Pain - Basic Science Implications for Analgesia & Analgesics

Pain - Basic Science Implications for Analgesia & Analgesics

Neural Plasticity Research GroupNeural Plasticity Research Group

Department of Anesthesia and Critical CareDepartment of Anesthesia and Critical Care

Massachusetts General Hospital andMassachusetts General Hospital andHarvard Medical SchoolHarvard Medical School

Clifford J. WoolfClifford J. Woolf

Is there a basis for theIs there a basis for theseparation of painseparation of painon the basis ofon the basis of

• ChronicityChronicity• IntensityIntensity• MechanismsMechanisms

Pain ChronicityPain Chronicity

AcuteAcuteChronicChronic

Persistence or RecruitmentPersistence or Recruitment

Pain ChronicityPain Chronicity

Acute Acute - Transient / Recurrent - Transient / Recurrent - Reversible- Reversible

ChronicChronic - Long lasting/Reversible- Long lasting/Reversible- Persistent / Irreversible- Persistent / Irreversible

Pain IntensityPain Intensity

MildMildModerateModerate

SevereSevere

Continuum or DiscreteContinuum or DiscreteStimulus or ResponseStimulus or Response

Pain Mechanism

Etiological Factorsinflammation/tissue damage/nerve lesions

Pain Sydromespost-operative/arthritic/back pain/neuropathic

Multiple Pain MechanismsMultiple Pain Mechanisms

• Nociception

• Peripheral sensitization

• Central sensitization

• Ectopic excitability

• Decreased inhibition/

Structural reorganization

Multiple Pain SymptomsMultiple Pain Symptoms

• Spontaneous Pain

Superficial/Deep

Continuous/Intermittent

• Evoked Pain

Thermal/Mechanical

Allodynia

Hyperalgesia

Role of COX-2selective/specific

inhibitors

Noxiousstimulus

Transduction Conduction Transmission

primary sensory neuron central neuron

Modulation

NociceptionNociception

“Ouch” Pain

Nociceptor ActivatorsNociceptor Activators

Heat

H+

VR1

ASIC TRPV3

Bradykinin

B1/B2 DRASIC/mDEG

Mechanical

generator potential

action potentials

Nociception – TransductionNociception – Transduction

Cold

CRM1

COX-2 Insensitive

Afferent Central Terminal

Glutamate

Sub P

Activity

NK1

mGluR

NMDA

AMPAAMPA

VGCCGABAA

AdensosineOpiateCB1

Dorsal Horn Neuron

Transmission/ModulationTransmission/Modulation

COX-2Insensitive

Nociception is not COX-2

Sensitive

Nociception is not COX-2

Sensitive

Innocuous/Noxiousstimulus

Reduced Transduction Threshold

primary sensory neuron central neuron

Peripheral SensitizationPeripheral Sensitization

Primary hyperalgesiaPrimary heat allodynia

Inflammation

There are prostanoid and non-prostanoid sensitizers

Peripheral SensitizationPeripheral Sensitization

PKC

PKA

(SNS/SNS2)

VR1

Ca2+

PG

EP/IP

AACox-2PGS

Primary sensory neuronperipheral terminal

Tissue Tissue damagedamage

MacrophageMacrophage

Mast Mast cellcell

IL1, IL6TNF

H+ COX-2Sensitive

Nai

ve 12h6h

Skin

Noxiousstimulus

Increased Pain Responsiveness

primary sensory neuron central neuron

Central SensitizationCentral Sensitization

Secondary hyperalgesiaTactile allodynia

IrritantsTissue damageInflammation

Brush-Evoked Mechanical Allodynia

Weak synapseinnocuous

stimulusnon-painful sensation

innocuous stimulus

painful sensation

Increased synaptic strength

AA fibre mechanoreceptor fibre mechanoreceptor

Central Sensitization – Central Pain Hypersensitivity

Central Sensitization – Central Pain Hypersensitivity

Central Terminal

Glutamate

Sub P

PKC

Activity

PKA

NK1

mGluR

NMDA TyrS/T

S/T

IP3

Ca2+

AMPAAMPA

pERKsrc

Central Sensitization - Acute PhaseCentral Sensitization - Acute Phase

COX-2Insensitive

tRN

AN

aïve

1 H

r2

Hrs

4 H

rs6

Hrs

24 H

rs

12 H

rs

48 H

rs

COX-2

-actin

COX-2 Induction in the Spinal Cord - InflammationCOX-2 Induction in the Spinal Cord - Inflammation

Cox-2 is not induced in the

Spinal Cord by Peripheral Nerve Injury

Cox-2 is not induced in the

Spinal Cord by Peripheral Nerve Injury

Cox2

Actin

Sham

12 h

24 h

72 h

7 d

100112

11597 88Cox2 band

intensity

Primary sensory neuroncentral terminal

PGE2

EP

EP/IP

COX-2

Nociceptive dorsalhorn neuron

Inhibitoryinterneuron EP

Glycine receptor

++

++

++

––

Central Sensitization Late Phase (Inflammation)Central Sensitization Late Phase (Inflammation)

COX-2Sensitive

There are COX-2 sensitive peripheral andcentral components of inflammatory pain

Cox-2 inhibitors can only act when COX-2is induced - time lag for induction

There are non-prostanoid contributors toinflammatory pain - ceiling effect

Peripheral nerve injury may not be sensitiveto COX-2 inhibitors

A B C

1 2 3

Etiology

Mechanism

Symptom

A B C

1 2 3

Etiology

Mechanism

Symptom

Need to differentiate Analgesicand Anti-hypersensitivity drugs

Temporal and Intensity characteristicsof pain do not reflect mechanisms and may not be useful predictors of analgesic action

Pain Mechanisms and Drug Mechanismsmay provide the most useful input fordetermining Indication and Efficacy

Need mechanism sensitive/specificoutcome measures in additionto global pain scores

Need clinical trials that validatemechanistic hypotheses

Need to consider labeling claims in lightof action of a drug with specificpain mechanism(s) as well as empiricalclinical data on efficacy

Are there global analgesics?