8/12/2019 pain bs

1/26

Pain - Basic Science

Implications forAnalgesia & Analgesics

Neural Plasticity Research GroupDepartment of Anesthesia and Critical Care

Massachusetts General Hospital andHarvard Medical School

Clifford J. Woolf

8/12/2019 pain bs

2/26

Is there a basis for theseparation of painon the basis of

Chronicity

IntensityMechanisms

8/12/2019 pain bs

3/26

Pain Chronicity

AcuteChronic

Persistence or Recruitment

8/12/2019 pain bs

4/26

Pain Chronicity

Acute - Transient / Recurrent- Reversible

Chronic - Long lasting/Reversible- Persistent / Irreversible

8/12/2019 pain bs

5/26

Pain Intensity

Mild

ModerateSevere

Continuum or Discrete

Stimulus or Response

8/12/2019 pain bs

6/26

Pain Mechanism

Etiological Factors

inflammation/tissue damage/nerve lesions

Pain Sydromespost-operative/arthritic/back pain/neuropathic

8/12/2019 pain bs

7/26

Multiple PainMechanisms

Nociception

Peripheral sensitization

Central sensitization

Ectopic excitability

Decreased inhibition/

Structural reorganization

8/12/2019 pain bs

8/26

Multiple PainSymptoms

Spontaneous Pain

Superficial/Deep

Continuous/Intermittent

Evoked Pain

Thermal/Mechanical

Allodynia

Hyperalgesia

8/12/2019 pain bs

9/26

Role of COX-2

selective/specificinhibitors

8/12/2019 pain bs

10/26

Noxious

stimulus

Transduction Conduction Transmission

pr imary sensory neuron central neuron

Modulation

Nociception

Ouch Pain

8/12/2019 pain bs

11/26

Nocicepto r Act ivators

Heat

H+

VR1

ASIC TRPV3

Bradykinin

B1/B2 DRASIC/mDEG

Mechanical

generator potential

action potentials

Nociception Transduction

Cold

CRM1

COX-2 Insensitive

8/12/2019 pain bs

12/26

Afferent Central

Terminal

Glutamate

Sub P

Activity

NK1

mGluR

NMDA

AMPA

VGCCGABAAAdensosine

Opiate

CB1

Dorsal Horn

Neuron

Transmission/Modulation

COX-2

Insensitive

8/12/2019 pain bs

13/26

Nociception is not COX-2Sensitive

8/12/2019 pain bs

14/26

Innocuous/Noxious

stimulus

Reduced Transduction Threshold

pr imary sensory neuron central neuron

Peripheral Sensitization

Primary hyperalgesiaPrimary heat allodynia

Inflammation

8/12/2019 pain bs

15/26

There are prostanoid and non-prostanoid sensitizers

Peripheral Sensitization

PKC

PKA

(SNS/SNS2)

VR1

Ca2+

PG

EP/IP

AA Cox-2PGS

Primary sensory neuron

peripheral terminal

Tissuedamage

Macrophage

Mast

cell

IL1, IL6TNF

H+ COX-2Sensitive

12h6h

Skin

8/12/2019 pain bs

16/26

Noxious

stimulus

Increased Pain Responsiveness

pr imary sensory neuron central neuron

Central Sensitization

Secondary hyperalgesiaTactile allodynia

Irritants

Tissue damage

Inflammation

8/12/2019 pain bs

17/26

Brush-Evoked Mechanical Allodynia

Weaksynapseinnocuous

st imulusnon-painfu lsensat ion

innocuous

st imuluspainfu l

sensat ion

Increasedsynapticstrength

A fibre mechanoreceptor

Central Sensitization Central Pain Hypersensitivity

C t l S iti ti A t

8/12/2019 pain bs

18/26

Central Terminal

Glutamate

Sub P

PKC

Activity

PKA

NK1

mGluR

NMDA TyrS/T

S/T

IP3

Ca2+

AMPA

pERKsrc

Central Sensitization - AcutePhase

COX-2

Insensitive

8/12/2019 pain bs

19/26

COX-2

-actin

COX-2 Induction in theSpinal Cord - Inflammation

8/12/2019 pain bs

20/26

Cox-2 is not induced in theSpinal Cord by PeripheralNerve Injury

Cox2

b-Actin

Cox2 band

intensity

l i i i

8/12/2019 pain bs

21/26

Primary sensory neuroncentral terminal

PGE2

EP

EP/IP

COX-2

Nociceptive dorsal

horn neuron

Inhibitory

interneuron EP

Glycine receptor

+

+

+

Central Sensitization LatePhase (Inflammation)

COX-2

Sensitive

8/12/2019 pain bs

22/26

There are COX-2 sensitive peripheral and

central components of inflammatory pain

Cox-2 inhibitors can only act when COX-2

is induced - time lag for induction

There are non-prostanoid contributors to

inflammatory pain - ceiling effect

Peripheral nerve injury may not be sensitive

to COX-2 inhibitors

8/12/2019 pain bs

23/26

A B C

1 2 3

Etiology

Mechanism

Symptom

8/12/2019 pain bs

24/26

A B C

1 2 3

Etiology

Mechanism

Symptom

8/12/2019 pain bs

25/26

Need to differentiate Analgesicand Anti-hypersensitivity drugs

Temporal and Intensity characteristics

of pain do not reflect mechanisms and maynot be useful predictors of analgesic action

Pain Mechanisms and Drug Mechanisms

may provide the most useful input fordetermining Indication and Efficacy

8/12/2019 pain bs

26/26

Need mechanism sensitive/specific

outcome measures in addition

to global pain scores

Need clinical trials that validate

mechanistic hypotheses

Need to consider labeling claims in light

of action of a drug with specific

pain mechanism(s) as well as empiricalclinical data on efficacy

Are there global analgesics?