The Pathophysiology and Pharmaceutical Treatment of Gout FACULTY:

The Pathophysiology and
Pharmaceutical Treatment of Gout
Release Date: 11/21/2011
Expiration Date: 11/21/2014
FACULTY:
J. Dufton, M.D.
FACULTY AND ACCREDITOR DISCLOSURE
STATEMENTS:
Mr. Dufton has no actual or potential conflict of interest in relation to this program.
ACCREDITATION STATEMENT:
Pharmacy
PharmCon Inc is accredited by the Accreditation Council for Pharmacy
Education as a provider of continuing pharmacy education.
Program No.: 0798-0000-11-088-H04-P
Credits: 2 contact hour, 0.2 CEU
Nursing
Pharmaceutical Education Consultants, Inc. has been approved as a provider
of continuing education for nurses by the Maryland Nurses Association which is
accredited as an approver of continuing education in nursing by the American
Nurses Credentialing Center’s Commission on Accreditation.
Program No.: N-712
Credits: 2 contact hour, 0.2 CEU
TARGET AUDIENCE:
This accredited program is targeted pharmacists and nurses practicing in hospital and
community pharmacies. Estimated time to complete this monograph and posttest is 120
minutes.
DISCLAIMER:
PharmCon, Inc does not view the existence of relationships as an implication of bias or
that the value of the material is decreased. The content of the activity was planned to be
balanced and objective. Occasionally, authors may express opinions that represent
their own viewpoint. Participants have an implied responsibility to use the newly
acquired information to enhance patient outcomes and their own professional
development. The information presented in this activity is not meant to serve as a
guideline for patient or pharmacy management. Conclusions drawn by participants
should be derived from objective analysis of scientific data presented from this
monograph and other unrelated sources.
Program Overview:
To provide pharmacists and nurses with an understanding of the pathophysiology and
pharmaceutical treatment of gout..
OBJECTIVES:
After completing this program, participants will be able to:



Understand the prevalence and incidence of gout,
List pathophysiology, primary symptoms and main risk factors,
Identify the most commonly used pharmaceuticals and their potential side
effects.
The Pathophysiology of Gout
Gout is considered the most common type of inflammatory arthritis and is typically associated with a
reduction in quality of life for those who suffer from it.1 High levels of serum uric acid, termed
hyperuricemia, are a necessary prerequisite for the development of gout. As uric acid levels in the blood
serum rise and the saturation threshold is exceeded within bodily fluids, monosodium urate crystals
precipitate out of solution and become deposited in and around joints, especially peripherally located
synovial joints. Urate crystals are sharp, needle-like structures that become lodged within joint capsules,
cartilage, ligaments and tendons. The most commonly affected area is the first metatarsophalangeal joint,
often referred to as the first knuckle of the big toe.
Symptoms
Clinical symptoms of gout include severe pain (often described as “excruciating”), acute inflammation,
redness, fever as high as 102 °F with or without chills, long-term joint damage with successive bouts, and
deposits of the urate crystals (called tophi) on or under the surface of the skin, most notably within or on
the ears. Due to the inflammation and pain, affected joints typically lose significant range of motion and
stability. Weight-bearing becomes difficult or impossible. Light pressure, such as the weight of a single
bed sheet, can be too painful to bear for some sufferers during acute episodes. Modifications in physical
activity, posture, sleeping and footwear are often needed during acute gout attacks.
Gouty arthritis can develop very quickly, with the first episode often occurring in the middle of the night.
Gout attacks are characterized by a rapid onset and buildup of pain (usually within 2-4 hours). In men, the
initial gout attack is usually monoarticular, involving only one joint, although later attacks may be
polyarticular and involve multiple joints. In postmenopausal women, the attacks are commonly oligo- or
polyarticular and involve the proximal joint of the big toe and (in decreasing order of frequency) the
heels, knees, wrists, fingers and elbows.2 The natural course of untreated acute gout varies from several
hours to several weeks, although it typically subsides after 5-10 days only to come back weeks or months
later depending on lifestyle and dietary habits.3 In subsequent attacks, tophi lumps develop and might be
seen just under the skin in the outer ear, hands, feet, elbows or knees. Gout usually affects overweight
men beyond the age of 40 and with a family history of gout, but it can occur at any age of adulthood and
within women, especially those who are postmenopausal.
Prevalence and Incidence
Epidemiological evidence from the United States, United Kingdom, China and other countries suggests
that gouty arthritis is becoming more prevalent, especially in aged men. For example, research conducted
in the United States indicates that the prevalence of gout increased from 2.9 diagnosed cases per 1,000
people in 1990 to 5.2 diagnosed cases per 1,000 people ten years later in 1999.4 The group most notably
affected by gout in the United States is men older than 75 years. The incidence of self-reported gouty
arthritis also increased in the United States from the 1960s and was noted to be 8.4 cases per 1,000 people
in 1992.5
Epidemiological surveys conducted in the United Kingdom also suggest an increase in gout prevalence,
with 9.5 cases per 1,000 people reported in 1993.6 Subsequent studies conducted in the United Kingdom
from 2000 to 2005 found the prevalence of self-reported gout to be as high as 14 cases per 1,000 people.7
Random population surveys conducted in China suggest an increase in self-reported gout prevalence from
3.6 cases per 1,000 people in 2002 to 5.3 cases per 1,000 in 2004.8
Dufton – Pathophysiology and Treatment for Gout
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It should be noted that most of the research conducted on the prevalence of gout was based upon clinical
assessments, self-reports and medical record or database reviews. However, these are not as sensitive or
as specific as microscopic identification of monosodium urate crystals within inflamed joints which is
considered the “gold standard” for gout diagnosis.9 Identification of intracellular urate crystals in the
synovial fluid or tophus substantiates the diagnosis of gout, but it does not exclude other causes of joint
inflammation such as acute pseudogout, active rheumatoid arthritis, or in rare cases, septic arthritis.10
Crystal-induced arthritis can mimic septic arthritis in terms of severe pain, fever, high synovial white
blood cell count and other constitutional symptoms. Septic arthritis should be suspected in patients with
worsening synovitis despite treatment of suspected acute gout. Synovial fluid gram stain and culture are
critical in aiding with the diagnosis in such patients.
Several studies have also examined the incidence of gouty arthritis. For example, the Framingham Heart
Study, which followed over 5,000 people for almost three decades, discovered that the incidence of gout
per 1,000 people was 1.4 women and 4.0 men, indicating that gout is almost three-times more common in
men.11 In other studies, gout incidence was also higher in men than in women and the rates increased with
advancing age.
Risk Factors
Several risk factors have been identified for the development of gout including hyperuricemia.
Hyperuricemia, or high levels of uric acid in the blood serum, is considered the most essential factor in
the pathogenesis of gout. In a Taiwanese study, the prevalence of gout was over four times higher in men
who had been previously diagnosed with asymptomatic hyperuricemia.12 Uric acid precipitates out of
solution and forms urate crystals when it reaches a saturation threshold that is partially dependent on pH
levels and other biochemical factors.
Genetic factors are also fairly evident in gout, but gene expression is quite variable, which accounts for
the differences in an individual’s genotype and phenotype. Because the kidneys excrete the majority of
uric acid from the body, families with genetic conditions limiting kidney clearance often have a higher
incidence of gout.13 For example, a certain gene codes for human “urate transporter-1,” which is
important for controlling reabsorption of uric acid from the proximal tubules of the kidneys. As such,
urate transporter-1 is targeted by many drugs that influence serum uric acid levels in efforts to reduce the
prevalence of gout.
A direct link between gout and diet has been recognized for centuries, which is why gout has been labeled
the “rich man’s arthritis” for many years. In general, diets high in purines, which are found in abundance
in organ meats, cured meats, seafood, some vegetables, aged cheese, and red wine and beer, significantly
increase the risk of gout because the purines are metabolized into uric acid within the body. In scientific
studies, dietary consumption of meats and seafood was found to be associated with the highest risks of
gout, whereas consumption of certain dairy products such as milk appeared to offer protection.14 Other
identified risk factors include consumption of sugar-sweetened soft drinks, candy, and sugary
carbohydrates such as donuts, whereas other protective factors include consumption of caffeinated coffee
and high doses (greater than 1,500 mg daily) of vitamin C.15 Excessive alcohol consumption (seven or
more drinks within 48 hours) is a well-established trigger of acute gout attacks.16
Specific purine-rich foods to avoid or minimize in order to reduce the risk of acute gout attacks include
beef, liver, kidney, game meats, goose, pork, sweetbreads, anchovies, herring, sardines, mackerel,
mussels, crab, shrimp, lobster, caviar, mussels, mushrooms, yeast, asparagus, spinach, cauliflower, peas,
beans, lentils, most nuts and seeds, wheat, rye and essentially any form of alcohol.17
Dufton – Pathophysiology and Treatment for Gout
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Sluggish metabolism, obesity, hypertension and diabetes are also associated with gout. Amongst people
with gout, the prevalence of metabolic syndrome is about 2.5 times more common compared to those
without gout.18 The Framingham Heart Study identified obesity and high blood pressure as risk factors for
developing gout.11 Diuretic use is a significant risk factor for gout, but the relationship is somewhat
confounded because diuretic therapy is often recommended for hypertension, renal disease and cardiac
failure, which are also linked with gout. As such, there is uncertainty whether the diuretics or the disease
conditions contribute more to the pathophysiology of gout. Gout can also result from blood disorders or
cancers such as leukemia.
Gout and osteoarthritis often affect the same joints, such as the first metatarsophalangeal joints, the tarsal
joints of the ankle and the synovial joints of the knees, elbows and wrists.19 These findings suggest that
osteoarthritis may predispose one to urate crystal deposition and gout, but more research is needed to
explore this association before conclusions can be drawn.
Differential Diagnosis
Generalist physicians are often the first to see patients with gout and therefore they play a critical role in
the diagnosis and management of gouty arthritis. In a recent study, only 0.02 percent of gout was
diagnosed, treated and managed by rheumatologists (joint specialists), whereas family physicians
accounted for 77 percent of cases, subspecialists other than rheumatologists accounted for 18 percent and
general internists about 4 percent.20
In addition to other forms of arthritis, differential diagnoses for gout must include acute trauma. Fractures
of the big toe or other joints can be ruled out via radiographs, although sprains and strains can be more
problematic. “Turf toe” (hyperextension sprain of the ligaments surrounding the first metatarsophalangeal
joint) occurs from excessive running on artificial turf or walking on other substrates with inappropriate
shoes such as flip-flops. Turf toe mimics much of the symptomatology of gout in terms of pain and joint
dysfunction, but it does not involve fever or urate crystal deposits. Further, turf toe does not usually
exhibit the degree of inflammation and redness that a gouty toe does.
Complications
Properly treated, gout rarely poses a long-term health threat. Left untreated, gout can develop into a
painful and disabling chronic disorder. Chronic gout attacks can destroy cartilage and bone, causing
irreversible joint dysfunction and disability. A gout survey conducted in 2006 suggested that 66 percent
of people with gout considered the pain to be the worst they ever experienced, while an estimated 75
percent claimed that flare-ups made walking very difficult and about 70 percent reported trouble playing
sports or even putting on socks and shoes.18 If gout is not treated, tophi (chalky clumps of urate crystals)
can grow to the size of golf balls and cause a variety of problems in joints and organs. Kidney stones
occur in 10-40 percent of gout patients and about 25 percent of those with chronic hyperuricemia develop
kidney disease, which sometimes culminates in kidney failure.13 Although, it should be noted that in most
cases the kidney disease comes first and causes high concentrations of uric acid secondarily due to
reduced filtering. Other conditions that are associated with long-term gout include cataracts, dry eye
syndrome and lung complications.
Alternative Therapies
Non-pharmaceutical or “alternative” therapies for gout are not well investigated, but their popularity over
the years suggests some efficacy. However, herbs, supplements and tinctures that may be beneficial for
some people may be harmful for others. Common alternative strategies to combat gout include
Dufton – Pathophysiology and Treatment for Gout
Page 3
consumption of antioxidant-rich foods or strong antioxidant supplements such as vitamins C and E in
efforts to minimize joint tissue damage, eating sour cherries and cranberries or drinking their juices in
attempts to dissolve the urate crystals, avoiding purine-rich foods, reducing alcohol consumption, and
increasing purified water consumption to dilute the crystals and help flush them out of the body. To
combat pain and inflammation, non-pharmacological compounds commonly used include
methylsulfonylmethane (MSM), Harpagophytum procumbens (Devil’s claw), Uncaria tomentosa (Cat's
claw), Ananus comosus (bromelain) and Curcuma longa (turmeric).21 Acupuncture and homeopathic
tinctures are also utilized for pain and inflammation control, although no scientific studies have examined
their effectiveness for acute gout attacks. Alternating hot and cold compresses is a simple inflammation
control method that is backed by some research in regards to acute gouty arthritis.22
In conclusion, gout is the most common form of inflammatory arthritis and its prevalence and incidence
have risen in recent decades. Numerous risk factors for the development of gout in both men and women
have been established and include hyperuricemia, genetic factors, age, purine-rich diet, alcohol
consumption, sluggish metabolism, obesity, diuretic use, renal disease, hypertension and possibly
osteoarthritis. Gout can mimic other types of arthritis and joint injuries, so urate crystals from joint fluid
must be identified for accurate diagnosis. Alternative therapies have been used to combat gout for
centuries, although pharmaceutical treatment is the best researched and most utilized by modern
medicine. Untreated, gout can cause significant short-term and long-term disability.
The Pharmaceutical Treatment of Gout
The majority of patients who experience gout are cared for by their family physicians. Although both the
physician and patient may easily recognize that they are dealing with an acute gout attack, errors in
selecting the most appropriate medication and proper dose are common. The clinical stages of gout are
divided into the asymptomatic hyperuricemia stage, the intermittent acute flare-up stage and the chronic
tophi-forming stage.23,24 Treatment of gout usually commences after the first acute attack, especially if
podagra is involved. The aims of treatment are threefold: to alleviate the pain and inflammation
associated with acute attacks, to prevent future attacks and to decrease uric acid levels in the serum. As
such, anti-inflammatories, analgesics and urate-lowering drugs are typically deployed in combination to
combat gout.
The critical issues when starting drug therapy for acute gout are rapid initiation of the therapy, adequate
drug dosing and appropriate duration of therapy. The options available for the treatment of gout are
nonsteroidal anti-inflammatory drugs (NSAIDs), systemic and intra-articular corticosteroids, colchicine
and xanthine oxidase inhibitors.
1)
NSAIDs for the Treatment of Gout
In a patient without complications, NSAIDs are the preferred therapy for the treatment of acute gout
attacks. Combination therapy with NSAIDs and colchicine is used by 50-64 percent of rheumatologists
when treating acute gout attacks.25 NSAIDs reduce joint pain and improve joint function through antiinflammatory and analgesic properties, but they do not prevent the progression of disease. NSAIDs
mainly inhibit prostaglandins that are present in many cell types and responsible for the inflammation
response. Common over-the-counter NSAIDs include ibuprofen (Advil, Motrin, Midol), naproxen (Aleve,
Naprosyn) and aspirin. More powerful prescription NSAIDs include celecoxib (Celebrex), diclofenac
(Voltaren) and indomethacin (Indocin). Due to low-cost and convenience, ibuprofen is the most
commonly used NSAID for the symptoms of gout.26
Dufton – Pathophysiology and Treatment for Gout
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Ibuprofen is used to reduce inflammation, pain and fever, which are all common symptoms of acute gout
attacks. Ibuprofen works by inhibiting the enzyme cyclooxygenase (COX), which converts arachidonic
acid to prostaglandin H2 (PGH2). PGH2, in turn, is converted by other enzymes to several other
prostaglandins, which mediate pain, inflammation and fever, and to thromboxane A2, which stimulates
platelet aggregation and blood clot formation. Like most other NSAIDs, ibuprofen is considered a
nonselective COX inhibitor; that is, it inhibits two isoforms of cyclooxygenase, COX-1 and COX-2. The
analgesic, antipyretic, and anti-inflammatory activity of ibuprofen appears to be achieved mainly through
inhibition of COX-2, whereas inhibition of COX-1 would be responsible for unwanted effects on platelet
aggregation and the gastrointestinal system.27
Typical adult dosage of ibuprofen for gout (as well as for osteoarthritis and rheumatoid arthritis) is 400800 mg orally every 6-8 hours up to a maximum daily dose of 3,200 mg based on patient response and
tolerance.28 Treating physicians may decide to prescribe a higher initial dose of ibuprofen to stop an acute
gout attack, followed by lower daily doses to prevent future attacks. High doses and long-term use of
ibuprofen, like all NSAIDs, can cause significant side effects.
Ibuprofen may cause life-threatening heart or circulation problems such as heart attack or stroke,
especially with long-term use. Ibuprofen should not be administered to gout patients just before or after
heart bypass surgery as it can lead to chest pain, weakness, shortness of breath, slurred speech or
problems with vision or balance. Ibuprofen can also cause serious effects on the stomach or intestines,
including bleeding and perforation. These conditions can be fatal and can occur without warning,
especially in older adults. Risk factors for gastrointestinal complications include history of ulcer,
concomitant use of glucocorticoids or anticoagulants, cardiovascular disease, dosage, and age greater than
75 years. Symptoms of gastrointestinal bleeding include black, bloody or tarry stools, and coughing up
blood or vomit that looks like coffee grounds. Patients with a history of stomach ulcers or ulcerative
colitis should be especially cautious with ibuprofen or other NSAID use. It should be noted that high-dose
H2 blockers and proton-pump inhibitors are “gastro-protective” agents, helping decrease NSAIDassociated gastrointestinal ulcerations.
Other serious side effects caused by ibuprofen and other NSAIDs include renal insufficiency and elevated
liver enzymes. Renal complications are increased in patients with preexisting renal disease, congestive
heart failure, coronary artery disease, cirrhosis, those receiving diuretics and the elderly. Ibuprofen and
other NSAIDs are not recommended in patients with edema, congestive heart failure, nephritic syndrome,
cirrhosis, or high levels of serum creatinine.
The FDA has categorized ibuprofen in category D for pregnancy. As such, taking ibuprofen during the
last 3 months of pregnancy may harm the unborn baby. It is not known whether ibuprofen passes into the
breast milk or if it can harm a nursing baby.
Allergic reaction to ibuprofen is not uncommon. Signs of an allergic reaction include hives, difficulty
breathing, facial, tongue and throat swelling, headache and dizziness. Less serious ibuprofen side effects
may include upset stomach, mild heartburn, diarrhea, constipation, bloating, nervousness, blurred vision
and tinnitus (ringing in the ears).
Dufton – Pathophysiology and Treatment for Gout
Page 5
2)
Corticosteroids for the Treatment of Gout
Corticosteroids are a class of steroid hormones that are produced naturally in the adrenal cortex.
Corticosteroids are involved in a wide range of physiologic actions such as stress response, immune
response and regulation of inflammation, among others behaviors. Glucocorticoids are a type of
corticosteroid that interact with several inflammatory processes, including antigen presentation to T-cells,
reduction in prostaglandin and leukotriene synthesis, migration of monocytes, lymphocytes and
neutrophils, as well as macrophage and fibroblast production of cytokines, which all combine to hamper
inflammatory and autoimmune responses.29 Common glucocorticoids used for the treatment of gout
include methylprednisolone (Medrol) and prednisone (Deltasone, Meticorten, Orasone) which are
categorized as Group-A hydrocortisones based on their chemical structures. Allergic reactions to one
member of a group typically indicate an intolerance of all members of the group, which is known as the
“Coopman classification”.30
Synthetic glucocorticoids are used in the treatment of joint pain and inflammation and can be taken orally
or injected directly into an arthritic joint capsule. Glucocorticoids not only display anti-inflammatory
properties, but they reduce the occurrence and progression of joint damage. For example, oral
prednisolone in combination with disease-modifying anti-rheumatic drugs (DMARDs) and NSAIDs
significantly decreases joint erosions.29 Glucocorticoids as a monotherapy are generally reserved for gout
sufferers who cannot take either NSAIDs or colchicine due to allergy or other contraindications.
High doses of oral steroids, such as prednisone and methylprednisolone, are commonly prescribed to
suppress acute gout flare-ups. Daily doses less than 7.5 mg are well tolerated to control pain long-term,
but ACR guidelines recommend daily doses below 5 mg due to glucocorticoid side effects. Prednisone
can be given at high doses of 35 mg for 1-3 days and then tapered over 1-2 weeks, which reduces the
likelihood of side effects. In a randomized controlled trial, 35 mg of prednisolone daily for 5 days was
found to be as effective as 500 mg twice daily of naproxen in patients with acute gout.29 Further, the
patients with gout did not report any serious adverse effects from the short-term use of systemic
corticosteroids. Intramuscular, intravenous and intra-articular injections may also be used, although joints
should not be injected more than 3 times yearly.31
The long-term side effect profile for corticosteroids includes osteoporosis, suppression of the
hypothalamus, pituitary and adrenal glands, Cushing’s syndrome, weight gain, emotional instability,
depression, hypertension, erectile dysfunction, myopathy, impaired wound healing, reduced infection
fighting ability, gastritis, colitis, glucose intolerance, diabetes mellitus and skin atrophy. Clinical and
experimental evidence indicates that corticosteroids can cause permanent eye damage by inducing central
serous retinopathy, which can also manifest as cataracts and glaucoma.32 Calcium and vitamin D
supplementation is recommended in the prevention for those on corticosteroids. In regards to pregnancy,
corticosteroids display a small but significant teratogenic effect, causing a few birth defects per 1,000
pregnant women treated.33
3)
Colchicine for the Treatment of Gout
Colchicine is a very common generic drug used to treat gout and it was originally extracted from the
Colchicum autumnale plant (meadow saffron). Oral colchicine has been used for over 40 years as an
unapproved drug with no prescribing information, dosage recommendations, or drug interaction warnings
approved by the U.S. Food and Drug Administration until July of 2009. Colchicine in combination with
probenecid (which improves the kidneys' ability to remove uric acid from the body) was approved by the
FDA prior to 1982, but it wasn’t until 2009 that it was approved as a monotherapy for the treatment and
prophylaxis of acute gout flares.34 Despite its relatively high toxicity, many physicians still use colchicine
Dufton – Pathophysiology and Treatment for Gout
Page 6
at dosages of 0.6 mg every 1-2 hours for acute gout attacks until the patient is pain-free or diarrhea
ensues. The FDA-approved dose of oral colchicine (Colcrys) for the treatment of acute gout is a single 1.2
mg dose followed by a 0.6 mg dose (for a total of 1.8 mg) within 12 hours from the onset of symptoms.35
Research suggests that low-dose colchicine is effective for acute gout if started within 12 hours of
symptoms, although there is a need to avoid colchicine or adjust the dose in patients with renal or hepatic
impairment and/or those who are taking drugs that interact with colchicine.36
Colchicine inhibits microtubule polymerization by binding to tubulin, one of the main constituents of
microtubules. Availability of tubulin is essential to mitosis, thus colchicine essentially acts as a “mitotic
poison.” In addition to inhibiting mitosis, colchicine also inhibits neutrophil motility and activity, leading
to a net anti-inflammatory effect. Colchicine is primarily eliminated by the hepatobiliary tract, although
renal excretion accounts for 10-20 percent of colchicine elimination in patients with normal kidney
function.35
Colchicine is often recommended when a patient is unable to take NSAIDs such as ibuprofen. However,
the drug’s effectiveness is usually offset by intolerable side effects. Common side effects of colchicine
usage include gastrointestinal upset, nausea, vomiting, diarrhea and neutropenia, although high doses can
also damage bone marrow and lead to anemia, which is related to the hyper-inhibition of mitosis. Primary
side effects associated with all mitotic inhibitors are muscle damage and peripheral neuropathy, or
numbness and tingling in the hands and feet due to peripheral nerve damage.
Symptoms of colchicine poisoning start within 2-5 hours after the toxic dose has been ingested and
include burning in the mouth and throat, fever, vomiting, diarrhea, abdominal pain and kidney failure.
Onset of multiple-system organ failure may occur within 24-72 hours. There is no specific antidote for
colchicine, although various treatments do exist and recovery may begin within 6-8 days.37
4)
Xanthine Oxidase Inhibitors for Gout
It is important to note that resolution of the acute attack by controlling inflammation and pain is not a cure
for gout. As such, employing urate-lowering therapy in efforts to reduce serum urate levels below the
threshold of super-saturation is essential in allowing the dissolution of existing urate crystals in the joints
and to stop the deposition of new crystals. Medication that blocks uric acid production is classified as
xanthine oxidase inhibitors, which include allopurinol (Zyloprim, Aloprim) and febuxostat (Uloric).
Xanthine oxidase inhibitors work by non-competitively blocking the molybdenum pterin center which is
the active site on xanthine oxidase. Xanthine oxidase is needed to oxidize both hypoxanthine and xanthine
to uric acid in the body. As such, allopurinol and febuxostat inhibit xanthine oxidase, which reduces
production of uric acid.
There is evidence to suggest that if serum uric acid levels are maintained at or below 6.0 mg/dL, then gout
attacks can be reduced, crystals can be depleted from joints, tophi deposits can be reduced and their
recurrence prevented.38,39,40 Urate-lowering therapy is most effective when initiated about 2-4 weeks after
resolution of the first acute gouty attack and should be continued long-term if not lifelong. Urate-lowering
therapy should not be initiated during acute gout attacks, although it should be continued if administered
for previous attacks. It is important to emphasize that urate-lowering therapy should not be stopped once
initiated because intermittent usage can lead to recurrent gout attacks.41
Dufton – Pathophysiology and Treatment for Gout
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When starting urate-lowering therapy, or even prior to, it is important to also initiate anti-inflammatory
agents such as low-dose oral colchicine, glucocorticoids or NSAIDs such as ibuprofen because xanthine
oxidase inhibitors do not make a significant impact on inflammation, pain or fever.
The most commonly used urate-lowering drug is allopurinol, which was approved by the FDA in 1966
and normally used in a preventative capacity for the chronic tophi-forming stage of gout. Allopurinol is
approved at daily doses of 100-800 mg daily, although the standard dose of allopurinol that achieves
serum urate levels below 6.0 mg/dL is at least 300 mg daily. In the United States, 95 percent of dosing is
≤ 300 mg daily, which achieves the target urate level in less than half of cases.42
The main limitation for the use of allopurinol is the concern of increased toxicity in patients with renal
failure.43 Clinicians are also concerned about the more common severe side effects of allopurinol use,
such as rash formation with eosinophilia, low blood counts, systemic symptoms and Stevens–Johnson
syndrome.44
Febuxostat is a fairly new xanthine oxidase inhibitor that was approved by the FDA in February of 2009,
and it is quickly becoming a leading choice in the treatment of chronic gout and hyperuricemia.
Febuxostat is especially valuable in patients with allopurinol hypersensitivity and in patients with kidney
disease. Unlike allopurinol, febuxostat inhibits oxidized as well as reduced forms of xanthine oxidase
because it cannot be easily displaced from the molybdenum pterin site. Further, febuxostat is metabolized
mainly by the liver with little intact drug excreted through the kidneys. As such, febuxostat is much
friendlier on the kidneys compared to allopurinol.
The CONFIRMS trial presented at the 73rd Annual Scientific Meeting of the American College of
Rheumatology showed that febuxostat 80 mg was superior to febuxostat 40 mg and allopurinol 300/200
mg at achieving a serum urate level < 6.0 mg/dL.45 Febuxostat 40 mg and allopurinol 300/200 mg were
comparable in patients with normal renal function, but in patients with mild/moderate renal impairment,
both febuxostat doses were more efficacious than allopurinol and equally safe.
The reported side effects of febuxostat considered relatively common included rash, nausea, diarrhea,
headache, joint achiness and reduced liver function as measured by hepatic serum enzyme levels.46
In conclusion, the primary aims of the treatment of gout are threefold: to alleviate the pain and
inflammation associated with acute attacks, to prevent future attacks and to decrease uric acid levels in
the blood serum. The mainstays of acute gout management are NSAIDs, colchicine and systemic or intraarticular corticosteroids. NSAIDs are preferable to colchicine because they cause fewer side effects.
Successful treatment occurs with the prompt initiation of high-dose, short-term NSAIDs such as
ibuprofen. Since many gout patients have conditions that preclude the use of NSAIDs or colchicine,
systemic glucocorticoids are commonly used to treat acute gout attacks. Intra-articular injections of
glucocorticoids are appropriate with mono- or oligoarticular involvement. Urate-lowering therapy with
the use of xanthine oxidase inhibitors helps reduce serum urate levels and lower the risk of recurrent
flare-ups and tophi formation.
Dufton – Pathophysiology and Treatment for Gout
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