Neurobiologie van Pijn - Home | Ziekenhuis Oost …...comprises the neospinothalamic and...

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LiZa Modulaire Opleiding Pijn 2016

Neurobiologie van PijnProf. Dr. Bart Morlion

To Do

• Definities

• Perifere mechanismen: nociceptoren, primaire afferenten

• Centrale mechanismsen: dorsale hoorn, pain matrix

• Contextuele en cognitieve modulatie van pijn

• Sensitisatieprocessen

• Transitie acute naar chronische pijn

• Klinische pijnsyndromen

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Definitie van Pijn

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

Nociceptie (pijnzin)

…het vermogen van een organisme om weefselbeschadigingof dreigendeweefselbeschadigingwaar te nemen

IASP: Het neurale proces van codering van (potentieel) schadelijke stimuli.

• Gevolgen van deze codering

• autonoom (vb. verhoogde bloeddruk)

• gedragsmatig (vb. terugtrekken of meer complex pijngedrag).

• Pijnervaring is niet noodzakelijk.

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Waarom pijn?

Pijn als beschermend mechanisme

Processen in nociceptie

• Transductie

• Transmissie

• Modulatie

• Perceptie

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272 Neuropharmacology of Neural Systems and DisordersPART 3

Spinoreticular tract

Paleospinothalamic tract

Neospinothalamic tract

Spinal cord

Spinal cord

Ascendingpathways

Ascendingpathways

Dorsalhorn

Descendingpathways

DorsalrootganglionPrimary

afferentnociceptiveaxons

Rostroventral medulla

Brainstemreticularformation

Periaqueductalgray area

Intralaminarthalamic nucleus

Ventroposterolateralthalamic nucleus (VPL)

Descendingprojectionsfrom amygdala

Somatosensorycortex

Nociceptive pathways. A primary afferent (or first order) nociceptive neuron synapses in the superficial lay-ers of the dorsal horn. Morphologically, these are bipolar neurons with cell bodies in the dorsal root ganglion (or inthe head, the trigeminal ganglion) and bifurcated axons that project both to the periphery and to the spinal cord(or in the head to the trigeminal nucleus of the brainstem). Axons of dorsal horn (or second-order) nociceptiveneurons cross the midline and ascend in the spinoreticular or spinothalamic tracts (right). The spinothalamic tractcomprises the neospinothalamic and paleospinothalamic tracts. In the neospinothalamic tract, second-order neu-rons synapse in the ventroposterolateral nucleus of the thalamus (VPL), and third-order neurons project tosomatosensory regions of the cerebral cortex. In the paleospinothalamic tract, second-order neurons synapse inthe intralaminar thalamic nuclei and project to association cortex and limbic structures. Descending analgesic sys-tems believed to originate with cortical neurons and neurons of the amygdala (left) activate descending analgesicsystems by activating neurons in periaqueductal gray area (PAG) of the brainstem. A projection from the PAG to therostral ventral medulla that descends to the dorsal horn mediates opiate-dependent descending analgesia.

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273Pain and Inflammation CHAPTER 11

also respond to noxious thermal stimuli. The majorityof C fibers in cutaneous nerves have higher thresholdsthan those of myelinated axons, and respond nonselec-tively to noxious mechanical, thermal, and chemicalstimuli. They are therefore known as polymodal noci-ceptors. Activation of C fibers is mediated by a widerange of endogenous chemicals that are released inresponse to damaged tissue or inflammation.

SENSITIZATIONAt sites of tissue damage, diffusable mediators,including arachidonic acid metabolites such asprostaglandins and leukotrienes, cytokines such asinterleukin-1 (IL-1), chemokines, and growth factorssuch as NGF, induce a form of neural plasticity withinnociceptors called sensitization. The area of sensitizednociceptors usually extends beyond the borders of

tissue damage . While some mediators such asbradykinin can both activate and sensitize noci-ceptors, sensitization per se does not cause pain.Instead, sensitization decreases the thresholds for acti-vation of nociceptors. Thus, previously innocuousstimuli, such as light touch, now activate nociceptorsand are experienced as painful; this is termed allody-nia. Moreover, the response to noxious stimuli is exag-gerated, referred to as hyperalgesia. At its mostextreme, sensitization might produce pain in theabsence of a stimulus (ie, spontaneous pain). Possiblemechanisms of sensitization include second messenger–dependent phosphorylation of TRP channels and Na+

channels in pain pathway neurons in a manner thatalters their thresholds for opening.

Heightened sensitivity to previously innocuousstimuli presumably serves the adaptive purpose ofleading an organism to protect an injured area in the

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11–4

Receptors and channels on the peripheral terminals of primary nociceptors. The detail is from a sec-tion of a hypothetical cutaneous free nerve ending. It shows a transient receptor potential (TRP) channel, the TRPV1channel, that is gated by capsaicin and heat, an acid-sensing ion channel (ASIC), and a voltage-gated Na+ channelthat might be activated by the generator potentials caused by stimulating the TRP and ASIC channels. Voltage-gated K+ and Ca2+ channels (not shown) would also be expressed. Many G protein-coupled receptors might beexpressed as described in the text. Shown are the bradykinin B2 and P2Y ATP receptors, which signal primarily viaGq, and the prostaglandin PGE2 EP receptors different subtypes of which signal via Gi/o or other G proteins. Anotherreceptor family, the tyrosine receptor kinases, is represented by TrkA, the nerve growth factor (NGF) receptor.

11–2

Primary nociceptor peripheral terminal

PGE2

NGF

ATP

Bradykinin

H+

Capsaicin/Heat

Na+

EP

TrkA

P2Y

B2

ASIC

TRPV1


NMDA receptor–mediated, long-lasting increase inthe excitability of dorsal horn neurons .

Multiple Pathways to the BrainAxons of projection neurons from the dorsal horncross the midline and ascend into the anterolateralquadrant of the spinal cord (see ). However, asmall but significant number of axons remain ipsilat-eral. These uncrossed axons may contribute to thereturn of pain after unilateral neurosurgical lesions ofthe anterolateral spinal cord have been made to allevi-ate intractable pain. Most of the nociceptive neuronsthat ascend into the anterolateral quadrant terminatein the reticular formation of the brainstem (spinoretic-ular tract) and in the thalamus (spinothalamic tract).The spinoreticular tract, which originates largely inlaminae VII and VIII of the dorsal horn of the spinalcord, lacks precise topographical information in thatthe reticular neurons receive dorsal horn inputs thatrepresent wide receptive fields. The reticular neuronssend projections to many brain regions, among which

is a prominent input to the thalamus (the reticulothal-amic tract). Consistent with this wiring pattern is thetheory that the spinoreticular tract contributes to gen-eral aspects of pain perception; for example, it mayalert an individual to the onset of pain.

Neurons in the spinothalamic tract originate in lam-inae I and V–VII. A related projection extends fromlaminae I and V of the dorsal horn to the midbrain(spinomesencephalic tract). A major target of this spin-omesencephalic tract is the periaqueductal gray matter(PAG) of the midbrain. Neurons of the PAG representan important site of convergence between ascendingaxons that carry sensory information from the spinalcord and descending axons that arise from neurons inbrain structures involved in the processing of emotion,such as the amygdala (Chapter 14). Although the PAGreceives nociceptive input from the spinal cord, it is nota pain relay nucleus because destruction of the PAGdoes not alter pain threshold. Rather, the PAG appearsto be involved in the brain’s endogenous system ofanalgesia. Other nociceptive neurons project to the

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Neurogenic inflammation. Tissue injury causes the release of bradykinin and the activation of cyclooxyge-nases, which in turn leads to the generation of prostaglandins and other mediators, such as K+ and H+. Bradykininsand prostaglandins activate and sensitize neurons. Substance P and CGRP, released in retrograde fashion from freenerve endings, dilate local blood vessels. Substance P has also been shown to cause fluid and protein toextravasate from vessels and to trigger the release of histamine from mast cells. (Adapted with permission fromKandel ER, Schwartz JH, Jessell TM. Principles of Neural Science. 4th ed. New York: McGraw-Hill; 2000.)

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Lesion Bradykinin

ProstaglandinK+

Mast cell

Spinal cord

Histamine

CGRP

CGRP

Bloodvessel

Substance P

Dorsal rootganglion neuron

Substance P

Primary afferentnociceptor

Serotonin

Platelets

H+


hypothalamus and amygdala, where they most likelymediate some of the autonomic, emotional, and neu-roendocrine responses to pain.

Neurons that project from the dorsal horn (or fromthe trigeminal nucleus) to the thalamus segregate intotwo divisions. In the lateral division of the spinothala-mic tract, axons that relay information from the trunkand extremities terminate in the ventroposterolateral(VPL) nucleus of the thalamus, and axons that relayinformation from the trigeminal system terminate inthe ventroposteromedial (VPM) nucleus of the thala-mus. In the medial division, axons terminate mostly inthe intralaminar nuclei of the thalamus.

Because the lateral division is phylogeneticallyrecent, it is often called the neospinothalamic tract (see

). It is somatotopically organized and is respon-sible for the localizing and discriminative aspects ofpain. Consistent with this function, the dorsal hornneurons of laminae I and V, from which theneospinothalamic tract originates, have small receptivefields that permit accurate localization of nociceptivestimuli. The VPL and VPM nuclei of the thalamusreceive inputs from all modalities of somatic sensa-tion. Less than 10% of the neurons in these thalamicnuclei respond to nociceptive stimuli; the majorityrespond to touch and proprioceptive inputs from

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Neurotransmitters and receptors on synapses in the dorsal horn. The nerve terminal on the left is thecentral terminal of a primary nociceptive neurons (with its cell body in the dorsal root ganglion, or DRG). Theprocess on the right is from the dendrite of a dorsal horn nociceptive neuron. Shown in the extrasynaptic regionsof the primary nociceptive terminal are three G protein-coupled receptors (µ opiate, CB1 cannabinoid, and α2-adrenergic) that can inhibit neurotransmitter release in response to analgesic signals described in the text. Thispresynaptic terminal releases glutamate and multiple peptides, perhaps substance P and CGRP. The dorsal hornneuron is shown expressing the AMPA glutamate receptor, which mediates fast synaptic transmission, the sub-stance P (NK1) receptor, and the CGRP receptor, all of which mediate pronociceptive signals. It is also shownexpressing the µ opioid receptor, which could mediate antinociceptive signals. Finally, it expresses TrkB, the recep-tor for brain-derived neurotrophic factor (BDNF), which may be released from activated microglia, to contribute tocentral sensitization, a process that can contribute to chronic neuropathic and inflammatory pain.

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CB1

CGRP

Primary nociceptorcentral terminal(presynaptic)

Dendrite of dorsal horn neuron

(postsynaptic)

NK1

AMPA

SynapseTrkB

α2

µµ

Laminae of the dorsal horn of the spinal cord. A. One of several possible synaptic arrangements of Aδ andC fibers. Aδ fibers synapse on projection neurons in lamina I. These neurons receive indirect input from C fibers thatsynapse on interneurons in lamina II. Lamina V neurons are projection neurons that receive direct inputs from bothAδ fibers and C fibers that carry information about innocuous stimuli (not shown). (Adapted with permission fromKandel ER, Schwartz JH, Jessell TM. Principles of Neural Science, 4th ed. New York: McGraw-Hill; 2000.) B. Descendinganalgesia in the dorsal horn. Projections from the rostral ventral medulla synapse on enkephalinergic interneuronsin lamina II. These interneurons in turn synapse on dorsal horn neurons in lamina I, inhibiting their firing andthereby interrupting the flow of nociceptive information.

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Dorsalhorn


To thalamus

I

II

+

Enkephalin

From rostroventralmedulla

B

I

II

Aδ fiber

C fiber

Aβ fiber

III

IV

V

VI

A

281

•Transductie

•Transmissie

•Modulatie

•Perceptie

Perifere nociceptie

Spinale integratie

Centrale verwerking

Pijnervaring

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25 °C43 °C

Activation of thermoTRPs by naturally occurringcompounds.

53 °C -10 °C30 -> 40°C

Noxious Warm Warm Noxious ColdCold

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Primary afferent axons

The Pain Matrix

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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

The Thalamus as the Second Interface: Integrating Cognitive and Emotional Signals

CNS/ELB/10/2011/408

Wrijven helpt !

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Nocicepsis

Pijnervaring

Pijnlijden

Pijngedrag Motivationeel

Affectief

Cognitief

Sensorisch-discriminatief

Aandacht naar pijn Aandacht naargeluidstonen

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

Modulatie van pijn door aandacht

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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

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Presbyalgos ?

Pain threshold Pain tolerance

Reduced efficacy of the endogenous analgesic

system

Reduced function and density of peripheral nerve fibres


Spinoreticular tract

Paleospinothalamic tract

Neospinothalamic tract

Spinal cord

Spinal cord

Ascendingpathways

Ascendingpathways

Dorsalhorn

Descendingpathways

DorsalrootganglionPrimary

afferentnociceptiveaxons

Rostroventral medulla

Brainstemreticularformation

Periaqueductalgray area

Intralaminarthalamic nucleus

Ventroposterolateralthalamic nucleus (VPL)

Descendingprojectionsfrom amygdala

Somatosensorycortex

Nociceptive pathways. A primary afferent (or first order) nociceptive neuron synapses in the superficial lay-ers of the dorsal horn. Morphologically, these are bipolar neurons with cell bodies in the dorsal root ganglion (or inthe head, the trigeminal ganglion) and bifurcated axons that project both to the periphery and to the spinal cord(or in the head to the trigeminal nucleus of the brainstem). Axons of dorsal horn (or second-order) nociceptiveneurons cross the midline and ascend in the spinoreticular or spinothalamic tracts (right). The spinothalamic tractcomprises the neospinothalamic and paleospinothalamic tracts. In the neospinothalamic tract, second-order neu-rons synapse in the ventroposterolateral nucleus of the thalamus (VPL), and third-order neurons project tosomatosensory regions of the cerebral cortex. In the paleospinothalamic tract, second-order neurons synapse inthe intralaminar thalamic nuclei and project to association cortex and limbic structures. Descending analgesic sys-tems believed to originate with cortical neurons and neurons of the amygdala (left) activate descending analgesicsystems by activating neurons in periaqueductal gray area (PAG) of the brainstem. A projection from the PAG to therostral ventral medulla that descends to the dorsal horn mediates opiate-dependent descending analgesia.

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273Pain and Inflammation CHAPTER 11

also respond to noxious thermal stimuli. The majorityof C fibers in cutaneous nerves have higher thresholdsthan those of myelinated axons, and respond nonselec-tively to noxious mechanical, thermal, and chemicalstimuli. They are therefore known as polymodal noci-ceptors. Activation of C fibers is mediated by a widerange of endogenous chemicals that are released inresponse to damaged tissue or inflammation.

SENSITIZATIONAt sites of tissue damage, diffusable mediators,including arachidonic acid metabolites such asprostaglandins and leukotrienes, cytokines such asinterleukin-1 (IL-1), chemokines, and growth factorssuch as NGF, induce a form of neural plasticity withinnociceptors called sensitization. The area of sensitizednociceptors usually extends beyond the borders of

tissue damage . While some mediators such asbradykinin can both activate and sensitize noci-ceptors, sensitization per se does not cause pain.Instead, sensitization decreases the thresholds for acti-vation of nociceptors. Thus, previously innocuousstimuli, such as light touch, now activate nociceptorsand are experienced as painful; this is termed allody-nia. Moreover, the response to noxious stimuli is exag-gerated, referred to as hyperalgesia. At its mostextreme, sensitization might produce pain in theabsence of a stimulus (ie, spontaneous pain). Possiblemechanisms of sensitization include second messenger–dependent phosphorylation of TRP channels and Na+

channels in pain pathway neurons in a manner thatalters their thresholds for opening.

Heightened sensitivity to previously innocuousstimuli presumably serves the adaptive purpose ofleading an organism to protect an injured area in the

11–3

11–4

Receptors and channels on the peripheral terminals of primary nociceptors. The detail is from a sec-tion of a hypothetical cutaneous free nerve ending. It shows a transient receptor potential (TRP) channel, the TRPV1channel, that is gated by capsaicin and heat, an acid-sensing ion channel (ASIC), and a voltage-gated Na+ channelthat might be activated by the generator potentials caused by stimulating the TRP and ASIC channels. Voltage-gated K+ and Ca2+ channels (not shown) would also be expressed. Many G protein-coupled receptors might beexpressed as described in the text. Shown are the bradykinin B2 and P2Y ATP receptors, which signal primarily viaGq, and the prostaglandin PGE2 EP receptors different subtypes of which signal via Gi/o or other G proteins. Anotherreceptor family, the tyrosine receptor kinases, is represented by TrkA, the nerve growth factor (NGF) receptor.

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Primary nociceptor peripheral terminal

PGE2

NGF

ATP

Bradykinin

H+

Capsaicin/Heat

Na+

EP

TrkA

P2Y

B2

ASIC

TRPV1


NMDA receptor–mediated, long-lasting increase inthe excitability of dorsal horn neurons .

Multiple Pathways to the BrainAxons of projection neurons from the dorsal horncross the midline and ascend into the anterolateralquadrant of the spinal cord (see ). However, asmall but significant number of axons remain ipsilat-eral. These uncrossed axons may contribute to thereturn of pain after unilateral neurosurgical lesions ofthe anterolateral spinal cord have been made to allevi-ate intractable pain. Most of the nociceptive neuronsthat ascend into the anterolateral quadrant terminatein the reticular formation of the brainstem (spinoretic-ular tract) and in the thalamus (spinothalamic tract).The spinoreticular tract, which originates largely inlaminae VII and VIII of the dorsal horn of the spinalcord, lacks precise topographical information in thatthe reticular neurons receive dorsal horn inputs thatrepresent wide receptive fields. The reticular neuronssend projections to many brain regions, among which

is a prominent input to the thalamus (the reticulothal-amic tract). Consistent with this wiring pattern is thetheory that the spinoreticular tract contributes to gen-eral aspects of pain perception; for example, it mayalert an individual to the onset of pain.

Neurons in the spinothalamic tract originate in lam-inae I and V–VII. A related projection extends fromlaminae I and V of the dorsal horn to the midbrain(spinomesencephalic tract). A major target of this spin-omesencephalic tract is the periaqueductal gray matter(PAG) of the midbrain. Neurons of the PAG representan important site of convergence between ascendingaxons that carry sensory information from the spinalcord and descending axons that arise from neurons inbrain structures involved in the processing of emotion,such as the amygdala (Chapter 14). Although the PAGreceives nociceptive input from the spinal cord, it is nota pain relay nucleus because destruction of the PAGdoes not alter pain threshold. Rather, the PAG appearsto be involved in the brain’s endogenous system ofanalgesia. Other nociceptive neurons project to the

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11–5

Neurogenic inflammation. Tissue injury causes the release of bradykinin and the activation of cyclooxyge-nases, which in turn leads to the generation of prostaglandins and other mediators, such as K+ and H+. Bradykininsand prostaglandins activate and sensitize neurons. Substance P and CGRP, released in retrograde fashion from freenerve endings, dilate local blood vessels. Substance P has also been shown to cause fluid and protein toextravasate from vessels and to trigger the release of histamine from mast cells. (Adapted with permission fromKandel ER, Schwartz JH, Jessell TM. Principles of Neural Science. 4th ed. New York: McGraw-Hill; 2000.)

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Lesion Bradykinin

ProstaglandinK+

Mast cell

Spinal cord

Histamine

CGRP

CGRP

Bloodvessel

Substance P


Substance P

Primary afferentnociceptor

Serotonin

Platelets

H+


hypothalamus and amygdala, where they most likelymediate some of the autonomic, emotional, and neu-roendocrine responses to pain.

Neurons that project from the dorsal horn (or fromthe trigeminal nucleus) to the thalamus segregate intotwo divisions. In the lateral division of the spinothala-mic tract, axons that relay information from the trunkand extremities terminate in the ventroposterolateral(VPL) nucleus of the thalamus, and axons that relayinformation from the trigeminal system terminate inthe ventroposteromedial (VPM) nucleus of the thala-mus. In the medial division, axons terminate mostly inthe intralaminar nuclei of the thalamus.

Because the lateral division is phylogeneticallyrecent, it is often called the neospinothalamic tract (see

). It is somatotopically organized and is respon-sible for the localizing and discriminative aspects ofpain. Consistent with this function, the dorsal hornneurons of laminae I and V, from which theneospinothalamic tract originates, have small receptivefields that permit accurate localization of nociceptivestimuli. The VPL and VPM nuclei of the thalamusreceive inputs from all modalities of somatic sensa-tion. Less than 10% of the neurons in these thalamicnuclei respond to nociceptive stimuli; the majorityrespond to touch and proprioceptive inputs from

11–1

Neurotransmitters and receptors on synapses in the dorsal horn. The nerve terminal on the left is thecentral terminal of a primary nociceptive neurons (with its cell body in the dorsal root ganglion, or DRG). Theprocess on the right is from the dendrite of a dorsal horn nociceptive neuron. Shown in the extrasynaptic regionsof the primary nociceptive terminal are three G protein-coupled receptors (µ opiate, CB1 cannabinoid, and α2-adrenergic) that can inhibit neurotransmitter release in response to analgesic signals described in the text. Thispresynaptic terminal releases glutamate and multiple peptides, perhaps substance P and CGRP. The dorsal hornneuron is shown expressing the AMPA glutamate receptor, which mediates fast synaptic transmission, the sub-stance P (NK1) receptor, and the CGRP receptor, all of which mediate pronociceptive signals. It is also shownexpressing the µ opioid receptor, which could mediate antinociceptive signals. Finally, it expresses TrkB, the recep-tor for brain-derived neurotrophic factor (BDNF), which may be released from activated microglia, to contribute tocentral sensitization, a process that can contribute to chronic neuropathic and inflammatory pain.

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CB1

CGRP

Primary nociceptorcentral terminal(presynaptic)

Dendrite of dorsal horn neuron

(postsynaptic)

NK1

AMPA

SynapseTrkB

α2

µµ

Laminae of the dorsal horn of the spinal cord. A. One of several possible synaptic arrangements of Aδ andC fibers. Aδ fibers synapse on projection neurons in lamina I. These neurons receive indirect input from C fibers thatsynapse on interneurons in lamina II. Lamina V neurons are projection neurons that receive direct inputs from bothAδ fibers and C fibers that carry information about innocuous stimuli (not shown). (Adapted with permission fromKandel ER, Schwartz JH, Jessell TM. Principles of Neural Science, 4th ed. New York: McGraw-Hill; 2000.) B. Descendinganalgesia in the dorsal horn. Projections from the rostral ventral medulla synapse on enkephalinergic interneuronsin lamina II. These interneurons in turn synapse on dorsal horn neurons in lamina I, inhibiting their firing andthereby interrupting the flow of nociceptive information.

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Dorsalhorn


To thalamus

I

II

+

Enkephalin

From rostroventralmedulla

B

I

II

Aδ fiber

C fiber

Aβ fiber

III

IV

V

VI

A

281

Transitie van acute naar chronische pijn

Perifere sensitizatieNiet-schadelijke prikkels activeren het pijnsysteem

Centrale sensitizatieAmplificatie van synaptische

overdracht

Spontane pijn&

Overgevoeligheid voor pijn

• Affectieve stoornissen• Angst & Depressie• Catastroferen• Kwaadheid

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

geheugenstoornissen

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Patient Environment(trauma, stress)

Comorbidconditions

Patient Surgery

AnaesthesiaAnalgesia

Patient

Pain

Post-operativeadjuvanttherapies

Persistent postsurgical pain

PreoperativeIntraoperative and

postoperative healing periodDelayed

Postoperative Period

• Anxiety & Depression• Catastrophizing• Stressful life events• Genes• Impaired pain modulation• Other pain states• Obesity • Sleep• Stress

• Nerve injury•Tissue ischaemia• Surgical technique•Anaesthetic technique• Pain facilitationoramplification• Proinflammatory state

• Postoperative pain-hyperalgesia• Chemotherapy orradiation therapy• Repeat surgery• Psychosocial factors

Pain

Adapted from Wu and Raja, Lancet, 2011.

Yellow flags: possible risk factors for chronicity of LBP

Psychological

• Emotional issues: anxiety or depression

• Fear avoidance behaviour (profound worry about aggravating LBP when doing

normal activities)

• Inappropriate fears or beliefs

• Unrealistic treatment expectations

Social

• Isolation

• Beliefs held by important othersMorlion, B. Nat. Rev. Neurol. 9, 462–473 (2013)

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Centrale Sensitisatie & Pijn

• 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)

• Ook sensorische en chemische overgevoeligheid• bemoeilijkt farmacotherapie

Allodynie

Hyperalgesie

normaal

Stimulus Intensiteitschadelijk

Pijns

ensa

tie

onschadelijk

insultPijn na een niet-

schadelijke stimulus

Verhoogde pijngevoeligheid

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Chronische pijn is een bio-psychosociaal fenomeen

• “Paradigm shift” in de concepten: bio-psychosociale aandoening met fysische, gedragsmatige, werk-gerlateerde en socioeconomische factoren

• Zelfs indien initieel een letsel in eenwelbepaalde anatomische structuurgeïdentificeerd kon worden zal de pijnervaring en dysfunctioneren bepaald wordendoor meerdere psychosociale factoren:• Vroegere pijnervaringen• Overtuigingen, geloof, ziektetheorie• Algemene en psychosociale gezondheid• Jobtevredenheid• Economische status, juridische procedures

• De aanpak van chronische pijn is multimodaal en zonodig multidisciplinair, met alsdoel pijn maximaal te verminderen, kwaliteit van leven te bevorderen, functie, zelfstandigheid en mobiliteit te verbeteren, nood aan gezondheidsvoorzieningen teverminderen

Adapted from Morlion, B. Nat. Rev. Neurol. 9, 462–473 (2013)

Klinische pijnsyndromen

Nociceptief Inflammatoir Neuropathisch Disfunctioneel

Schadelijke stimuli OntstekingPerifere pathologie

Laesie of ziekte in het somatosensorisch systeem

perifeer of centraal

Geen schadelijke stimuliGeen ontsteking

Geen zenuwschadeGeen perifere pathologie

Beschermend Heling / Herstel / Pathologisch

Pathologisch Pathologisch

Hoge drempel

Lage drempel

Adapted from Woolf C.

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Pain matrix

Achterhoorn van het ruggenmerg

Hoge drempel

Nociceptoren(C-vezels; Aδ-vezels) Activatie en Sensitisatie

Nociceptieve pijn

Neuropathische pijn

• Pijn ontstaan als direct gevolg van een laesie of ziekte in het (perifeer of centraal) somatosensorisch systeem

Morlion B. Nature Reviews Neurology 2013

464 | AUGUST 2013 | VOLUME 9 www.nature.com/nrneurol

ergonomic modifications did not lead to improvements in outcomes for patients with this condition.30

The latest paradigm shift in the thinking about CLBP parallels the evolution in concepts of chronic pain in

general. The biopsychosocial model of chronic pain rec-ognizes chronic pain as a combination of physical dysfunc-tion, beliefs, coping strategies, distress, illness behaviour and social interactions31. Since the introduction of the

Spinal cord

Abnormalcentral processing

Abnormalcentral processing

PainAutonomic response

Withdrawal reflex

Noxious stimuliHeatColdIntense mechanical forceChemical irritants

Neuropathic painNeural lesionPositive and negative symptoms

Nociceptorsensory neuron

Adaptive, high-threshold painEarly warning system (protective)

a

Spontaneous painPain hypersensitivity

PeripheralinflammationPositivesymptoms

Adaptive, low-threshold painTenderness promotes repair(protective)

c

b

InflammationMacrophageMast cellNeutrophilGranulocyteTissue damage


Maladaptive, low-threshold painDisease state of nervous system

Stroke

Dysfunctional painNo neural lesionNo inflammationPositive symptoms


Peripheralnerve damage

Normal peripheraltissue and nerves

Injury

Figure 1 | Mechanisms in low back pain: an overview of the three classes of pain. a | Nociceptive pain is physiological protective pain involving activation of high-threshold nociceptor neurons by noxious mechanical, chemical or thermal stimuli. b | Inflammatory pain is pain hypersensitivity involving detection of active peripheral tissue inflammation by nociceptors and sensitization of the nociceptive system. c | Pathological pain is not adaptive, has no protective function and can be divided into two types: neuropathic and dysfunctional. Neuropathic pain is a maladaptive plasticity due to a lesion or disease that affects the somatosensory system and alters nociceptive signal processing so that responses to noxious and innocuous stimuli are enhanced and pain is felt in the absence of stimuli. Conversely, dysfunctional pain is the result of nociceptive signalling amplification in the absence of neural lesions or inflammation. Reproduced with permission of the American Society for Clinical Investigation © Woolf, C. J. J. Clin. Invest. 120, 3742–3744 (2010).

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

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