This document discusses evidence from a clinical trial comparing the NSAIDs etoricoxib and diclofenac for treating pain. The trial involved over 34,000 patients randomized to receive either etoricoxib or diclofenac. Results showed that etoricoxib was as effective as diclofenac at reducing pain, as measured by changes in WOMAC pain scores, but had a more favorable gastrointestinal safety profile with fewer ulcer complications compared to diclofenac. Therefore, the clinical evidence demonstrated that etoricoxib provided comparable pain relief to diclofenac with a reduced risk of gastrointestinal side effects.

1. From clinical evidence to clinical practice
1
Reumatologi Klinik Bandung 2013

2. Pain – an unpleasant sensory & emotional
experience associated with actual & potential
tissue damage, or described in terms of such
damage, or both.
(International Association for the Study of Pain)

3. Descartes
Stimulus response model
Ascending pain
N +
N
Spinal cord

4. Nociception (noxious stimuli)
Neuropathic (functional abnormalities
of the nervous system)

5. Location
Duration
Frequency
Underlying cause
Intensity

6. • Acute pain –<30 days’ duration
• Chronic pain - >6 months
• Subacute pain – from the end of the
first month to the beginning of the
seventh month of continued pain
• Recurrent acute pain – persists over an
extended period of time but occurs
mainly as isolated episodes

8. ➢ VAS=0->4
➢ VAS=4->7
➢ VAS>7

9. Interventional
Neural Blockade
Potent
opioid +/- adjuvant
Weak
+/- adjuvant
opioid
Simple +/- adjuvant
analgesia

10. • attempt to determine etiology of pain
• causative or symptomatic treatment
• the definitive cure of the pain
syndrome

11. • Patient interview • Patient examination
– Pain history – General
– Medical history examination
– Drug history – Systems
– Social history examination

12. • Goal of therapy – minimal pain &
maximal function
• nonpharmacologic treatment
options (kind words, a gentle touch,
just being present)
• pharmacologic treatment

13. Non Opioids
 Paracetamol
 NSAIDS
 COX 2 inhibitors
Opioids
 Weak
 Strong
Naloxone
13
Reumatologi Klinik Bandung 2013

14.  Acetaminophen (Paracetamol)
 Non-steroidal anti inflammatory
drugs (NSAIDS)
 COX 2 inhibitors
14
Reumatologi Klinik Bandung 2013

15.  Effects
› Anti-inflammatory
› Analgesic
› Anti-pyretic
› Anti-platelet
15
Reumatologi Klinik Bandung 2013

16. NSAIDS COX 2 INHIBITORS
 Diclofenac (Voltaren)  Celecoxib (Celebrex)
 Mefenamic Acid  Etoricoxib (Arcoxia)
(Ponstan)  Parecoxib (Dynastat)
 Ibuprofen ( Osdtarin)
 Meloxicam ( Movicox)
 Naproxen (Gesiprox)
 Ketoprofen
(Kaltrofen, Profenide)
 Ketorolac (Toradol)
17
Reumatologi Klinik Bandung 2013

17. • sole treatment for mild to moderate
pain
• adjunct to other analgesics for more
severe pain
• for both acute & chronic pain

18.  Postoperative – mild to moderate pain
 Orthopedic – acute low back pain1,2
 Dental – periodontitis
 Oral surgery – 3rd molar surgery
 Gynecological – dysmenorrhea
 Urological – renal colic
1
Griffin et al. Do NSAIDs help in acute or chronic low back pain?
Am Fam Physician 2002;65
2
Tulder et al. Non-steroidal anti-inflammatory drugs for low-back pain.
The Cochrane Database of Systematic Reviews 2000, Issue 2.
Art. No.: CD000396. DOI: 10.1002/14651858 Vimolluck Sanansilp, Siriraj

19.  Ceiling effect to analgesia
 Adverse effects
› Gastric ulceration
› Reduction in renal blood flow
› Platelet inhibition
› Allergic reactions
 Bronchospasm
 Cross allergy is common
 Gastritis and functional thrombocytopenia are common with
therapeutic doses
 Precautions – prolonged use can lead to
› Renal failure
› Increased risk of myocardial infarct and stroke
20
Reumatologi Klinik Bandung 2013

20. More GI side toxicity
Anti-thrombotic
Less GI side effect
Thromboxane Inhibition
( COX-1 mediated )
Prothrombotic
Prostacyclin Inhibition
( COX-2 mediated )
Celecoxib Diclofenac Ibuprofen ASA
Etoricoxib Naproxen

21.  Drug : Class effect ? No
Individual properties ? :
Dose Ye Dose-
s related
Molecule/Chemistry Yes
Half-life Yes
Effect to BP & sodiumYe
s
Ye
 Duration of Rx
s

23. 39,984 patients screened
5283 patients not
randomized
34,701 patients randomized to treatment
Etoricoxib 60 and 90 mg pooled Diclofenac 150 mg
17,412 started treatment 17,289 started treatment
ITT Population ITT Population
Not included in Not included in
per protocol population per protocol population
223 (1.3%) <75% compliant 463 (2.7%) <75% compliant
388 (2.2%) took nonstudy 362 (2.1%) took nonstudy
NSAID >10% of time NSAID >10% of time
16,819 (96.6%) 16,483 (95.3%)
in per protocol population in per protocol population
ITT=intention-to-treat; NSAID=nonsteroidal anti-inflammatory drug.
Adapted from Cannon CP, et al. Lancet. 2006;368:1771–1781.

24. Primary End Point
7
Etoricoxib 60 and 90 mg pooled (320 events)
6 Diclofenac 150 mg (323 events)
Cumulative Incidence,
5 Etoricoxib vs diclofenac
HR=0.95 (95% CI: 0.81, 1.11)
% (95% CI)
4
3
2
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;368:1771–1781.

25. mITT (14 Days) Analysis
In Patients With OA In Patients With RA
15 Etoricoxib 60 mg OA 15 Etoricoxib 90 mg RA
Diclofenac 150 mg OAa Diclofenac 150 mg RA
Etoricoxib 90 mg OA
Diclofenac 150 mg OAb
Mean Change ±SE
Mean Change ±SE
10 10
5 5
0 0
–0.5 –0.5
BL1 4 8 12 16 20 24 28 32 36 BL1 4 8 12 16 20 24 28 32 36
Months Months
mITT=modified intention-to-treat; OA=osteoarthritis; RA=rheumatoid arthritis;
SE=standard error; BL=baseline.
a
For etoricoxib 60 mg cohort.
b
For etoricoxib 90 mg cohort.

26. mITT (14 Days) Analysis Etoricoxib
Diclofenac 150 mg
3.0 P<0.001 P=0.030
P=0.027 2.53
2.43
2.5
2.16
2.0
Patients, %
1.63 1.61
1.5
1.11
1.0
0.5
0.0
60 mg vs Diclofenac 90 mg vs Diclofenac 90 mg vs Diclofenac
Osteoarthritis Rheumatoid Arthritis
mITT=modified intention-to-treat; CI=confidence interval.
a
Difference in proportions (95% CI).

27. 3.0
Etoricoxib 60 and 90 mg pooled (176 events)
Diclofenac 150 mg (246 events) All confirmed
2.5
eventsa
Cumulative Incidence,
Etoricoxib vs diclofenac
HR=0.69 (95% CI: 0.57, 0.83) P=0.0001
2.0
% (95% CI)
1.5
1.0 Complicated
events
P=0.561
0.5
Etoricoxib vs diclofenac
HR=0.91 (95% CI: 0.67, 1.24)
0
0 6 12 18 24 30 36 42
GI=gastrointestinal; ITT=intention-to-treat;Months CI=confidence interval; HR=hazard
ratio.
Patients at risk for upper GI events, no.
Etoricoxib 17,412 13,704 10,972 8400 6509 4063 821
a
These included uncomplicated 10,396
Diclofenac 17,289 13,190 (perforation, ulcer, and bleeds) and
8027 6306 3867 820
complicated (perforation, obstruction, and bleeds) events.
Adapted from Laine L, et al. Lancet. 2007;369:465–473; Cannon CP, et al.
Lancet. 2006;368:1771–1781.

28. mITT (14 Days) Analysis
3.0
Etoricoxib P=0.284
Diclofenac 150 mg 0.50 (–0.36, 1.37)a
2.5
2.30
2.0
1.80
Patients, %
P=0.895
1.5 0.04 (–0.49, 0.57)a
P=0.696
0.07(–0.24, 0.37)a
1.02 0.98
1.0
0.81 0.75
0.5
0.0
60 mg vs Diclofenac 90 mg vs Diclofenac 90 mg vs Diclofenac
Osteoarthritis Rheumatoid Arthritis
mITT=modified intention-to-treat; CI=confidence interval.
a
Difference in proportions (95% CI).

29. Etoricoxib
20 Diclofenac 150 mg
P<0.001b
15
12.56
Rate/100 PY
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.
a
Events within 1 year of treatment; bFor both COX proportion hazard and stratified log-rank test.

30. Is an NSAID needed ?
Inflammation ? Yes
No
Use non-pharmacologic Is there a contraindication to NSAID ?
or other pharmacologic Rx Yes - Renal insufficiency ( CrCl < 30 )
- Allergic reaction
- Concurrent GI injury
No
Is there a reason that a classical NSAID cannot be used ?
- GI risk+ & Bleeding risk
No Yes
Use classical NSAID Use COX-2 inhibitor
( or classical NSAID + PPI+)
No Is patient at increased risk for CV events ? Yes
Select NSAID on the basis of GI risk Avoid NSAID esp. COX-2 inhibitor

31. 32
Reumatologi Klinik Bandung 2013