Neurobiologie van PijnProf. dr. Bart Morlion

Pijn is een onplezierige, sensorische en emotionele ervaring die gepaard gaat met feitelijke of mogelijke

weefselbeschadiging of die beschreven wordt in termen van een dergelijke

beschadiging.

IASP 1979

Definitie van pijn

• PAIN“An unpleasant sensory and emotional experience associated with actualor potential tissue damage, or described in terms of such damage.”1

• Alternative proposals: • “Pain is a distressing experience associated with actual or potential tissue damage, with sensory,

emotional, cognitive and social components.” 2

• “An aversive sensory and emotional experience typically caused by, or resembling that caused by, actual or potential tissue injury. 3

• CHRONIC PAIN“Persistent or recurrent pain lasting longer than 3 months”

1. IASP 1994 & 20082. Williams AC, Craig KD. Updating the definition of pain. Pain. 2016;157(11):2420-33. proposed by the IASP Definition of Pain Taskforce Aug 2019.4. Treede R-D, et al. et al. Pain. 2019;160:19–27

Definitions of Pain

MG30 Chronic pain

MG30.0 Chronic primary painMG30.1 Chronic cancer related painMG30.2 Chronic postsurgical or post traumatic painMG30.3 Chronic secondary musculoskeletal painMG30.4 Chronic secondary visceral painMG30.5 Chronic neuropathic painMG30.6 Chronic secondary headache or orofacial painMG30.Y Other specified chronic painMG30.Z Chronic pain, unspecifiedMG31 Acute painMG3Z Pain, unspecified

ICD. Available from: https://icd.who.int/dev11/l-m/en#/http%3a%2f%2fid.who.int%2ficd%2fentity%2f1581976053. Accessed August 2019.

ICD-11 adopted !

Persistent or recurrent pain lasting longer than 3 months

DuurAcuutChronisch

MechanismeNociceptief / InflammatoirNeuropathischNociplastischGemengd

IntensiteitMildMatigErnstig

AandoeningenKankerNiet-kanker

andereAchtergrondpijnDoorbraakpijn

Turk D. Pain terms and taxonomies. In: Loeser JD, Chapman CR, Turk D, editors. Bonica’s Pain Management: Lippincott Wlliams & Wilkins; 2001. p. 18-25.;

Classificatie van pijn

…het vermogen van een organisme om weefselbeschadiging of dreigende weefselbeschadiging waar te nemenIASP: Het neurale proces van codering van (potentieel) schadelijkestimuli.• Gevolgen van deze codering• autonoom (vb. verhoogde bloeddruk)• gedragsmatig (vb. terugtrekken of meer complex pijngedrag).• Pijnervaring is niet noodzakelijk.

Nociceptie (pijnzin)

CIPA

Pijn als beschermend mechanisme

Pijn is een biopsychosociaal fenomeen

• Affectieve stoornissen• Angst & Depressie• Catastroferen• Kwaadheid

• Maladaptieve coping• Afname veerkracht• Eigen ziektetheorie• Niet-verkwikkende slaap• Vermoeidheid• Stijfheid en kinesiofobie• Concentratie- en geheugenstoornissen

Pijn

0

Graphic composed by the author

Neurobiologie van pijn

• Transductie

• Transmissie

• Modulatie

• Perceptie

• Transductie• Temperatuur Warmte: TRPV1, TRPV2, TRPV3, TRPV4, P2X3• Temperatuur Koude: TRPM8, TRPA1• Mediatoren bij weefselschade : P2X3, P2Y, Bradykinine B1/2, 5-HT3 en andere 5-HT• Mechanoreceptoren: TRPV4, TRPC/V/P• Inflammatoire mediatoren en targets: H+, PG, NGF, IL-1, TNF, Ligand en Spanningsafhankelijke kanalen

(bv. TRPV1, NaV1.9, NaV1.7 en NaV1.8)

• Transmissie• NaV1.7, NaV1.8, NaV1.9, NaV1.1, NaV1.2, NaV1.6

• Modulatie• Excitatorisch: Glutamaat, ATP, Neuropeptiden, BDNF• Inhibitorisch: Glycine, MOR, CB1/CB2 GABA• Microglia activatie: ATP via P2X4, P2X7, CCL, BDNF, Fractaline

Neurofarmacologie

25 °C43 °C53 °C -10 °C30 -> 40°C

Noxious Warm Warm Noxious ColdCold

0

Graphic composed by the author

Neurobiologie van pijn

• Transductie

• Transmissie

• Modulatie

• Perceptie

Primary afferent axons

0

Graphic composed by the author

Neurobiologie van pijn

• Transductie

• Transmissie

•Modulatie

• Perceptie

SensorenVoelers, metertjes

Filter in het ruggenmerg

“Gate Control Theory” Melzack en Wall 1965

SG T ACTIONSYSTEM

CENTRALCONTROL

+

+

+

--

-

INPUT

L

S

• Aangename prikkels kunnen pijnpoorten sluiten.

• De hersenen kunnen ook pijnpoorten sluiten.

De Poorttheorie

TENS & neurostimulation (SCS)

0

Graphic composed by the author

Neurobiologie van pijn

• Transductie

• Transmissie

• Modulatie

• Perceptie

Perifere nociceptie

Spinale integratie

Centrale verwerking

Pijnervaring

Both

Pain

Brain regions that may modulate pain and emotion

Thalamus

Anterior cingulate cortexAffective component

Prefrontal cortexProcessing of affective aspects of

sensory stimulationExecutive functions:

Working memory; decision making; planning and judgment

HippocampusAversive input and memory

Amygdalamemory of emotional reactions

fear and anxiety

Insular cortex

Somatosensory cortex

Striatum

Pijn en Emotie

This slidekit is copyright protected by Eli Lilly Co. and may not be reproduced without permission

C

NS

/EL

B/

10

/2

01

1/4

08

Modulatie van pijn door aandacht

Aandacht naar pijn Aandacht naargeluidstonen

Adapted from Bushnell et al. Proc Natl Acad Sci USA 1999;96(14):7705-09.

Slechte stemming + pijn Goede stemming + pijn

Adapted from Villemure et al. J Neurosci 2009;29(3):705-15.

Modulatie van pijn door stemming

Zwakke associatie tussen stimulus en pijnlijke ervaring

Fillingim R. in Bonica's Management of Pain, Eds. Fishman SM, et al. Lippincott Williams & Wilkins: Philadelphia; 2010.

Individual Difference Factors

De patiënt

Rugpijn

.

Hulpvraag

Vind de oorzaak !Repareer het !Genees het !

• Er moet iets gebroken zijn !• Een verschoven wervel !• Ik mag me niet bewegen want dan

maak ik het erger !

0

• Transductie

• Transmissie

• Modulatie

• Perceptie

Perifere sensitizatieNiet-schadelijke prikkels activeren het pijnsysteem

Centrale sensitizatieAmplificatie van synaptische overdracht

Spontane pijn &Overgevoeligheid voor pijnNociceptieve

inflammatoireprocessen

Zenuwschade

Centrale processen

Graphic composed by the author

Transitie van acute naar chronische pijn: maladaptieve neuroplasticiteit

NMDA Receptor

Neuroplasticity in Spinal Cord Processing: Wind-up and Long-term Potentiation

AMPA=Alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid; Mg2+=Magnesium block; NK-1=Neurokinin-1 receptor; NMDA=N-methyl-D-aspartic acid.

NK1 AMPA NMDACa2+

NK1 AMPA NMDA

Mg2+

Ca2+

NK1 AMPA NMDACa2+

Mg2+

Mg2+

Glutamate Substance P

• Centrale sensitisatie– Amplificatie van neurale signaalprocessen

in het centraal zenuwstelsel dat overgevoeligheid voor pijn uitlokt.

– Betekent niet dat de pijn niet reëel is, of ingebeeld, enkel dat de pijn niet geactiveerd wordt door schadelijke stimuli.

• Hyperalgesie =hevigere pijnreactie op schadelijke stimuli

• Allodynie =pijnlijke reactie op onschadelijke stimuli

Centrale Sensitisatie & PijnCentral Sensitivity Syndromes (CSS)

Yunus Seminars in Arthritis and Rheumatism 2008

Overbeschermd !

Allodynie

Hyperalgesie

normaal

Stimulus Intensiteitschadelijk

Pijn

sens

atie

onschadelijk

insultPijn na een niet-

schadelijke stimulus

Verhoogde pijngevoeligheid

R E V I E W

NATURE NEUROSCIENCE VOLUME 17 | NUMBER 2 | FEBRUARY 2014 193

For instance, congenital insensitivity to pain with anhidrosis (HSAN-IV, CIPA) is a result of recessive loss-of-function mutations in the TRKA receptor gene (see ref. 7 for review). This result helped to consolidate pre-clinical findings that have implicated TRKA and its ligand NGF in nociceptor sensitization8 and has eventually led to both targets being pursued by the drug development industry, with promising results: tanezumab, an NGF antibody, has reached phase III of clinical trials for the treatment of hip and knee osteoarthritis and may also be effective in other chronic pain conditions, such as back pain and interstitial cystitis (see http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM295205.pdf). Similarly, a linkage study of a Chinese family in 2004 identified a previously unknown target in primary erythermalgia, the sodium channel subunit Nav1.7 (SCN9A). Mutations in SCN9A can result in indifference to pain and paroxysmal extreme pain9. Animal studies have since confirmed the presence of Nav1.7 in 85% of nociceptors and its importance for processing both mechanical and inflammatory painful stimuli9. Several sodium chan-nel blockers are now in phase IIa clinical trials to test their efficacy against pain of diverse etiologies. Finally and most recently, another sodium channel subunit has emerged as a potential target, with a gain-of-function mutation having been reported in Nav1.9 (SCN11A) as another cause of pain insensitivity7.

In contrast with rare Mendelian conditions, the study of pain genetics in the wider community presents a more complex picture. What everyone can agree on is that a sizable degree of risk is indeed accounted for by genetics: most heritabil-ity estimates from twin studies range from 13–60% depending on the pain phenotype and cohort examined5, and heritability can reach 30% for severe chronic pain even in the general population10. As to identifying the genes responsible, the pain field has mostly conducted case-control candidate gene asso-ciation studies that have revealed a wide variety of risk alleles. Loci for which a positive association has been reported are involved in neurotransmitter systems (COMT, OPRM1, GCH1, 5HTR2A, ADRB2), ion channel function (KCNS1, CACNA2D3)

and immune function (IL1, TNF)6. For most of these, the mecha-nistic steps by which any single nucleotide polymorphism (SNP) or haplotype identified might confer risk toward chronic pain in later life are not very clear, although more functional, pre-clinical studies are beginning to emerge (for example, see refs. 11,12). More worryingly, as summarized recently6, results are often not replica-ble, not least because of issues with poor phenotyping, population stratification and sample size.

Recently, genome-wide association studies (GWASs) have been employed, providing unbiased screening of common variants. However, many of the GWASs published, despite examining pain-ful disorders such as osteoarthritis13, lumbar disc degeneration14 or endometriosis15, barely mention pain, let alone measure it directly. There are notable exceptions: several large-scale GWASs and a meta-analysis in migraine research16, a study of molar extraction, which only examined acute post-surgical pain and may have been somewhat underpowered with only 100 participants17, a study of opioid sensi-tivity that revealed a SNP close to the CREB1 gene18, and a GWAS meta-analysis of chronic widespread pain syndrome. The latter study merged and re-analyzed previously collected genotyping data to identify previously unknown variants in two genes (CCT5 and FAM173B), the expression of which was found to be altered in a mouse model of pain19.

What could be improved to help elucidate the genetic risk factors for chronic pain? A fundamental question that remains and the answer to which will greatly influence study design is whether many genes

Table 1 Examples of studies examining the emergence or incidence of chronic painSize of patient cohort Condition or surgery Incidence (%)

Diabetes 15,692 Total incidence of neuropathy 48Painful neuropathy 34

Postsurgical pain 159,000 Amputation 30–50479,000 Breast surgery 20–30Unknown Thoracotomy 30–40609,000 Inguinal hernia repair 10598,000 Bypass surgery 30–50220,000 Caesarean section 10

Lower back pain 448 Pain 5 years after first presentation: prospective study 36.9180 Pain 12 months after initial consultation: prospective study 34

Neck pain 5,277 Incidence of chronic neck pain in cohort of patients reporting at least one episode of acute neck pain: prospective study

18

Only a minority of acute pain sufferers, disease affected and surgical patients will develop chronic pain1–3.

AcP

Me

Me

GC

CG

CG

GC

GC

TA

AT

AT

CG

TA

Brain vulnerable networks

Risk for chronic pain

Hardware at birth• Gender, genotype and

epigenetic profile

Environmental influences• Acute injury or disease at

critical developmental periods • Stressful life events

Gene ! environmentinteractions

• Personality and psychology (for example, pessimism,

neuroticism, anxiety,catastrophizing,

reward bias)

Innate mechanisms Acquired mechanisms

Priming

Figure 1 Various risk factors have been identified for chronic pain, such as genetic, environmental and personality factors. Evidence for potential mechanisms underpinning these risk factors is emerging at molecular, cellular and network levels.

Vulnerability and resilience toward developing chronic pain

Denk F., McMahon S. & Tracey I. Nature Neuroscience Vol. 17, 192-200; 2014

Risicofactoren voor persisterende postoperatieve pijn

Althaus A, et al. Eur J Pain. 2012;16:901-910 ; Schug SA, Bruce J. Pain Rep. 2017;2(6):e627.; Van Den Kerkhof EG, et al. Clin J Pain. 2013;29:2–8.

6 domeinen• Genetisch• Demografisch• Psychosociaal• Pijn• Klinisch• Chirugisch

12

3037

68

82

71

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5

Patie

nts

(%)

No. of risk factors

CPSP at 6 months

Nociceptief Inflammatoir Neuropathisch Nociplastisch

Schadelijke stimuli Ontsteking

Perifere pathologie

Laesie of ziekte in het somatosensorisch systeem perifeer of centraal

Geen schadelijke stimuliGeen ontstekingGeen zenuwschadeGeen perifere pathologie

Beschermend Heling / Herstel / Pathologisch Pathologisch Pathologisch

Hoge drempel Lage drempel

Klinische pijnsyndromen

Adapted from 1. Woolf C. Ann Intern Med. 2004;140:441–51. 2. Kosek E, et al. Pain 2016;157:1382–6.

The descriptor is primarily intended for patients suffering from chronic pain conditions characterized by evidence of altered nociceptive processing, such as those currently labelled as:• Fibromyalgia• CRPS• Nonspecific chronic low-back pain• Irritable bowel syndrome• Other “functional” visceral pain disordersIn addition, patients suffering initially from nociceptive pain, such as osteoarthritis, may develop alterations in nociceptive processing manifested as altered descending pain inhibition, accompanied by spread of hypersensitivity.

Kosek E, et al. Pain 2016;157:1382–6.

Nociplastic Pain

• Higher pain intensity• More widespread referred pain• Occasionally hyperesthesia and allodynia• Poor relation between pain and radiographic evidence• Typical comorbidity of chronic pain• Fatigue• Sleep disturbance• Cognitive disturbance

POSITION PAPE

R

Assessment a

nd manifestatio

n of central

sensitisat

ion across

different

chronic pain

conditions

L. Arendt-N

ielsen1, B. M

orlion2 , S. P

errot3 , A. D

ahan4 , A. D

ickenson

5, H.G. Kres

s6 , C. W

ells7 ,

D. Bouhass

ira8 , A. M

ohr Drewe

s9

1 SMI, School o

f Medicine, Aa

lborgUnive

rsity,Aalbo

rg, Denmark

2 The Leuven Centr

e for Algolog

y, Universi

ty Hospitals L

euven, Univ

ersityof Le

uven,Belgiu

m

3 INSERM U987

, PainCente

r, Cochin Hosp

ital, Paris Desca

rtes University,

Paris,Franc

e

4 Department o

f Anesthes

iology, Leid

en University

Medical Cen

ter, Leiden

, TheNethe

rlands

5 Neuroscien

ce Physiology

& Pharmacolo

gy, Univers

ity College Londo

n, UK

6 Department o

f Special A

naesthesia

and PainThera

py, Medizin

ischeUnive

rsit!at/AKH

Wien, Vienna

, Austria

7 PainMatters

Ltd, Liverp

ool, UK

8 INSERM U987

Centre d’Eva

luation et de

Traitement d

e la Douleur, H

opital Ambrois

e Par"e,Boulo

gne Billancourt

, France

9 Mech-Sense,

Department o

f Gastroen

terology and Hepa

tology, Clin

ical Institut

e, Aalborg

University

Hospital, A

alborg, De

nmark

Correspon

dence

Lars Arendt

-Nielsen

E-mail: LAN@hst.aa

u.dk

Funding sourc

es

Gr!unenthal

kindlyspons

oreda meeting

where all au

thorscould

meet and discu

ss

the outline of the

paper.

Conflict of

interest

Lars Arendt

-Nielsen: S

peaker and

consul-

tancyfees from

Allergan, G

r!unenthal,

Ono,

Abbott, Bo

ehringer-In

gelheim, Bris

tol-Myers

Squibb, Da

iichi Sankyo

, Shionogi,

Ironwood

Pharma, Eli

Lilly,Mundip

harma, Pu

rdue,

PierreFabre

, Sanofi-Av

entis,Toray

, Vertex

Pharmaceut

icals,UCB,

FertinPharm

a, Zeal-

and Pharma, an

d received unres

tricted

research grant

s fromShion

ogi, Gr!unen

thal,

and Merck.Bart M

orlion: Spe

akerand/o

r

consultancy

fees fromAstel

las, Gr!unen

thal,

Boehringe

r-Ingelheim

, Mundipharm

a, Pfizer,

Zambon,TEVA

. Serge Perro

t: Speaker

and

consultancy

fees fromGr!une

nthal,Bristo

l-

MyersSquib

b, Daiichi S

ankyo, Mundip

harma,

Sanofi-Aven

tis, UCB, R

oche,and receiv

ed

unrestricte

d research grant

s fromUCB.

Albert Dah

an: Speake

r/consultan

cy fees from

Gr!unenthal

and MSD Netherland

s. Anthony

Dickenson:

Speaker an

d consultancy

fees

fromAaler

gan,Gr!une

nthal,and TEVA

. Hans

G. Kress: Sp

eakerand consu

ltancyfees f

rom

Angelini/CS

C, Astellas

, bene-Arz

neimittel,

Bionorica Ethics

, Boehring

er-Ingelheim

, Dr.

Reddy’s, G

r!unenthal,

IBSA,Mundip

harma,

Nevro, Pfize

r, St.Jude,

and TEVA. Chri

s

Wells: Speake

r andconsu

ltancyfees from

Gr!unenthal,

Indivior, G

SK. Didier

Bouhassira

:

Abstract

Different

neuroplas

tic processes

canoccur

alongthe

nociceptiv

e

pathways a

nd may be important in

the transition

fromacute

to chronic

painand

for diagnosis

anddeve

lopment

of optimal manag

ement

strategies.

Theneur

oplastic proce

ssesmay resul

t in gain(sens

itisation)

or loss(dese

nsitisation

) of function

in relation to the

incoming

nociceptiv

e signals. Su

ch processes p

lay important ro

les in chronic pain,

andaltho

ughthe

clinical manife

stations differ

across cond

ition

processes,

theyshare

some commonmechan

isticfeatu

res.The

fundamental

understan

dingand

quantitativ

e assessment of partic

ularly

some of the central sensi

tisation mechan

isms canbe trans

latedfrom

preclinica

l studies into

theclinic

. Theclinic

al perspectiv

es are

implementat

ion of such nove

l information

intodiagn

ostics, mechan

istic

phenotypi

ng,preve

ntion, perso

nalised

treatment,

anddrug

developm

ent.The

aims of thispape

r are to introduce

anddiscu

ss (1)

some common fundamental

central pain

mechanisms, (2) how

they

may translate

intothe

clinical signs

andsymptom

s across differ

ent

chronic pain

conditions

, (3)how

to evaluate gain

andloss of fu

nction

usingquan

titative pain

assessment tools

, and(4) the implicat

ionsfor

optimising

prevention

andmanag

ementof pain.

Thechron

ic pain

conditions

selected

for thepape

r areneur

opathic pain

in general,

musculoskel

etalpain

(chronic low

backpain

andosteo

arthritic pain

in

particular)

, andvisce

ral pain(irrita

ble bowel syndrome in partic

ular).

Thetrans

lational mechan

isms addressed

arelocal

andwidesp

read

sensitisati

on, centra

l summation

, anddesce

ndingpain

modulation.

Significan

ce: Centra

l sensitisati

onis an

important manife

station

involved in many differ

ent chron

ic paincond

itions. Cen

tral sensit

isation

can be different t

o assess and

evaluate as the manife

stations vary

from

paincond

itionto pain

condition.

Understan

dingcentr

al sensitisati

on

may promote

better profi

lingand

diagnosis

of painpatie

ntsand

developm

ent of new

regimes fo

r mechanism based

therapy. S

ome of the

mechanisms unde

rlying centr

al sensitisati

on canbe trans

latedfrom

© 2017Europ

ean Pain Federation

- EFIC!

Eur JPain

!! (2017) !!–!!

1

Arendt-Nielsen L ,et al. Eur J Pain 2018;22:216–41.

Translation of central sensitization to the clinic

Med

isch-

tech

nisc

h

Psyc

hoso

ciaa

lBR

EIN

Bew

egin

g

Multimodaallangdurig and individueel

Pharmacotherapy

Interventions

Adapted from Morlion B. . Nat. Rev. Neurol. 462-473 (2013)

Controle strategieën: werkbaar of niet-werkbaar?