update in nociceptive pain treatment
TRANSCRIPT
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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$hemota4is!nammatoryresponse'ascularpermeability
Prostaglandin%
( P+%
Prostaglandin@α
( P+@α
Prostaglandin!
( P+!
Thrombo4ane.
( TF.
'asodilatation,diuresis andnatriuresis
!nhibits
'asodilatation,diuresis andnatriuresis
'asodilatation,diuresis andnatriuresis
Cenin release
'asoconstriction
↑ platelet
aggregation
Schematic diagram of the arachidonic acidpathay
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In
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+ole of C$-/ 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
Currently Availa*le Painedications
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
$epatic necrosis 0ithoerdose, alcohol use
"ramadol
• Mixed actions opioid agonist plusnorepinephrine(serotonin reupta>einhi*itor
• ?seful in patients0ith contraindicationto C)!-# specificinhi*itor ornonspecific &SA+<therapy
• &ausea, constipation,dro0siness
• May induce psychicand physicaldependence
• o0ers seizurethreshold
DParacetamol in some countries3
C tl A il *l P i
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Currently Availa*le Painedications
Mechanism ofAction 1enefits Aderse Effects
)pioids
• 1ind to opioid
receptors, producingagonist action thatinhi*its pain impulses
Effectie in seere
pain of addiction0hen used properly
Respiratory
depression
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Pain echanisms8 Peripherally and Centrally Induced C$-/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