CURRICULUM VITAE

NAMA : dr. Rudy Hidayat, SpPD-KR

TTL : Malang, 3 Mei 1975
PEKERJAAN : Staf Divisi Reumatologi
Departemen Ilmu Penyakit Dalam FKUI/
RSUPN Ciptomangunkusumo Jakarta
PENDIDIKAN :
Pendidikan Dokter Umum
Pendidikan Spesialis Penyakit Dalam
Pendidikan Subspesialis Reumatologi

1992-1999 FKUB
2004-2008 FKUI
2009-2011 FKUI

ORGANISASI : Ikatan Dokter Indonesia (IDI)

Perhimpunan Ahli Penyakit Dalam Indonesia (PAPDI)
Ikatan Reumatologi Indonesia (IRA)
Perhimpunan Osteoporosis Indonesia (PEROSI)

How To Choose NSAID

For Chronic Pain Treatment ?
Rudy Hidayat
Rheumatology Division, Internal Medicine Department
FMUI/Ciptomangunkusumo Hospital

Definition of Pain

An unpleasant sensory or
emotional experience
associated with actual or
potential tissue damage; or
described in such terms.

INTRODUCTION
PAIN

ACUTE
34 %

CHRONIC
CHRONIC
66%

NOCICEPTIVE
80 %

CANCER
4%

>3
BULAN

NEUROPHATIC
20 %

NON CANCER
96 %

Pain assesment
Pain assesment
Onset
Duration (acute, chronic)
Rythme (continuous, come and go,
fluctuating, etc)

Intensity/severity depent on patient

experiance

Aggravating or releaving factors

Pain assessment scales

(Intensity)
Visual analog scale (VAS)

Verbal pain intensity scale

No
pain

Mild
pain

Moderate Severe Very

pain
pain Severe
pain

Worst
possible
pain

Worst
possible
pain

No
pain

Faces scale

0-10 numeric pain intensity scale

1
No
pain

Moderate
pain

10

Worst
possible
pain

Portenoy RK, Kanner RM. Eds. Pain Management: Theory and Practice.1996:8-10
McCaffery M. Pasero C. Pain: Clinical Manual. Mosby.Inc.1999:16

Pain assesment
Impact of pain :
Quality of live
Quality of sleep, appetite, ADL, relationship

mood-crying/anger/suicide, concentration)

Other symptoms :
nausea, constipation
itching, drowsiness, confusion, weakness

Nociceptive Pain

Mixed Pain

Neuropathic Pain

Pain caused by injury to

body tissues
(musculoskeletal,
cutaneous or visceral)2
Include inflammatory pain

Pain with
Nociceptive and
neuropathic
components

Pain initiated or caused by a

primary lesion or dysfunction
in the nervous system
(either peripheral or
central nervous system)1

Examples

Pain due to inflammation

Limb pain after a fracture
Joint pain in osteoarthritis
Postoperative visceral pain

Common descriptors2
Aching
Sharp
Throbbing

Examples

Examples

Low back pain with

radiculopathy
Cervical
radiculopathy
Cancer pain
Carpal tunnel
syndrome

Peripheral
Postherpetic neuralgia
Trigeminal neuralgia
Diabetic peripheral neuropathy
Postsurgical neuropathy
Posttraumatic neuropathy
Central
Poststroke pain
Common descriptors2
Burning
Tingling
Hypersensitivity to touch or cold

1. International Association for the Study of Pain. IASP Pain Terminology.

2. Raja et al. in Wall PD, Melzack R (Eds). Textbook of pain. 4th Ed. 1999.;11-57

Model Bio-psiko-sosial
Penatalaksanaan Nyeri Kronik
Terapi kognitif

Anti-depressants/
psychotropics

Restorasi fungsional
Perilaku nyeri
Penderitaan

Relaksasi
Spiritual

Persepsi
nyeri
Opioid

Adjuvants
OAINS?
Acetaminophene

Neural augmentation
Bedah ablatif

Nosiseptif

Local block

OAINS
Pembedahan
Modalitas fisik

WHO Analgesic Ladder

4
3

2
1

interventional
therapy

Opioid for moderate to severe pain

Non-opioid Adjuvant
Opioid for mild to moderate pain
Non-opioid Adjuvant
Non-opioid Adjuvant
WHO, Switzerland, 1996

INTRODUCTION
Chronic pain has a worldwide prevalence of 1055%1

Non-steroidal anti-inflammatory drugs (NSAIDs) are

effective analgesic, anti-inflammatory and antipyretic drugs2
Inhibit cyclo-oxygenase (COX) enzymes, leading to reduced
production of prostaglandins, which activate pain/inflammatory
responses

NSAIDs inhibit COX-1 and COX-2

COX-1-derived prostanoids may be needed for regulatory functions
throughout the body, especially GI tract, kidney, platelets3
COX-2, found in joints and muscles, contributes to pain and
inflammation3,4
1.
2.
3.
4.

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

Rang HP et al. Pharmacology 2007, 6th Edition, Churchill Livingstone, London. Section 2; Page 228.
Hinz B, Brune K. J Pharmacol Exp Ther 2002;300(2):36775.
Chou R et al. Drug Class Review. Portland (OR): Oregon Health & Science University; 2006.

Symptomatic relief of Chronic pain

Non selective NSAIDs are the most commonly used treatment
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

Diclofenac
is the
leading
NSAID 1

10

20

30

40

50

% respondents 2
aData

from 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.

COX 1 / COX 2 SELECTIVITY OF NSAID

COX-2
selective

Pref.
COX-2

non
selective

Pref.
COX-1

COX-1
selective

Konsentrasi OAINS yang dibutuhkan untuk

menghambat 50% aktivitas
enzim COX-1 dan COX-2

(Chaiamnuay et al, 2006).

The Oxford league table of analgesic efficacy

Diclofenac 100

NNT

Paracetamol 1000 + Codeine 60

Rofecoxib 50

Diclofenac 50
Naproxen 440

Ibuprofen 600
Piroxicam 20

Naproxen 550
Paracetamol 1000

Paracetamol 650 + Codeine 60

Aspirin 650

Aspirin 650 + Codein 30

0

THE IMPLICATION OF NSAID SELECTIVITY

Cardiovascular risk

Gastrointestinal risk

Thrombosis,
Myocardial
Infarction

Bleeding Ulcer
Complication

Discontinuation

Discontinuation

Blood
Pressure
Increase

COX-2

COX-1
Adapted from : Antman EM, et al. Circulation 2007;115:1634-42

Diclofenac in chronic pain

Used as a reference standard in clinical trials,
including recent several large-scale outcomes studies:
Study (duration)

Patients

MEDAL2

OA, RA

34,701 Etoricoxib 60/90 mg qd

Diclofenac 50/75 mg bid

Safety (CV/GI)

OA, RA

8,059

Safety (GI/CV)

(3 years)

CLASS3
(65 weeks)

SUCCESS-14
(12 weeks)

aResults

1.
2.
3.
4.

OA

Treatments

Celecoxib 400 mg bid

Ibuprofen 800 mg tid
Diclofenac 75 mg bid

13,194 Celecoxib 100/200 mg bid

Diclofenac 50 mg bid
Naproxen 500 mg bida

Primary outcomes

Safety (GI/CV)

were provided for celecoxib versus the combined diclofenac/naproxen group

IMS 2010
Cannon CP et al. Lancet 2006;368:177181.
Witter J. Celebrex Capsules (Celecoxib) NDA 20-998/S-009 Medical Officer Review 2000.
Singh G et al. Am J Med 2006;119:25566.

CLASS, Pfizer sponsored RCT

No superior efficacy of Celecoxib vs diclofenac is shown

Diclofenac 75 mg bid (n=1,996)

Celecoxib 400 mg bid (n=3,987)
Ibuprofen 800 mg tid (n=1,985)

0.1

0.2

0.20
0.23
0.25

0.3

Change from baseline

in mean VAS score

Change from baseline

in mean score

2
4
6

4.7

6.6

Witter J. Celebrex Capsules (Celecoxib) NDA 20-998/S-009 Medical Officer Review 2000.

6.7

MEDAL, MSD sponsored RCT

No superior efficacy of etoricoxib vs diclofenac is shown

Diclofenac 50 or 75 mg bid (n=16,483)

Etoricoxib 60 or 90 mg od (n=16,819)

9.8
9.0

0.2
0.4
0.6

0.61

0.67

0.8

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

Patients (%)

Change from baseline

in Likert units

GI safety profile of diclofenac ?

Compared with the selective COX-2 inhibitors ?!

External factors could modify the

risk of GI events
GI events are related to nonselective COX-1 inhibition
Diclofenac has more
specificity to COX-2 than
COX-1
Recent RCTs had shown little
or no difference between COX-2
inhibitors & diclofenac (MEDAL1,
CLASS2 & SUCCESS-13)
1. Cannon CP et al. Lancet 2006;368:177181.
2. Witter J. Celebrex Capsules (Celecoxib) NDA 20-998/S-009 Medical Officer Review 2000.
3. Singh G et al. Am J Med 2006;119:25566.

External factors could modify the risk of

GI events1,2
Previous history of upper GI ulceration or bleeding
Especially if patient aged >65 years

Concomitant use of medications with an increased GI risk:

Low-dose aspirin for cardiovascular protection
Corticosteroids

Other NSAIDs
Drugs that alter platelet activity (eg. antiplatelet agents, selective
serotonin reuptake inhibitors, anticoagulants)

Others
1. Lanas A, Sopea F. Gastroenterol Clin North Am 2009;38:33352.
2. Hinz B, Brune K. J Pharmacol Exp Ther 2002;300(2):36775.

GI events are related to COX-1 inhibition?

Relative COX-1/2 selectivity
(increasing COX-2 selectivity)

Diclofenac has more specificity to COX-2 than COX-1

Ketoprofen

11
10
9
8
7
6
5
4
3
2
1
0

Indomethacin
Aspirin
Naproxen
Tolmetin
Ibuprofen
Fenoprofen
Diflunisal
Piroxicam
Sulindac

Diclofenac
0

4
5
6
7
Relative GI toxicity
(increasing toxicity)

10

11

Hence, diclofenac may have a relatively low GI risk compared with

other traditional NSAIDs
Mitchell JA, Warner TD. Br J Pharmacol 1999;128:112132.

Patients with increased GI risk

Different strategies for reducing GI toxicity with NSAIDs

1. Use lowest effective doses, shortest duration of

treatment

According to drugs prescribing information

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.
2.
3.
4.

FDA. Information for Healthcare Professionals: Valdecoxib (marketed as Bextra). 2005. (ww.fda.gov)
FDA. Vioxx (rofecoxib) Questions and Answers. 2004. (ww.fda.gov)
Miller DR. Clin Pharm 1992;11(8):690704.
Lanas A, Sopea F. Gastroenterol Clin North Am 2009;38:33352.

CV comparison for Diclofenac vs COX-2 inhibitors

Voltaren has CV Risk Smaller than NSAIDs and coxib1

Medal Studi : Etoricoxib 90 mg signifikan increasing congestive heart failure (CHF) than
Diclofenac 150 mg (0.4% vs 0.2%; P=0.487) 2
The Medal Study also suggested discontinuation of therapy due to an increase in blood
pressure higher Etoricoxib(0.9 1.9%) than Voltaren (0.4 0.8%) 3
1.Roumie CL et al. Pharmacoepidemiology and drug safety 2009; 18: 10531063.
2. Krum et al. European Journal of Heart Failure (2009) 11, 542550
3. Krum et al. Journal of Hypertension 2009, 27:886893.

So, how to choose NSAID for chronic pain ?

Consider the diagnosis ? Chronic pain due to nociceptive,
neurophatic or mixed pain?

Consider the past and present history, especially GI and

cardiovascular events? Renal function?

Choose NSAID due to pharmacokinetic and

pharmacodinamic profile (onset of action, half life, COX
selectivity, risk of side effect)

Dose and Duration of treatment

Monitor the respons of treatment

Monitor the side effect