Update in Managing Acute and

Chronic Pain. Focus on Etoricoxib

 P atients

A re

In

I cant stand this! N eed

The International Association for the Study of Pain
defines it as:

An unpleasant sensory and emotional experience associated

with actual or potential tissue damage or described in terms
of such damage.
 Unrelieved Pain

USA Survey 1999: “40% 0f Chronic

(moderate to severe) pain pts. reported that their pain is
“Out of Control”
and
“They had not found adequate relief”
despite advanced in new pain medications
 Perception Mechanism of Pain

Pain

Modulation
Descending
modulation Dorsal Horn

Ascending
input
Dorsal root
ganglion
Transmission

Transduction
Spinothalamic
Peripheral
tract
nerve

Trauma
Peripheral
nociceptors

Adapted from Gottschalk A et al. Am Fam Physician. 2001;63:1981, and Kehlet H et al. Anesth Analg. 1993;77:1049.
 Long-Term Consequences of Acute Pain Potential for
Progression to Chronic Pain Structural Remodeling
Sensitization

Surgery CNS
or Peripheral Peripheral Neuroplasticity
injury Nociceptive Nociceptive
causes Fibers Fibers
inflammation Hyperactivity

Transient Sustained
Activation Activation

ACUTE CHRONIC
PAIN PAIN

Woolf CJ, et al. Ann Intern Med. 2004;140:441-451; Petersen-Felix S, et al. Swiss Med Weekly. 2002;132:273-278; Woolf CJ. Nature.1983;306:686-688; Woolf
CJ, et al. Nature. 1992;355:75-78.
 TYPES OF PAIN

• ACUTE PAIN • VISCERAL PAIN

• CHRONIC PAIN • REFERRED PAIN
• CUTANEOUS PAIN • NEUROPATHIC PAIN
• DEEP SOMATIC PAIN • PHANTOM PAIN
 Differences between acute and chronic pain

Acute Pain Chronic Pain

• Less than 6 weeks • Several weeks/years

• Incidence common • Incidence, often

neglected

• Well defined • Poorly defined

• Reasonably easy to assess • Difficult to assess

 Differences between acute and chronic pain
Acute Pain Chronic Pain

• Known cause treatable • Often unable to define

• Logical treatment cause

• Reliant on experience

• Completely focused on the and experiments

pain • Pain takes over and

becomes part of life
 Differences between acute and chronic pain
Acute Pain Chronic Pain

• Emotional State / Anxiety • Emotional State /

• Medication helpful
• Results good
• Pain is a “Symptom”
Depression
• Medication may help
• Results often
disappointing
• Pain is the “Disease”
 Pain pathways
Acute and Chronic Pain are different:

Acute Pain
•Useful function, warning to protect body from injury

Chronic Pain
•Pain no longer serving useful function ongoing/
constant
ASSOCIATION OF INADEQUATE PAIN RELIEF
(IPR) WITH QUALITY OF LIFE: EVIDENCE
FROM THE SURVEY OF OSTEOARTHRITIS
REAL WORLD THERAPIES (SORT)

A poster presentation
Conaghan PG, et al. Rheumatology Advance Access published August 23, 2014
 Response to Analgesics

IPR

n = 630

n = 536
N =1166

Conaghan PG, et al. Rheumatology Advance Access published August 23, 2014
 Prescribed Medication Use
22.78
Alternative 19.42
20.9
79.81
NSAID 71.27
75.24
15.93
Opiods 27.93
22.36
3.7 Non-IPR IPR All patients
Other medication 4.98
4.39
35
Paracetamol 45.59
40.67

Any analgesic
100

0 20 40 60 80 100 120

Percentage of Patients

Conaghan PG, et al. Rheumatology Advance Access published August 23, 2014
 WOMAC* Scores
*WOMAC - Western Ontario and McMaster Universities Arthritis Index

60 56.8 55
53.5
50

40
33.6
28.4 29.9
30

20

10

0
Pain Stiffness Physical Function
Non-IPR IPR

All WOMAC scores indicate worse

outcomes for IPR participants.
A higher score indicates worse outcome.
Scale 0-100 p<0.000

Conaghan PG, et al. Rheumatology Advance Access published August 23, 2014
 Aggressively treated in Acute Management
Acute pain should be aggresively treated for the
following reasons:
• Patient comfort

• Prevent adverse physiology and physiological consequences of

unrelieved pain

• Reduce risk of developing chronic pain

What is the “Best Way” to manage pain?

• FIRST, DO NO HARM
Therefore, the “best way” is a BALANCE

Effective Analgesic
Patient Modalities
Safety
 Multimodal Treatment

Pharmacotherapy
Opioids, nonopioids, adjuvant
analgesics
Physical Medicine and Interventional
Rehabilitation Approaches
Injections,
Assistive devices, electrotherapy
neurostimulation
Strategies for Pain
and Associated
Disability
Complementary and Psychological Support
Alternative Medicine Psychotherapy,
Massage, supplements group support

Lifestyle Change
Exercise, weight loss

Fine PG, et al. J Support Oncol. 2004;2(suppl 4):5-22.

Portenoy RK, et al. In: Lowinson JH, et al, eds. Substance Abuse: A Comprehensive Textbook. 4th ed. Philadelphia, PA: Lippincott, Williams &
Wilkins; 2005:863-903.
 Nociceptive Vs Neuropathic Pain

Nociceptive Mixed Type Neuropathic

Caused by a
Pain combination of both Pain
Caused by activity in primary injury or Initiated or caused by
neural pathways in secondary effects primary lesion or
response to potentially dysfunction in the
tissue-damaging stimuli nervous system

CRPS*

Postherpetic
Postoperative neuralgia
Arthritis Trigeminal
pain
neuralgia
Sickle cell Neuropathic
Mechanical crisis
low back pain low back pain Central post-
Distal stroke pain
Sports/exercise polyneuropathy
injuries (eg, diabetic, HIV)

*Complex regional pain syndrome

 Pain Management
 PHARMACOLOGIC :
Analgesics broadly divided into
• Non opioid,Opioid & Ajuvant
• Non Opioid: Cox-2 (Etoricoxib), NSAID, Salicylate,
Acetaminophen.
• Adjuvant :Antidepresant,Corticosteroid.

 NON PHARMACOLOGIC
 NSAIDs and COXIBS
Highly effective for pain relieve and inflammation
• More effective than paracetamol
• Better tolerated than opiates
• Key strategy for maintaining function
•Acceptable safety profile
• Mostly predictable side effects

22 September 2012
 And...COXIBS, unlike NSAIDs
• Do not cause bleeding or ulceration in the upper or lower GI
tract
• Do not interfere with platelet function
• Do not interfere with antiplatelet effect of aspirin
• Do not precipitate asthma in ‘aspirin sensitive’ people

22 September 2012
 Etoricoxib
Powerfull in Acute and Chronic Pain
Etoricoxib showed 24 minutes fast onset of action
& 24 hours long last
Pain Relief Score* Over 24 Hours
Etoricoxib 120 mg had a 24-minute onset of action**
(Dose ranging study)
3.5
3.0
Mean PR score (±SE)*

Etoricoxib 180 mg (n=74)

2.5 Etoricoxib 120 mg (n=76)
Etoricoxib 240 mg (n=76)
2.0 Etoricoxib 60 mg (n=75)
1.5
Ibuprofen 400 mg (n=47)
1.0
Placebo (n=49)
0.5
0.0
0 1 2 3 4 5 6 7 8 12 24
Time (hour) postdose
 Etoricoxib 120 mg had a 24-minute or less onset of action in 50% of patients
 Etoricoxib 120 mg sustained a longer duration of action than ibuprofen

SE = standard error
p<0.001 for etoricoxib 60 and 120 mg and ibuprofen 400 mg vs. placebo over eight hours; p≤0.025 for etoricoxib 120 mg vs. ibuprofen 400 mg over eight hours
Study included 60, 120, 180, and 240 mg dose for etoricoxib.
*Pain relief (PR) rated on a 0- to 4-point scale (0 = none, 1 = a little, 2 = some, 3 = a lot, 4 = complete); **Median time to onset in 50% of patients
Adapted from Malmstrom K et al. Clin Ther 2004;26:667-79
 Etoricoxib showed superior efficacy over
Paracetamol/Codeine and comparable with Naproxen
Pain Relief Score* Over 8 Hours
3.5 Etoricoxib 120 mg
3.0 (n=50)
Naproxen sodium 550 mg
2.5 (n=51)
2.0
1.5
Paracetamol/codeine
1.0 600/60 mg (n=50)
0.5 Placebo (n=50)

0.0
0 1 2 3 4 5 6 7 8
Time (hour) postdose

• Etoricoxib 120 mg had a sustained 24-hour duration of action; time to rescue medication was
significantly longer vs. paracetamol/codeine 600/60 mg (p<0.001)

p<0.001 for etoricoxib 120 mg, naproxen sodium 550 mg, and paracetamol/codeine 600/60 mg vs. placebo at eight hours;
p<0.001 for etoricoxib 120 mg and naproxen sodium 550 mg vs. paracetamol/codeine 600/60 mg at eight hours
*PR rated on a 0- to 4-point scale (0 = none, 1 = a little, 2 = some, 3 = a lot, 4 = complete)
Adapted from Malmstrom K et al. Clin J Pain 2004;20:147-55
 Osteoarthritis
Dose-Ranging Study – WOMAC Pain Subscale*
Etoricoxib produced substantial pain relief similar to diclofenac
0
More
Mean change from baseline in

Etoricoxib 60 mg once daily (n=112)

pain
–10 week 0 to 52
Placebo (n=60) Diclofenac 50 mg three times daily (n=102) week
8 to 52
pain level

–20

p<0.001
–30
p=NS

–40

–50 Less
pain
R 2 4 6 8 14 20 26 34 42 52

Placebo- Active-comparator–controlled
controlled
Weeks postrandomization

Re-randomization took place at week 6

NS = not significant
*0- to 100-mm visual analog scale (VAS) (0 = no pain to 100 = extreme pain)
Adapted from Gottesdiener K et al Rheumatology 2002;41:1052–1061; Curtis S et al. Poster presented at EULAR, 2001.
Chronic Low Back Pain
Etoricoxib vs Placebo (Phase 3):
Roland–Morris Disability Questionnairea,b

Etoricoxib significantly reduced limitation of movement

Combined Results
0
–1
LS Mean Change, ±SE

–2
–3
–4
–5
–6
62%
P ≤ 0.001c
–7
–8 Improvement
–9
–10
S R 1 2 4 8 12
Weeks in Study

Placebo (n=217) Etoricoxib 60 mg (n=207) Etoricoxib 90 mg (n=211)

aCombined results from 2 studies; b0–24 scale (decrease in score indicates improvement); cP0.001 for both etoricoxib doses vs placebo
at 4 and 12 weeks.
 Chronic Low Back Pain
Etoricoxib vs. Diclofenac :
Low Back Pain Intensity Scale Response* (Primary Efficacy Measure)

0
LS mean change ( SE)

–10

–20

–30

–40

–50
S R 1 2 4
Week in study

Etoricoxib 60 mg (n=222) Diclofenac 50 mg three times daily (n=218)

LS = least squares; SE = standard error; Screening (S) to baseline (R) = washout period
*0- to 100-mm VAS (0 = no pain; 100 = extreme pain)
Adapted from Zerbini C et al Curr Res Med Opin (in press).
 Etoricoxib 60 mg was as effective as high-dose diclofenac
(50 mg 3 times daily)
• In a 6-week study of patients with OA
– Patients reported comparable pain relief on the WOMAC pain subscale and improvements in WOMAC stiffness
and physical function subscale scores
– The percentage of patients reporting a good or excellent response on PGART was similar for ARCOXIA
and diclofenac
Reduction in pain (WOMAC pain subscale)b

ARCOXIA 60 mg once daily (n=253) More

pain
Mean change from baseline

Diclofenac 50 mg 3 times daily (n=258)

in pain level

P=NS
Less
pain

Weeks postrandomization

Adapted from Zacher et al.

OA=osteoarthritis; WOMAC=Western Ontario and McMaster Universities Osteoarthritis Index; PGART=patient global assessment of response to therapy; NS=not
significant; R=randomization.
a
ARCOXIA 60 mg is the maximum recommended daily dose for the treatment of OA; b0-100 mm VAS (0 = no pain to 100 = extreme pain).
1. Zacher J et al. Curr Med Res Opin. 2003;19:725–736.
Osteoarthritis
Etoricoxib 60 mg vs Diclofenac (Phase 4): PGARTa at 4 Hoursb (Day 1)

Etoricoxib therapy resulted in significantly more patients with good or excellent

responses vs initial dose of diclofenac

Etoricoxib
60 mg 14 23 31 30 2
(n=187)

Diclofenac
50 mgd 15 24 42 18 1
(n=199)

None Poor Fair Good Excellent

Patients, %

a0- to 4-point Likert scale (0=excellent to 4=none); b4 hours ± 15 minutes after the first dose (morning); cP=0.007 for etoricoxib 60 mg
vs diclofenac 50 mg for good or excellent responses; dInitial dose.
Adapted from Zacher J, et al. Curr Med Res Opin. 2003;19(8):725–736.
 Etoricoxib 30 mg demonstrated
comparable efficacy to high-dose ibuprofen (800 mg 3 times daily)
• In a 12-week clinical study of patients with OA
– Patients experienced relief across multiple efficacy end points including WOMAC pain subscale, WOMAC
physical function subscale, and PGADS

Combined primary end points (WOMAC subscales and PGADS) over 12-week period
Ibuprofen ARCOXIA
800 mg 30 mg
Placeboc 3 times dailyc once dailyc
(n=104) (n=210) (n=214)
More
pain
LS mean change

-16.53 to -13.55

-26.53 to -22.97 Less

-27.89 to -23.68
d pain
d

Adapted from Wiesenhutter et al.

OA=osteoarthritis; WOMAC=Western Ontario and McMaster Universities Osteoarthritis Index; PGAD =patient global assessment of disease status.
aTrademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA.
bARCOXIA 60 mg is the maximum recommended daily dose for the treatment of OA.
cRanges in LS mean changes in the primary end points.
dP<0.001 vs placebo.
1. Wiesenhutter CW et al. Mayo Clin Proc. 2005;80:470–479.
 Etoricoxib 30 mg demonstrated
comparable efficacy to celecoxib (200 mg daily)
• In 2 identical 26-week clinical studies of patients with OA
– Patients experienced relief across multiple efficacy end points including WOMAC pain subscale, WOMAC
physical function subscale, and PGADS over 12 and 26 weeks
Reduction from baseline in WOMAC pain subscale score: analysis of TWA over 12 weeksb
Celecoxib ARCOXIA
200 mg 30 mg
Placebo once daily once daily More
(n=126) (n=112) (n=236) (n=246) (n=228) (n=243) pain
Study Study Study Study Study Study
1 2 1 2 1 2
Mean reduction
in score

-12.4
-14.6

Less
-24.7 pain
c -26.7 -27.1
-27.8
c c c

Adapted from Bingham et al.

OA=osteoarthritis; WOMAC=Western Ontario and McMaster Universities Osteoarthritis Index; PGADS=patient global assessment of disease status;
TWA =time-weighted average.
aARCOXIA 60 mg is the maximum recommended daily dose for the treatment of OA.
bTWA represents average treatment effect through trial duration and takes into account the value at any given time point and duration of those values over the entire study

period.
cP<0.001 vs placebo.

1. Bingham CO 3rd et al. Rheumatology (Oxford). 2007;46:496–507.

 Acute Gouty Arthritis
Etoricoxib vs. Indomethacin (Phase III): Joint Swelling*
Etoricoxib as effective as indomethacin in reducing swelling
0.0 0.0
Study 1 Study 2
–0.5
LS mean change from

–0.5
baseline ( SE)

–1.0 –1.0

–1.5 –1.5

–2.0 –2.0

–2.5 –2.5

R 2 5 8 R 2 5 8 Improved
Day in study Day in study
response

Etoricoxib 120 mg Indomethacin 150 mg**

(n=74 study 1, n=101 study 2) (n=73 study 1, n=86 study 2)

*Investigator assessment; 0- to 3-point Likert scale (0 = none, 1 = palpable, 2 = visible, 3 = bulging beyond joint margins); **50 mg three times daily
Adapted from Boice JA et al. Poster presented at EULAR, 2002; Navarra S et al. Poster presented at APLAR, 2002; Schumacher HR Jr et al BMJ 2002;324:1488–1492; Rubin
BR et al Arthritis Rheum 2004;50:598–606.
 THE POWER STUDY
Etoricoxib improves pain, function and quality of life: result of
a real-world effectiveness trial
H. Y. LIN, et al., International Journal of Rheumatic Disease,
2010

34
 The POWER Study
• A multicenter, prospective, open-label, single arm, 4-week study
in patients with OA.
• OA patients taking NSAIDs or other analgesic were switched
directly to etoricoxib 60 mg once daily for 4 weeks without prior
medication washout.
• Main Objective : To demonstrate the effectiveness of etoricoxib
in the management of OA patients with suboptimal pain control
after using standard therapy (NSAID, Cox-2, acetaminophen,
etc)  Measure by the proportion of patients with clinically
significant response (≥30% reduction in pain VAS ) after 4 week
study drug treatment.

H. Y. LIN, et al., International Journal of Rheumatic Disease, 2010

 Study Design

An open, single-arm, prospective, observational Large and real-life

study in patients with OA enrollment plan

Multicenter

500 patients from 16 sites

No wash-out Dec. 2007 ~ Nov. 2008

A real-life practice Efficacy

QoL
Etoricoxib 60 mg once daily

-4 Screen 4
Existing Treatment
Not satisfied Weeks of treatment

H. Y. LIN, et al., International Journal of Rheumatic Disease, 2010

 Patient disposition
- Enrolled 500 OA patients and 419 subjects completed the study
- 81 patients who can’t complete the study were mostly due to lost
to follow-up and withdrew consent

Patient entry into the study (n=500)

Excluded (n=81) Included into baseline analysis (N=500)

Discontinued due to lack of efficacy (N=10, 12.3%)
Discontinued due to AE (N=15, 18.5%)
Lost to follow up (N=19, 23.5%) Included into week 4 analysis
Withdrew consent (N=37, 45.7%) WOMAC / BPI (N=419)
-Outside study window period (n=8) TSQM (N=418)
-Refused to complete questionnaire/ (N=7)
-Due to family concern (N=8) IGART (N=430)
-Due to other diseases (N=4)
SF36 (N=418)
-Went to other hospital (N=3)
-Too far/ inconvenient (N=5) EQVAS / EQ5D (N=420)
-Stopped taking study drug but took
non-study drug (N=2)

H. Y. LIN, et al., International Journal of Rheumatic Disease, 2010

 Comorbidities
- A real-life enrollment including :
39% of Hypertension and 11% of Diabetes patients

N=496 N %
None 140 (28.23%)
Hypertension 194 (39.11%)
Osteoporosis 94 (18.95%)
Diabetes 53 (10.69%)
Peptic ulcer disease 31 (6.25%)
Cardiovascular disease (CHF, heart attack) 22 (4.44%)
Asthma 14 (2.82%)
Cancer 12 (2.42%)
Anemia 11 (2.22%)
Kidney disease 8 (1.61%)
Lung disease 7 (1.41%)
Obesity 6 (1.21%)

H. Y. LIN, et al., International Journal of Rheumatic Disease, 2010

 Pain regimens at baseline
- Top baseline regimens : 21% for celecoxib and 16% for meloxicam
N=500 N %
Cox-2-inhibitor 103 (20.6%)
Celecoxib 103 (20.6%)
NSAID 288 (57.6%)
Meloxicam 82 (16.4%)
Diclofenac 58 (11.6%)
Etodolac 36 (7.2%)
Tiaprofenic acid 14 (2.8%)
Naproxen 7 (1.4%)
Nabumetone 5 (1.0%)
Nimesulide 4 (0.8%)
Others 90 (18.0%)
Analgesics 65 (13.0%)
Acetaminophen / Paracetamol 63 (12.6%)
Mefenamic acid 4 (0.8%)
Corticosteroids 23 (4.6%)
Others
Ultracet/tramadol 31 (6.2%)
Propoxyphene 4 (0.8%)
Aspirin 18 (3.6)
 Primary endpoint

After 4-week treatment with etoricoxib :

- 70% of patients experienced pain relief
- 52% of patients experienced over 30% reduction in pain (significant improvement)

% of responder Patient with pain VAS ≥ 40 mm rated by investigator

80 N=274 Q1- During the last 48 hours, rate how much pain have you experienced when walking
on flat surface on WOMAC pain VAS scale: 0=no pain ~ 100= extreme pain
70 70 %
N=204
60 52%
50 N=167
N=140
43%
40 36%
30

20

10

0
≥0% ≥30% ≥40% ≥50%
% of VAS reduction after 4-week treatment with etoricoxib
H. Y. LIN, et al., International Journal of Rheumatic Disease, 2010
 Investigator’s Global Assessment
of Response to Therapy (IGART)

- Patient % of Good to Excellent is increasing from 2 to 43% in IGART

after 4-week etoricoxib treatment

P<0.05 Baseline (n=500)

70.00% Week 4 (n=430)
57.6% * P<0.05
60.00%

50.00%
36.4%
40.00%
35.4% 36.7%
30.00%
2% 43%
20.00%
16.1%
10.00% 5.8% 6.1%
4.4%
1.6%
0.00%
None Poor Fair Good Excellent

Trend test - Mantel-Maenszel Test

 Disease impact on work and daily activities before
and after drug switching

For those who are employed, average

1 day they missed from work due to OA pain at Day
baseline but reduced to 0.4 day after 4-week Baseline (n=100)
treatment with ARCOXIA 2 Week 4 (n=78)
During the past 4 weeks, how many whole days 1.0 * P<0.05
and how half days did the patient miss from 0.4 *
1
work because of problems associated with
his/her OA pain?
0 Baseline week 4

For all patient, average 6 days they were unable

to do daily housework due to OA pain at baseline Day
Baseline (n=492)
but reduced to 3.5 days after 4-week treatment 7 6.0
6
Week 4 (n=413)
with ARCOXIA
5 * P<0.05
4 3.5 *
During the past 4 weeks, how many
days was the patient unable to do 3
2
his/her daily housekeeping work
1
because of problems associated with 0
his/her OA pain Baseline week 4
 Acute Gouty Arthritis
Etoricoxib vs. Indomethacin (Phase III):
Patient Assessment of Paina
Etoricoxib produced substantial improvement vs. baseline at 4 hours

0.0 0.0
Study 1b,c Study 2d,e
LS mean change from

–0.5 –0.5
baseline ( SE)

–1.0 –1.0

–1.5 –1.5

–2.0 –2.0

–2.5 –2.5

–3.0 –3.0
R 4 hr 2 3 4 5 6 7 8 R 4 hr 2 3 4 5 6 7 8
Day in study Day in study
Etoricoxib 120 mg Indomethacin 150 mgf
(n=72 study 1, n=101 study 2) (n=71 study 1, n=83 study 2)
Rheumatoid Arthritis
Etoricoxib showed superior efficacy vs naproxen 1000mg (Patient Global
Assessment of Pain Over 12 Weeks)

US (n=803)
0

–5
LS Mean Change in Pain
–10
–11.38
Intensity, VAS

–15

–20
–20.52b
–25

–27.19b
–30
P<0.001

Improvement
Placebo Etoricoxib 90 mg Naproxen 1000 mgd
(US: n=314; Int: n=348) (US: n=321; Int: n=351) (US: n=168; Int: n=177)

a0- to 100-mm VAS (0=no pain to 100=extreme pain); bP<0.001 for both etoricoxib and naproxen vs placebo; cP=0.665 for etoricoxib
vs naproxen; d500 mg twice daily.
VAS=visual analog scale; NS=not significant.
Adapted from Matsumoto AK, et al. J Rheumatol. 2002;29(8):1623–1630
 Etoricoxib were significantly more effective in relieving spinal pain associated with
Ankylosing Spondylitis during the first 6 weeks and the entire 52-week course vs
Naproxen 1000mg

Part 1 Part 2
0
LS Mean Change From

–10
Baseline, ±SE

–20

–30

–40
b,c

–50
S R 2 4 6 8 16 26 34 43 52
Weeks in Study
Placebo Etoricoxib 90 mg Etoricoxib 120 mg Naproxen 1000 mgd
(n=93) (n=126) (n=123) (n=125)

a0-
to 100-mm VAS (0=none to 100=severe); bP<0.050, etoricoxib 90 mg versus naproxen; cP<0.010, etoricoxib 120 mg versus naproxen;
d500mg twice daily.
Adapted from van der Heijde D, et al. Arthritis Rheum. 2005;52(4):1205–1215.
 The Percentage of Ankylosing Spondylitis patients with a good to excellent
response on the PGART was significantly greater for etoricoxib than naproxen
1000mg at 6 Weeks

Percentage of Good-to-Excellent Responders

80
71.6%b,c 69.2%c,d
70
60 54.5%d
Responders, %

50
40
30 25.0%

20
10
0
Placebo Etoricoxib Etoricoxib Naproxen
(n=93) 90 mg 120 mg 1000 mge
(n=103) (n=92) (n=99)

a0-
to 4-point scale (0=excellent, 4=no response); bP=0.013 versus naproxen; cP<0.001, all therapies versus placebo; dP=0.052 versus naproxen;
e500mg twice daily.
Adapted from van der Heijde D, et al. Arthritis Rheum. 2005;52(4):1205–1215.
Safety Profile of Etoricoxib
Primary Endpoint
MEDAL Program: Cumulative Incidence 34.701 3,5
of Confirmed Thrombotic CV Events (PP) Patients Years

Etoricoxib 60 mg and 90 mg demonstrated comparable CV events vs Diclofenac 150 mg

7
Etoricoxib 60 and 90 mg pooled (320 events)
6 Diclofenac 150 mg (323 events)

5 Etoricoxib vs diclofenac
Cumulative Incidence,

HR=0.95 (95% CI: 0.81, 1.11)

4
% (95% CI)

1
P=0.496
0
0 6 12 18 24 30 36 42
Months
Patients at risk
Etoricoxib 16,819 13,359 10,733 8277 6427 4024 805
Diclofenac 16,483 12,800 10,142 7901 6213 3832 815

CV = cardiovascular; PP = per protocol; CI = confidence interval; HR = hazard ratio

Adapted from Cannon CP et al. Lancet. 2006; in press.
 34.701 MEDAL Program 3,5
Patients Years
GI tolerability in patients with OA and RA (n=34,701)

Etoricoxib 60 mg and 90 mg demonstrated superior GI tolerability and superior safety

based on PUBs vs diclofenac 150 mg

The incidences of discontinuations from hepatic-related adverse experiences were

significantly lower for etoricoxib 60 mg and 90 mg treatment groups compared with
diclofenac 150 mg treatment groups for both OA and RA patients in 3 studies
 Secondary End Point
MEDAL Study: Discontinuations 34.701 3,5
Patients Years
Due to Clinical GI AEsa
Etoricoxib 60 mg and 90 mg demonstrated superior GI tolerability vs diclofenac 150 mg

Etoricoxib
20
Diclofenac 150 mg

P<0.001b
15
Rate/100 PY

12.56
P<0.001b
P<0.001b
10
8.20
7.42
6.83

5 3.79 4.15

0
60 mg/day vs 90 mg/day vs 90 mg/day vs
Diclofenac Diclofenac Diclofenac
Patients With OA Patients With RA

GI=gastrointestinal; AEs=adverse events; mITT=modified intention-to-treat; PY=patient-years; OA=osteoarthritis;

RA=rheumatoid arthritis; COX=cyclooxygenase.
aEvents within 1 year of treatment; bFor both COX proportion hazard and stratified log-rank test.
 Etoricoxib vs Nonselective NSAIDs:
GI PUBs
Etoricoxib had lower incidence of confirmed PUBs in the clinical
development program*
0.06
Etoricoxib 60 mg (n=3142)
Nonselective NSAIDs combined** (n=1828)
Cumulative incidence

0.04
~55%
p<0.001
Risk
reduction
0.02

0.00
0 90 180 270 360 450 540
Days (active treatment period)

NSAIDs = nonsteroidal anti-inflammatory drugs; PUBs = perforations, ulcers, bleeds

*Combined analysis of 10 clinical trials in OA, RA, and chronic low back pain; **Naproxen 1000 mg/day, ibuprofen 2400 mg/day,
or diclofenac 150 mg/day
Adapted from Hunt RH et al Am J Gastroenterol 2003;98:1725–1733; Curtis S et al. Poster presented at EULAR, 2002.
 Clinical Development Program
Etoricoxib vs Nonselective NSAIDs: GI-Related Discontinuationsa
Etoricoxib had a lower incidence of discontinuations
in the clinical development program
0.12

0.10
40%–45%
Cumulative Rate

P<0.001
0.08 Risk
reduction

0.06

0.04

0.02 Etoricoxib ≥60 mg (n=2,670)

Nonselective NSAIDs combinedc (n=1,358)
0.00
0 90 180 270 360 450 540

Days, Active Treatment Period

aGI adverse events or abdominal pain; bCombined analysis of 8 clinical trials in OA, RA, and chronic low back pain;
cNaproxen 1,000 mg/day or diclofenac 150 mg/day.

Adapted from Harper S, et al. Poster presented at: EULAR, 2002; 12–15 June 2002; Stockholm, Sweden.
 34.701 MEDAL Program 3,5
Patients Years

Etoricoxib had significantly fewer discontinuations

due to hepatic AEs vs diclofenac 150 mg
The incidence of hepatic-related adverse experiences resulting in discontinuations were significantly lower in the ARCOXIA 60 mg and
90 mg treatment groups, compared with diclofenac 150 mg treatment groups for both OA and RA patients in all 3 studies

Adapted from Cannon et al.

*More patients on diclofenac 150 mg discontinued treatment due to significant liver test abnormalities (ALT, AST) or other hepatic events compared to ARCOXIA 60 mg and 90 mg
CI= confidence interval; EDGE=Etoricoxib vs Diclofenac Sodium Gastrointestinal Tolerability and Effectiveness
 Take Home Message
• Patient’s pain report should be considered
• Assessment of pain should be regularly carried out and managed promptly
• Intervention of pain relief should be individualized
• Not to postpone pain relief but to consider Inter-disciplinary team approach
• Acute and Chronic Pain are different
• NSAIDs & COXIBs are highly effective for pain relieve and inflammation
• Etoricoxib is COX2 inhibitor with proven efficacy & safety
 Etoricoxib 60 mg was as effective as high-dose diclofenac (50 mg 3 times daily)
 Etoricoxib 30 mg demonstrated comparable efficacy to celecoxib (200 mg daily)
 Etoricoxib 60 mg and 90 mg demonstrated comparable CV events vs Diclofenac
150 mg
 Etoricoxib 60 mg and 90 mg demonstrated superior GI tolerability and superior
safety based on PUBs vs diclofenac 150 mg