is there rational nsaid combination in pain management

8/3/2019 Is There Rational Nsaid Combination in Pain Management

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Aznan Lelo

Dep. Farmakologi & Terapeutik,Fakultas KedokteranUniversitas Sumatera

Utara

9 Oktob r 2011 MS Pain M dan


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Pain Market

PAIN100%

ACUTE34%

CHRONIC66%

NEUROPHATIC

20%

NOCICEPTIVE

80%

CANCER4%

NON-CANCER96%

Nyoman Kertia, 2010


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Common issues of NSAIDs

Different chemical families Different pharmacokinetics and potency Common mechanism of action (COX inhibition)

Different selectivity to COX-1 and COX-2

Common clinical indicationsAnalgesic (CNS and peripheral effect) may involve

non-PG related effectsAntipyretic (CNS effect)

Anti-inflammatory (mainly by PG inhibition)Effective dose for analgesic anti-inflammatory

antipyretic

Common analgesic ceiling effectlimitedefficacy


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Factors to consider when

choosing NSAID as pain killerDrug issues

Efficacy

Tolerability

Safety

Dosage

Cost

Patient issues

Type, severity

Risk factors: GI,platelet, renal and

cerebro-cardiovascular

system.

Co-prescription.

Co-morbidity.

Compliance.BENEFITSefficacy

RISKSsafety


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NSAID adjuvantanalgesic

weak opioid(codeine)paracetamol

or NSAID

adjuvant analgesic

Strong opioid NSAID

adjuvant analgesic

Principles of AnalgesicPrescribing

WHO Analgesic Ladder

0 1 2 3 4 5 6 7 8 9 1

0

Pain tolerance

Pain threshold

mildmild moderatmoderat severesevere


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Critical approachesin selecting medicines

Therapeuticeffect

Adverse reaction

Minimal Maximal

Maximal Yes ?

Minimal ? No

NNH

SMALLEST

GREATEST

(> 100)

NNT

GREATEST

SMALLEST(2-4)

ere are two reasons to withdraw from the treatment eitherno efficacy (NNT very high) or

serious adverse reactions (NNH very low).


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0

10

20

30

40

50

60

Placebo Celecoxib

200mg

Celecoxib

400mg

Naproxen

1000mg

Diclofenac

150mg

Withdraw

al(%)

55%

23%

0

5

10

15

20

25

etoricoxib 90 mg diclofenac 150 mg

gastrointestinal

hypertension

discontinuationrate(%)

19 %

9 %

2.3 %0.7 %

Henti terapikarenatidak

merasakanefek terapi

Henti terapi

karenamerasakan

efek samping


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number needed to treat (NNT) for at least 50% pain reliefover 4-6 hours in patients with moderate to severe pain,

all oral analgesics except morphine, pethidine and ketorolac


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NNT of NSAIDs at different doses

NSAID Dose NNT

Ibuprofen 50 mg 4.7

100 mg 3.7

200 mg 2.7

400 mg 2.5

600/800 mg 1.7

Diclofenac 25 mg 2.6

50 mg 2.7

100 mg 1.8

200 mg 4.5

400 mg 3.7

600/800 mg 3.0

0

10

20

30

40

50

Placebo C2x100 C2x200 C2x400

PlaceboCelecoxib2 x 100

Celecoxib2 x 200

Celecoxib2 x 400

PercentResponders

Incidence of Hypertension

as adverse effect of Rofecoxib

0

2

4

6

8

1 0

R o f e c o x i b 1 2 . 5 m g

( n = 1 2 1 5 )

R o f e c o x i b 2 5 . 0 m g

( n = 1 6 1 4 )

R o f e c o x i b 5 0 . 0 m g ( n = 4


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Etoricoxib:efficacy-dose response at 6 weeks

Shibuya RB, 2009


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Mild vs Severe PainMild Severe

Drug Low dose High dose

Potent agent

Acute vs Chronic Pain

Acute ChronicDrug Rapid onset Long durationDuration of

painShort, self limiting,well-characterized

Persists after healing, 3months

Component Nociceptive NociceptiveNeuropathic


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T-max and Onset of action of

NSAIDs

Onset NSAID T-max (hr)

RapidDiclofenac 0.8

Nimesulide 1.2 2.7

SlowCelecoxib 2 4Meloxicam 6


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T-1/2 and Duration of action of

NSAIDs

Duration NSAID T-1/2 (hr)

short Diclofenac 1.1Nimesulide 1.8 4.7

moderate Celecoxib 11

Naproxen 14

long Meloxicam 20

Etoricoxib 22


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NSAID use

Acute inflammatory pain or

Breakthrough pain

Short half-life NSAID Ibuprofen, diclofenac, etc

Chronic inflammatory pain

Long half-life NSAID Oxicam, COXIB


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Etoricoxib, a long half-life (22 hours):dosage and efficacy

Painindications

Dose(mg)

Note

Chronic pain

OA 30 60 Curtis SP, et.al.2005

Acute pain

Gouty arthritis 120 Maximum 8days

Dysmenorrhea 120 Maximum 8da sAcute Pain Severe Pain

?? ??


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Slowly Chronic

How to change the onset of

action of the long half-life NSAID

Time

Co

ncentration

Effective concentration

Acute

NSAID long half life

long durationbut slow onset

increasedthe dose !

By increasing the

dose ???:onset becomes earlier

but adverse effects

enhanced

tional?

Sa

ve?Ethi

c?

Dan

gerou


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PG

ALGESIA

POLYMORPHS

TNF-

IL-6

IL-1

IL-8

SYMPATHETICNERVE

MACROPHAGES

FIBROBLASTS

COX-2

INFLAMMATION

PG BK

NOCICEPTOR

PG

Ferreira, 1993

BBB BBB BBB BBB BBB BBB BBB BBB BBB

Prostaglandin HYPERALGESIA

DICLOFENAC

andNimesulide

DICLOFENAC

and allAcidic

NSAIDs

DICLOFENAC

and allNon-COXIB


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Capone ML, et al. Int J Immunopathol Pharmacol.

16(2 Suppl):49-58,2003.

Clinical pharmacology of

selective COX-2 inhibitors

Acidic COX-2 inhibitors

have been hypothesized that thispeculiar chemical feature may lead to

an enhanced concentration in

inflammatory sitesthat may translate into

an improved clinical efficacy


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Tissue concentrations of total radiolabeled componentsat 1, 4, 8 and 24 h after oral administration of

[14C] diclofenac sodium at a dose of 2 mg/kg to male rats

injected with carrageenan (T) or saline (C) into the leftfront footpad and the left hind paw

Concentration of total radiolabeledcomponents (nmol/g)

1 hour 4 hours 8 hours 24 hours

Tissue T C T C T C T C

Injection sitenape neck

0.79 0.12

0.18 1.20 0.30

tc 1.30 0.10

tc 0.20 0.04

nd

Untreatedfootpads

0.16 0.04

0.20 0.15 0.10

0.20 tc nd nd nd

Injection sitefootpads

1.00 0.23

0.12 1.30 0.5

nd 0.84 0.10

nd tc nd

Schweitzer A, N Hasler-Nguyen N, Zijlstra J. BMC, 2009


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Mekanisme kerja AINS

Mekanis-me

Ibu-profen

Diclo-fenac

Piro-xicam

Cele-coxib

Etori-coxib

COX-1 ++ + + - -

COX-2 + ++ + ++ +++

COX-3 + +++ ? ? ?

Anti-BK + + + ? ?

K-opener ? + ? ? ?

TembusBBB

+ + + ? ?


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plateletaggregation

plateletaggregation

GI

bleeding

GIbleeding

GIbleeding

plateletaggregation

COX-1inhibitor

COX-2inhibitor

moreheart attack

fewerheart attack


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

Bleeding UlcerComplications

Degree of Selectivity

Blood PressureIncrease

Discontinuation

Thrombosis,Myocardial Infarction

Etoric

oxib

Celec

oxib

Diclofe

nac

Rofec

oxib

Nap

roxe

n

Ibup

rofen

Discontinuation

Cardiovascular Risk Gastrointestinal Risk

COX-2 COX-1

The Implications of NSAIDSelectivity


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Ototoxic

Bronchospam CHF

Hepatotoxic UGIB

Bleeding Nephrotoxic

TocolyticAllergy

Color blindness

Adverse Effects of NSAIDs

Mechanism of = Mechanism of

therapeutic effects adverse effects

UGIB


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PGD2inhibits platelet

aggregation,vasodilator

PGE2vasodilator,

hyperalgesia

PGF2alfabronchodilatationmyometrial contr.

hyperalgesia

PGI2inhibits platelet

aggregation,vasodilator,

hyperalgesia

TXA2stimulates platelet

aggregation,vasoconstriction

5-HPETE

LTA4

LTB4

chemotaxis

LTC4

LTD4

LTE4

brochoconstrictionincreasevascular

permeability

cyclicendoperoxides

phospholipids

arachidonic acid

COX LOXCOX-1COX-2


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RESPIRATORY TOXICITY

PGsLTs

AANSAID

bronchodilatation

NSAID-induced asthma

bronchoconstriction


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Risk Factors of

Ulcer Complications from NSAIDs

2 .23 .5

5 .66 .1

6 .47

913 . 5

1 3 5 7 9 11 13 15

S te ro i d t he rapyH .py l o r i i n f e c t i on

A g e > 7 0 y rP r i o r u n c o m p l i c at e d P U

An t i c o a g u l a n tH i g h - d o s e N S A I D

M u l t i p l e N S A I D s ( i n c l u d i n g AS A )P r i o r c o m p l i c at e d P U

Relative risk


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0.82

8

18

0

5

1 01 5

2 0

N o R i s k F a c to r 1 -2 F a c to r s 3 F a c to r s 4 F a c to r s

Number of Risk Factors &

Incidence of Ulcer Complications

Silverstein FE.Ann Intern Med1995;123:24

NNH 125

NNH 50

NNH 12

NNH 5

inciden

ceofulcer(%)


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NSAID GI

Toxicity

generallyvaries

with half-

life of the

agent

NSAID Diclofenac Naproxen Piroxicam

Dose (mg/d) 100 750 20

Half-life (hr) 1.5 14 50

24 hr fecal bloodloss (mL) 0.53 +/- 0.21 2.76 +/- 2.22 1.16 +/- 0.62

Henry, et al. BMJ.312:1563,2000; Scharf, et al. Aust N Z J Med

Shortest half-life

Low

estGIrisk


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The pattern of NSAID plasma concentration

based on the dose and half-life of drug given

0

200

400

600

800

1000

1200

1400

1600

0 2 4 6 8 10 12 14 16 18 20 22 24

Plasmaconcen

tration(mg/L 500 mg tid, 2 hrs

1500 mg od, 2 hrs500 mg tid, 12 hrs

1500 mg od, 12 hrs

Drug accumulation

3 x 1 1 x 3Efek terapeutik Efek samping obat

Choose the shortest half-life


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Nociceptive VS neuropathic painNociceptive VS neuropathic pain

Neuropathic painInitiated or caused byprimary lesion ordysfunction in thenervous system

Nociceptive painCaused by activity in

neural pathway inresponse to

potentially tissue-damaging stimuli

Postoperativepain

MechanicalLBP

Sport /exerciseinjuries

Sickle cellcrisis

ARTHRITIS PHN

NeuropathicLBP

Distalpolyneuropat

hy (e.g.diabetic)

Central poststroke pain

Trigeminal

neuralgia

CRPS

International Association for the Study of Pain. IASP Pain Terminology.Raja et al. in Wall PD, Melzack R (Eds). Textbook of pain. 4th Ed.

Mixedpain

Caused by acombination of both

primary injury orsecondary effects

Adjuvant

ANALGESICNSAID


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Adjuvant Analgesics

Defined as drugs with other indications

that may be analgesic in specific

circumstances

Numerous drugs in diverse classes

Sequential trials are often needed

Multipurpose analgesics

Adj t A l i f


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Adjuvant Analgesics forNeuropathic Pain

Class ExamplesAntidepressants amitriptyline, desipramine,

nortriptyline, paroxetine, venlafaxine,citalopram, others

Anticonvulsants gabapentin, phenytoin, carbamazepine,clonazepam, topiramate,oxcarbazepine, others

Alpha-2 adrenergicagonists

tizanidine, clonidine

Local anesthetics mexiletine, tocainide

NMDA receptorAntagonists

dextromethorphan, ketamine,amantadine

Miscellaneous baclofen, calcitonin

Topical lidocaine, lidocaine/prilocaine,capsaicin, NSAIDs

Steroids rednisone, dexamethasone

NNT and NNH adjuvant


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NNT and NNH adjuvantanalgesia for chronic non-

cancer painDrug NNT NNH

Phenytoin 2.1 9.5

TCAs 2.4 2.7Carbamazepine 3.3 1.9

Pregabalin 3.3 7.0

Gabapentin 5.0 2.5Mexiletine 10 510

Codeine 18 2


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The role of neurotropicvitamin in alleviating pain

Investigators Year Animal Vitamin BsHanck & Weiser 1985 Rats B12

Granados-Soto et al 2004 Rats B12 + diclofenac

Rocha-Gonzlez et al 2004 Rats B1, B6, B12 +diclofenac

Medina-Santilln et al 2004 Rats B1, B6, B12 +ketorolac

Wang et al 2005 Rats B1, B6, B12

Caram-Salas et al 2006 Rats B1, B6, B12 +dexametasone

Song et al 2009 Rats B1


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The role of neurotropicvitamin in alleviating pain

Investigators Year Subject Vitamin BsMazzoni &Valenti 1964 Patients B1

Hieber 1974 Patients B12

Mder 1988 Cervico-

brachialgia

B1, B2, B9

Vetter et al 1988 Patients B1, B6, B12 +diclofenac

Brggemann et al 1990 Patients B1, B6, B12 +diclofenac

Abbas & Swai 1997 DM B1, B6Mauro et al 2002 LBP B12

Peters et al 2006 Patients B1, B6, B12, B9

Mibielli et al 2009 Patients B1, B6, B12 +diclofenac

Percentage of patients


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Percentage of patientsdischarged with pain score

(VAS)

Galvan-Montano A, et al. Cir Cir 2010;78:400-9


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Efek Analgetik dan NeuroprotektifVitamin Neurotropik

(Zimmerman, 2006)

1. NMDA receptorantagonism

2. Block at Ca2+ channels

3. Blok of cytokine formation (eg: TNF-)and receptor binding

TNF , growth factors,IL 1 , IL 8VitaminB complex


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PAGPAG

Cerebral cortex

Hypothalamus

Spinoreticularafferents

NRMNRM NRPGNRPG

Inter-Inter-

neuronneuronInter-Inter-

neuronneuron

SpinoreticulothalamicPain Projection

C fibers

Enkephalin

5-HT NE

- -

DE

SCE

NDIN

G

DE

SCE

NDIN

G

P

ATHWAY

P

ATHWAY

ASCENDING

ASCENDING

PATHWAY

PATHWAY

Neurotropic vitamins increase the production of

serotonin and noradrenalin, then inhibit the


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NSAID has limited efficacy due to theceiling effect

For acute inflammatory pain Short half-life NSAID (diclofenc)

For chronic inflammatory pain Long half-life NSAID (oxicam) The best and safest adjuvant analgesic

is neurotropic vitamin

For mixed pain With inflammation NSAID + adjuvant

analgesic (DOLOFENAC) Without inflammation paracetamol +

dj t l i (DOLONEUROBION)

is there rational nsaid combination in pain management

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