Official reprint from UpToDate www.uptodate.com ©2015 UpToDate

AuthorMichael A Becker, MD

Section EditorH Ralph Schumacher, MD

Deputy EditorPaul L Romain, MD

Treatment of acute gout

All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Oct 2015. | This topic last updated: Jul 31, 2015.

INTRODUCTION — Acute gout (or a gout flare) is an intensely painful and disabling inflammatory arthritis, usuallyinvolving a single joint but occasionally involving two or more joints. The goal of therapy in an acute gout attack isprompt and safe termination of pain and disability. Without therapy, acute gouty arthritis usually resolvescompletely within a few days to several weeks, particularly in early disease. However, symptoms improve morequickly with administration of any of a broad array of antiinflammatory drugs. (See "Clinical manifestations anddiagnosis of gout", section on 'Acute gouty arthritis'.)

Upon resolution of an acute attack, the patient is said to have entered a symptom-free (interval, intercritical, orbetween attacks) period. However, flares of acute gout recur in the great majority of patients; with more frequentepisodes, attacks may be more severe and prolonged, with consequent shortening of asymptomatic periods.Patients with recurrent flares and those who develop chronic arthritis can benefit from long-term prophylactictherapy with a urate-lowering agent to prevent further recurrences of acute gout and chronic tophaceous disease.(See "Prevention of recurrent gout" and "Clinical manifestations and diagnosis of gout", section on 'Intercriticalgout and recurrent gouty arthritis'.)

The management of acute gouty arthritis will be reviewed here. The approach to asymptomatic hyperuricemia; thepathophysiology, clinical manifestations and diagnosis of gout; and the prevention of recurrent gout after resolutionof the acute attack are discussed separately. (See "Asymptomatic hyperuricemia" and "Pathophysiology of goutyarthritis" and "Clinical manifestations and diagnosis of gout" and "Prevention of recurrent gout".)

GENERAL THERAPEUTIC PRINCIPLES — Several classes of antiinflammatory agents are effective for thetreatment of acute gout, including nonsteroidal antiinflammatory drugs (NSAIDs), colchicine, systemic andintraarticular glucocorticoids, and biologic agents that inhibit the action of interleukin (IL)-1 beta [1-3]; a set ofgeneral principles is important in the effective management of acute gout, regardless of the specificantiinflammatory agent used. These include the following:

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Treatment should start as soon as possible after the patient perceives the beginning of an attack, preferablywithin several hours of symptom onset. More rapid and complete resolution of symptoms occurs the earlierthat treatment is introduced, especially if treatment is initiated at the full recommended dose of the chosenantiinflammatory agent. Patients should be continued on treatment for the duration of the attack, usually atreduced doses once a significant reduction in symptoms is achieved.

Complete cessation of treatment can usually be safely done within two to three days of complete resolutionof the attack, except in the case of oral glucocorticoids, for which slower dose tapering may be needed toavoid a recurrent attack. The duration of therapy for the acute attack may range from only a few days (eg, ina patient treated within hours of symptom onset) to several weeks (eg, in a patient begun on treatment afterfour or five days of symptoms). Most patients require treatment for no more than five to seven days if begunon therapy within 12 to 36 hours of symptom onset.

Urate-lowering therapies are of no benefit for acute gout and should generally not be initiated during an acuteattack. However, in patients already receiving these agents (eg, allopurinol, febuxostat, probenecid,benzbromarone, or pegloticase), the urate-lowering medication should be continued without interruption.There is no benefit to temporary discontinuation, and subsequent reintroduction after a period off the agent

INITIAL TREATMENT CHOICES — The choice of medications depends upon the comorbidities that are present,the effectiveness of past treatments, patient preferences for use, and the experience of the clinician with jointinjection. Despite wide use in the treatment of acute gout attacks, the various antiinflammatory agents have onlyinfrequently been compared with placebo or with each other in randomized trials. We take the following approachto the initial treatment of acute attacks of gout (algorithm 1):

Our approach to the patient with acute gout is based upon the available data and our clinical experience. Ourrecommendations are generally consistent with the approaches recommended by the European League AgainstRheumatism (EULAR) and the American College of Rheumatology (ACR) [5-7].

NSAID therapy

Administration of NSAIDs — We suggest the administration of a potent oral NSAID, such as naproxen (500mg twice daily) or indomethacin (50 mg three times daily), for reduction of acute gouty inflammation in mostpatients with acute gout.

We generally prefer nonselective NSAIDs over other agents because they are inexpensive, readily available to

may predispose to another attack. Therapeutic recommendations for acute gout attacks in patients receivingurate-lowering agents are the same as those for patients not taking antihyperuricemic therapy. (See"Prevention of recurrent gout", section on 'Initiation and duration of therapy'.)

Treatment of acute gout attacks does not differ substantially in patients with or without clinically apparenttophi, although the presence of tophi is an indication for the initiation of long-term urate-lowering therapy afterattack resolution to prevent or reverse chronic gouty arthropathy. Urate-lowering therapy is discussedseparately. (See "Prevention of recurrent gout".)

Important comorbidities (and their ongoing therapies) that are frequent among gout patients may affect drugsafety or effectiveness, especially in older patients (see 'Older adults' below); consideration of thesedisorders is critical in the choice of antiinflammatory treatment for acute gout. The following factors are ofparticular importance in selecting an agent:

Renal function•Cardiovascular disease, including heart failure or poorly controlled hypertension•Gastrointestinal disease, including peptic ulcer disease•Concurrent medication use•Drug allergy•Diabetes mellitus, especially if poorly controlled•

Adjunctive measures, none of which are of proven efficacy, are often administered for symptom relief andinclude icing the affected joint [4], resting the joint that is involved, and administering analgesic medications(eg, acetaminophen or opioids). These measures do not substitute for effective antiinflammatory treatment ofthe acute gout attack.

We treat most patients able to take an oral medication with a nonsteroidal antiinflammatory drug (NSAID).(See 'NSAID therapy' below.)

An oral low-dose colchicine regimen may be used in patients who are able to take an oral medication but whohave contraindications to NSAIDs (eg, moderate or more severe chronic kidney disease [CKD], active pepticulcer disease, or a history of NSAID-intolerance). (See 'Colchicine therapy' below.)

In patients with contraindications to the use of both NSAIDs and colchicine, we prefer intraarticular, oral, orparenteral glucocorticoids, depending upon the number of involved joints, the experience of the clinician withjoint injection techniques, and the need, if present, for parenteral rather than orally administered therapy. (See'Glucocorticoids' below.)

patients at the onset of an attack (some without a prescription), and, in our experience and in available studies, aseffective and at least as safe as other agents [8-13]. NSAIDs are most effective if treatment is initiated within 48hours of the onset of symptoms. The dose may be reduced after a significant reduction in symptoms hasoccurred, but the frequency of dosing should be maintained for several more days for optimal antiinflammatoryeffect. High-dose celecoxib (a single dose of 800 mg followed by 400 mg twice daily), a cyclooxygenase (COX)-2selective inhibitor, is an alternative to nonselective NSAIDs [14]. (See 'Efficacy and safety of NSAIDs' below.)

The NSAID can be discontinued one or two days after clinical signs have completely resolved. Typically, the totalduration of NSAID therapy for an acute attack is five to seven days. It is likely to be shorter in patients treatedwithin the first 24 hours of symptom onset and may be longer in patients in whom treatment is not begun untilseveral days later.

There are important contraindications to NSAIDs, including:

Adverse effects are uncommon with brief courses of therapy but may include gastrointestinal intolerance andworsening of renal function.

In an attack of several days’ duration prior to starting therapy, a longer course of treatment may be necessary. Insuch patients, added interventions to prevent NSAID gastropathy (eg, use of a proton pump inhibitor) may be ofbenefit, particularly in patients at increased risk due to advanced age or to a prior history of ulcer disease or ofgastrointestinal bleeding. (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity" and"NSAIDs (including aspirin): Secondary prevention of gastroduodenal toxicity".)

Aspirin is not used to treat acute gout because of the paradoxical effects of salicylates on serum urate, resultingfrom renal uric acid retention at low doses (<2 to 3 g/day) and from uricosuria at higher doses [15-18]. However,low-dose aspirin that is being used for cardiovascular prophylaxis generally does not need to be discontinuedduring the treatment of acute gout, although these very low doses can increase serum uric acid levels modestly insome patients [17,18]. There is one report that low-dose aspirin can increase the risk of acute gout attacks inpatients with established gout who were not being treated with allopurinol [17-19].

Efficacy and safety of NSAIDs — Complete or nearly complete resolution of the pain and disability of anacute flare typically occurs within several days to one week. There are few high-quality randomized trials ofNSAIDs for acute gouty arthritis [5,8,14,20], and there are no randomized trials that compare NSAIDs withcolchicine. A number of trials have compared different NSAIDs with each other, without any apparent differencesin efficacy [8-14]. One additional study showed superiority of an NSAID (tenoxicam) over placebo [5]. In onerandomized trial, treatment with high doses of celecoxib (a single dose of 800 mg followed by 400 mg twice daily)was of comparable efficacy to indomethacin (50 mg three times daily) [14].

Caution is necessary in patients with known cardiovascular disease or with multiple risk factors for atheroscleroticcoronary disease, since an increased risk of myocardial infarction, stroke, and heart failure has been associatedwith use both of selective COX-2 inhibitors (coxibs) and some nonselective NSAIDs. Whether such risk isincreased in patients receiving short courses of NSAIDs for acute gout is unknown. (See "COX-2 selective

CKD with creatinine clearance (CrCl) of less than 60 mL/min per 1.73 m (see "Nonselective NSAIDs:Overview of adverse effects", section on 'Renal effects' and "Overview of the management of chronic kidneydisease in adults", section on 'Definition and classification' and "Assessment of kidney function")

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Active duodenal or gastric ulcer (see "NSAIDs (including aspirin): Primary prevention of gastroduodenaltoxicity" and "NSAIDs (including aspirin): Secondary prevention of gastroduodenal toxicity")

Cardiovascular disease, particularly heart failure or hypertension that is difficult to control (see "NonselectiveNSAIDs: Adverse cardiovascular effects" and "COX-2 selective inhibitors: Adverse cardiovascular effects")

NSAID allergy

Ongoing treatment with anticoagulants

inhibitors: Adverse cardiovascular effects" and "Nonselective NSAIDs: Adverse cardiovascular effects".)

Colchicine therapy

Administration of colchicine — In patients with NSAID intolerance or with an absolute (or often relative)contraindication to NSAIDs (see 'NSAID therapy' above), we suggest the use of oral colchicine. In our experience,oral colchicine is most likely to be effective if treatment is started within 12 to 24 hours of symptom onset, andincipient attacks may frequently be aborted by using low-dose oral colchicine as soon as the patient perceives thefirst sign of an attack. We generally do not use colchicine for acute attacks that have been ongoing for more than72 to 96 hours because of the diminished likelihood of benefit. (See 'Efficacy of oral colchicine' below.)

There are several low-dose regimens that may be effective. As an example, the US Food and Drug Administration(FDA) has approved a schedule for the first 24 hours of colchicine treatment for acute gout flare, recommending aninitial dose of 1.2 mg of oral colchicine, followed one hour later by another 0.6 mg, for a total dose on the first dayof therapy of 1.8 mg [21]. In our experience, an alternative low-dose colchicine regimen that has been equallyeffective calls for 0.6 mg (or 0.5 mg, available in countries other than the US) three times on the first day of flaretreatment [5]. Approximately 60 percent of patients will not achieve a 50 percent reduction in pain within 24 hourswith either first day approach alone, but most patients will respond further over several days with these doses.Patients should be continued on treatment for the duration of the attack, usually at reduced doses (eg, 0.6 mgonce or twice daily as tolerated) once a significant response is achieved. Complete cessation of treatment can besafely done within two to three days of complete resolution of the attack. In patients already receiving colchicineprophylaxis, the dose used for prevention of attacks during symptom-free intervals should be resumed after thehigher dose is taken in place of the usual prophylactic dose on the first day of therapy for the acute attack. Acolchicine dose reduction is required for patients with a CrCl of <45 mL/minute. (See 'General therapeuticprinciples' above.)

Contraindications to the use of colchicine with these doses and schedules of administration include:

Concomitant use of a medication that moderately to strongly inhibits P-gp and/or CYP3A4 may be permitted inpatients with normal renal and hepatic function if there is no other reasonable alternative to colchicine, but thisgenerally requires significant dose reduction and limits on the frequency of colchicine administration [23]. (See'Safety of colchicine' below.)

Common adverse effects of colchicine may include diarrhea and abdominal cramping, but these are less likely inpatients who receive no more than 1.8 mg in total on the first day compared with patients receiving higher doses,such as 0.6 mg every one to two hours until symptom relief or intolerance (as was historically employed) [24].

When low-dose colchicine therapy is ineffective or is minimally effective in suppressing acute gout in a timelyfashion, alternative antiinflammatory agents, including oral and intraarticular glucocorticoids, may be required. Inpatients without contraindications to NSAID use, supplemental therapy with a NSAID in an antiinflammatoryregimen may also be cautiously employed. (See 'Initial treatment choices' above and 'Glucocorticoids' below.)

Efficacy of oral colchicine — Colchicine for the treatment of acute gouty arthritis has not been extensivelystudied in randomized trials [24,25], even though it was used for centuries for the treatment of acute gout. Oralcolchicine (uncombined with another active ingredient, such as probenecid) was first formally approved by theFDA for use in the US for the treatment of acute gout in 2009 [21,22].

In our experience, incipient gout attacks may be aborted with oral colchicine taken at the onset of the first

Use of colchicine (eg, for prophylaxis) within the prior 14 days in patients with severe hepatic impairment orsevere renal impairment (CrCl of <30 mL/min)

Concomitant use of a medication that strongly inhibits the cytochrome P450 system component CYP3A4(table 1) or that inhibits the membrane P-glycoprotein multidrug resistance transporter (P-gp) in the presenceof renal or hepatic impairment [22] (see 'Safety of colchicine' below)

symptom. Whether colchicine therapy offers more rapid or complete relief of gout flares than alternativeantiinflammatory agents is not established and awaits adequate head-to-head comparisons. Side effects are lesslikely when a low-dose regimen is used at the onset of flare symptoms, and such regimens appear to achieve adegree of benefit comparable to that achieved with higher colchicine doses. These points were illustrated by theresults of the Acute Gout Flare Receiving Colchicine Evaluation (AGREE) trial, a randomized trial that comparedtreatment administered within 12 hours of flare onset using low-dose colchicine (1.8 mg total over one hour), veryhigh-dose colchicine (4.8 mg total over six hours), and placebo [25]. A significantly greater proportion of patients inthe low-dose and high-dose colchicine treatment groups (38 and 33 percent), compared with those receivingplacebo (16 percent), achieved a 50 percent reduction in pain by 24 hours from treatment initiation without the useof rescue medication. This trial was limited by the short duration of treatment.

Safety of colchicine — Colchicine is contraindicated in patients with advanced renal or hepatic impairment (inboth acute gout flare treatment and in long-term flare prophylaxis) because both the kidneys and liver participate incolchicine metabolism, in large part through the action of the cell membrane P-gp and through the availability of thecytochrome P450 system component CYP3A4. Similarly, long-term colchicine treatment in patients with milderrenal or hepatic impairment in combination with agents strongly inhibiting P-gp or utilizing CYP3A4 (table 1) hasbeen associated with a greater risk for colchicine toxicity due to the resulting increased serum concentration ofcolchicine [26].

Gastrointestinal symptoms (diarrhea, abdominal pain, nausea and vomiting) and readily reversible peripheralneuropathy are the most common adverse reactions to colchicine administration. More severe colchicine toxicity,which may include combinations of serious, life-threatening, or fatal adverse events such as blood cytopenias,rhabdomyolysis or myopathy, peripheral neuropathy, liver failure, or severe cutaneous eruption, has only rarelybeen reported in patients receiving brief administration of this agent for acute gout flare, as in a patient treated withvery high-dose colchicine together with multiple drugs affecting colchicine levels over an eight-day period [27]. Weare cautious and do not use colchicine to treat acute gout in patients with mild renal or hepatic impairment if theyare receiving strong P-gp inhibitors or agents strongly reducing CYP3A4 availability. In addition, we use colchicinefor acute gout flare in patients with normal renal or hepatic function receiving concomitant agents of this type onlyif no alternative is available. Such patients require reduction of the colchicine dose, depending upon the affectedpathways. Care should also be taken in combining use of colchicine with the wider array of less strong CYP3A4inhibitors, including statins, other lipid-lowering drugs, erythromycin, and grapefruit juice (table 1). Dosingguidelines for colchicine have been proposed for those patients with normal renal and hepatic function who arereceiving interacting agents or who have received them within 14 days [23]. These guidelines limit the size of theinitial dose and the frequency at which dosing may be repeated.

More commonly used inhibitors of P-gp include cyclosporine, tacrolimus, amiodarone, quinidine, azole antifungals,verapamil (and some other calcium channel blockers), vinca alkaloids, erythromycin, clarithromycin, and others[28]. Commonly used strong CYP3A4 inhibitors include human immunodeficiency virus (HIV) protease inhibitors,clarithromycin (and other macrolide antibiotics), azole antifungals, and others (table 1) [29]. A number of drugsinhibit both P-gp and CYP3A4, including cyclosporine, verapamil, diltiazem, erythromycin, clarithromycin, andothers.

More detailed information on dosing requirements for colchicine and other specific drugs and on drug interactions,as well as a more detailed list of medications in each group, is available using Lexi-Interact, the drug interactionprogram, which can be accessed through a link in the drug information topic.

We do not administer colchicine intravenously, and we strongly advise against such use because of the risk ofserious adverse effects, including death, which are associated with the intravenous administration of this drug.

Glucocorticoids

Administration and choice of glucocorticoid — In patients with contraindications to the use of both NSAIDsand colchicine, the choice of therapy depends upon several factors, including the number of involved joints, theexperience of the clinician with joint injection techniques, and the need, if present, for parenteral rather than orally

administered therapy:

Intraarticular glucocorticoids — We suggest arthrocentesis with joint fluid aspiration and analysis followedby intraarticular injection of glucocorticoids for patients who are unable to take oral medications, who have onlyone or two actively inflamed joints, and in whom infection has been excluded. We use triamcinolone acetonide (40mg for a large joint [eg, knee], 30 mg for a medium joint [eg, wrist, ankle, elbow], and 10 mg for a small joint) orequivalent doses of methylprednisolone acetate. (See "Joint aspiration or injection in adults: Technique andindications" and "Joint aspiration or injection in adults: Complications".)

Joint aspiration and injection are commonly used in rheumatology and orthopedic practice but, except for kneeinjection, are much less frequently done in primary care practice because of the experience required.

Evidence of the benefit of intraarticular glucocorticoids has been limited to small, open-label trials, although, in ourexperience, such treatment is usually highly effective and works quickly, often within 24 hours [30]. A 2013systematic review of the safety and efficacy of intraarticular glucocorticoid injection for acute gout could notidentify any randomized trials of intraarticular glucocorticoids that met the inclusion criteria, illustrating the verylimited formal evidence available regarding the efficacy and safety of this approach [31]. Indirect evidencesupporting the use of intraarticular glucocorticoid injections in gout includes the significant benefit that may resultfrom such injections for the treatment of rheumatoid arthritis and osteoarthritis. (See "Use of glucocorticoids in thetreatment of rheumatoid arthritis", section on 'Intraarticular therapy' and "Initial pharmacologic therapy ofosteoarthritis", section on 'Intraarticular glucocorticoids'.)

Oral glucocorticoids — We suggest the use of oral glucocorticoids for patients who cannot take NSAIDs orcolchicine and who are not candidates for intraarticular glucocorticoid injection because of polyarticular disease.We also suggest the use of oral glucocorticoids if a clinician with adequate expertise in these techniques is notreadily available. We use prednisone (or other equivalent glucocorticoid) in doses of 30 to 50 mg once daily or in

One or two actively inflamed joints – Arthrocentesis followed by intraarticular injection of glucocorticoids maybe used in patients unable to take NSAIDs or colchicine who have only one or two actively inflamed joints.However infection should be excluded, and expertise with this technique is required. (See 'Intraarticularglucocorticoids' below.)

Glucocorticoid joint injection should be withheld in patients in whom a diagnosis of gout has not previouslybeen established or in whom the clinical history and physical examination suggest the alternative oradditional possibility of joint infection. To achieve this critical distinction, joint aspiration should be carried outwith examination of the synovial fluid by Gram stain and culture, by cell count and differential white cellcount, and by polarized light microscopy for urate or other crystals that are pathognomonic either for gout(urate crystals) or pseudogout (acute calcium pyrophosphate crystal arthritis). (See "Clinical manifestationsand diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease".)

It is important to note that septic arthritis and acute gout can coexist, so, even if gout has been diagnosed inthe past, caution should be taken in the use of glucocorticoid joint injection if the current clinical picture isuncertain, even in a patient with well-established gout.

Not candidates for joint injection – Oral glucocorticoids may be used for patients who cannot take NSAIDs orcolchicine and who are not candidates for intraarticular glucocorticoid injection because of polyarticulardisease. Glucocorticoids should be used with caution in patients with heart failure, poorly controlledhypertension, or glucose intolerance, but they may be used in patients with moderate to severe renalinsufficiency. (See 'Oral glucocorticoids' below.)

Need for parenteral (non-intraarticular) therapy – In patients who are unable to take oral agents and who arenot appropriate candidates for intraarticular injection, we use parenteral glucocorticoids. Although reported tobe efficacious for gout flare treatment, corticotropin (adrenocorticotropic hormone [ACTH]) cost and limitedavailability restrict the use of parenteral ACTH treatment. (See 'Parenteral glucocorticoids' below.)

two divided doses until flare resolution begins, and we then taper the dose of glucocorticoids, usually over 7 to 10days.

The data on efficacy of oral glucocorticoids are limited but support clinical experience which suggests thatprednisone and prednisolone are safe and effective when administered in this fashion and that these agents reducesymptoms to a similar extent as NSAIDs [32-34]. However, rebound attacks are relatively common onceglucocorticoids are withdrawn, especially in patients who have previously suffered a number of prior attacks,whose intercritical periods have progressively shortened, and who are not receiving prophylactic therapy. For thisreason, slower tapering of the glucocorticoid dose with extension of the course to 10 to 14 or even 21 days isadvisable in such patients. In the rare patient who keeps flaring during oral glucocorticoid tapering, such that urate-lowering therapy has never been initiated, allopurinol treatment can often be successfully initiated withconcomitant antiinflammatory treatment [35]. (See "Prevention of recurrent gout".)

Common adverse effects of short-term, moderate- to high-dose glucocorticoid use include mood changes,hyperglycemia, increased blood pressure, and fluid retention, but most patients tolerate glucocorticoids in therapidly tapering regimens used for acute gout. Frequent and repeated courses of glucocorticoids should be avoidedto limit adverse effects. This can usually be achieved by appropriate preventive therapy. (See "Major side effectsof systemic glucocorticoids" and "Prevention of recurrent gout".)

Parenteral glucocorticoids — In patients who are unable to take medications orally and who are notcandidates for intraarticular glucocorticoid injection, we generally suggest treatment with intravenous orintramuscular glucocorticoids. The choice of glucocorticoid and the route of administration depend upon the clinicalcontext:

Few studies have adequately evaluated the benefit of systemic parenteral glucocorticoids [36]; these studies andthe few randomized trials had significant limitations in quality and strength of evidence. Nonetheless, someexperts report this approach to be effective and well-tolerated [1,5,8,37].

SPECIAL CIRCUMSTANCES

Patients on anticoagulation — In patients on anticoagulants, we use one of the following approaches:

Older adults — A systematic review of clinical trials for treatment of gout suggested that all of these agents were

In hospitalized patients with polyarticular involvement, with existing or easily established intravenousaccess, and with no contraindications to glucocorticoids, we suggest intravenous administration of aparenteral glucocorticoid. The dose and frequency depend upon the agent chosen. A typical dose is 20 mg ofmethylprednisolone administered intravenously twice daily, with stepwise reduction by half of each dosewhen improvement begins and with maintenance of at least 4 mg twice daily (or oral equivalent) for fivedays.

Intramuscular glucocorticoid injection has also been widely used for acute gout management, usually with aninitial dose of triamcinolone acetate (40 to 60 mg) that may need to be repeated once or twice (at intervals ofat least 48 hours) if benefit fades or if resolution of the flare is not achieved.

We use low-dose colchicine, in the absence of contraindications and in patients initiating treatment promptlyafter flare onset, because of its efficacy, convenience, lack of effect on blood clotting, and lack of need for aprocedure. (See 'Colchicine therapy' above.)

Joint aspiration and injection with glucocorticoids are another option, if only one or two joints are involved,and can be done safely even with anticoagulation. (See 'Intraarticular glucocorticoids' above and "Jointaspiration or injection in adults: Technique and indications", section on 'Approach to the patient onanticoagulants'.)

Oral glucocorticoids can be used if there is polyarticular involvement or if arthrocentesis cannot be performedfor other reasons. (See 'Oral glucocorticoids' above.)

likely to be efficacious in older patients [38]; however, the management of acute gout in older patients iscomplicated by the greater prevalence of comorbidities, the use of multiple medications, and reductions in renalfunction associated with aging [39,40]. These safety concerns reduce the proportion of patients for whomnonsteroidal antiinflammatory drugs (NSAIDs) or colchicine may be preferred agents, but these drugs can be usedin patients who lack such contraindications. However, we avoid the use of indomethacin in older adults because ofthe greater risk of adverse effects with this medication compared with other NSAIDs, consistent with the BeersCriteria for potentially inappropriate medication use in older adults [41]. Glucocorticoids are generally tolerated inshort-term use for acute attacks in patients in whom NSAIDs or colchicine may pose an increased risk. (See'General therapeutic principles' above and "Drug prescribing for older adults".)

Contraindications to the use of NSAIDs which are of particular concern in older adults include the presence ofheart failure, renal impairment, or gastrointestinal disease. Contraindications to colchicine include gastrointestinalintolerance, dosing restrictions in patients with renal and hepatic dysfunction, and potential drug interactions andalso may include the high cost of therapy. General principles and special concerns in prescribing drugs in thispopulation are discussed in more detail separately. (See "Drug prescribing for older adults".)

End-stage renal disease and transplantation — We generally treat patients with advanced chronic kidneydisease (CKD) or end-stage renal disease requiring maintenance dialysis with intraarticular, oral, or parenteralglucocorticoids. In patients with residual kidney function, including patients on peritoneal dialysis, NSAIDs shouldbe avoided because of the risk of worsening of renal function; any use of NSAIDs in this setting should only bedone in consultation with the patient’s nephrologist. In patients on chronic hemodialysis, NSAIDs may be used asan alternative to glucocorticoids, particularly in patients with milder attacks in whom lower doses and shortercourses can be employed. Other concerns in patients on hemodialysis include concomitant use of anticoagulationand risk of gastrointestinal toxicity. Colchicine is generally avoided in hemodialysis patients with acute gout flaresbecause it is not removed by dialysis, and therefore these patients have a heightened risk of colchicine toxicity.(See "NSAIDs: Acute kidney injury (acute renal failure)" and 'Intraarticular glucocorticoids' above and 'Oralglucocorticoids' above and 'Parenteral glucocorticoids' above.)

Acute gout in organ transplant recipients should only be managed by clinicians experienced with these clinicalproblems because of the complexities of management due to reduced uric acid excretion and because of thefrequent accompanying use of cyclosporine. Colchicine, NSAIDs, and glucocorticoids can potentially be used, butlimits on dosing, frequency, and duration of therapy usually apply. Treatment in this setting is discussed in moredetail separately. (See "Hyperuricemia and gout in renal transplant recipients", section on 'Colchicine' and"Hyperuricemia and gout in renal transplant recipients", section on 'Nonsteroidal antiinflammatory agents' and"Hyperuricemia and gout in renal transplant recipients", section on 'Increased glucocorticoid dose'.)

RESISTANT DISEASE — In patients with symptoms that are not improving as expected, the patients’ adherenceto the treatment program should be assessed. Also, alternative agents should be considered, depending upon whathas already been tried, and the diagnosis should be reevaluated. Arthrocentesis may be required to exclude othercauses of a flare of acute inflammatory arthritis, including infection, if it was not already performed during theattack. It is important to not become overly concerned if attacks do not resolve within one to three days of startingtreatment. Most acute flares of gout resolve within 7 to 10 days, regardless of the type of therapy, and resolutionis much more rapid if the patient is treated early in the attack. Thus, truly resistant disease is uncommon, althoughsome attacks may resolve slowly, especially if treatment is not started early or if there is extensive polyarticulardisease leading to chronic gouty arthritis, where near continuous joint inflammation is noted. (See "Clinicalmanifestations and diagnosis of gout", section on 'Acute gouty arthritis' and "Clinical manifestations and diagnosisof gout", section on 'Differential diagnosis of acute gouty arthritis'.)

The management of patients with persistent symptoms due to a confirmed acute flare of gout depends upon theprior therapy and upon the patients’ comorbidities:

In patients being treated with nonsteroidal antiinflammatory drugs (NSAIDs), a more prolonged course oftherapy than usual may be required in some patients with persistent symptoms, especially if treatment was

INVESTIGATIONAL THERAPY — IL-1 is an important mediator of gouty inflammation and a potential therapeutictarget in acute gout [42]. Thus, agents inhibiting IL-1 action are under study for the treatment of acute gout. (See"Pathophysiology of gouty arthritis".)

Anakinra (100 mg daily, administered subcutaneously) is the preferred IL-1 antagonist for use in acute goutbecause of its short half-life of IL-1 blockade and its relatively modest cost compared with other alternative IL-1inhibitors, such as canakinumab. Canakinumab has been evaluated and approved for acute gout in the EuropeanUnion [43]; it is expected to become available in Europe for use in the treatment of patients with acute goutyarthritis who have frequent attacks and who cannot be effectively managed with other treatment options. (See"Randomized clinical trials in rheumatoid arthritis of biologic agents that inhibit IL-1, IL-6, and RANKL", section on'Anakinra' and "Cryopyrin-associated periodic syndromes and related disorders", section on 'Canakinumab'.)

Evidence of benefit from the inhibition of IL-1 effects includes the following:

not started until the flare was ongoing for several days. Patients with a flare that appears resistant to anadequate course of NSAID therapy may respond to treatment with glucocorticoids. (See 'Glucocorticoids'above.)

In patients who are being treated with colchicine but who do not have contraindications to NSAIDs, it may benecessary to switch to NSAID therapy if no improvement is seen within several days, especially if the attackwas not treated early. In patients in whom NSAIDs are contraindicated, glucocorticoids may be required.(See 'NSAID therapy' above and 'Administration of colchicine' above and 'Glucocorticoids' above.)

The management of recurrent (or “rebound”) attacks following treatment with glucocorticoids is discussedabove. (See 'Oral glucocorticoids' above.)

Interleukin (IL)-1 inhibition may be of benefit in selected patients. We use anakinra, an IL-1 receptorantagonist protein, only in gout patients with frequent flares in whom all other available treatments have failedor in whom “rebound flares” occur even when glucocorticoid treatment is appropriately tapered. Although IL-1antagonist agents are available in some countries for the treatment of conditions other than gout, such asanakinra for rheumatoid arthritis and canakinumab and rilonacept for cryopyrin-associated periodicsyndromes, only the first two have shown clear efficacy in treatment of acute gout and their use for thisindication remains investigational in the United States (see 'Investigational therapy' below).

Anakinra – Beneficial effects of IL-1 inhibition were seen in some patients in open-label pilot studies of therecombinant IL-1 receptor antagonist, anakinra, with 100 mg daily given subcutaneously until symptoms ofacute gouty arthritis improved [44-46]. However, some patients respond only partially to such treatment, andrecurrent flares are common within one to six weeks after stopping therapy. The short biological half-life ofanakinra, which mandates daily subcutaneous administration, makes this agent an unlikely candidate forgout flare prophylaxis but may, in the case of acute gout flares, provide an advantage in safety, sinceblocking of IL-1 beta action is rapidly reversed when treatment of this agent is discontinued.

Canakinumab – Canakinumab is a fully humanized, long-acting monoclonal antibody that blocks IL-1 betasignaling; it can be effective for the treatment of acute gout in patients who have a history of multiple flaresand who have either refractoriness or contraindication to acute flare treatment with NSAIDs and/or colchicine[43,47].

The efficacy and safety of canakinumab (a single subcutaneous injection of 150 mg plus a placebointramuscular injection) were evaluated in such patients in comparison with triamcinolone acetonide (a singleintramuscular injection of 40 mg plus a placebo subcutaneous injection) in two identically designedrandomized trials (one in the US and the other in Europe and other non-US countries) involving a total of 456patients [43]. Canakinumab resulted in a significantly greater reduction in a mean 72-hour pain score using a100 mm visual analog scale (decrease of 35.7 versus 25 mm).

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SUMMARY AND RECOMMENDATIONS

Four patients in the published trials, all receiving canakinumab, required hospitalization for treatment ofinfections (one abscess of the jaw, one abscess of the forearm, pneumonia, and gastroenteritis), but therewere no opportunistic infections. Other adverse events that were most common with canakinumab includedlow neutrophil counts and low platelet counts.

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Basics topics (see "Patient information: Gout (The Basics)")

Beyond the Basics topics (see "Patient information: Gout (Beyond the Basics)")

The goal of therapy in an acute gout attack is prompt and safe termination of pain and disability. Whilesymptoms will usually resolve without therapy within a few days to several weeks, symptoms improve morequickly with administration of antiinflammatory drugs. More rapid and complete resolution of symptomsoccurs the earlier that treatment is introduced. Treatment with urate-lowering therapies is ineffective for acutegout, but urate-lowering therapy should not be initiated during an acute attack nor interrupted in patients onsuch therapy at the time of an acute attack. (See 'General therapeutic principles' above and "Prevention ofrecurrent gout".)

We suggest nonsteroidal antiinflammatory drugs (NSAIDs), rather than colchicine or glucocorticoids, as first-line therapy for most patients with acute gout and with no contraindications to their use (Grade 2B). Wetypically administer a potent NSAID (such as naproxen 500 mg twice daily or indomethacin 50 mg threetimes daily) for reduction of acute gouty inflammation. The NSAID can be discontinued one or two days afterclinical signs have completely resolved. Typically, the total duration of NSAID therapy for an acute attack isfive to seven days. It is likely to be shorter in patients who are treated within the first 24 hours of symptomonset and may be longer in patients in whom treatment is not begun until several days later. Aspirin isusually avoided because of the paradoxical effects of salicylates on serum urate. (See 'Administration ofNSAIDs' above and 'Efficacy and safety of NSAIDs' above.)

In patients with NSAID intolerance or with an absolute or relative contraindication to NSAIDs, we suggestthe use of low-dose oral colchicine (1.5 to 1.8 mg in two or three divided doses in the first 24 hours, followedby tapering of the dose until resolution of the attack), rather than glucocorticoids (Grade 2B). We limitcolchicine therapy to patients seen during the first 48 hours of an acute flare. Particular attention should begiven to dose adjustment in patients receiving inhibitors of the cytochrome P450 system componentCYP3A4 or inhibitors of the membrane P-glycoprotein multidrug resistance transporter (P-gp). Patientsshould not be treated with intravenously administered colchicine. (See 'Administration of colchicine' aboveand 'Efficacy of oral colchicine' above and 'Safety of colchicine' above.)

In patients who are unable to take oral medications, who have only one or two actively inflamed joints, and inwhom infection has been excluded, we suggest intraarticular injection of glucocorticoids (Grade 2B). Weprefer triamcinolone acetonide (40 mg for a large joint [eg, knee], 30 mg for a medium joint [eg, wrist, ankle,elbow], and 10 mg for a small joint) or equivalent doses of methylprednisolone acetate. (See 'Intraarticular

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glucocorticoids' above.)

In patients who cannot take NSAIDs or colchicine and who are not candidates for intraarticular glucocorticoidinjection, we suggest use of oral glucocorticoids (Grade 2B). We often use prednisone in doses of 30 to 50mg per day (as a single dose or two divided doses) or another equivalent glucocorticoid until pain anddisability begin to resolve, and we then taper over at least 7 to 10 days and over at least 10 to 14 days inpatients with multiple prior flares. (See 'Oral glucocorticoids' above.)

For patients with polyarticular involvement who are unable to take oral medications, have existing or easilyestablished intravenous access, and have no contraindications to glucocorticoids, we suggest systemicadministration of an intravenous glucocorticoid (Grade 2B). The dose and frequency depend upon the agentchosen. A typical dose is 20 mg methylprednisolone twice daily, with stepwise reduction by half of eachdose when improvement begins and with maintenance of at least 4 mg twice daily (or oral equivalent) for atleast five days. For patients with no intravenous access, intramuscular glucocorticoids may be used. (See'Parenteral glucocorticoids' above.)

An additional alternative for patients who are unresponsive to any other available approach and who havefrequent recurrent attacks is an interleukin (IL)-1 inhibitor, such as anakinra or canakinumab (whereavailable). The benefits of these agents for symptomatic relief need to be balanced with the potential forincreased risk for serious infections. (See 'Resistant disease' above.)

In patients who are anticoagulated, we use low-dose oral colchicine. We use intraarticular or oralglucocorticoids for the treatment of acute attacks if colchicine is contraindicated. We generally treat acutegout in patients with advanced chronic kidney disease (CKD) or with end-stage renal disease requiringmaintenance dialysis with intraarticular, oral, or systemic glucocorticoids. (See 'Patients on anticoagulation'above and 'End-stage renal disease and transplantation' above.)

GRAPHICS

Initial management of acute gout

NSAIDs: nonsteroidal antiinflammatory drugs.* Adjust dose in patients with renal insufficiency.

Adapted and revised from: Algorithms for the diagnosis and management ofmusculoskeletal complaints. Am J Med 1997; 103:49S. Original figure modifiedfor this publication. Illustration used with the permission of Elsevier Inc. All rightsreserved.

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Cytochrome P450 3A4 (CYP3A4) inhibitors and inducers*

Stronginhibitors

Atazanavir

Boceprevir

Ceritinib

Clarithromycin

Cobicistat andcobicistatcontainingcoformulations

Darunavir

Idelalisib

Indinavir

Itraconazole

Ketoconazole

Lopinavir

Nefazodone

Nelfinavir

Ombitasvir­paritaprevir­ritonavir

Ombitasvir­paritaprevir­ritonavir plusdasabuvir

Posaconazole

Ritonavir andritonavircontainingcoformulations

Saquinavir

Telaprevir

Telithromycin

Voriconazole

Moderateinhibitors

Amiodarone

Aprepitant

Cimetidine

Ciprofloxacin

Conivaptan

Crizotinib

Cyclosporine

Delavirdine

Desipramine

Diltiazem

Dronedarone

Erythromycin

Fluconazole

Fosaprepitant

Grapefruit juice

Isavuconazole(isavuconazoniumsulfate)

Mifepristone

Netupitant

Nilotinib

Tibolone

Verapamil

Strong inducers

Carbamazepine

Dexamethasone

Enzalutamide

Fosphenytoin

Lumacaftor

Mitotane

Pentobarbital

Phenobarbital

Phenytoin

Primidone

Rifabutin

Rifampin(rifampicin)

Rifapentine

St. John's wort

Moderateinducers

Bexarotene

Bosentan

Dabrafenib

Efavirenz

Eslicarbazepine

Etravirine

Modafinil

Nafcillin

Data are for systemic drug forms. Degree of inhibition or induction may be altered by dose,method, and timing of administration. Specific drug interactions and management suggestionsmay be determined by using Lexi­Interact, the drug interactions program included withUpToDate. Refer to UpToDate topics on specific agents and indications for further details.

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* The CYP3A4 inhibitors and inducers listed in this table are relevant for determining potentialinteractions of drugs that are CYP3A subfamily substrates.¶ Less potent effect on CYP3A4 reported in some references.

Data from Lexicomp Online. Copyright © 1978­2015 Lexicomp, Inc. All Rights Reserved

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