An NSAID would be an appropriate first-line therapy for the acute treatment of
gout in E.J. because his renal function is normal. Assuming his blood pressure is
adequately controlled, a short course of ibuprofen 800 mg now and every 8 hours
until resolution of symptoms (usually 7–10 days) is appropriate. The ibuprofen
should be prescribed on a scheduled basis rather than “as needed” to reduce
inflammation and prevent breakthrough pain. The dose of 2,400 mg/day does not
exceed the maximum recommended dose of 3,200 mg/day.
NONPHARMACOLOGIC INTERVENTIONS
CASE 45-2, QUESTION 6: What adjunctive therapies would be beneficial for E.J.?
The use of ice, reduction of alcohol consumption, and minor diet modification may
be effective and can be considered for E.J.
The benefit of ice application to the affected joint in acute gouty arthritis should not
be overlooked. Evidence from a systematic review indicates the application of ice to
an affected joint for 30 minutes four times daily for 1 week reduced the pain of a gout
attack when used in conjunction with oral steroids or colchicine.
Excessive alcohol intake is known to be a risk factor for acute gout episodes. Beer
was believed to be more problematic for gout than other alcoholic beverages
because of its high purine content. The Health Professionals Follow-Up study
examined a cohort of patients with new diagnoses of gout over a 12-year time frame
and found that when beer, spirits, and wine intake were examined, the greatest risk
was with beer with a significant, but lesser, risk with spirits. Interestingly, wine,
even more than two drinks/day, was not associated with an increased risk of gout. A
smaller, independent study found that the quantity of alcohol consumed in the 24
hours before an acute attack is more important than the type of beverage consumed.
34 guidelines recommend avoiding
overuse by advocating moderation in alcohol consumption. The ACR recommends no
more than two servings per day for males and one serving per day for women.
Despite lack of evidence, the ACR also recommends avoiding alcohol use during an
acute attack and frequent, poorly controlled gout attacks.
or at least limit his alcohol intake to no more than 2 servings per day.
Diet has a twofold effect on the epidemiology of gout. First, obese patients are at a
greater risk of developing elevated SUA levels, and gout might, in part, be related to
insulin resistance of obesity.
In a prospective, longitudinal study of male health
professionals, weight gain was strongly associated with an increased risk of gout,
and weight loss was associated with a decreased risk.
Second, much of the uric acid produced daily comes from metabolism of food. The
excessive dietary intake of purine-rich foods, without a concomitant increase in
urinary excretion, can lead to elevated SUA concentrations.
protein and purine-rich foods that are detrimental and the true impact of these foods
on the incidence of increased SUA and gout episodes are controversial issues due to
the quality of evidence available.
56,57 Despite the lack of strong evidence, it is
reasonable for clinicians to recommend patients limit certain foods (e.g., organ
meats, beef, lamb, pork shellfish, products containing high-fructose corn syrup).
Interestingly, low-fat or nonfat dairy products and coffee consumption have been
associated with a decreased incidence of gout.
7,58 E.J. should be encouraged to limit
or avoid purine-rich meats and fructose-containing beverages/foods and encouraged
to increase consumption of low-fat dairy products.
QUESTION 1: V.D. is a 72-year-old woman who was brought to the emergency department complaining of
pressure is 160/96 mm Hg. What therapeutic option would be appropriate for V.D.?
The combination of V.D.’s advanced age, acute exacerbation of heart failure, and
renal dysfunction is patient-specific parameters that are relative contraindications or
precautions for the use of NSAIDs for the treatment of acute gout. Therefore,
alternative treatments should be considered. Colchicine is the next drug to consider,
but because she is now receiving diltiazem (a moderate CYP3A4 inhibitor) the dose
be tapered over the course of 10 to 21 days to avoid rebound gout symptoms. It is
decided to give V.D. 1.2 mg of colchicine for one dose only, which is appropriate to
avoid the diltiazem drug interaction.
her pain is gone. Should ULT be prescribed at discharge to prevent another gout attack?
ULT should be initiated only when patients with gout have recurrent acute attacks
(at least two attacks per year), urate tophi, uric acid stones, or chronic kidney disease
(Stage 2 and up) with prior gout attack and current hyperuricemia.
indications are absent, ULT should not be prescribed. Long-term ULT should not be
started for V.D. at this time because criteria for therapy (see ACR, EULAR, and
BSR/BHPR guidelines in Table 45-3)
17,33,34 are not met, and initiation of ULT during
an acute episode can mobilize urate from tissues, compounding the problem.
A patient’s complete medication list should be reviewed to rule out drug-induced
hyperuricemia before adding a medication to decrease SUA concentration. Perhaps,
the only treatment needed would be to discontinue the offending agent. Common
medications known to increase SUA include thiazide and loop diuretics, niacin,
calcineurin inhibitors (e.g., cyclosporine and tacrolimus), and aspirin.
of the ACR guidelines recommend continuing low-dose aspirin (used for
cardioprotection) in patients with hyperuricemia unless with benefits of
discontinuation (i.e., reduction in risk of a gout attack) outweigh the risks.
The association between hyperuricemia and diuretics is well known and is dose
; however, the clinical importance of
diuretic-induced gout attacks is now somewhat controversial. Clinicians often
discontinue the diuretic, irrespective of possible ancillary benefits of diuretics
(especially in HTN and CHF). A 2012 systematic review showed a trend toward
increased risk for acute gout with thiazide and loop diuretics; however, the extent of
the risk and its clinical significance is still unknown. Therefore, the authors state
there is not enough evidence to support discontinuation of these agents in populations
that have shown benefit for other comorbidities.
In certain cases where diuretics
are thought to be a contributing factor to the precipitation of a gout attack,
discontinuation of diuretic therapy may be reasonable, particularly if alternatives are
available and appropriate for a patient.
GOAL OF URATE-LOWERING THERAPY
CASE 45-3, QUESTION 3: V.D. experienced another episode of acute gout 2 months later, which was
time? If so, when would you initiate treatment?
The general goals for lowering SUA concentrations are the elimination of acute
gout attacks and the mobilization of urate crystals from soft tissue. The SUA
concentration in a patient who has clinical gout should be decreased to 6 mg/dL or
17,34 which is below the saturation point for MSU. However, because some
patients may experience continued gouty arthritis attacks even when the SUA is < 6
mg/dL, the ACR and BSR/BHPR guidelines recommend a goal of less than 5 mg/dL
17,34 The BSR/BHPR guidelines recommend as standard of care
waiting 1 to 2 weeks after an acute attack to begin ULT due to risk of a recurrent
34 A small, short trial studied the effect of starting allopurinol during an acute
flare and was found not to worsen pain or risk of a recurrent flare. V.D. fits the
criteria for initiating ULT (2 attacks in less than 1 year); however, this should be
preceded by a consideration of whether drug-induced hyperuricemia could be a
contributing factor. V.D.’s initial episode of gout after aggressive diuresis with IV
furosemide was likely the cause of her first gout attack, but she is not currently on any
drugs that cause hyperuricemia.
Clinical practice guidelines recommend allopurinol as a first-line agent for gout
It inhibits the production of uric acid and thereby decreases SUA
concentrations. A 2014 systematic review of 2 clinical trials, with methodological
limitations, shows that when compared to placebo allopurinol was superior at
achieving target SUA concentrations, but failed to significantly reduce the frequency
61 The ability of allopurinol to lower SUA concentrations is
dose related. An allopurinol dose of 300 mg/day is typical maintenance dose, despite
evidence to support that more than 50% of patients are unable to achieve target SUA
62, 63 Larger doses up to 800 to 900 mg/day may be needed for
those with more severe disease.
The recommended initial dose of allopurinol is 50 to 100 mg once daily and then
increased in 50- to 100-mg/day increments every 2 to 5 weeks until the SUA
concentration is at the desired goal of less than 6 mg/dL or until patient
17,33,34 Starting at a low dose and titrating slowly hypothetically can
reduce the risk for hypersensitivity reactions and improve tolerance in renal
Allopurinol has been associated with a life-threatening hypersensitivity syndrome
that may include a desquamative, erythematous rash, fever, elevated liver function
tests, and renal failure. Although hypersensitivity reactions are rare (1:1,000 in US),
If allopurinol hypersensitivity occurs, the drug should be
stopped immediately because this can lead to skin necrosis, exfoliative dermatitis,
Stevens–Johnson syndrome, toxic epidermal necrolysis, and even death.
who recover should avoid future use of allopurinol, although some have been able to
be desensitized and tolerate low doses.
These adverse effects are more common in patients with concomitant diuretic use
and preexisting renal insufficiency; therefore, dose adjustment in patients with renal
In the past, a nomogram based on CrCl has been used
to reduce the risk of these adverse effects in renal impairment, but a subsequent
67 challenged its efficacy and the ACR guidelines
method. ACR guidelines state that doses of greater than 300 mg may be used in
patients with renal impairment (Stage 4 or greater) with slow titration, close
monitoring, and patient education.
17 A table detailing significant allopurinol drug
interactions can be found online in Table 45-5.
Febuxostat, a nonpurine XO inhibitor, was approved by the FDA in February 2009
for chronic management of hyperuricemia in patients with gout.
selective than allopurinol for XO and does not inhibit other enzymes involved in
purine and pyrimidine metabolism. A 2012 Cochrane systematic review, with
methodological limitations, evaluated six trials comparing febuxostat to allopurinol
for clinical SUA-lowering effect, and found febuxostat more effective than
allopurinol 300 mg in achieving SUA of less than 6 mg/dL. An important
consideration in evaluating the evidence is that although the studies allowed upward
titration of febuxostat to achieve maximal SUA lowering, the allopurinol dosage was
not titrated to greater than 300 mg daily.
69 Because the urate-lowering effect with
allopurinol is known to be dose-related, and some patients have required up to 900
mg/day to achieve a SUA less than 6 mg/dL, these results may not have allowed for
an adequate comparison of efficacy between the two drugs. The same review
revealed that compared to standard doses of allopurinol higher doses of febuxostat,
120 mg and 240 mg daily, increased the risk of gout flares; however, long-term
follow-up studies did not detect an increased risk of flares. The FDA-approved dose
in the United States is 80 mg daily; however, doses of up to 240 mg daily are
In addition, adverse effects were shown to be minor and similar between both
drugs in comparative studies with increases in liver function tests, nausea, diarrhea,
arthralgias, and rash being the most common adverse effects with greater than 1%
62,68,70,71 Because febuxostat is more widely used, the clinician should note
that thromboembolic cardiovascular events have been reported to the FDA adverse
event reporting system. There are two ongoing clinical trials evaluating
cardiovascular risk in both allopurinol and febuxostat.
The starting dose of febuxostat is 40 mg once daily with a recommended dose
increase to 80 mg once daily if SUA concentration is not less than 6 mg/dL by 2
weeks of therapy. It does not require dose adjustments for CrCl greater than 30
mL/minute, and the labeling provides no recommendations for use in patients with
68 A table detailing significant febuxostat drug
interactions can be found online in Table 45-6.
product should be chosen for V.D.?
↑ The rate of skin appears much higher with allopurinol
coadministration than with either drug alone.
Allopurinol Anticoagulants, oral ↑ Data are conflicting. The anticoagulant action of some
agents may be enhanced, but probably not that of warfarin.
Allopurinol Cyclophosphamide ↑ Myelosuppressive effects of cyclophosphamide may be
enhanced increasing the risk of bleeding or infection.
Allopurinol Theophyllines ↑ Theophylline clearance may be decreased with large
allopurinol doses (600 mg/day) leading to increased plasma
theophylline levels and possible toxicity.
Allopurinol Thiopurines ↑ Clinically significant increases in pharmacologic and effects
of oral thiopurines have occurred.
ACE inhibitors Allopurinol ↑ There is possibly a higher risk of hypersensitivity reaction
when these agents are coadministered than when each drug
Aluminum salts Allopurinol ↓ Pharmacologic effects of allopurinol may be decreased.
Allopurinol ↑ Coadministration may increase the incidence of
hypersensitivity reactions to allopurinol.
Allopurinol ↓ Uricosuric agents that increase the excretion of urate are
also likely to increase the excretion of oxipurinol and thus
lower the degree of inhibition of xanthine of xanthine
a↑ = object drug increased; ↓ = object drug decreased.
Source: Facts & Comparisons eAnswers; http://online.factsandcomparisons.com/MonoDisp.aspx?
monoID=fandchcp13090&quick=176221%7c5&search=176221%7c5&isstemmed=True&NDCmapping=-
1&fromTop=true#firstMatch. Accessed June 18, 2015.
Although febuxostat is clearly efficacious in lowering SUA concentrations,
allopurinol is also effective when the dose is appropriately titrated to response and
goal SUA concentration. The ACR guidelines
17 do not recommend one over another
therapy. A 2015 cost-effectiveness analysis (from a US payer perspective) found
febuxostat to be a cost-effective option compared to allopurinol at achieving a SUA
level < 6 mg/dL despite the fact that the total cost of allopurinol treatment over 5
years was less ($1,882 difference between medications).
Health and Clinical Excellence (NICE), an organization that provides medical
guidance to healthcare practitioners of the public health system in the United
Kingdom, issued a document in 2008 that recommends febuxostat be used only in
patients who are intolerant of or have contraindications to allopurinol therapy or for
those who cannot achieve adequate SUA concentration lowering on allopurinol
75 V.D. does not have any contraindications to allopurinol therapy. She is on
chronic warfarin, which may interact with allopurinol.
her international normalized ratio 5 to 7 days after allopurinol therapy is initiated and
with any allopurinol dosage adjustments.
Probenecid is the only uricosuric agent available in the United States. Clinical
practice guidelines recommend it as an second-line therapy to XO inhibitors for
patients who are unable to take at least one XO inhibitor due to tolerability,
contraindications, or significant drug interactions.
17 The clinical evidence for the
class of uricosurics is limited to comparisons of benzbromarone, which is not
available in the Unites states, to allopurinol. A 2014 Cochrane review concluded that
there were no differences between these agents in the number of acute gout attacks
prevented or the number of patients who discontinued therapy due to side effects.
However, due to the lack of head-to-head comparisons, clinicians must be cautious in
extrapolating these results to probenecid. Uricosurics should not be administered to
patients with impaired renal function or urolithiasis. It is well absorbed orally, and
plasma concentrations peak within 2 to 4 hours. Its biologic half-life is 6 to 12 hours,
and its active metabolites extend the duration of action. The usual initial dose of
probenecid (250 mg twice daily for the first week of therapy) can be increased to
500 mg twice a day. If necessary, the dose can be increased further to 2 to 3 g/day.
Uricosuric therapy should begin with small doses because the excretion of large
amounts of uric acid increases the risk of urate stone formation in the kidney. High
fluid intake to maintain urine flow of at least 2 L/day also minimizes renal stone
formation. This gradual approach to the initiation of ULT also decreases the
likelihood of precipitating an acute attack of gout. Common adverse effects include
Probenecid inhibits secretion of penicillins into the renal tubule, and thereby
prolongs the serum half-life of penicillin and increases penicillin serum
concentrations. Probenecid can also compete with salicylates for renal tubular
transport, but its interactions with salicylates involve several mechanisms.
78 Lowdose aspirin for cardioprotection is unlikely to interfere with probenecid therapy.
Interestingly, high-dose aspirin (e.g., greater than 1 g) has uricosuric activity of its
Recombinant Urate Oxidase Drugs (Uricase)
Uricase, an enzyme endogenous in many animal species other than humans, converts
uric acid to allantoin, which is much more soluble than uric acid and, therefore, more
readily excreted into urine. Recently, two recombinant urate oxidase drugs have been
developed for the treatment of hyperuricemia and gout. However, the high-incidence
serious adverse reactions (23%–24%) as well as cost prohibit routine use. Rather,
they should be considered as alternatives when all other ULTs have failed.
Febuxostat ↓ Concomitant ingestion of an antacid containing magnesium
hydroxide and aluminum hydroxide with an 80-mg single dose
of febuxostat has been shown to delay absorption of
febuxostat (approximately 1 hour) and to cause a 31%
and 15% decrease in AUC. Because
AUC rather than Cmax was related to drug effect, change
observed in AUC was not considered clinically significant.
Therefore, febuxostat may be taken without regard to
Febuxostat Didanosine ↑ Systemic exposures of didanosine are increased during
coadministration. Concurrent use is contraindicated.
↑ Febuxostat is a xanthine oxidase inhibitor. Inhibition of
xanthine oxidase by febuxostat may cause increased plasma
concentration of these drugs, leading to toxicity. Concurrent
use with azathioprine or mercaptopurine is contraindicated.
Use with caution when administering with theophylline.
a↑ = object drug increased; ↓ = object drug decreased.
Rasburicase was initially approved by the FDA for the management of hyperuricemia
in children who are receiving cytotoxic chemotherapy likely to result in tumor lysis
syndrome, and later received approval for the same indication in adults. Rasburicase
is administered as a short IV infusion of 0.2 mg/kg daily for up to 5 days.
comparative short-term study in patients with renal impairment found rasburicase
was significantly more effective than allopurinol in lowering SUA concentrations at
82 Although lower-quality studies show significant
reductions in SUA, rasburicase is not indicated for the treatment of hyperuricemia in
patients with gout, due to its short half-life and immunogenicity. Until further studies
confirm safety and longer-term efficacy in nonchemotherapy-related hyperuricemia,
rasburicase should be reserved for patients with hyperuricemia who are at risk for
Pegloticase, the other available recombinant uricase drug available, has been shown
to be effective in reducing SUA concentrations in patients who were refractory to
conventional treatment in a few small randomized controlled trials.
FDA approval in 2010 for treatment in this limited population. Pegloticase is
administered IV for 2 hours as a dose of 8 mg every 2 weeks.
85 and infusion site reactions, so each dose must be preceded by
prophylaxis with an antihistamine and corticosteroid. It is contraindicated in patients
with glucose-6-phosphate dehydrogenase deficiency, and the usual gout flare
prophylaxis is recommended for the first 6 months after initiation. Finally,
antipegloticase antibodies occurred in the majority of patients studied, and this can
ameliorate the SUA-lowering effects by decreasing the half-life of pegloticase. The
full implication of this is unknown.
Some medications (e.g., ascorbic acid, antihypertensive agents, and fenofibrate) used
to treat conditions commonly seen in conjunction with gout have been proven to have
uricosuric properties. However, the currently available trials evaluating these agents
have significant limitations and uric acid lowering is minimal. It is also important to
note that to date no trials evaluating their effectiveness on clinically relevant
outcomes (e.g., gout attacks) have been published. If future randomized trials show
promise, some patients with hyperuricemia might be managed better by selecting
drugs to manage comorbid conditions rather than requiring the use of the more
Vitamin C has a urate-lowering effect that is believed to be mediated by competition
with urate for renal tubular reabsorption.
86 However, clinical practice guidelines do
not address its place in therapy, and there is a lack of high-quality evidence to
support routine use for the prevention of gout attacks.
In a case–control study, calcium channel blockers and losartan have been shown to
decrease the risk of incidence gout.
89 Other antihypertensive agents (e.g., β-blockers,
diuretics, angiotensin-converting enzyme inhibitors, and nonlosartan angiotensin II
receptor blockers) were also studied and were found to have increased risk of gout.
When used with diuretics, losartan appears to mitigate the hyperuricemic effect of the
It does not seem to be a class effect for the class of angiotensin II receptor
blockers because, in a study, patients on losartan achieved significantly lower SUA
concentrations than an irbesartan-treated group.
In patients with hyperuricemia and
HTN, losartan and calcium channel blockers may be a viable option depending on
Fenofibrate has been shown to decrease SUA concentrations by increasing renal
In addition to therapeutic lifestyle changes, fibrates (i.e.,
gemfibrozil, fenofibrate) or niacin is commonly used for the treatment of
hypertriglyceridemia. However, with a history of gout and hyperuricemia, a fibrate
would be preferred over niacin because niacin can induce hyperuricemia.
Fenofibrate is a reasonable option for patients requiring a decrease in triglycerides
and a history of gout; however, the selection of a medication to manage this comorbid
condition also involves other clinical variables that might be equally
FLARE PROPHYLAXIS DURING INITIATION OF ULT
Paradoxically, initiation of ULT can precipitate acute gout attacks. Guidelines
recommend prophylaxis with anti-inflammatory agents for all patients when ULT is
32–34 The following anti-inflammatory agents should be considered, in order
of preference: colchicine, low-dose NSAIDs, and oral corticosteroids.
when choosing prophylactic therapy, one should also consider patient comorbidities,
3 months may be reasonable in patients without evidence of tophi who achieve SUA
target concentrations. V.D. would be a candidate for flare prophylaxis. As stated
above, V.D.’s advanced age, acute exacerbation of heart failure, and renal
dysfunction are patient-specific parameters that are relative contraindications or
precautions for the use of long-term NSAID therapy for flare prophylaxis. Colchicine
would be a reasonable option because it is considered first line and she tolerated
colchicine during acute attacks. The colchicine dose for flare prophylaxis is 0.6 mg
once or twice daily for 6 weeks. V.D. should be monitored for adverse drug
In addition to monitoring for subjective and objective evidence of drug-related
adverse effects, SUA concentrations should be monitored monthly until at goal, then
every 6 to 12 months, thereafter. The optimal duration of ULT is unclear. Patients
with mild gout may go years without experiencing repeat attacks after discontinuation
of ULT. Lower SUA concentrations during treatment correlate with a longer interval
between acute attacks or before tophi reappear. The majority of patients on long-term
ULT are likely to experience recurrent acute attacks, tophi, or both if treatment is
93 The decision when to discontinue ULT should be made based primarily on
patient preference after a shared-informed discussion.
QUESTION 1: T.M., a 50-year-old man, is seen by his physician for a routine evaluation. His physical
concentration of 9.5 mg/dL. Should his hyperuricemia be treated?
Individuals with high SUA concentrations are more likely to develop acute gouty
arthritis than normouricemic individuals. A large percentage of hyperuricemic
patients may never experience an acute attack of gout.
excessive to treat all hyperuricemic individuals with uric acid-lowering medications
for lifetime solely to prevent acute attacks of gouty arthritis. If an attack should occur,
it can be treated quickly and easily, and if the patient has at least two attacks in a
year, ULT can be considered. The ACR guidelines chose not to address this
condition due to lack of quality evidence.
The key issue in the treatment of hyperuricemia concerns the effect of uric acid on
renal function. Renal disease was commonly associated with gout, and renal failure
was believed to be the eventual cause of death in as many as 25% of gouty patients.
However, the coexistence of gout and renal insufficiency without HTN is rare.
Therefore, the consensus now seems to be that hyperuricemia by itself has no
deleterious effect on renal function.
The pharmacist has an important role in the education and management of gout. As
noted several times in this chapter, there are significant drug–drug interactions
associated with a majority of the medications used to treat both acute and chronic
gout. A 2008 retrospective cohort study showed that 28% of patients did not meet
with a provider prior to initiation of ULT and 56% of patients were nonadherent with
97 Patient education about the role of the medication, including the importance of
adherence and how to monitor for and manage adverse drug reactions in the treatment
of gout, is an essential part of therapy. In the cases where a provider visit did not
occur prior to starting ULT, a pharmacist could have been a resource for education.
Pharmacists are equipped with the knowledge and skills to monitor for drug–drug
interactions, monitor and educate about medication adherence, and provide general
education about gout and lifestyle recommendations. Also, open communication with
the patient’s primary-care provider has the potential to improve the patient
experience related to this condition.
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