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Drugs 2004; 64 (21): 2399-2416

REVIEW ARTICLE 0012-6667/04/0021-2399/$34.00/0


2004 Adis Data Information BV. All rights reserved.
Management of Acute and Chronic
Gouty Arthritis
Present State-of-the-Art
Naomi Schlesinger
Department of Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood
Johnson Medical School, New Brunswick, New Jersey, USA
Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2400
1. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2401
1.1 Incidence. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2401
1.2 Prevalence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2401
1.3 Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2402
2. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2402
3. Treatment Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2403
4. Nonpharmacological Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2403
5. Pharmacological Treatment of Acute Gouty Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2404
5.1 Colchicine and NSAIDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2404
5.1.1 Oral Colchicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2404
5.1.2 Intravenous Colchicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2405
5.1.3 Oral NSAIDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2405
5.2 Intra-articular Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2406
5.3 Systemic Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2406
5.4 Corticotropin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2407
5.5 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2408
6. Pharmacological Treatment of Chronic Gouty Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2408
6.1 Uricosuric Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2409
6.1.1 Probenecid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2409
6.1.2 Sulfinpyrazone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2409
6.1.3 Benzbromarone. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2409
6.1.4 Micronised Fenofibrate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2409
6.1.5 Losartan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2410
6.2 Uricostatic Drugs (Xanthine Oxidase Inhibitors) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2410
6.2.1 Allopurinol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2410
6.2.2 Oxipurinol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2410
6.2.3 Febuxostat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2411
6.3 Comparing Uricosuric Drugs and Allopurinol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2411
6.4 Uricolytic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2412
6.4.1 Urate Oxidase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2412
6.5 Urate-Lowering Drugs: Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2412
7. Colchicine Prophylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2412
8. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2413
2400 Schlesinger
There are three stages in the management of gout: (i) treating the acute attack; Abstract
(ii) lowering excess stores of uric acid to prevent flares of gouty arthritis and to
prevent tissue deposition of urate; and (iii) providing prophylaxis to prevent acute
flares. It is important to distinguish between therapy to reduce acute inflammation
in acute gout and therapy to manage hyperuricaemia in patients with chronic
gouty arthritis.
During the acute gouty attack nonpharmacological treatments such as topical
ice and rest of the inflamed joint are useful. NSAIDs are the preferred treatment in
acute gout. The most important determinant of therapeutic success is not which
NSAID is chosen, but rather how soon NSAID therapy is initiated. Other
treatments include oral and intravenous colchicine, intra-articular and systemic
corticosteroids, and intramuscular corticotropin.
Optimal treatment of chronic gout requires long-standing reduction in serum
uric acid. The urate-lowering drugs used to treat chronic gout are the uricosuric
drugs, the uricostatic drugs, which are xanthine oxidase inhibitors, and the
uricolytic drugs. Xanthine oxidase inhibitors such as allopurinol, oxipurinol and
febuxastat should be used as first-line treatment in patients with renal calculi,
renal insufficiency, concomitant diuretic therapy and ciclosporin (cyclosporine)
therapy, and urate overproduction. Uricosuric drugs include probenecid, benz-
bromarone, micronised fenofibrate and losartan. They are the urate-lowering
drugs of choice in allopurinol-allergic patients and underexcretors with normal
renal function and no history of urolithiasis. The use of recombinant urate oxidase
in patients with chronic gout is limited by the need for parenteral administration,
the potential antigenicity and production of anti-urate oxidase antibodies, and
declining efficacy.
The effectiveness of colchicine prophylaxis as an isolated therapy is still to be
confirmed by placebo-controlled trials. Another issue is prophylaxis with
NSAIDs. There are no comparative studies with colchicine.
Through the centuries, gout has been considered important to note that a sustained elevation of SUA
as a disease of the wealthy that was associated with is virtually essential for the development of gout, but
rich food and wine. It is the most common in- by itself is insufficient to cause the disease. The
flammatory arthritis in men over 40 years. There are majority of patients with hyperuricaemia never de-
four clinical stages: (i) asymptomatic hyperuri- velop symptoms associated with uric acid excess.
caemia; (ii) acute gouty arthritis; (iii) intercritical The risk of damage beyond the musculoskeletal
gout (intervals between acute attacks); and (iv) system from protracted hyperuricaemia or recurrent
chronic tophaceous gout. Demonstration of intra- attacks of gout is small. Urolithiasis is uncommon,
articular monosodium urate (MSU) crystals is ne- with the annual incidence being approximately 1%
cessary to establish a definitive diagnosis of gouty in patients with gout and 0.3% in those with other-
arthritis. wise asymptomatic hyperuricaemia. In patients with
The serum uric acid (SUA) level is the single gout the incidence of uric acid stones was 23% in
most important risk factor for developing gout.
[1]
those with urinary uric acid levels <600 mg/day
The SUA level is elevated when it exceeds 6.4 mg/ compared with 50% in those with urinary uric acid
dL, the limit of solubility of MSU in serum at 37C. levels >1000 mg/day.
[2]
The urinary solubility of
In the Normative Aging Study, the 5-year cumula- uric acid depends on its concentration in urine and
tive risk of gout development in subjects whose the urinary pH. At a pH <5.5 nearly 100% of uric
SUA level was <7 mg/dL was 0.6% and in those acid exists in an undissociated form. The three
whose level was 10 mg/dL was 30.5%.
[1]
It is mechanisms responsible for uric acid-related stone
2004 Adis Data Information BV. All rights reserved. Drugs 2004; 64 (21)
Management of Gouty Arthritis 2401
formation are an acidic urinary milieu,
[1]
dehydra- any site. The most common sites for the tophi to
tion
[2]
and hyperuricosuria.
[3]
One or more of these appear are digits of the hands and feet as well as in
factors may be found in patients with uric acid- the olecranon bursa. Tophi of the helix or antihelix
related calculi. Persistently acidic urine (i.e. pH of the ear are classical but less common. Tophi may
<5.5) is the most important factor predisposing pa- be associated with a destructive deforming arthritis
tients with gout to the formation of uric acid stones. and may ulcerate, in which case secondary infection
MSU may initiate calcium oxalate stone formation may be a problem.
by the induction of heterogeneous nucleation or by
1. Epidemiology
absorption of certain inhibitors. Patients with
hyperuricosuric calcium stones have a urinary pH of
>5.5.
[2]
1.1 Incidence
Wortmann
[3]
uses the analogy gout is like
There is little data on the incidence of gout; it is
matches. Everyone has uric acid in his or her blood;
difficult to accurately measure incidence and preva-
high levels of uric acid may cause gout. When too
lence of a disease that is episodic and recurrent.
much uric acid accumulates around a persons
In Sudbury, MA, USA the estimated annual inci-
joints, the uric acid acts like a match. An acute gout
dence of gout in the 1960s was 1 per 1000.
[8]
Campi-
attack may be likened to setting the joint on fire.
[3]
on et al.,
[1]
using data from the Normative Aging
Acute gouty arthritis is characterised by rapid onset
Study, prospectively studied the incidence of gouty
and build-up of pain. During an acute gouty attack
arthritis in relation to SUA level. More than 2000
the patient endures exquisite pain associated with
healthy men born between 1884 and 1945 were
warmth, redness, swelling and decreased range of
included in this study and followed up for a mean of
motion of the affected joint. The initial episode is
14.9 years. When SUA levels were >9 mg/dL, the
usually monoarticular. The first metatarsopha-
annual incidence of gout was 4.9% and the cumula-
langeal joint is the initial one involved in approxi-
tive incidence of the first gouty attack was 22% in 5
mately half of the patients. Other joints involved (in
years. For those with SUA levels of 78.9 mg/dL,
decreasing order of frequency) are insteps, heels,
the cumulative incidence was 3% at 5 years.
knees, wrists, fingers and elbows.
[4]
In his classical
description of the onset of an acute gouty attack,
1.2 Prevalence
Thomas Sydenham (London, 1683), a long-sufferer
from gout, wrote: The victim goes to bed and
Gouty arthritis is the most common inflammatory
sleeps quietly. About two in the morning he is
arthritis in men over 40 years.
[9]
The National Health
awakened by a pain in the great toe; rarely in the
Interview Survey from 1983 to 1985 determined the
heel, ankle or instep. The pain resembles that of a
prevalence rate of self-reported gout to be 13.6 cases
dislocated bone[It] becomes so exquisitely pain-
per 1000 men and 6.4 cases per 1000 women. These
ful as not to endure the weight of clothes nor the
numbers reflect an approximate 3-fold increase in
shaking of the room by a person walking in.
[5]
the prevalence of gout since 1969.
[10]
In contrast,
Systemic symptoms and sign of fatigue, fever and
cases of physician-diagnosed gout suggest a consist-
chills may accompany the acute gouty arthritis. The
ently lower prevalence rate: 5.06.6 cases per 1000
natural course of the untreated gouty arthritis varies
men and 1.03.0 cases per 1000 women.
[11,12]
A
from episodes that last several hours to several
higher prevalence of hyperuricaemia and gout has
weeks.
been reported in younger patients who have had
renal transplants and were treated with ciclosporin Chronic tophaceous gout usually develops after
(cyclosporine).
[13,14]
The prevalence of gout among 10 years or more of acute intermittent gout, although
renal transplant patients is estimated at 213%.
[14]
rarely patients have presented with tophi as their
initial manifestation of the disease.
[6]
In transplant The prevalence of gout in different geographical
patients tophi are more common and may occur regions has been well documented. The results sug-
within 5 years or less of renal transplantation.
[7]
gest that environmental, racial and hereditary differ-
Tophi appear as firm swellings and may appear at ences may influence the development of gout. As in
2004 Adis Data Information BV. All rights reserved. Drugs 2004; 64 (21)
2402 Schlesinger
the US,
[15]
gout is on the increase in New Zea- diagnosis. Wallace et al.
[27]
published preliminary
land.
[16]
Filipinos living in the US have a higher criteria for the diagnosis of gout in 1977. Thirteen
frequency of hyperuricemia and gout than other US minor criteria for the diagnosis of acute gout were
men.
[17]
It has recently become clear that the season- described: more than one attack of acute arthritis;
al variation in acute gout attacks is remarkably simi- maximum inflammation developed within a day;
lar around the world, in geographical areas that monoarthritis; redness over joints; painful/swollen
differ widely and over many years.
[18]
first metatarsophalangeal joint; unilateral first
metatarsophalangeal joint attack; unilateral tarsal
1.3 Pathophysiology
joint attack; tophus; hyperuricaemia; asymptomatic
swelling within a joint on radiograph; subcortical
Urate oxidase, an end product of purine metabol-
cysts without erosions on radiograph; MSU crystals
ism, is an enzyme that converts uric acid to allantoin
in synovial fluid during attack; and synovial fluid
and is lacking in humans. The solubility of MSU is a
culture negative for organism during attack. Six of
direct function of temperature. At 37C the maxi-
13 minor criteria or one major criteria (MSU crys-
mum solubility of urate in physiological saline is
tals in synovial fluid or tophus) are required to make
6.8mg per 100mL, but at 30C it is only 4.5mg per
the diagnosis of gout by these preliminary criteria.
100mL.
[19]
If SUA concentration is increased for a
sustained period of time, MSU will come out of
solution to form crystals. Micro tophi will subse-
quently form, particularly in the cooler parts of the
body such as distal extremities, olecranon bursa and
ears. Sustained hyperuricaemia is a risk factor for
acute gouty arthritis, tophaceous gout and uric acid
nephrolithiasis. However, most patients with
hyperuricaemia will never have an attack of gout
and no treatment is required, although it is prudent
to determine the cause of hyperuricaemia and cor-
rect it if possible.
[20]
Uric acid production is increased after puberty in
males and after menopause in females. The predom-
inant cause of hyperuricaemia in most patients is
under-secretion of urate by the kidneys. Lower
clearance of urate is seen in all gout patients com-
pared with normal controls.
[21]
The main causes of
hyperuricaemia are listed in table I.
2. Diagnosis
During the 1960s, McCarty and Hollander
[22]
de-
scribed the currently accepted method for establish-
ing a definite diagnosis of gout: needle aspiration of
the acutely inflamed joint or suspected tophus. Even
when clinical appearance strongly suggests gout,
diagnosis has to be confirmed by needle aspira-
tion.
[23]
MSU crystals can be observed in >95% of
patients experiencing attacks of acute gouty arthri-
tis.
[24]
In some asymptomatic patients, MSU crystals
are also detected in joints in which there is no
inflammation
[25,26]
and this is also felt to confirm the
Table I. Causes of hyperuricaemia
Increased uric acid production
Genetic causes
enzymatic defects
hypoxanthine-guanine phosphoribosyl transferase deficiency
(Lesch-Nyhan syndrome)
phosphoribosylpyrophosphate synthetase overactivity
glucose-6-phosphatase deficiency (von Gierkes disease)
fructose 1-phosphate aldolase deficiency
Acquired causes
high purine diet/obesity
hypertriglyceridaemia
alcohol (ethanol) consumption
myeloproliferative disorders
lymphoproliferative disorders
chemotherapy
psoriasis
Reduced uric acid excretion
Genetic causes
polycystic kidney disease
Downs syndrome
Acquired causes
hypertension, chronic renal failure (any aetiology)
drugs (ciclosporin [cyclosporine], thiazides, furosemide
[frusemide] and other loop diuretics, ethambutol,
pyrazinamide, low-dose aspirin [acetylsalicylic acid],
levodopa, nicotinic acid)
metabolic/endocrine abnormalities: lactic acidosis, ketosis,
hypothyroidism, hyperparathyroidism
lead intoxication
postoperative dehydration or starvation
sarcoidosis
toxaemia of pregnancy
2004 Adis Data Information BV. All rights reserved. Drugs 2004; 64 (21)
Management of Gouty Arthritis 2403
3. Treatment Overview Many patients with gout are overweight and
weight reduction through gradual caloric restriction
and exercise can enhance renal excretion of urate When considering treatment for gouty arthritis
and lowering of SUA level.
[33,34]
An observational avoidance of factors that may lessen development of
acute gouty attacks must be stressed. It is important study followed up patients with gout on a diet mod-
to distinguish between therapy to reduce acute in- erately decreased in calories and increased in pro-
flammation in acute gout and therapy to manage tein.
[34]
The mean SUA level decreased by 18% after
hyperuricaemia in patients with chronic gouty ar- 4 months of dietary intervention. This was accompa-
thritis. Current treatment for acute and chronic gout nied by a 67% reduction in monthly gouty attack
is based more on practitioners experience than on frequency. The investigators recommended re-eval-
evidence-based medicine.
[27-29]
uation of the current dietary recommendations for
There are three stages in the management of gout: patients with gout. They advocated limitation of
(i) treating the acute attack; (ii) lowering excess carbohydrate intake, an increased proportional in-
stores of uric acid to prevent flares of gouty arthritis take of protein and the use of unsaturated fat since
and to prevent tissue deposition of MSU crystals; they all enhance insulin sensitivity and, therefore,
and (iii) providing prophylaxis to prevent acute may promote a reduction in SUA. They suggested
flares. that a lowered insulin resistance results in increased
uric acid clearance from the renal tubule as a result
of stimulation by insulin of tubular ion exchange.
4. Nonpharmacological Treatment
An alcohol-restricted diet in patients with gout is
Gout is a metabolic disorder. It is influenced by
of importance. Alcohol consumption is closely asso-
dietary factors, including overeating, obesity, alco-
ciated with hyperuricaemia and gout. It is estimated
hol (ethanol) abuse, and hyperlipidaemia and insulin
that half of patients with gout drink excessively.
[35]
resistance syndrome. Avoiding factors that may
A number of mechanisms have been implicated in
contribute to the development of gout among
the pathogenesis of alcohol-induced hyperuri-
asymptomatic hyperuricaemic patients may reduce
caemia. Acute alcohol excess may cause temporary
gouty attacks. Avoiding diuretics, weight gain and
lactic acidaemia, reduced renal urate excretion and
alcohol consumption may lead to a decrease in
hyperuricaemia, whereas long-term alcohol intake
gouty arthritis. In a population survey conducted in
stimulates purine production by accelerating the
19912 in Kin Hu Kinmen, Taiwan
[30]
alcohol con-
degradation of adenosine triphosphate to adenosine
sumption and central obesity were found to be inde-
monophosphate via the conversion of acetate to
pendent predictors of gout among hyperuricaemic
acetyl coenzyme A in the metabolism of alcohol.
[35]
patients, irrespective of SUA level. In a prospective
In addition, people who binge tend to forget to take
study of 233 asymptomatic hyperuricaemic men,
[31]
their urate-lowering drugs.
SUA level, alcohol consumption, use of diuretics
Joint motion may increase inflammation due to
and excessive weight gain were independent factors
experimental gouty arthritis, whereas rest of affect-
affecting the onset of gout.
ed joints may aid in its resolution.
[36]
Less med-
The main approaches to dietary measures in gout
ication is needed if the patient can rest the affected
are the traditional low purine, low protein, alcohol
joint for 12 days.
[37]
restricted diet versus a weight-reducing, and purine
unlimited, calorie- and carbohydrate-restricted diet Cold applications may be a useful adjunct to
with increased proportional intake of protein and treatment of acute gouty arthritis. In a prospective
unsaturated fat. An observational study found that a randomised trial, patients with acute gouty arthritis
strict purine-free diet will reduce the SUA level by treated with topical ice had a greater reduction in
1520%.
[32]
However, a rigid purine-free diet can pain (p = 0.021), joint circumference and synovial
rarely be sustained for a long period of time. Moder- fluid volume compared with the control group.
[38]
In
ation in dietary purines rather than a strict purine- an animal study, heat application to an inflamed
free diet may be helpful.
[33]
joint exacerbated the inflammation.
[39]
2004 Adis Data Information BV. All rights reserved. Drugs 2004; 64 (21)
2404 Schlesinger
Table II. Treatment of acute gout
Confirm diagnosis by joint aspiration: intracellular monosodium urate crystals in synovial fluid
Initial treatment with NSAIDs, unless risk factors for their use: age >65 years (relative risk); creatinine clearance <50 mL/min; poorly
controlled congestive heart failure; history of or active peptic ulcer disease; anticoagulation therapy; hepatic dysfunction. NSAIDs should
be used early in the attack. Higher doses need to be used in the first 2448 hours. It does not matter which NSAID is used
If one to two joints are involved, intra-articular corticosteroid treatment is beneficial
In severe oligo- or polyarticular gouty attack or if NSAIDs are not tolerated or contraindicated, use systemic corticosteroids (7- to 14-day
taper). Parenteral, intramuscular or intravenous corticosteroids or corticotropin may be helpful, especially in renal failure
Oral colchicine should be used within 2448 hours of onset of an acute attack. Colchicine should be used cautiously because of its
toxicity. Intravenous colchicine should probably not be used for treatment of acute gout
Do not treat hyperuricaemia during the acute attack
5. Pharmacological Treatment of Acute pected to interfere with many leucocyte functions,
Gouty Arthritis including diapedesis (ameboid movement),
mobilisation, lysosomal degranulation and, most
Table II provides an overview of the treatment
importantly, leucocyte chemotaxis. These effects
for acute gout.
may be mediated at least in part by a decrease in the
expression of adhesion molecules on neutrophil
5.1 Colchicine and NSAIDs
membranes.
The absorption of oral colchicine is rapid but
Colchicine and NSAIDs are effective in the treat-
incomplete (time to maximum concentration = 2
ment of acute gout. In recent American reviews of
hours; bioavailability = 2550%). However, absorp-
gout treatment NSAIDs and colchicine are stated to
tion can be highly variable. The onset of action
be effective alternatives for treatment of acute gouty
(relief of gout pain) is 8 hours when given intra-
arthritis.
[40,41]
venously and approximately 24 hours when given
5.1.1 Oral Colchicine orally. The terminal half-life of colchicine after an
oral dose in patients with normal renal and hepatic Colchicine is an alkaloid derived from the au-
functions is 9 hours, whereas in patients with renal tumn crocus, Colchicum autumnale. Colchicum in
failure it is two to three times the normal (about 24 the form of extracts from the bulb of the meadow
hours) and in cirrhotic patients with renal failure it is saffron (Colchicum autumnale) was known from
ten times the normal (approximately 4 days).
[47]
antiquity, though it came into widespread use only
around 1800.
[5,42]
Padanius Dioscorides, a Greek Only one placebo-controlled trial of colchicine
surgeon in the Roman army during the rule of Nero treatment in acute gout has been performed to
(AD5468), first described the meadow saffron in date.
[48]
All other data reported were accumulated by
his influential De Materia Medica, a pharmacopeia reviews rather than by prospective studies. In this
that systematically described about 600 plants.
[43]
placebo-controlled study, Ahern et al.
[48]
studied 43
Throughout the years, many historians, physicians patients (40 men, 3 women); 22 patients received
and pharmacopeias have noted the beneficial effects colchicine 1mg then 0.5mg every 2 hours until com-
of Colchicum extracts for the treatment of gout. It plete response or toxicity and 21 patients were in the
was not until 1820 that colchicine, the pharmacolog- placebo group. No NSAIDs were used during the
ically active constituent of the plant, was isolated by study. All patients had MSU crystals in the synovial
the French chemists Pelletier and Caventon.
[44]
The fluid. In this placebo-controlled study, two-thirds of
absolute configuration was determined by Corrodi the colchicine-treated patients improved after 48
and Hardegger
[45]
in 1955. hours but only one-third of the patients receiving
The precise mechanism by which colchicine re- placebo demonstrated similar improvement. Oral
lieves the intense pain of gout is not known. How- colchicine was shown to be efficacious in two-thirds
ever, it is believed that the major relief of pain of patients presenting with acute gout. It was more
involves the major pharmacological action of col- effective when used within 24 hours of an acute
chicine: binding to tubulin dimers.
[46]
It is also sus- attack. However, >80% of patients experienced nau-
2004 Adis Data Information BV. All rights reserved. Drugs 2004; 64 (21)
Management of Gouty Arthritis 2405
sea, vomiting, diarrhoea and abdominal pain after If the medication extravasates, it can cause tissue
oral administration of colchicine before full clinical necrosis. Within the vessels, it can also cause throm-
improvement.
[48]
This narrow benefit to toxicity ra- bophlebitis. Granulocytopenia is a prime complica-
tio has limited the use of colchicine. Colchicine has tion of intravenous colchicine. The white blood cell
the smallest benefit to toxicity ratio of the drugs that count should be measured before infusion. Other
are used in the management of gout.
[49]
complications include disseminated intravascular
coagulation, renal failure, hepatocellular toxicity,
Colchicine is the classical medication for gout
seizures and shock.
but should not be the preferred drug for the treat-
ment of acute gout. It is most effective during the
Two letters published in recent years
[53,54]
sup-
first 1224 hours of an attack and its effectiveness
ported the use of intravenous colchicine for acute
declines with the duration of inflammation.
gout. Stephan
[54]
stated that intravenous colchicine
A clinical response to colchicine is not pathogno- is his treatment of choice for a patient with acute
monic for gout and can be seen with pseudogout, gouty attack, and also stated that it is important
sarcoid arthropathy, psoriatic arthritis and calcific therapeutically and diagnostically as well. On the
tendonitis. other hand, many clinicians have advocated restric-
tion or outright ban of intravenous colchicine ther-
Doses of colchicine, as advised by the British
apy because serious systemic reactions can occur
National Formulary, are: 1mg initially followed by
with intravenous colchicine administration and in-
500g every 23 hours until relief of pain is ob-
appropriate use of the drug is not uncommon.
[52,55]
tained or vomiting or diarrhoea occurs, or until a
Severe adverse effects include bone marrow sup-
total dose of 6mg has been reached; the course
pression, renal failure, alopecia, disseminated in-
should not be repeated within 3 days.
[50]
To prevent
travascular coagulation, hepatic necrosis, diarrhoea,
adverse effects, Morris et al.
[51]
suggested that col-
seizures, arrhythmias leading to complete heart
chicine should be used at lower doses in acute gouty
block, and death.
arthritis: 500g three times daily or less frequently,
especially in patients with renal impairment.
[51]
5.1.3 Oral NSAIDs
5.1.2 Intravenous Colchicine
NSAIDs are the drugs of choice in most patients
Colchicine can also be administered intra- with gout who do not have underlying health prob-
venously. While therapy by this route can quickly lems. The most important determinant of therapeutic
abort an attack of gout, it should be employed only success is not which NSAID is chosen, but rather
in unusual circumstances because it is potentially how soon NSAID therapy is initiated. In >90% of
deadly. This therapy is banned in some countries patients, complete resolution of the attack occurs
because of a 2% fatality rate. Intravenous colchicine within 58 days of initiation of therapy. Unfortu-
should be used cautiously, if at all, in patients with nately, the use of NSAIDs is limited by adverse
renal insufficiency or hepatic dysfunction. effects. Adverse effects include gastropathy, ne-
phropathy, liver dysfunction, CNS dysfunction and
When given intravenously, colchicine 1mg is
reversible platelet dysfunction. They also may cause
diluted in 20mL of isotonic sodium chloride solution
fluid overload in patients with congestive heart fail-
without glucose and pushed over 1020 minutes in a
ure (CHF). NSAID therapy should be used with
secure intravenous line. A maximum of 4mg is
great caution in patients with peptic ulcer disease,
given over 24 hours, and no further colchicine
low creatinine clearance, liver disease and poorly
should be given for the next week.
[52]
compensated CHF, and in patients receiving an-
Colchicine should not be used if the glomerular
ticoagulation therapy.
[56,57]
Adverse effects of
filtration rate (GFR) is <10 mL/min, and the dose
NSAIDs are also more pronounced in elderly.
[58]
should be decreased by at least half if the GFR is
<50 mL/min. Colchicine should also be avoided in Maximum dosages should be given immediately
patients with hepatic dysfunction, biliary obstruc- after the onset of symptoms or at the time of diag-
tion or an inability to tolerate diarrhoea.
[52]
nosis and continued for 24 hours after complete
2004 Adis Data Information BV. All rights reserved. Drugs 2004; 64 (21)
2406 Schlesinger
Table III. Double-blind NSAID trials in acute gout
Study (year) NSAIDs No. of pts Regimen Qualifiers/diagnosis Outcomes
Smyth and Percy
[59]
IND vs PBZ 28 (31 IND: 200, 150, 100 mg/ Clinical criteria Subjective: pain
(1973) attacks) day Objective: heat, erythema
PBZ: 800, 600, 400 mg/ swelling, ESR (p < 0.001 PBZ
day vs IND)
Ruosti and Vainio
[60]
IND vs PQZ 18 PQZ: 300mg tid or bid SUA Improvement in 23 days
(1978) IND: 50mg tid or bid Crystals in some x-rays
Altman et al.
[61]
KET vs IND 59 KET: 100mg tid MSU crystals or clinical >90% pain relief in both
(1988) IND: 50mg tid criteria groups. Complete relief day
5: 7 pts KET group, 6 pts
IND group
Weiner et al.
[62]
FEN vs PBZ 30 FEN: 3.6g first day then MSU crystals Both as effective. Reduction
(1979) 3g od in pain, heat, swelling,
PBZ: 700mg first day redness on day 4: 77% in
then 400mg od FEN, 81% in PBZ
Shrestha et al.
[63]
IM KTL vs PO 20 KTL: 60mg IM and PO Wallace criteria 2-hour decreased pain 50%
(1995) IND placebo (except in 2 pts in each
IND: 50mg tid for 2 days group)
then 50mg bid for 5 days IND group 24 hours: no
and IM placebo change in pain score
KTL: rebound pain after 6
hours
Maccagno et al.
[64]
ETL vs NAP 61 ETL: 300mg bid Clinical criteria No statistical difference
(1991) NAP: 500mg bid between the groups
Schumacher et al.
[65]
ETC vs IND 150 ETC: 120mg od Wallace criteria No statistical difference
(2002) IND: 50mg tid between the groups
bid = twice a day; ESR = erythrocyte sedimentation rate; ETC = etoricoxib; ETL = etodolac; FEN = fenoprofen; IM = intramuscular; IND =
indometacin; KET = ketoprofen; KTL = ketorolac; MSU = monosodium urate; NAP = naproxen; od = once daily; PBZ = phenylbutazone; PO
= oral; PQZ = proquazone; pts = patients; SUA = serum uric acid; tid = three times daily.
resolution of the acute attack, then tapered quickly 19 men. Joints involved were 11 knees, four
over 23 days. metatarsophalangeal joints, three ankles and two
wrists. All had MSU crystals identified in the joints. A number of head-to-head studies show equiva-
After intra-articular injection of triamcinolone, in 11 lence between many NSAIDs (table III).
[59-65]
There
joints (55%) the attack had resolved at 24 hours and are no randomised controlled trials directly compar-
in nine joints (45%) at 48 hours. All of the attacks ing colchicine to NSAIDs.
were fully resolved at 48 hours.
5.2 Intra-articular Corticosteroids
5.3 Systemic Corticosteroids
Intra-articular corticosteroids are currently ac-
Corticosteroids can be given to those patients cepted as beneficial when only one or two joints are
who cannot use NSAIDs or colchicine. Corticoster- actively inflamed.
[66]
Patients with polyarticular
oids can be given orally, intravenously, intramuscu- gout who demonstrate suboptimal or delayed res-
larly, intra-articularly or indirectly via corticotropin. ponse to oral NSAIDs or who have contraindica-
tions to usual NSAIDs may also benefit from ad- Prednisone can be given at a dose of approxi-
junctive corticosteroid injections into joints with mately 30mg for 13 days and then tapered over 12
persistent synovitis.
[67]
Ensuring that the joint is not weeks. Tapering more rapidly can result in a re-
infected prior to injecting intra-articular corticoster- bound flare. Using parenteral corticosteroids confers
oids is particularly important. no advantage unless the patient cannot take oral
medications. In a recent open-label trial,
[68]
small intra-articu-
lar doses of triamcinolone (10mg in knees and 8mg In a prospective trial using systemic corticoster-
in small joints) helped resolve 20 attacks of gout in oid treatment for acute gout in-patients who had
2004 Adis Data Information BV. All rights reserved. Drugs 2004; 64 (21)
Management of Gouty Arthritis 2407
contraindications to use of NSAIDs, Groff et al.
[69]
performed in 11 patients who did not have a history
noted improvement within 1248 hours. Thirteen of gout. The most commonly documented indica-
consecutive patients with 15 episodes of acute gout tions for corticotropin were CHF (n = 18), chronic
were treated with systemic corticosteroids. Suffi- renal failure (CRF) [n = 20], history of gastrointesti-
cient records were available on 12 patients and 13 nal bleeding (n = 10) and lack of response to
attacks (mean age 65 years; seven men and five NSAIDs or colchicine (n = 6). Patients with acute
women). Eight of the 12 patients had their diagnosis gout had a mean age of 66 years (range 4393
confirmed by MSU crystals. In 11 of 13 attacks years). Patients were treated with corticotropin
complete resolution of the signs and symptoms oc- intravenously (n = 27), intramuscularly (n = 6) or
curred within 7 days and within 10 days in the
subcutaneously (n = 5). Thirty-four episodes of gout
remainder. Patients with more than five involved
were treated with corticotropin 40IU every 8 hours
joints required longer courses of therapy (mean 17
and four episodes were treated with 80IU every 8
days). Nine patients received an initial dose of pred-
hours. Doses were tapered each day according to
nisone 2050 mg/day with a tapering dose over a
clinical improvement (decrease in synovitis, im-
mean time of 10.5 days (420 days). Three patients
proved range of motion). The most common regi-
with greater than five joints involved, longer dura-
men (90%) was 40IU every 8 hours then 40IU every
tion of symptoms and one with multiple myeloma
12 hours and then 40IU once daily. Duration of
received either intravenous prednisolone or a pro-
therapy was 114 days. Prophylactic colchicine was
longed prednisone taper over a mean of 17 days.
given in 79% of patients (n = 30) as the corticotrop-
Comparison of different dose administration regi-
in was tapered. A 97% resolution rate was reported.
mens has not been done.
In some patients resolution was within the first day.
Alloway et al.
[70]
reported 23 patients presenting
Mean time to complete resolution was 5.5 days. A
within 5 days of onset of an acute gouty attack. They
relapse rate of 11% (n = 4) was noted. The investi-
noted that resolution of all symptoms occurred at an
gators concluded that corticotropin is effective in
average of 8 days for patients treated with in-
patients with multiple medical problems such as
dometacin 50mg orally three times daily and 7 days
CHF, CRF and gastrointestinal bleeding.
for patients treated with triamcinolone 60mg intra-
In a prospective study involving 76 patients who
muscularly. Despite the fact that the triamcinolone-
presented within 24 hours of onset of an acute gouty
treated patients tended to have a longer duration of
attack, Axelrod and Preston
[73]
compared parenteral
symptoms before the onset of therapy and a greater
corticotropin (a single dose of 40IU administered
number of joints involved, resolution of all symp-
intramuscularly) with oral indometacin 50mg four
toms tended to occur more quickly. However, the
times daily with food until pain subsided. For subse-
difference was not statistically significant.
quent attacks patients continued treatment with the
assigned study medication and were followed up for
5.4 Corticotropin
1 year. During each treatment course the patients
The exact mechanism of action of corticotropin is were treated and observed for 5 hours until released.
largely unknown. The use of corticotropin is be- Patients reported for follow-up 57 days after each
lieved to exert its main beneficial effect by adrenal attack and were assessed for time to pain relief and
corticosteroid release. New evidence shows that cor- ability to walk. Diagnosis was confirmed by MSU
ticotropin could be responsible, at least in part, for crystals in all patients. The mean pain interval from
its efficacy in human gouty arthritis by local activa- administration of the study drug to complete pain
tion of melanocortin receptor(s), specifically the relief was 3 1 hour with corticotropin and 24 10
melanocortin type 3 receptor.
[71]
hours with indometacin (p < 0.0001). Pain resolved
Ritter et al.
[72]
conducted a retrospective review within 4 hours and no adverse effects were noted in
of 33 patients with acute gout (38 episodes) and five 36 patients who received corticotropin intramuscu-
patients with acute pseudogout (five episodes) who larly for their gouty attack. The investigators con-
received corticotropin. These patients had multiple cluded that the patients who received corticotropin
medical problems. A diagnostic arthrocentesis was experienced a quicker onset of pain relief than those
2004 Adis Data Information BV. All rights reserved. Drugs 2004; 64 (21)
2408 Schlesinger
who received oral indometacin. However, the study and, possibly, other new agents in the treatment of
patients had to present within 24 hours of the onset acute gout.
of an acute gouty attack, could not have tophaceous
gout or renal insufficiency, and could not be taking
6. Pharmacological Treatment of
colchicine, allopurinol or probenecid. Therefore,
Chronic Gouty Arthritis
their results may not be reproducible in a more
complicated patient population. In addition, their
Long-term control of hyperuricaemia in order to
study was not blinded and adverse effects with corti-
prevent gouty attacks and sequelae of long-standing
cotropin were not mentioned.
hyperuricaemia, such as chronic tophaceous gout,
Siegel et al.
[74]
prospectively compared patients
urate nephropathy and uric acid stones, is important.
receiving a single dose of intramuscular corticotrop-
Optimal treatment requires long-standing reduc-
in 40IU (n = 16) with patients receiving intramuscu-
tion in SUA. Maintaining the SUA level at <6 mg/
lar triamcinolone 60mg (n = 15) in acute gout. Both
dL, and not just within the normal range, has been
groups had similar mean times to complete resolu-
proposed to help assure resolution of tophi and
tion (7.9 and 7.6 days, respectively). The triamci-
eventual cessation of acute gouty attacks. Bomalaski
nolone group required fewer repeat injections com-
et al.
[26]
showed that MSU crystals persisted in 58%
pared with the corticotropin group. Repeat injection
of asymptomatic knees of patients with nontopha-
was needed in 9 of 15 patients receiving corticotrop-
ceous gout despite lowering of SUA level to
in but only 5 of 16 receiving triamcinolone, and
<7.1 mg/dL for varying periods. In a prospective
many corticotropin-treated patients required a third
study by Li-Yu et al.,
[75]
57 patients were divided
injection to treat rebound attacks. This could have
into two groups: one that had a SUA level >6 mg/dL
been related to a lack of equivalent doses between
and one that had SUA level successfully lowered to
the two medications. Thus, there are no convincing
6 mg/dL for at least 1 year. Joint knee aspirates
data that such therapy is superior to corticosteroids.
were performed in 32 patients. Fifty-six percent of
patients who maintained their SUA level <6 mg/dL
had MSU crystals depleted from their knee joints 5.5 Summary
and seemed to do better than the other group.
The options available for the treatment of acute The evidence on when to start urate-lowering
gouty attacks are NSAIDs, colchicine, corticoster- drugs is conflicting and controversial. Because the
oids, corticotropin and intra-articular corticoster- initial attacks of gout are infrequent, self-limited and
oids. In a patient without complications, NSAIDs easily treated, long-term therapy is often not indicat-
are the preferred therapy. ed. Many patients will have a long duration between
attacks: 1 year in 62% of patients, 12 years in 16% The most important determinant of therapeutic
of patients, 25 years in 11% of patients, 510 years success is not which NSAID is chosen, but rather
in 6% of patients and no recurrence in 10 years in how soon NSAID therapy is initiated. In >90% of
7% of patients.
[76]
Some advocate that only patients patients complete resolution of the attack occurs
who experience more than four episodes per year within 58 days of initiation of therapy. Unfortu-
should be given such treatment;
[77]
others recom- nately, the use of NSAIDs is limited by adverse
mend that urate-lowering treatment is cost effective, effects. NSAID therapy should be avoided in pa-
even in patients with one recurrent gouty attack per tients with peptic ulcer disease, low creatinine clear-
year.
[78]
ance, liver disease and poorly compensated CHF,
and in patients receiving anticoagulation therapy. Cost effectiveness of urate-lowering therapy has
Adverse effects of NSAIDs are also more pro- been studied, with the conclusion that therapy is cost
nounced in elderly patients. saving in patients who have two or more attacks a
year.
[78]
Randomised, long-term, prospective, placebo-
controlled trials are needed to evaluate the therapeu- In all cases, the benefits and risks of treatment
tic role of colchicine versus NSAIDs, use of cortico- need to be judged based on the individual patient.
steroids and corticotropin, as well as urate oxidase For instance, in an elderly patient with multiple
2004 Adis Data Information BV. All rights reserved. Drugs 2004; 64 (21)
Management of Gouty Arthritis 2409
Table IV. Treatment of chronic gout
Start urate-lowering drugs only in patients who have two or more attacks a year
Urate-lowering drugs should not be started during an acute attack
Uricosuric drugs are the urate-lowering drugs of choice in allopurinol-allergic patients, and underexcretors with normal renal function
and no history of urolithiasis
Use allopurinol in patients with renal calculi, renal insufficiency, concomitant diuretic or ciclosporin (cyclosporine) therapy or urate
overproduction
Use concomitant colchicine prophylaxis until serum uric acid has been at desired level for some months and no recent gouty attacks
have occurred (612 months)
Monitor serum uric acid and aim for serum uric acid <6.0 mg/dL. Check serum uric acid level every 36 months. Adjust urate-lowering
drug dose according to serum uric acid level
6.1.1 Probenecid
medical problems and renal insufficiency, the risks
Probenecid (5001000mg twice daily) is an ef-
of therapy to lower uric acid levels may outweigh
fective urate-lowering drug in patients with gout,
the benefits.
hyperuricaemia due to underexcretion, normal renal
Expert opinion suggests that urate-lowering
function and no history of renal stones or massive
drugs should not be started during an acute attack.
tophi.
[79]
Probenecid is well absorbed from the gas-
Whether starting urate-lowering drugs during the
trointestinal tract and has a half-life of 612
acute attack may lead to a more intense and pro-
hours.
[79]
Its metabolism is rapid and major metabo-
longed attack is questionable. Typically, they should
lite is acylmonoglucuronide. Forty percent of the
be started 68 weeks after the attack has resolved.
drug is excreted in this form in the urine within 48
If the patient develops an acute gouty attack
hours.
when starting urate-lowering drugs they should not
6.1.2 Sulfinpyrazone
be discontinued as this will only cause another flux
Sulfinpyrazone is not in great use secondary to its in the uric acid level.
adverse effects profile.
The urate-lowering drugs used to treat chronic
gout are the uricosuric drugs, the uricostatic drugs,
6.1.3 Benzbromarone
which are xanthine oxidase inhibitors, and the
Benzbromarone is not readily available in the
uricolytic drugs.
US. As opposed to probenecid and sulfinpyrazone,
Table IV provides an overview of treatment for which lose their efficacy as the urate-lowering drug
chronic gout. in patients who have lower creatinine clearance,
benzbromarone retains its uricosuric effect at doses
of 25150 mg/day in patients who have a creatinine
6.1 Uricosuric Drugs
clearance >25 mL/min.
[80]
However, it should be
noted that there is concern that benzbromarone is
Uricosuric drugs act on the uric acid anion trans-
hepatotoxic.
port pathway inhibiting post-secretory renal proxi-
6.1.4 Micronised Fenofibrate mal tubule reabsorption of uric acid, augmenting its
renal excretion and, thereby, reducing SUA.
[79]
Fenofibrate is a fibric acid derivative, which is a
When uricosuric drugs are started, intense uricosuria lipid-lowering agent. It has been shown to reduce
may result in deposition of uric acid crystals in the renal tubular reabsorption of uric acid enhancing its
renal tubules, urinary stones and worsening renal renal excretion.
[81]
The uricosuric effect is indepen-
function. To minimise this risk uricosuric drugs are dent of the lipid-lowering effect. The uricosuric
started at low doses and gradually increased over effect of fenofibrate is associated with a SUA reduc-
26 weeks. The risk of renal stones is reduced by tion of 2035% in both healthy people and patients
marinating a high urine volume (>2 L/day) and al- with gout who have normal renal function. It may be
kalinising the urine with sodium bicarbonate four useful in patients with gout who have hyper-
times daily. lipidaemia.
2004 Adis Data Information BV. All rights reserved. Drugs 2004; 64 (21)
2410 Schlesinger
6.1.5 Losartan
other day. The final dose in a patient with a plasma
Losartan is an angiotensin II receptor antagonist.
creatinine of 2 mg/dL will be half of the dose given
It is an antihypertensive medication. Losartan
in a patient with normal renal function.
[84,85]
Al-
reduces SUA level and raises the urinary level of
lopurinol may interfere with hepatic metabolism of
uric acid but, unlike other uricosurics, losartan si-
oral anticoagulants as well as theophylline levels. In
multaneously raises urine pH so that undissociated
addition, medications such as azathioprine and mer-
uric acid supersaturation fails to rise. As a result,
captopurine are inactivated by xanthine oxidase.
stone formation risk from acute uric acid nephropa-
When allopurinol is given concomitantly with these
thy falls when losartan is taken.
[82]
Both losartan and
agents, the dose of these agents should be reduced to
its metabolite E 3174 inhibit renal tubular reabsorp-
2530% of the initial dose to avoid catastrophic
tion of uric acid and increase its urinary excre-
haematological consequences.
tion.
[82]
The uricosuric effect is independent of the
Uric acid lowering upon treatment with allopuri-
angiotensin receptor antagonism of losartan. The
nol is dose dependent. Many patients are maintained
drug may be particularly useful in patients with gout
on a fixed dose of allopurinol (usually 100 or
who have hypertension and ciclosporin-treated
300 mg/day) and dose is not adjusted to SUA level.
transplant patients.
Most believe that patients with chronic gout need
SUA levels to be kept low to prevent further attacks.
6.2 Uricostatic Drugs (Xanthine Allopurinol holidays have been studied. Urate
Oxidase Inhibitors) levels rise when allopurinol is stopped and tophi and
attacks can recur.
[86]
In a prospective randomised
study by Bull and Scott,
[87]
intermittent administra-
6.2.1 Allopurinol
tion of allopurinol was found to be less effective in
Allopurinol is a structural analogue of hypoxan-
controlling gouty attacks than continuous treatment.
thine. As a xanthine oxidase inhibitor it interferes
In the group treated continuously (n = 20) SUA
with the conversion of hypoxanthine to xanthine and
levels were controlled and no further attacks of gout
of xanthine to uric acid, leading to a reduction in
occurred after 2 years. In the group treated intermit-
SUA and urine uric acid levels, and an increase in
tently (n = 20) SUA levels fell during administration
serum and urinary hypoxanthine and xanthine
of the drug but rose rapidly afterwards. In 7 of the 20
levels. Allopurinol reduces the levels of urate in the
patients, attacks of gouty arthritis persisted.
blood and urine and increases the levels of the urate
Up to 5% of patients are unable to tolerate al-
precursors xanthine and hypoxanthine. Allopurinol
lopurinol because of adverse effects. These include
has a short half-life of approximately 40 minutes.
[79]
gastrointestinal irritation, bone marrow suppression,
Most of the allopurinol is itself metabolised by
and a hypersensitivity syndrome that can range from
xanthine oxidase to oxipurinol, which is the active
a skin rash to a life-threatening illness in which the
metabolite and is responsible for most of its effects
patients develop toxic epidermal necrolysis, fever,
on urate and purine metabolism. Oxipurinol has a
hepatitis, eosinophilia and worsening renal func-
half-life of 1428 hours and is largely excreted by
tion.
[84]
The exact mechanisms for these reactions
the kidney. Therefore, it is oxipurinol that is princi-
are not known, but accumulation of oxipurinol as a
pally responsible for the clinical effect of inhibition
result of renal failure and/or coadministration of
of xanthine oxidase. The maximum effect in lower-
thiazide diuretics have been implicated.
[85]
In pa-
ing SUA levels is seen within 14 days.
[79]
tients who have exhibited sensitivity to allopurinol,
Allopurinol is the most commonly prescribed
in-hospital desensitisation may be needed for con-
urate-lowering agent, primarily because of its once-
tinuation of allopurinol.
[84]
daily administration and its great efficacy.
[83]
It can
be given in a single morning dose of 300mg initially
6.2.2 Oxipurinol
and increased to 800mg if needed. Dosage adjust-
ments are necessary in patients with impaired creati- Oxipurinol is the active metabolite of allopurinol.
nine clearance. In patients with renal failure; the Its half-life is 915 times longer than that of al-
initial dose would be 50100mg every day or every lopurinol. Oxipurinol has been shown to be of sig-
2004 Adis Data Information BV. All rights reserved. Drugs 2004; 64 (21)
Management of Gouty Arthritis 2411
nificant help in at least 50% of patients who are In a much-needed prospective, parallel-group,
allergic to allopurinol.
[84]
Evidence of toxicity iden- open-label study of 86 male patients with chronic
tical to that seen with allopurinol was observed in gout who fulfilled the 1977 American Rheumatism
30% of treated patients. Its usefulness in gout pa- Association preliminary criteria for the classifica-
tients who are sensitive to allopurinol has not been tion of gout,
[95]
the efficacy of allopurinol and benz-
studied. bromarone were compared in reducing serum
urate.
[80]
Patients were randomised into two groups: Oxipurinol is not commercially available in the
one group received allopurinol 300 mg/day and the US, but can be obtained through the manufacturer
other received benzbromarone 100 mg/day. Both (ILEX Oncology, San Antonio, TX, USA) on a
groups included underexcretors and normal excret- compassionate basis.
ers of uric acid. Patients receiving allopurinol show-
6.2.3 Febuxostat ed a mean reduction of serum urate of 2.75 mg/dL,
Febuxostat is a novel oral non-purine selective while patients receiving benzbromarone had a
inhibitor of xanthine oxidase/dehydrogenase which 5.04 mg/dL reduction in their serum urate. Fifty-
is currently being developed for hyperuricaemia three percent of patients receiving allopurinol and
associated with gout. Febuxostat has no significant 100% of patients receiving benzbromarone achieved
effect on guanine deaminase, hypoxanthine guanine optimal serum urate levels at such doses. Renal
phosphoribosyltransferase or purine nucleoside function improved and no renal stones were observ-
phosphorylase, which are enzymes involved in pu- ed among the benzbromarone-treated group. Benz-
rine metabolism, and had no effect on orotate bromarone was found to be effective (including
phosphoribosyltransferase or orotidine monophos- underexcretors of urate) in controlling serum urate
phate decarboxylase, enzymes involved in pyrimi- levels in doses ranging from 50 to 100 mg/day.
dine metabolism. In in vivo animal studies, febuxos- Allopurinol was not tested at higher doses, which
tat was potent in lowering SUA and urine uric acid may be needed in some patients.
levels.
[88,89]
In a study comparing allopurinol treatment with
The drug is mostly metabolised by the liver and a
uricosuric drug treatment in 183 gouty patients by
mild-to-moderate renal impairment does not seem to
Weinberger and Pinkhas,
[96]
patients treated with
alter its urate-lowering effects.
[90]
Febuxostat was
allopurinol for a prolonged period of time had disap-
well tolerated in patients with gout treated for up to
pearance of attacks after 4 years of treatment, while
4 weeks.
[91]
The incidence of adverse events for
uricosuric therapy did not cause the same decrease
patients receiving febuxostat was similar to placebo,
in appearance of attacks. This is compatible with
with the majority of events being mild and self-
other studies, indicating that allopurinol is more
limiting. The most frequently reported adverse
effective in reducing the frequency of gouty at-
events by patients receiving febuxostat included di-
tacks.
[97,98]
arrhoea, pain, back pain, headache and arthralgia.
In a prospective study by Scott
[99]
comparing
Phase III studies are currently ongoing.
long-term effects of allopurinol with those of
uricosuric treatment in uncomplicated gout, no clear
6.3 Comparing Uricosuric Drugs advantage to the use of allopurinol versus
and Allopurinol probenecid was observed. In this study 37 men were
allocated to receive either allopurinol (n = 20) or
In a survey of prescribing practices in Ontario, uricosuric drugs (n = 17). Mean follow-up was 18.6
Canada, 99% of rheumatologists elected to start months for the allopurinol group and 19.6 months
allopurinol as their urate-lowering drug therapy.
[92]
for patients taking uricosuric drugs. Allopurinol was
In another study 66% of rheumatologists prescribed given at dosages of 300 mg/day (n = 12), 400 mg/
allopurinol as their initial urate-lowering drug,
[93]
day (n = 6) and 600 mg/day (n = 2). Dosage was
while in yet another study 30% of French rheu- decided dependent on SUA level. The goal was a
matologists never used uricosurics.
[94]
No studies normal SUA level (6 mg/dL in men and postmeno-
have evaluated these differences in approach. pausal women and 5 mg/dL in pre-menopausal
2004 Adis Data Information BV. All rights reserved. Drugs 2004; 64 (21)
2412 Schlesinger
women). Probenecid, on the other hand, was started inherent antigenicity of these preparations. Since
at 1 g/day and increased to 2 g/day in all patients in humans lack urate oxidase, all urate oxidase prepa-
the group after 2 weeks in order to achieve an rations are potentially antigenic with long-term use.
adequate uricosuric response. Five patients on Anti-urate oxidase antibodies develop in about
probenecid were changed to sulfinpyrazone 400 mg/ 714% of patients and can cause declining effi-
day secondary to adverse effects (flatulence, pruri- cacy.
[101]
tus, difficulty swallowing or bad taste). All patients Several conjugates of urate oxidase with PEGs
received daily colchicine (0.5mg twice to three have been investigated to overcome these prob-
times daily). Colchicine was withdrawn after several lems
[102,103]
and have reduced antigenicity and in-
months in patients who became free of symptoms. creased circulating half-life compared to non-re-
Despite the difference in dosages the mean SUA combinant urate oxidases. Recombinant urate oxi-
level was lower in the group receiving allopurinol dases include A. flavus non-pegylated recombinant
(4.7 mg/dL [range 2.65.5 mg/dL]) versus the mean urate oxidase (rasburicase) and recombinant C. utilis
SUA in the group receiving uricosuric drugs urate oxidase-PEG 20. They are currently in use in
(5.2 mg/dL [range 3.87.3 mg/dL]). Half of the pa- Europe and are undergoing clinical trials in the US
tients of both groups had no further attacks at the last (albeit principally for tumour lysis syndrome).
assessment. Long-term urate oxidase treatment for chronic
gout has not been evaluated.
6.4 Uricolytic Drugs
6.5 Urate-Lowering Drugs: Summary
6.4.1 Urate Oxidase
Allopurinol is the urate-lowering drug of choice.
Urate oxidase is present in many animals, but not
Febuxastat, which is in development, may become a
in humans. It is an enzyme that oxidises urate to
leading choice of xanthine oxidase inhibitors.
allantoin. Unlike urate, allantoin is highly soluble
Uricosuric drugs such as probenecid are the urate-
and is more readily excreted in the urine. Unlike
lowering drugs of choice in allopurinol-allergic pa-
allopurinol, which inhibits further uric acid synthe-
tients, and underexcretors with normal renal func-
sis, urate oxidase also breaks down pre-existing uric
tion and no history of urolithiasis. The use of recom-
acid. Urate oxidase from mammals and micro-or-
binant urate oxidase in patients with chronic gout is
ganisms have been administered to humans with
limited by the need for parenteral administration, the
hyperuricaemia and gout. Preparations include re-
potential antigenicity and production of anti-urate
combinant and non-recombinant urate oxidases.
oxidase antibodies, and declining efficacy.
Non-recombinant urate oxidases include: Aspergil-
lus flavus urate oxidase (Uricozyme

1
, Sanofi-
7. Colchicine Prophylaxis
Synthelabo, Paris, France); monomethoxy polyethy-
lene glycol (PEG)-modified Candida utilis urate Wortmann,
[3]
in his expert opinion, states that
oxidase and PEG-modified Arthrobacter proto- colchicine prevents acute gouty attacks in 85% of
formiae urate oxidase. patients initiating treatment with urate-lowering
Uricozyme

has been introduced in France and drugs and should be discontinued after the serum
Italy but is not available in the US. The drug has urate has been controlled and the patient has not
been used mainly for prevention of malignancy- had an acute attack for 13 months.
[3]
The basis for
associated hyperuricaemia and tumour lysis syn- this recommendation is not given. Emmerson
[78]
re-
drome.
[100]
commended continuing colchicine intake for at least
Although successful in lowering SUA levels, a year, again without supporting data. Ben-Chetrit
these therapies have had limited application as a and Levy
[104]
recommended a daily prophylactic
result of undesirable biochemical properties of the dose of approximately 1mg and stated the effective-
enzymes used, the short circulating half-life and ness of the drug in preventing attacks and diminish-
1 The use of trade names is for product identification purposes only and does not imply endorsement.
2004 Adis Data Information BV. All rights reserved. Drugs 2004; 64 (21)
Management of Gouty Arthritis 2413
ing their severity in an update on colchicine. attack and take additional colchicine, indometacin
Others
[77,79]
emphasised the risks of routine colchi- or phenylbutazone until the attack subsided. Only
cine treatment in all patients being treated with attacks judged as moderate or severe by the investi-
urate-lowering drugs and stated that the actual risk gators were incorporated in the analysis. The inves-
of precipitating an attack of gout is, at the most, tigators analysed only the patients (n = 38) who
24%. showed a sustained reduction in SUA level as they
assumed that these were the compliant patients. The
The practice of using colchicine as prophylaxis
investigators concluded that treatment with colchi-
against acute gouty attacks was introduced by Co-
cine 1.5 mg/day in divided doses significantly re-
hen
[105]
over 50 years ago. In 1961, Yu and Gut-
duced the frequency of attacks of acute gout in
man
[106]
analysed the use of colchicine prophylaxis
patients whose hyperuricaemia was controlled by
in gout over a mean period of 5 years in 208 patients.
probenecid.
They compared colchicine alone in 119 patients
No randomised controlled trial has examined pre-
with a combination of colchicine and probenecid in
scription of colchicine as a single drug therapy for
89 patients. The doses of colchicine ranged from 0.5
the prophylaxis of acute gouty arthritis. The effec-
to 2 mg/day for a duration ranging from 2 to >10
tiveness of colchicine prophylaxis as an isolated
years. They concluded that both colchicine alone
therapy is still to be confirmed by placebo-control-
and in combination with probenecid was effective in
led trials. Another issue is prophylaxis with
preventing acute gout.
[106]
However, the investiga-
NSAIDs. There are no comparative studies with
tors reported on the outcome of only 208 of their 614
colchicine.
patients. Patients who were excluded were also pre-
In summary, the effectiveness of colchicine pro-
scribed colchicine but their outcomes were not re-
phylaxis as an isolated therapy is still to be con-
ported. In addition, the patients were instructed to
firmed by placebo-controlled trials.
abort attacks by immediately taking extra doses of
colchicine (2 or 3mg for 12 days). They were also
instructed not to drink alcohol and some were on a
8. Conclusion
low purine diet. In addition, they were all put on
uricosuric drugs from the start of the prophylactic
The options available for the treatment of acute
colchicine regimen or shortly after.
gouty attacks are NSAIDs, colchicine, corticoster-
oids, corticotropin and intra-articular corticoster- In 1982, Yu
[107]
published a reappraisal after 20
oids. In a patient without complications, NSAIDs years (outcome of 540 patients) of the efficacy of
are the preferred therapy. The most important deter- colchicine prophylaxis in articular gout. Once again,
minant of therapeutic successs is not which NSAID this uncontrolled study showed that colchicine di-
is chosen, but rather how soon NSAID therapy is minishes recurrence of gouty attacks. Again, many
initiated. patients were prescribed urate-lowering drugs. Li-
Long-term control of hyperuricaemia in order to Yu et al.,
[75]
in a study of urate-lowering drugs,
prevent gouty attacks and sequelae of long-standing showed that the frequency of attacks was reduced in
hyperuricaemia, such as chronic tophaceous gout, the patients given colchicine prophylaxis compared
urate nephopathy and uric acid stones, is important. with those who stopped taking colchicine, even
The urate-lowering drugs used to treat chronic gout among those with urate levels lowered for 1 year. In
are the uricosuric drugs, uricostatic drugs, which are 1974, Paulus et al.
[49]
published the results of a
xanthine oxidase inhibitors, and the uricolytic drugs. randomised controlled trial that evaluated prophy-
lactic colchicine therapy in patients treated with Allopurinol is currently the urate-lowering drug
probenecid. In this 6-month, double-blind study of of choice. Febuxastat, which is in development, may
51 patients with recurrent tophaceous and nontopha- be safer than allopurinol in patients with renal fail-
ceous gout, patients were randomly allocated to ure and may become a leading choice in our use of
receive probenecid 1.5 g/day and colchicine 1.5 mg/ xanthine oxidase inhibitors. Uricosuric drugs such
day or probenecid 1.5 g/day with placebo. In the as probenecid and benzobramone are the urate-low-
event of an acute attack patients were to record the ering drugs of choice in allopurinol-allergic patients,
2004 Adis Data Information BV. All rights reserved. Drugs 2004; 64 (21)
2414 Schlesinger
15. Adams PF, Hendershot GE, Marano MA. Current estimates
and under-excretors with normal renal function and
from the National Health Interview Survey, 1996. Series 10.
no history of urolithiasis. Recombinant urate oxi-
No. 200 [online]. Available from URL: http://www.cdc.gov/
nchs/data/series/sr_10/10_200_1.pdf [Accessed 2003 Jan 5]
dase lowers SUA levels rapidly. Their use in pa-
16. Klemp P, Shelley A, Stansfield SA, et al. Gout is on the increase
tients with chronic gout is limited by the need for
in New Zealand. Ann Rheum Dis 1997; 56: 22-6
parenteral administration, the potential antigenicity
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Filipinos: interaction of heredity and environment. Am J Hum
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declining efficacy.
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