Gout Flares

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Treatment of gout flares

Authors: Michael A Becker, MD, Angelo L Gaffo, MD, MsPH
Section Editor: Nicola Dalbeth, MBChB, MD, FRACP
Deputy Editor: Paul L Romain, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2019. | This topic last updated: Dec 04, 2019.
INTRODUCTION
A gout flare is an intensely painful and disabling inflammatory arthritis, usually involving a single joint but occasionally involving two or more joints. The
goal of therapy in a gout flare is prompt and safe termination of pain and disability. Without therapy, the gout flare usually resolves completely within a
few days to several weeks, particularly in early disease. However, symptoms improve more quickly with administration of any of a broad array of
antiinflammatory drugs. (See "Clinical manifestations and diagnosis of gout", section on 'Gout flares'.)
Upon resolution of a gout flare, the patient is said to have entered a symptom-free (interval, intercritical, or between flares) period. However, flares
recur in the great majority of patients; with more frequent episodes, flares may be more severe and prolonged, with consequent shortening of
asymptomatic periods. Patients with recurrent flares and those who develop chronic arthritis or tophi can benefit from long-term prophylactic therapy
with a urate-lowering agent to prevent further recurrences of gout flare and chronic tophaceous disease. (See "Pharmacologic urate-lowering therapy
and treatment of tophi in patients with gout" and "Clinical manifestations and diagnosis of gout", section on 'Intercritical gout and recurrent gout
flares'.)
The management of gout flares will be reviewed here. The approach to asymptomatic hyperuricemia; the pathophysiology, clinical manifestations, and
diagnosis of gout; and the prevention of recurrent gout after resolution of the gout flares are discussed separately. (See "Asymptomatic
hyperuricemia" and "Pathophysiology of gout" and "Clinical manifestations and diagnosis of gout" and "Pharmacologic urate-lowering therapy and
treatment of tophi in patients with gout".)
GENERAL THERAPEUTIC PRINCIPLES
Several classes of antiinflammatory agents are effective for the treatment of gout flares, including systemic and intraarticular glucocorticoids,
nonsteroidal antiinflammatory drugs (NSAIDs), colchicine, and biologic agents that inhibit the action of interleukin (IL)-1 beta [1-3]. A set of general
principles is important in the effective management of a gout flare, regardless of the specific antiinflammatory agent used. These include the following:
● Early treatment – Treatment should start as soon as possible after the patient perceives the beginning of a flare, preferably within several hours
of symptom onset. More rapid and complete resolution of symptoms occurs the earlier that treatment is introduced, especially if treatment is
initiated at the full recommended dose of the chosen antiinflammatory agent. Patients should be continued on treatment for the duration of the
flare, usually at reduced doses once a significant reduction in symptoms is achieved.
● Duration of therapy – Complete cessation of treatment for a gout flare can usually be safely done within two to three days of complete resolution
of the flare; however, in the case of oral glucocorticoids, we sometimes taper more slowly to lower the risk of a recurrent ("rebound") flare. (See
'Oral glucocorticoids' below and 'Administration of NSAIDs' below and 'Administration and standard dosing of colchicine' below.)
The duration of therapy for a gout flare may range from only a few days (eg, in a patient treated within hours of symptom onset) to several weeks
(eg, in a patient begun on treatment after four or five days of symptoms). Many patients require antiinflammatory treatment for a gout flare for no
more than five to seven days if begun on therapy within 12 to 36 hours of symptom onset.
● Gout flare prophylaxis – Low-dose antiinflammatory therapy should generally be continued during the early months of urate-lowering treatment
[4-8]. The intent of this treatment, called antiinflammatory gout flare prophylaxis, is to reduce the risk of additional flares, which are common early
in the course of urate-lowering treatment. (See "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on
'Prophylaxis during initiation of urate-lowering therapy'.)
● Continuing urate-lowering therapy during flares – In patients already receiving urate-lowering pharmacotherapy at the time of a gout flare (eg,
allopurinol, febuxostat, probenecid, lesinurad, 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 may predispose to
another flare.
However, urate-lowering therapies are of no direct benefit in the treatment of a gout flare, and whether to initiate a urate-lowering agent along
with antiinflammatory therapy during a flare is controversial, as discussed separately. (See "Pharmacologic urate-lowering therapy and treatment
of tophi in patients with gout", section on 'Initiation and duration of urate-lowering pharmacotherapy'.)
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Therapeutic recommendations for gout flares in patients receiving urate-lowering agents are the same as those for patients not taking such
therapy. (See "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Initiation and duration of urate-
lowering pharmacotherapy'.)
● Tophaceous gout – Treatment of a gout flare does not differ substantially in patients with or without clinically apparent tophi, although the
presence of tophi is an indication for the initiation of long-term urate-lowering pharmacotherapy either during or following resolution of a gout flare
to prevent or reverse chronic gouty arthritis and joint damage. Urate-lowering therapy is discussed separately. (See "Pharmacologic urate-
lowering therapy and treatment of tophi in patients with gout".)
● Comorbidities – Important comorbidities (and their ongoing therapies) that are frequent among gout patients may affect antiinflammatory drug
safety or effectiveness, especially in older patients (see 'Older adults' below); consideration of these circumstances is critical in the choice of
antiinflammatory treatment for a gout flare. The following factors are of particular importance in selecting an agent:
• Renal function
• Cardiovascular disease, including heart failure, poorly controlled hypertension, and coronary artery disease
• Gastrointestinal disease, including peptic ulcer disease
• Concurrent medication use
• Diabetes mellitus, especially if poorly controlled
• Drug allergy or intolerance
• Concurrent infection
● Adjunctive measures – Adjunctive measures, none of which are of proven efficacy, are often administered for symptom relief and include icing
the affected joint [9], resting the joint that is involved, and administering analgesic medications (eg, acetaminophen or opioids). In the infrequent
patient who requires opioid therapy, these agents should be used in the lowest doses and for the shortest duration necessary. These measures
do not substitute for effective antiinflammatory treatment of the gout flare.
INITIAL TREATMENT
Several different therapies, including systemic and intraarticular glucocorticoids, nonsteroidal antiinflammatory drugs (NSAIDs), and colchicine, are
each effective for the treatment of the gout flare; there is no single best agent for all patients experiencing a flare. The availability of multiple classes of
agents and approaches likely to provide treatment benefit permits the opportunity to choose which therapy, based upon an assessment of specific
features of the individual patient and the flare history, is most likely to achieve benefit and minimize the risk of adverse therapeutic consequences
(algorithm 1). (Related Pathway(s): Gout: Initial management of adults with a gout flare.)
Factors affecting drug choice — Factors that may influence the choice of medication include:
● Patient-related medical factors – These include patient comorbidities (nature, number, and current clinical status); past medical history,
especially of kidney, liver, cardiovascular, and gastrointestinal disease and diabetes; concomitant medication use; suspicion of concurrent
infection; allergies; and childbearing status.
● The patient's gout history – In patients with a previously established diagnosis of gout (see "Clinical manifestations and diagnosis of gout",
section on 'Diagnosis'), these include total flare number, recent rate of flare occurrence, and patient prior flare experience with specific therapies
(antiinflammatory agent tolerability and effectiveness).
● Differential diagnosis of flare symptoms – In patients in whom the current flare is atypical for the patient's prior gout flares, the diagnosis of
gout has not been established, or the flare occurs in a high-risk setting, particular attention should be directed to the likelihood of an alternative or
an accompanying cause of acute inflammatory arthritis (eg, infection). In patients who require arthrocentesis and synovial fluid analysis and
culture to exclude infection, we avoid oral (as well as intraarticular) glucocorticoids until the results of these studies are available, but these
conditions would not preclude treatment with an NSAID or colchicine. (See 'Choice of agent' below and "Clinical manifestations and diagnosis of
gout", section on 'Differential diagnosis of a gout flare'.)
● Characteristics of the gout flare – Variables that may influence the choice of agent and route of therapy with respect to the current flare include
the duration of flare from symptom onset to therapeutic assessment, the number of affected joints and the injection accessibility of the inflamed
joint(s), and the clinical setting in which the flare is occurring (eg, during initiation of urate-lowering therapy, during a postoperative period, or
when the patient is unable to take medications by mouth).
● Logistic factors and patient preference – These include issues such as drug availability and cost, the location of the patient (eg, home or
clinic), clinician expertise, and patient acceptance of arthrocentesis and joint injection.
Choice of agent — We take the following approach to patients with a gout flare (algorithm 1), which depends upon knowledge of the contextual
medical and other factors that influence the relative safety and efficacy of each agent in individual patients (see 'Factors affecting drug choice' above)
(related Pathway(s): Gout: Initial management of adults with a gout flare):
● Oral therapies – In patients with established gout experiencing a gout flare typical of prior flares and able to take oral medications, we suggest
oral glucocorticoids or NSAIDs; colchicine is another option for some patients.
Oral glucocorticoids – We use oral glucocorticoids in many patients, particularly those who are not candidates for intraarticular
glucocorticoid injection and those who have contraindications to use of NSAIDs. The initial dose is 30 to 40 mg of prednisone or prednisolone
given once daily or in a divided twice-daily dose; the duration of therapy depends upon several factors. (See 'Oral glucocorticoids' below.)
Glucocorticoids are similar in efficacy to other agents and have no greater risk of adverse effects in most patients, although other options
may be preferred in patients with suspected or concomitant infection, prior glucocorticoid intolerance, brittle diabetes, and those who are in a
postoperative period in whom glucocorticoids may increase risk of impaired wound healing. In addition, NSAIDs or low-dose colchicine may
be preferred over glucocorticoids in patients with frequently recurrent gout flares to avoid excessive total glucocorticoid dosing over time.
Caution in the initiation of oral glucocorticoid flare therapy is also called for when: either a first or recurrent gout flare is accompanied by
fever, chills, or other systemic symptoms or clinical signs suggesting intercurrent infection; the flare is not typical of the patient's prior flares (if
any); or the diagnosis of gout is not supported by prior urate crystal demonstration in a synovial fluid or tophus aspirate or by application of a
"diagnostic rule" [10,11] utilizing a set of clinical, historic, and laboratory criteria (see "Clinical manifestations and diagnosis of gout", section
on 'Diagnosis of a gout flare'). In these circumstances, we perform arthrocentesis and synovial fluid analysis and culture, if feasible. We avoid
oral (as well as intraarticular) glucocorticoid administration for flare mitigation until the results of these studies are available, but these
conditions would not preclude initiation of antiinflammatory treatment with an NSAID or colchicine.
• NSAIDs – A reasonable alternative to oral glucocorticoids is a potent oral NSAID, such as naproxen (500 mg twice daily) or indomethacin
(50 mg three times daily). NSAIDs are a particularly appropriate alternative in younger patients (less than 60 years old) who lack renal,
cardiovascular, or active gastrointestinal disease. Different NSAIDs appear comparably effective when used at full doses, and the ready
availability of several NSAIDs without a prescription may favor their use in some patients. (See 'NSAID therapy' below.)
• Colchicine – A reasonable alternative to glucocorticoids or NSAIDs is colchicine, which is at least comparably effective to the other agents
when taken within 24 hours of onset of a gout flare. Colchicine should be administered in a total dose on day 1 not to exceed 1.8 mg, either
taken as 0.6 mg three times on the first day or by taking 1.2 mg for the first dose followed by 0.6 mg an hour later; on subsequent days,
colchicine is taken once or twice daily until flare resolution. In some countries, colchicine is available as a 0.5 mg rather than as a 0.6 mg pill.
(See 'Colchicine therapy' below.)
High-dose colchicine dosing regimens (persistent hourly doses until resolution of flare) are discouraged because of unacceptably high
toxicity.
Colchicine is a particularly convenient agent for patients already taking this medication for flare prophylaxis and for patients who have the
drug available at home for use only at the onset of a gout flare.
A reduced dose of colchicine may be required in patients with diminished renal or hepatic function or potential drug interactions, and
colchicine should be avoided in patients with severe renal or hepatic impairment and in patients on certain medications, particularly those
that strongly inhibit the cytochrome P450 system component CYP3A4 (table 1) or that inhibit the membrane P-glycoprotein (P-gp) drug efflux
pump (table 2), which may result in dangerously increased colchicine drug levels. (See 'Administration and standard dosing of colchicine'
below and 'Dosing in renal or hepatic impairment or with risk of drug interactions' below.)
● Parenteral glucocorticoids – In patients with established gout who present with a typical flare limited to one or two joints, flare reduction can
usually be accomplished with parenteral glucocorticoids:
• Candidates for arthrocentesis and joint injection – Glucocorticoid intraarticular injection is an alternative to the use of orally administered
glucocorticoids, NSAIDs, or colchicine in patients with only one or two actively inflamed joints and whose clinical evaluation suggests a low
risk for joint infection (see 'Intraarticular glucocorticoids' below). Patients unable to take oral medications but otherwise fitting this clinical
profile are also candidates for this approach, which requires ready access to a clinician with expertise in joint aspiration and injection. (See
'Intraarticular glucocorticoids' below.)
• Not candidates for arthrocentesis and injection – In the rare patient with established gout, a flare affecting more than two joints (or joints
inaccessible to injection), and/or who is unable to take oral medication, we suggest treatment with intravenous or intramuscular
glucocorticoids. The choice of glucocorticoid and the route of administration depend upon the clinical context. (See 'Parenteral
glucocorticoids' below.)
● Initial combination therapy – In selected patients with severe polyarticular flares, particularly in patients who have previously responded only
partially to monotherapy, we sometimes combine intraarticular glucocorticoids with one or two oral agents (eg, colchicine plus either NSAIDs or
oral glucocorticoids in the same doses used for oral monotherapy). (See 'Glucocorticoid therapy' below and 'NSAID therapy' below and
'Colchicine therapy' below.)
● Concomitant anticoagulation therapy – In patients receiving anticoagulation, the treatment options include low-dose oral colchicine, which is
most effective when taken within 24 hours of flare onset, and intraarticular, intravenous, or oral glucocorticoids. (See 'Patients on anticoagulation'
below.)
● Persistent symptoms – The management of patients with persistent symptoms due to a confirmed gout flare depends upon the prior therapy
and upon patient comorbidities. Useful interventions include more prolonged treatment courses than usual, switching or combining agents, and
the use of interleukin (IL)-1 inhibitors. (See 'Resistant disease or unable to take other therapies' below and 'Investigational therapy' below.)
Despite widespread use in the treatment of gout flares, the various classes of antiinflammatory agents had, until about 2002 to 2005, only infrequently
been compared with placebo [12,13] or with one another in randomized trials [4,7,14]. The results of efforts to obtain more evidence of the relative
efficacy of these agents are reflected in the guidelines of the major professional groups [6-8], which state that a glucocorticoid (given orally, by
intraarticular injection, or parenterally), an oral NSAID, and oral colchicine in a low-dose regimen each has substantial efficacy in reducing or
preventing full expression of the symptoms and signs of a gout flare [15-26].
Our approach to the patient with a gout flare is based upon the available data and our clinical experience; this approach is generally consistent with
that recommended by the European League Against Rheumatism (EULAR), the American College of Rheumatology (ACR), the American College of
Physicians (ACP), and the British Society for Rheumatology (BSR) [4-8,27].
Glucocorticoid therapy
Administration and choice of glucocorticoid — Glucocorticoids are highly effective as rapidly acting antiinflammatory agents. The chosen route
of administration depends upon several factors, including the number of involved joints, patient preference, the timely availability of the patient and the
clinician, the experience of the clinician with joint injection techniques, the need in some patients for parenteral rather than orally administered
glucocorticoid therapy, and patient preference. For these reasons, as well as the generally favorable benefit/risk profile of oral glucocorticoid use [22-
24,26], glucocorticoids are administered orally much more commonly in practice than by parenteral routes. (See 'Oral glucocorticoids' below and
'Intraarticular glucocorticoids' below and 'Parenteral glucocorticoids' below.)
Glucocorticoids should be used with caution and close monitoring in patients with heart failure, poorly controlled hypertension, or glucose intolerance,
but they may be used in patients with moderate to severe renal insufficiency.
Several randomized trials comparing oral glucocorticoid (or, in one case, intramuscular glucocorticoid) with NSAID therapy for gout flare indicate that
glucocorticoids are at least as efficacious as NSAID therapy and may have fewer serious adverse outcomes [22-24,26]. Glucocorticoid treatment also
offers routes of administration appropriate for some patients who are either not candidates for oral antiinflammatory drug therapy or who might benefit
from intraarticular glucocorticoid therapy. For these reasons, as well as the ready availability and modest cost, glucocorticoid therapy is increasingly
favored by most [6-8], but not all [27], expert guideline panels for first-line gout flare treatment.
Oral glucocorticoids — We suggest oral glucocorticoids (eg, prednisone or prednisolone) for most patients with a gout flare, particularly for those
who are not candidates for intraarticular glucocorticoid injection because of polyarticular disease or who do not have ready access to a clinician with
expertise in arthrocentesis and injection. We use prednisone (or an equivalent glucocorticoid) in doses of 30 to 40 mg once daily or in two divided
doses until flare resolution begins, and we then taper the dose of glucocorticoids, usually over 7 to 10 days.
Rebound flares are relatively common once glucocorticoids are withdrawn, especially in patients who have previously suffered a number of prior
flares, whose intercritical periods have progressively shortened, and who are not receiving antiinflammatory flare prophylaxis; in these groups of
patients, slower tapering of the glucocorticoid dose with extension of the duration of the taper to 14 or even 21 days is advisable.
Shorter glucocorticoid courses (eg, prednisone 30 to 40 mg daily for five days or those provided by tapered packs of oral prednisone or
methylprednisolone) can be effective in many cases. In the authors' experience, they commonly lead to incomplete resolution and rebound flares,
mainly in more complicated or more severe gout flares. Thus, clinical follow-up is needed to assure an adequate treatment course, although a clinical
trial comparing prednisolone with naproxen for treatment of gout flares did not describe rebound flares in any of the 59 patients who took prednisolone
for five days when followed three weeks later [22].
In the rare patient who keeps flaring during oral glucocorticoid tapering, and in whom urate-lowering therapy has never been initiated, urate-lowering
therapy (eg, allopurinol) can often be successfully initiated with concomitant antiinflammatory treatment [28]. (See "Pharmacologic urate-lowering
therapy and treatment of tophi in patients with gout".)
Common adverse effects of short-term, moderate- to high-dose glucocorticoid use include mood changes, hyperglycemia, increased blood pressure,
and fluid retention (see "Major side effects of systemic glucocorticoids"), but most patients tolerate glucocorticoids well in the rapid tapering regimens
used for a gout flare. Frequent and repeated courses of glucocorticoids should be avoided to limit adverse effects. In the long term, such patients will
benefit more from concomitant initiation of antiinflammatory gout flare prophylaxis and serum urate-monitored urate-lowering therapy. (See
"Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Prophylaxis during initiation of urate-lowering
therapy'.)
Several randomized trials comparing oral glucocorticoids with NSAID therapy for gout flare indicate that glucocorticoids such as prednisone and
prednisolone are at least as efficacious as NSAIDs and may have fewer serious adverse outcomes [22-24]. As an example, in one randomized trial,
416 patients with a gout flare presenting to an emergency department within three days of symptom onset were treated with either prednisolone (30
mg administered orally once daily for five days) or indomethacin (50 mg administered orally three times daily for two days, then 25 mg three times
daily for three days) [24]. There was no significant difference between the groups in the degree to which pain was reduced either in the emergency
department or during the subsequent two weeks. During the first two hours in the emergency department, adverse events (mostly dizziness,
sleepiness, and nausea) were more frequent in the group receiving indomethacin (19 versus 6 percent), but the frequency of side effects did not differ
between the groups from days 1 to 14. No serious adverse events were observed.
Intraarticular glucocorticoids — We suggest arthrocentesis with joint fluid aspiration and intraarticular injection of glucocorticoids for patients
with gout who have only one or two actively inflamed joints or are unable to take oral medications, and (in either situation) for whom the likelihood of
infection is judged remote. Use of this approach is contingent upon the ready availability of a clinician with expertise in such procedures and the
accessibility of the inflamed joint(s) to injection.
We use 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 "Joint aspiration or injection in adults: Technique and indications" and "Joint aspiration or
injection in adults: Complications".)
Glucocorticoid joint injection should be withheld in patients in whom a diagnosis of gout has not previously been established or in whom the clinical
history and physical examination suggest the alternative or additional possibility of joint infection. To achieve this critical distinction, joint aspiration
should be carried out in such patients, with examination of the synovial fluid by Gram stain and culture, by cell count and differential white cell count,
and by polarized light microscopy for urate or other crystals that are pathognomonic either for gout (urate crystals) or acute calcium pyrophosphate
crystal deposition disease (pseudogout). (See "Clinical manifestations and diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease".)
Importantly, septic arthritis and a gout flare can coexist; therefore, even if gout has been diagnosed in the past, caution should be taken in the use of
glucocorticoid joint injection if the current clinical picture is uncertain, even in a patient with well-established gout.
Evidence of the benefit of intraarticular glucocorticoids has been limited to small, open-label trials, although, in our experience, such treatment is
usually highly effective and works quickly, often within 24 hours [29]. However, a 2013 systematic review of the safety and efficacy of intraarticular
glucocorticoid injection for gout flares could not identify any randomized trials of intraarticular glucocorticoids that met the inclusion criteria, illustrating
the very limited formal evidence available regarding the efficacy and safety of this approach [30].
Indirect evidence supporting the use of intraarticular glucocorticoid injections in gout includes the significant benefit that may result from such
injections for the treatment of rheumatoid arthritis and osteoarthritis. (See "Use of glucocorticoids in the treatment of rheumatoid arthritis", section on
'Intraarticular therapy' and "Management of moderate to severe knee osteoarthritis", section on 'Limited role of intraarticular glucocorticoid injections'.)
Parenteral glucocorticoids — In patients who are unable to take medications orally and who are not candidates for intraarticular glucocorticoid
injection, we generally suggest treatment with intravenous or intramuscular glucocorticoids. The choice of glucocorticoid and the route of
administration depend upon the clinical context:
● In hospitalized patients with polyarticular involvement, with existing or easily established intravenous access, and with no contraindications to
glucocorticoids, we suggest intravenous administration of a parenteral glucocorticoid. The dose and frequency depend upon the agent chosen. A
typical dose is 20 mg of methylprednisolone administered intravenously twice daily, with stepwise reduction by half of each dose when
improvement begins and with maintenance of at least 4 mg twice daily (or oral equivalent) for five days.
● Intramuscular glucocorticoid injection has also been reported to be effective [26,31] for gout flare management, usually with an initial dose of
triamcinolone acetate (40 to 60 mg) that may need to be repeated once or twice (at intervals of at least 48 hours) if benefit fades or if resolution of
the flare is not achieved.
Few randomized trials have adequately evaluated the benefit of systemic parenteral glucocorticoids [32]; the published studies and the few
randomized trials had significant limitations in quality and strength of evidence. Nonetheless, some experts report this approach to be effective and
well tolerated [1,14,33,34].
Corticotropin (adrenocorticotropic hormone [ACTH]) has also been reported to be efficacious for gout flare treatment, but cost and limited availability
restrict the use of parenteral ACTH treatment.
NSAID therapy
Administration of NSAIDs — We use a potent oral NSAID, such as naproxen (500 mg twice daily) or indomethacin (50 mg three times daily), as
an alternative to glucocorticoids for treatment of a gout flare, particularly in younger patients (less than 60 years old) with neither renal or
cardiovascular comorbidities or active gastrointestinal disease. Nonselective NSAIDs of all types are inexpensive, readily available to patients at the
onset of a flare (some without a prescription), and, in our experience, probably as effective and safe as other agents [14-19] for this indication and with
treatment for a limited duration [14,17-20]. Other orally administered NSAIDs (and initial doses) that may be used, for example, include ibuprofen (800
mg three times daily), diclofenac (50 mg twice daily), meloxicam (15 mg daily), and celecoxib (200 mg twice daily). 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.
NSAIDs are most effective when treatment is initiated within 48 hours of the onset of symptoms. The dose may be reduced after a significant
decrease in symptoms has occurred, but the frequency of dosing should be maintained for several more days for optimal antiinflammatory effect.
Celecoxib, a cyclooxygenase (COX)-2 selective inhibitor, is an alternative to nonselective NSAIDs; in a randomized trial in gout flares, a single 800 mg
dose of celecoxib followed by 400 mg twice daily was comparable in efficacy to indomethacin 50 mg three times daily [20]. In practice, we would use a
lower dose, 200 mg twice daily, which is the maximal dose suggested for rheumatoid arthritis. (See 'Efficacy of NSAIDs' below.)
The NSAID can be discontinued two to three days after clinical signs have completely resolved. Typically, the total duration of NSAID therapy for a
gout flare is five to seven days. It is likely to be shorter in patients treated within the first 24 hours of symptom onset and may be longer in patients in
whom treatment is not begun until several days later.
There are important contraindications to NSAIDs, including:
● Chronic kidney disease (CKD) with creatinine clearance (CrCl) of less than 60 mL/minute per 1.73 m2. (See "Nonselective NSAIDs: Overview of
adverse effects", section on 'Renal effects' and "Overview of the management of chronic kidney disease in adults", section on 'Definition and
classification' and "Assessment of kidney function".)
● Active duodenal or gastric ulcer. (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity" and "NSAIDs (including
aspirin): Secondary prevention of gastroduodenal toxicity".)
● Cardiovascular disease, particularly heart failure or hypertension that is difficult to control.
Caution is necessary in patients with known cardiovascular disease or with multiple risk factors for atherosclerotic coronary disease since an
increased risk of myocardial infarction, stroke, and heart failure has been associated with use of both nonselective NSAIDs and COX-2 selective
inhibitors (coxibs). Whether such risk is increased in patients receiving short courses of NSAIDs for a gout flare is unknown.
● NSAID allergy.
● Ongoing treatment with anticoagulants. (See 'Patients on anticoagulation' below.)
Adverse effects are uncommon with brief courses of therapy but may include gastrointestinal intolerance and worsening of renal function.
In a flare of several days' duration prior to starting therapy, a longer course of treatment may be necessary. In such patients, added interventions to
prevent NSAID gastropathy (eg, use of a proton pump inhibitor) may be of benefit, particularly in patients at increased risk due to advanced age or to
a prior history of ulcer disease or gastrointestinal 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 gout flares because of the paradoxical effects of salicylates on serum urate, resulting from renal uric acid retention at low
doses (<2 to 3 g/day) and from uricosuria at higher doses [35-38]. However, low-dose aspirin that is being used for cardiovascular prophylaxis
generally does not need to be discontinued during the treatment of a gout flare, although these very low doses can increase serum urate levels
modestly in some patients [37,38]. There is one report that low-dose aspirin can increase the risk of gout flares in patients with established gout who
were not being treated with allopurinol [39].
Efficacy of NSAIDs — 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 [4,14,20,40], and there are no randomized trials that compare
NSAIDs with colchicine. Several randomized trials comparing oral glucocorticoid (or in one case, intramuscular glucocorticoid) with NSAID therapy for
gout flare indicate similar benefit, although glucocorticoids may have fewer adverse effects, particularly in comparison with indomethacin [22-24,26]. A
number of trials have compared different NSAIDs with each other, without any apparent differences in efficacy [14-20]. One additional study showed
superiority of an NSAID (tenoxicam) over placebo [13]. In one randomized 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) [20].
Colchicine therapy — We use low-dose oral colchicine for gout flare therapy in two circumstances:
● In patients with glucocorticoid and NSAID intolerance or with absolute (or often relative) contraindications to glucocorticoid and NSAID use, we
use low-dose oral colchicine therapy for a gout flare. (See 'Glucocorticoid therapy' above and 'NSAID therapy' above.)
● In patients initiating antiinflammatory gout flare therapy within 24 hours of symptom onset, colchicine is an alternative to glucocorticoids and
NSAIDs when the patient and clinician prefer colchicine over the other options based upon prior clinical experience and drug availability.
In our experience, incipient gout flares may frequently be aborted by use of low-dose oral colchicine as soon as the patient perceives the first sign of a
flare. For this reason, we use colchicine as an alternative to glucocorticoids or NSAIDs for flare treatment in patients with prior flares successfully
treated with colchicine. We prescribe such patients a supply of this agent for home use to allow early initiation of low-dose treatment (see
'Administration and standard dosing of colchicine' below) at the first symptom of flare recurrence.
Patients receiving ongoing colchicine antiinflammatory gout flare prophylaxis should also be instructed in the low-dose colchicine gout flare regimen in
the event that a gout flare develops during prophylaxis. (See "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout",
section on 'Prophylaxis during initiation of urate-lowering therapy'.)
In patients who have initiated gout flare therapy with an NSAID and have either experienced an adverse event warranting an alternative
antiinflammatory agent or have had no pain reduction, we would consider use of colchicine rather than an oral glucocorticoid as the second-line agent
only if time since flare onset is within 36 hours. We generally do not initiate colchicine as first-line therapy for gout flares that have been ongoing for
more than 36 hours because of the diminished likelihood of benefit, and we prefer to initiate treatment during the first 24 hours because of the greater
likelihood of benefit. (See 'Efficacy of oral colchicine' below.)
Administration and standard dosing of colchicine — There are several low-dose colchicine regimens that may be effective for management of
a gout flare. As an example, the US Food and Drug Administration (FDA) has approved a schedule for the first 24 hours of colchicine treatment for a
gout flare, recommending an initial dose of 1.2 mg of oral colchicine, followed one hour later by another 0.6 mg, for a total dose on the first day of
therapy of 1.8 mg [21,34,41]. In our experience, an alternative low-dose colchicine regimen that has been equally effective calls for 0.6 mg (or 0.5 mg)
three times on the first day of flare treatment [4]. In many countries other than the United States the medication is formulated as a 0.5 mg pill, which
we would use in place of the 0.6 mg dose indicated here and elsewhere in this topic review.
Approximately 60 percent of patients will not achieve a 50 percent reduction in pain within 24 hours of colchicine treatment. Patients should be
continued on treatment for the duration of the gout flare at reduced doses (eg, 0.6 mg once or twice daily as tolerated). Complete cessation of
treatment can be safely done within two to three days of complete resolution of the gout flare.
In patients already receiving colchicine prophylaxis (0.6 mg once to twice daily) at the time of their flare, the higher total daily dose for flare of 1.8 mg
is taken in place of the usual prophylactic dose on the first day of therapy for the flare. From day 2 until 48 hours after flare resolution, we supplement
to provide 0.6 mg twice daily (total 1.2 mg per day), then resume the previous prophylaxis dose. (See 'General therapeutic principles' above.)
The most common adverse effects of colchicine, diarrhea and abdominal cramping [21,42], are less likely in patients 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) [12,21].
When low-dose colchicine therapy is ineffective or minimally effective in suppressing the gout flare in a timely fashion, alternative antiinflammatory
agents, including glucocorticoids or NSAIDs, may be required. In patients without contraindications to NSAID or glucocorticoid use, supplemental oral
therapy with an NSAID or with a glucocorticoid (given orally, by intraarticular injection, or parenterally) may also be used. (See 'Glucocorticoid therapy'
above and 'NSAID therapy' above.)
Dosing in renal or hepatic impairment or with risk of drug interactions — In patients with renal or hepatic impairment and in patients using or
recently completing (within the previous 14 days) treatment with medications that may inhibit the cytochrome P450 system component CYP3A4 (table
1) and/or the P-gp efflux pump (table 2), the size of the initial and subsequent doses and the frequency of colchicine administration may need to be
reduced or colchicine may need to be avoided altogether. (See 'Precautions' below.)
Numerous drugs inhibit CYP3A4 (table 1) and/or P-gp (table 2) and are responsible for the large number of colchicine drug interactions. CYP3A4 is
found in hepatocytes and transforms colchicine to inactive metabolites. P-gp is found in epithelial cells lining the gastrointestinal tract, kidney proximal
tubules, bile duct membranes, and the blood-brain barrier. Inhibition of P-gp within the intestinal lumen increases colchicine oral bioavailability.
Inhibition of P-gp at bile-ductule membranes and impaired renal or hepatic function decrease colchicine clearance [43]. Both effects contribute to
increasing serum concentrations and prolong colchicine half-life.
Colchicine has a narrow therapeutic margin, and drug accumulation is associated with severe, and sometimes fatal, consequences (see 'Safety of
colchicine' below). It is therefore essential that prescribers perform regular assessments of drug interactions, organ function, and other factors that
can influence serum concentrations and prescribe a reduced dose and/or frequency when warranted, or avoid its use entirely. (See 'Precautions'
below.)
Dosing guidelines for colchicine have been proposed by one manufacturer for those patients with normal renal and hepatic function who are receiving
interacting agents or who have received them within 14 days, and guidelines for colchicine administration in patients with renal or hepatic impairment
who are not using an interacting medication have also been described [41]. 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.
More common examples of medications that may result in adverse interactions, with increased colchicine levels, include:
● P-gp inhibitors – More commonly used inhibitors of P-gp include macrolide antibiotics (azithromycin, clarithromycin, erythromycin), cyclosporine,
tacrolimus, amiodarone, quinidine, azole antifungals, verapamil, and others (table 2).
● CYP3A4 inhibitors – Commonly used strong CYP3A4 inhibitors include HIV protease inhibitors, pharmacokinetic-boosting agents such as those
used in HIV therapeutics (ritonavir, cobicistat), clarithromycin, azole antifungals, and others (table 1) [44].
A number of drugs inhibit both P-gp and CYP3A4, including pharmacokinetic-boosting agents (cobicistat, ritonavir), cyclosporine, verapamil,
erythromycin, clarithromycin, and others.
Care should also be taken in combining use of colchicine with the wider array of less potent CYP3A4 inhibitors, including diltiazem, fluconazole, and
grapefruit juice (table 1); and drugs with potential for additive side effects, such as myotoxicity in combination with a statin or fibrate (eg, gemfibrozil).
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 Lexicomp drug interactions program included with UpToDate.
Precautions — Our approach to the use of colchicine in patients with renal or hepatic impairment or potential drug interactions is to take the
following precautions:
● Colchicine contraindicated – Colchicine is contraindicated in the presence of any degree of renal or hepatic impairment in patients receiving a
P-gp inhibitor (table 2) or an agent that strongly reduces CYP3A4 availability (table 1) [34,41,42]. We also avoid colchicine in patients with organ
impairment if they have recently (eg, within the past 14 days) completed treatment with a P-gp or strong CYP3A4 inhibitor.
● Colchicine use at a reduced dose ONLY IF no other therapeutic options – In a small number of these patients in whom there are no other
therapeutic alternatives, we use colchicine for gout flare treatment at a reduced dose and/or frequency with close monitoring.
Colchicine dosing adjustments for gout flares should generally follow the guidelines provided in the manufacturer’s FDA-approved prescribing
information [41].
In patients at particularly high risk, with multiple factors that may potentially increase colchicine exposure beyond safe levels, colchicine should be
administered by a clinician with expertise in using the drug in these high-risk groups. Usually, no more than 0.3 mg is administered on day of flare
and this dose is not repeated for three to seven days or more in such patients, depending upon the individual factors that are present. These
particularly high-risk groups include:
• Patients on colchicine prophylaxis within the past 14 days, with normal renal and hepatic function, but who have taken a strong CYP3A4
inhibitor (table 1) or a drug that inhibits P-gp (table 2) within the last 14 days [42].
• Patients on colchicine prophylaxis within the past 14 days, with any renal or hepatic impairment, who have taken a moderate CYP3A4
inhibitor (table 1) within the last 14 days.
• Patients regardless of recent colchicine use, who have advanced renal or hepatic impairment (CrCl of <30 mL/minute or Child-Pugh class C
cirrhosis or equivalent, respectively) who are not receiving any interacting medications.
Examples of 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 1) or P-gp (table 2) inhibitors
(eg, additive myotoxicity with combined use of statin and colchicine). The Lexicomp drug interactions tool available within UpToDate should
be consulted for additional information.
• Advanced age.
• Chronic ill health and debility.
• Use of more than one medication that can interact with colchicine.
• Combinations of multiple factors, some of which alone may not be problematic but which in combination can increase risk of colchicine
accumulation.
All patients using colchicine should be advised about the potential for adverse events on colchicine therapy and to stop therapy and report to their
clinician if symptoms of toxicity arise, especially diarrhea, but also vomiting, dysesthesias, or weakness. Close monitoring of pertinent organ function
and clinical status may be required and should be individualized depending upon the patient's clinical status.
We advise all patients who are prescribed colchicine not to consume grapefruit juice (a CYP3A4 inhibitor) or grapefruit while using colchicine.
We do not administer colchicine intravenously, and we strongly advise against such use because of the risk of serious adverse effects, including
death, which are associated with the intravenous administration of this drug. Due to this concern, in many countries, an intravenous form of colchicine
is no longer available.
Efficacy of oral colchicine — Colchicine for the treatment of gout flares has not been extensively studied in randomized trials [12,21] even though
it was used for centuries for the treatment of a gout flare. Oral colchicine (uncombined with another active ingredient, such as probenecid) was first
formally approved by the FDA for use in the United States for the treatment of gout flares in 2009 [45].
In our experience, incipient gout flares may be aborted with oral colchicine taken at the onset of the first symptom. Whether colchicine therapy offers
more rapid or complete relief of gout flares than alternative antiinflammatory agents is not established and awaits adequate head-to-head
comparisons. Side effects are less likely when a low-dose regimen is used at the onset of flare symptoms, and such regimens appear to achieve a
degree of benefit comparable to that achieved with higher colchicine doses.
These points were illustrated by the results of the Acute Gout Flare Receiving Colchicine Evaluation (AGREE) trial, a randomized trial that compared
treatment administered within 12 hours of flare onset using low-dose colchicine (1.8 mg total over one hour), very high-dose colchicine (4.8 mg total
over six hours), and placebo [21]. A significantly greater proportion of patients in the low- and high-dose colchicine treatment groups (38 and 33
percent), compared with those receiving placebo (16 percent), achieved a 50 percent reduction in pain by 24 hours from treatment initiation without
the use of rescue medication. This trial was limited by the short duration of treatment.
Safety of colchicine — Gastrointestinal symptoms (diarrhea and abdominal cramping, as well as abdominal pain, nausea, and vomiting) are the
most common adverse reactions to colchicine administration during the limited duration of treatment of a gout flare [41].
A readily reversible peripheral neuropathy or more severe organ failure may occur in instances of more persistent colchicine dosing, but severe
colchicine toxicities may develop insidiously with prolonged colchicine therapy. These 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. The latter
outcomes have only rarely been reported in patients receiving brief administration of this agent for a gout flare, as in a patient treated with very high-
dose colchicine together with multiple drugs affecting colchicine levels over an eight-day period [46].
SPECIAL CIRCUMSTANCES
Patients on anticoagulation — In patients on anticoagulants, we use one of the following approaches:
● In patients initiating treatment promptly after flare onset, in the absence of contraindications, we use low-dose colchicine because of its efficacy,
convenience, lack of effect on blood clotting, and lack of need for arthrocentesis and joint injection with a glucocorticoid preparation. (See
'Colchicine therapy' above.)
● In patients with polyarticular involvement or if arthrocentesis cannot be performed for other reasons, oral glucocorticoids can be used (see 'Oral
glucocorticoids' above and 'Intraarticular glucocorticoids' above and "Joint aspiration or injection in adults: Technique and indications", section on
'Approach to the patient on anticoagulants'). Caution and closer monitoring should be exercised if there is a history of peptic ulcer disease or
gastrointestinal bleeding.
● Joint aspiration and injection with a glucocorticoid provide another option if only one or two joints are involved; this can be done safely even with
anticoagulation by a clinician highly experienced in arthrocentesis. Care is necessary to avoid a hemarthrosis. (See 'Intraarticular glucocorticoids'
above and "Joint aspiration or injection in adults: Technique and indications", section on 'Approach to the patient on anticoagulants'.)
● Selected patients on anticoagulation who are unable to be treated with either glucocorticoids or colchicine may be managed, if necessary, with
celecoxib, which lacks the antiplatelet effect of the nonselective nonsteroidal antiinflammatory drugs (NSAIDs), but retains some potential for
gastrointestinal toxicity. (See 'Efficacy of NSAIDs' above and "Overview of COX-2 selective NSAIDs", section on 'Reduction in gastroduodenal
toxicity' and "Overview of COX-2 selective NSAIDs", section on 'Lack of platelet inhibition and use during anticoagulation'.)
● An alternative for patients on anticoagulation and with multiple medical comorbidities that preclude use of first-line therapies (eg, renal failure,
gastrointestinal bleeding) is a short-acting interleukin (IL)-1 inhibitor, such as anakinra. (See 'Resistant disease or unable to take other therapies'
below.)
Older adults — The management of gout flares in older patients is complicated by the greater prevalence of comorbidities, the use of multiple
medications, and reductions in renal function associated with aging [47,48], although a systematic review of clinical trials for treatment of gout
suggested that all of the antiinflammatory agents discussed here were likely to be efficacious in older patients [49].
These safety concerns reduce the proportion of patients for whom NSAIDs or colchicine may be preferred agents, although these drugs can be used
in patients who lack such contraindications. However, we avoid the use of indomethacin in older adults because of the greater risk of adverse effects
with this medication compared with other NSAIDs, consistent with the Beers Criteria for Potentially Inappropriate Medication Use in Older Adults [50].
(See 'General therapeutic principles' above and "Drug prescribing for older adults".)
Glucocorticoids are generally tolerated in short-term use for gout flares in patients in whom NSAIDs or colchicine may pose an increased risk. (See
'Administration and choice of glucocorticoid' above and 'Efficacy of NSAIDs' above and 'Safety of colchicine' above.)
Contraindications to the use of NSAIDs that are of particular concern in older adults include the presence of heart failure, renal impairment, or
gastrointestinal disease.
Contraindications to colchicine include gastrointestinal intolerance, dosing restrictions in patients with renal and hepatic dysfunction, and potential
drug interactions, and also may include the high cost of therapy. Colchicine myopathy and peripheral neuropathy can be subtle in older adults.
Complaints of weakness and functional decline while taking colchicine should prompt a careful neurologic examination, laboratory evaluation including
a serum creatine kinase, and empirical drug discontinuation. General principles and special concerns in prescribing drugs in this population are
discussed in more detail separately. (See "Drug prescribing for older adults" and "Drug-induced myopathies", section on 'Colchicine'.)
End-stage kidney disease and transplantation — We generally treat patients with advanced chronic kidney disease (CKD) or end-stage kidney
disease requiring maintenance dialysis with intraarticular, oral, or parenteral glucocorticoids. (See 'Glucocorticoid therapy' above.)
In patients on chronic hemodialysis, NSAIDs may be used as an alternative to glucocorticoids, particularly in patients with milder gout flares in whom
lower doses and shorter courses can be employed (see 'NSAID therapy' above). Other concerns in patients on hemodialysis include concomitant use
of anticoagulation and risk of gastrointestinal toxicity.
In patients with residual kidney function, including patients on peritoneal dialysis, NSAIDs should be avoided because of the risk of worsening of renal
function; any use of NSAIDs in this setting should only be done in consultation with the patient's nephrologist. (See "NSAIDs: Acute kidney injury
(acute renal failure)".)
Colchicine is generally avoided in hemodialysis patients with gout flares because it is not removed by dialysis, and therefore these patients have a
heightened risk of colchicine toxicity. (See 'Dosing in renal or hepatic impairment or with risk of drug interactions' above and 'Safety of colchicine'
above.)
Gout flares in organ transplant recipients should only be managed by clinicians experienced with these clinical problems because of the complexities
of management due to reduced uric acid excretion and because of the frequent accompanying use of cyclosporine. Colchicine, NSAIDs, and
glucocorticoids can potentially be used, but limits on dosing, frequency, and duration of therapy usually apply. 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
● In pregnant women with a gout flare, we generally use oral glucocorticoid therapy (see 'Glucocorticoid therapy' above). The use of NSAIDs is
limited to the first 20 to 30 weeks of gestation, and we avoid use of colchicine in pregnant women. (See 'NSAID therapy' above.)
Potential contraindications to glucocorticoids in such patients include poorly controlled hypertension or diabetes, in addition to other usual
concerns. We also employ symptomatic treatment measures, such as icing and protection of the affected site of inflammation.
● In breastfeeding women, we use either glucocorticoids or NSAID therapy (see 'Glucocorticoid therapy' above and 'NSAID therapy' above) while
continuing to avoid the use of colchicine.
Gout flares are exceedingly uncommon during pregnancy and lactation, paralleling the low prevalence of hyperuricemia in women of childbearing age
in most populations (see "Asymptomatic hyperuricemia", section on 'Epidemiology'). Thus, the occurrence of an acute inflammatory arthritis
resembling gout during pregnancy or breastfeeding should direct attention to the exclusion of alternative diagnoses, such as septic arthritis. (See
"Clinical manifestations and diagnosis of gout", section on 'Differential diagnosis'.)
Despite its rarity, gout flares during pregnancy and/or lactation have been reported among women with familial juvenile hyperuricemic nephropathy
[51,52] (see "Autosomal dominant tubulointerstitial kidney disease (medullary cystic kidney disease)", section on 'ADTKD due to mutations in the
UMOD gene (ADTKD-UMOD)'), unspecified "renal impairment," and gestational diabetes [53].
Although antiinflammatory doses of an NSAID (eg, naproxen, ibuprofen, or indomethacin) have been effective in some pregnant patients with a gout
flare, use of NSAIDs is limited to the first two trimesters of pregnancy because of concerns about NSAID-induced premature closure of the ductus
arteriosus later in pregnancy. NSAID therapy should also be withheld during pregnancy in the presence of impaired renal function. The use of NSAIDs
during pregnancy and lactation is described in detail separately. (See "Safety of rheumatic disease medication use during pregnancy and lactation",
section on 'NSAIDs'.)
Data directly derived from treatment of gout in pregnant and lactating women are fragmentary, although studies of colchicine in pregnant and
breastfeeding patients with familial Mediterranean fever (FMF) and patients with pericardial diseases have not found increased adverse effects with its
use [54,55]. However, reports of chromosomal damage associated with colchicine exposure and the detection of colchicine in breast milk [56] raise
concerns regarding the safety of colchicine during pregnancy and lactation [27,55].
In the infrequent patient with recurrent flares during pregnancy or breastfeeding who requires prophylaxis to prevent gout flares, we use daily low-
dose glucocorticoids, given the need to avoid both colchicine and NSAIDs.
RESISTANT DISEASE OR UNABLE TO TAKE OTHER THERAPIES
In patients with symptoms that are not improving as expected, the patients' adherence to the treatment program should be assessed. Additionally,
alternative agents should be considered, depending upon what has already been tried, and the diagnosis should be reevaluated. Arthrocentesis may
be required to exclude other causes of a flare of acute inflammatory arthritis, including infection, if joint aspiration was not already performed during
the gout flare.
It is important not to become overly concerned if gout flares do not resolve within one to three days of starting treatment. Most gout flares resolve
within 7 to 10 days, regardless of the type of therapy, and resolution is much more rapid if the patient is treated early in the flare. Thus, truly resistant
disease is uncommon, although some gout flares may resolve slowly, especially if treatment is not started early or if there is extensive polyarticular
disease leading to chronic gouty arthritis, in which near-continuous joint inflammation is present. (See "Clinical manifestations and diagnosis of gout",
section on 'Gout flares' and "Clinical manifestations and diagnosis of gout", section on 'Differential diagnosis of a gout flare'.)
The management of patients with persistent symptoms due to a confirmed gout flare depends upon the prior therapy and upon the patients'
comorbidities:
● In patients being treated with nonsteroidal antiinflammatory drugs (NSAIDs), a more prolonged course of therapy than usual may be required in
some patients with persistent symptoms, especially if treatment was not started until the flare was ongoing for several days. Patients with a flare
that appears resistant to an adequate course of NSAID therapy may respond to treatment with glucocorticoids. (See 'Glucocorticoid therapy'
above.)
● In patients who are being treated with colchicine but who do not have contraindications to glucocorticoids or NSAIDs, it may be necessary to
switch to one of these therapies if no improvement is seen within several days, especially if the gout flare was not treated early. (See
'Administration and standard dosing of colchicine' above and 'NSAID therapy' above and 'Glucocorticoid therapy' above.)
● The management of recurrent (or "rebound") gout flares following treatment with glucocorticoids is discussed above. (See 'Oral glucocorticoids'
above.)
● In patients in whom a joint injection was not used for the initial management of a flare, an intraarticular glucocorticoid injection could still be
performed later, alone or in combination with an oral agent, in patients with persistent symptoms. (See 'Intraarticular glucocorticoids' above.)
● Interleukin (IL)-1 inhibition may be of benefit in selected patients. We use anakinra, an IL-1 receptor antagonist protein, only in gout patients with
frequent and/or documented gout flares in whom other available treatments have failed, are contraindicated, or in whom "rebound flares" occur
even when glucocorticoid treatment is appropriately tapered.
Although IL-1 antagonist agents are available in some countries for the treatment of conditions other than gout, such as anakinra for rheumatoid
arthritis, canakinumab for systemic juvenile idiopathic arthritis, and canakinumab and rilonacept for cryopyrin-associated periodic syndromes, only
the first two have shown clear efficacy in treatment of gout flares, and their use for this indication remains investigational in the United States.
Canakinumab has been approved in the European Union for use in patients with more than three gout flares annually that are refractory to
treatment with alternative agents. (See 'Investigational therapy' below.)
INVESTIGATIONAL THERAPY
Interleukin (IL)-1 is an important mediator of gouty inflammation and a potential therapeutic target in gout flares [57]. Thus, agents inhibiting IL-1
action are under study for the treatment of gout flares (see "Pathophysiology of gout"). These include:
● Anakinra – Anakinra (100 mg daily, administered subcutaneously) is the preferred IL-1 antagonist for use in a gout flare because of its short half-
life of IL-1 blockade and its relatively modest cost compared with other alternative IL-1 inhibitors, such as canakinumab. (See "Overview of
biologic agents and kinase inhibitors in the rheumatic diseases", section on 'IL-1 inhibition' and "Treatment of rheumatoid arthritis in adults
resistant to initial biologic DMARD therapy", section on 'Resistant to standard therapies'.)
The efficacy of anakinra, a recombinant IL-1 receptor antagonist, for gout flares has been suggested in observational studies [58-60] and further
documented in a randomized trial [61]:
• Beneficial effects of IL-1 inhibition were seen in some patients in open-label pilot studies of anakinra, with 100 mg daily given subcutaneously
until symptoms of the gout flare improved [58-60].
• In a randomized trial involving 88 patients with a crystal-proven gout flare, anakinra (100 mg daily for five consecutive days) resulted in
similar degrees of benefit to usual antiinflammatory flare treatment (with either colchicine, oral glucocorticoids, or full-dose naproxen) with
respect to magnitude of change in pain from baseline through days 2 to 4 of treatment; anakinra resulted in comparable safety and
improvements in pain, index joint swelling, and tenderness at day 5 [61].
The randomized trial [61] did not follow patients long enough to evaluate the observation in prior reports [58-60] that recurrent flares were not
uncommon among anakinra-treated patients within one to six weeks after stopping therapy. The short biologic half-life of anakinra, which
mandates daily subcutaneous administration, makes this agent an unlikely candidate for gout flare prophylaxis but may, in the case of gout flares,
provide an advantage in safety, since blocking of IL-1 beta action is rapidly reversed when treatment with anakinra is discontinued.
● Canakinumab – Canakinumab has been evaluated [62] and approved in the European Union for treatment of refractory gout flares. It is indicated
for use in the treatment of patients with at least three gout flares annually that cannot be effectively managed with other antiinflammatory
treatment options. (See "Cryopyrin-associated periodic syndromes and related disorders", section on 'Canakinumab'.)
Canakinumab is a fully humanized, long-acting monoclonal antibody that blocks IL-1 beta signaling; it can be effective for the treatment of gout
flares in patients who have a history of multiple flares and who have either refractoriness or contraindication to gout flare treatment with
nonsteroidal antiinflammatory drugs (NSAIDs) and/or colchicine [62,63]. Canakinumab has also shown effectiveness in preventing gout flares.
(See "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Prophylaxis during initiation of urate-
lowering therapy'.)
A small number of trials support the effectiveness of canakinumab in treating gout flares:
• The efficacy and safety of canakinumab (a single subcutaneous injection of 150 mg plus a placebo intramuscular injection) were evaluated in
such patients in comparison with triamcinolone acetonide (a single intramuscular injection of 40 mg plus a placebo subcutaneous injection) in
two identically designed randomized trials (one in the United States and the other in Europe and other non-United States countries) involving
a total of 456 patients [63]. Canakinumab administration resulted in a significantly greater reduction in mean 72-hour pain score using a 100
mm visual analog scale (decrease of 35.7 versus 25 mm).
Four patients in the published trials, all receiving canakinumab, required hospitalization for treatment of infections (one abscess of the jaw,
one abscess of the forearm, pneumonia, and gastroenteritis), but there were no opportunistic infections. Other adverse events that were
most common with canakinumab included low neutrophil counts and low platelet counts.
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 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 5th to 6th 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 10th to 12th 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)")
SUMMARY AND RECOMMENDATIONS
The goal of therapy in a gout flare is prompt and safe termination of pain and disability. Symptoms will usually resolve without therapy within a
few days to several weeks but improve more quickly with administration of one of several classes of antiinflammatory drugs. More rapid and
complete resolution of symptoms occurs the earlier that treatment is introduced. Initiation of treatment with urate-lowering pharmacotherapies is
of no direct benefit in treating a gout flare, but ongoing urate-lowering therapy should not be interrupted in patients on such therapy at the time of
a flare. (See 'General therapeutic principles' above and "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout".)
● The choice of therapy for a gout flare depends upon an individual patient assessment of multiple factors, including patient age, comorbidities, and
associated medical therapies; flare characteristics and past responses to therapy; the number of affected joints and their accessibility to
arthrocentesis and injection; and patient and clinician preferences (algorithm 1). (See 'Initial treatment' above.) (Related Pathway(s): Gout: Initial
management of adults with a gout flare.)
● In most patients who can take oral medications, we suggest oral glucocorticoids or nonsteroidal antiinflammatory drugs (NSAIDs) for the
treatment of gout flares (Grade 2C). Colchicine is a safe and effective alternative for some patients. All three of these antiinflammatory agents are
effective; the choice depends upon multiple individual factors (algorithm 1) (see 'Choice of agent' above) (related Pathway(s): Gout: Initial
management of adults with a gout flare):
• We use oral glucocorticoids in many patients, particularly for those who are not candidates for intraarticular glucocorticoid injection and those
who have contraindications to use of NSAIDs: prednisone or prednisolone, at an initial dose of 30 to 40 mg once daily or in a divided twice-
daily dose until flare resolution begins, then we taper the dose, usually over 7 to 10 days. Because rebound flares occur more frequently with
glucocorticoids than with alternative agents, especially among patients with multiple recent flares, we extend the course of glucocorticoid
tapering to 14 to 21 days in such individuals. (See 'Oral glucocorticoids' above.)
Other options (eg, NSAIDs, colchicine) may be preferred in patients with concomitant infection, prior glucocorticoid intolerance, brittle
diabetes, and those who are in a postoperative period in whom glucocorticoids may increase risk of impaired wound healing. NSAIDs or low-
dose colchicine may also be preferred over glucocorticoids in patients with frequently recurrent gout flares to avoid excessive total
glucocorticoid dosing over time.
• A reasonable alternative to oral glucocorticoids for a gout flare is a potent oral NSAID, such as naproxen (500 mg twice daily) or
indomethacin (50 mg three times daily). NSAIDs are particularly appropriate in younger patients (less than 60 years old) who lack renal,
cardiovascular, or active gastrointestinal disease. (See 'NSAID therapy' above.)
NSAIDs are most effective when treatment is initiated within 48 hours of the onset of symptoms. The NSAID can be discontinued two to three
days after clinical signs have completely resolved. Typically, the total duration of NSAID therapy for a gout flare is five to seven days. It is
likely to be shorter in patients who are treated within the first 24 hours of symptom onset and may be longer in patients in whom treatment is
not begun until several days later. Aspirin is not used for the treatment of gout flares because of the paradoxical effects of salicylates on
serum urate.
• Another reasonable alternative to glucocorticoids or NSAIDs is colchicine, which is at least comparably effective to the other agents when
taken within 24 hours of onset of a gout flare. Colchicine should be administered in a total dose on day 1 not to exceed 1.8 mg, either taken
as 0.6 mg three times on the first day or taken as 1.2 mg for the first dose followed by 0.6 mg an hour later. Most patients will not achieve
complete resolution of pain within 24 hours but will respond further over several days of continued dosing at 0.6 mg once or twice daily, as
tolerated, with stepwise reduction in the dose as the flare gradually resolves. Colchicine flare treatment can be discontinued within two to
three days of flare resolution. In some countries, colchicine is available as a 0.5 mg pill rather than a 0.6 mg pill. (See 'Colchicine therapy'
above.)
Colchicine is a particularly convenient agent for patients already taking this medication for flare prophylaxis and for patients who have the
drug available at home for use only at the onset of a gout flare. Patients already receiving colchicine gout flare prophylaxis should resume
the prophylaxis dose within one or two days of gout flare therapy. Particular attention should be given to avoidance of colchicine
administration in patients with moderate to severe renal or hepatic disease receiving inhibitors of the cytochrome P450 system component
CYP3A4 or inhibitors of the membrane P-glycoprotein multidrug resistance transporter (P-gp). Drug interactions can also be identified by use
of the Lexicomp drug interactions program included in UpToDate. (See 'Colchicine therapy' above and 'Dosing in renal or hepatic impairment
or with risk of drug interactions' above.)
● In patients who are unable to take oral medications and/or who have only one or two actively inflamed joints (and in whom infection has been
excluded), we suggest arthrocentesis and intraarticular injection of glucocorticoids (Grade 2C). We prefer 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 glucocorticoids' above.)
● For patients with polyarticular involvement who are unable to take oral medications, have existing or easily established intravenous access, and
have no contraindications to glucocorticoids, we suggest systemic administration of an intravenous glucocorticoid (Grade 2C). The dose and
frequency depend upon the agent chosen. A typical dose is 20 mg methylprednisolone twice daily, with stepwise reduction to half of each dose
when improvement begins and with maintenance of at least 4 mg twice daily (or oral equivalent) for at least five days. For patients with no
intravenous access, intramuscular glucocorticoids may be used. (See 'Parenteral glucocorticoids' above.)
● For patients who are unresponsive to any other available approach and who have frequent recurrent gout flares, an additional option is an
interleukin (IL)-1 inhibitor, such as anakinra or canakinumab. The benefits of these agents for symptomatic relief need to be balanced with the
potential for increased risk for serious infections. (See 'Resistant disease or unable to take other therapies' above.)
● In patients who are anticoagulated, we use low-dose colchicine or oral glucocorticoids. We use intraarticular glucocorticoids for the treatment of
gout flares if oral agents are contraindicated. We generally treat gout flares in patients with advanced chronic kidney disease (CKD) or with end-
stage kidney disease requiring maintenance dialysis with intraarticular, oral, or systemic glucocorticoids. (See 'Patients on anticoagulation' above
and 'End-stage kidney disease and transplantation' above.)
Use of UpToDate is subject to the Subscription and License Agreement.
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7. Qaseem A, Harris RP, Forciea MA, Clinical Guidelines Committee of the American College of Physicians. Management of Acute and Recurrent
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9. Schlesinger N, Detry MA, Holland BK, et al. Local ice therapy during bouts of acute gouty arthritis. J Rheumatol 2002; 29:331.
10. Janssens HJ, Fransen J, van de Lisdonk EH, et al. A diagnostic rule for acute gouty arthritis in primary care without joint fluid analysis. Arch
Intern Med 2010; 170:1120.
11. Kienhorst LB, Janssens HJ, Fransen J, Janssen M. The validation of a diagnostic rule for gout without joint fluid analysis: a prospective study.
Rheumatology (Oxford) 2015; 54:609.
12. Ahern MJ, Reid C, Gordon TP, et al. Does colchicine work? The results of the first controlled study in acute gout. Aust N Z J Med 1987; 17:301.
13. Garcia de la Torre I. A comparative, double-blind, parallel study with tenoxicam vs placebo in acute gouty arthritis. Invest Med Int 1987; 14:92.
14. Sutaria S, Katbamna R, Underwood M. Effectiveness of interventions for the treatment of acute and prevention of recurrent gout--a systematic
review. Rheumatology (Oxford) 2006; 45:1422.
15. Schumacher HR Jr, Boice JA, Daikh DI, et al. Randomised double blind trial of etoricoxib and indometacin in treatment of acute gouty arthritis.
BMJ 2002; 324:1488.
16. Rubin BR, Burton R, Navarra S, et al. Efficacy and safety profile of treatment with etoricoxib 120 mg once daily compared with indomethacin 50
mg three times daily in acute gout: a randomized controlled trial. Arthritis Rheum 2004; 50:598.
17. Maccagno A, Di Giorgio E, Romanowicz A. Effectiveness of etodolac ('Lodine') compared with naproxen in patients with acute gout. Curr Med
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18. Lomen PL, Turner LF, Lamborn KR, et al. Flurbiprofen in the treatment of acute gout. A comparison with indomethacin. Am J Med 1986; 80:134.
19. Altman RD, Honig S, Levin JM, Lightfoot RW. Ketoprofen versus indomethacin in patients with acute gouty arthritis: a multicenter, double blind
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20. Schumacher HR, Berger MF, Li-Yu J, et al. Efficacy and tolerability of celecoxib in the treatment of acute gouty arthritis: a randomized controlled
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21. Terkeltaub RA, Furst DE, Bennett K, et al. High versus low dosing of oral colchicine for early acute gout flare: Twenty-four-hour outcome of the
first multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison colchicine study. Arthritis Rheum 2010;
62:1060.
22. Janssens HJ, Janssen M, van de Lisdonk EH, et al. Use of oral prednisolone or naproxen for the treatment of gout arthritis: a double-blind,
randomised equivalence trial. Lancet 2008; 371:1854.
23. Man CY, Cheung IT, Cameron PA, Rainer TH. Comparison of oral prednisolone/paracetamol and oral indomethacin/paracetamol combination
therapy in the treatment of acute goutlike arthritis: a double-blind, randomized, controlled trial. Ann Emerg Med 2007; 49:670.
24. Rainer TH, Cheng CH, Janssens HJ, et al. Oral Prednisolone in the Treatment of Acute Gout: A Pragmatic, Multicenter, Double-Blind,
Randomized Trial. Ann Intern Med 2016; 164:464.
25. Liu Y, Li ZC, Chen JB, et al. Therapeutic efficacy of small doses of colchicine combined with glucocorticoid for acute gouty arthritis. Med J Chin
Peoples Liberation Army 2015; 40:652.
26. Zhang YK, Yang H, Zhang JY, et al. Comparison of intramuscular compound betamethasone and oral diclofenac sodium in the treatment of
acute attacks of gout. Int J Clin Pract 2014; 68:633.
27. Hui M, Carr A, Cameron S, et al. The British Society for Rheumatology Guideline for the Management of Gout. Rheumatology (Oxford) 2017;
56:e1.
28. Taylor TH, Mecchella JN, Larson RJ, et al. Initiation of allopurinol at first medical contact for acute attacks of gout: a randomized clinical trial. Am
J Med 2012; 125:1126.
29. Fernández C, Noguera R, González JA, Pascual E. Treatment of acute attacks of gout with a small dose of intraarticular triamcinolone
acetonide. J Rheumatol 1999; 26:2285.
30. Wechalekar MD, Vinik O, Schlesinger N, Buchbinder R. Intra-articular glucocorticoids for acute gout. Cochrane Database Syst Rev 2013;
:CD009920.
31. Alloway JA, Moriarty MJ, Hoogland YT, Nashel DJ. Comparison of triamcinolone acetonide with indomethacin in the treatment of acute gouty
arthritis. J Rheumatol 1993; 20:111.
32. Janssens HJ, Lucassen PL, Van de Laar FA, et al. Systemic corticosteroids for acute gout. Cochrane Database Syst Rev 2008; :CD005521.
33. Groff GD, Franck WA, Raddatz DA. Systemic steroid therapy for acute gout: a clinical trial and review of the literature. Semin Arthritis Rheum
1990; 19:329.
34. Colchicine and other drugs for gout. Med Lett Drugs Ther 2009; 51:93.
35. Yu TF, Gutman AB. Study of the paradoxical effects of salicylate in low, intermediate and high dosage on the renal mechanisms for excretion of
urate in man. J Clin Invest 1959; 38:1298.
36. Yu TF, Dayton PG, Gutman AB. Mutual suppression of the uricosuric effects of sulfinpyrazone and salicylate: A study in interactions between
drugs. J Clin Invest 1963; 42:1330.
37. Caspi D, Lubart E, Graff E, et al. The effect of mini-dose aspirin on renal function and uric acid handling in elderly patients. Arthritis Rheum
2000; 43:103.
38. Segal R, Lubart E, Leibovitz A, et al. Renal effects of low dose aspirin in elderly patients. Isr Med Assoc J 2006; 8:679.
39. Zhang Y, Neogi T, Chen C, et al. Low-dose aspirin use and recurrent gout attacks. Ann Rheum Dis 2014; 73:385.
40. van Durme CM, Wechalekar MD, Buchbinder R, et al. Non-steroidal anti-inflammatory drugs for acute gout. Cochrane Database Syst Rev 2014;
:CD010120.
41. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf (Accessed on April 12, 2019).
42. Terkeltaub RA. Colchicine update: 2008. Semin Arthritis Rheum 2009; 38:411.
43. Niel E, Scherrmann JM. Colchicine today. Joint Bone Spine 2006; 73:672.
44. Yu DK. The contribution of P-glycoprotein to pharmacokinetic drug-drug interactions. J Clin Pharmacol 1999; 39:1203.
45. Colcrys FDA Approval Letter. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2009/022351s000ltr.pdf (Accessed on February 10, 201
0).
46. Bouquié R, Deslandes G, Renaud C, et al. Colchicine-induced rhabdomyolysis in a heart/lung transplant patient with concurrent use of
cyclosporin, pravastatin, and azithromycin. J Clin Rheumatol 2011; 17:28.
47. Stamp LK, Jordan S. The challenges of gout management in the elderly. Drugs Aging 2011; 28:591.
48. Singh H, Torralba KD. Therapeutic challenges in the management of gout in the elderly. Geriatrics 2008; 63:13.
49. Fravel MA, Ernst ME. Management of gout in the older adult. Am J Geriatr Pharmacother 2011; 9:271.
50. American Geriatrics Society 2012 Beers Criteria Update Expert Panel. American Geriatrics Society updated Beers Criteria for potentially
inappropriate medication use in older adults. J Am Geriatr Soc 2012; 60:616.
51. Simmonds HA, Cameron JS, Goldsmith DJ, et al. Familial juvenile hyperuricaemic nephropathy is not such a rare genetic metabolic purine
disease in Britain. Nucleosides Nucleotides Nucleic Acids 2006; 25:1071.
52. Lhotta K, Gehringer A, Jennings P, et al. Familial juvenile hyperuricemic nephropathy: report on a new mutation and a pregnancy. Clin Nephrol
2009; 71:80.
53. van Veen TR, Haeri S. Gout in pregnancy: a case report and review of the literature. Gynecol Obstet Invest 2015; 79:217.
54. Rabinovitch O, Zemer D, Kukia E, et al. Colchicine treatment in conception and pregnancy: two hundred thirty-one pregnancies in patients with
familial Mediterranean fever. Am J Reprod Immunol 1992; 28:245.
55. Adler Y, Charron P, Imazio M, et al. 2015 ESC Guidelines for the diagnosis and management of pericardial diseases: The Task Force for the
Diagnosis and Management of Pericardial Diseases of the European Society of Cardiology (ESC)Endorsed by: The European Association for
Cardio-Thoracic Surgery (EACTS). Eur Heart J 2015; 36:2921.
56. Ben-Chetrit E, Scherrmann JM, Levy M. Colchicine in breast milk of patients with familial Mediterranean fever. Arthritis Rheum 1996; 39:1213.
57. Martinon F, Pétrilli V, Mayor A, et al. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006; 440:237.
58. So A, De Smedt T, Revaz S, Tschopp J. A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Res Ther 2007; 9:R28.
59. Chen K, Fields T, Mancuso CA, et al. Anakinra's efficacy is variable in refractory gout: report of ten cases. Semin Arthritis Rheum 2010; 40:210.
60. Tran AP, Edelman J. Interleukin-1 inhibition by anakinra in refractory chronic tophaceous gout. Int J Rheum Dis 2011; 14:e33.
61. Janssen CA, Oude Voshaar MAH, Vonkeman HE, et al. Anakinra for the treatment of acute gout flares: a randomized, double-blind, placebo-
controlled, active-comparator, non-inferiority trial. Rheumatology (Oxford) 2019.
62. Schlesinger N, Alten RE, Bardin T, et al. Canakinumab for acute gouty arthritis in patients with limited treatment options: results from two
randomised, multicentre, active-controlled, double-blind trials and their initial extensions. Ann Rheum Dis 2012; 71:1839.
63. So A, De Meulemeester M, Pikhlak A, et al. Canakinumab for the treatment of acute flares in difficult-to-treat gouty arthritis: Results of a
multicenter, phase II, dose-ranging study. Arthritis Rheum 2010; 62:3064.
Topic 1666 Version 38.0
GRAPHICS
Initial management of gout flare for patients with known diagnosis of gout*
NSAID: nonsteroidal antiinflammatory drug; GI: gastrointestinal; PPI: proton pump inhibitor; eGFR: estimated glomerular filtration rate.
* This algorithm is applicable to nonpregnant adult gout patients who do not have an organ transplant.
¶ For additional information, refer to the UpToDate topic on the clinical manifestations and diagnosis of gout.
Δ For additional information, including specific dosing and treatment regimens, as well as other details, refer to the UpToDate topic on treatment of gout flares. In patients not already receiving long-term urate-loweri
present with a flare, clinicians should discuss plans for such therapy. Ongoing urate-lowering therapy should be continued during treatment of the gout flare. For additional information, refer to the UpToDate topics on
modification and other strategies to reduce the risk of gout flares and progression of gout and on pharmacologic urate-lowering therapy and treatment of tophi in patients with gout.
Graphic 121286 Version 1.0
Cytochrome P450 3A (including 3A4) inhibitors and inducers
Strong inhibitors Moderate inhibitors Strong inducers Moderate inducers

Atazanavir Amiodarone* Apalutamide Bexarotene
Clarithromycin Aprepitant Carbamazepine Bosentan
Cobicistat and cobicistat-containing Ceritinib Enzalutamide Cenobamate

coformulations
Cimetidine* Fosphenytoin Dabrafenib
Darunavir
Conivaptan Lumacaftor Dexamethasone ¶
Idelalisib
Crizotinib Mitotane Efavirenz
Indinavir
Cyclosporine* Phenobarbital Eslicarbazepine
Itraconazole
Diltiazem Phenytoin Etravirine
Ketoconazole
Duvelisib Primidone Lorlatinib
Lopinavir
Dronedarone Rifampin (rifampicin) Modafinil
Mifepristone
Erythromycin Nafcillin
Nefazodone
Fedratinib Rifabutin
Nelfinavir
Fluconazole Rifapentine
Ombitasvir-paritaprevir-ritonavir
Fosamprenavir St. John's wort
Ombitasvir-paritaprevir-ritonavir plus
Fosaprepitant*
dasabuvir
Grapefruit juice
Posaconazole
Imatinib
Ritonavir and ritonavir-containing
coformulations Isavuconazole (isavuconazonium
sulfate)
Saquinavir
Lefamulin
Telithromycin
Letermovir
Voriconazole
Netupitant
Nilotinib
Ribociclib
Schisandra
Verapamil
◾ For drug interaction purposes, the inhibitors and inducers of CYP3A metabolism listed above can alter serum concentrations of drugs that are dependent upon the
CYP3A subfamily of liver enzymes, including CYP3A4, for elimination or activation.
◾ These classifications are based upon US Food and Drug Administration (FDA) guidance. [1,2] Other sources may use a different classification system resulting in some agents
being classified differently.
◾ Data are for systemic drug forms. Degree of inhibition or induction may be altered by dose, method, and timing of administration.
◾ Weak inhibitors and inducers are not listed in this table with exception of a few examples. Clinically significant interactions can occasionally occur due to weak inhibitors and
inducers (eg, target drug is highly dependent on CYP3A4 metabolism and has a narrow therapeutic index). Accordingly, specific interactions should be checked using a drug
interaction program such as Lexicomp interactions included within UpToDate.
◾ Refer to UpToDate topics on specific agents and indications for further details.
* Classified as a weak inhibitor of CYP3A4 according to FDA system. [1]

¶ Classified as a weak inducer of CYP3A4 according to FDA system. [1]
Data from: Lexicomp Online (Lexi-Interact). Copyright © 1978-2020 Lexicomp, Inc. All Rights Reserved.
References:
1. US Food & Drug Administration. Clinical drug interaction studies - Study design, data analysis and clinical implications; Guidance for industry (October 24, 2017) available at:
https://www.fda.gov/media/82734/download.
2. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: FDA.gov website.
Inhibitors and inducers of P-glycoprotein (P-gp) drug efflux pump (P-gp multidrug resistance transporter)
Inhibitors of P-gp Inducers of P-gp

Amiodarone Lopinavir-ritonavir Apalutamide
Azithromycin (systemic) Neratinib Carbamazepine
Carvedilol Ombitasvir-paritaprevir-ritonavir (Technivie) ¶ Fosphenytoin
Clarithromycin Osimertinib Phenobarbital*
Cobicistat and cobicistat-containing coformulations* Propafenone Phenytoin
Cyclosporine (systemic) Quinidine Rifampin (rifampicin)
Daclatasvir Quinine St. John's wort
Dronedarone Ranolazine
Elagolix Ritonavir and ritonavir-containing coformulations ¶
Eliglustat Rolapitant
Erythromycin (systemic) Simeprevir
Flibanserin Tacrolimus (systemic)*
Fostamatinib Tamoxifen*
Glecaprevir-pibrentasvir Telaprevir
Itraconazole Ticagrelor*
Ivacaftor Velpatasvir
Ketoconazole (systemic) Vemurafenib
Lapatinib Verapamil
Ledipasvir
◾ Inhibitors of the P-gp drug efflux pump (also known as P-gp multidrug resistance transporter) listed above may increase serum concentrations of drugs that are substrates
of P-gp, whereas inducers of P-gp drug efflux may decrease serum concentrations of substrates of P-gp.
◾ Examples of drugs that are substrates of P-gp efflux pump include: Apixaban, colchicine, cyclosporine, dabigatran, digoxin, edoxaban, rivaroxaban, and tacrolimus.
◾ The degree of effect on P-gp substrate serum concentration may be altered by dose and timing of orally administered P-gp inhibitor or inducer.
◾ These classifications are based upon US FDA guidance. [1,2] Other sources may use a different classification system resulting in some agents being classified differently.
◾ Specific drug interaction effects may be determined by using Lexi-Interact, the drug interactions program included with UpToDate. Refer to UpToDate clinical topics on
specific agents and conditions for further details.
P-gp: P-glycoprotein; US FDA: US Food and Drug Administration.

* Minor clinical effect or supportive data are limited to in-vitro effects (ie, clinical effect is unknown).
¶ The combination of ombitasvir-paritaprevir-ritonavir plus dasabuvir (Viekira Pak) is not a significant inhibitor of P-gp efflux pump. [3]
Data from: Lexicomp Online (Lexi-Interact). Copyright © 1978-2020 Lexicomp, Inc. All Rights Reserved.
References:
1. US Food & Drug Administration. Clinical drug interaction studies - Study design, data analysis and clinical implications; Guidance for industry (October 24, 2017) available at:
https://www.fda.gov/downloads/drugs/guidances/ucm292362.pdf.
2. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: FDA.gov website.
3. Menon RM, Badri PS, Wang T, et al. Drug-drug interaction profile of the all-oral anti-hepatitis C virus regimen of paritaprevir/ritonavir, ombitasvir, and dasabuvir. J Hepatol 2015;
63:20.
Contributor Disclosures
Michael A Becker, MD Grant/Research/Clinical Trial Support: Takeda [Urate-lowering drug safety/efficacy in gout (Febuxostat, colchicine)]; Horizon [Urate-lowering
drug safety/efficacy in gout (Pegloticase)]; Ardea Biosciences/AstraZeneca and Ironwood [Urate-lowering drug safety/efficacy in gout (Lesinurad)]. Consultant/Advisory
Boards: Takeda Pharmaceuticals [Gout drug development (Febuxostat, colchicine)]; Horizon [Gout drug development (Pegloticase)]; Ardea Biosciences/AstraZeneca
and Ironwood [Gout drug development (Lesinurad)]; CymaBay Therapeutics/Kowa Pharmaceuticals [Gout drug development (Arhalofenate)]. Angelo L Gaffo, MD,
MsPH Grant/Research/Clinical Trial Support: Amgen [Gout (Denosumab)]. Nicola Dalbeth, MBChB, MD, FRACP Grant/Research/Clinical Trial Support: AstraZeneca
[Gout (Lesinurad)]; Amgen [(Denosumab)]. Speaker's Bureau: Janssen [Psoriatic arthritis]; Horizon [Gout (Pegloticase)]. Consultant/Advisory Boards: AstraZeneca
[Gout (Lesinurad)]; Takeda [Gout (Febuxostat)]; Horizon [Gout (Pegloticase)]; Dyve Bio; Hengrui [Gout]. Paul L Romain, MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process,
and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to
UpToDate standards of evidence.
Conflict of interest policy

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Treatment of gout flares

GENERAL THERAPEUTIC PRINCIPLES

There are important contraindications to NSAIDs, including:

● Cardiovascular disease, particularly heart failure or hypertension that is difficult to control.

● Ongoing treatment with anticoagulants. (See 'Patients on anticoagulation' below.)

• Chronic ill health and debility.

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

Pregnancy and lactation

RESISTANT DISEASE OR UNABLE TO TAKE OTHER THERAPIES

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

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

SUMMARY AND RECOMMENDATIONS

Use of UpToDate is subject to the Subscription and License Agreement.

1. Neogi T. Clinical practice. Gout. N Engl J Med 2011; 364:443.

41. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf (Accessed on April 12, 2019).

Topic 1666 Version 38.0

Graphic 121286 Version 1.0

Cytochrome P450 3A (including 3A4) inhibitors and inducers

Strong inhibitors Moderate inhibitors Strong inducers Moderate inducers

Clarithromycin Aprepitant Carbamazepine Bosentan

Cobicistat and cobicistat-containing Ceritinib Enzalutamide Cenobamate

* Classified as a weak inhibitor of CYP3A4 according to FDA system. [1]

Graphic 76992 Version 65.0

Inhibitors of P-gp Inducers of P-gp

Azithromycin (systemic) Neratinib Carbamazepine

Carvedilol Ombitasvir-paritaprevir-ritonavir (Technivie) ¶ Fosphenytoin

Clarithromycin Osimertinib Phenobarbital*

Cobicistat and cobicistat-containing coformulations* Propafenone Phenytoin

Cyclosporine (systemic) Quinidine Rifampin (rifampicin)

Daclatasvir Quinine St. John's wort

Elagolix Ritonavir and ritonavir-containing coformulations ¶

Erythromycin (systemic) Simeprevir

Flibanserin Tacrolimus (systemic)*

Ketoconazole (systemic) Vemurafenib

P-gp: P-glycoprotein; US FDA: US Food and Drug Administration.

Graphic 73326 Version 47.0

Conflict of interest policy

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