Gout and Hyperuricemia
Clinical Snapshot
Gout is caused by chronic hyperuricemia leading to the deposition of monosodium urate (MSU) crystals in joints, periarticular soft tissue (cartilage, tendon, bursa), and renal tissue (glomeruli, interstitium, tubules), producing gouty arthritis, tophi, or uric acid nephrolithiasis/nephropathy. It is the most common cause of inflammatory arthritis in adults. Disease progresses through 4 clinically distinct stages — asymptomatic hyperuricemia, acute gouty flare, intercritical gout (the asymptomatic interval between flares, when flare prophylaxis and urate-lowering therapy are managed), and chronic tophaceous gout — and management differs meaningfully by stage: an acute flare needs fast anti-inflammatory treatment, while sustained hyperuricemia needs a treat-to-target urate-lowering strategy that, once started, continues indefinitely.[1][2]
Recognize the Condition
Acute gouty flare
Abrupt onset of excruciating pain and inflammation in a joint, classically overnight or in the early morning, often severe enough that the patient cannot tolerate even light pressure (such as a bedsheet) on the affected joint. Attacks typically resolve spontaneously over days to about a week if untreated, though resolution can take longer in longstanding disease. The 1st metatarsophalangeal (MTP) joint (podagra) is the single most common site, especially for a first attack; other frequently involved sites in decreasing order include the midfoot/instep, ankle, heel, knee, wrist, finger joints, and elbow. Acute gouty bursitis can occur in the prepatellar or olecranon bursa. There is a predilection for joints already damaged by osteoarthritis. A first attack is usually monoarticular; polyarticular presentations become more common with recurrent attacks, in older-onset disease, and in women, who also have a higher relative frequency of upper-limb joint involvement than men.
Intercritical gout
The asymptomatic interval between flares. Without urate-lowering therapy, subsequent attacks tend to become more frequent, more severe, longer-lasting, and increasingly polyarticular with upper-extremity involvement and constitutional symptoms, and erosive joint damage and tophi can develop even during this "quiet" phase.
Chronic tophaceous gout
Tophi are painless, chalky nodular deposits of MSU crystals that develop after years of sustained, inadequately controlled hyperuricemia. They can cause joint destruction and visible deformity even though they are not themselves painful. Common locations include the synovium, subchondral bone, the digits of the hands and feet, the olecranon bursa, the Achilles tendon, and the helix of the ear, though tophi can occur anywhere, including rarely the cardiac conduction system. The strongest risk factor for tophus development is the degree and duration of uncontrolled serum urate elevation; aggressive correction of hyperuricemia is the key preventive and therapeutic strategy, and tophi gradually resorb and can fully resolve after sustained serum urate control.
The 4 clinical stages of gout
Asymptomatic hyperuricemia
Elevated serum urate without any clinical manifestations. Not itself an indication for urate-lowering therapy.
Acute gouty flare
The first symptomatic event, or any subsequent flare; needs fast anti-inflammatory treatment, ideally started within 24 hours of onset.
Intercritical gout
The asymptomatic period between flares; the phase where flare prophylaxis and treat-to-target urate-lowering therapy are managed.
Chronic tophaceous gout
Tophi, and often erosive joint damage, after years of inadequately controlled hyperuricemia.
Risk Factors
Drugs associated with hyperuricemia and gout
- Alcohol.
- Cyclosporine and tacrolimus.
- Cytotoxic chemotherapy.
- Diuretics — thiazide and loop diuretics specifically (not other antihypertensive classes).
- Ethambutol and pyrazinamide.
- Interferon plus ribavirin.
- Levodopa.
- Nicotinic acid (niacin).
- Low-dose salicylates (e.g., low-dose ASA).
- Teriparatide.
Conditions associated with hyperuricemia and gout
- Excessive alcohol intake.
- Atherosclerosis and ischemic heart disease.
- Chronic kidney, glomerular, or interstitial renal disease.
- Diabetes and metabolic syndrome.
- Dietary factors — high purine intake, high-fructose corn syrup.
- Hyperlipidemia and hypertension.
- Lead intoxication.
- Myeloproliferative disorders and some malignancies.
- Obesity.
- A personal history of urolithiasis.
- Rarely, genetic or acquired causes of uric acid overproduction.
Additional patient-level risk factors
- Male sex over age 40, or postmenopausal status in women — estrogen has a uricosuric effect, so gout is uncommon in premenopausal women.
- A first flare before age 30 in men or age 50 in women without a clear precipitant — suggests an inherited purine-metabolism enzyme abnormality and warrants further workup.
- A prior gout flare — the single strongest predictor of a future flare.
- Chronic kidney disease stage 3 or higher.
- Solid organ transplantation (calcineurin inhibitor use plus reduced renal clearance).
Red Flags & Refer
Gout and septic arthritis can look identical at the bedside, and a dramatic response to colchicine does not exclude infection — escalate to arthrocentesis and, where indicated, emergency assessment for any of the following.
- Any acute monoarticular joint that is hot, swollen, and exquisitely tender in a patient with fever, systemic toxicity, immunocompromise, a prosthetic joint, recent joint surgery/instrumentation, or genuine diagnostic uncertainty — synovial fluid Gram stain and culture are mandatory before treating empirically as gout; septic arthritis is a joint-threatening emergency and can coexist with gout.
- Polyarticular flare accompanied by hemodynamic instability or marked systemic symptoms.
- A first flare before age 30 in men or age 50 in women without a clear precipitant — evaluate for an inherited enzyme abnormality of purine metabolism rather than managing as routine gout.
- Any rash, especially with fever, mucosal involvement, or systemic symptoms, appearing after a recent allopurinol start — stop allopurinol immediately, do not rechallenge, and refer urgently; this can herald allopurinol hypersensitivity syndrome, which can progress to Stevens-Johnson syndrome or toxic epidermal necrolysis.[3]
- Colchicine prescribed or continued alongside a strong CYP3A4 or P-glycoprotein inhibitor (e.g., clarithromycin) in a patient with renal or hepatic impairment — this combination has caused fatal colchicine toxicity and needs the dose reduced or the interacting drug avoided.[4]
- Extensive or destructive tophaceous disease, tophi at a high-risk site (e.g., causing nerve compression), or draining/ulcerated tophi.
- Refer to a specialist for: an unclear cause of hyperuricemia, inability to reach the target serum urate despite adequate therapy, persistent symptoms or signs of gout despite treatment, or multiple or serious adverse effects from urate-lowering therapy.
Assessment & Diagnosis
Differentiating an acute hot, swollen joint
| Feature | Gout | Septic arthritis | CPPD (pseudogout) | Cellulitis |
|---|---|---|---|---|
| Typical onset | Abrupt, often overnight; peaks within 24 hours | Abrupt, progressive over hours to 1-2 days; often with systemic illness | Abrupt, a similar tempo to gout | Develops over hours to days, spreading outward |
| Classic joint(s) | 1st MTP (podagra), midfoot, ankle, knee | Any joint; often a single large weight-bearing joint (knee, hip) or a prosthetic joint | Knee most common; wrist, shoulder | Overlying soft tissue rather than the joint itself, though it can overlie and mimic a joint |
| Fever / systemic illness | Possible, usually mild | Common, can be marked, especially with bacteremia | Possible, usually mild | Possible if extensive or with lymphangitis |
| Skin over the joint | Erythematous, warm, exquisitely tender | Erythematous, warm, tense effusion | Erythematous, warm | Diffuse erythema with indistinct, spreading borders; no true joint effusion |
| Synovial fluid crystals | Needle-shaped, negatively birefringent monosodium urate crystals | Absent, unless coexisting crystal disease | Rhomboid, weakly positively birefringent calcium pyrophosphate crystals | Not applicable — arthrocentesis is not indicated unless true joint involvement is suspected |
| Synovial fluid Gram stain / culture | Negative | May be positive; culture is the definitive test | Negative | Not applicable |
| Response to colchicine | Rapid, often dramatic | No true response — inflammation is driven by infection, not crystals | Often responds, less predictably than gout | No response |
| Confirmatory step | Synovial fluid crystal analysis | Synovial fluid Gram stain and culture — mandatory whenever septic arthritis cannot be excluded clinically | Synovial fluid crystal analysis; can coexist with gout | Clinical diagnosis; blood cultures if systemically unwell |
Gout and septic arthritis can coexist, and a dramatic response to colchicine does not exclude infection — when there is any diagnostic uncertainty, arthrocentesis with synovial fluid cell count, Gram stain, culture, and crystal analysis is mandatory before treating empirically as gout.
History
- Precipitants of the acute attack — acute illness, surgery, trauma, alcohol intake, a high-purine meal, or a drug from the hyperuricemia-associated list in Risk Factors.
- Pattern and location of joint or bursa involvement, and whether the joint was previously damaged (e.g., by osteoarthritis).
- Character of the episode — abrupt onset, severity, nocturnal or early-morning onset, inability to tolerate light pressure on the joint.
- Time course — most flares resolve spontaneously over days if untreated; longer courses are more common in longstanding disease.
- Presence of a known tophus, and prior gout flares (number, frequency, and whether they involved 1 or multiple joints).
Physical examination
- Confirm the joint/bursa involvement pattern described above.
- Examine specifically for tophi at their common locations (digits, olecranon bursa, Achilles tendon, helix of the ear).
Investigations
- Serum urate — supportive but not definitive; a normal level during a flare does not rule out gout, since urate can transiently fall during an acute attack.
- Synovial fluid analysis — the diagnostic gold standard: identification of intracellular, needle-shaped, negatively birefringent monosodium urate crystals under polarized microscopy confirms the diagnosis. Send synovial fluid for cell count, Gram stain, and culture in the same tap whenever septic arthritis has not been confidently excluded — this is not optional when there is diagnostic uncertainty.
- Imaging (ultrasound double-contour sign, dual-energy CT showing urate deposition, or conventional radiography showing punched-out erosions with overhanging sclerotic margins in established disease) — useful when the diagnosis remains uncertain after history, exam, and available fluid analysis, or to document structural damage in chronic disease. Not required for a classic presentation in a patient with prior crystal-proven gout — do not routinely re-image or re-tap every recurrent, typical flare.
Presumptive versus definitive diagnosis
A presumptive diagnosis of gout is supported by the triad of acute monoarthritis, hyperuricemia, and a dramatic response to colchicine, but a definitive diagnosis requires identification of intracellular monosodium urate crystals in synovial fluid.
2015 ACR/EULAR gout classification criteria
Developed as a research classification tool (entry criterion: at least 1 episode of swelling, pain, or tenderness in a peripheral joint or bursa), not a mandatory clinical diagnostic requirement — synovial fluid crystal identification remains the clinical gold standard. Identification of MSU crystals in a symptomatic joint, bursa, or tophus is sufficient on its own to classify gout without needing to sum the remaining domains below.[5]
| Domain | Finding | Points |
|---|---|---|
| Pattern of joint/bursa involvement (ever) | Ankle or midfoot (as part of a mono/oligoarticular episode, without 1st MTP involvement) | 1 |
| 1st MTP joint involved (as part of a mono/oligoarticular episode) | 2 | |
| Characteristics of symptomatic episodes ever (erythema over the joint; cannot bear touch/pressure; great difficulty walking or using the joint) | 1 characteristic present | 1 |
| 2 characteristics present | 2 | |
| 3 characteristics present | 3 | |
| Time course (≥2 episodes, each with ≥2 of: time to maximal pain <24h, resolution in ≤14 days, complete resolution between episodes) | 1 typical episode | 1 |
| Recurrent typical episodes | 2 | |
| Clinical evidence of tophus | Present | 4 |
| Serum urate (ideally measured off ULT and ≥4 weeks from any flare) | Under 240 µmol/L | -4 |
| 360 to under 480 µmol/L | 2 | |
| 480 to under 600 µmol/L | 3 | |
| 600 µmol/L or over | 4 | |
| Synovial fluid analysis of a symptomatic joint/bursa | MSU-negative | -2 |
| Imaging | Urate deposition on ultrasound (double-contour sign) or dual-energy CT | 4 |
| Gout-related joint damage on conventional radiography (hands and/or feet, at least 1 erosion) | 4 |
A total score of 8 or more classifies the patient as having gout.
Treatment Targets
- Terminate the acute flare as quickly as possible — start anti-inflammatory therapy within 24 hours of flare onset.
- Reach and maintain a treat-to-target serum urate below 360 µmol/L for most patients.
- For patients with more severe disease (e.g., tophaceous gout), reach a lower target of under 300 µmol/L until visible/palpable urate crystal burden has resolved, then relax the maintenance target to under 360 µmol/L to prevent new tophi.
- Prevent flare recurrence, especially during the higher-risk period immediately after starting urate-lowering therapy, with anti-inflammatory prophylaxis.
- Prevent or reverse gout complications — erosive joint damage, tophi, uric acid nephrolithiasis, and urate nephropathy.
- Identify and manage associated comorbidities — metabolic syndrome, hypertension, dyslipidemia, and cardiovascular and renal disease.
- Sustain adherence to urate-lowering therapy indefinitely once started — this is lifelong treatment, not a fixed course.
Choose Initial Treatment
Acute flare therapy
1st line colchicine, an NSAID, or an oral/intra-articular corticosteroid are all appropriate initial options for an acute gout flare — start within 24 hours of onset. Choose based on patient factors: prefer an NSAID when renal function is normal and there is no significant GI or cardiovascular risk; prefer a corticosteroid (oral, or intra-articular if 1-2 large joints are accessible) when renal impairment, GI bleeding risk, or NSAID/colchicine intolerance is present; prefer colchicine when the patient presents within about 36 hours of onset, has normal renal and hepatic function, and is not on an interacting drug — use the current low-dose regimen only, never the older repeated-hourly high-dose regimen.[6]
Combination therapy is appropriate for severe symptoms, polyarticular attacks, large-joint involvement, or an inadequate response to monotherapy — combine colchicine plus an NSAID, colchicine plus an oral corticosteroid, or an intra-articular corticosteroid plus an oral agent.
Do not stop or alter the dose of an existing urate-lowering therapy during an acute flare — continue it unchanged, since interrupting it can exacerbate or prolong the attack.
When to start urate-lowering therapy
ULT is not indicated for a first, isolated flare or for asymptomatic hyperuricemia alone. Start ULT when any of the following is present: at least 1 subcutaneous tophus; more than 1 previous flare with other flares otherwise infrequent; frequent flares, defined as 2 or more per year; comorbid chronic kidney disease stage 3 or higher; a history of urolithiasis; radiographic damage attributable to gout; or a serum urate concentration over 535 µmol/L.[1] ULT can and should be started during an active flare, provided effective anti-inflammatory flare therapy is given concurrently — do not delay initiation to the intercritical period.
Flare prophylaxis when starting ULT
Start low-dose colchicine or a low-dose NSAID at the same time as any ULT and continue for at least 3-6 months, since initiating ULT transiently increases flare risk as urate crystals mobilize; continue prophylaxis longer if the patient is still experiencing flares at 6 months.[1]
Choice of first-line ULT agent
1st line, all patients including CKD stage ≥3 allopurinol — start at 100 mg/day or less (50 mg/day if eGFR is 29 mL/min/1.73m² or under), then titrate upward toward the serum urate target; allopurinol is preferred over febuxostat given febuxostat's cardiovascular caution. Consider HLA-B*58:01 screening before starting in patients of Han Chinese, Korean, Thai, or African descent, who carry a higher prevalence of this allele and a correspondingly higher risk of severe allopurinol hypersensitivity syndrome.[3]
2nd line — use when allopurinol is not tolerated or insufficient at the maximum tolerated dose febuxostat, starting at 40 mg/day. Use with caution or avoid in patients with established cardiovascular disease, given the cardiovascular mortality signal versus allopurinol seen in postmarketing trial data.[7][8][9]
Alternative/add-on a uricosuric (probenecid) can be used as monotherapy when a xanthine oxidase inhibitor is not an option, or added to a xanthine oxidase inhibitor for combination therapy if the urate target is not reached — but only when creatinine clearance is 50 mL/min or higher and there is no history of urolithiasis.
Non-Pharmacologic Treatment
- Apply ice to the affected joint during an acute flare as an appropriate adjunct to pharmacologic therapy.
- Recommend a structured weight-loss program for patients with overweight or obesity, regardless of current disease activity.
- Encourage regular exercise and adequate hydration.
- Limit purine intake regardless of disease activity — advise avoiding organ meats high in purine content (sweetbreads, liver, kidney) and limiting beef, lamb, pork, and high-purine seafood (sardines, shellfish).
- Limit high-fructose corn syrup intake regardless of disease activity.
- Limit alcohol intake regardless of disease activity — particularly beer, though wine and spirits also count — to under 2 servings/day for men or under 1 serving/day for women; advise avoiding alcohol entirely during periods of frequent flares or poorly controlled gout.
- Review the patient's medication list for nonessential hyperuricemic drugs (see Risk Factors) and discontinue or substitute where feasible; preferentially select losartan when an ARB is otherwise indicated for another reason, and switch hydrochlorothiazide to an alternative antihypertensive class when feasible.
- Continue low-dose ASA for cardiovascular protection when it is already indicated — do not stop it solely because of a gout diagnosis, but recognize it may increase the importance of adequate ULT.
- Dietary supplements, including vitamin C, are not recommended specifically for lowering serum urate — current evidence is insufficient to support this use.
Special Populations
Pregnancy
Gout is uncommon in premenopausal women because estrogen has a uricosuric effect; when a flare does occur in pregnancy, oral or intra-articular corticosteroids are generally the preferred treatment. Avoid NSAIDs, particularly from around 20 weeks' gestation onward, given fetal renal effects and the risk of premature closure of the ductus arteriosus. Colchicine has more accumulated pregnancy safety experience than urate-lowering therapy (from long-standing use in familial Mediterranean fever) and may be considered under specialist guidance if corticosteroids are inadequate, though it is not the first choice. Xanthine oxidase inhibitors (allopurinol, febuxostat) and probenecid are generally not initiated in pregnancy given insufficient safety data — defer ULT initiation to the postpartum period unless a specialist determines ongoing therapy is essential.
Breastfeeding
Corticosteroids are compatible with breastfeeding. NSAIDs are generally compatible for short-term use. Colchicine transfer into breast milk appears low; use the lowest effective dose. Data on allopurinol and probenecid in lactation are limited — weigh benefit and risk with specialist input, and prefer an alternative when one is adequate.
Pediatrics
Gout is rare in children. Pediatric gout warrants specialist evaluation for an underlying inherited enzyme disorder of purine metabolism (e.g., hypoxanthine-guanine phosphoribosyltransferase deficiency in Lesch-Nyhan syndrome, or PRPP synthetase overactivity) or a secondary cause such as malignancy or tumor lysis, rather than routine adult-pattern management. Probenecid is contraindicated under age 2.
Renal impairment
Allopurinol: reduce the starting dose to 50 mg/day if eGFR is 29 mL/min/1.73m² or under; titrate cautiously and more slowly, monitoring renal function.[10] Febuxostat: no dose adjustment is required across mild-to-severe CKD, though the cardiovascular risk-benefit assessment still applies. Colchicine: reduce the dose/frequency or avoid when combined with a strong CYP3A4 or P-glycoprotein inhibitor in the setting of renal impairment — this combination has caused fatal toxicity.[4] NSAIDs: avoid in significant renal impairment (ClCr under 30 mL/min). Probenecid/uricosurics: not appropriate as first-line monotherapy if ClCr is under 50 mL/min, and effectiveness declines further as renal function worsens.
Hepatic impairment
Reduce or avoid colchicine with interacting drugs as above, and use general caution with colchicine in significant hepatic impairment. Monitor liver enzymes with both allopurinol (rare hepatotoxicity) and febuxostat (more frequent mild transaminase elevation), and use febuxostat with caution in significant hepatic impairment.
Monitoring & Follow-Up
- During an acute flare: confirm symptom resolution and tolerance of the chosen agent within the expected timeframe.
- Serum urate: recheck every 2-5 weeks during ULT titration; once the target is reached, recheck every 6 months.
- Renal function, CBC, and liver enzymes periodically while on allopurinol or febuxostat, and for patients on colchicine, particularly if an interacting drug is added.
- Watch closely for a new rash in the first weeks after starting allopurinol — instruct the patient to report this immediately, and do not continue allopurinol if hypersensitivity is suspected.
- Track flare frequency and tophus size/number over time as measures of treatment adequacy — both should decline once serum urate has been sustained below target.
- Reassess the ongoing need for anti-inflammatory flare prophylaxis at 3-6 months after ULT initiation; continue longer if the patient is still experiencing flares.
- Periodically reassess associated comorbidities — blood pressure, lipids, glucose/HbA1c, and weight — given the established link between gout and metabolic syndrome.
- Colchicine therapy in gout has also been associated with a reduced risk of cardiovascular events in cohort data — an incidental benefit worth being aware of in patients with overlapping cardiovascular risk factors, though this association is not itself a reason to add colchicine for a patient who does not otherwise have gout.[11]
- Community pharmacists are well positioned to catch ULT nonadherence, since patients often stop therapy once symptom-free without understanding that lifelong continuation is required to prevent recurrence and complications.
Common Errors to Avoid
- Stopping or altering the dose of urate-lowering therapy during an acute flare — continue it unchanged.
- Starting ULT without concurrent flare prophylaxis (colchicine or a low-dose NSAID).
- Treating asymptomatic hyperuricemia — this is not an indication for ULT.
- Starting ULT after a first, isolated gout flare without any of the specific indications present.
- Using the outdated repeated-hourly high-dose colchicine regimen instead of the current low-dose regimen.
- Missing a dangerous colchicine interaction (a strong CYP3A4 or P-glycoprotein inhibitor such as clarithromycin) in a patient with renal or hepatic impairment — this combination is potentially fatal.
- Not considering HLA-B*58:01 screening before starting allopurinol in a patient of Han Chinese, Korean, Thai, or African descent.
- Choosing febuxostat ahead of allopurinol as first-line ULT without a specific reason to avoid allopurinol.
- Starting a uricosuric in a patient with ClCr under 50 mL/min or a history of urolithiasis.
- Continuing a thiazide or loop diuretic without considering an alternative when clinically feasible in a patient with gout.
- Treating an acutely inflamed joint as gout without considering septic arthritis, especially with fever, systemic toxicity, or genuine diagnostic uncertainty.
- Assuming a normal serum urate level during a flare excludes gout.
Clinical Decision Algorithm
Drug Tables
How to use this table: doses are adult doses and require patient-specific confirmation, including renal/hepatic adjustment. Select any drug name to open its complete Pharmasist Drug Database page.
Antimitotics
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Colchicine | Acute flare (standard): 1.2 mg PO at first sign of flare, then 0.6 mg 1 hour later (total 1.8 mg); start prophylactic dosing 12 hours later Acute flare (age >70, or on a P-glycoprotein inhibitor): 0.6 mg PO at once, then 0.3 mg every other day prophylactically; use with caution Acute flare (on a strong CYP3A4 inhibitor): 0.6 mg PO, followed by 0.3 mg 1 hour later, then 0.3 mg every other day prophylactically Flare prophylaxis (standard): 0.6 mg PO once or twice daily | Common at higher doses: abdominal pain/cramps, diarrhea, nausea, vomiting. Rare: neuropathy, myopathy, bone marrow suppression. | Increases HMG-CoA reductase inhibitor (statin) levels — monitor for statin myotoxicity. Fatalities reported with strong CYP3A4 inhibitors or P-glycoprotein inhibitors (e.g., clarithromycin, cyclosporine) in renal/hepatic impairment — dose-reduce or avoid. Avoid grapefruit juice. | Contraindicated with severe renal or hepatic impairment combined with a strong CYP3A4/P-glycoprotein inhibitor. |
Corticosteroids, intra-articular
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Methylprednisolone acetate | Large joints: 20-80 mg intra-articularly Medium joints: 10-40 mg intra-articularly Small joints: 4-10 mg intra-articularly | Not usually significant after a single intra-articular injection. | None significant with single intra-articular use. | Ideal at the time of diagnostic arthrocentesis for 1-2 accessible joints; not suited to polyarticular involvement. |
| Methylprednisolone acetate/lidocaine | Large joints: 20-80 mg methylprednisolone acetate intra-articularly Medium joints: 10-40 mg methylprednisolone acetate intra-articularly Small joints: 4-10 mg methylprednisolone acetate intra-articularly | Not usually significant after a single intra-articular injection. | None significant with single intra-articular use. | Lidocaine-containing formulation often preferred for injection comfort. Suggested maximum of 1 injection per joint every 3 months. |
| Triamcinolone acetonide | Large joints: 5-15 mg intra-articularly, maximum 40 mg Small joints: 2.5-5 mg intra-articularly, maximum 10 mg | Not usually significant after a single intra-articular injection. | None significant with single intra-articular use. |
Corticosteroids, systemic
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Methylprednisolone sodium succinate | Acute flare: 0.5-2 mg/kg IV or IM as a single dose | Not usually significant after a single injection. | Use when oral prednisone cannot be used. | |
| Prednisone | Acute flare: 0.5 mg/kg PO daily for 5 days (effective range 20-50 mg/day) Flare prophylaxis: ≤10 mg/day PO | Short-term use: GI disturbance, glucose intolerance, fluid retention, insomnia/mood changes. Long-term effects are numerous and are not the intent of short-course gout therapy. | Barbiturates, phenytoin, and rifampin decrease corticosteroid effect. | Doses under 20 mg/day may be ineffective. A low dose of colchicine or an NSAID given concurrently helps prevent rebound flare when the corticosteroid is stopped. |
Nonsteroidal anti-inflammatory drugs (NSAIDs)
No good evidence that one NSAID is more effective than another for gout. Avoid in patients with a history of peptic ulcer disease, cardiovascular risk factors, renal failure, or asthma; consider adding a PPI in patients at risk for peptic ulcer disease. Avoid NSAIDs in severe renal impairment (ClCr under 30 mL/min).
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Celecoxib | Acute flare: 800 mg PO once, then 400 mg 12 hours later, then 400 mg PO BID for 7 days | GI: dyspepsia, epigastric pain, nausea/vomiting, GI ulcers/bleeding. Cardiovascular: MI, stroke, heart failure, fluid retention, hypertension. Nephrotoxicity. CNS: dizziness, drowsiness, headache. Skin rashes. | Increased bleeding with anticoagulants/antiplatelet agents. May decrease antihypertensive effect. ACE inhibitors/ARBs/diuretics: increased acute kidney injury risk. May raise lithium levels. SSRIs: increased GI bleeding risk. | High-dose celecoxib is a reasonable alternative to a nonselective NSAID with generally better GI tolerability. |
| Indomethacin | Acute flare: 75 mg PO once, then 50 mg Q6H for 2 days, then 50 mg Q8H for 1 day, then 25 mg Q8H for 1 day Flare prophylaxis: 25 mg PO BID | Same NSAID class effects as above. | Same NSAID class interactions as above. | |
| Naproxen | Acute flare: 750 mg PO once, then 500 mg PO BID for 4-5 days Flare prophylaxis: 250 mg PO BID | Same NSAID class effects as above. | Same NSAID class interactions as above. |
Uricosurics
Contraindicated in gross uric acid overproducers (elevated urine uric acid). Urine alkalinization is not recommended with uricosuric therapy. Confirm creatinine clearance before selecting therapy — avoid as first-line monotherapy if ClCr is under 50 mL/min or with urolithiasis.
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Probenecid | Starting dose: 500 mg PO once or twice daily Titration: May increase by 500 mg every 4 weeks if required Maximum: 2 g/day | May precipitate a flare during the initial phase of therapy; renal calculi; headache; GI irritation; hypersensitivity reactions. | Increases levels of some drugs (e.g., methotrexate). Salicylates reduce the uricosuric effect. | Liberal fluid intake helps prevent stones. Available in Canada only through Health Canada's Special Access Program or as a compounded product. |
| Losartan | Dosing: 50 mg PO once daily | Hypotension, hyperkalemia, renal insufficiency, rare angioedema, headache, dizziness. | Diuretics: hypotension. Potassium-sparing diuretics/ACE inhibitors: hyperkalemia. NSAIDs: may increase BP/fluid retention/renal failure risk. Lithium: toxicity risk. | Uricosuric effect is not an approved indication in Canada; use as antihypertensive selection preference in a gout patient who otherwise needs an ARB. Monitor creatinine and potassium 7-14 days after initiation or dose changes. |
| Fenofibrate | Dosing: Per current lipid-management dosing guidance | Myalgia, transaminase elevation, GI upset. | Increased myopathy risk with statins. | Has a modest uricosuric effect, but switching or adding fenofibrate specifically to lower urate is not recommended — the risk of fenofibrate's adverse effects outweighs this benefit; use only when fenofibrate is otherwise indicated for its lipid effect. |
Xanthine oxidase inhibitors
The mainstay of treat-to-target therapy; can be started during a flare as long as effective anti-inflammatory treatment has also been started. Urate levels should be checked every 6 months once the target has been reached.
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Allopurinol | Starting dose (normal renal function): ≤100 mg PO daily Starting dose (eGFR ≤29 mL/min/1.73m²): 50 mg PO daily Renal impairment (ClCr 30-60 mL/min): Decrease initial dose to 50 mg/day Renal impairment (ClCr under 15-30 mL/min): 50 mg every 2 days Usual maintenance / maximum: Around 300 mg/day; maximum 800 mg/day, divided if over 300 mg/day to improve tolerability | Skin rash, GI upset, hepatotoxicity, fever. Rare but potentially fatal severe hypersensitivity syndrome; rare xanthine stones. May precipitate a flare during the initial phase of therapy. | Increases half-life of azathioprine and 6-mercaptopurine — reduce their dose to one-quarter to one-third of usual when co-administered. May increase cyclophosphamide toxicity. Inhibits hepatic warfarin metabolism. Increased rash incidence with ampicillin/amoxicillin. | To prevent flares on initiation, give a prophylactic NSAID or colchicine for at least 3-6 months. Desensitization can be achieved in some patients with mild reactions, but sensitivity may recur. |
| Febuxostat | Starting dose: 40 mg PO daily Titration: May increase to 80 mg PO daily after 2 weeks if urate remains above target Maximum (Canada): 80 mg/day | Nausea, arthralgia, skin rash (more at higher dose), elevated liver aminotransferases. May precipitate a flare during the initial phase of therapy. Cardiovascular mortality signal versus allopurinol. | Azathioprine and mercaptopurine metabolism is decreased by febuxostat, risking significant toxicity — do not use together. | To prevent flares on initiation, give a prophylactic NSAID or colchicine for 2-3 weeks at minimum (longer per the standard 3-6 month recommendation). Use with caution or avoid in established cardiovascular disease. |
Agents not routinely available or not approved for this indication in Canada
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Pegloticase | Availability: Not marketed in Canada | Infusion reactions, anaphylaxis, gout flares on initiation. | A recombinant pegylated uricase used for refractory tophaceous gout in patients who have failed or cannot tolerate standard ULT. Not available in Canada. | |
| Benzbromarone | Availability: Special Access Program only | Hepatotoxicity (rare but serious), GI upset. | A uricosuric available in Canada only through Health Canada's Special Access Program, for patients not responsive to conventional uricosuric therapy. | |
| Anakinra | Specialist-directed protocol: 100 mg SC once daily, typically for 3 days | Injection-site reaction, headache, infection risk. | Avoid with concurrent infection. | An IL-1 receptor antagonist reserved for gout flares in patients who have failed or cannot take colchicine, NSAIDs, or corticosteroids. Not an approved indication in Canada — specialist-directed only. |
| Canakinumab | Specialist-directed protocol: 150 mg SC as a single dose | Injection-site reaction, back pain, arthralgia, headache, hypotension. | Avoid with concurrent infection. | An IL-1 beta inhibitor reserved for gout flares in patients who have failed or cannot take colchicine, NSAIDs, or corticosteroids. Not an approved indication in Canada — specialist-directed only. |
References
- 2020 American College of Rheumatology Guideline for the Management of Gout — Arthritis Care & Research, American College of Rheumatology (FitzGerald JD, Dalbeth N, Mikuls T, et al.). Arthritis Care Res (Hoboken) 2020;72(6):744-760
- 2016 updated EULAR evidence-based recommendations for the management of gout — Annals of the Rheumatic Diseases, European Alliance of Associations for Rheumatology (Richette P, Doherty M, Pascual E, et al.). Ann Rheum Dis 2017;76(1):29-42
- Use of HLA-B*58:01 genotyping to prevent allopurinol induced severe cutaneous adverse reactions in Taiwan: national prospective cohort study — BMJ (Ko TM, Tsai CY, Chen SY, et al., Taiwan Allopurinol-SCAR Consortium). BMJ 2015;351:h4848
- Fatal interaction between clarithromycin and colchicine in patients with renal insufficiency: a retrospective study — Clinical Infectious Diseases (Hung IF, Wu AK, Cheng VC, et al.). Clin Infect Dis 2005;41(3):291-300
- 2015 Gout Classification Criteria: An American College of Rheumatology/European League Against Rheumatism Collaborative Initiative — Arthritis & Rheumatology (Neogi T, Jansen TLTA, Dalbeth N, et al.). Arthritis Rheumatol 2015;67(10):2557-2568
- High versus low dosing of oral colchicine for early acute gout flare — Arthritis & Rheumatism (Terkeltaub RA, Furst DE, Bennett K, et al.). Arthritis Rheum 2010;62(4):1060-1068
- Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout — New England Journal of Medicine (White WB, Saag KG, Becker MA, et al., CARES Investigators). N Engl J Med 2018;378(13):1200-1210
- Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomised, open-label, non-inferiority trial — The Lancet (Mackenzie IS, Ford I, Nuki G, et al., FAST Study Group). Lancet 2020;396(10264):1745-1757
- Summary Safety Review — ULORIC (febuxostat): Assessing the potential risk of cardiovascular fatal outcomes — Health Canada. Health professional risk communication, November 4, 2019
- The safety and efficacy of allopurinol dose escalation in people with gout: a randomised controlled trial — Annals of the Rheumatic Diseases (Stamp LK, Chapman PT, Barclay ML, et al.). Ann Rheum Dis 2017;76(9):1522-1528
- Effects of colchicine on risk of cardiovascular events and mortality among patients with gout: a cohort study using electronic medical records linked with Medicare claims — Annals of the Rheumatic Diseases (Solomon DH, Liu CC, Kuo IH, et al.). Ann Rheum Dis 2016;75(9):1674-1679
Professional reference only. Apply clinical judgment and verify patient-specific decisions against current authoritative guidance and product information.