highlight on the role of NSAIDs and COX-2 inhibitors in the management of arthritis pain management

1. A Current Arthritis Pain Management
Without Compromising the Patient's
Safety
Rachmat Gunadi Wachjudi
Perhimpunan Reumatologi Indonesia
Cabang Bandung

2. ARTHRITIS PAIN
2

3. Osteoarthritis and Rheumatoid
Arthritis: Disease State Overview

4. Factors Implicated in the Development of OA
Obesity Aging
Anatomic
abnormalities Genetic and
metabolic
Microfractures diseases
and bony Abnormal stresses Abnormal cartilage
remodeling Inflammation
Loss of joint
stability Immune
Compromised cartilage system
Trauma activity
Biophysical changes Biochemical changes
• Collagen network fracture • Inhibitors reduced
• Proteoglycan unraveling • Proteolytic enzymes increased
Cartilage breakdown
Mandelbaum B et al. Orthopedics. 2005;28(2 suppl):s207-s214.
Adapted with permission from 2002 Medtronic Sofamor Danek, Basic Bone Biology.

5. EULAR Diagnostic Criteria for Knee OA (2010)
■ Based on review of studies from 1950-2008 and expert consensus
■ Focuses on clinical diagnosis: presence of three symptoms and
three signs correctly diagnoses 99% of cases
Symptoms
1 Persistent knee pain √
2 Limited morning stiffness √
3 Reduced function √
Signs
4 Joint crepitus √
5 Restricted movement √
6 Bony enlargement √
EULAR=European League Against Rheumatism.
Zhang W et al. Ann Rheum Dis. 2010;69(3):483-489.

6. ACR Diagnostic Criteria for Knee OA (1986)
■ Clarified and standardized definition of osteoarthritis
 Joint symptoms and signs associated with defective integrity of
articular cartilage and changes in underlying joints at bone margin
■ Focuses on clinical examination of knee pain plus:
Presence of 3 of the following
1 Age >50 years √
2 Morning stiffness <30 minutes √
3 Joint crepitus on active motion √
4 Bony tenderness √
5 Bony enlargement √
6 No palpable warmth of synovium √
■ Sensitivity, 95%; specificity, 69%
ACR=American College of Rheumatology.
Altman RD et al. Arthritis Rheum. 1986;29(8):1039-1049.

7. Goals of OA Management:
OARSI Recommendations
Maintain and
improve joint
mobility
Reduce Reduce
joint pain and physical
stiffness disability
Knee and Hip OA:
Goals of
Treatment
Improve Educate
HRQoL patients
Limit
progression of
joint damage
HRQoL=health-related quality of life; OARSI=Osteoarthritis Research Society International.
Zhang W et al. Osteoarthritis Cartilage. 2008;16(2):137-162.

8. Integrated Approach to Treating Patients With OA
Nonpharmacologic Pharmacologic
■ Patient education ■ APAP
■ Phone contact (promote self-care) ■ Oral NSAIDs
■ Referral to physical therapist ■ Topical NSAIDs and capsaicin
■ Aerobic, strengthening, and/or water- ■ Corticosteroid injections
based exercise ■ Hyaluronate injections
■ Weight reduction ■ Glucosamine, chondroitin sulphate,
■ Walking aids, knee braces and/or diacerein
■ Proper footwear, insoles ■ Weak opioids and narcotic analgesics
■ Thermal modalities for refractory pain*
■ TENS
■ Acupuncture
Surgical
■ Total joint replacement ■ Lavage/debridement in knee OA†
■ Unicompartmental knee replacement ■ Joint fusion after failure of joint
■ Osteotomy and other joint preserving replacement
surgical procedures
* Pain resistant to ordinary treatment. † Controversial.
TENS=transcutaneous electrical nerve stimulation.
Zhang W et al. Osteoarthritis Cartilage. 2008;16(2):137-162.

9. US Prevalence of
Rheumatoid Arthritis (RA)
■ May affect between 1.3 and 1.5 million
adults1,2
 Incidence lowest in individuals aged ≤34 years
 Incidence increases progressively with age
 Occurs more commonly in women than in men
* Costs in 2005 US dollars.
1. Myasoedova E et al. Arthritis Rheum. 2010;62(6):1576-1582.
2. Helmick CG et al. Arthritis Rheum. 2008;58(1):15-25.
3. Birnbaum H et al. Curr Med Res Opin. 2010;26(1):77-90.

10. Hand RA
Photos from Towheed TE, Anastassiades TP. Can Fam Phys. 1994;40:1303-1309. Used with permission.

11. 2010 ACR / EULAR Diagnostic Criteria for RA
Criterion Score
1 large joint 0
2-10 large joints 1
A Joint Involvement* 1-3 small joints (± large-joint involvement) 2
4-10 small joints (± large-joint involvement) 3
>10 joints (at least 1 small joint) 5
Negative RF and negative ACPA 0
B Serology† Low-positive RF or low-positive ACPA 2
High-positive RF or high-positive ACPA 3
Acute-Phase Normal CRP and normal VHS 0
C
Reactants‡ Abnormal ESR or CRP Total score ≥6/10
Total score ≥6/10 1
needed to classify
needed to classify
Duration of Less than 6 weeks definite RA
definite RA 0
D
Symptoms§ 6 or more weeks 1
* Any swollen or tender joint on examination. Excluded are distal interphalangeal joints, first carpometacarpal joints, and first
metatarsophalangeal joints. Large joints = shoulders, elbows, hips, knees, and ankles. Small joints = metacarpophalangeal joints, proximal
interphalangeal joints, 2nd through 5th metatarsophalangeal joints, thumb interphalangeal joints, and wrists. The >10 category can include large
and small joints, and other joints not listed elsewhere (eg, temporomandibular, acromioclavicular, or sternoclavicular). † Negative: IU values
≤ULN for lab and assay. Low-positive: IU > ULN but ≤3x ULN. High-positive: IU >3x ULN. When only RF-positive or RF-negative is known,
positive scored as low-positive. ‡ Normal/abnormal determined by local lab standards. § Patient self-report of duration of signs/symptoms of
synovitis in joints clinically involved at time of assessment, regardless of treatment status.
ACPA=anti-citrullinated protein/peptide antibodies; CRP=C-reactive protein; VHS =erythrocyte sedimentation rate; RF=rheumatoid factor.
Aletaha D et al. Arthritis Rheum. 2010;62(9):2569-2581.

12. Goals of RA Management
Early and Sustained
Suppression of Disease Activity
Prevent or
Reduce pain control joint
damage
Prevent Maximize
functional patient
decline quality of life
ACR Subcommittee on Rheumatoid Arthritis Guidelines. Arthritis Rheum. 2002;46(2):328-346.

13. Treatment Options for Patients With RA1-3
NSAIDs  Symptomatic treatment to reduce joint swelling and pain
 Reduce/prevent joint damage, preserve joint integrity and function
 Methotrexate, leflunomide, hydroxychloroquine, minocycline,
DMARDs sulfasalazine
(biologic and  Etanercept, infliximab, adalimumab (TNF inhibitors)
nonbiologic)  Rituximab (anti-CD20)
 Abatacept (cytotoxic T-lymphocyte antigen 4 immunoglobulin)
 Tocilizumab (anti-interleukin 6 receptor)
 Short-term use during flare-ups (oral or intramuscular)
Glucocorticoids
 Local treatment for individual active joints (intra-articular)
 Carpal tunnel release, synovectomy, resection of metatarsal heads,
Surgery total joint arthroplasty, joint fusion
Supportive  Patient education, cognitive-behavioral interventions
Strategies  Rehabilitation interventions
DMARDs=disease-modifying antirheumatic drugs; TNF=tumor necrosis factor.
1. ACR Subcommittee on Rheumatoid Arthritis Guidelines. Arthritis Rheum. 2002;46(2):328-346.
2. Saag KG et al. Arthritis Rheum. 2008;59(6):762-784.
3. Smolen JS et al. Lancet. 2007;370(9602):1861-1874.

14. Distinguishing OA From RA1
Characteristic OA RA
Prevalence in US adults 27 million2 1.3–1.5 million3,4
Pathophysiologic process Degenerative Autoimmune
Hips, knees, spine,
Commonly affected joints Hands, feet
fingers
Typically symmetrical
No Yes
involvement
Morning stiffness Transient Persistent
Joint swelling Hard tissue Soft tissue
Hand involvement Distal joints Proximal joints
Extraarticular involvement No Yes
Elevated autoimmune markers No Yes
1. Goldman L, Ausiello D. Cecil Textbook of Medicine. 23rd ed. Philadelphia, PA: Saunders Elsevier; 2007.
2. Lawrence RC et al. Arthritis Rheum. 2008;58(1):26-35.
3. Helmick CG et al. Arthritis Rheum. 2008;58(1):15-25.
4. Myasoedova E et al. Arthritis Rheum. 2010;62(6):1576-1582.

15. Celecoxib
Efficacy in Osteoarthritis

16. CELECOXIB vs. diclofenac:
6-week Knee OA Trial
McKenna et al. 2001: Patient’s Assessment of Pain
Patient’s Assessment of Pain (VAS): Mean change at
week 6 *p=0.001 vs. placebo
Mean Change (mm)
Less Pain
placebo celecoxib diclofenac
(n=200) 100 mg BID 50 mg TID
(n=199) (n=199)
VAS=visual analogue scale.
McKenna F et al. Scand J Rheumatol 2001;30:11–18.

17. CELECOXIB vs. diclofenac:
6-week Knee OA Trial
McKenna et al. 2001: American Pain Society – Pain
Measure
American Pain Society (APS) Pain Measure:
Worst Pain in the Past 24 Hours
Baseline Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7
0.0
-0.5
p=0.05, active treatment vs.
Mean Change in Score
placebo (days 1-7).
-1.0
Less Pain
-1.5
-2.0
-2.5
-3.0
placebo (n=200)
-3.5
celecoxib 100 mg BID (n=199)
-4.0 diclofenac 50 mg TID (n=199)
McKenna F et al. Scand J Rheumatol. 2001;30:11-18.

18. Celecoxib
Efficacy in Rheumatoid arthritis

19. Adult RA: Celecoxib Significantly Reduced the
Number of Tender/Painful and Swollen Joints
Tender/Painful Joints Swollen Joints
0
Reduction in Mean Number of
Affected Joints at 12 Weeks
-5
-5.5
-6.9*
-7.6 -7.5*
-10 -9.5 -9.1*
t ne m v o p m
e r I
-11.6*
-11.7*
-15
Placebo (n=231)
Celecoxib 100 mg BID (n=240)
Celecoxib 200 mg BID (n=235)
-20 Naproxen 500 mg BID (n=225)
* P<.05 vs placebo.
Simon LS et al. JAMA. 1999;282(20):1921-1928.

20. Adult RA: Celecoxib and Naproxen Improved
Physical Function
0.4
HAQ-FDI Score at 12 Weeks
LS Mean Improvement in
0.29*
0.3
0.22*
0.2 0.17
0.1
0.1
0
Placebo Celecoxib Celecoxib Naproxen
(n=231) 100 mg BID 200 mg BID 500 mg BID
(n=240) (n=235) (n=225)
* Statistically significant vs placebo.
HAQ-FDI=Health Assessment Questionnaire Functional Disability Index.
Zhao SZ et al. Arthritis Care Res. 2000;13(2):112-121.

21. Celecoxib
Efficacy in Ankylosing Spondilitis

22. Ankylosing Spondylitis: Celecoxib and Naproxen Reduced
Pain, Disease Activity, and Functional Impairment (12 Weeks)
Pain Intensity Disease Activity BASFI
10
Baseline to Week 12 (100 mm VAS)
LS Mean (± SE) Change From
0
-10
-20 †
-30
t ne m v o p m
e r I
* Placebo
Celecoxib 200 mg QD
-40
Celecoxib 400 mg QD
Naproxen 500 mg BID
-50
P<.001 for all active treatments vs placebo.
* P<.05 vs celecoxib 200 mg QD.
† P<.01 vs celecoxib 200 mg QD.
BASFI=Bath Ankylosing Spondylitis Functional Index.
Barkhuizen A et al. J Rheumatol. 2006;33(9):1805-1812.

23. Celecoxib
Gastrointestinal Safety Profile

24. Guidelines for Prevention of
NSAID-Related Ulcer Complications
(ACG Practice Guidelines 2009)
za FL et al. Am J Gastroenterol 2009;104:728-738

25. Celecoxib vs Omeprazole aNd
Diclofenac in patients with
Osteoarthritis and Rheumatoid
arthritis (CONDOR)
Chan FKL et al. Lancet 2010. DOI:10.1016/S0140-6736(10)60673-3
n FKL et al. Lancet 2010. DOI:10.1016/S0140-6736(10)60673-3

26. Inclusion Criteria

27. Chan FKL et al. Lancet 2010. DOI:10.1016/S0140-6736(10)60673-3

28. RESULT OF CONDOR STUDY 2010
Patient with celecoxib has lower risk on gastrointestinal events than
those with diclofenac SR + omeprazole
4 3.8
Proportion of patients %
3.5
(81 events,
3
95% CI, 2.9-
2.5
4.3)
2
1.5
0.9
1
0.5 (20 events, 95%
CI, 0.5-1.3)
0
celecoxib 200 mg BID (n=2238)
diclofenac SR 75 mg BID + omeprazole 20 mg OD (n=2246)
P<0.0001
Chan FKL et al. Lancet 2010; DOI:10.1016/S0140-6736(10)60673-3

29. Conclusion CONDOR Study
 Risk of clinical outcomes throughout the upper
& lower GI tract was lower in patients treated
with a COX-2-selective NSAID than in those
receiving a non-selective NSAID plus a PPI.
 Celecoxib, when used alone, carries less risk
of clinically significant events through the entire
GI tract when compared with diclofenac +
omeprazole
Chan FKL et al. Lancet 2010. DOI:10.1016/S0140-6736(10)60673-3

30. Celecoxib
Cardiovascular Safety

31. Boxed Warning for All Prescription NSAIDs
Cardiovascular Risk
Cardiovascular Risk
NSAIDs may cause an increased risk of serious cardiovascular thrombotic
NSAIDs may cause an increased risk of serious cardiovascular thrombotic
events, myocardial infarction, and stroke, which can be fatal. This risk may
events, myocardial infarction, and stroke, which can be fatal. This risk may
increase with duration of use. Patients with cardiovascular disease or risk
increase with duration of use. Patients with cardiovascular disease or risk
factors for cardiovascular disease may be at greater risk.
factors for cardiovascular disease may be at greater risk.
[Product] is contraindicated for the treatment of perioperative pain in the
[Product] is contraindicated for the treatment of perioperative pain in the
setting of coronary artery bypass graft (CABG) surgery.
setting of coronary artery bypass graft (CABG) surgery.
Gastrointestinal Risk
Gastrointestinal Risk
NSAIDs, including [product], cause an increased risk of serious
NSAIDs, including [product], cause an increased risk of serious
gastrointestinal adverse events including bleeding, ulceration, and
gastrointestinal adverse events including bleeding, ulceration, and
perforation of the stomach or intestines, which can be fatal. These events
perforation of the stomach or intestines, which can be fatal. These events
can occur at any time during use and without warning symptoms. Elderly
can occur at any time during use and without warning symptoms. Elderly
patients are at greater risk for serious gastrointestinal (GI) events.
patients are at greater risk for serious gastrointestinal (GI) events.

32. APTC Composite End Point (Adjudicated):
Celecoxib vs ns-NSAIDs
Meta-analysis of 25 RCTs
2.0
P =.59 (NS)
Relative Risk (CI) of Serious
1.5
CV Adverse Events
1.0 0.90
1.0 (95% CI: 0.60-1.33)
49 events
54 events
0.5
0
ns-NSAIDs Celecoxib 200-800 mg daily
(n=13,990) (n=19,773)
White et al. Am J Cardiol. 2007. 09/25/09

33. Celecoxib
Renal & Hepar Safety Profile

34. CELECOXIB vs. diclofenac
Dahlberg et al. 2009: CV / renal & hepatic AEs
Incidence of patients with treatment-related
CV, renal, and hepatic AEs
6 5.2
5 4.1
% Patients
4
3
1.7
2 1.1
1
0
CV / renal AE Hepatic AE
celecoxib 200 mg OD diclofenac 50 mg BID
One-year, randomized, multicentre, double-blind, parallel-group study to assess the AE-related discontinuation rate with
celecoxib and diclofenac in elderly patients with OA.
No p-values reported for related/not-related-to-treatment incidence. Significantly fewer patients in the celecoxib group than
the diclofenac group experienced cardiovascular/renal AEs (70/458 vs. 95/458, p=0.039) or hepatic AEs (10/458 vs. 39/458,
p<0.0001).
Dahlberg LE et al. Scand J Rheumatol 2009;38:133-143.

35. SUMMARY
■ Arthritis Pain is major health problem in elderly patients
■ Selective COX-2 inhibitors relief pain by selectively inhibit
COX-2 enzyme which is mainly responsible for
inflammation and pain process
■ Celecoxib is scientifically proven to alleviate arthritis pain
(OA, RA, and AS)
■ Celecoxib, when used alone, carries less risk of clinically
significant events through the entire GI tract when
compared with diclofenac + omeprazole
■ Celecoxib is the only coxib approved by US FDA
■ Celecoxib has a well-tolerated safety profille
35
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37. THANK YOU
37
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