ORIGINAL INVESTIGATION

Lack of Efficacy of Acetaminophen in Treating

Symptomatic Knee Osteoarthritis
A Randomized, Double-blind, Placebo-Controlled Comparison
Trial With Diclofenac Sodium
John P. Case, MD; Algis J. Baliunas; Joel A. Block, MD

Background: Recommendations state that acetamino-
phen should be used in preference to nonsteroidal anti-
inflammatory drugs in the initial treatment of symptom-
atic osteoarthritis (OA) of the hip or knee, because of lesser
toxicity and the pervasive belief that acetaminophen is
not only effective in treating OA pain but is of equal an-
algesic efficacy as nonsteroidal anti-inflammatory drugs.
Methods: This was a randomized, double-blind, placebo-
controlled trial of diclofenac sodium, 75 mg twice daily,
vs acetaminophen, 1000 mg 4 times daily, in 82 sub-
jects with symptomatic OA of the medial knee. Osteo-
arthritis was quantitated radiographically, and subjects
met stringent baseline pain criteria. The primary evalu-
ation of efficacy used the Western Ontario and McMas-
ter Universities Osteoarthritis Index, with evaluations at
screening, baseline, and 2 and 12 weeks after treatment.
Intention-to-treat analysis was used.
Results: Twenty-five subjects were randomized to di-
clofenac, 29 to acetaminophen, and 28 to placebo. The
groups were closely matched for age, sex, body mass
index, prior use of OA medications, baseline pain, and
radiographic features. At 2 and 12 weeks, clinically and
statistically significant (P⬍.001) improvements were
seen in the diclofenac-treated group; however, no sig-
nificant improvements were seen in the acetamino-
phen-treated group (P = .92 at 2 weeks and .19 at 12
weeks). Stratification of subjects according to baseline
pain, prestudy OA medication, and radiographic grade
showed no clear pattern of preferential response to
diclofenac, and did not reveal a subset of subjects who
responded to acetaminophen.
Conclusions: Diclofenac is effective in the symptom-
atic treatment of OA of the knee, but acetaminophen is
not. A review of the literature reveals that there is scanty
published evidence for a therapeutic effect of acetami-
nophen relative to placebo in patients with OA of the knee,
because most published studies use active comparators
(ie, nonsteroidal anti-inflammatory drugs) only. The ad-
vocacy of acetaminophen use in subjects with OA of the
knee should be reconsidered pending further placebo-
controlled studies.
Arch Intern Med. 2003;163:169-178

From the Section of
Rheumatology, Rush Medical
College, Rush University
(Drs Case and Block), the
Division of Rheumatology,
Cook County Hospital
(Dr Case), and Rush Medical
College, Rush University
(Mr Baliunas), Chicago, Ill.
L
ARGELY BASED on a single in-
fluential study by Bradley
and colleagues, 1,2 clinical
guidelines for the pharma-
cological management of os-
teoarthritis (OA) of the hip and knee, ema-
nating from both sides of the Atlantic
Ocean, continue to emphasize the initial
use of the pure analgesic, acetamino-
phen, over nonsteroidal anti-inflamma-
tory drugs (NSAIDs).3-7 In the initial study
by Bradley and colleagues,1 acetamino-
phen, 4000 mg/d, was equivalent to ibu-
profen, 1200 or 2400 mg/d; the investi-
gators subsequently reanalyzed their data
to show that the magnitude of underly-
ing knee pain did not alter the apparently
equivalent pain relief afforded by the pure
analgesic (acetaminophen) relative to
analgesic/anti-inflammatory (NSAID)
therapy.2 Until recently, only one other
randomized double-blind trial compar-
ing acetaminophen, 2600 mg/d, with an
NSAID (naproxen, 750 mg/d) had been
published in the English-language litera-
ture, a study by Williams and colleagues8
that also showed analgesic equivalence.
Despite the recommended practice
guidelines and the underlying evidence
from the randomized clinical trials, pa-
tients seem to prefer NSAIDs to acetami-
nophen in the symptomatic treatment of
OA based on perceived increased efficacy,
according to 2 studies9,10 that examined the
issue. Moreover, recent data support the
presence of a significant inflammatory
component in the pathophysiology of
OA, indirectly challenging the notion that
the anti-inflammatory effect of an NSAID
provides no added analgesic benefit rela-
tive to the pure analgesia of agents such
as acetaminophen.11,12

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 Some studies8,10 suggest that tolerance, particularly
gastrointestinal, of acetaminophen is greater than that
of cyclooxygenase-nonselective NSAIDs. However, the
advent and increasingly widespread use of cyclooxygen-
ase 2–specific NSAIDs, such as celecoxib and rofecoxib,
which seem to have a more favorable gastrointestinal
tolerability profile,13,14 renders the toxicity profile of ace-
taminophen less compelling.
As a component of an investigation of the effect of pain
relief on dynamic loading in patients with OA of the me-
dial knee,15 we performed a randomized, double-blind, 12-
week trial of diclofenac sodium, 75 mg twice daily; ace-
taminophen, 1000 mg 4 times daily; and placebo in patients
with symptomatic radiographically defined OA of the me-
dial knee across a broad spectrum of disease, similar to what
would be seen in clinical practice.
METHODS
PATIENT POPULATION
Subjects (aged 40-75 years) with unilaterally symptomatic
idiopathic OA of the knee were drawn from the clinical pa-
tient population of the Section of Rheumatology, Rush-
Presbyterian-St Luke’s Medical Center, Chicago. To be consid-
ered for the study, patients had to meet radiographic and clinical
enrollment criteria. The radiographic criteria consisted of the
presence of radiographic OA (modified Kellgren-Lawrence
grade16,17 ⱖ1) in addition to evidence of medial compartment
involvement, as evidenced by possible or definite medial joint
space narrowing or osteophytes.18 The clinical criteria in-
cluded the presence of preenrollment ambulatory pain (de-
fined as a visual analog scale score of ⱖ30 mm on the 100-mm
scale corresponding to question 1 of the Western Ontario and
McMaster Universities Osteoarthritis Index19 [WOMAC] pain
section [visual analog version 3.0]); moderate pain, by a 5-point
Likert scale; or increased pain (defined as an increase of ⱖ10
mm by the visual analog scale or ⱖ1 by the Likert scale) dur-
ing a 2-week washout period following discontinuation of
preexisting analgesic and/or anti-inflammatory OA medica-
tions. In addition, patients had to be capable of independent
ambulation without the aid of a cane or walker and had to fall
within 1 SD of weight for their height and age according to the
Metropolitan Life Insurance Company tables.20 Exclusion cri-
teria included prior intolerance to either of the study medica-
tions or a history of an NSAID allergy or intolerance, func-
tional class I or IV,21 history of peptic ulcer disease or of
significant other gastrointestinal disease, significant hepatic ab-
normality (aspartate aminotransferase, alanine aminotransfer-
ase, or alkaline phosphatase level ⬎20% above the upper limit
of normal), renal insufficiency (creatinine level ⬎1.2 mg/dL
[⬎106 µmol/L]), hematologic disease (hemoglobin level ⬍9
g/dL, white blood cell count ⬍4.0 ⫻ 103/µL, or platelet count
⬍120⫻103/µL), presence of joint disease other than OA, pres-
ence of joint replacements in the lower extremity, use of sub-
stances that might interfere with pain perception (tranquiliz-
ers, hypnotic agents, or excessive alcohol intake), and
anticoagulation therapy. Subjects were not permitted the use
of nonstudy pain medications during the trial.
The study was a randomized, double-blind, placebo-
controlled trial consisting of a screening and enrollment visit,
when all prestudy OA medications were discontinued (week
−2); a randomization visit corresponding to baseline (and fol-
lowed immediately by treatment allocation) (week 0); and 2
study visits while taking the assigned study medication (weeks
2 and 12). In addition, a telephone interview was performed
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at week 6 to document any medical events and to encourage
follow-up for the final (12-week) study visit. Clinical assess-
ments were performed at weeks −2 (for the purpose of enroll-
ment and screening), 0, 2, and 12. The study was approved and
monitored by the Rush-Presbyterian-St Luke’s Medical Center
Human Investigation Committee (Institutional Review Board).
RADIOGRAPHIC ASSESSMENT
At baseline, standard anteroposterior weight-bearing x-ray films
of the knees and the mechanical axis of the study extremity were
obtained by standard clinical methods.22 X-ray films were in-
terpreted in a random and blinded fashion by a rheumatolo-
gist ( J.P.C.) experienced in the Kellgren-Lawrence scale,16 and
assigned a grade according to the published method as modi-
fied for the knee by Felson et al,17 which weighs the presence
of qualitative joint space narrowing equally with osteophytes
in early (stage 1 or 2) OA.
CLINICAL ASSESSMENT
This consisted of an interview and examination by a physician,
and the supervised self-administration of the 2 disease-specific
study instruments, the WOMAC19 (which is specific for OA of
the hips or knees) and the Lequesne Algofunctional Index for
the Knees (Lequesne index).23 These 2 validated indexes are the
most widely used OA-specific instruments for outcome mea-
surement in patients with OA and are recommended as core out-
come measures by OMERACT (Outcome Measures in Rheuma-
toid Arthritis Clinical Trials).24 Subjects’ conditions were evaluated
by the WOMAC and the Lequesne index at enrollment (week
−2), baseline (week 0) (corresponding to randomization to treat-
ment arm), and weeks 2 and 12. The WOMAC consists of 24
questions grouped in 3 subscores: pain (5 questions), stiffness
(2 questions), and function (17 questions). The Lequesne in-
dex consists of 3 sections: pain or discomfort (which includes
stiffness) (5 questions), walking (maximum capable distance and
use of a walking aid, comprising 2 questions), and function (4
questions). The WOMAC was selected prospectively as the in-
strument of primary analysis; a recent study25 suggests that it has
a better responsiveness than the Lequesne index. In addition, sub-
ject and physician global assessment of arthritis activity was as-
sessed at each visit by a 5-point Likert scale (ranging from “asymp-
tomatic” to “very severe”). Assessment for the presence of
ambulatory pain by a 5-point Likert scale was also an enroll-
ment criterion, as previously described. Ancillary data included
subject and physician global assessment of arthritis activity by a
5-point Likert scale.
TREATMENT ALLOCATION
Subjects were randomized to treatment with diclofenac so-
dium (Ciba-Geigy Corp, Summit, NJ), 75 mg twice daily;
acetaminophen (McNeil Consumer Products Co, Fort Wash-
ington, Penn), 1000 mg (two 500-mg tablets) 4 times daily; or
either or both of matching diclofenac and placebo capsules.
The placebos were supplied by the respective manufacturers
of the active medications and were identical in appearance to
the active medications. All subjects, hence, took diclofenac or
placebo, 1 tablet twice daily, and acetaminophen or placebo,
2 tablets 4 times daily (a total of 10 tablets daily). Compliance
was assessed by pill count at each study visit.
STATISTICAL ANALYSES
By using the total WOMAC score as the primary outcome vari-
able, it was estimated, based on pilot data, that to achieve 95%
power to detect significant between-group differences with a
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 Table 1. Baseline Characteristics by Treatment Group*

Treatment Group

Diclofenac Sodium Acetaminophen Placebo

Characteristic (n = 25) (n = 29) (n = 28)
Age, y 62.9 ± 7.6 62.1 ± 11.4 61.7 ± 9.0
Male-female ratio 10:15 14:15 17:11
Height, m 1.68 ± 0.10 1.70 ± 0.11 1.73 ± 0.12
Weight, kg 76.9 ± 11.5 76.8 ± 13.0 81.3 ± 12.7
BMI 27.0 ± 2.6 26.4 ± 3.7 27.0 ± 2.8
Study knee, right-left ratio 13:12 17:12 12:16
Prestudy pain medications (week −2)†
None 7 (28) 7 (24) 10 (36)
NSAID or high-dose aspirin‡ 17 (68) 18 (62) 17 (61)
Acetaminophen 0 3 (10) 0
NSAID or high-dose aspirin‡ and acetaminophen 1 (4) 1 (3) 1 (4)
Prestudy WOMAC variables (week −2)
Pain 185.5 ± 87.8 158.9 ± 60.1 172.9 ± 108.5
Stiffness 95.1 ± 47.7 82.8 ± 55.5 95.3 ± 51.8
Function 643.0 ± 297.8 536.0 ± 260.3 655.2 ± 385.6
Total 923.6 ± 388.1 777.7 ± 350.6 923.4 ± 530.2
Radiographic features§
Modified Kellgren-Lawrence grade (0-4) 2.3 ± 0.8 2.0 ± 1.0 2.2 ± 0.8
Medial joint space narrowing (0-3) 1.8 ± 0.7 1.5 ± 0.8 1.5 ± 0.7
Medial osteophytes (0-3)
Femoral 0.9 ± 0.9 0.8 ± 1.1 0.8 ± 0.9
Tibial 0.7 ± 0.7 0.7 ± 0.6 0.9 ± 0.7
Lateral joint space narrowing (0-3) 0.5 ± 0.9 0.2 ± 0.4 0.4 ± 0.7
Lateral osteophytes (0-3)
Femoral 0.9 ± 1.0 0.8 ± 1.1 0.9 ± 1.1
Tibial 0.7 ± 0.7 0.5 ± 0.7 0.7 ± 1.0
Mechanical axis, degrees varus 4.4 ± 7.0 4.8 ± 5.3 4.1 ± 5.6

Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by the square of height in meters); NSAID, nonsteroidal anti-inflammatory
drug; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.
*Data are given as mean ± SD unless otherwise indicated. There were no significant between-group differences for any variable (P⬎.05).
†Data are given as number (percentage) of patients. Percentages may not total 100 because of rounding.
‡Defined as greater than 325 mg/d.
§Numbers in parentheses are ranges.

significance level of .05 would require approximately 23 sub-
jects in each treatment group, defining a clinically significant
difference as 20% improvement in the total WOMAC scale.26
Data analysis was performed on an intention-to-treat basis, with
imputation of missing data points as suggested in the WOMAC
guidelines27 and by using last-observation-carried-forward
methods.28 A 1-way analysis of variance (ANOVA) was used
to compare differences in treatment groups at 0 (baseline),
2, and 12 weeks, and groupwise changes between weeks 0 and
2 and weeks 0 and 12. All post hoc analyses were performed
assuming equal variances using the Bonferroni method. Paired-
sample t testing (2 tailed) was used to compare changes in the
WOMAC and Lequesne index and their subsections between
weeks 0 and 2 and weeks 0 and 12.
Software used for analysis was Statistical Product and Ser-
vice Solutions, version 10 (SPSS Inc, Chicago, Ill). Statistical sig-
nificance was defined as Pⱕ.05. Clinical significance was inter-
preted as an improvement of at least 20% in the study variable.26
RESULTS
BASELINE SUBJECT CHARACTERISTICS
AND STUDY FLOW
Eighty-two subjects met the clinical and radiographic cri-
teria at enrollment (week −2) and were randomized (week
0): 25 to diclofenac, 29 to acetaminophen, and 28 to pla-
cebo. The characteristics of the subjects at enrollment and
randomization are given in Table 1. There were no sig-
nificant differences between the groups in any of the in-
dicated variables. Overall, more subjects took NSAIDs or
high-dose (⬎325 mg/d) aspirin (55 subjects [67%]) than
acetaminophen (3 subjects [4%]) or no prestudy OA medi-
cations (24 subjects [29%]); subjects taking NSAIDs or
high-dose aspirin and acetaminophen (n = 3) were in-
cluded in the NSAID/high-dose aspirin group in the per-
centile analysis.
Seven subjects withdrew from the trial between
weeks 0 and 2 (3 in the diclofenac-treated group and 2
each in the acetaminophen-treated and placebo groups).
Fourteen subjects withdrew from the trial between
weeks 2 and 12 (2 in the diclofenac-treated group, 5 in
the acetaminophen-treated group, and 7 in the placebo
group). Overall, during the 12-week trial, 5 subjects
withdrew from the diclofenac-treated group, 7 from the
acetaminophen-treated group, and 9 from the placebo
group. Adverse effects were the leading cause of with-
drawal from the diclofenac-treated group (3 of 5 sub-
jects) and inefficacy from the acetaminophen-treated
group (5 of 7 subjects). The 9 withdrawals from the pla-
cebo group were due to inefficacy (n=4), nonknee pain
(n=2), and other reasons (n=3). None of the groupwise
differences reached the level of statistical significance
(P=.11, by ANOVA).

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 Table 2. Clinical Response at Week 2 and Week 12 Compared With Baseline (Week 0), by Treatment Group

Week 2 − Week 0 Week 12 − Week 0

Week 0 Week 2 Week 12
Variable Score* Score* Difference* P Value % Improvement† Score* Difference* P Value % Improvement†
Diclofenac Sodium–Treated Patients (n = 25)
WO
Pain 199.8 ± 101.5 139.6 ± 105.2 −60.2 ± 68.3 ⬍.001 30.1 146.0 ± 101.2 −53.9 ± 79.3 .002 27.0
Stiffness 97.1 ± 50.4 66.1 ± 49.5 −31.0 ± 31.8 ⬍.001 31.9 66.4 ± 48.6 −30.7 ± 39.4 .001 31.6
Function 669.3 ± 371.6 499.8 ± 395.6 −169.6 ± 185.0 ⬍.001 25.3 506.3 ± 383.2 −163.0 ± 201.5 ⬍.001 24.4
Sum 966.2 ± 498.7 705.5 ± 535.8 −260.7 ± 268.0 ⬍.001 27.0 718.6 ± 515.7 −247.6 ± 294.1 ⬍.001 25.6
LeQ
Pain 4.7 ± 1.9 3.6 ± 2.3 −1.1 ± 2.0 .01 23.4 4.0 ± 2.0 −0.7 ± 2.0 .11 ...
Walking 2.0 ± 1.6 1.7 ± 1.5 −0.2 ± 1.0 .23 ... 1.8 ± 1.6 −0.2 ± 1.7 .57 ...
Function 3.6 ± 1.2 1.7 ± 1.5 −1.9 ± 1.7 ⬍.001 52.8 3.3 ± 1.3 −0.4 ± 1.2 .15 ...
Sum 10.3 ± 3.5 8.6 ± 4.3 −1.7 ± 3.0 .009 16.5 9.0 ± 4.0 −1.2 ± 3.0 .05 11.7
Acetaminophen-Treated Patients (n = 29)
WO
Pain 210.8 ± 86.3 206.1 ± 101.2 −4.7 ± 58.4 .67 ... 186.9 ± 121.5 −23.8 ± 83.2 .13 ...
Stiffness 95.7 ± 57.2 88.9 ± 57.2 −6.9 ± 30.9 .24 ... 86.8 ± 59.3 −8.9 ± 24.2 .06 ...
Function 657.0 ± 262.5 664.8 ± 315.3 7.8 ± 123.1 .74 ... 615.2 ± 360.2 −41.8 ± 205.6 .28 ...
Sum 963.5 ± 374.8 959.8 ± 452.5 −3.8 ± 197.1 .92 ... 889.0 ± 520.4 −74.6 ± 300.0 .19 ...
LeQ
Pain 4.9 ± 2.0 4.7 ± 2.3 −0.3 ± 1.9 .45 ... 4.3 ± 2.6 −0.8 ± 2.3 .08 ...
Walking 1.9 ± 1.6 1.9 ± 1.6 −0.1 ± 1.3 .78 ... 2.1 ± 1.5 0.2 ± 1.8 .52 ...
Function 3.7 ± 0.9 1.9 ± 1.6 −1.7 ± 1.8 ⬍.001 45.9 3.4 ± 1.5 −0.3 ± 1.5 .28 ...
Sum 10.4 ± 3.3 9.9 ± 4.0 −0.6 ± 3.4 .36 ... 9.6 ± 4.7 −1.0 ± 4.0 .22 ...
Placebo-Treated Patients (n = 28)
WO
Pain 198.6 ± 110.9 197.1 ± 118.8 −1.5 ± 52.3 .88 ... 183.4 ± 122.9 −15.3 ± 98.7 .42 ...
Stiffness 97.8 ± 49.3 88.1 ± 50.4 −9.6 ± 27.6 .08 ... 80.6 ± 50.9 −17.1 ± 41.4 .04 17.5
Function 697.1 ± 375.2 661.5 ± 359.4 −35.6 ± 129.9 .16 ... 611.5 ± 365.4 −85.6 ± 223.2 .05 ...
Sum 993.5 ± 519.7 946.8 ± 516.3 −46.8 ± 197.3 .22 ... 875.5 ± 520.5 −118.0 ± 348.9 .08 ...
LeQ
Pain 5.0 ± 2.0 4.9 ± 2.3 −0.1 ± 2.2 .79 ... 4.7 ± 2.4 −0.3 ± 2.3 .77 ...
Walking 1.9 ± 1.6 1.9 ± 1.8 0.0 ± 1.1 .86 ... 1.8 ± 1.9 −0.1 ± 1.3 .88 ...
Function 3.0 ± 1.6 1.9 ± 1.8 −1.1 ± 1.7 .002 36.7 3.1 ± 1.7 0.1 ± 1.1 .73 ...
Sum 9.9 ± 4.1 10.0 ± 4.7 −0.1 ± 2.7 .89 ... 9.6 ± 4.9 −0.3 ± 3.5 .66 ...

Abbreviations: LeQ, Lequesne Algofunctional Index for the Knees; WO, Western Ontario and McMaster Universities Osteoarthritis Index.
*Data are given as mean ± SD.
†Improvement from baseline; tabulated only for statistically significant results (Pⱕ.05).

Pill counts performed at each study visit demon-
strated greater than 90% compliance, and there was no
difference in compliance between the 2- and 4-times-
daily medications (data not shown).
CLINICAL RESPONSE
Using the primary end point, the WOMAC, only the di-
clofenac-treated group was significantly improved at 2 and
12 weeks compared with baseline (Table 2). This was
true for the 3 WOMAC subscales and the total WOMAC.
At a significance level of P⬍.001, clinically significant im-
provement (ⱖ20%) was seen at 2 weeks in the pain, stiff-
ness, and function subscales and in the total WOMAC.
Similar improvement was seen at 12 weeks in the diclo-
fenac-treated group in the pain, stiffness, and function sub-
scales and in the total WOMAC, although the level of sig-
nificance was somewhat less for pain and stiffness than for
function and the total WOMAC. Although the total
Lequesne index was significantly improved in the diclo-
fenac-treated group at 2 weeks and marginally improved
at 12 weeks, there was variability in the significance level
of the Lequesne index subscales. The Lequesne index pain
and function subscales were statistically significantly im-
proved at 2 weeks, but not at 12 weeks, and the Lequesne
index distance-walked subscale was not statistically sig-
nificantly improved at either time point. Clinically, greater
than 20% improvement was seen in the Lequesne index
pain and function subscales at 2 weeks only. Twenty per-
cent clinical improvement in the total Lequesne index was
not seen at either time point.
In marked contrast, in the acetaminophen-treated
group, the results by WOMAC (subscales and sum) at 2
and 12 weeks were statistically and clinically insignifi-
cant. These results were indistinguishable from those for
placebo. At 2 weeks, the Lequesne index function sub-
scale improved in the acetaminophen-treated group and
in the placebo group. The Lequesne index pain, distance-
walked, and sum variables were never statistically or clini-
cally significantly improved from baseline, mirroring the
results in the placebo group. These results are summa-
rized in Table 2.

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 The groupwise responses over time in the WOMAC A Week 0 (Baseline)
pain, stiffness, and function subscales and in the total 400 Week 2
P = .002
WOMAC are shown graphically in the Figure. Week 12
P < .001
There were no significant between-group changes
in subject or physician global assessment of arthritis 300

activity as analyzed by ANOVA (data not shown), with

Pain Score
the exception of a difference in the physician global
200
assessment at week 12 relative to week 0 that favored
the acetaminophen-treated group (a mean±SD improve-
ment of 2.7±0.5) relative to the diclofenac-treated group 100
(a mean ± SD improvement of 2.4 ± 0.5), a difference
of borderline statistical significance (P = .04). The P = .003
P = .002
mean±SD change in the placebo group (2.4±0.5) at 12 0
weeks was not significantly different from the change in Diclofenac Sodium Acetaminophen Placebo
Treatment Group
the diclofenac- and acetaminophen-treated groups
(P=.81 and .19, respectively). There were no between- B
group differences in the subject or physician global 180
P = .001 P = .04
assessments at 2 weeks. To determine whether the 160 P < .001
response to acetaminophen or to diclofenac was in part 140
dependent on the degree of underlying OA pain,2 sub-
120
jects were stratified into tertiles of baseline pain accord-

Stiffness Score
ing to the WOMAC (where the maximum pain section 100

score is 500). The tertiles corresponded to 144.9 or less 80

for the lowest pain tertile (27 subjects in the 3 treatment 60
groups), 145.0 to 230.9 for the middle pain tertile (28
40
subjects), and 231.0 or greater for the highest pain ter-
tile (27 subjects). 20 P = .01
P = .04
For the diclofenac-treated group, in the lowest pain 0
Diclofenac Sodium Acetaminophen Placebo
tertile (n = 10), there was significant improvement by
Treatment Group
t test between weeks 0 and 2 in the WOMAC pain (52.7%
improvement, P = .002), stiffness (44.7% improvement, C
1200
P=.02), and function (40.6% improvement, P=.02) sub- P < .001
scales and in the total WOMAC (43.4% improvement, P < .001
1000
P=.007). At 12 weeks, persistent marginally significant
improvement was seen in the pain (29.4%, P =.04) and 800
stiffness (24.1%, P = .05) subscales, but not in the func-
Function Score

tion subscale (P = .08) or in the total WOMAC (P=.06). 600

In the middle pain tertile, statistically significant im-
provement at 2 weeks was seen in the WOMAC stiff- 400
ness (29.7% improvement, P = .03) and function (24.7%
improvement, P=.02) subscales and in the total WOMAC 200
P < .001
(23.4% improvement, P = .02). At 12 weeks, statistically P = .004
significant improvement was seen in the WOMAC func- 0
Diclofenac Sodium Acetaminophen Placebo
tion subscale only (26.3% improvement, P = .03). Fi- Treatment Group
nally, in the highest pain tertile, statistically significant
D
improvement was seen at 2 weeks in the pain (29.4% im-
1600
provement, P= .04) and stiffness (24.1% improvement, P < .001
P =.05) subscales and at 12 weeks in the WOMAC pain 1400 P < .001
(29.0% improvement, P= .03) and stiffness (24.4% im- 1200
provement, P= .04) subscales and in the total WOMAC
(18.8% improvement, P = .05). Responses at 2 weeks are 1000
Total Score

shown by P value in Table 3. 800

In the acetaminophen-treated and placebo groups,
600
in contrast, there were no statistically significant changes
in the WOMAC pain, stiffness, or function subscales or 400
in the total WOMAC at 2 or at 12 weeks for any of the 3 200 P < .001
pain tertiles (data not shown). P = .002
Application of ANOVA according to pain tertile 0
Diclofenac Sodium Acetaminophen Placebo
yielded results similar to the t test: diclofenac efficacy was Treatment Group
inconsistent and not clearly related to the degree of base-
Mean ± SD Western Ontario and McMaster Universities Osteoarthritis Index
line pain, shown in Table 4, at 2 weeks. Acetamino- pain (A), stiffness (B), and function (C) subscale scores and total score (D),
phen was never superior to placebo (data not shown). A by treatment group over time. P values are shown where significant.

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 Table 3. Stratification by Baseline Variables of WOMAC Response (Using the t Test)
at Week 2 in the Diclofenac Sodium–Treated Group

P Value†

Baseline Variable No. of Subjects* Pain Stiffness Function Total

Pain tertile
Lowest 10 .002 .02 .02 .007
Middle 8 .11 .03 .02 .02
Highest 7 .04 .05 .08 .06
Prestudy OA medications
Non-NSAIDs‡ 7 .12 .08 .05 .05
NSAIDs 17 .001 .001 .002 .001
Kellgren-Lawrence grade
1 or 2 12 .009 .006 .007 .005
3 or 4 7 .03 .02 .01 .01
Medial joint space narrowing
0 or 1 7 .04 .02 .005 .009
2 or 3 12 .004 .008 .03 .02

Abbreviations: NSAID, nonsteroidal anti-inflammatory drug; OA, osteoarthritis; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.
*In the diclofenac sodium–treated group.
†For statistically significant (boldface) results (Pⱕ.05).
‡Subjects taking no prestudy OA medications (n = 24) or acetaminophen (n = 3).

Table 4. Stratification by Baseline Variables of WOMAC Response (Using ANOVA) at Week 2

in the Diclofenac Sodium–Treated Group

P Value†

Baseline Variable Comparison* Pain Stiffness Function Total

Pain tertile
Lowest (n = 27) Diclofenac with acetaminophen .05 .16 .054 .03
Diclofenac with placebo .04 .50 .06 .05
Middle (n = 28) Diclofenac with acetaminophen .49 .11 .02 .06
Diclofenac with placebo .23 .19 .05 .07
Highest (n = 27) Diclofenac with acetaminophen .11 .96 .09 .11
Diclofenac with placebo .09 .71 .64 .37
Prestudy OA medications
None or acetaminophen* (n = 27‡) Diclofenac with acetaminophen .15 .23 .007 .01
Diclofenac with placebo .80 .99 .02 .08
NSAIDs (n = 52) Diclofenac with acetaminophen .01 .10 .004 .004
Diclofenac with placebo .004 .08 .80 .03
Kellgren-Lawrence grade
1 or 2 (n = 47) Diclofenac with acetaminophen .002 ⬍.001 ⬍.001 ⬍.001
Diclofenac with placebo .003 .002 .002 .001
3 or 4 (n = 24) Diclofenac with acetaminophen .85 ⬎.999 .28 .42
Diclofenac with placebo .37 ⬎.999 .48 .46
Medial joint space narrowing
0 or 1 (n = 34) Diclofenac with acetaminophen .005 ⬍.001 ⬍.001 ⬍.001
Diclofenac with placebo .002 ⬍.001 ⬍.001 ⬍.001
2 or 3 (n = 34) Diclofenac with acetaminophen .63 .99 .41 .47
Diclofenac with placebo .29 .99 .70 .56

Abbreviations: ANOVA, analysis of variance; NSAID, nonsteroidal anti-inflammatory drug; OA, osteoarthritis; WOMAC, Western Ontario and McMaster
Universities Osteoarthritis Index.
*Acetaminophen was never significantly different from placebo.
†For statistically significant (boldface) results (Pⱕ.05).
‡Three patients took no prestudy OA medications.

sample size limitation may have compromised the power
to detect a difference in the diclofenac-treated groups by
t test and ANOVA.
Subjects were stratified according to prestudy OA
medication (NSAID, n = 52; acetaminophen, n =3; or no
analgesic or anti-inflammatory prestudy OA medica-
tion, n=24). Because of the few individuals who took ace-
taminophen before the study, these subjects were grouped
along with the no prestudy OA medication group to form
a non–NSAID-pretreated group (n=27). By t test, there
were no significant differences at 2 or 12 weeks for the
non–NSAID-pretreated subjects in the diclofenac- or ace-

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taminophen-treated groups (data not shown). In the
NSAID-pretreated subgroup, in contrast, a statistically sig-
nificant response was seen in treatment with diclofenac,
but not with acetaminophen (shown for diclofenac at week
2 in Table 3). An ANOVA in general was similar, with a
more consistent response to diclofenac relative to ace-
taminophen or placebo seen in the NSAID-pretreated sub-
group compared with the non–NSAID-pretreated group
(shown at 2 weeks in Table 4). Differences as a function
of the prestudy OA medication regimen may, however,
represent an artifact of sample size, there being roughly
twice as many subjects in the NSAID-pretreated than the
non–NSAID-pretreated groups.
Grouping by Kellgren-Lawrence grade into ques-
tionable or mild radiographic OA (grades 1 or 2 [n=47])
and moderate or severe radiographic OA (grades 3 or 4
[n=24]) showed significant improvement in both group-
ings at 2 and 12 weeks in the diclofenac-treated group
only (t test; shown for 2 weeks for diclofenac in Table
3). The relative efficacy of diclofenac to acetaminophen
and to placebo was reflected similarly by ANOVA at 2
weeks, but not at 12 weeks (data shown for 2 weeks in
Table 4).
Finally, stratification by degree of qualitative me-
dial joint space narrowing18 as 0 or 1 (n = 34) or 2 or 3
(n = 34) yielded results by t test at 2 weeks similar to
those demonstrated in subgroup stratification by Kell-
gren-Lawrence grade: diclofenac was effective regard-
less of the degree of joint space narrowing (Table 3),
and acetaminophen was conversely ineffective (data
not shown). The efficacy of diclofenac was not seen,
however, at 12 weeks (data not shown). The ANOVA
by degree of joint space narrowing showed diclofenac
superior to acetaminophen and to placebo at 2 weeks
for grade 0 or 1 joint space narrowing, but not for
greater degrees of qualitative joint space narrowing
(Table 4). The efficacy of diclofenac relative to aceta-
minophen and placebo in this subanalysis was not seen
at 12 weeks. Sample size limitation may explain the lack
of statistically significant efficacy at 12 weeks or, alter-
nately, waning of therapeutic efficacy with time.29
POST HOC
POWER VALIDATION
To determine the power of the study to reject the hy-
pothesis of no difference between the acetaminophen
and placebo groups, a post hoc analysis based on the
data of Table 2 was performed: 20% improvement26 in
the initial mean total WOMAC for the acetaminophen-
treated group (963.5) represents a difference at 2 weeks
of 192.7. The SD of this hypothetical difference was
taken as 268.0, representing the SD of the difference in
the total WOMAC for the diclofenac-treated group at 2
weeks. This SD is larger than that of the observed SD of
the difference at 2 weeks in the acetaminophen-treated
group (197.1) and, hence, is more conservative. For a
size of 29 subjects in the acetaminophen-treated group,
these estimates yield a calculated power to reject the
1-sided null hypothesis of no difference between the
acetaminophen-treated and placebo groups of greater
than 98%.
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COMMENT
This study is in agreement with prior studies30-32 in
showing that diclofenac, 75 mg twice daily, effectively
relieved knee pain in patients with OA at 2 and 12
weeks and resulted in improvements in stiffness and
function; in contrast, acetaminophen, 1 g 4 times daily,
did not differ from placebo in any of these variables.
More subjects withdrew from the diclofenac-treated
group because of intolerance to the medication rather
than inefficacy; the opposite was true in the acetamino-
phen-treated group.
Consistent with an apparent patient preference for
NSAID therapy relative to acetaminophen therapy in those
with OA,9,10 2 recently published studies demonstrate
that greater efficacy is obtained with NSAIDs than with
acetaminophen. Pincus et al33 showed that diclofenac (ad-
ministered in a regimen identical to that used in the pres-
ent study) plus misoprostol was superior to acetamino-
phen in OA of the hip or knee in a randomized crossover
study, at a cost of greater adverse effects. Similarly, Geba
et al,34 in a randomized double-blind trial of acetamino-
phen and 2 cyclooxygenase 2–specific NSAIDs, cele-
coxib and rofecoxib, demonstrated that rofecoxib, 25
mg/d, was superior to acetaminophen and had a similar
tolerability profile.
On the other hand, the 2 older studies cited earlier,
by Bradley et al1 and Williams et al,8 reached the appar-
ently opposite conclusion, namely, that NSAIDs (ibu-
profen and naproxen, respectively) are of no greater
efficacy in OA of the knee than is acetaminophen. Rec-
onciling the seemingly disparate results of the 2 re-
cently published studies and this study with the older and
widely cited earlier investigations3-7 may be approached
by careful consideration of the differing underlying meth-
ods (summarized in Table 5). Systematically, these may
be broadly classified as differences in (1) study design
and analysis, (2) patient and disease selection, and (3)
outcome measurement and interpretation.
Regarding study design and analysis, to our knowl-
edge, this study represents only the second published,
randomized, double-blind, placebo-controlled trial of
acetaminophen in patients with OA (MEDLINE search,
keywords osteoarthritis or osteoarthrosis and acetamino-
phen or paracetamol), following a study in 25 patients
with OA of the knee by Amadio and Cummings35 that
showed efficacy of acetaminophen at a dose of 1 g four
times daily (the dose used in the present study). The
studies by Bradley,1 Williams,8 and Geba34 and col-
leagues were randomized double-blind studies without a
placebo, and the study by Pincus et al33 was a random-
ized, double-blind, crossover study (also without a
placebo). Hence, all comparison studies of NSAIDs vs
acetaminophen subsequent to that of Amadio and Cum-
mings are grounded in the fundamental belief of the
validity of that 1 small study.
Second, research practice dictates that primary analy-
sis be undertaken with intention to treat, generally us-
ing last-observation-carried-forward methods for data im-
putation.36,37 The older studies either did not use8 or did
not indicate the use1,35 of such methods (which had not
yet been widely accepted as the standard); more re-
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 Table 5. Published Trials of Acetaminophen and Acetaminophen/NSAIDs

OA Severity Improvement*

No. of ITT/LOCF X-ray Duration, Outcome Aceta- NSAID

Source Subjects Design Placebo Analysis Film Clinical Site wk Measure minophen NSAID Superior†
Amadio and 25 RDB Yes ? Bilateral Pain, Knee 6 ? + NA NA
Cummings,35 OPs tenderness,
1983 and and swelling
JSN or warmth
Bradley et al,1 184 RDB No ? K-L 2 “Knee pain” Knee 4 HAQ pain + + −
1991 or 3 (Likert scale)
Walking pain − + +
(Likert scale)
Rest pain − + −
(Likert scale)
Williams et al,8 178 RDB No No/No OPs “Knee pain” Knee 6 Rest VAS − + +
1993 Walking VAS + + −
Pincus et al,33 227 RDB No ? K-L 2-4 VAS pain Knee and 6 Targeted NA NA +
2001 crossover score, 30 of hip WOMAC
100
Geba et al,34 382 RDB No Yes/No No ACR clinical Knee 6 WOMAC + + +
2002 criteria, subscales
degree of (not the
pain varied whole
by prestudy instrument)
medication
Present study 82 RDB Yes Yes/Yes K-L 1-4 VAS and Likert Knee 12 WOMAC ⬎ LeQ − + +
scale

Abbreviations: ACR, American College of Rheumatology; HAQ, Health Assessment Questionnaire; ITT, intention to treat; JSN, joint space narrowing;
K-L, Kellgren-Lawrence grade; LeQ, Lequesne Algofunctional Index for the Knees; LOCF, last observation carried forward; minus sign, absence; NA, data not applicable;
NSAID, nonsteroidal anti-inflammatory drug; OA, osteoarthritis; OPs, osteophytes; plus sign, presence; question mark, unknown; RDB, randomized double-blind trial;
VAS, visual analog scale.
*The presence or absence of a statistically significant difference from baseline.
†The presence or absence of a statistically significant superiority of an NSAID to acetaminophen.

cently, Pincus et al33 did not indicate the use of inten-
tion to treat/last observation carried forward and Geba
et al34 used a modified intention-to-treat protocol that did
not use last observation carried forward for the primary
(WOMAC) data. Finally, the efficacy of pharmacologi-
cal therapy in patients with OA may wane with time29;
however, the studies cited were all of roughly the same
medium-term duration. The present study (at 12 weeks)
is longer. Nevertheless, there seemed to be some dimi-
nution in the efficacy of diclofenac at 12 weeks relative
to 2 weeks (Table 2 and the Figure).
Concerning patient and disease selection, these dif-
fered substantially in the NSAID/acetaminophen stud-
ies cited. All but the study by Geba et al34 used radio-
graphic criteria of various degrees of rigor, and all required
the presence of knee pain (or, in the case of the study by
Amadio and Cummings, 35 tenderness, swelling, or
warmth). The studies by Geba34 and Pincus33 and col-
leagues and the present study required a quantitated mini-
mum degree of knee pain. The pain requirement, how-
ever, differed in the study by Geba et al, depending on
whether the prestudy OA medication was acetamino-
phen or an NSAID, which may have potentially affected
the differential pain responses in the researchers’ non-
crossover design. All 5 published studies and the pres-
ent one were of OA of the knee; OA of the hip was the
disease in a few (22%) of the subjects in the study by Pin-
cus et al. Most (55 [67%]) of the subjects in the present
study were taking NSAIDs or high-dose aspirin before
the study, which may reflect relatively severe manifes-
tations of disease and/or the rheumatology clinic popu-
lation out of which the patients were recruited.38 Of the
studies in Table 5, only the study by Geba et al describes
the nature of the subjects’ prestudy OA medications: 77%
were taking NSAIDs in that study, possibly reflecting dis-
ease more severe than that in the present study. Prior treat-
ment with diclofenac did not abrogate an apparent clini-
cal response on subsequent treatment with acetaminophen
in the study by Pincus et al.
Last, in outcome measurement and, above all, in in-
terpretation, there were differences between the present
and prior studies. Numerous investigations25,39-41 have
demonstrated the superiority in patients with OA of dis-
ease-specific instruments such as the Lequesne index and,
especially, the WOMAC. The older studies1,8,35 in Table
5 appeared before the widespread acceptance of these in-
struments and perforce relied on less accurate mea-
sures, such as a single-question visual analog scale or
Likert scale scores. The reliance on the joint-specific tar-
geted WOMAC (directed toward a single joint rather than
toward the whole lower extremities in the conventional
WOMAC application19), as used by Pincus et al,33 is unique
among the recent studies, but has been used success-
fully in the evaluation of surgical outcome in patients with
OA of the hip.42
The most compelling explanation for the dispar-
ate results of these studies (ie, whether acetaminophen
is as effective as NSAIDs or, indeed, is an effective

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analgesic at all in patients with OA of the knee) may
be the emphasis placed by the researchers on their
interpretation of their results. The study by Bradley et
al1 found a statistically significant pain response for
acetaminophen in only 1 of 3 variables investigated,
yet concluded that acetaminophen was equivalent to
high-dose ibuprofen (which itself was significantly
effective in all 3 variables). Similarly, Williams et al8
found acetaminophen effective in 1 of 2 variables and
naproxen effective in both of them and superior to
acetaminophen in 1 of them, yet concluded that effi-
cacy was similar between the 2 drugs. The study by
Pincus et al33 showed that diclofenac was more effec-
tive than acetaminophen, but does not indicate the
presence or lack of statistical or clinical efficacy for
either treatment arm alone and, like the study by Geba
et al34 (and the studies by Bradley1 and Williams8 and
colleagues), lacks a placebo control.
The relatively few patients examined in this study lim-
ited the power of subgroup analysis (Tables 3 and 4), spe-
cifically, the capacity to clearly discern whether some clini-
cal subsets of patients with OA of the knee derive greater
benefit than do others, as suggested by the Pincus et al,33
but not the Bradley et al,1,2 data. On the other hand, this
study, although smaller than all but the 1 investigation that
showed a statistically significant effect of acetaminophen
vs placebo (by Amadio and Cummings35), used the rigor-
ously validated, currently recommended outcome assess-
ments19,23,36; is placebo controlled; and is of sufficient power
(⬎98%) to argue compellingly for the lack of substantial
efficacy of acetaminophen in subjects with clinically and
radiographically quantified idiopathic OA of the knee.
Thus, whereas the bulk of the literature that ascribes sub-
stantial benefit to acetaminophen in patients with OA
is based on trials of active comparators, it seems from this
study that the effect vs placebo may be considerably more
modest, and in the absence of larger scale, randomized,
placebo-controlled trials of acetaminophen in patients with
OA of the knee, the widespread emphasis5-7 on its use in
patients with OA should be reconsidered.
Accepted for publication June 11, 2002.
This study was supported in part by a Specialized
Center of Research osteoarthritis grant AR39239 from the
National Institutes of Health, Bethesda, Md; and an intra-
mural development grant from the Rush Arthritis and Or-
thopedics Institute, Chicago, Ill (Dr Case). Mr Baliunas
was the recipient of a Dean’s Summer Research Fellowship
from Rush Medical College, Chicago.
We thank Richard F. Loeser, MD, for a critical read-
ing of the manuscript.
Corresponding author and reprints: John P. Case, MD,
Section of Rheumatology, Rush Medical College, Rush Uni-
versity, 1725 W Harrison St, Suite 1017, Chicago, IL 60612
(e-mail: jcase@rush.edu).
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