PIN XV PB PAPDI

Makassar 14-16 Oktober 2017

How to choose
NSAIDs for chronic pain?

dr.B.P.Putra Suryana SpPD-KR, FINASIM

Divisi Reumatologi, Ilmu Penyakit Dalam
FK Brawijaya RS dr.Saiful Anwar Malang
 Curriculum Vitae
dr.B.P.Putra Suryana SpPD-KR
Lecturer / Medical Staff
Rheumatology Division
Brawijaya University Saiful Anwar
Hospital , Malang .
1. Principle investigator in Clinical trial on
Rilonacept in gouty arthritis.
2. Co-investigator in Clinical trial on
Tocilizumab in RA.
3. Principle investigator in Clinical trial on
Belimumab in SLE.
4. Actemra Asia Pacific Advisory Board.
5. IRA Working Group on Ankylosing
Spondylitis Recommendation.
6. APLAR Working Group on Rheumatoid
Arthritis Recommendation (2013-2015)
7. APLAR Working Group on RA
Recommendation Revision (2015-now)
Disclosure :
Speaker for Pfizer, MSD, Roche, Abbott, Tanabe,
Combiphar, Sanofi-Aventis , Novartis.
 INTRODUCTION
Chronic pain has a worldwide prevalence of
1055%1

Non-steroidal anti-inflammatory drugs (NSAIDs) are

effective analgesic, anti-inflammatory and
antipyretic drugs2

NSAIDs are widely prescribed for various rheumatic

diseases mainly osteoarthritis (OA), rheumatoid
arthritis (RA), and ankylosing spondylitis (AS).

NSAIDs used are associated with GIT problem, CV

disease, and renal problems.

1. Harstall C, Opsina M. IASP: Clinical Updates 2003;XI(2):14.

2. Rang HP et al. Pharmacology 2007, 6th Edition, Churchill Livingstone, London. Section 2; Page 228.
 The prescription of NSAIDs
Types of prescription medicine used for the treatment of chronic paina

Beta/CC blocker
Muscle relaxant
Anti-epileptic
DMARD/steroid
Triptan
Tricyclic/SSRI/SNRI
Barbiturate/ergotamine
Strong opioid
COX-2 inhibitor
Paracetamol
Weak opioid
NSAID

0 10 20 30 40 50
% respondents2
aDatafrom a subgroup of patients (19%) who reported prescription medication use for pain in a large survey
conducted in Europe/Israel (n=46,394). CC = calcium channel blockers; DMARD = disease-modifying anti-
rheumatic drugs
1. IMS 2010
2. Breivik H et al. Eur J Pain 2006;10:287333.
 Inflammation and pain

SP=substance P ; BK=bradikinine ; PLs=phospholipids ; PGs=prostaglandins ; 5HT=5-

hydroxytryptamine
 MECHANISM OF ACTION OF NSAIDS
Normal condition Inflammation
Arachidonic acid
COX-1 COX-2
(constitutive)
X T-NSAIDs
X (inducible)

PGH2 PGH2

PGE2 PGI2 TXA2 PGE2 PGI2 TXA2

Stomach Stomach Platelets Synovial membrane,

Kidney Kidney endothelium, vascular
Brain Endothelium smooth muscle, WBCs, brain
GI protection
platelet inflammation
vasodilation aggregation pain
renal perfusion vasoconstriction fever
inhibit platelet
aggregation
NSAID=nonsteroidal anti-inflammatory drug; COX=cyclooxygenase. Adapted from Wallace JL. Am J Med. 1999;107(6A):11S17S; Hinz B, et al. J Pharmacol Exp Ther.
2002;300(2):367375; Vanegas H, et al.; Prog Neurobiol. 2001;64(4):327363; Furst DE. Am J Med. 1999;107(6A):18S26S; Vane JR, et al. Annu Rev Pharmacol Toxicol. 1998;38:97120;
Fung HB, et al. Clin Ther. 1999;21(7):11311157.
COX-1/COX-2 selectivity of NSAIDs
 Osteoarthritis
Hand OA

Knee OA with joint pain and crepitus

 NSAIDs in OA Recommendation

EULAR Recommendation for Osteoarthritis, 2009

Osteoarthritis
Dose-Ranging Study WOMAC Pain Subscale*

Etoricoxib produced substantial pain relief similar to diclofenac

Part 1 Part 2 Extension
0
More
Etoricoxib 60 mg once daily (n=112)
pain
week 0 to 52
baseline in pain level

10
Mean change from

Placebo (n=60) Diclofenac 50 mg three times daily

(n=102) week 8 to 52
20

p<0.001
30
p=NS

40

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

Placebo- Active-comparatorcontrolled
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;41:10521061; Curtis S et al. Poster presented at EULAR, 2001.
Two multi-centre, 26-
week, double-blind,
placebo-controlled,
non-inferiority studies
were conducted;
etoricoxib 30 mg qd,
celecoxib 200 mg qd
or one of two
placebo groups
WOMAC Pain Subscale
Bingham, et al. Rheumatology 2007;46:496
507
 Ankylosing Spondylitis

Enthesitis

Sacroiliitis
 The ASAS / EULAR recommendations
for ankylosing spondylitis

Zochling J, van der Heijde D, Burgos-Vargas R, et al. ASAS/EULAR recommendations for the management of
ankylosing spondylitis. Ann Rheum Dis 2006; 65: 44252.
 Ankylosing Spondylitis
Etoricoxib vs Naproxen:
Patient Assessment of Spine Paina (Parts 1 and 2)
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;
d500 mg twice daily.
Adapted from van der Heijde D, et al. Arthritis Rheum. 2005;52(4):12051215.
 Rheumatoid Arthritis

Rheumatoid
Severe joint erosions nodul
causes joint deformities
ACR Guidelines for RA
(2002 Update)
Establish diagnosis of RA early

Initiate Therapy
Patient Education
Start DMARD(s) within 3 months
Consider NSAID
Consider local or low dose systemic steroids
Physical/Occupational Therapy

Inadequate response within 3

months

Change or Add DMARD(s)

 NSAIDs in rheumatic pain
No 1 prescribed NSAID1
Used as a reference standard in clinical trials,
including recent several large-scale outcomes
studies:
Study (duration) Patients n Treatments Primary outcomes
MEDAL2 OA, RA 34,701 Etoricoxib 60/90 mg qd Safety (CV/GI)
(3 years) Diclofenac 50/75 mg bid
CLASS3 OA, RA 8,059 Celecoxib 400 mg bid Safety (GI/CV)
(65 weeks) Ibuprofen 800 mg tid
Diclofenac 75 mg bid
SUCCESS-14 OA 13,194 Celecoxib 100/200 mg bid Safety (GI/CV)
(12 weeks) Diclofenac 50 mg bid
Naproxen 500 mg bida

aResults were provided for celecoxib versus the combined diclofenac/naproxen group
1. IMS 2010
2. Cannon CP et al. Lancet 2006;368:177181.
3. Witter J. Celebrex Capsules (Celecoxib) NDA 20-998/S-009 Medical Officer Review 2000.
4. Singh G et al. Am J Med 2006;119:25566.
 CLASS Study
Diclofenac 75 mg bid (n=1,996)
Celecoxib 400 mg bid (n=3,987)
Ibuprofen 800 mg tid (n=1,985)

0 0
baseline in mean

baseline in mean
Change from

Change from
2

VAS score
0.1
score

4
4.7
0.20
0.2
0.23
6 6.6
0.25 6.7

0.3 8

Witter J. Celebrex Capsules (Celecoxib) NDA 20-998/S-009 Medical Officer Review 2000.
 MEDAL Study
Diclofenac 50 or 75 mg bid (n=16,483)
Etoricoxib 60 or 90 mg od (n=16,819)

0
9.8
9.0
baseline in Likert

0.2
Change from

Patients (%)
units

0.4

0.6 0.61
0.67

0.8

Cannon CP et al. Lancet 2006;368(9549):177181.

 MEDAL study: Upper & Lower GI
event
Diclofenac 50 or 75 mg bid (n=16,483)
1.2 HR: 0.69 Etoricoxib 60 or 90 mg od (n=16,819)
Event rate (per 100 patient years)

(95% CI: 0.570.83)

1.0
0.97

0.8

0.6 0.67

0.4
0.38
0.32 0.30 0.32
0.2 0.23
0.19

0
Combined Complicated Lower Lower
symptomatic and GI events GI events GI bleeding
complicated upper
GI events

Cannon CP et al. Lancet 2006;368(9549):177181.

Laine L et al. Gastroenterology 2008;135(5):151725.
 CLASS study: Upper GI events
Clinically significant Clinically significant
upper GI eventsb upper GI events or
gastroduodenal ulcers
Diclofenac 75 mg bid (n=1,996)
Celecoxib 400 mg bid (n=3,987)
0.8 Ibuprofen 800 mg tid (n=1,985) 2.0
* ***
* 1.76
Week 52 crude ratea

1.72

Week 52 crude ratea

0.55
0.6 0.62
1.5
0.55 1.30
0.50
0.4 0.43 1.0 1.05

0.2 0.26 0.26 0.5 0.64 0.68

0 0
Overall Patients not Overall Patients not
population taking aspirin population taking aspirin
*p<0.05, ***p<0.001 versus celecoxib. aRates and p values from uncensored data
bUpper GI bleeding, perforation or gastric outlet obstruction

Witter J. Celebrex Capsules (Celecoxib) NDA 20-998/S-009 Medical Officer Review 2000.
MEDAL Program Result : Cumulative Incidence
of Confirmed Thrombotic CV Events
Primary end point (per protocol)
7
Etoricoxib 60 and 90 mg pooled (320 events)
6 Diclofenac 150 mg (323 events)
Cumulative Incidence,

5 Etoricoxib vs diclofenac
Hazard Ratio=0.95 (95% CI: 0.81, 1.11)
% (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 8,277 6,427 4,024 805
Diclofenac 16,483 12,800 10,142 7,901 6,213 3,832 815

Adapted from Cannon CP, et al. Lancet. 2006;368:17711781.

 Strategies for reducing GI toxicity

1. Use lowest effective doses, shortest duration of

treatment
2. Use a selective COX-2 inhibitor
BUT several withdrawn due to cardiovascular/other risks1,2
3. Co-administer NSAID + prostaglandin analogue
Supplements stomach in prostaglandins not synthesized due
to COX inhibition3
4. Co-administer NSAID + proton pump inhibitor (PPI)
Suppresses gastric acid secretion, protecting upper GI tract
Reduces NSAID-associated dyspepsia and gastric injury4

1. FDA. Information for Healthcare Professionals: Valdecoxib (marketed as Bextra). 2005.

(ww.fda.gov)
2. FDA. Vioxx (rofecoxib) Questions and Answers. 2004. (ww.fda.gov)
3. Miller DR. Clin Pharm 1992;11(8):690704.
4. Lanas A, Sopea F. Gastroenterol Clin North Am 2009;38:33352.
Slide source from Prof.Angel Lanas, Asian Advisory Board Meeting, Shanghai, 21 Aug 2007.
 SO2CH3

Cl

N
CH3

Clinical pharmacology and pharmacokinetics of

Etoricoxib
 Pharmacokinetic profiles of the selective COX-2 inhibitors

Lumiracoxib1 Celecoxib2 Valdecoxib3 Rofecoxib4 Etoricoxib5

Oral bioavailability (%) 74 20606 83 ~93 ~100

Time to maximal plasma 2.3 2.8 2.25 23 ~1

concentration (hr)

Maximal plasma 5964 705 161.1 207 3600

concentration (ng/mL) (200 mg (200 mg (10 mg od (25 mg (120 mg at
single dose) single dose) for 14 days) single dose) steady state)

Elimination half-life (hr) 4 11.2 8.11 17 ~22

Volume of distribution (L) 9 429 86 86 ~120

Extent of binding to ~996 ~97 ~98 ~87 ~92

plasma proteins (%)

Main pathway of liver CYP 2C96 CYP 2C9 CYP 3A4 CYP Cytosolic CYP 3A4
metabolism 2C9 enzymes CYP 2C9
CYP 2D6
CYP 1A2

1Hartmann, et al. 2003; 2Celebrex PI, Feb 2005; 3Bextra PI, Nov 2004; 4Vioxx PI, Sep 2004; 5Arcoxia PI, Feb 2005; 6Brune, et al. 2004
 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; p0.025 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
 BIOEKUIVALEN STUDY Orinox vs Arcoxia
Mean plasma concentration-time profiles of etoricoxib in human
subjects (n = 27) after a single dose oral administration etoricoxib
tablets produced by PT Dexa Medica (Test drug) - ORINOX and the
reference (Reference drug = Arcoxia) : COMPARABLE (Similar)

Putri, RSI et al. 2016. Summary Report of Bioequivalence Study. Data on file
 SUMMARY
NSAIDs are mainstay of treatment for
chronic pain in OA and AS, and temporarily
used for RA.
Etoricoxib provide comparable efficacy with
traditional NSAIDs for chronic pain in OA
and AS, with better safety.
The most important risk factors for NSAID
related GI complication are age, ASA, and
ulcer history.

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