The Journal of International Medical Research

2012; 40: 1357 1370

Efficacy and Tolerability of Celecoxib

versus Naproxen in Patients with
Osteoarthritis of the Knee: a Randomized,
Double-blind, Double-dummy Trial
MN ESSEX, P BHADRA

AND

GH SANDS

Pfizer Inc., New York, New York, USA

OBJECTIVE: To assess the efficacy and
tolerability of celecoxib versus naproxen
in patients with osteoarthritis (OA) of the
knee.
METHODS:
This
6-month,
randomized, double-blind, double-dummy
trial was conducted at 47 centres in the
USA. Patients with OA of the knee were
randomized to receive 200 mg celecoxib
orally once daily or 500 mg naproxen
orally twice daily. The primary endpoint
was defined as a 20% improvement from
baseline to 6 months in Western Ontario
and McMaster Universities (WOMAC) OA
total score. RESULTS: A total of 586 out of
589 randomized patients received at least

one dose of celecoxib (n = 294) or naproxen

(n = 292). The primary endpoint (6-month
response rate) was achieved by 52.7% and
49.7% of patients in the celecoxib and
naproxen treatment groups, respectively.
Significantly fewer discontinuations due to
gastrointestinal adverse events occurred in
patients receiving celecoxib than in those
receiving naproxen (4.1% versus 15.1%,
respectively). CONCLUSIONS: Over the 6month study period, celecoxib provided
similar improvements in OA symptoms to
naproxen. In addition, celecoxib provided
better upper gastrointestinal tolerability
than naproxen.

KEY WORDS: CELECOXIB; EFFICACY; KNEE; NAPROXEN; NONSTEROIDAL ANTI-INFLAMMATORY

OSTEOARTHRITIS; TOLERABILITY: WOMAC SCORE

Introduction
Osteoarthritis (OA) of the knee is a major
cause of pain and physical disability in the
elderly,1 with symptomatic disease affecting
10% of men and 13% of women aged 60
years in the USA.2 While changes in the
musculoskeletal system associated with
aging increase the propensity for OA, factors
such as joint injury, obesity and genetic
predisposition are important in determining
which joints are affected and the severity of

DRUGS;

disease.1,3,4 The prevalence of OA of the knee

is expected to increase as obesity rates rise
and the population continues to age.2,5
Many patients with OA take medication
for long periods of time and have a number
of comorbidities requiring the use of
concomitant medication, increasing the
likelihood of adverse events6 10 including
gastrointestinal (GI) injury.11,12 There is an
increasing demand for more effective and
safer OA treatments. Clinical guidelines

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Celecoxib versus naproxen in osteoarthritis of the knee
often recommend the use of nonsteroidal
anti-inflammatory drugs (NSAIDs) for the
relief of pain and inflammation associated
with OA.13 19 The cyclo-oxygenase 2 (COX2) selective NSAID celecoxib has proven
efficacy in relieving pain and improving
physical function in patients with OA.20 26
Many studies of NSAIDs for the treatment
of OA have been relatively short-term (6 12
weeks),20,22,23,25,27,28 but patients with
arthritis generally take medication for longer
periods. In order for physicians to employ
evidence-based medicine, data from longer
treatment periods are needed. The present 6month, randomized, double-blind, doubledummy trial was conducted in 47 centres in
the USA in patients with symptomatic OA of
the knee in order to evaluate the efficacy and
tolerability of daily celecoxib compared with
naproxen.

Patients and methods

PATIENTS
This 6-month, multicentre, randomized,
double-blind, double-dummy trial was
conducted in 47 centres in the USA between
March 2004 and January 2005. Men and
women aged 40 years, with OA of the knee
diagnosed according to American College of
Rheumatology criteria29 and who were
determined by their physician to be eligible
for chronic NSAID therapy, were considered
for inclusion. Patients whose knee OA was in
a flare state and who demonstrated
functional capacity classification29 grades I,
II or III at the baseline visit were eligible for
inclusion. Women of childbearing age were
required to be using adequate contraception,
not breastfeeding and to have a negative
urine pregnancy test within 14 days before
the baseline visit.
Exclusion criteria were: (i) acute flare of
inflammatory arthritis or gout/pseudogout
within the past 2 years; (ii) acute trauma at

the index joint within the past 3 months

with active symptoms; (iii) surgery on the
index joint within the past 6 months or
surgery on the nonindex joint within the
past 3 months; (iv) anticipated need for
surgery or another invasive procedure on the
index and/or nonindex joints during the
study; (v) physical therapy on the index joint
or use of a mobility assisting device (e.g.
cane) for < 6 weeks prior to the screening
visit; (vi) use of a walker-assisting device;
(vii) use of oral (at 4 weeks before the first
dose of study medication), intramuscular (at
2 months), intra-articular (at 3 months)
or soft tissue (at 2 months) injections of
corticosteroids;
(viii)
intra-articular
injections of hyaluronic acid in the index
joint 9 months before the first dose of study
medication; (ix) use of paracetamol 24 h
before the baseline visit; (x) use of
anticoagulants or lithium; (xi) use of
glucosamine and/or chondroitin sulphate,
unless the dose had been stable for > 4
months or discontinued for 4 months; (xii)
known sensitivity to nonselective or COX-2
selective NSAIDs, sulphonamides, aspirin or
related compounds; (xiii) oesophageal,
gastric, pyloric channel or duodenal
ulceration 60 days prior to the first dose of
study medication; (xiv) history of GI
perforations, obstructions or bleeding; (xv)
active GI disease; (xvi) renal or hepatic
disease; (xvii) significant bleeding disorder;
(xviii) diagnosis of unstable cardiovascular
disease 6 months prior to study entry; or
(xix) clinically significant laboratory
abnormalities at screening.
The use of nonstudy NSAIDs, antacids,
histamine-2 receptor antagonists or protonpump inhibitors was prohibited, with the
exception of aspirin at a stable dose of 325
mg/day for cardiovascular prophylaxis and
calcium-containing antacids for osteoporosis
prevention.
The
use
of
analgesics

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MN Essex, P Bhadra, GH Sands

Celecoxib versus naproxen in osteoarthritis of the knee
(paracetamol dose of 2 g/day for 3
consecutive days) for reasons other than
arthritis was permitted if absolutely
necessary, but not within 24 h of any visit.
Topical pain relief to nonindex joints was
allowed except within 48 h of any visit.

STUDY DESIGN
Patients were randomized at study entry in a
1 : 1 ratio to receive either 200 mg celecoxib
orally once daily or 500 mg naproxen orally
twice daily, using a computer-generated
randomization scheme. All patients took
study medication in the form of capsules
(active drug or placebo) twice daily to
maintain blinding.
There were five study visits, defined as:
screening (1 14 days prior to the first dose
of study medication); baseline (within 24 h
before the first dose of study medication;
index joint designated at this visit); month 1
(days 27 33 after the first dose of study
medication); month 3 (days 86 94 after the
first dose of study medication); and month 6
(days 175 185 after the first dose of study
medication). Patients completed a 2-day
washout period for analgesic medication
before the baseline visit. Those who stopped
taking study medication were encouraged to
remain in the study and complete the
scheduled visits, but could be discontinued
from the study at any time by the
investigator or at the patients request.
The institutional review board and/or an
independent ethics committee at each centre
approved the protocol. The study was
conducted in accordance with the
Declaration of Helsinki,30 International
Conference on Harmonisation good clinical
practice guidelines,31 the US Food and Drug
Administration (FDA) regulations32 and
local regulatory requirements. All patients
provided written informed consent prior to
enrolment.

STUDY ENDPOINTS
The primary efficacy endpoint was the
Western Ontario and McMaster Universities
(WOMAC)33 total score response rate at
month 6, defined as a 20% improvement in
total WOMAC OA score from baseline to 6
months. The WOMAC scale includes three
subscales that are combined to generate a
total score. The three subscales are: pain (five
questions, each response ranging from 0 4);
stiffness (two questions, each response
ranging from 0 4); and physical function
(17 questions, each response ranging from 0
4). A reduction in score indicates
improvement. Those patients who did not
complete 6 months of treatment were
considered nonresponders for the purposes of
this study.
Secondary efficacy endpoints included
changes from baseline to month 6 in: total
and subscale WOMAC scores; the patients
and physicians global assessments of
arthritis; and the patients assessment of
arthritis pain using a 0 100 mm visual
analogue scale (VAS; 0 mm, no pain; 100
mm, very severe pain). For the patients
global assessment of arthritis, patients rated
their condition on a scale of 1 5 (1, very
good [asymptomatic and no limitation of
normal activities]; 5, very poor [very severe,
intolerable symptoms and inability to carry
out normal activities] in answer to the
question: Considering all the ways the OA
in your knee affects you, how are you doing
today? The physicians global assessment of
arthritis was a similar five point scale,
indicating the physicians opinion based on
the patients disease signs. The patients and
physicians global assessments of arthritis
and the VAS data were assessed at baseline
and months 1, 3 and 6.
Other endpoints included the patients
assessment of arthritis pain response rate at
month 6 (a 20% improvement in VAS score

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MN Essex, P Bhadra, GH Sands

Celecoxib versus naproxen in osteoarthritis of the knee
from baseline) and the change from week 1
to month 6 in GI distress score for patients
remaining on study medication for 6 months
compared with those who prematurely
discontinued study treatment. GI distress
score was measured on a VAS scale of 0 100
mm (0 mm, no distress; 100 mm, complete
distress).34,35 Patients were required to record
GI distress scores weekly in a diary and
changes were calculated using the value at
week 1 as baseline.

SAFETY ASSESSMENTS
Safety assessments included monitoring for
adverse events (adverse drug reactions,
illnesses with onset during the study and
exacerbation of previous illnesses) and any
clinically significant changes in vital signs at
screening, baseline, and months 1, 3, and 6
or early termination. Adverse events were
summarized using the Medical Dictionary
for Regulatory Affairs preferred terms36 and
were subjectively classified by the
investigator as mild, moderate or severe.

STATISTICAL ANALYSES
The sample size was calculated based on the
primary efficacy endpoint (total WOMAC
score response rate). Based on assumptions
derived from studies carried out in the
celecoxib development programme and
postmarketing
information
it
was
anticipated that the response rates for
celecoxib and naproxen would be
approximately 37% and 25%, respectively. A
sample of 250 patients per treatment group
would, therefore, provide 80% power for a
two-sided test at the 5% level of significance.
Efficacy analyses were performed on the
modified intent-to-treat (mITT) population
(all randomized patients who received at
least one dose of study medication and had
at least one postbaseline follow-up efficacy
measurement),
and
safety/tolerability

analyses were performed on the safety

population (all randomized patients who
received at least one dose of study
medication).
The CochranMantelHaenszel test was
used to analyse the primary efficacy
endpoint, the changes in the patients and
physicians global assessments of arthritis
and patients assessment of arthritis pain
(VAS) from baseline to month 6, and the
patients assessment of arthritis pain
response rate at month 6. A general linear
model was used to analyse the changes in
total and subscale WOMAC scores from
baseline to month 6, and the change in GI
distress score from week 1 to month 6.
Descriptive statistics were used to summarize
treatment-emergent adverse events. All
statistical tests were two-sided and were
performed using the SAS statistical package
version 8.0 or higher (SAS Institute Inc.,
Cary, NC, USA). A P-value < 0.05 was
considered statistically significant.

Results
A total of 589 patients were randomized to
the two treatments (celecoxib n = 296,
naproxen n = 293); two patients in the
celecoxib group and one in the naproxen
group did not receive study medication but
underwent at least one postbaseline efficacy
measure. The safety and mITT populations,
therefore, comprised 586 patients (celecoxib
n = 294, naproxen n = 292). Demographic
and baseline clinical characteristics of the
two study groups are shown in Table 1. The
majority of patients were Caucasian females.
There were no statistically significant
between-group differences in demographic
or clinical characteristics at baseline.
A similar percentage of patients remained
on study medication for 6 months in both
groups
(celecoxib
202/294
[68.7%],
naproxen 189/292 [64.7%]; Fig. 1). The

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Celecoxib versus naproxen in osteoarthritis of the knee

TABLE 1:
Demographic and clinical characteristics at baseline of patients with osteoarthritis (OA) of
the knee who were randomized to receive either 200 mg celecoxib orally once daily or
500 mg naproxen orally twice daily for 6 months
Celecoxib
n = 296

Characteristic

60.0 10.7 (39 92)

Age, yearsa
Genderb
Males
104 (35.1)
Females
192 (64.9)
Race/ethnic originb
Caucasian
210 (70.9)
Black
36 (12.2)
Asian
28 (9.5)
Other
22 (7.4)
Time from diagnosis of OA in index
7.2 8.1 (0.003 51.44)
knee to screening visit, years
American College of Rheumatology criteria29
functional capacity classificationb
I
5 (1.7)
II
224 (75.7)
III
67 (22.6)
IV
0 (0.0)
WOMAC33 OA total scorea
53.9 14.8 (11 90)

Naproxen
n = 293
60.7 11.1 (39 89)
95 (32.4)
198 (67.6)
213 (72.7)
34 (11.6)
24 (8.2)
22 (7.5)
8.5 9.0 (0.003 52.35)

6 (2.0)
217 (74.1)
70 (23.9)
0 (0.0)
54.3 15.1 (15 93)

Data presented as mean SD (range), or n (%) of patients.

WOMAC, Western Ontario and McMaster Universities.
No statistically significant between-group differences (P 0.05): ageneral linear model with treatment and
centre as factors; bCochranMantelHaenszel test stratified by centre.

median duration of treatment was 177.5

days (range 1 253 days) in the celecoxib
group and 176.0 days (range 1 203 days) in
the naproxen group. Fewer patients in the
celecoxib group than in the naproxen group
discontinued treatment because of an
adverse event considered by the investigator
to be related to study medication (18/294
[6.1%] and 38/292 [13.0%], respectively).
Information regarding concomitant
medication use was provided by 284 patients
in the celecoxib group and 283 patients in
the
naproxen
group.
Concomitant
medication was used by 246 patients in each
group (86.6% and 86.9% in the celecoxib
and naproxen groups, respectively). The
most commonly used medications in the
celecoxib and naproxen groups were aspirin

(55 and 61 patients, respectively),

multivitamins (39 and 38 patients,
respectively) and tocopherol (25 and 30
patients, respectively).
There was no significant between-group
difference in response rate, with similar
numbers of patients in the celecoxib and
naproxen groups having a 20%
improvement in total WOMAC score from
baseline to month 6 (Table 2). There were
also no significant between-group differences
in response rate in the pain, stiffness, or
physical function WOMAC subscales.
Improvements in both the patients and
physicians global assessments of arthritis
from baseline to month 6 were similar in
both groups (Table 3). In addition, there was
no significant between-group difference in

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Celecoxib versus naproxen in osteoarthritis of the knee

Screened
(n = 747)
Not randomized
(n = 158)
Randomized
(n = 589)

Celecoxib 200 mg once daily

(n = 296)

Naproxen 500 mg twice daily

(n = 293)

294a patients received

treatment and were evaluable
for adverse events

292a patients received

treatment and were evaluable
for adverse events

202 patients remained on

study drug for 6 months

189 patients remained on

study drug for 6 months

44 patients discontinued
due to adverse events

64 patients discontinued
due to adverse events

Two patients in the celecoxib group and one in the naproxen group did not receive study
medication but underwent at least one postbaseline efficacy measure, so the safety and
modified intent-to-treat populations comprised 586 patients (celecoxib n = 294, naproxen
n = 292)

FIGURE 1: Flow chart showing the process of screening, treatment randomization and
treatment withdrawals for the patients with osteoarthritis of the knee who were
randomized to receive either 200 mg celecoxib orally once daily or 500 mg naproxen
orally twice daily for 6 months
the least square mean change in patients
assessment of arthritis pain (VAS score) from
baseline to month 6 (39.3 and 41.2 for
celecoxib and naproxen, respectively). The
VAS pain score response rates (20%
improvement from baseline to month 6)
were also not significantly different between
the two groups (63.2% and 58.6%,
respectively). There were also no significant
between-group differences in the change in
GI distress score throughout the study period
(Fig. 2).

Serious adverse events were experienced

by 3.1% (9/294) of patients in the celecoxib
group and by 2.7% (8/292) in the naproxen
group (Table 4). The majority of serious
adverse events were considered unrelated to
the study drugs. Serious treatment-related
adverse events occurred in 0.7% (2/294) of
patients in the celecoxib group (one case
each of atrial fibrillation and anaphylaxis)
and 0.3% (1/292) in the naproxen group
(thrombocytopenia). There was one reported
serious GI adverse event (haemorrhage),

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Celecoxib versus naproxen in osteoarthritis of the knee

TABLE 2:
Change from baseline to month 6 (or early termination) in total and subscale Western
Ontario and McMaster Universities (WOMAC) osteoarthritis scores33 in patients with
osteoarthritis of the knee who were randomized to receive either 200 mg celecoxib orally
once daily or 500 mg naproxen orally twice daily for 6 months (modified intent-to-treat
population, n = 586)
WOMAC total or subscale
Totala
Respondersb, n (%)
LSM change (SE)
Pain subscale
Respondersb, n (%)
LSM change (SE)
Stiffness subscale
Respondersb, n (%)
LSM change (SE)
Physical function subscale
Respondersb, n (%)
LSM change (SE)

Celecoxib
n = 294

Naproxen
n = 292

155 (52.7)
22.2 (1.1)

145 (49.7)
22.6 (1.1)

163 (55.4)
4.9 (0.2)

147 (50.3)
5.0 (0.2)

153 (52.0)
1.8 (0.1)

150 (51.4)
1.9 (0.1)

155 (52.7)
15.4 (0.8)

146 (50.0)
15.7 (0.8)

aSum

of pain, stiffness and physical function subscale scores.

with 20% decrease (improvement) in WOMAC score from baseline to month 6.
LSM, least squares mean.
No statistically significant between-group differences (P 0.05); general linear model with change from
baseline as dependent variable and factors for treatment, centre and baseline WOMAC score (total or
subscale, as appropriate) as covariates.
bPatients

which occurred in a patient receiving

naproxen, but this was not considered
treatment-related. Serious cardiovascular
adverse events were reported in five patients;
three in the celecoxib group (exacerbation of
coronary artery disease; severe bradycardia
and arrhythmia; atrial fibrillation) and two
in the naproxen group (small vessel
ischaemic disease; chest pain). The episode
of atrial fibrillation in the celecoxib group
was the only serious cardiovascular adverse
event considered to be treatment related by
the investigator. There were no myocardial
infarctions, strokes or deaths during the
study period.
The numbers of all-cause and treatmentrelated adverse events were similar in both
groups (Table 4), with GI adverse events
being the most commonly reported (Table 5).
When GI disorders were stratified by severity,

fewer moderate or severe GI adverse events

occurred in the celecoxib group than the
naproxen group (37 moderate/seven severe
and 54 moderate/13 severe, respectively). In
addition, fewer patients in the celecoxib
group than in the naproxen group
experienced moderate or severe nausea (six
and nine patients, respectively), abdominal
pain (one and six patients, respectively), or
dyspepsia (19 and 21 patients, respectively).
The numbers of patients discontinuing
due to all-cause and treatment-related
adverse events were lower in the celecoxib
group than in the naproxen group (Table 4).
The most common adverse events that led to
discontinuation were GI disorders (Table 5).
Although GI adverse events were reported at
similar frequencies in the two treatment
groups they were less often cited as the
reason for discontinuation by patients

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Celecoxib versus naproxen in osteoarthritis of the knee

TABLE 3:
Patients and physicians global assessments of arthritis at baseline, month 6 (or early
termination) and change from baseline in patients with osteoarthritis of the knee who
were randomized to receive either 200 mg celecoxib orally once daily or 500 mg
naproxen orally twice daily for 6 months
Celecoxib
Global assessment measure
Baseline, n
Very good
Good
Fair
Poor
Very poor
Month 6, na
Very good
Good
Fair
Poor
Very poor
Change from baseline, na
Improvedb
No change
Worsenedc

Naproxen

Patient

Physician

Patient

Physician

296
(0.0)
(0.0)
(22.0)
(67.6)
(10.5)
285
47 (16.5)
126 (44.2)
95 (33.3)
14 (4.9)
3 (1.1)
285
152 (53.3)
130 (45.6)
3 (1.1)

296
(0.0)
(0.0)
(24.3)
(67.9)
(7.8)
285
41 (14.4)
136 (47.7)
87 (30.5)
18 (6.3)
3 (1.1)
285
155 (54.4)
127 (44.6)
3 (1.1)

293
(0.0)
(0.0)
(25.3)
(61.4)
(13.3)
285
59 (20.7)
122 (42.8)
85 (29.8)
14 (4.9)
5 (1.8)
285
155 (54.4)
125 (43.9)
5 (1.8)

293
(0.0)
(0.0)
(23.9)
(66.2)
(9.9)
285
48 (16.8)
138 (48.4)
82 (28.8)
16 (5.6)
1 (0.4)
285
156 (54.7)
128 (44.9)
1 (0.4)

0
0
65
200
31

0
0
72
201
23

0
0
74
180
39

0
0
70
194
29

Data presented as n (%) of patients.

a
Percentages based on the number of patients from the modified intent-to-treat population of 586 patients
for whom there were data at the month 6/early termination visit.
b
Reduction of at least two grades or a change to very good.
c
Increase of at least two grades or a change to very poor.
No statistically significant between-group differences (P 0.05); CochranMantelHaenszel test stratified by
centre.

receiving celecoxib than by those receiving

naproxen (P < 0.0001; Table 5). Upper
abdominal pain, abdominal distension,
constipation, dyspepsia, gastro-oesophageal
reflux disease and nausea were among those
symptoms associated with the largest
between-group differences in rate of
discontinuation for GI adverse events. When
these GI adverse events were combined,
celecoxib was significantly better tolerated
by patients than naproxen (P = 0.0028).

Discussion
In this 6-month trial, 200 mg celecoxib once
daily demonstrated similar efficacy to 500
mg naproxen twice daily in the treatment of

symptoms associated with OA. This finding

was consistent across various measures,
including a 20% improvement in WOMAC
scores, patient assessment of arthritis pain
(VAS score), and both the patients and
physicians global assessments of arthritis
from baseline to month 6. These 6-month
study results support findings from 12-week
trials in OA patients in which 200 mg
celecoxib once daily demonstrated similar
efficacy in terms of pain relief and
improvement in physical function to 500 mg
naproxen twice daily.20,22,25
Celecoxib was generally well tolerated,
with a similar incidence of general adverse
events to that seen with naproxen. The

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Celecoxib versus naproxen in osteoarthritis of the knee

Change in GI distress (VAS)

A Patients who completed the study

4
2
0
2
4
6
8
10
12
14
16
18

Treatment group

Celecoxib 200 mg once daily (n = 202)

Naproxen 500 mg twice daily (n = 189)

20
1

9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30
Time in study (weeks)

Change in GI distress (VAS)

B Patients who prematurely discontinued treatment followed to the time of discontinuation

Treatment group

4
2
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
1

Celecoxib 200 mg once daily (n = 92)

Naproxen 500 mg twice daily (n = 103)

9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
Time in study (weeks)

FIGURE 2: Week by week change from baseline (week 1) in gastrointestinal (GI)

symptoms, as measured by the GI distress score (visual analogue scale [VAS]), for the
patients with osteoarthritis of the knee who were randomized to receive either 200
mg celecoxib orally once daily or 500 mg naproxen orally twice daily for 6 months
(compiled from the modified intent-to-treat population of 586 patients for whom
there were data; n values shown in the Fig.)
change in GI distress (VAS score) was similar
in the two treatment groups, but there were
fewer discontinuations due to GI adverse
events in patients receiving celecoxib than in
those receiving naproxen, suggesting
celecoxib may have a more favourable GI
tolerance profile than naproxen. The results
of the present study are consistent with other
trials that have demonstrated improved GI
tolerance of celecoxib over nonselective

NSAIDs,20,21,25,37 and evidence suggests that

celecoxib is associated with fewer tolerancerelated GI adverse events than nonselective
NSAIDs.37 39 The current study was not
designed to evaluate differences between the
two drugs in the incidence of serious GI
events, such as bleeding or ulcer, but the
single serious GI adverse event reported (GI
haemorrhage) in a patient receiving
naproxen was not deemed to be treatment-

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Celecoxib versus naproxen in osteoarthritis of the knee

TABLE 4:
Overview of treatment-emergent adverse events in patients with osteoarthritis of the
knee who were randomized to receive either 200 mg celecoxib orally once daily or 500
mg naproxen orally twice daily for 6 months (safety population, n = 586)
All-cause
Adverse event measure
Totala
1
Seriousb
Severec
Discontinuation of treatment
Dose reduction or temporary
discontinuation

Treatment-related

Celecoxib
n = 294

Naproxen
n = 292

Celecoxib
n = 294

Naproxen
n = 292

443
193 (65.6)
9 (3.1)
25 (8.5)
44 (15.0)
9 (3.1)

458
197 (67.5)
8 (2.7)
24 (8.2)
64 (21.9)
11 (3.8)

194
124 (42.2)
2 (0.7)
10 (3.4)
30 (10.2)
6 (2.0)

234
142 (48.6)
1 (0.3)
10 (3.4)
49 (16.8)
6 (2.1)

Data presented as number of adverse events or n (%) of patients.

Includes data up to 30 days after the last dose of study medication.
A total of two patients (one in each treatment group) discontinued due to adverse events that were not
treatment-emergent and are not included in this table.
aAn adverse event occurring more than once in the same patient was counted once. A patient with two or
more adverse events contributed once to the count for each different adverse event.
bAny adverse event that resulted in death, was life-threatening, required inpatient hospitalization or
prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, or resulted in
congenital anomaly/birth defect.
cDetermined subjectively by the investigator (mild, moderate, or severe).

related. Practitioners must balance these

current findings with the increased risk of
serious GI adverse events known to be
associated with NSAIDs.11,12
The occurrence of serious cardiovascular
adverse events was infrequent and similar in
the two treatment groups, although the
current study was neither designed nor
powered to investigate cardiovascular
adverse events. There is evidence to suggest
that all NSAIDs may increase cardiovascular
risk to a similar level,8 10 and all
prescription NSAIDs, including celecoxib
and naproxen, have received the same
cardiovascular warning from the FDA.40 The
PRECISION trial, in which celecoxib is being
compared with naproxen and ibuprofen, is
expected to answer the question of overall
benefitrisk of NSAIDs in the treatment of
arthritis pain. Given the importance of GI
and cardiovascular safety with NSAID use,

American College of Rheumatology19 and

National Institute for Health and Clinical
Excellence16,41
guidelines
stress
the
importance of the assessment of relevant risk
factors in individual patients prior to
treatment selection.
The current study assessed a wide range of
patient-reported outcomes covering efficacy
and safety over a 6-month treatment period.
Although this trial was completed several
years ago, data regarding long-term efficacy
and tolerability of treatments for conditions
such as OA remain relevant for current
patient care. Patients must be able to tolerate
medication in order to receive the efficacy
benefits, and information on relative
tolerability is useful when clinicians make
treatment decisions for their patients. A
strength of the present study was the use of
naproxen, one of the most commonly used
NSAIDs in the USA, as the active comparator.

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MN Essex, P Bhadra, GH Sands

Celecoxib versus naproxen in osteoarthritis of the knee

TABLE 5:
Incidence of all-cause treatment-emergent adverse events reported in 2% of patients
with osteoarthritis of the knee who were randomized to receive either 200 mg celecoxib
orally once daily or 500 mg naproxen orally twice daily for 6 months (safety population,
n = 586)
Patients reporting adverse
event
Adverse event

Celecoxib
n = 294

Gastrointestinal disorders
128
Dyspepsia
41
Abdominal distension
21
Diarrhoea
20
Nausea
19
Abdominal discomfort
13
Flatulence
11
Abdominal pain, upper
11
Gastro-oesophageal reflux disease 9
Constipation
7
Abdominal pain
5
Stomach discomfort
5
General disorders
34
Drug ineffective
13
Peripheral oedema
5
Infections and infestations
29
Nasopharyngitis
5
Upper respiratory tract infection
4
Musculoskeletal disorders
45
Arthralgia
18
Back pain
9
Nervous system disorders
24
Headache
8
Skin and subcutaneous disorders
11
Rash
6

Naproxen
n = 292

(43.5)
(13.9)
(7.1)
(6.8)
(6.5)
(4.4)
(3.7)
(3.7)
(3.1)
(2.4)
(1.7)
(1.7)
(11.6)
(4.4)
(1.7)
(9.9)
(1.7)
(1.4)
(15.3)
(6.1)
(3.1)
(8.2)
(2.7)
(3.7)
(2.0)

138
46
16
11
24
12
12
18
6
10
8
6
36
11
11
37
8
7
29
10
4
26
6
13
4

(47.3)
(15.8)
(5.5)
(3.8)
(8.2)
(4.1)
(4.1)
(6.2)
(2.1)
(3.4)
(2.7)
(2.1)
(12.3)
(3.8)
(3.8)
(12.7)
(2.7)
(2.4)
(9.9)
(3.4)
(1.4)
(8.9)
(2.1)
(4.5)
(1.4)

Discontinuation due to
adverse event
Celecoxib
n = 294
12
2
2
1
2
1
0
1
0
1
1
0
18
12
1
1
0
0
9
2
1
3
2
1
1

(4.1)
(0.7)
(0.7)
(0.3)
(0.7)
(0.3)
(0.0)
(0.3)
(0.0)
(0.3)
(0.3)
(0.0)
(6.1)
(4.1)
(0.3)
(0.3)
(0.0)
(0.0)
(3.1)
(0.7)
(0.3)
(1.0)
(0.7)
(0.3)
(0.3)

Naproxen
n = 292
44
5
4
1
6
2
1
5
3
4
3
1
19
11
2
2
0
0
7
2
1
2
1
1
0

(15.1)a
(1.7)
(1.4)
(0.3)
(2.1)
(0.7)
(0.3)
(1.7)
(1.0)
(1.4)
(1.0)
(0.3)
(6.5)
(3.8)
(0.7)
(0.7)
(0.0)
(0.0)
(2.4)
(0.7)
(0.3)
(0.7)
(0.3)
(0.3)
(0.0)

Data presented as n (%) of patients.

Includes data up to 30 days after the last dose of study medication.
If a patient had more than one occurrence in the same category, only the most severe occurrence was included.
a
P < 0.0001 versus celecoxib group; Fishers exact test.

In addition, the celecoxib dose used was that

approved and recommended by the FDA for
treatment of OA. The current study, therefore,
provides valuable information to help
physicians make treatment decisions for their
patients with OA.
The findings of the current study are
limited by the short-term nature of the
treatment period relative to the years of drug

therapy usually received by patients with OA.

The efficacy and tolerability of celecoxib for
OA treatment over a 1 2-year period has,
however, been previously demonstrated.37,42,43
While these current data are limited to 6
months, the numerous efficacy and
tolerability measures may provide useful
information for practitioners when choosing
therapy for their patients with OA.

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MN Essex, P Bhadra, GH Sands

Celecoxib versus naproxen in osteoarthritis of the knee
In summary, celecoxib provided relief of
OA symptoms and improvement in physical
function that was similar to naproxen over a
6-month period. In addition, fewer celecoxibtreated patients discontinued therapy due to
GI adverse events compared with those
patients treated with naproxen, suggesting
that celecoxib provided favourable GI
tolerability. These data may be useful to
physicians
when
making
treatment
decisions for their patients with OA.

Acknowledgements
The study was sponsored by Pfizer Inc., New
York, New York, USA. Editorial support was
provided by Dr Christina Campbell,
PAREXEL, Uxbridge, UK and was funded by
Pfizer Inc.

Conflicts of interest
Dr Margaret Noyes Essex, Dr Pritha Bhadra,
and Dr George Sands are full-time employees
of Pfizer Inc.

Received for publication 26 April 2012 Accepted subject to revision 26 May 2012
Revised accepted 23 July 2012
Copyright 2012 Field House Publishing LLP
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Authors address for correspondence

Dr Margaret Noyes Essex
US Medical Affairs Pain and Neuroscience, Pfizer Inc., 235 East 42nd Street, New York,
NY 10017, USA.
E-mail: margaret.essex@pfizer.com

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