Gout: Treatment of flares

INTRODUCTION — 

A gout flare is intensely painful and disabling. Typically, a gout flare affects a single joint, although flares affecting multiple joints commonly occur. Without therapy, a gout flare usually resolves completely within a few days to several weeks, particularly in early disease. However, symptoms improve faster with treatment [1].

Flares recur in the great majority of patients who are not on urate-lowering therapies. With more frequent episodes, flares may be more severe and prolonged, and asymptomatic periods become shorter. For some with severe gout, flares may progress from discrete episodes to a chronic form of arthritis.

The management of gout flares will be reviewed here. Other aspects of management for gout, including urate-lowering therapy and nonpharmacologic strategies, are discussed elsewhere:

●(See "Gout: Pharmacologic urate-lowering therapy and treatment of tophi".)

●(See "Gout: Nonpharmacologic strategies for prevention and treatment".)

The pathophysiology, clinical manifestations, and diagnosis of gout are also discussed separately:

●(See "Gout: Pathophysiology".)

●(See "Gout: Clinical manifestations and diagnosis".)

PRETREATMENT CONSIDERATIONS

Exclude alternate diagnoses — A gout flare can mimic or coexist with other forms of inflammatory arthritis, including septic arthritis, even in a patient with well-established gout. Before initiating treatment, it is important to ensure that mimics of gout have been reasonably excluded. Indications for pretreatment evaluation by a clinician include:

●There is a high risk for infection (eg, immunocompromise, current treatment for infection, systemic or focal signs or symptoms of infection such as chills and fever)

●Features that raise suspicion for an alternative diagnosis (eg, history of trauma)

●In patients with established gout, features that are atypical for their usual gout flares

Patients with one or more of the above features should be urgently evaluated (within 24 hours) by a clinician and typically require arthrocentesis and synovial fluid analysis to exclude infection. The treatment of possible gout flares in these circumstances and differential diagnosis of gout are discussed separately. (See 'Selection of agent' below and "Gout: Clinical manifestations and diagnosis", section on 'Differential diagnosis'.)

Initiate therapy quickly — Once the diagnosis has been established and infection seems less likely, treatment should start as soon as possible, preferably within hours of symptom onset. More rapid and complete resolution of symptoms occurs the earlier that treatment is introduced. We encourage patients with established gout to maintain a supply of gout flare medication at home to allow initiation of treatment at the first sign of flare.

Continue or initiate chronic therapies for gout — For patients who are taking urate-lowering therapy (eg, allopurinol, febuxostat, probenecid), we continue these medications without interruption during gout flares. There is no benefit to temporary discontinuation of urate-lowering therapy.

When patients are not taking urate-lowering therapy but have an indication to do so, we discuss the pros and cons of such therapy with patients. Urate-lowering therapy may be started during a gout flare or an intercritical period. Indications for and choice of urate-lowering therapy are discussed in detail elsewhere. (See "Gout: Pharmacologic urate-lowering therapy and treatment of tophi", section on 'Indications'.)

Nonpharmacologic strategies can also reduce the risk of future gout flares. Some strategies can be implemented relatively quickly and may be done while patients are being treated for a gout flare (eg, adjustment of medications that affect urate balance) while others require more time (eg, management of related comorbid conditions, dietary modification). (See "Gout: Nonpharmacologic strategies for prevention and treatment".)

INITIAL THERAPY

Selection of agent — Patients with gout flares typically require initiation of a systemic antiinflammatory agent, such as a glucocorticoid, nonsteroidal antiinflammatory drug (NSAID), colchicine, or interleukin 1 (IL-1) inhibitor. These are all effective treatment options and should be started as soon as possible after the onset of the gout flare.

The choice of antiinflammatory agent will largely depend on whether there is a factor that strongly influences the risks of adverse effects related to certain therapies (eg, concern for septic arthritis as a concomitant or alternative diagnosis, comorbid conditions such as kidney disease). Other factors include the provider's familiarity with these agents, cost considerations, and the patient's familiarity, access, and prior successful use of a medication. The selection of an agent is outlined in the algorithm (algorithm 1) and summarized below:

●Suspicion for septic arthritis – When there is suspicion for septic arthritis as a concurrent or alternative diagnosis, we pursue additional evaluation (see 'Exclude alternate diagnoses' above). We avoid all forms of glucocorticoids (ie, intraarticular and systemic) or IL-1 inhibitors until septic arthritis can reasonably be excluded (eg, synovial fluid white blood cell count and Gram stain without clear signs of infection). Patients may still be treated empirically for a possible gout flare with an NSAID or colchicine if these medications are not otherwise contraindicated.

●No suspicion for septic arthritis – When there is not suspicion for septic arthritis, we choose an antiinflammatory therapy (specifically a systemic glucocorticoid, NSAID, or colchicine) based on the presence of any contraindications to specific therapies, drug availability, and patient preference (see 'Systemic glucocorticoids' below and 'Nonsteroidal antiinflammatory drugs' below and 'Colchicine' below). Specific therapies may be preferred for patients with certain factors, such as older age (ie, >65 years old), use of anticoagulation, end-stage kidney disease and/or transplantation, and pregnancy or lactation. (See 'Special patient populations' below.)

For patients with a gout flare affecting ≤2 joints that are amenable to injection, treatment with intraarticular glucocorticoids (eg, triamcinolone acetonide) may be offered as an alternative to systemic therapy if the patient has timely access (ie, within 24 hours) to a practitioner with sufficient expertise (see 'Intraarticular glucocorticoids' below). If patients have contraindications to all first line options, then we use anakinra. (See 'Interleukin 1 blockade' below.)

Our management approach is generally aligned with guidelines issued by the American College of Rheumatology (ACR) [2] and European Alliance of Associations for Rheumatology (EULAR, formerly the European League Against Rheumatism) [3]. When comparing various oral systemic treatments, several randomized trials evaluating glucocorticoids versus NSAIDs for gout flares demonstrated that glucocorticoids, when used at an appropriate dose and duration, are at least as efficacious as NSAIDs and may be associated with fewer serious adverse outcomes, particularly in comparison with indomethacin [4-7]. Glucocorticoids are therefore increasingly favored by expert guideline panels as first-line therapy for gout flares [3,8,9]. However, nonselective NSAIDs of all types are inexpensive and readily available to patients at the onset of a flare (some without a prescription), and short courses are probably as effective and safe as other agents [10-16] for this indication [10,13-15,17]. While short courses of colchicine are generally safe and effective, they may carry a slightly higher risk of drug-related adverse effects. As an example, a randomized open-label trial of 399 participants with gout flares compared naproxen 750 mg oral dose followed by 250 mg every eight hours for seven days with low-dose colchicine 0.5 mg three times daily for four days; at seven days, there was no difference in pain intensity, but naproxen caused fewer adverse effects (eg, diarrhea and headaches) [16].

Dosing, duration, and efficacy of therapies

Glucocorticoids

Systemic glucocorticoids

●Contraindications – In general, we avoid using systemic glucocorticoids in patients with concurrent infection, brittle diabetes, recent surgery with an unhealed wound, and/or history of glucocorticoid allergy or intolerance. More information on contraindications to and adverse effects associated with glucocorticoids is provided elsewhere. (See "Major adverse effects of systemic glucocorticoids".)

●Administration and dosing – We typically use oral glucocorticoids unless patients are unable to take them, in which case we offer intravenous or intramuscular formulations depending on the care setting.

•Oral – When using oral glucocorticoids, we give prednisone 40 mg daily (or its equivalent) until the flare resolves, followed by a taper. Premade glucocorticoid dose pack preparations may be used, but for some patients, the duration and rate of tapering may lead to an unsatisfactory response, leading to a need for redosing.

•Intravenous – When patients cannot take oral glucocorticoids and are admitted to an inpatient care setting, we use methylprednisolone 20 mg administered intravenously twice daily, with a rapid transition to oral glucocorticoids once patients can take enteral therapy.

•Intramuscular – When patients cannot take oral glucocorticoids and are in the outpatient setting, we use triamcinolone acetate 40 to 60 mg (or an equivalent dose of methylprednisolone), which can be repeated every 48 hours until the flare has resolved. The same dose and frequency are typically continued throughout the course.

●Duration – The duration of therapy for a gout flare should be tailored to each patient's needs and may range from only a few days to several weeks (particularly for patients with severe or polyarticular flares). Many patients who are treated promptly (ie, within 12 to 36 hours of symptom onset) require treatment for no more than 5 to 10 days; however, those who have severe flares or who experience a delay in initiating treatment may need extended treatment for several weeks. For patients with a history of relapsing or refractory disease who are taking glucocorticoids, we extend the taper to 14 to 21 days since shorter courses may increase the risk of rebound flares.

Patients who are initiating urate-lowering pharmacotherapy around the time of a gout flare may benefit from a prolonged course of antiinflammatory therapy for prophylaxis of flares; colchicine and NSAIDs are used more commonly for this indication than glucocorticoids. This is discussed in more detail elsewhere. (See "Gout: Pharmacologic urate-lowering therapy and treatment of tophi", section on 'Prophylaxis during initiation of urate-lowering therapy'.)

●Efficacy – Evidence comparing oral glucocorticoids with NSAIDs for the treatment of a gout flare is summarized above (see 'Selection of agent' above). Few randomized trials have adequately evaluated the benefit of systemic parenteral glucocorticoids [7,18]; the published studies and the few randomized trials have significant limitations in quality and strength of evidence [10,19]. A network meta-analysis of randomized trials found parenteral glucocorticoids appeared to have similar efficacy as other strategies used to treat gout flares [20].

We do not use corticotropin (adrenocorticotropic hormone [ACTH]) due to issues with cost and availability.

Intraarticular glucocorticoids

●Contraindications – Intraarticular glucocorticoids should not be given to patients with known or suspected septic arthritis. In patients taking anticoagulation, we use alternative therapies (eg, colchicine or systemic glucocorticoids), but an experienced provider may also be able to safely inject one or two joints with intraarticular glucocorticoids. (See 'Patients on anticoagulation' below.)

●Dosing and administration – We use a single injection of triamcinolone acetonide (40 mg for a large joint [eg, knee], 30 mg for a medium joint [eg, wrist, ankle, elbow], and 10 to 20 mg for a small joint (eg, first metatarsophalangeal) for a small joint), as outlined in the table (table 1). Methylprednisolone acetate can also be used. More information on the approach to arthrocentesis and medication dosing are discussed in more detail elsewhere. (See "Joint aspiration and injection in adults: Indications and technique" and "Intraarticular and soft tissue injections: What agent(s) to inject and how frequently?".)

●Efficacy – In our experience, a single injection of intraarticular glucocorticoids is usually highly effective, and patients experience relief within 24 hours. However, published evidence supporting the use of intraarticular glucocorticoids is limited to small, open-label trials [21]. A 2013 systematic review noted that this practice has never been examined in a randomized study [22]. Evidence of effectiveness in other inflammatory arthritis (eg, rheumatoid arthritis) also support its use in gout, which is discussed in the respective disease treatment topics.

Nonsteroidal antiinflammatory drugs

●Contraindications – There are multiple contraindications to NSAID use, which are more common in older adults. These include kidney disease (ie, estimated glomerular filtration rate [eGFR] <60), hyperkalemia, duodenal or gastric ulcer, poorly controlled hypertension, moderate to severe or uncompensated heart failure, cirrhosis, unmodifiable drug interactions (eg, anticoagulation), and known allergy or intolerance. Potential drug interactions, considerations in patients with certain comorbidities, and adverse drug effects are described in detail separately.

●Choice of NSAID and dosing – We use naproxen (500 mg twice daily) or indomethacin (50 mg three times daily). Other orally administered NSAIDs (and initial doses) that may be used include ibuprofen (800 mg three times daily), diclofenac (50 mg two to three times daily), meloxicam (15 mg daily), and celecoxib (200 mg twice daily; alternatively, some experts treat with a single initial dose of 400 mg followed by 200 mg twice daily) (table 2) [17].

Aspirin is not used to treat gout flares. However, low-dose aspirin used for cardiovascular prophylaxis should be continued during the treatment of a gout flare despite this effect [23,24].

Coadministration of a proton pump inhibitor may be indicated in patients who are at high risk of developing NSAID gastropathy. (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity".)

Patients should not be treated concurrently with more than one NSAID and should be queried regarding their medications (including over-the-counter therapies) to avoid such unintended use. Combination NSAIDs with glucocorticoids should also be avoided where possible due to the risk of peptic ulcer disease.

●Duration – As with the duration of systemic glucocorticoids and colchicine, the course of NSAIDs varies depending on the severity of the patient's presentation and the rapidity with which they begin treatment.

For patients who are simultaneously starting urate-lowering pharmacotherapy, treatment with an NSAID at a lower dose may be extended for three to six months to prevent flares. When patients who are at risk of NSAID toxicity require a prolonged course of NSAIDs (especially NSAIDs that are the strongest prostaglandin inhibitors, such as indomethacin), we periodically monitor the complete blood count (CBC) and basic metabolic panel.

●Efficacy – In our experience, complete or nearly complete resolution of the pain and disability of a gout flare typically occurs within several days to one week. There are relatively few high-quality randomized trials of NSAIDs for gout flares [10,17,25,26].

A number of trials have compared different NSAIDs, without any apparent differences in efficacy [10-15,17]. As an example, in one randomized trial, treatment with high doses of celecoxib (a single dose of 800 mg followed by 400 mg twice daily) was as effective as indomethacin (50 mg three times daily) [17]. In our experience and with the best evidence available, all fully dosed NSAIDs should be equally efficacious for treating gout flares.

Colchicine

●Contraindications – Colchicine is contraindicated in the presence of any degree of kidney or hepatic impairment in patients who are actively using or have recently taken (eg, within the past 14 days) a P-glycoprotein (P-gp) inhibitor (table 3) or an agent that strongly reduces availability of the cytochrome P450 system component CYP3A4 (table 4) [27-29]. These agents include some commonly used antimicrobial agents (eg, clarithromycin, ketoconazole, antiretroviral drugs) and antihypertensive agents (eg, verapamil). Concurrent use of these medications with colchicine may thus increase the risk of myelosuppression, and fatal pancytopenia may ensue [30].

Care should also be taken when combining colchicine with the wider array of less potent CYP3A4 inhibitors, including diltiazem, fluconazole, and grapefruit juice (table 4), and drugs with potential for additive side effects (eg, myotoxicity related to a statin or fenofibrate). Guidance for dosing colchicine in such patients is discussed below.

Patients receiving colchicine should have their medication regimen regularly analyzed for drug interactions, particularly when initiating and adjusting therapy; this may be done by use of the drug interactions program included with UpToDate.

●Administration and dosing – We only use oral formulations of colchicine. Depending on the size of colchicine tablet available, we use an initial dose of 1 to 1.2 mg, followed one hour later by another 0.5 to 0.6 mg, for a total dose on the first day of therapy of 1.5 to 1.8 mg [27,29,31]. Subsequently, the colchicine dose should be reduced to 0.5 to 0.6 mg twice daily until 48 hours after resolution of the flare.

In patients already receiving colchicine prophylaxis (0.5 or 0.6 mg once to twice daily) at the time of their flare, this higher dose regimen is temporarily used in place of the usual prophylactic dose, which may be resumed once the flare has been treated.

We do not increase colchicine beyond standard doses. In a randomized study of patients with a gout flare, colchicine 1.8 mg was found to be equally effective as high-dose colchicine (4.8 mg) at reducing pain by at least 50 percent in 24 hours (response rate 37.8 versus 32.7 percent). However, the high dose was associated with an increased risk of adverse events, including diarrhea and emesis [31].

In addition, we do not administer colchicine intravenously and strongly advise against such use because of the risk of serious adverse effects, including death. Due to this concern, intravenous colchicine is no longer available in many countries.

●Modified dosing – In patients with multiple factors that may potentially increase colchicine exposure beyond safe levels, we use no more than 0.3 mg on day 1 of flare. Subsequently, we administer no more than 0.3 mg every three days until the flare has resolved. These particularly high-risk groups include:

•Patients on colchicine prophylaxis within the past 14 days, with normal kidney and hepatic function, who have taken a strong CYP3A4 inhibitor (table 4) or a drug that inhibits P-gp (table 3) within the last 14 days [28].

•Patients on colchicine prophylaxis within the past 14 days, with any kidney or hepatic impairment, who have taken a moderate CYP3A4 inhibitor (table 4) within the last 14 days.

•Patients regardless of recent colchicine use, with advanced kidney or hepatic impairment (creatinine clearance of <30 mL/minute or Child-Pugh class C cirrhosis or equivalent, respectively) who are not receiving any interacting medications. Patients with kidney or hepatic impairment who are receiving an interacting medication should not receive colchicine.

Additional factors that may affect dosing and further mandate a need for reduced dose and frequency of administration or avoidance of colchicine altogether include:

•Additional drug interactions beyond those recognized from drugs that are moderate or strong CYP3A4 (table 4) or P-gp (table 3) inhibitors (eg, additive myotoxicity with combined use of statin and colchicine). The drug interactions program available within UpToDate should be consulted for additional information.

•Use of more than one medication that can interact with colchicine.

•Advanced age. (See 'Older adults' below.)

•Chronic ill health and debility.

•Combinations of multiple factors, some of which alone may not be problematic but which in combination can increase risk of colchicine accumulation.

Dosing guidelines for colchicine have been proposed by one manufacturer for those patients with normal kidney and hepatic function who are receiving interacting agents or who have received them within 14 days [32], and guidelines for colchicine administration in patients with kidney or hepatic impairment who are not using an interacting medication have also been described [29]. However, formal guidelines for dose adjustment in patients with multiple interacting factors have not been established, and our approach, which is based upon our personal experience, may differ in some limited respects from the manufacturer's guidelines.

●Duration – As noted above, we continue colchicine until 24 to 48 hours after the gout flare resolves.

When patients with a flare are also initiating urate-lowering pharmacotherapy, colchicine may be continued at a lower dose (eg, 0.6 mg daily) for three to six months to prevent gout flares. (See "Gout: Pharmacologic urate-lowering therapy and treatment of tophi", section on 'Colchicine prophylaxis'.)

●Monitoring for toxicity – All patients using colchicine should be advised about the potential for and management of adverse events on colchicine therapy. Colchicine is a lipophilic alkaloid with a narrow therapeutic margin, and therefore toxicity can occur without markedly elevated doses. Caution should be taken to avoid unintended intoxication, as can occur with drug interactions. Close monitoring of pertinent organ function and clinical status may be required and should be individualized depending upon the patient's clinical status.

The most common adverse reactions to colchicine are gastrointestinal symptoms, including diarrhea, abdominal pain and cramping, nausea, and vomiting [29]. Severe colchicine toxicities may also occur, including cytopenias, rhabdomyolysis or myopathy, peripheral neuropathy, liver failure, or severe cutaneous eruption. Patients who develop diarrhea, emesis, dysesthesias, or weakness should be instructed to stop therapy immediately. However, these outcomes are rare among patients who receive a short course of colchicine for a gout flare [33].

●Efficacy – Colchicine has been used for centuries to treat gout flares, but it has not been extensively studied in randomized trials [31,34]. In one trial, more patients had a 50 percent reduction in pain at 24 hours with colchicine compared with those taking placebo (36 versus 16 percent) [31].

Interleukin 1 blockade — IL-1 is an important mediator of gouty inflammation [35], and agents that inhibit IL-1 can effectively treat gout flares. The biology of, dosing for, contraindications to, and adverse effects of IL-1 inhibitors are discussed in more detail elsewhere. (See "Interleukin 1 inhibitors: Biology, principles of use, and adverse events".)

●Anakinra – Anakinra is a convenient IL-1 inhibitor to treat gout flares because of its short half-life. The typical dose is 100 mg subcutaneously every day until flare resolution.

Randomized trials have demonstrated that anakinra is as effective as standard-of-care therapies for the treatment of gout flares, although there may be an increased risk of rebound flares.

•In a randomized trial of 88 patients with a crystal-proven gout flare, anakinra (100 mg daily for five consecutive days) was associated with similar short-term improvements in pain, tenderness, and swelling compared with standard-of-care therapies (eg, colchicine, oral glucocorticoids naproxen) [36].

•In another randomized trial of 165 patients with a gout flare who were not candidates for NSAID or colchicine therapy, anakinra in doses of 100 to 200 mg daily provided similar reductions in pain as a single 40 mg injection of intramuscular triamcinolone after 24 to 72 hours [37].

●Canakinumab – Canakinumab has been approved in the European Union and the United States for treatment of patients who have at least three flares annually that cannot be managed with other treatment options [38,39]. Canakinumab is also effective for gout flare prophylaxis. For gout flares, it is typically given as a one-time dose of 150 mg subcutaneously. (See "Gout: Pharmacologic urate-lowering therapy and treatment of tophi", section on 'Prophylaxis during initiation of urate-lowering therapy'.)

Two randomized trials comprising 456 patients with gout flare demonstrated that canakinumab 150 mg was associated with greater reductions in pain at 72 hours compared with intramuscular triamcinolone acetate [39].

Supportive measures for all patients — Patients with gout flares may benefit from supportive measures, including limitation of activities that worsen pain and brief, intermittent application of ice or cool packs (eg, for 20 minutes at a time every few hours) to affected areas. Depending on the joints and/or bursae involved, temporary use of immobilizing braces, splints, or orthoses can also help reduce pain (eg, a protective orthosis for gouty olecranon bursitis).

While limited data on the efficacy of supportive measures are available, ice application is included in the 2020 ACR gout management guidelines [2].

SPECIAL PATIENT POPULATIONS — 

Certain patient populations with gout flares may benefit from using one approach over another due to increased risks of adverse effects.

Patients on anticoagulation — For most patients who develop a gout flare while taking anticoagulants, we use colchicine given its lack of effect on blood clotting (see 'Colchicine' above). When colchicine is contraindicated, oral glucocorticoids can be used; however, caution and closer monitoring are required if there is a history of peptic ulcer disease or gastrointestinal bleeding. (See 'Systemic glucocorticoids' above.)

If both colchicine and oral glucocorticoids are contraindicated and the flare affects ≤2 joints that are amenable to injection, a highly experienced clinician can safely administer intraarticular glucocorticoids. Care is necessary to avoid a hemarthrosis, although this complication is very rare in our experience. (See 'Intraarticular glucocorticoids' above and "Joint aspiration and injection in adults: Indications and technique", section on 'Patients on anticoagulation'.)

If none of the above strategies are feasible, patients may be managed with celecoxib. Celecoxib is a cyclooxygenase 2 (COX-2) selective nonsteroidal antiinflammatory drug (NSAID) that lacks the antiplatelet effect of the nonselective NSAIDs but retains some potential for gastrointestinal toxicity. We do not use nonselective NSAIDs in patients taking anticoagulation. (See "Overview of COX-2 selective NSAIDs", section on 'Reduction in toxicities with COX-2 selective NSAIDs (coxibs)'.)

Older adults — In older adults, we typically use oral glucocorticoids to manage gout flares. Older adults are often intolerant of or have contraindications to both NSAIDs and colchicine, especially given the greater prevalence of comorbidities (eg, kidney dysfunction, heart failure, gastrointestinal disease) in this population [40,41]. Caveats regarding the choice of therapy in older adults are discussed in detail elsewhere and summarized below in the setting of gout (see "Drug prescribing for older adults"):

●Glucocorticoids – Older adults generally tolerate brief courses of oral glucocorticoids well. (See 'Systemic glucocorticoids' above.)

●NSAIDs – Contraindications to the use of NSAIDs that are of particular concern in older adults include the presence of heart failure, kidney dysfunction, or gastrointestinal disease. In the absence of such contraindications, we still do not use indomethacin in older adults because of the greater risk of adverse effects with this medication compared with other NSAIDs [42]. (See 'Nonsteroidal antiinflammatory drugs' above.)

●Colchicine – Colchicine myopathy and peripheral neuropathy can be subtle in older adults, although brief courses (eg, less than a week) for gout flares should not be associated with these complications. In case of longer courses or frequent use, complaints of weakness and functional decline while taking colchicine should prompt a careful neurologic examination, laboratory evaluation including serum creatine kinase, and empirical drug discontinuation. (See 'Colchicine' above.)

A systematic review suggested that all of the antiinflammatory agents discussed above are efficacious in older patients [43].

End-stage kidney disease and transplantation — We generally treat patients with advanced chronic kidney disease or end-stage kidney disease requiring maintenance dialysis with intraarticular or systemic glucocorticoids. (See 'Glucocorticoids' above.)

We do not use NSAIDs in patients with residual kidney function, including patients on peritoneal dialysis, due to the risk of worsening kidney function; any use of NSAIDs in this setting should only be done in consultation with the patient's nephrologist. We also generally avoid colchicine in end-stage kidney disease due to the risk of colchicine-induced side effects. Interleukin 1 (IL-1) inhibitors can be a safe and effective alternative when other options are contraindicated.

When glucocorticoids are contraindicated, we modify treatment as follows:

●Chronic hemodialysis – In patients on chronic hemodialysis who cannot use glucocorticoids, NSAIDs may be used as an alternative, particularly in patients with milder gout flares in whom lower doses and shorter courses can be employed. However, patients on hemodialysis may have an increased risk of gastrointestinal toxicity [44]. (See 'Nonsteroidal antiinflammatory drugs' above.)

●Kidney transplant – Gout flares in kidney transplant recipients should ideally be managed in consultation with clinicians with expertise in this area given the complexities of addressing reduced uric acid excretion, which is worsened by use of calcineurin inhibitors. Treatment in this setting is discussed in more detail separately. (See "Hyperuricemia and gout in kidney transplant recipients", section on 'Selection of initial antiinflammatory therapy'.)

Pregnancy and lactation — Gout flares are exceedingly uncommon during pregnancy and lactation, paralleling the low prevalence of hyperuricemia in females of childbearing age in most populations. Despite its rarity, gout flares during pregnancy and lactation have been reported [45-47]. Our approach to treatment of gout flares in pregnant and breastfeeding patients is as follows:

●Pregnancy – In most pregnant patients, we use systemic glucocorticoids to treat gout flares. We avoid systemic glucocorticoids in patients with the typical contraindications discussed above as well as those with poorly controlled hypertension or diabetes, since these complications can have serious implications during pregnancy. In those with recurrent flares, we give daily low-dose glucocorticoids for prophylaxis. (See 'Systemic glucocorticoids' above.)

In patients who cannot take glucocorticoids, alternative options to treat gout flares include colchicine and, for selected patients, NSAIDs. We do not use NSAIDs in patients with impaired kidney function or later in pregnancy (ie, at or after 20 weeks of gestation) due to an increased risk of fetal kidney dysfunction and premature closure of the fetal ductus arteriosus.(See 'Colchicine' above and 'Nonsteroidal antiinflammatory drugs' above.)

●Lactation – In breastfeeding patients, we use either glucocorticoids or NSAIDs to treat gout flares (see 'Systemic glucocorticoids' above and 'Nonsteroidal antiinflammatory drugs' above). We generally avoid the use of colchicine during lactation.

The safety of using glucocorticoids, NSAIDs, and colchicine during pregnancy and lactation is described in detail separately. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Glucocorticoids' and "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'NSAIDs' and "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Colchicine'.)

RESISTANT OR REFRACTORY DISEASE

Reassess the diagnosis — In patients who do not completely respond to therapy, we reevaluate the diagnosis and assess adherence. Advanced musculoskeletal imaging (ultrasound or dual-energy computerized tomography [DE CT]) and arthrocentesis may be required to confirm the diagnosis or to exclude other causes of a flare of acute inflammatory arthritis, including infection, if these tests were not already performed during the suspected gout flare. (See "Gout: Clinical manifestations and diagnosis", section on 'Differential diagnosis'.)

Rebound flare — If patients initially improve but experience a recurrence of symptoms after tapering or discontinuing therapy, they may have a "rebound" gout flare. This is more common when therapy is tapered or discontinued too quickly (eg, less than five days).

If rebound flare seems likely in a patient who was taking systemic glucocorticoids, we increase back to the last effective dose until symptoms are controlled and then resume the taper over two to three weeks. In patients who were taking an NSAID or colchicine, we likewise resume therapy and extend the course for two to three weeks.

Partial response — We consider patients to have a partial response to therapy if they gradually improve but do not return to their premorbid baseline. This is more common among patients who started treatment several days after the start of the gout flare. In such cases, treatment may need to be extended for up to four weeks or changed due to disease resistance. (See 'Resistant disease' below.)

Resistant disease — We consider patients to have resistant disease if there is no clinical improvement after three days of treatment. Subsequent management depends on the type of therapy initially used:

●Resistant to systemic glucocorticoids – For such patients, we optimize the dose and delivery of glucocorticoids. If the dose is lower than 40 mg of prednisone or its equivalent, we increase the dose to that level. If the flare happens in a hospitalized patient with a functional IV, we consider giving one or two days of intravenous glucocorticoids. If the flare occurs in a patient already receiving high doses of intravenous glucocorticoids, we consider the patient to have refractory disease. (See 'Refractory disease' below.)

For patients who have persistent disease affecting only one or two joints, intraarticular glucocorticoids are an option if they have not been given recently (ie, within the past three months) and if this intervention is readily available. Intraarticular and systemic glucocorticoids can be combined. (See 'Intraarticular glucocorticoids' above.)

●Resistant to NSAIDs or colchicine – For such patients, we switch to systemic glucocorticoids (see 'Systemic glucocorticoids' above). Intraarticular glucocorticoids may also be added for patients who have persistent disease affecting only one or two joints if they have not been given recently (ie, within the past three months) and if this intervention is readily available. (See 'Intraarticular glucocorticoids' above.)

●Resistant to intraarticular glucocorticoids – For such patients, we initiate a systemic antiinflammatory therapy (ie, systemic glucocorticoids, NSAIDs, or colchicine) depending on comorbid conditions and patient preferences. (See 'Selection of agent' above.)

Refractory disease — For patients who cannot tolerate or do not respond to the standard therapies discussed above, we start anakinra or canakinumab. (See 'Interleukin 1 blockade' above.)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Gout and other crystal disorders".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Gout (The Basics)")

●Beyond the Basics topics (see "Patient education: Gout (Beyond the Basics)")

PATIENT PERSPECTIVE TOPIC — 

Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Gout".)

SUMMARY AND RECOMMENDATIONS

●Pretreatment considerations – Early treatment of a gout flare leads to more rapid and complete resolution of the flare. However, gout and septic arthritis may present similarly. Glucocorticoids should be avoided until septic arthritis can be reasonably excluded. (See 'Pretreatment considerations' above.)

●Treatment of gout flare

•Selection of agent – The selection of antiinflammatory therapy for a gout flare depends on whether there is a factor that strongly influences the risks of adverse effects related to certain therapies, as outlined in the algorithm (algorithm 1) (see 'Selection of agent' above):

-Suspicion for septic arthritis – In such cases, we pursue additional evaluation and consider empiric treatment for a possible gout flare with a nonsteroidal antiinflammatory drug (NSAID) or colchicine. (See 'Exclude alternate diagnoses' above and 'Nonsteroidal antiinflammatory drugs' above and 'Colchicine' above.)

-No suspicion for septic arthritis – In such cases, we choose an antiinflammatory therapy (specifically a systemic glucocorticoid, NSAID, or colchicine) based on the presence of any contraindications to specific therapies, drug availability, and patient preference (see 'Systemic glucocorticoids' above and 'Nonsteroidal antiinflammatory drugs' above and 'Colchicine' above). For patients with a gout flare affecting one to two joints, intraarticular glucocorticoids are an alternative to systemic therapy if treatment can be delivered in a timely manner (ie, within 24 hours). (See 'Intraarticular glucocorticoids' above.)

•Dosing and administration – Guidance for dosing and administration include (see 'Dosing, duration, and efficacy of therapies' above):

-Systemic glucocorticoids – We use prednisone 40 mg daily or, in patients who require parenteral therapy, intravenous methylprednisolone 20 mg twice daily or intramuscular triamcinolone acetate 40 to 60 mg every two days. We continue glucocorticoids until flare resolution. We avoid using systemic glucocorticoids in patients with concurrent infection, brittle diabetes, and recent surgery with an unhealed wound. (See 'Systemic glucocorticoids' above.)

-NSAIDs – Any NSAID can be used in full doses (eg, naproxen 500 mg twice daily) until a few days after the flare has resolved. We avoid NSAIDs in older patients and others who are at higher risk of drug-related adverse effects (eg, kidney injury, cardiovascular disease, gastrointestinal bleeding). (See 'Nonsteroidal antiinflammatory drugs' above.)

-Colchicine – On the first day of therapy, we give 1.2 mg of oral colchicine followed one hour later by 0.6 mg. On subsequent days, we administer colchicine 0.6 mg twice daily until 48 hours following the flare. Colchicine may need to be adjusted or avoided in patients with impaired liver or kidney function and in patients taking drugs that impact the cytochrome P450 system. (See 'Colchicine' above.)

●Special patient populations

•Patients on anticoagulation – In patients taking anticoagulation, we use colchicine or oral glucocorticoids to avoid increasing the risk of bleeding that may occur with NSAIDs. An experienced provider may also be able to safely inject one or two joints with intraarticular glucocorticoids. (See 'Patients on anticoagulation' above.)

•Older adults – For older adults, we typically use systemic or intraarticular glucocorticoids to manage a gout flare, as they are often intolerant of or have contraindications to both NSAIDs and colchicine. (See 'Older adults' above.)

•Patients with chronic kidney disease – In patients with impaired kidney function, we use systemic or intraarticular glucocorticoids and avoid colchicine and NSAIDs. In patients on chronic hemodialysis, NSAIDs may be used as an alternative to glucocorticoids. (See 'End-stage kidney disease and transplantation' above.)

●Resistant or refractory disease – In patients who do not respond completely to therapy, we reevaluate the diagnosis and assess adherence (see 'Reassess the diagnosis' above). We then adjust therapy depending on the type of therapeutic response:

•Partial response or rebound flare – Patients who have had a partial response or experience a rebound flare after an initial response may need longer courses of their initial therapy. (See 'Rebound flare' above and 'Partial response' above.)

•Resistant disease – In patients who do not improve after three days of treatment, we adjust therapy depending on the agent initially used. For patients who are resistant to NSAIDs or colchicine, we switch to systemic glucocorticoids. For those resistant to systemic glucocorticoids, we optimize the glucocorticoid dose and delivery (eg, increasing to 40 mg of prednisone or its equivalent, administering one to two days of intravenous glucocorticoids in hospitalized patients). Intraarticular glucocorticoids may be appropriate to add in patients with only one or two affected joints. (See 'Resistant disease' above.)

•Refractory disease – In patients who are refractory to standard therapies, options include interleukin 1 (IL-1) inhibition (ie, anakinra 100 mg subcutaneously daily until flare resolution) or one dose of canakinumab 150 mg subcutaneously. (See 'Refractory disease' above and 'Interleukin 1 blockade' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Michael A Becker, MD, who contributed to an earlier version of this topic review.