, 36 and 48 hours There were no funding sources or declarations of interest for this trial

Risk of bias Colchicine for acute gout (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

26

Ahern 1987

(Continued)

Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Low risk bias)

Computer-generated random numbers (information received after communication with authors)

Allocation concealment (selection bias)

Low risk

Allocation was concealed and held in pharmacy (information received after communication with authors)

Blinding of participants and personnel Low risk (performance bias) All outcomes

Matching placebo control was used, implying that participants were blinded. It was not stated in the report whether or not study personnel were blinded, however in fact both study personnel and participants were blinded (information received after communication with authors)

Blinding of outcome assessment (detection Low risk bias) All outcomes

Outcome assessors were blinded (information received after communication with authors)

Incomplete outcome data (attrition bias) All outcomes

Low risk

2 participants were excluded because of inability to understand visual analogue scales - it is not clear whether or not these participants were randomised but it is unlikely that this would have affected the trial outcome

Selective reporting (reporting bias)

Low risk

All prespecified outcomes were reported although it is not clear if the criterion of improvement (50% reduction from baseline score) was pre-specified

Other bias

Low risk

No other potential sources of bias identified

Terkeltaub 2010 Methods

Design: multicentre randomised controlled trial Blinding: participants and study personnel were blinded to treatment allocation. As all outcomes were self reported there were no independent outcome assessors Sample size: not described Analysis: intention-to-treat analysis planned Withdrawals: 1 participant in the placebo group withdrew

Participants

575 participants randomised (prior to acute gout attack) to the trial (192 in low-dose colchicine, 193 in high-dose colchicine and 190 in placebo group), of which 185 (74 in low-dose colchicine, 52 in high-dose colchicine and 59 in placebo group) had a flare


27

Terkeltaub 2010

(Continued)

and provided outcome data (390 did not have a flare or had a ’non qualifying flare’). Baseline data were only provided for those with a flare Mean (SD) age: 51.9 (10.09) years (high-dose colchicine group), 51.4 (11.79) years (low-dose colchicine group), 51.2 (11.36) years (placebo group) Gender: 176/185 (95%) men of those who had a flare and provided outcome data Inclusion criteria: adult male and postmenopausal female patients with a confirmed past diagnosis of gout (according to the American College of Rheumatology classification criteria) and having had 2 gout flares within the prior 12 months Exclusion criteria: not described Interventions

Group 1: low-dose colchicine (1.2 mg followed by 0.6 mg in 1 hour followed by placebo doses every hour for 5 hours (1.8 mg total)) Group 2: high-dose colchicine (1.2 mg followed by 0.6 mg every hour for 6 hours (4.8 mg total)) Group 3: placebo (2 placebo capsules initially, followed by 1 placebo capsule every hour for 6 hours) Patients were permitted to stop study medication due to AEs. Rescue medication (individualised to each patient by his or her study physician, e.g. nonsteroidal anti-inflammatory drugs (NSAIDs)) was permitted if intolerable pain continued after taking at least 1 dose of study drug Uric acid-lowering therapy was not to be discontinued at the onset of flare

Outcomes

Outcomes recorded by patients at prespecified time points for pain using a standardised diary: pain was recorded at baseline, hourly for the first 8 hours and every 8 hours thereafter (while awake) until 72 hours following the initial dose or symptom resolution; recording at 24 hours mandatory Study physicians at each site assessed patients within 48 hours after onset of symptoms and up to 3 more visits, the last being 7 days after flare onset (they reviewed the patient diaries and recorded pertinent data on standardised case report forms) Primary outcome 1. Number who responded to treatment: responders were defined as having a pretreatment pain score within 12 hours of flare onset and a 50% reduction in pain within 24 hours of the first dose of study medication without the use of rescue medication during that time frame with pain recorded on an 11-point Likert scale that ranged from 0 (no pain) to 10 (worst possible pain) a. Intensity of pain recorded on an 11-point Likert scale that ranged from 0 (no pain) to 10 (worst possible pain) b. Rescue medication use within the first 24 hours (individualised to each patient by his or her study physician, e.g. nonsteroidal anti-inflammatory drugs) if intolerable pain continued after taking at least 1 dose of study drug Secondary outcomes 2. Treatment response based on the target joint pain score 32 hours after the first dose 3. Treatment response based on at least a 2-unit reduction in the target joint pain score 24 hours after the first dose 4. Treatment response based on at least a 2-unit reduction in the target joint pain score 32 hours after the first dose 5. Adverse events: nausea, vomiting, diarrhoea and abdominal pain at each time point of the patient-rated pain, along with an open-ended question about other AEs. The intensity of AEs was graded as mild, moderate or severe based on the study physicians’


28

Terkeltaub 2010

(Continued)

clinical judgement 6. Serious adverse events were recorded based upon established US Food and Drug Administration (FDA) definitions Notes

The number of participants in each group included as the ’safety population’ was not equal due to the method of inclusion in the study (many patients were randomised but only those who had a gout flare were included) Only a responder analysis was presented - mean (SD) pain scores at each time point were not presented This trial was registered at ClinicalTrials.gov identifier: NCT00506883 on 23 July 2007. The trial was sponsored by URL Pharma. The Chief Medical Officer for URL Pharma and had key roles in the study design data collection, data analysis and writing of the manuscript. Prior to the start of the study, URL Pharma agreed that the authors had full rights to submit the manuscript for publication; URL Pharma approval of the content of the submitted manuscript was not required, and publication of the manuscript was not contingent upon the approval of URL Pharma Declaration of interest for primary investigators was not provided

Risk of bias Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Unclear risk bias)

Method of randomisation is not described

Allocation concealment (selection bias)

Low risk

At the randomisation visit the investigator dispensed a blister card containing 8 identical-looking capsules (in a combination of active drug and placebo capsules) for use during their next gout flare. Quote “over encapsulated (to preserve double blindedness) colchicine and matching over encapsulated placebo were provided”

Blinding of participants and personnel Low risk (performance bias) All outcomes

Both participants and study personnel were blinded to treatment

Blinding of outcome assessment (detection Low risk bias) All outcomes

The study physicians at each site were blinded to treatment. The participant assessed pain, symptoms, adverse events and rescue medication by using a standardised diary; and were unaware of treatment

Incomplete outcome data (attrition bias) All outcomes

7/52 (13.5%) in the high-dose colchicine group, 3/74 (4%) in the low-dose colchicine group and 4/59 (6.8%) in the placebo group did not complete full follow-up, either because of lack of ben-

Low risk


29

Terkeltaub 2010

(Continued)

efit, loss to follow-up or for other unclear reasons (ClinicalTrials.gov identifier: NCT00506883 on 23 July 2007) Selective reporting (reporting bias)

Unclear risk

This trial was registered 23 July 2007 but trial recruitment began in April 2007 and final data collection occurred in October 2007. For benefit only a responders analysis was presented. The mean (SD) pain scores were not presented. The methods also state that symptoms were collected but this is not reported

Other bias

Unclear risk

Site of flare and number of joints affected was not presented. If baseline differences existed this may have affected the results. The numbers of participants by group treated at each site was not specified but it is stated that some sites did not have patients in all treatment groups While the number of randomised participants in each group was approximately equal, the numbers of participants in each group who had an acute attack of gout and therefore had outcome data available was not equal

MCP: metacarpophalangeal joint MTP: metatarsophalangeal joint PIP: proximal interphalangeal joint AE: adverse event CI: confidence interval NSAID: non-steroidal anti-inflammatory drug SD: standard deviation

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Schlesinger 2002

Randomised controlled trial of local ice therapy - both groups treated with similar doses of prednisolone and colchicine


30

DATA AND ANALYSES

Comparison 1. High-dose colchicine versus placebo

Outcome or subgroup title 1 Proportion with 50% or greater decrease in pain score from baseline 1.1 12 hours 1.2 24 hours 1.3 32 to 36 hours 1.4 48 hours 1.5 Last time point 2 Proportion with 50% or greater decrease in clinical score from baseline 2.1 12 hours 2.2 24 hours 2.3 36 hours 2.4 48 hours 3 All adverse events 4 Gastrointestinal adverse events (diarrhoea, vomiting or nausea)

No. of studies

No. of participants

2

1 2 2 1 2 1

1 1 1 1 1 2

43 124 124 43 124

124

Statistical method

Effect size

Risk Ratio (M-H, Random, 95% CI)

Subtotals only

Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)

2.39 [0.52, 10.99] 2.88 [1.28, 6.48] 2.16 [1.28, 3.65] 1.91 [1.05, 3.49] 1.97 [1.20, 3.24] Totals not selected

Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Random, 95% CI)

0.0 [0.0, 0.0] 0.0 [0.0, 0.0] 0.0 [0.0, 0.0] 0.0 [0.0, 0.0] Totals not selected 3.81 [2.28, 6.38]

Comparison 2. Low-dose colchicine versus placebo

Outcome or subgroup title 1 Proportion with 50% or greater decrease in pain score from baseline 1.1 24 hours 1.2 32 hours 2 All adverse events 3 Gastrointestinal adverse events (diarrhoea, vomiting or nausea)

No. of studies

No. of participants

Statistical method

Effect size

1

Risk Ratio (M-H, Random, 95% CI)

Totals not selected

1 1 1 1

Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0] 0.0 [0.0, 0.0] Totals not selected Totals not selected


31

Comparison 3. High-dose versus low-dose colchicine

Outcome or subgroup title 1 Proportion with 50% or greater decrease in pain score from baseline 1.1 24 hours 1.2 32 hours 2 All adverse events 3 Gastrointestinal adverse events (diarrhoea, vomiting or nausea)

No. of studies

No. of participants

Statistical method

Effect size

1

Risk Ratio (M-H, Fixed, 95% CI)

Totals not selected

1 1 1 1

Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0] 0.0 [0.0, 0.0] Totals not selected Totals not selected

Analysis 1.1. Comparison 1 High-dose colchicine versus placebo, Outcome 1 Proportion with 50% or greater decrease in pain score from baseline. Review:

Colchicine for acute gout

Comparison: 1 High-dose colchicine versus placebo Outcome: 1 Proportion with 50% or greater decrease in pain score from baseline

Study or subgroup

Colchicine high-dose

Placebo

Risk Ratio MH,Random,95% CI

Weight


n/N

n/N

5/22

2/21

100.0 %

2.39 [ 0.52, 10.99 ]

22

21

100.0 %

2.39 [ 0.52, 10.99 ]

9/22

2/21

33.0 %

4.30 [ 1.05, 17.61 ]

17/52

4/29

67.0 %

2.37 [ 0.88, 6.38 ]

74

50

100.0 %

2.88 [ 1.28, 6.48 ]

1 12 hours Ahern 1987

Subtotal (95% CI) Total events: 5 (Colchicine high-dose), 2 (Placebo) Heterogeneity: not applicable Test for overall effect: Z = 1.12 (P = 0.26) 2 24 hours Ahern 1987 Terkeltaub 2010

Subtotal (95% CI)

Total events: 26 (Colchicine high-dose), 6 (Placebo) Heterogeneity: Tau2 = 0.0; Chi2 = 0.46, df = 1 (P = 0.50); I2 =0.0% Test for overall effect: Z = 2.56 (P = 0.010) 3 32 to 36 hours Ahern 1987

16/22

7/21

63.9 %

2.18 [ 1.13, 4.21 ]

Terkeltaub 2010

19/52

5/29

36.1 %

2.12 [ 0.88, 5.08 ]

0.01

0.1

Favours placebo

1

10

100

Favours colch high-dose

(Continued . . . )


32

(. . . Study or subgroup

Placebo

n/N

n/N

74

50

100.0 %

2.16 [ 1.28, 3.65 ]

16/22

8/21

100.0 %

1.91 [ 1.05, 3.49 ]

22

21

100.0 %

1.91 [ 1.05, 3.49 ]

Subtotal (95% CI)


Weight

Continued) Risk Ratio MH,Random,95% CI


Total events: 35 (Colchicine high-dose), 12 (Placebo) Heterogeneity: Tau2 = 0.0; Chi2 = 0.00, df = 1 (P = 0.96); I2 =0.0% Test for overall effect: Z = 2.87 (P = 0.0041) 4 48 hours Ahern 1987

Subtotal (95% CI)

Total events: 16 (Colchicine high-dose), 8 (Placebo) Heterogeneity: not applicable Test for overall effect: Z = 2.10 (P = 0.035) 5 Last time point Ahern 1987

16/22

8/21

67.8 %

1.91 [ 1.05, 3.49 ]

Terkeltaub 2010

19/52

5/29

32.2 %

2.12 [ 0.88, 5.08 ]

74

50

100.0 %

1.97 [ 1.20, 3.24 ]

Subtotal (95% CI)

Total events: 35 (Colchicine high-dose), 13 (Placebo) Heterogeneity: Tau2 = 0.0; Chi2 = 0.04, df = 1 (P = 0.84); I2 =0.0% Test for overall effect: Z = 2.69 (P = 0.0072) Test for subgroup differences: Chi2 = 0.78, df = 4 (P = 0.94), I2 =0.0%

0.01

0.1

Favours placebo

1

10

100



33

Analysis 1.2. Comparison 1 High-dose colchicine versus placebo, Outcome 2 Proportion with 50% or greater decrease in clinical score from baseline. Review:


Comparison: 1 High-dose colchicine versus placebo Outcome: 2 Proportion with 50% or greater decrease in clinical score from baseline

Study or subgroup


Placebo

n/N

n/N

Risk Ratio

Risk Ratio

1/22

0/21

2.87 [ 0.12, 66.75 ]

5/22

0/21

10.52 [ 0.62, 179.27 ]

11/22

1/21

10.50 [ 1.48, 74.38 ]

14/22

5/21

2.67 [ 1.17, 6.12 ]

M-H,Fixed,95% CI

M-H,Fixed,95% CI

1 12 hours Ahern 1987 2 24 hours Ahern 1987 3 36 hours Ahern 1987 4 48 hours Ahern 1987

0.005

0.1

1

Favours placebo

10

200


Analysis 1.3. Comparison 1 High-dose colchicine versus placebo, Outcome 3 All adverse events. Review:


Comparison: 1 High-dose colchicine versus placebo Outcome: 3 All adverse events

Study or subgroup

Terkeltaub 2010

Colchicine

Placebo

n/N

n/N

40/52

8/29

Risk Ratio

Risk Ratio

M-H,Fixed,95% CI

M-H,Fixed,95% CI 2.79 [ 1.52, 5.12 ]

0.01

0.1

Favours colchicine


1

10

100

Favours placebo

34

Analysis 1.4. Comparison 1 High-dose colchicine versus placebo, Outcome 4 Gastrointestinal adverse events (diarrhoea, vomiting or nausea). Review:


Comparison: 1 High-dose colchicine versus placebo Outcome: 4 Gastrointestinal adverse events (diarrhoea, vomiting or nausea)

Study or subgroup

Colchicine

Placebo

n/N

n/N

Ahern 1987

22/22

5/21

50.1 %

3.91 [ 1.89, 8.09 ]

Terkeltaub 2010

40/52

6/29

49.9 %

3.72 [ 1.80, 7.70 ]

74

50

100.0 %

3.81 [ 2.28, 6.38 ]

Total (95% CI)


Weight


Total events: 62 (Colchicine), 11 (Placebo) Heterogeneity: Tau2 = 0.0; Chi2 = 0.01, df = 1 (P = 0.92); I2 =0.0% Test for overall effect: Z = 5.10 (P < 0.00001) Test for subgroup differences: Not applicable

0.05

0.2

Favours colchicine

1

5

20

Favours placebo

Analysis 2.1. Comparison 2 Low-dose colchicine versus placebo, Outcome 1 Proportion with 50% or greater decrease in pain score from baseline. Review:


Comparison: 2 Low-dose colchicine versus placebo Outcome: 1 Proportion with 50% or greater decrease in pain score from baseline

Study or subgroup

Colchicine low-dose

Placebo



n/N

n/N

28/74

4/29

2.74 [ 1.05, 7.13 ]

31/74

5/29

2.43 [ 1.05, 5.64 ]

1 24 hours Terkeltaub 2010 2 32 hours Terkeltaub 2010

0.01

0.1

Favours placebo


1

10

100

Favours colch low-dose

35

Analysis 2.2. Comparison 2 Low-dose colchicine versus placebo, Outcome 2 All adverse events. Review:


Comparison: 2 Low-dose colchicine versus placebo Outcome: 2 All adverse events

Study or subgroup

Colchicine low-dose

Placebo

n/N

n/N

27/74

8/29

Terkeltaub 2010

Risk Ratio

Risk Ratio

M-H,Fixed,95% CI

M-H,Fixed,95% CI 1.32 [ 0.68, 2.56 ]

0.01

0.1

1


10

100

Favours placebo

Analysis 2.3. Comparison 2 Low-dose colchicine versus placebo, Outcome 3 Gastrointestinal adverse events (diarrhoea, vomiting or nausea). Review:


Comparison: 2 Low-dose colchicine versus placebo Outcome: 3 Gastrointestinal adverse events (diarrhoea, vomiting or nausea)

Study or subgroup

Terkeltaub 2010

Colchicine low-dose

Placebo

n/N

n/N

19/74

6/29

Risk Ratio

Risk Ratio

M-H,Fixed,95% CI

M-H,Fixed,95% CI 1.24 [ 0.55, 2.79 ]

0.01

0.1



1

10

100

Favours placebo

36

Analysis 3.1. Comparison 3 High-dose versus low-dose colchicine, Outcome 1 Proportion with 50% or greater decrease in pain score from baseline. Review:


Comparison: 3 High-dose versus low-dose colchicine Outcome: 1 Proportion with 50% or greater decrease in pain score from baseline

Study or subgroup


Colchicine low-dose

n/N

n/N

Risk Ratio

Risk Ratio

17/52

28/74

0.86 [ 0.53, 1.41 ]

19/52

31/74

0.87 [ 0.56, 1.36 ]

M-H,Fixed,95% CI

M-H,Fixed,95% CI

1 24 hours Terkeltaub 2010 2 32 hours Terkeltaub 2010

0.1 0.2

0.5

1


2

5

10


Analysis 3.2. Comparison 3 High-dose versus low-dose colchicine, Outcome 2 All adverse events. Review:


Comparison: 3 High-dose versus low-dose colchicine Outcome: 2 All adverse events

Study or subgroup

Terkeltaub 2010


Colchicine low-dose

n/N

n/N

40/52

27/74

Risk Ratio

Risk Ratio

M-H,Fixed,95% CI

M-H,Fixed,95% CI 2.11 [ 1.51, 2.95 ]

0.01

0.1



1

10

100


37

Analysis 3.3. Comparison 3 High-dose versus low-dose colchicine, Outcome 3 Gastrointestinal adverse events (diarrhoea, vomiting or nausea). Review:


Comparison: 3 High-dose versus low-dose colchicine Outcome: 3 Gastrointestinal adverse events (diarrhoea, vomiting or nausea)

Study or subgroup

Terkeltaub 2010


Colchicine low-dose

n/N

n/N

40/52

19/74

Risk Ratio

Risk Ratio

M-H,Fixed,95% CI

M-H,Fixed,95% CI 3.00 [ 1.98, 4.54 ]

0.01

0.1


1

10

100


APPENDICES Appendix 1. Cochrane CENTRAL search strategy #1 MeSH descriptor Gout explode all trees #2 gout*:ti,ab #3 MeSH descriptor Acute Disease, this term only #4 acute:ti,ab #5 (#1 OR #2) #6 (#3 OR #4) #7 (#5 AND #6) #8 MeSH descriptor Colchicine explode all trees #9 “autumn crocus”:ti,ab #10 “meadow saffron”:ti,ab #11 (colchic* or colcrys):ti,ab #12 (#8 OR #9 OR #10 OR #11) #13 (#7 AND #12)


38

Appendix 2. MEDLINE search strategy 1. exp gout/ 2. gout$.tw. 3. Acute Disease/ 4. acute.tw. 5. 1 or 2 6. 3 or 4 7. 5 and 6 8. exp Colchicine/ 9. autumn crocus.tw. 10. meadow saffron.tw. 11. colchic$.tw. 12. colcrys.tw. 13. or/8-12 14. 7 and 13 15. randomized controlled trial.pt. 16. controlled clinical trial.pt. 17. randomized.ab. 18. placebo.ab. 19. drug therapy.fs. 20. randomly.ab. 21. trial.ab. 22. groups.ab. 23. or/15-23 24. (animals not (humans and animals)).sh. 25. 23 not 24 26. 14 and 25

Appendix 3. EMBASE search strategy 1. exp gout/ 2. gout$.tw. 3. acute disease/ 4. acute.tw. 5. 1 or 2 6. 3 or 4 7. 5 and 6 8. colchicine/ 9. colchic$.tw. 10. autumn crocus.tw. 11. meadow saffron.tw. 12. colcrys.tw. 13. or/8-12 14. 7 and 13 15. (random$ or placebo$).ti,ab. 16. ((single$ or double$ or triple$ or treble$) and (blind$ or mask$)).ti,ab. 17. controlled clinical trial$.ti,ab. 18. RETRACTED ARTICLE/ 19. or/14-18 20. (animal$ not human$).sh,hw. 21. 19 not 20 22. 14 and 21 Colchicine for acute gout (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

39

WHAT’S NEW Last assessed as up-to-date: 8 April 2014.

Date

Event

Description

8 April 2014

New citation required and conclusions have changed

Conclusions changed and change in authors.

8 April 2014

New search has been performed

New search. Added one trial, Terkeltaub 2010.

HISTORY Protocol first published: Issue 1, 2002 Review first published: Issue 4, 2006

Date

Event

Description

24 September 2008

Amended

Converted to new review format. CMSG ID: C097-R

CONTRIBUTIONS OF AUTHORS IvE and RB wrote the review; IvE and MW screened initial search results and identified studies that fulfilled the inclusion criteria; IvE and RB extracted data and entered data into RevMan; and IvE, MW and RB performed ’Risk of bias’ assessment. All authors contributed to the interpretation of the review and approved the final draft.

DECLARATIONS OF INTEREST Irene van Echteld has no declerations of interest. Mihir Wechalekar has no declerations of interest. Naomi Schlesinger has no declerations of interest. Rachelle buchbinder has no declerations of interest. Daniel Aletaha has no declerations of interest.


40

SOURCES OF SUPPORT Internal sources • Cochrane Musculoskeletal Group, Australian Editorial Base, Australia.

External sources • No sources of support supplied

DIFFERENCES BETWEEN PROTOCOL AND REVIEW We included gastrointestinal adverse events (diarrhoea, vomiting or nausea) rather than total adverse events in the ’Summary of findings’ tables.

INDEX TERMS Medical Subject Headings (MeSH) Colchicine [∗ administration & dosage; adverse effects]; Gout [∗ drug therapy]; Gout Suppressants [∗ administration & dosage; adverse effects]; Pain Management [methods]; Randomized Controlled Trials as Topic; Time Factors

MeSH check words Humans


41

Evaluating appropriate use of prophylactic colchicine for gout flare prevention.

Acute myelomonocytic leukaemia and multiple myeloma after sulphinpyrazone and colchicine treatment of gout.

Mechanism of action of colchicine in the treatment of gout.

Therapeutic test with colchicine in diagnosis of gout.

Chuanhu anti-gout mixture versus colchicine for acute gouty arthritis: a randomized, double-blind, double-dummy, non-inferiority trial.

Beyond Gout: Colchicine Use in the Cardiovascular Patient.

Treatment of acute gout.

Acute neuromyopathy after colchicine treatment.

Acute arthralgia (gout?) after tricrynafen.

Colchicine for treatment of acute or recurrent pericarditis.

A randomized trial of colchicine for acute pericarditis.

A randomized trial of colchicine for acute pericarditis.

Is There a Role for Colchicine in Acute Coronary Syndromes?

A randomized trial of colchicine for acute pericarditis.

A randomized trial of colchicine for acute pericarditis.

Association Between Colchicine and Risk of Diabetes Among the Veterans Affairs Population With Gout.

Treatment of acute gout: a systematic review.

Letter: Ibuprofen in acute polyarticular gout.

"Gangrenous Finger" Proven to be Acute Gout.

Letter: Drug-precipitated acute attacks of gout.

Acute gout after carpal tunnel release.

Colchicine for pericarditis.

Colchicine for pericarditis.

Allopurinol for chronic gout.