Pain is subjective Self-experience Experience depends on circumstances Pain can cause many different...

Pain is subjective

• Self-experience• Experience depends on circumstances• Pain can cause many different reactions:

– Activate autonomic system (heart rate, blood pressure, sweating, etc.)

– Muscle activity– Mood (fear, anxiety, depression)– Prevent sleep

Pain occurs with different

degrees of severity

• Mild pain:Does not interfere noticeably with everyday life

• Moderate pain:May cause some annoyance and perceived as unpleasant

• Severe chronic pain:Affects a person’s entire life in major ways

There are many forms of pain

• Mild pain:

Does not interfere noticeably with everyday life

• Moderate pain:

May cause some annoyance and may be perceived as unpleasant

• Severe pain:

Affects a person’s entire life in major ways

Different forms of pain

• Acute pain

• Chronic pain

• Somatic pain

• Neuropathic pain

• Central neuropathic pain

Pain has many different forms, but the same name

Tinnitus has many different forms but the same name

There are different types of pain

• Somatic and visceral pain (Stimulation of nociceptors) – Pain ceases when stimulation ceases

• Neuropathic pain– Pain is related to the nervous system

• Central neuropathic pain– Plastic changes in the function of the CNS– May be persistent

It is important to have different names for for different

disorders • We cannot think about matters that do not

have names

• The same words is used to describe very different forms of tinnitus and pain

• Using the same names for fundamentally different disorders is a disadvantage in studying and treating such disorders

Severe pain affects a person’s entire life in major ways

• Prevent or disturb sleep• Interfere with or prevents intellectual work • May cause suicide May involve limbic structures causing affective

reactionsOften accompanied by abnormal sensations from

touch

How prevalent is severe pain?

Some pain was reported by 86% of

individuals above the age of 65(Iowa study, 1994)

The prevalence of severe pain was 33% for people at age 77 and above (Swedish study, 1996)

Pain

“The only tolerable pain is someone else’s pain”René Leriche, French surgeon, 1879–1955

There are different types of pain

• Somatic and visceral pain (Stimulation of nociceptors) – Pain ceases when stimulation ceases

• Neuropathic pain– Pain is related to the nervous system

• Central neuropathic pain– Plastic changes in the function of the CNS– May be persistent

Pain

Non-nocicieptorpain

Stimulation ofnociceptors

Muscle pain

Somaticpain

Viscerapain

Fast painslow pain

Referredpain

Lesions tonerves or

cns

Centralneuropathic

pain

Inflamatory Neuropathicpain

• Central neuropathic pain:– Pain sensation caused by abnormal neural activity

in the CNS• Hyperacusis:

– Sounds are perceived louder than normal• Allodynia:

– Sensation of pain from normally innocuous stimulation (such as light touch)

• Hyperpathia:– Exaggerated and prolonged reactions to painful

stimuli

Somatic and visceral pain (Stimulation of nociceptors)

• Burning (temperature)• Injury• Inflammation• Chemicals• Compression of spinal nerve roots (nervi nervorum)

Muscle pain

MUSCLE TONE(general tone)

Contractileactivity

Viscoelastic tone(specific tone)

Electrogenicspasm

(pathological)

Contracture(no EMGactivity)

Electrogeniccontraction

(normal)

Viscoelasticstiffness

Elasticstiffness

Relationship between commonly used terms to characterize muscle tension: Tone, stiffness, contracture, and spasm

K

K

K

J J J J

Tension type headaches with trigger zones in the temporalis muscle (), in suboccipital, sternocleidomastoid and upper trapezius muscles (), from where pain attacks can be elicited

Neuropathic pain

• Pain of the nervous system

• Neuralgias

• Anesthesia dolorosa

• Root pain

• Stroke pain

Neuropathic pain

• All pain of neural origin

The term is mostly used by neurologists for pain caused by disorders of peripheral nerves and cranial nerves

Normal Neuropathic

Central neuropathic pain

• Plastic changes in the function of the CNS(WDR neurons, thalamus)

Acute pain may promote development of central neuropathic

pain

• Central neuropathic pain is a neurologic disorder

Acute pain sensation may not be a sign of pathology

Pain sensation can be elicited by:

• Stimulation of nociceptors

• Overstimulation of other receptors

Acute pain has two phases: A fast (sharp) and a slow

(burning) sensation

• The slow and delayed pain is mediated by unmyelinated fibers (C-fibers).

• The fast phase is mediated by myelinated fibers (A).

Time

Time

Time

First pain Second pain

X

X

C fiber

DRG

DRG

DRG

DRG

DRG

DRG

Ad fiber

Fast and slow pain are different

• Fast pain (stinging):– Well defined with regards to location– Its strength is defined

• Slow pain (aching):– Diffuse, poorly localized anatomically– Difficult the estimate its strength

Different types of nerve fibers carry different kinds of pain

Temperature

There are four different temperature receptors:

Cool and warmth (sensory receptors)

Cold and heat (nociceptors)

Temperature

1. Cool and warmth receptors mediate sensation of temperature

2. Cold and heat receptors are nociceptors that mediate sensation of pain.

3. Cool and warmth receptors are innervated by small myelinated (A fibers, diameter 1-5 m, conduction velocity 5-30 m/sec).

4. Cold and heat receptor are innervated by unmyelinated fibers (C-fibers, diameter 0.2-2 m; conduction velocity 0.5-1 m/sec).

DRG

Receptors

Wide dynamic range neuron

THE ANTERIOR LATERAL SYSTEM MEDIATES PAIN

SENSATIONS

The spinothalamic tract is the best known of the anteriorlateral tracts

Brainstemreticular

formation

Ventralthalamus

PAG

DRG

cortex

Association cortex

Spinothalamictract

Dorsalthalamus

Midline

DorsalhornReceptor

SI

Spinothalamic tract

Spinalnerves

Anterolateralfuniculus

Trigeminalnerve

Reticularformation

Nonspecific (dorsal)thalamic nucleiCortex

Brain stem

Spinalcord

Brainstemreticular

formation

Ventralthalamus

PAG

DRG

cortex

Association cortex

Spinothalamictract

Dorsalthalamus

Midline

DorsalhornReceptor

SI

Trigeminalganglion

Thalamus

Cerebralcortex

Motornuclei

RFBrainstem

Midbrain

Spinalcord

III

SI

SII

VPL

VPI

Brainstem

Anteriror portionof STT

MIDLINEAscending projections of the anterior portion of the STT from neurons in lamina IV-V of the spinal horn.

VPI: Ventral posterior inferior (nuclei of thalamus); VPL: Ventral posterior lateral (nuclei of thalamus); SI: Primary somatosensory cortex; SII: secondary somatosensory cortex

III

3a (SI)

DorsalAnteriorinsula

VPIVMpo

Brainstem

Thalamus

Area 24c

PAG

Lateralportionof STT

MIDLINE

Projections of the lateral portion of the STT from cells in lamina I of the dorsal horn

SI (contralat.)

VPIVMpo

SII (contralat.) SII(ipsilateral)

Lateralportionof STT

DRG

III

MIDLINE

Projection of unmyelinated C fibers.

Notice: Projection to SII is bilateral but only the SI receives input from C fibers

Reticularformationof melulla

Dorsalhorn

DRG

Receptor

Reticularformationof pons

cortex

AssociationcortexMidline

Dorsalthalamus

SI

Spinoreticular tract

Dorsalhorn

DRG

Receptor

Periaqueductal grayPAG

Hypothalamus-amygdala

limbic system

Midline

Spinomesencephalic tract

Reticularformation

Ventralthalamus

cortex

Limbic system

Prefrontalcortex

SMP

Association cortex

AROUSAL

Anteriorlateral tract

Mediallemniscus

Dorsalthalamus

SII

"WHERE"

"WHAT"SI

Pathways involved in mediating the sensation of nociceptor pain

Hypothalamus

Amygdala

Locus coeruleus

Nucleus cuneiformis

Pontomedularreticular

formation

DRG

Fromnociceptors

Dorsalhorn

RVM

PAG

Ascendingpain pathways

Frontal lobe

Input to the periaquaductal gray (PAG) and pathways that modulate transmission of pain signals by the PAG through the rostral ventromedial medulla(RVM) pathway.

Dorsolateral pontomesencephalic tegmentum pathway (DLTP).

DLPT

DRG

Fromnociceptors

Dorsalhorn

PAG

Ascending(crossed)

pain pathways

NA serotoninpathway

DRG

Nociceptorfiber

Lamina Iinterneuron

Lamina IIinterneuron

Presynapticinhibition

Post synapticinhibition

From raphenucleus

To thalamus

Descending pathways from raphe nucleus (NA-serotonin pathway)

NA-serotoninpathway

Forebrain

Thalamus

Forebrain

Spinalpain neuron

NST

Innervation by the vagus nerve of organs in the lower abdomen involving the nucleusof the solitary tract (NST)

DLF: Dorsolateral funiculusVLF: Ventrolateral funiculusRVM: Rostroventral medulla

Visceral pain is different from somatic pain

• Inconsistent sensations

• Sometimes referred pain to body surface

• Often inescapable

Spinal cord

T11-L4

S3-S4

Viceralafferents

Uterus

Efferent

Nociceptors

Viceralafferents

DRGDRG

Viceralafferents

Painfibers

Viceralreceptors

Bladder

Visceral afferent innervation in the lower body and motor (efferent) innervation.

PAG

RVM5HT

non 5HT

DLPTNE

non NE

Dorsalhorn Primary

afferents

Thalamus

+ _

Two-way connections between PAG, DLPT and RVM and their connections to the dorsal horn

DRG

Fromnociceptor

Off-neuron(Morphineexcites)

On-neuron(Morphine inhibits)

Thalamus

Nocieptivedorsal

horn neuron

The dual input to dorsal horn cells from RVM

Hypothalamus

Dorsomedialthalamus

PAG

STT

Amygdala

Associationcotices

Reticularformation

Cingulategyrus

Spinothalamic tract activate dorsomedial thalamus

Corticalreceptivefield

Cerebral cortex

Cortex

Spinal cord

DRG

Receptive fields

Hypothesis about expansion of receptive field and creation of trigger points by unmasking of dormant synapses

0

10

20

30

40

50

N=8

7.53(0.36) 3.83

(0.94)

46.21(5.92)

6.08(1.08)

45.59(8.06)

4.84(0.52)

Trigger point

Adjacentnon-tendermuscle

N=29 N=25

Normalsubjects

Tensionheadachepatients

Fibromyalgiapatients

Mean EMG amplitudes recorded from a muscle at a trigger point and at an adjacent non-tender muscle

Itch

• The basis of itching is poorly understood but it has similarities with pain.

CENTRAL NEUROPATHIC PAIN MAY INVOLVE THE

SYMPATHETIC NERVOUS SYSTEM

• REFLEX SYMPATHETIC DYSTROPHY, RSD

Role of sympathetic nervous system

in neuropathic pain

1. Sympathetic system is activated by stimulation of pain fibers

2. Sympathetic fibers secrete nor-epinephrine near mechanoreceptors

3. Sensitivity of mechanoreceptors increases4. Activation of sympathetic system increases5. Result: A viscous circle that causes RSD

Increased activity

Activation of thesympathetic

nervous system

Nociceptorsensitization

Liberation of noradrenalin

Trauma cause activation of pain fibers (C-fibers), which sensitize WDR neurons

Sensitized WDR neurons cause pressure to activate pain circuits (allodynia)

Mechanoreceptors are activated by epinephrine that is secreted from sympathetic nerves in absence of mechanical stimulation

Chronic excitation ofvisceral and deepsomatic afferents

Abnormalregualation of bloodflow and sweating

SwellingTrophic changes

Trauma with/withoutperipheral

nerve lesion

Pain

MOVEMENTDISORDERS

ABNORMALACTIVITY IN

MOTONEURONSTO SKELETAL

MUSCLE

ABNORMALSYMPATHETIC

ACTIVITY(VASO-SUDOMOTOR

ORTHERABNORMALITIES?

ABNORMAL STATE OFAFFERENT NEURONS

Sympatheticblock

Central lesion

DISTORTEDINFORMATION

PROCESSING INSPINAL CORD

Contemporary hypotheses of neural mechanisms involved in generating CRPS I and II following trauma

CRPS: Complex regional pain syndrome

Neuropathic pain

• Pain of the nervous system

• Neuralgias

• Anesthesia dolorosa

• Root pain

• Stroke pain


• Plastic changes in the function of the CNS(WDR neurons, thalamus)


• All pain of neural origin

The term is mostly used for pain caused by disorders of peripheral nerves and cranial nerves

Central neuropathic pain may be caused by:

• Chronic inflammation

• Sensitization of skin receptors

• Changes in the connectivity of the CNS (through neural plasticity)

Acute pain may promote development of central neuropathic

pain

• Central neuropathic pain is a neurologic disorder

Wide dynamic range neurons

Central neuropathic pain may develop from peripheral nerve

injuries

• The pain is referred to the peripheral location

• Treatment of that location will not help

• The patient and the surgeon are both frustrated

Central neuropathic pain may involve changes in function

• Normally innocuous stimulation becomes painful (allodynia)

• Stimuli that normally cause mild pain cause an exaggerated reaction (hyperpathia)

Central neuropathic pain is often accompanied by altered perception of touch and pain

stimuli

• Touch may cause pain (allodynia)

• Increased sensitivity to pain (hyperalgesia)

• Painful stimulation may cause exaggerated reaction to pain and prolonged pain (hyperpathia)

Central neuropathic pain may involve changes in function

• Normally innocuous stimulation becomes painful (allodynia)

• Stimuli that normally cause mild pain cause an exaggerated reaction (hyperpathia)

Allodynia: Pain from normally innocuous stimulation (of the skin)

Hyperalgesia: Extreme sensitiveness to painful stimuli.

Hyperpathia: Exaggerated subjective response to painful stimuli, with a continuing sensation of pain after the stimulation has ceased.

Neuropathic painNormal

From: Møller and Pinkerton, 1997

Pain

Tingling

Temporal integration

A B

Temporal integration during development of carpal tunnel syndrome

From: Møller and Pinkerton, 1997

Site A Site B Site C

2

4

6

8

10

12

14

1 cm

Before burn

After burn

CA

B

D

Mechanicalhyperalgesia

Flare

BA

Hyperalgesia from experimentally induced burns

Hypothesis for referred pain and sensitization of different nociceptors

Sensitization

• Peripherally:– Receptors

• Centrally– Increased synaptic efficacy– Expression of new neurotransmitters– Neuromodulators – Morphological re-organization

From: Møller: Sensory Systems, 2002

• “Wind-up”– Response to second stimulus is stronger than

the response to the first one

• Change in temporal integration

Other phenomena associated with chronic pain

40

30

20

10

00 10 20

ControlNMDA antagonist

Stimulus number

"Wind-up" is NMDA mediated. Response with and without an NMDA antagonist.

Severe neuropathic pain affects a person’s entire life in

major ways

• Prevent or disturb sleep• Interfere with or prevent• Intellectual work Involve limbic structures causing affective

reactions

How do we explain these symptoms and signs physiologically and

anatomically?

Where is the neural activity that give a sensation of pain

generated?

The anatomical location of the abnormality that cause pain may be different from that to which the pain

is referred

• Referred pain

• Central neuropathic pain

The abnormal neural activity that causes symptoms are not

generated at the location where the symptoms are felt

Example:

• Posttraumatic central neuropathic pain

• Phantom pain

Central pain pathways for pain

• PROJECT TO PRIMARY CORTICES WITH SPATIAL INFORMATION (“WHERE”)

• PROJECT OBJECTIVE INFORMATION (“WHAT”) TO MANY DIFFERENT PARTS OF THE CNS.

• NON-CLASSICAL PATHWAYS ALSO CONTRIBUTES TO AROUSAL

SUMMARY OF PATHWAYS INVOLVED IN MEDIATING THE SENSATION OF PAIN

CENTRAL PAIN PATHWAYS PROJECT TO PRIMARY CORTICES WITH SPATIAL INFORMATION (“WHERE”)

OBJECTIVE INFORMATION (“WHAT”) TO MANY DIFFERENT PARTS OF THE CNS (FOR EXAMPLE THE AMYGDALA)

NON-CLASSICAL INFORMATION ALSO CONTRIBUTES TO AROUSAL


Reversal of neural plasticity

• “TENS” (transderm electric nerve stimulation) has been used for many years in treatment of chronic pain

• Recently, sound stimulation in various forms have been introduced in treatment of severe tinnitus

Severe neuropathic pain affects a person’s entire life in

major ways

• Prevent or disturb sleep• Interfere with or prevent• Intellectual work Involve limbic structures causing affective

reactions

How can pain information reach the amygdala?

• Through the thalamus

• Through routes that are enhanced by expression of neural plasticity (re-routing of information)


Connections from a sensory system to the amygdala “the high route”

Connections from a sensory system to the amygdala “the low route”


The amygdala is involved in fear and other mood disorders


Connections from the amygdala

INESCAPABLE PAIN INVOLVES OTHER PARTS

OF THE CNS THAN ESCAPABLE PAIN

Activate different columns in the PAG coordinating either active of

passive coping

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