Neuropathic pain

When the neuron is getting hurt!

Welcome...
Speaker: Surat Tanprawate, MD, MSc, FRCPT Date: Tuesday, 5 July 2011 Time: 12.15-13.00 pm. Venue: Boonsom Room, Fifth Floor Internal 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.

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Outline of My talk... Pain and its mechanism

>> Neuropathic pain <<

Neuropathic pain in specic

neurological disorder

Treatment strategies
>> Mechanism based treatment << >> Treatment guideline <<
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Rene Descartes, 16th century

Tuesday, July 5, 2011

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

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The continuum of pain

Insult

Acute pain

Chronic pain

> 3-6 months

-Serves a protective function -Usually apparent noxious insult -Serves no protective function -Degrades health and function

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Pain classication
A. Nociceptive pain
heat, cold, intense mechanical force, chemical irritants

B. Inammatory pain
peripheral inammation, positive symptoms

C.Pathological pain
1. Neuropathic pain 2. Dysfunctional pain
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Neuroanatomy of Pain
1. Afferent pathway
I) nociceptors (pain receptors) II) afferent nerve ber III) spinal cord network

2. Central nervous system

limbic system, reticular formation, thalamus, hypothalamus, cortex

3. Efferent pathway

bers connecting the reticular formation, midbrain, substantial gelatinosa..>>> Modulating pain sensation

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

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Mechanism associated with peripheral sensitization to pain

axonal reex

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

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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 allodynia

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Afferent nerve ber and spinal cord network

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Pain input to the spinal cord

Projecting neurons in lamina I
receive A-delta and C bers info

Neurons in lamina II receive input

from C bers 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) bers information.

Tuesday, July 5, 2011

Pain input to the spinal cord

Projecting neurons in lamina I
receive A-delta and C bers info

Neurons in lamina II receive input

from C bers 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) bers information.

lamina V cells>> details about the stimulus, and lamina I cells >> whether it is painful
or not A-delta and C bers 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 conned to nearby neurons but SP can diffuse and affect other populations of neurons because there is no specic reuptake
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The three forms of neural plasticity

Clifford J. Woolf, et al. Science 288, 1765 (2000); Tuesday, July 5, 2011

Temporal summation of second pain (windup)

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Wide-up and central sensitization

Mechanisms of early-onset central sensitization:
Windup>>homosynaptic activitydependent plasticity characterized by a progressive increase in ring from dorsal horn neurons during a train of repeated low-frequency Cber or nociceptor stimulation

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Normal impulse transmission

Impulses reach terminals of presynaptic neuron

Presynaptic neuron

Substance P

Glutamate

Synaptic cleft

NMDA receptor is blocked by Mg2+

Postsynaptic neuron

NK-1

NMDA receptor

AMPA receptor

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Normal impulse transmission

Glutamate is released into synaptic cleft

Presynaptic neuron

Substance P

Glutamate

Synaptic cleft

NMDA receptor remains blocked by Mg2+

NMDA receptor

Postsynaptic neuron

NK-1

AMPA receptor

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Normal impulse transmission

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

Presynaptic neuron

Substance P

Glutamate

Synaptic cleft

NMDA receptor remains blocked by Mg2+

Postsynaptic neuron

NK-1

AMPA receptor

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Development of central sensitization

Injury or trauma causes increased nerve activity

Presynaptic neuron

Substance P

Glutamate

Synaptic cleft NMDA receptor

NMDA receptor is blocked by Mg2+

Postsynaptic neuron

NK-1

AMPA receptor

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Development of central sensitization

Substance P and excessive levels of glutamate are released into the synaptic cleft

Presynaptic neuron

Substance P

Glutamate

Synaptic cleft NMDA receptor

NMDA receptor is blocked by Mg2+

Postsynaptic neuron

NK-1

AMPA receptor

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Development of central sensitization

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

Presynaptic neuron

Substance P

Glutamate

Synaptic cleft NMDA receptor

Postsynaptic neuron

NK-1

AMPA receptor

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Development of central sensitization

Glutamate molecules can now bind to AMPA and NMDA receptors

Presynaptic neuron

Substance P

Glutamate

Synaptic cleft

Postsynaptic neuron

AMPA receptor

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Development of central sensitization

Increased impulses transmitted to postsynaptic neuron

Presynaptic neuron

Substance P

Glutamate

Synaptic cleft

Postsynaptic neuron

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Central nervous system

The portion of CNS involved in the

interpretation of the pain signals are the limbic system, reticular formation, thalamus, hypothalamus, and cortex

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The brain rst 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
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Efferent analgesic system

Its role:-inhibition of afferent pain signals

Mechanism:- pain afferents stimulates the neurons in periaqueductal gray (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 the spinal cord to the dorsal horn - there inhibit or block transmission of nociceptive signals at the level of dorsal horn

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Descendent antinociceptive system

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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.
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Pathophysiology of neuropathic pain

Peripheral mechanisms Peripheral neuron hyperexcitability

Loss of inhibitory controls Central mechanisms Central neuron hyperexcitability (central sensitization)

Abnormal discharges

NeP

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Medications for neuropathic pain

Descending inhibitory pathways (NE/5HT, opioid receptors) Central sensitization
Gabapentin Lamotrigine Levetiracetam Oxcarbazepine Pregabalin Dextromethorphan Ketamine Methadone Memantine Alpha adrenergic agents Opioids SNRIs SSRIs Tramadol TCAs

Ca2+

NMDA

Peripheral mechanisms
Carbamazepine Lamotrigine Lidocaine Oxcarbazepine Topiramate TCAs

Na+

NE: norepinephrine; 5HT: 5-hydroxytryptamine; NMDA: N-Methyl D-Aspartate; SNRI: selective norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor; TCA: tricyclic antidepressants
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Neuropathic pain in neurological disorders

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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 decit in the painful area is a prominent feature (anesthesia dolorosa) organ(tissue) stimulus

Phantom pain-pain localized into non-existing Long-lasting pain after short-lasting pain
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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
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Chronic regional pain syndrome (CRPS)

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Thalamic pain syndrome

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Painful polyneuropathy

Jerry R. Mendell NEJM 348;13

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Jerry R. Mendell NEJM 348;13

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Pathways Leading to Pain in Peripheral Neuropathy and Potential Sites of Pharmacologic Interventions.

Jerry R. Mendell NEJM 348;13

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EFNS neuropathic pain treatment guidelines-2010 revision

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Diabetic painful polyneuropathy

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Post herpetic neuralgia

First line

Second line

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Classical Trigeminal Neuralgia

First line

Second line

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Central pain

First line

Second line

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Algorithm for neuropathic pain treatment; Pain 2005

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Thank you for your kind attention

www.openneurons.com

Tuesday, July 5, 2011