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Allopurinol
Reports
Evaluation of allopurinol use in patients with gout
STEVEN C. ZELL AND JANNET M. CARMICHAEL
Abstract:
The use of long-term allo-
purinol therapy in patients with
gout was evaluated.
A pharmacy computer printout
was used to identify all outpatients
for whom allopurinol had been
prescribed during a six-month peri-
od in 1985 at a large Veterans Ad-
ministration medical center. Medi-
cal records were reviewed to (1)
classify patients as either having or
not having definite indications for
allopurinol treatment, (2) deter-
mine whether physicians had or-
dered roentgenographic and lab-
oratory tests for presence of mono-
sodium urate crystals, uric acid
excretion, and renal function, and
(3) identify gout-associated risk fac-
tors and disease entities that could
cause hyperuricemia. A pharmacy
record of all allopurinol and pro-
benecid prescriptions for the six-
month period was obtained, along
with cost data.
Of the 286 patients who received
allopurinol, 32 received the drug
for an indication that could not def-
initely be established as gout. Of
the 254 remaining patients, only 45
(17.7%) had a definite indication for
allopurinol use as defined by the
pharmacy and therapeutics com-
mittee. Although pretreatment
measurement of serum creatinine
was common, only a few patients
underwent joint aspiration, a 24-
hour urine collection, or roentgen-
ography of affected joints. Large
proportions of the patients were
found to have gout-associated risk
factors. If the 209 patients without
definite indications for allopurinol
therapy had been treated with pro-
benecid instead of allopurinol, the
annual cost savings would have
been about $3700.
Most of the patients receiving al-
lopurinol for gout could reasonably
have been treated with a uricosuric
agent such as probenecid at a lower
cost. Generally, physicians did not
use diagnostic tests optimally be-
fore prescribing allopurinol and
did not attempt to modify risk fac-
tors for gout.
Index terms:
Allopurinol; Costs;
Drug use; Gout; Patients; Pharmacy
and therapeutics committee; Physi-
cians; Prescribing; Probenecid; Pro-
tocols; Rational therapy; Tests, lab-
oratory; Uricosuric agents
Am J Hosp Pharm.
1989; 46:1813-6
Attacks of gout are provoked by the release of
monosodium urate crystals into joint cavities.
1
Epi-
demiologic data directly correlate serum uric acid
concentration with the risk of developing gout
2
;
thus, the prophylactic control of hyperuricemia is a
mainstay of drug treatment.
34
The first priority in the management of gout is
the control of joint pain and inflammation. Non-
steroidal anti-inflammatory drugs and colchicine
are of proven value for these indications.
5
Al-
though gouty attacks are unpleasant, patients with
gout—whose mortality is principally influenced
by cardiovascular disease—generally live as long
as age-matched patients without gout.
6
The renal
complications of nephrolithiasis and urate ne-
phropathy are well known/ but the possibility that
chronic uncontrolled hyperuricemia is the primary
cause of nephropathy in patients with gout is un-
proved. Longitudinal studies of patients with hy-
peruricemia have not demonstrated deterioration
of renal function, and patients with chronic renal
disease who have received long-term allopurinol
therapy have not derived a therapeutic benefit rel-
ative to age-matched control patients:
5
Thus, ac-
ceptable reasons for treating symptomatic hyper-
uricemia are limited to the prevention of recurrent
arthritis and tophaceous gout.
Allopurinol is not the only drug effective in the
long-term management of symptomatic hyperuri-
cemia. Most patients (80-90%) with gout underex-
crete uric acid and can be managed effectively with
a uricosuric agent such as probenecid.
9
Allopurinol
can also be used in underexcretors of uric acid, but
its superiority over probenecid for such patients
has not been proved. Thus, more widespread use of
probenecid should be considered, especially if the
drug is less costly than allopurinol.
The use of allopurinol far exceeds that of proben-
ecid in our institution's ambulatory-care clinics;
nearly 90% of patients with chronic gout receive
allopurinol, and it is the third most common drug
prescribed for our outpatients. The pharmacy and
therapeutics (P&T) committee proposed that the
use of long-term allopurinol therapy in patients
with gout be evaluated. The objectives were to (1)
determine the percentage of such patients who had
a definite indication for allopurinol therapy, (2)
examine physicians' use of roentgenographic and
laboratory tests in establishing the diagnosis of
gout, (3) establish the rates of occurrence of treat-
able risk factors—hypertension, obesity, and hy-
perlipidemia— commonly associated with gout,
STEVEN C. ZELL, M.D., FACP, is Assistant Professor of Medi-
cine, and JANNET M. CARMICHAEL, PHARM.D., is Associate Pro-
fessor of Medicine, Veterans Administration Medical Center
and School of Medicine, University of Nevada, Reno.
Address reprint requests to Dr. Zell at the Department of
Internal Medicine, Veterans Administration Medical Center,
1000 Locust Street, Reno, NV 89520.
Copyright® 1989, American Society of Hospital Pharmacists,
Inc. All rights reserved. 0002-9289/89/0901-1813$01.00.
Vol 46 Sep 1989 American Journal of Hospital Pharmacy
1813
Reports
Allopurinol
and (4) determine the potential cost savings if uri-
cosuric agents were used when allopurinol therapy
was not mandatory.
Methods
We reviewed the medical records of outpatients
at the Veterans Administration Medical Center in
Reno, Nevada. The medical center is a residency
training site for the University of Nevada, and the
ambulatory-care clinics had more than 66,000 visits
in the 1985 fiscal year. The study was approved by
the university's human subject committee and in-
cluded assessment of the prescribing behavior of
both house staff and faculty physicians. Defini-
tions established by the P&T committee for the
study are listed in the appendix. All patients stud-
ied were to have definite or probable gout.
We obtained a pharmacy computer printout that
listed all patients for whom allopurinol had been
prescribed during six months in 1985. A nonphysi-
cian research assistant reviewed the medical re-
cords of the identified patients and eliminated
from the study those patients for whom there was
insufficient documentation that allopurinol was
being used for gout. We then classified the patients
as either having definite indications for allopuri-
nol treatment (see appendix) or not having those
indications.
We reviewed the medical records to assess how
physicians used roentgenographic and laboratory
tests in general and to determine if the following
diagnostic measures had been performed: (1) joint
aspiration to confirm the presence of monosodium
urate crystals, (2) 24-hour urine collection for
quantitation of uric acid excretion, (3) roentgeno-
graphic examination of affected joints, and (4) pre-
treatment analysis of renal function. We also
checked the medical records to see if they indicated
the presence of gout-associated risk factors and dis-
ease entities with increased cell-turnover rates that
could cause hyperuricemia.
We obtained a pharmacy record of original and
refill prescriptions for allopurinol and probenecid
for the same six-month period. The pharmacy com-
puter generated cost data based on the number of
tablets dispensed and drug acquisition costs.
Results
During the six-month period, 286 patients re-
ceived allopurinol, but 32 received the drug for an
indication that could not definitely be established
as gout. Of the 254 remaining patients, only 45
(17.7%) had a definite indication for allopurinol
use as defined by the P&T committee (Table 1).
Pretreatment measurement of serum creatinine
concentration was performed in 51% of patients,
but 24-hour urine specimens were obtained for
only 3 of the 209 patients who did not have a
1814
American Journal of Hospital Pharmacy Vol 46 Sep
Table 1.
Occurrence of Definite Indications for Allopurinol Use
Indication
% Occurrence
(n =
254)
Nephrolithiasisa
7.1
Chronic renal Insufficiency
4.7
Idiopathic uric acid overproduction
3.5
Tophaceous gout
2.0
Psoriasis
1.2
Hematologic cancers
1.2
a Five patients had nephrolithiasis and one additional indication.
Table
2.
Occurrence of Treatable Risk Factors for Gout
Risk Factora
% Occurrence
Hypercholesterolemla
(n =
121)
24.8
Hypertriglyceridemia
(n =
116)
47.4
Obesity
(n =
224)
50.9
Hypertension
(n =
254)
57.9
Diuretic use
(n =
254)b
56.3
a n =
Number of medical records in which information was sufficient to
determine if a risk factor was present.
b Includes use of thiazide diuretics or furosemide.
definite indication for treatment with allopurinol.
Joint aspiration was performed in 4.3% of all the
patients, and 1.6% of all the patients had definite
gout. Only 20% of the patients had undergone
roentgenography of symptomatic joints; 79% of the
roentgenograms were read as normal or nondiag-
nostic.
The majority of the patients had hypertension;
97% of these patients were receiving thiazide diur-
etics or furosemide (Table 2). Hyperlipidemia and
obesity were also common and often coexisted
with hypertension. More than 30% of the patients
were obese and received thiazide diuretics for the
treatment of hypertension.
During the study period, the average daily dos-
age of allopurinol was 300 mg, and the average
monthly cost to the medical center was $3.11. In
comparison, the average daily probenecid dosage
of 1 g had an average monthly cost of $1.64. If the
209 patients without definite indications for allo-
purinol had been treated with probenecid, the an-
nual cost savings would have been approximately
$3700.
Discussion
A large majority of the patients did not have
conditions that necessitated the use of allopurinol
and did not have contraindications to the use of
uricosuric agents. The liberal use of allopurinol
may be a result of physicians' failure to employ a
stepped-care approach to the diagnosis and treat-
ment of gout.
1989
Allopurinol
Reports
Only a few patients underwent joint aspiration;
thus, nearly all the patients were classified as hav-
ing probable gout. The physicians made little ef-
fort to use other diagnostic tests that are helpful in
the evaluation of arthritic complaints, and they
based the diagnosis of probable gout on clinical
grounds. Roentgenographic films of affected joints
may show changes consistent with gouty arthritis,
but such films were used rarely. The clinical pre-
sentation of other diseases, such as infectious ar-
thritis and pseudogout, may be similar to that of
gout. Thus, the use of stricter diagnostic guidelines
might lead to a reduction in allopurinol use and
reveal the presence of other treatable diseases.
After the diagnosis of gout is made and the acute
attack is treated, the physician confronts a host of
long-term treatment options. Colchicine, nonste-
roidal anti-inflammatory drugs, probenecid, or al-
lopurinol may be used if drug therapy is neces-
sary.
10
Determining whether the patient overpro-
duces or underexcretes uric acid may be valuable
when long-term drug therapy is considered.
5,9
Al-
though this step is not necessary in patients with a
clear indication for allopurinol therapy, the physi-
cians in this study rarely ordered a 24-hour urine
collection for any patient. Collection can be cum-
bersome and inconvenient in the ambulatory-care
setting,
15
but 80-90% of patients without a primary
indication for allopurinol therapy underexcrete
uric acidl° and can be effectively treated with a
uricosuric agent.
Although no comparative studies have been
done to assess the relative safety of allopurinol and
probenecid, the adverse effects of both drugs often
preclude their unrestricted use. About 5-10% of
patients receiving long-term probenecid treatment
experience nausea, heartburn, flatulence, or consti-
pation.
16
A mild pruritic rash, drug fever, and renal
disturbances can also occur. Allopurinol causes ad-
verse effects in 3-5% of patients
17
and may cause
hepatotoxicity,
15
acute interstitial nephritis,
19
fe-
ver with severe exfoliative dermatitis, and various
hematologic abnormalities.
17
Treatment of gout in many of our patients could
have included modification of risk factors. Thia-
zide diuretics were commonly used in these pa-
tients. Because such drugs can cause uric acid re-
tention,
20
physicians should consider substituting
treatment with peripheral vasodilators or other
nondiuretic antihypertensive drugs when the di-
agnosis of gout is made. Weight reduction may
have beneficial effects on uric acid metabolism,
21
but referrals to the nutrition clinic or recommenda-
tions for weight loss were not evident in the medi-
cal records.
Neither allopurinol nor probenecid is clearly su-
perior for the treatment of hyperuricemia, but our
acquisition cost for typical dosages was lower for
probenecid. Physicians should consider the cost
savings that would occur if they prescribed pro-
benecid for patients without clear indications for
allopurinol therapy.
Conclusion
Most of the patients receiving allopurinol for
gout could reasonably have been treated with a
uricosuric drug. The physicians rarely attempted to
classify patients as overproducers or underexcre-
tors of uric acid, did not commonly examine syno-
vial fluid or use roentgenographic tests as diagnos-
tic aids, and made little apparent attempt to modify
the risk factors for gout. Preferential use of proben-
ecid in patients without definite indications for
allopurinol may reduce drug costs.
References
1.
Boss GR, Seegmiller JE. Hyperuricemia and gout: classifica-
tion, complications and management.
N Engl J Med.
1979;
300:1459-68,
2.
Hall AP, Barry PE, Dawber TR et al. Epidemiology of gout
and hyperuricemia: a long-term population study.
Am J
Med.
1967; 42:27-37.
3.
Gall EP. Hyperuricemia and gout: a modern approach to
diagnosis and treatment.
Postgrad Med.
1979; 65:163-71.
4.
Rodnan GP, Robin JA, Tolchin SF et al. Allopurinol and
gouty hyperuricemia: efficacy of a single daily dose.
JAMA.
1975; 231:1143-7.
5.
Simkin PA. Management of gout.
Ann Intern Med.
1979;
90:812-6.
6.
Yu T-F, Talbott JH. Changing trends of mortality in gout.
Semin Arthritis Rheum.
1980; 10:1-9.
7.
Emmerson BT. Therapeutics of hyperuricemia and gout.
Med J Aust.
1984; 141:31-6.
8.
Rosenfeld JB. Effect of long-term allopurinol administra-
tion on serial GFR in normotensive and hypertensive hy-
peruricemic subjects.
Adv Exp Med Biol.
1974; 41:581-96,
9.
Palella TD, Kelley WN. An approach to hyperuricemia and
gout.
Geriatrics.
1984; 39:89-102.
10.
Lo B. Hyperuricemia and gout.
West J Med.
1985; 142:104-7.
11.
Wallace SL, Robinson H, Mas AT et al. Preliminary criteria
for the classification of the acute arthritis of primary gout.
Arthritis Rheum.
1977; 20:895-900.
12.
Bierman EL, Hirsch J. Obesity. In: Williams RH, ed. Text-
book of endocrinology. Philadelphia: W. B. Saunders Com-
pany; 1981:907-21.
13.
Bierman EL, Glomset JA. Disorders of lipid metabolism. In:
Williams RH, ed. Textbook of endocrinology. Philadelphia:
W. B. Saunders Company; 1981:876-906.
14.
Cockcroft DW, Gault MH. Prediction of creatinine clearance
from serum creatinine.
Nephron.
1976; 16:31-41.
15.
Simkin PA, Paxson CS, Wilson WF et al. Uric acid excretion:
assessment from spot midmorning serum and urine sam-
ples.
Arthritis Rheum.
1978; 21:592-3.
16.
Bartels EC, Matossian GS. Gout: six year follow-up on pro-
benecid (Benemid) therapy.
Arthritis Rheum.
1959; 2:193-
202.
17.
McInnes GT, Lawson DH, Jick H. Acute adverse reactions
attributed to allopurinol in hospitalized patients.
Ann
Rheum Dis.
1981; 40:245-9.
18.
Al-Kawas FH, Seeff LB, Berendson RA et al. Allopurinol
hepatotoxicity.
Ann Intern Med.
1981; 95:588-90.
19.
Grussendorf M, Andrassy K, Waldherr R et al. Systemic
hypersensitivity to allopurinol with acute interstitial ne-
phritis.
Am J Nephrol.
1981; 1:105-9.
20.
Cannon PJ, Stason WB, Demartini FE et al. Hyperuricemia
in primary and renal hypertension.
N Engl J Med.
1966;
275:457-64,
21.
Emmerson BT. Alteration of urate metabolism by weight
reduction.
Aust N Z J Med.
1973; 3:410-2.
Vol 46 Sep 1989 American Journal of Hospital Pharmacy
1815
Reports
Allopurinol
Appendix—Definitions Established
for Allopurinol-Use Evaluation
Definite indications for allopurinol use:
Uric acid overpro-
duction, states of increased cell turnover (e.g., leukemia, lym-
phoma, myeloproliferative disorders, polycythemia vera, psori-
asis, therapy with cytotoxic drugs), tophaceous gout, and con-
traindication to use of uricosuric agents (e.g., chronic renal
insufficiency, nephrolithiasis).
1,3,5,7,1
°
Definite gout:
Acute arthritis of the first metatarsophalan-
geal joint, concurrent tophi or hyperuricemia, and monosodium
urate crystals in syrtovial fluid obtained by joint aspiration."
Probable gout:
Same as for definite gout, but without exami-
nation of synovial fluid."
Tophaceous gout:
Presence of tophi and typical changes
(sharply defined marginal erosions of subchondral bone) in
roentgenograms of symptomatic joints, interpreted by a radiol-
ogist as being consistent with gout.
Uric acid overproduction:
Presence of more than 800 mg of
uric acid in a 24-hour urine collection, with the patient on an
unrestricted diet.
Hypertension:
Treatment with antihypertensive medica-
tions, or diastolic blood pressure more than 90 mm Hg during at
least three outpatient visits.
Obesity:
Weight more than 20% above ideal body weight.
12
Hyperlipidemia:
Serum cholesterol or triglyceride concen-
tration exceeding the 90th percentile for the age-adjusted brack-
et.
13
Chronic renal insufficiency:
Pretreatment creatinine clear-
ance estimated to be less than 30 mL/ min."
