Update in Nociceptive Pain Treatment

8/17/2019 Update in Nociceptive Pain Treatment

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Update in NociceptivePain Treatment

A. Husni Tanra

Dept. of Anesthesiology, Intensive Care andPain anagement!aculty of edicine, Hasanuddin University a"assar


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Peripheral sensitization

After Tissue Injured


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5/7/16

IN!#AATI$N

Prostaglandins are one of a number of mediators ofthe inammatory process Source

▪ Tissue damage, degeneration (cell membranes

▪ !nammatory cells ("#$, macrophages %&ects

▪ 'asodilatation (redness

▪ !ncreased permeability (selling

▪ Pain▪ )ocalised heat or fe*er


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rostag an n ort sone orThyro'in P+ are synthesied in broad range of tissue types and

ser*e as- .utocrine

Paracrine P+ performing as a hause0eeping to regulate normal cell

acti*ity2

• $ortisone 3 Thyro4in are released from a single site butha*e broad systemic e&ect, it is called as-

– endocrine

$o4

.. P+s P+sParacrine

$o41..

P+s

P+s

.utocrine

eighboringcell

.utocrine

%pithelial cell


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(hat is prostaglandine) !s an eicosanoid (local hormone hich plays a big role in

normal physiologic as ell as in patophysiologic condition

Normal physiology Pathol. condition

• Blood clotting

• Ovulation

• Initiation of labor

• Bone metabolism

• Nerve groth ! development

• "ound healing

• #idney function

• Blood vessel tone• Immune response$ etcl

• Inflammation process

• Pain

• %elling

• isebut prostaglandin,0arena pertama ditemu0an dalamcairan prostat2

• Prostaglandin diprodu0si lo0al untu0 0ebutuhan lo0aldiberbagai organ tubuh


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Prostaglandin &ythesis The 0ey enym re8uired for con*ersion

arachidonic acid prostaglandin is$ycloo4igenase ($o4

199:, isoform of cycloo4ygenase asidenti;ed

$o41 < enym produce constituti*ely in +!,

0idney 3 platelate

.rachidonic .cid

Prostaglandin

$ycloo4ygenase

($o41997- .spirin,S.!


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Cell em*ranePhospholipids

ArachidonicAcid

Endoperoxides

Throm*o'ane

Prostaglandins

Prostacyclin

To'ic $'ygen +adicals

Cycloo'ygenase

C$-

Phospholipase

Tissue Trauma


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Mechanism of ProstanoidsMechanism of Prostanoids

Arachidonic acidArachidonic acid

CyclooxygenaseCyclooxygenase

ProstanoidsProstanoids

• Anti-inflammatory

• Analgesic• Antipyretic• Gastrointestinal toxicity• Renal toxicity

• Anti-inflammatory

• Analgesic• Antipyretic• Gastrointestinal toxicity• Renal toxicity

Protect

gastroduodenal

mucosa

Protect

gastroduodenal

mucosa

Support renal and

platelet function

Support renal and

platelet function

Mediate

inflammation, pain,

and feer

Mediate

inflammation, pain,

and feer

!!


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Arachidonic Acid

P++

PH/

P0/P!/.. PD/ PI/ T-A/

S.!S$ycloo4ygenase=1$ycloo4ygenase=


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Prostacycli

n

TH- A/ PD/ P0/ P!/

Arachidonic Acid Cascade

Arachidonic acid

"issue-specific isomerases

Prostaglandin G#

Prostaglandin $#

em*rane phospholipids

PhospholipaseA/

Adapted from !it1erald A et al. N Engl J Med .

C$-/C$-3

TH- 9throm*o'ane.


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COX-1 vs COX-2 Inhibitors

• Cyclooxygenase-1 (COX-1) was firstcharacterized in 19!s and is widely

distrib"ted in all tiss"es

• #elective COX-2$ an ind"cible for%$ wasidentified in early 199!s and fo"nd %ainly in

brain and &idney$ b"t a''ear widely in

infla%%ation area


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N&AID ) History

1>9?, @eli4 Ao&man (ahli 0imia Berman,bapa0nya menderita C. menemu0anasetilsalisilat (aspirin Tahun yang sama ditemu0an Parasetamol Deduanya di0enal sbg analgesi0 biasa (usual

analgesic 1971, 'ene d00 menemu0an enim

$ycloo4ygenase ($EF yang dpt diblo0 olehS.! atau .!S < anticycloo4ygenase

199:, ditemu0an $o4 yang merupa0anisoform $o41 yg muncul setelah terGadiinamasi dsb $o4ib

::, r2 Simmons menemu0an enim lain

yang dapat diblo0 oleh hanya paracetamol


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C$-3 vs C$-/

•Constitutive

•Present in most tissues

•&ynthesi1esprostaglandins :Ps;that regulate physiologicprocesses

•0specially important in

& gastric mucosa & "idneys & platelets & vascular endothelium

C$-3

• Induci*le :in mosttissues;

• Induced mainly at sitesof in2u#ois C et al2 FASEB J2 199>H1-1:6?=7?2


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N&AIDContraindications

ehydration Aypo*olemia ephroto4ic agents

.nticoagulants

Vimolluck Sanansilp, Siriraj


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N&AIDs and Asthma

Study of stable asthmatics gi*endiclofenac orally (Short et al2 :::

Jeasured P%@C and @%' 1 pre= and post

administration 56K had drop in *alues but ma4 15K one had to increase their medication

Suggest = acceptable in stable asthmatics

Vimolluck Sanansilp, Siriraj


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Prostaglandin

( P+

'asodilatation( ea0

( Jast cellmediator /

.rachidonic .cid

)eu0otrienes

Prostaglandins +

( P++

Prostaglandins A

( P+A

.naphyla4is

#ronchoconstriction$hemota4is!nammatoryresponse'ascularpermeability

Prostaglandin%

( P+%

Prostaglandin@α

( P+@α

Prostaglandin!

( P+!

Thrombo4ane.

( TF.

'asodilatation,diuresis andnatriuresis

!nhibits



Cenin release

'asoconstriction

↑ platelet

aggregation

Schematic diagram of the arachidonic acidpathay


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5/7/16

In


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+ole of C$-/ inIn


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Activation of the 0entral

Nervous %ystem

at the %pinal 0ord 1evel

Tissue 2amage Activation of the

Peripheral Nervous

%ystem

Transmission of the Pain

%ignal to the Brain

Pain

The Pain +esponse

%amad TA et al. Nature. '(()*+)(,+-)/.


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Arachidonic

Acid Arachidonic

Acid

T3A'T3A'

P45'P45'

P46'

P47'αP42'

P46'

P47'αP42'

P4I'P4I'

0ycloo8ygenase

9) or ':0ycloo8ygenase

9) or ':

Kam PCA Anesthesia 2000; 55: 442-229


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Cycloo'ygenase 0n1ymes

C$-3 $onstituti*e Potential 54 ↑ %4pressed- +! mucosa

Didneys

Platelets

'ascularendothelium

C$-/ !nducible

Potential >:4 ↑↑ %4pressed- Site of inGury

$S

The .rachidonic .cid $ascade and


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Adapted from Needleman P et al. J Rheumatol. );;-*'+9%uppl +;:,-.

Arachidonic Acid

0O3)90onstitutive:

0O3'9Inducible:

%tomach

Intestine

#idney

Platelet

Inflammatory %ite NA e8pression9&:

3TA>46T 7O> A

0O3' %P60I7I0

IN5IBITO>

9&:

N%AI2s

The .rachidonic .cid $ascade and$EF=1

and $EF= !nhibition


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? Aas been used as analgesic since L1:: years

? ::, anniel Simmons found a

*ariety of $EF called $EF ? hich issensiti*e to acetaminophen

? !t has analgesic 3 antipyretic but hasno anti=inammatory e&ect2

? (or" centrally, decrease pain =fever

? #asic component of multimodalanal esia

5;


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Acetominophen

Acetominophen should be the ;rstline analgetic agent in pain relief thanantiinammatory drugs due to itsfa*orable side e&ect and safety pro;le2

This consensus is recomendede by -12 .merican $ollege of Cheumatology2 .merican Pain Society

?2 %uropean )eague .gainst Cheumatism

(Schmiter, T2B2 Mpdate on guidelines for the treatment of chronic musculos0eletalpain2 $lin Cheumatol 5- S=S9, ::6


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+ole of Prostaglandins in PainA (or"ing Hypothesis

Peripheral Central %C&S'

"rauma(noxious stimulus

Release of arachidonic acid

↑ Prostaglandins

↑ Sensitiity of peripheral

nociceptors

Actiation of C&S at spinal

cord leel %reducing pain

threshold'

C)!-#

Pathophysiologic conditions

%eg, ischemia, hypoxia' or

inflammatory stimuli

Expression of C)!-#

↑ Prostaglandins

Central sensitization

A*normal pain sensitiity

Pain

+-*

+-./

PGES/


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C)!-# +nduction

in Spinal Cord

C)!-# +nduction

in +nflamed Pa0

Acute +nflammation-1ased Pain2 $argreaesModel

Hyperalge

sia

&>elling =

Hyperalgesia

$arrageenan

inGection

$EF= inductionSelling Thermal

sensiti*ity(Ja4imal by ?

hours

oral


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+ole of C$-/ in In


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C$-/ Induction Hypothesisand C$-/ &peci?c Inhi*itors

$EF= speci;c inhibitor therapy may or0 at both peripheral and central sites

▪ must readily cross blood=brain barrierfor $S e&ects1

pre*ent $EF= up=regulation in the $Sith early use

▪inhibition of central sensitiationcaused by $EF= induction (↓ prostaglandin synthesis,neurotransmitter release, neuronale4citability 3 Samad "A et al3 Trends Mol Med 3

#44#592:;4-.3#3 Samad "A et al3 Nature. #44564267-83

C tl A il *l P i


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Currently Availa*le Painedications

Mechanism of

Action 1enefits Aderse Effects&onspecific&SA+


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ips>y PE3 Harrison’s Principles of Internal Medicine. ;;92994-93+nsel PA3 Goodman and Gilman’s The Pharmacological Basis of Therapeutics3 ;;.2.7-873ACR Su*committee on )A Guidelines3 Arthritis Rheum3 #44456:2;48-83?ltram@ prescri*ing informationB3 Raritan, &2 )rtho-Mc&eil5 #443


Mechanism ofAction 1enefits Aderse Effects

AcetaminophenD

• +nhi*it prostaglandinsynthesis in the C&S/

Antipyretic andanalgesic actiity

ell tolerated

=e0 aderse effects

ittle or no anti-inflammatory actiity

$epatic necrosis 0ithoerdose, alcohol use

"ramadol

• Mixed actions opioid agonist plusnorepinephrine(serotonin reupta>einhi*itor

• ?seful in patients0ith contraindicationto C)!-# specificinhi*itor ornonspecific &SA+<therapy

• &ausea, constipation,dro0siness

• May induce psychicand physicaldependence

• o0ers seizurethreshold

DParacetamol in some countries3

C tl A il *l P i


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Mechanism ofAction 1enefits Aderse Effects

)pioids

• 1ind to opioid

receptors, producingagonist action thatinhi*its pain impulses

Effectie in seere

pain of addiction0hen used properly

Respiratory

depression


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Pain echanisms8 Peripherally and Centrally Induced C$-/3,/

1Samad T. et al2 Nature2 ::1HI1:-I71=I752Smith $B, Nhang O, Doboldt $J, et al2 Pharmacological analysis of cycloo4ygenase=1 in inammation2 Proc Natl Acad Sci USA2 199>H 95-1??1?=1??1>2

Peripheral

Trauma / inammation

Celease of arachidonic acidinduction of $EF=

Prostaglandins

Sensiti*ity of

peripheral nociceptors

$entral sensitiation

Pain

$entral

P). !)=1

!nduction of $EF=

Prostaglandins

.bnormal pain sensiti*ity

!)=6Q


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+ole of C$-/ inIn


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$EF=1 $EF=

C$-3 vs C$-/35

$onstituti*e in manytissues

Present in most tissues Synthesies P+s

that regulate physiologicprocesses %specially important in +astric mucosa Didneys Platelets

'ascular endothelium

!nducible (in most tissues !nduced mainly at sites of

inammation by cyto0ines

Synthesies P+s thatmediate inammation,pain, and fe*er

$onstituti*e e4pressionprimarily in

$S

Didneys

1eedleman P et al2 J Rheumatol2 1997HI(suppl I9-6=>2u#ois C et al2 FASEB J2 199>H1-1:6?=1:7?2?Samad T., Joore D., Saperstein ., et al2 !nterleu0in=1=mediated induction of $EF= in the $S contributes to inflammatory pain hypersensiti*ity2 Nature.::1HI1:-I71=I752

@ ?t f C$- /


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@ene?ts of C$-/Inhi*itionSparing $EF=1 reduces the ris0 of upper +! ad*erse e&ects1

o e&ect on bleeding time

$EF= inhibition results in anti=inammatory and analgesice&ects1

Selecti*ity for the $EF= enyme o&ers $omparable eRcacy to nonselecti*e S.!s studied?=6

o e&ect on platelets or bleeding time,7

1Stolt CC et al2 Am J Gastroenterol. ::H97-65=712o*ec0 CB et al2 Clin Drug Inest. ::1H1-I65=I762?Pa*el0a D et al2 Rheumatolog! 2 ::?HI-1:7=1152I#ensen " et al2 Rheumatolog! 2 ::HI1-1::>=1:1625aniels S% et al2 Clin "her. ::1H?-1:1>=1:?126ata on ;le2 !ntegrated Summary of %Rcacy2 .ugust 9, :::2 P;er !nc2, e Oor0, O27ata on ;le2 !ntegrated Summary of Safety !nformation2 .ugust 6, :::2 P;er !nc2, e Oor0, O2

s ory o non op o


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s ory o non op oanalgesia

1897 Aspirin1950 Paracetamol 1963 NSAIs

1971 Mec!anism o"#o$%11990 isco&er' o"

#()%**00* isco&er' o"

#()%3+ a &ariant o"

#()+ sensiti&e to

Dr Feli#$o%manSir

Sir John&ane


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PA+AC0TA$# (is aniline analgesic class2

Chemical name8

Par a ' acet !lamino(henol ParacetamolPara 'acet !lamino(henol .cetamoniphen

=acetyl=para = aminophenol

.P.Paniel Simmon (:: $EF=? inhibitor

Trade name8Panadol in MD, .ustralia, !ndonesia

Tyleno in MSEther name = Tempera = %&eralgan= atrin = $rocin (!ndia= .nocin = apa (#angladesh


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$ommonly used for relief offe*er, head aches and minorpain2

JaGor ingredient in numerouscold and u remedies2

!s a non prescription drug (freemar0eting

The most consume drug afteramo4icillin in !ndonesia2

P.C.$%T.JE) ($linical


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!s considered as a *ery safeanalgesic 3 anti pyretic

!t is safe from neonate to oldage, pregnant e*en lactationomen2

!t is *ery cheap analgesic, andthe only analgesic hich can beused for long term treatment 2

P.C.$%T.JE) (Safety


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The mystery as ho>paracetamol e'erts an

analgetic eect >ithoutaecting C$-3 and C$-

/)


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PA+AC0TA$#

.lthough paracetamol has been using for more than1:: years, but the mechanism of action stillcontro*ersial2

12 "hat is the mechanism of action ofparacetamolQ

2 "hich endogenous analgesic system areinuenced by paracetamolQ

?2 !s paracetamol is S.!QI2 !s paracetamol safe for li*er disease or ta0ing

anticoagulantsQ52 "hich formula has the best analgesic eRcacyQ62 "hich route of administrates has the better

pharmaco0inetic2

P$&&I@#0 0CHANI&


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P$&&I@#0 0CHANI&$! ACTI$N

12 !nhibition of cycloa4ygenaseisoenymes

2 !nteraction ith the endogenousopioid pathay

?2 .cti*ation of the serotoninergicpathay2

I2 !nhibition of E production52 Jodulation in endogen

cannabinoid system


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sGC

PKGI

Glutamate

NMDA-R

NOS

Ca

++

+

WIND-UP

Inhibition of NO synthesis

NO

Activation of endogenous


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Activation of endogenouscanna*inoids

A l i


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As conclusion, >e mayconclude that4

.nalgesic e&ect of paracetamol

in*ol*es a )sel*'s!nergistic

interaction beteen spinal andsupraspinal sites ith recruitment ofendogenous opiod pathays2

Paracetamol is an analgesic andantipyretic drug and has no or *erylittle anti=inammatory e&ect hichor0 centrally2


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lutathione

Conugation

Non to'ic

eta*olite

0'cretion

lucuronideConugation :2E;

NAPFI:Nacetylp*en1oGuinonimine;

Cytochrome P6727E

Bidney

Deacetylation

Paraaminophenol:PAP;

Jetabolism of Paracetamol

#iver

$'idation

alnutrition#o> protein diet!astingAlcoholism

#arge Dose0n1yme Inducers

AlcoholismPoor $'ygenation

BidneyDamage

#iverDamage

P@FI

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Update in Nociceptive Pain Treatment