The evolving The evolving concept of painconcept of pain

Dr E. FrohlichDr E. FrohlichMarch 2005March 2005GEMP IIIGEMP III

Pain Pain

most frequent cause of suffering andmost frequent cause of suffering and

Disability.Disability.

Seriously impairing quality of life inSeriously impairing quality of life in

millions of people around the globe. millions of people around the globe.

Acute easy to understand.Acute easy to understand.

Chronic ? Chronic ?

Epidemiological data:Epidemiological data:

Annually in the USAAnnually in the USA

15-20% population 15-20% population suffer acute pain suffer acute pain

25-30% -suffer chronic 25-30% -suffer chronic painpain

Traditional Clinico - pathological training Traditional Clinico - pathological training PAIN = SYMPTOMPAIN = SYMPTOM warning of serious illness or pathology.warning of serious illness or pathology.

Chronic pain = Often no pathology foundChronic pain = Often no pathology found

Examinations, investigations to establish Examinations, investigations to establish

responsible pathologyresponsible pathology

time consuming expensivetime consuming expensive delay treatment.delay treatment.

Pain Pain Universal described throughout historyUniversal described throughout history

Egyptians related pain to Egyptians related pain to injuryinjury

Plato - referred to pain as an Plato - referred to pain as an EMOTIONEMOTION

GENESIS GENESIS Pain = grief, sorrowPain = grief, sorrow Linking physical to emotionalLinking physical to emotional

Decartes-(17Decartes-(17thth century) century)

Separate biological fromSeparate biological from

EmotionalEmotional

Nociceptors Nociceptors →→

RopeRope → →

BellBell

19 th century19 th century 2 physiological2 physiological theories developed theories developed 1. Specificity (sensory) 1. Specificity (sensory) 2. Intensity (summation) 2. Intensity (summation)

BY end of the 19th centuryBY end of the 19th century

physiologistsphysiologists

MIND AND BODY ARE SEPARATE MIND AND BODY ARE SEPARATE

PSYCHOLOGY PSYCHOLOGY

separated from separated from

NEUROLOGY NEUROLOGY psychologistspsychologists

Unfortunate separation (Bio-Psycho-Social)Unfortunate separation (Bio-Psycho-Social)BUT BUT leading to the leading to the differentiationdifferentiation between between NOCICEPTION and PAINNOCICEPTION and PAIN

NOCICEPTION NOCICEPTION ≠ ≠ PAIN PAIN

-GA, LA-GA, LA-Trauma (Endorphine, Psychological?)-Trauma (Endorphine, Psychological?)-Beecher (2-Beecher (2ndnd world war) world war)-Denervation (Nociception reaching brain as -Denervation (Nociception reaching brain as

evidenced by sympathetic response.)evidenced by sympathetic response.)

NOCICEPTION WITH NO PAINNOCICEPTION WITH NO PAIN -GA- PAIN NEEDS CONCIOUSNESS-GA- PAIN NEEDS CONCIOUSNESS -LA-LA -Trauma, Beecher’s report,-Trauma, Beecher’s report,

PAIN with no NociceptionPAIN with no Nociception -Chronic pain -Chronic pain CRPS, NEUROPATHICCRPS, NEUROPATHIC PHANTOM LIMBPHANTOM LIMB -PHN,HIV, Multiple sclerosis-PHN,HIV, Multiple sclerosis

The 20th centuryThe 20th century

The gate control theoryThe gate control theory

1965 Melzack and Wall integrated 1965 Melzack and Wall integrated

-specialization of receptors -specialization of receptors

- central summation - central summation

- patterning and modulation - patterning and modulation

- influence of psychological factors. - influence of psychological factors.

GATE THEORY GATE THEORY Specificity theorySpecificity theorySpecialized Nociceptors- - YESSpecialized Nociceptors- - YES

Skin to brain-straight throughSkin to brain-straight through Push button? - NOPush button? - NO

Summation theorySummation theoryIntensity of stimulus ≠ pain perceptionIntensity of stimulus ≠ pain perceptionAmount and quality of pain determined byAmount and quality of pain determined byphysiological and psychological variablesphysiological and psychological variables

Pain not limited to specific Nociceptive pathways Pain not limited to specific Nociceptive pathways Result of Result of

Activity in several interactingActivity in several interacting pathwayspathways..

Gate control theoryGate control theory Central controlCentral control

Large diameter - Large diameter -

excitatory + actionexcitatory + action

systemsystem

inhibitory - +inhibitory - +

Small diameter Small diameter

SG

Central transmission

cells

gate controlgate control

The gate theoryThe gate theory

No Nociceptive pathwaysNo Nociceptive pathways

Transmission cells in spinal cord getTransmission cells in spinal cord get

excited or inhibited by large or small fibersexcited or inhibited by large or small fibers

19821982

Gate theory modified to include Gate theory modified to include

inhibitory inhibitory descendingdescending

mechanisms from brainstemmechanisms from brainstem

IASP IASP Pain Pain DefinitionDefinition

UnpleasantUnpleasant sensory sensory AND AND emotional emotional sensation. sensation. Associated with Associated with Actual Actual OR OR potentialpotential tissue damage. tissue damage. OR described in such terms.OR described in such terms.

Pain = Pain = Bio- Psycho- Social PhenomenonBio- Psycho- Social Phenomenon

PAIN ≠ NOCICEPTION ≠ PAINPAIN ≠ NOCICEPTION ≠ PAIN

Pain is always subjective, always Pain is always subjective, always personal.personal.

Pain expression and pain behavior depend Pain expression and pain behavior depend on cultural and environmental factors. on cultural and environmental factors.

There are more similarities then There are more similarities then differences between cultures /sexes re differences between cultures /sexes re experience of pain.experience of pain.

acute painacute pain

Acute pain (musculoskeletal / visceral organs.)Acute pain (musculoskeletal / visceral organs.)

- - signal signal for tissue damage, for tissue damage, protectiveprotective

phenomenon.phenomenon.

-prompts -prompts withdrawalwithdrawal, flight or fight sympathetic , flight or fight sympathetic

response, response, inflammation inflammation and and healing.healing.

-Therapy-Therapy is usually is usually effective.effective.

Acute pain/ injury Acute pain/ injury

well understood andwell understood and acceptedaccepted

by patient/Dr/societyby patient/Dr/society

Somatic pain differs from visceral pain in Somatic pain differs from visceral pain in

qualityquality and and localizing localizing ability. ability.

cutaneouscutaneous pain - from ectoderm, pain - from ectoderm,

-well localizes , sharp in nature. -well localizes , sharp in nature.

-Cutaneous tenderness, -Cutaneous tenderness,

-Hyperalgesia -primary / secondary -Hyperalgesia -primary / secondary

-Allodynia.-Allodynia.

Deep somaticDeep somatic structures structures (bone, periosteum, muscle tendon fascia) mesoderm(bone, periosteum, muscle tendon fascia) mesoderm

- less well localized - less well localized

- mimic visceral pain. - mimic visceral pain.

-pain can be referred/ radiate -pain can be referred/ radiate

-cause cutaneous hyperalgesia ,-cause cutaneous hyperalgesia ,

-provoke autonomic responses -provoke autonomic responses

and reflex muscle spasmand reflex muscle spasm

Visceral Visceral pain - Endodermal pain - Endodermal

viscera or peritoneum/pleuraviscera or peritoneum/pleura..

- Dull aching ,diffuse and poorly localizedDull aching ,diffuse and poorly localized

- autonomic phenomena autonomic phenomena

(sweating, nausea,bradycardia).(sweating, nausea,bradycardia).

Neurophysiologic endocrine and metabolic Neurophysiologic endocrine and metabolic response to injury:response to injury:

↑↑sympathetic tone- sympathetic tone- ↑ ↑ HR, CO,BP myocardial work.HR, CO,BP myocardial work. ↑ ↑ metabolic rate and 02 consumptionmetabolic rate and 02 consumption ↓ ↓ GI tone and motility (↓gastric emptying, GI tone and motility (↓gastric emptying, ileus)ileus) -↓ Urinary tract tone →urinary retention-↓ Urinary tract tone →urinary retention -↑skeletal muscle tone -↑skeletal muscle tone spasm spasm -↑ catabolism, hyperglycemia-↑ catabolism, hyperglycemia

ANXIETY, FEAR AND SUFFERINGANXIETY, FEAR AND SUFFERING

General considerations of chronic painGeneral considerations of chronic pain

Arbitrary definition- Arbitrary definition- -more then 3-6 months. -more then 3-6 months.

-The pain Outlasts the noxious stimulus and -The pain Outlasts the noxious stimulus and often the stimulus can not be identified. often the stimulus can not be identified.

Traditionally referred to as Traditionally referred to as cancer / non cancer related.cancer / non cancer related.

Viewed as a disease on its own rightViewed as a disease on its own right not a symptomnot a symptom.. Like any other disease it has specific : Like any other disease it has specific :

Peripheral Bio 1Peripheral Bio 1stst analgesics analgesics

Central Psycho 2Central Psycho 2ndnd analgesics analgesics

Metabolic SocialMetabolic Social

Inflammatory l surgical inter-Inflammatory l surgical inter-

Neuropathic -ventionsNeuropathic -ventions

Traumatic/neoplasticTraumatic/neoplastic

CHRONIC PAIN

ETIOLOGY SIGNS & SYMPTOMS TRETMENT

1982 Loeser published a conceptual 1982 Loeser published a conceptual model of the patient with pain.model of the patient with pain.

PAIN BEHAVIOR

SUFFERING

PAIN

NOCICEPTION

PAIN BEHAVIORPAIN BEHAVIOR

NeuroplasticityNeuroplasticity Experiences can change synapses and Experiences can change synapses and intracellular expressions. intracellular expressions. CNS LEARNS FROM EXPERIENCECNS LEARNS FROM EXPERIENCE

Information does not simply move through. Information does not simply move through.

changes in changes in neurotransmitter signals, neurotransmitter signals, Receptor expressionReceptor expression nature and number of synapses ,nature and number of synapses , neuronal structure and neural circuits ,neuronal structure and neural circuits , NERVOUS SYSTEM ADAPTS TO INFORMATION AND CHANGES NERVOUS SYSTEM ADAPTS TO INFORMATION AND CHANGES WITH IT. WITH IT.

....

NEUROTRANSMITTERSNEUROTRANSMITTERS

ExcitatoryExcitatory

Subst P, Neurokinine 1, GlutamateSubst P, Neurokinine 1, Glutamate

Activate AMPA receptorActivate AMPA receptor

Sensitize NMDASensitize NMDA

Acting on nervous system -Central Acting on nervous system -Central

-peripheral.-peripheral.

central sensitization, wind upcentral sensitization, wind up

Long Tem Potentiation and modulation. Long Tem Potentiation and modulation.

InhibitoryInhibitory

GlycinGlycin GABAGABA EndorphinesEndorphines NENE SerotoninSerotonin SomatostatinSomatostatin

ReceptorsReceptors

Opiate Opiate

At spinal AND supraspinal levelAt spinal AND supraspinal level

AND peripheryAND periphery

Receptors Ligands Receptors Ligands

μμ ββ Endorphines Endorphines

δδ Enkephalines Enkephalines

κκ Dynorphine Dynorphine

excite inhibitory neuronsexcite inhibitory neurons

ANALGESIA AND ANTIHYPERALGESIAANALGESIA AND ANTIHYPERALGESIA

Different mechanismsDifferent mechanisms

Opioids - Opioids -

not prevent central sensitizationnot prevent central sensitization

not have antihyperalgesic effectsnot have antihyperalgesic effects

Mu receptor agonistsMu receptor agonists

produce hyperalgesiaproduce hyperalgesia

BuprenorphineBuprenorphine

partial Mu agonist partial Mu agonist

K and Delta antagonistK and Delta antagonist

COX inhibitors- produce antihyperalgesiaCOX inhibitors- produce antihyperalgesia

Ketamine - antihyperalgesiaKetamine - antihyperalgesia

RECEPTORSRECEPTORS GABA - in brain and SCGABA - in brain and SC

GABA A GABA BGABA A GABA B

Ligand GABA GABALigand GABA GABA

BaclofenBaclofen

Function inhibitory Ca K Function inhibitory Ca K

ChannelsChannels

Modulated BenzoModulated Benzo

By BarbiturateBy Barbiturate

SteroidsSteroids

AnaestheticsAnaesthetics

Transient receptorsTransient receptors

VR1VR1

VRL-1 Vaniloid receptor like VRL-1 Vaniloid receptor like

Voltage gated channels, Voltage gated channels,

detect noxious heatdetect noxious heat

f MRIf MRI

Superficial Superficial versus versus deep somatic paindeep somatic pain..

Stimulate different areas of the brain.Stimulate different areas of the brain.

Deep somatic in brain area linked to Deep somatic in brain area linked to depressive withdrawn behavior.depressive withdrawn behavior.

Ion channels – Ion channels – Target for analgaesics Target for analgaesics

(GABA(A)) inhibitory(GABA(A)) inhibitoryAndAndNMDA – Excitatory receptorsNMDA – Excitatory receptorscomplex ion channels complex ion channels

Ligands regulate Voltage gated Ligands regulate Voltage gated Ca channels targets forCa channels targets foranalgesics analgesics

AntiepilepticsAntiepileptics

work via three major mechanisms work via three major mechanisms

--Block of voltage-activated Na channels.Block of voltage-activated Na channels.

-Potentiation of GABA -Potentiation of GABA

-Reduction of glutamate excitatory-Reduction of glutamate excitatory

transmission.transmission.

Ketamine Ketamine

Blocks -Blocks -sodiumsodium channels channels

-voltage-gated -voltage-gated potassiumpotassium channels channels

blocks NMDA receptor blocks NMDA receptor

ANALGESIAANALGESIA

++

ANTI-HYPERALGESIAANTI-HYPERALGESIA

ReducesReduces

excitability in superficial dorsal hornexcitability in superficial dorsal horn

NOVEL DRUGSNOVEL DRUGS

Ziconotide – Marine snail toxinZiconotide – Marine snail toxin

N-type voltage-gated N-type voltage-gated Ca channelCa channel blocker, blocker,

preventing the conduction of nerve signals. preventing the conduction of nerve signals.

Narrow therapeutic window, lag time for Narrow therapeutic window, lag time for onsetonset

offset of analgesia and adverse events.offset of analgesia and adverse events.

severe psychiatric and central nervous severe psychiatric and central nervous system adverse effects.system adverse effects.

Activation of GLIAL cellsActivation of GLIAL cells

Nerve growth factor - NGFNerve growth factor - NGF

Role in pain generation Role in pain generation

hyperalgesiahyperalgesia

Expressed in injured tissueExpressed in injured tissue

NGF antagonists – being developedNGF antagonists – being developed

Take home messageTake home message- Continuously evolving.Continuously evolving.- Concept changing from - Concept changing from dualisticdualistic to to integrativeintegrative.. (mind - body.)(mind - body.)- CNS undergoes CNS undergoes structuralstructural changes - Not changes - Not

static. static. - Chronic pain is a Chronic pain is a disease on its own rightdisease on its own right RequiringRequiring multidisciplinary approachmultidisciplinary approach, , aiming to improve aiming to improve COPINGCOPING not eliminate painnot eliminate pain..

We are only beginning to understand painWe are only beginning to understand pain

MechanismSMechanismS

Receptor agonists antagonists, Receptor agonists antagonists, channelopathies, genetic factorschannelopathies, genetic factors

Grouping of different pains according to their Grouping of different pains according to their mechanism of action will provide means for mechanism of action will provide means for specific Rx and management.specific Rx and management.