A Current Arthritis Pain Management Without Compromising the Patient's

Safety

Rachmat Gunadi Wachjudi

Perhimpunan Reumatologi IndonesiaCabang Bandung

ARTHRITIS PAIN

2

Osteoarthritis and Rheumatoid Arthritis: Disease State Overview

Factors Implicated in the Development of OA

Cartilage breakdown

ObesityObesity

Anatomic abnormalities

Anatomic abnormalities

Microfractures and bony

remodeling

Microfractures and bony

remodeling

Loss of joint stability

Loss of joint stability

TraumaTrauma

AgingAging

Genetic and metabolic diseases

Genetic and metabolic diseases

InflammationInflammation

Immune system activity

Immune system activity

Compromised cartilage

Biophysical changes• Collagen network fracture• Proteoglycan unraveling

Biochemical changes• Inhibitors reduced

• Proteolytic enzymes increased

Abnormal stresses Abnormal cartilage

Mandelbaum B et al. Orthopedics. 2005;28(2 suppl):s207-s214.Adapted with permission from 2002 Medtronic Sofamor Danek, Basic Bone Biology.

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 andthree signs correctly diagnoses 99% of cases

SymptomsSymptoms

1 Persistent knee pain √

2 Limited morning stiffness √

3 Reduced function √

SignsSigns

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.

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:

■ Sensitivity, 95%; specificity, 69%

Presence of 3 of the followingPresence 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 √

ACR=American College of Rheumatology.

Altman RD et al. Arthritis Rheum. 1986;29(8):1039-1049.

Goals of OA Management:OARSI Recommendations

Reducejoint pain and

stiffness

Reduce physical disability

ImproveHRQoL

Educate patients

Limitprogression of joint damage

Knee and Hip OA: Goals of Treatment

HRQoL=health-related quality of life; OARSI=Osteoarthritis Research Society International.

Zhang W et al. Osteoarthritis Cartilage. 2008;16(2):137-162.

Maintain and improve joint

mobility

Integrated Approach to Treating Patients With OA

NonpharmacologicNonpharmacologic PharmacologicPharmacologic

■ Patient education■ Phone contact (promote self-care)■ Referral to physical therapist■ Aerobic, strengthening, and/or water-based exercise■Weight reduction■ Walking aids, knee braces■ Proper footwear, insoles■ Thermal modalities■ TENS■ Acupuncture

■ APAP■ Oral NSAIDs■ Topical NSAIDs and capsaicin■ Corticosteroid injections■ Hyaluronate injections■ Glucosamine, chondroitin sulphate, and/or diacerein■ Weak opioids and narcotic analgesics for refractory pain*

SurgicalSurgical

■ Total joint replacement■ Unicompartmental knee replacement■ Osteotomy and other joint preserving surgical procedures

■ Lavage/debridement in knee OA†

■ Joint fusion after failure of joint replacement

* Pain resistant to ordinary treatment. † Controversial.

TENS=transcutaneous electrical nerve stimulation.

Zhang W et al. Osteoarthritis Cartilage. 2008;16(2):137-162.

US Prevalence ofRheumatoid Arthritis (RA)

■ May affect between 1.3 and 1.5 million adults1,2

Incidence lowest in individuals aged ≤34 yearsIncidence increases progressively with ageOccurs 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.

Hand RA

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

2010 ACR / EULAR Diagnostic Criteria for RA

CriterionCriterion ScoreScore

A Joint Involvement*

1 large joint 0

2-10 large joints 1

1-3 small joints (± large-joint involvement) 2

4-10 small joints (± large-joint involvement) 3

>10 joints (at least 1 small joint) 5

B Serology†

Negative RF and negative ACPA 0

Low-positive RF or low-positive ACPA 2

High-positive RF or high-positive ACPA 3

CAcute-Phase Reactants‡

Normal CRP and normal VHS 0

Abnormal ESR or CRP 1

DDuration of Symptoms§

Less than 6 weeks 0

6 or more weeks 1

Total score ≥6/10 Total score ≥6/10 needed to classify needed to classify

definite RAdefinite RA

Total score ≥6/10 Total score ≥6/10 needed to classify needed to classify

definite RAdefinite RA

* 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.

* 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.

Goals of RA Management

Reduce painReduce painPrevent or

control joint damage

Prevent or control joint

damage

Prevent functional

decline

Prevent functional

decline

Maximizepatient

quality of life

Maximizepatient

quality of life

Early and SustainedSuppression of Disease Activity

ACR Subcommittee on Rheumatoid Arthritis Guidelines. Arthritis Rheum. 2002;46(2):328-346.

Treatment Options for Patients With RA1-3

NSAIDsNSAIDs Symptomatic treatment to reduce joint swelling and pain

DMARDs DMARDs (biologic and (biologic and nonbiologic)nonbiologic)

Reduce/prevent joint damage, preserve joint integrity and function Methotrexate, leflunomide, hydroxychloroquine, minocycline,

sulfasalazine Etanercept, infliximab, adalimumab (TNF inhibitors) Rituximab (anti-CD20) Abatacept (cytotoxic T-lymphocyte antigen 4 immunoglobulin) Tocilizumab (anti-interleukin 6 receptor)

GlucocorticoidsGlucocorticoids Short-term use during flare-ups (oral or intramuscular) Local treatment for individual active joints (intra-articular)

SurgerySurgery Carpal tunnel release, synovectomy, resection of metatarsal heads,

total joint arthroplasty, joint fusion

Supportive Supportive StrategiesStrategies

Patient education, cognitive-behavioral interventions 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.

Distinguishing OA From RA1

CharacteristicCharacteristic OAOA RARA

Prevalence in US adults 27 million2 1.3–1.5 million3,4

Pathophysiologic process Degenerative Autoimmune

Commonly affected jointsHips, knees, spine,

fingersHands, feet

Typically symmetrical involvement

No Yes

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.

Celecoxib Efficacy in Osteoarthritis

McKenna F et al. Scand J Rheumatol 2001;30:11–18.VAS=visual analogue scale.

Less P

ain

Patient’s Assessment of Pain (VAS): Mean change at week 6

Mea

n C

ha

ng

e (m

m)

*p=0.001 vs. placebo

placebo(n=200)

celecoxib100 mg BID(n=199)

diclofenac50 mg TID(n=199)

CELECOXIB vs. diclofenac:6-week Knee OA TrialMcKenna et al. 2001: Patient’s Assessment of Pain

McKenna F et al. Scand J Rheumatol. 2001;30:11-18.

American Pain Society (APS) Pain Measure:Worst Pain in the Past 24 Hours

Mean

Ch

an

ge in

Score p=0.05, active treatment vs.

placebo (days 1-7).

-4.0

-3.5

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0Baseline Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7

placebo (n=200)

celecoxib 100 mg BID (n=199)

diclofenac 50 mg TID (n=199)

Less P

ain

CELECOXIB vs. diclofenac:6-week Knee OA TrialMcKenna et al. 2001: American Pain Society – Pain Measure

Celecoxib Efficacy in Rheumatoid arthritis

Adult RA: Celecoxib Significantly Reduced the Number of Tender/Painful and Swollen Joints

* P<.05 vs placebo.

Simon LS et al. JAMA. 1999;282(20):1921-1928.

Red

uct

ion

in M

ean

Nu

mb

er o

f A

ffec

ted

Jo

ints

at

12 W

eeks

-7.6

-5.5

-7.5*

-11.6*-11.7*

-9.1*

-6.9*

-9.5

-20

-15

-10

-5

0

Tender/Painful Joints Swollen Joints

Placebo (n=231)Celecoxib 100 mg BID (n=240)Celecoxib 200 mg BID (n=235)Naproxen 500 mg BID (n=225)

Imp

rove

me

nt

Adult RA: Celecoxib and Naproxen Improved Physical Function

LS

Mea

n Im

pro

vem

ent

inH

AQ

-FD

I Sco

re a

t 12

Wee

ks

Celecoxib100 mg BID

(n=240)

Celecoxib200 mg BID

(n=235)

Naproxen500 mg BID

(n=225)

Placebo(n=231)

0.17

0.29*

0.1

0.22*

0

0.1

0.2

0.3

0.4

* Statistically significant vs placebo.

HAQ-FDI=Health Assessment Questionnaire Functional Disability Index.

Zhao SZ et al. Arthritis Care Res. 2000;13(2):112-121.

Celecoxib Efficacy in Ankylosing Spondilitis

Ankylosing Spondylitis: Celecoxib and Naproxen Reduced Pain, Disease Activity, and Functional Impairment (12 Weeks)

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.

-50

-40

-30

-20

-10

0

10

Pain Intensity Disease Activity BASFI

PlaceboCelecoxib 200 mg QDCelecoxib 400 mg QDNaproxen 500 mg BID

LS

Me

an

(±

SE

) C

ha

ng

e F

rom

B

as

eli

ne

to

We

ek

12

(1

00

mm

VA

S)

†

*

Imp

rove

me

nt

CelecoxibGastrointestinal Safety Profile

Guidelines for Prevention of NSAID-Related Ulcer Complications(ACG Practice Guidelines 2009)

Lanza FL et al. Am J Gastroenterol 2009;104:728-738

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

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

Inclusion Criteria

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

RESULT OF CONDOR STUDY 2010

0.9

3.8

0

0.5

1

1.5

2

2.5

3

3.5

4

Pro

po

rtio

n o

f p

atie

nts

%

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

Patient with celecoxib has lower risk on gastrointestinal events than those with diclofenac SR + omeprazole

(20 events, 95% (20 events, 95% CI, 0.5-1.3)CI, 0.5-1.3)

(81 events, 95% CI, 2.9-4.3)

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

CelecoxibCardiovascular Safety

Boxed Warning for All Prescription NSAIDs

Cardiovascular Risk

NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk.

[Product] is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery.

Gastrointestinal Risk

NSAIDs, including [product], cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal (GI) events.

Cardiovascular Risk

NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk.

[Product] is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery.

Gastrointestinal Risk

NSAIDs, including [product], cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal (GI) events.

09/25/09

APTC Composite End Point (Adjudicated): Celecoxib vs ns-NSAIDs

Meta-analysis of 25 RCTs

White et al. Am J Cardiol. 2007.

Rel

ati

ve

Ris

k (C

I) o

f S

erio

us

CV

Ad

vers

e E

ven

ts

ns-NSAIDs(n=13,990)

Celecoxib 200-800 mg daily(n=19,773)

0.90(95% CI: 0.60-1.33)

2.0

1.5

0.5

0

1.01.0

49 events54 events

P =.59 (NS)

CelecoxibRenal & Hepar Safety Profile

Incidence of patients with treatment-related CV, renal, and hepatic AEs

1.71.1

4.1

5.2

0

1

2

3

4

5

6

CV / renal AE Hepatic AE

% P

atie

nts

celecoxib 200 mg OD diclofenac 50 mg BID

CELECOXIB vs. diclofenacDahlberg et al. 2009: CV / renal & hepatic AEs

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.

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

35Please see Full Prescribing Information available at this presentation.

37Please see Full Prescribing Information available at this presentation.

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