Neuropathic Pain: When the neuron is getting hurt!

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“When the neuron is getting hurt!”Neuropathic pain

Welcome...

Speaker: Surat Tanprawate, MD, MSc, FRCPTDate: Tuesday, 5 July 2011Time: 12.15-13.00 pm.Venue: Boonsom Room, Fifth FloorInternal Medicine Department

Special Lecture

Tuesday, July 5, 2011



“Pain is an unpleasant sensory and emotional experience

associated with actual or potential tissue damage or described in

terms of such damage.”







Outline of My talk...

•Pain and its mechanism

>> Neuropathic pain <<

•Neuropathic pain in specificneurological disorder

•Treatment strategies

>> Mechanism based treatment <<

>> Treatment guideline <<




Rene Descartes, 16th century




Rene Descartes, 16th century



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Terminology

• Pain duration: acute vs chronic pain

• Adaptive neuronal plasticity

sensitization (peripheral vs central)

cortical reorganization

•Pain symptom

hyperalgesia

allodynia




Chronicpain

Acutepain

Insult

The continuum of pain

> 3-6 months

-Serves a protective function

-Usually apparent noxious insult

-Serves no protective function

-Degrades health and function




Pain classification A.Nociceptive pain

heat, cold, intense mechanical force, chemical

irritants

B.Inflammatory pain

peripheral inflammation, positive symptoms

C.Pathological pain

1. Neuropathic pain

2. Dysfunctional pain








Neuroanatomy of Pain

1. Afferent pathway

I) nociceptors (pain receptors)

II) afferent nerve fiber

III) spinal cord network

2. Central nervous system

• limbic system, reticular formation, thalamus,

hypothalamus, cortex

3. Efferent pathway

• fibers connecting the reticular formation, midbrain,

substantial gelatinosa..>>> “Modulating pain

sensation”




Scholz J, C.J. Woolf. Nat Neurosci 5(suppl.) 2002




Mechanism associated

with peripheralsensitization to pain

axonal reflex




Scholz J, C.J. Woolf. Nat Neurosci 5(suppl.) 2002




Peripheral

sensitization

to pain:

Some definitions:

Hyperalgesia! increased

sensitivity to an already painful stimulus

Allodynia! normally non painful

stimuli are felt as painful (i.e .light touch of a

sun-burned skin)

Primary hyperalgesia

Primary heat allodyniaTuesday, July 5, 2011



Afferent nerve fiber and spinal cord network






•Projecting neurons in lamina I

receive A-delta and C fibers info

•Neurons in lamina II receive input

from C fibers and relay it to other

laminae

•Projecting neurons in lamina V(wide-dynamic range neurons)

receive A-delta, C and A-beta (low

threshold mechanoceptors) fibers

information.

Pain input to the spinal cord




•Projecting neurons in lamina I

receive A-delta and C fibers info

•Neurons in lamina II receive input

from C fibers and relay it to other

laminae

•Projecting neurons in lamina V(wide-dynamic range neurons)

receive A-delta, C and A-beta (low

threshold mechanoceptors) fibers

information.

Pain input to the spinal cord

•lamina V cells>> details about the stimulus, and lamina I cells >> whether it is painfulor not

• A-delta and C fibers release glutamate and peptides on dorsal horn neurons.

•Substance P(SP) is co-released with glutamate and enhances and prolongs the

action of glutamate

•Glutamate action is confined to nearby neurons but SP can diffuse and affect other

populations of neurons because there is no specific reuptake




The three forms of neural plasticity

Clifford J. Woolf, et al. Science 288, 1765 (2000);




Temporal summation of

second pain (windup)




Wide-up and central

sensitization

Mechanisms of early-onset

central sensitization:

Windup>>homosynaptic activity-

dependent plasticity characterized

by a progressive increase in firing

from dorsal horn neurons during a

train of repeated low-frequency C-fiber or nociceptor stimulation




Normal impulse transmission

Substance P

Presynapticneuron

Synaptic cleft

Glutamate

Postsynapticneuron

NMDA receptor is

blocked by Mg2+

AMPAreceptor

NMDAreceptor NK-1

Impulses reach terminals of presynaptic neuron




Substance P

Presynapticneuron

Synaptic cleft

Glutamate is released into synaptic cleft

Glutamate

Postsynapticneuron

AMPAreceptor

NMDAreceptor NK-1

NMDA receptor

remains blockedby Mg2+





Substance P

Presynapticneuron

Synaptic cleft

Glutamate binds to AMPA receptor and impulse is transmitted to postsynaptic neuron

Glutamate

Postsynapticneuron

NMDA receptor

remains blockedby Mg2+

NK-1


AMPAreceptor




Development of central sensitization

Injury or trauma causes increased nerve activity

NMDAreceptor NK-1

NMDA receptor is

blocked by Mg2+

Substance P

Synaptic cleft

Postsynapticneuron

Presynapticneuron

Glutamate

AMPAreceptor






Substance P binds to NK-1 receptors, causing NMDA receptors to release Mg2+ ions

NK-1NMDA

receptor


Substance P

Synaptic cleft

Postsynapticneuron

Presynapticneuron

Glutamate

AMPAreceptor




Glutamate molecules can now bind to AMPA and NMDA receptors


Substance P

Synaptic cleft

Postsynapticneuron

Presynapticneuron

Glutamate

AMPAreceptor




Increased impulses transmitted to postsynaptic neuron


Substance P

Synaptic cleft

Postsynapticneuron

Presynapticneuron

Glutamate




Central nervous system

• The portion of CNS involved in theinterpretation of the pain signals are the

limbic system, reticular formation,

thalamus, hypothalamus, and cortex


Th b i fi i h



The brain first perceives the

sensation of pain

• The thalamus, sensitive cortex

perceiving, describing, localizing

•Part of thalamus, brainstem and reticular

formation

identify dull longer-lasting, and diffuse pain

• The reticular formation and limbic system:control the emotional and affective response to

pain

Cortex, thalamus, and brainstem are interconnected with the hypothalamus, and autonomic

nervous system, the perception of pain is associated with an autonomic response







Efferent analgesic system

It’s role:-inhibition of afferent pain signals

Mechanism:-

- pain afferents stimulates the neurons in periaqueductalgray (PAG) - gray matter surrounding the cerebral

aqueduct in the midbrain results in activation of efferent

(descendent) anti-nociceptive pathways

- from there the impulses are transmitted through thespinal cord to the dorsal horn

- there inhibit or block transmission of nociceptive signals

at the level of dorsal horn




Descendent antinociceptive system




Descending pathways regulating

the transmission of pain

information:

Stimulation of PAG causes analgesia so

profound that surgery can be performed.

PAG stimulation can ameliorate

intractable pain.

PAG receives pain information via the

spinomesencephalic tract and inputs from

cortex and hypothalamus related to

behavioral states and to whether to

activate the pain control system.

PAG acts on raphe & locus ceruleus to

inhibit dorsal horn neurons via

interneurons and morphine receptors.




Pathophysiology of neuropathic pain

Peripheral neuronhyperexcitability

NeP

Central mechanisms

Central neuronhyperexcitability

(central sensitization)

Loss of inhibitory controls

Peripheral mechanisms

Abnormaldischarges




Medications for neuropathic pain

NE: norepinephrine; 5HT: 5-hydroxytryptamine; NMDA: N-Methyl D-Aspartate;

SNRI: selective norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor; TCA: tricyclic antidepressants

Alpha adrenergic agents

Opioids

SNRIs

SSRIs

Tramadol

TCAs

Descending inhibitory pathways

(NE/5HT, opioid receptors)

Central sensitization

Peripheral mechanisms

Gabapentin

Lamotrigine

Levetiracetam

OxcarbazepinePregabalin

Dextromethorphan

Ketamine

Methadone

Memantine

NMDA

Ca2+

CarbamazepineLamotrigine

Lidocaine

Oxcarbazepine

Topiramate

TCAs

Na+




Neuropathic pain in

neurological

disorders




Neuropathic pain

• Injury to or dysfunction of the nervous system

itself, peripheral or central

•Deaferentiation pain-form of neuropathic pain:

a term implying that sensory deficit in the

painful area is a prominent feature (anesthesia

dolorosa)

• Phantom pain-pain localized into non-existingorgan(tissue)

• Long-lasting pain after short-lasting pain

stimulus




Neuropathic pain in common

neurological disorders• Neuralgia

trigeminal neuralgia, post-herpetic neuralgia

• Chronic regional pain syndrome (CRPS)

• Painful peripheral neuropathy

• Thalamic pain syndrome

• Phantom limb pain







Chronic regionalpain syndrome

(CRPS)




Thalamic pain syndrome


Painful polyneuropathy



Jerry R. Mendell NEJM 348;13

Painful polyneuropathy






Pathways Leading to Pain in Peripheral Neuropathy and Potential




Sites of Pharmacologic Interventions.






P t h ti l i



First line Second line

Post herpetic neuralgia





Classical Trigeminal Neuralgia


C t l i




Central pain


Al ith f thi



Algorithm for neuropathic

pain treatment; Pain 2005







Thank you for yourkind attention

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Neuropathic Pain: When the neuron is getting hurt!