The Pathophysiology and Pharmaceutical Treatment of Gout · Gout attacks are characterized by a...

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.

Dufton – Pathophysiology and Treatment for Gout Page 1

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


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


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


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 anti-

inflammatory 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


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 400-

800 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 NSAID-

associated 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).


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


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


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 intra-

articular 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.


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