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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 1992-1999 FKUB

Pendidikan Spesialis Penyakit Dalam 2004-2008 FKUI

Pendidikan Subspesialis Reumatologi 2009-2011 FKUI

ORGANISASI : Ikatan Dokter Indonesia (IDI)

Perhimpunan Ahli Penyakit Dalam Indonesia (PAPDI)

Ikatan Reumatologi Indonesia (IRA)

Perhimpunan Osteoporosis Indonesia (PEROSI)

CURRICULUM VITAE



How To Choose NSAID

For Chronic Pain Treatment ?

Rudy idayat

Rheum atology Division Internal Medicine Department

FMUI/Ciptomangunkusumo Hospital



Definition of Pain

An unpleasant sensory oremotional experience

associated with actual orpotential tissue damage; or

described in such terms.



INTRODUCTION

ACUTE

34 %

CANCER

4 %

NON CANCER

96 %

NOCICEPTIVE

80 %

NEUROPHATIC

20 %

CHRONIC

66%

PAIN

CHRONIC

66%

> 3

BULAN



Pain assesment

Onset

Duration (acute, chronic)

Rythme (continuous, come and go,fluctuating, etc)

Intensity/severity depent on patient

experiance

Aggravating or releaving factors

Pain assesment



Pain assessment scales(Intensity)

Verbal pain intensity scale Visual analog scale (VAS)

No pain

Mild pain

Moderate pain

Severe pain

VerySevere pain

Worst possible

pain

No pain

Worst possible

pain

0-10 numeric pain intensity scale

No pain

Moderate pain

Worst possible

pain

1 2 3 4 5 6 7 8 9 10

0 1 2 3 4 5

Faces scale

Portenoy RK, Kanner RM. Eds. Pain Management: Theory and Practice.1996:8-10McCaffery 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



Examples

Peripheral

• Postherpetic neuralgia

• Trigeminal neuralgia

• Diabetic peripheral neuropathy

• Postsurgical neuropathy

• Posttraumatic neuropathyCentral

• Poststroke pain

Common d escr ip tors 2

• Burning

• Tingling

•Hypersensitivity to touch or cold

Examples

• Pain due to inflammation

• Limb pain after a fracture

• Joint pain in osteoarthritis

• Postoperative visceral pain

Common descr ip tors 2

• Aching

• Sharp

• Throbbing

Examples

• Low back pain with

radiculopathy

• Cervical

radiculopathy

• Cancer pain• Carpal tunnel

syndrome

Mixed PainPain with

Nociceptive and

neuropathic

components

Neuropathic PainPain initiated or caused by a

primary lesion or dysfunction

in the nervous system

(either peripheral or

central nervous system)1

Nociceptive PainPain caused by injury to

body tissues

(musculoskeletal,

cutaneous or visceral)2

Include inflammatory pain

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-sosialPenatalaksanaan Nyeri Kronik

Perilaku nyeri

Penderitaan

Persepsi

nyeri

Nosiseptif Local block

OAINSPembedahan

Modalitas fisik

Opioid

Adjuvants

OAINS?

Acetaminophene

Neural augmentation

Bedah ablatif

Anti-depressants/psychotropics

Relaksasi

Spiritual

Terapi kognitifRestorasi fungsional



WHO Analgesic Ladder

Non-opioid Adjuvant

Opioid for mild to moderate pain Non-opioid Adjuvant

Opioid for moderate to severe pain

Non-opioid Adjuvant

interventional

therapy

1

2

3

WHO, Switzerland, 1996

4



1. Harstall C, Opsina M. IASP: Clinical Updates 2003;XI(2):1−4.

2. Rang HP et al. Pharmacology 2007, 6th Edition, Churchill Livingstone, London. Section 2; Page 228.

3. Hinz B, Brune K. J Pharmacol Exp Ther 2002;300(2):367−75.

4. Chou R et al. Drug Class Review. Portland (OR): Oregon Health & Science University; 2006.

INTRODUCTION

Chronic pain has a worldwide prevalence of 10−55%1

Non-steroidal anti-inflammatory drugs (NSAIDs) areeffective analgesic, anti-inflammatory and antipyretic drugs2

• Inhibit cyclo-oxygenase (COX) enzymes, leading to reduced

production of prostaglandins, which activate pain/inflammatoryresponses

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 andinflammation3,4



Symptomatic relief of Chronic painNon selective NSAID’s are the most commonly used treatment

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

% respondents

0 10 20 30 40 50

NSAID

Weak opioid

Paracetamol

COX-2 inhibitor

Strong opioid

Barbiturate/ergotamine

Tricyclic/SSRI/SNRI

Triptan

DMARD/steroid

Anti-epileptic

Muscle relaxant

Beta/CC blocker

Types of prescription medicine used for the treatment of chronic paina

Diclofenac

is the

leading

NSAID 1

1. IMS 20102. Breivik H et al. Eur J Pain 2006;10:287−333.

2





COX 1 COX 2 SELECTIVITY OF NSAID

non

selective

Pref.

COX-2

COX-2

selective

COX-1

selective

Pref.

COX-1



Konsentrasi OAINS yang dibutuhkan untukmenghambat 50% aktivitasenzim COX-1 dan COX-2

(Chaiamnuay et al , 2006).



The Oxford league table of analgesic efficacy

0 1 2 3 4 5 6

Aspirin 650 + Codein 30

Paracetamol 650 + Codeine 60

Naproxen 550

Ibuprofen 600

Diclofenac 50

Paracetamol 1000 + Codeine 60

NNTDiclofenac 100

Rofecoxib 50

Naproxen 440

Piroxicam 20

Paracetamol 1000

Aspirin 650

0 1 2 3 4 5 6







THE IMPLICATION OF NSAID SELECTIVITY

Cardiovascular risk Gastrointestinal risk

COX-2 COX-1

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

Bleeding Ulcer

Complication

Discontinuation

Thrombosis,

Myocardial

Infarction

Blood

Pressure

Increase

Discontinuation





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

1. IMS 2010

2. Cannon CP et al. Lancet 2006;368:1771 –81.

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

4. Singh G et al. Am J Med 2006;119:255 –66.

Diclofenac in chronic pain

Study (duration) Patients n Treatments Primary outcomes

MEDAL2

(3 years) OA, RA 34,701 Etoricoxib 60/90 mg qdDiclofenac 50/75 mg bid Safety (CV/GI)

CLASS3 (≤65 weeks)

OA, RA 8,059 Celecoxib 400 mg bid

Ibuprofen 800 mg tid

Diclofenac 75 mg bid

Safety (GI/CV)

SUCCESS-14

(12 weeks)

OA 13,194 Celecoxib 100/200 mg bid

Diclofenac 50 mg bidNaproxen 500 mg bida

Safety (GI/CV)

aResults were provided for celecoxib versus the combined diclofenac/naproxen group



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

C

h a n g e f r o m b

a s e l i n e

i n m e a n s c o r e

0

−0.1

−0.2

−0.3

C

h a n g e f r o m b

a s e l i n e

i n m e a n V A S s c o r e

0

−2

−4

−6

−8

Diclofenac 75 mg bid (n=1,996)

Celecoxib 400 mg bid (n=3,987)

Ibuprofen 800 mg tid (n=1,985)

−0.23

−0.25

−0.20

−6.6 −6.7

−4.7

CLASS, Pfizer sponsored RCTNo superior efficacy of Celecoxib vs diclofenac is shown



MEDAL, MSD sponsored RCTNo superior efficacy of etoricoxib vs diclofenac is shown

Cannon CP et al. Lancet 2006;368(9549):1771−81.

C

h a n g e f r o m b

a s e l i n e

i n L i k e r t u n i t s

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

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

P a t i e n t s ( % )

0

−0.2

−0.4

−0.6

−0.8

−0.61 −0.67

9.8

9.0



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 non-

selective COX-1 inhibition

Diclofenac has morespecificity to COX-2 than

COX-1

Recent RCT’s had shown little

or no difference between COX-2inhibitors & diclofenac (MEDAL1,

CLASS2 & SUCCESS-13)

1. Cannon CP et al. Lancet 2006;368:1771 –81.

2. Witter J. Celebrex Capsules (Celecoxib) NDA 20-998/S-009 Medical Officer Review 2000.3. Singh G et al. Am J Med 2006;119:255 –66.



External factors could modify the risk ofGI events

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, selectiveserotonin reuptake inhibitors, anticoagulants)

• Others

1. Lanas A, Sopeña F. Gastroenterol Clin North Am 2009;38:333 –52.

2. Hinz B, Brune K. J Pharmacol Exp Ther 2002;300(2):367−75.

1,2



GI events are related to COX-1 inhibition? Diclofenac has more specificity to COX-2 than COX-1

Mitchell JA, Warner TD. Br J Pharmacol 1999;128:1121 –32.

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

other traditional NSAIDs

11

10

9

8

7

6

54

3

2

1

0

R e l a t i v e C O

X - 1 / 2 s e l e c t i v i t y

( i n c r e a s i n g C O X - 2 s e l e c t i v i t y )

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

(increasing toxicity)

Ketoprofen

Indomethacin

Aspirin

Naproxen

Tolmetin

Ibuprofen

Piroxicam

Sulindac

Diclofenac

DiflunisalFenoprofen



Patients with increased GI riskDifferent strategies for reducing GI toxicity with NSAID’s

1. Use lowest effective doses, shortest duration oftreatment

According to drug’s prescribing information

2. Use a selective COX-2 inhibitor

BUT several withdrawn due to

cardiovascular/other risks

1,2

3. Co-administer NSAID + prostaglandin analogue

Supplements stomach in prostaglandins not synthesized due toCOX 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):690−704.4. Lanas A, Sopeña F. Gastroenterol Clin North Am 2009;38:333 –52.

http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124649.htm






CV comparison for Diclofenac vs COX-2 inhibitorsVoltaren 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: 1053 –1063.

2. Krum et al. European Journal of Heart Failure (2009) 11, 542 –5503. Krum et al. Journal of Hypertension 2009, 27:886 –893.



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 andcardiovascular events? Renal function?

Choose NSAID due to pharmacokinetic andpharmacodinamic profile (onset of action, half life, COXselectivity, risk of side effect)

Dose and Duration of treatment

Monitor the respons of treatment

Monitor the side effect



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