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Pain - Basic Science Implications for Analgesia & Analgesics. Clifford J. Woolf. Neural Plasticity Research Group Department of Anesthesia and Critical Care Massachusetts General Hospital and Harvard Medical School. Is there a basis for the separation of pain on the basis of Chronicity

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pain basic science implications for analgesia analgesics

Pain - Basic Science Implications for Analgesia & Analgesics

Clifford J. Woolf

Neural Plasticity Research Group

Department of Anesthesia and Critical Care

Massachusetts General Hospital andHarvard Medical School

slide2

Is there a basis for the

  • separation of pain
  • on the basis of
  • Chronicity
  • Intensity
  • Mechanisms
slide3

Pain Chronicity

Acute

Chronic

Persistence or Recruitment

slide4

Pain Chronicity

Acute - Transient / Recurrent

- Reversible

Chronic - Long lasting/Reversible

- Persistent / Irreversible

slide5

Pain Intensity

Mild

Moderate

Severe

Continuum or Discrete

Stimulus or Response

slide6

Etiological Factors

inflammation/tissue damage/nerve lesions

Pain Mechanism

Pain Sydromes

post-operative/arthritic/back pain/neuropathic

multiple pain mechanisms
Multiple Pain Mechanisms
  • Nociception
  • Peripheral sensitization
  • Central sensitization
  • Ectopic excitability
  • Decreased inhibition/
  • Structural reorganization
multiple pain symptoms
Multiple Pain Symptoms
  • Spontaneous Pain
  • Superficial/Deep
  • Continuous/Intermittent
  • Evoked Pain
  • Thermal/Mechanical
  • Allodynia
  • Hyperalgesia
slide9

Role of COX-2

selective/specific

inhibitors

nociception
Nociception

Transduction Conduction Transmission

Modulation

Noxious

stimulus

“Ouch” Pain

primary sensory neuron central neuron

slide11

Nociception – Transduction

Nociceptor Activators

Cold

Heat

H+

Bradykinin

Mechanical

VR1

ASIC TRPV3

B1/B2

CRM1

DRASIC/mDEG

generator potential

action potentials

COX-2 Insensitive

transmission modulation
Transmission/Modulation

VGCC

COX-2

Insensitive

GABAA

Adensosine

Opiate

CB1

NMDA

Activity

Glutamate

AMPA

Sub P

mGluR

NK1

Afferent Central Terminal

Dorsal Horn

Neuron

peripheral sensitization
Peripheral Sensitization

Reduced Transduction Threshold

Primary hyperalgesia

Primary heat allodynia

Innocuous/Noxious

stimulus

Inflammation

primary sensory neuron central neuron

peripheral sensitization15

Skin

Naive

6h

12h

Peripheral Sensitization

Tissue

damage

Macrophage

IL1b, IL6TNFa

Mast

cell

Cox-2

PGS

AA

PG

COX-2

Sensitive

VR1

EP/IP

H+

Ca2+

PKC

PKA

(SNS/SNS2)

Primary sensory neuron

peripheral terminal

There are prostanoid and non-prostanoid sensitizers

central sensitization
Central Sensitization

Increased Pain Responsiveness

Secondary hyperalgesia

Tactile allodynia

Noxious

stimulus

Irritants

Tissue damage

Inflammation

primary sensory neuron central neuron

central sensitization central pain hypersensitivity
Central Sensitization – Central Pain Hypersensitivity

A fibre mechanoreceptor

Weak synapse

innocuous stimulus

non-painful sensation

Increased synaptic strength

innocuous stimulus

painful sensation

Brush-Evoked Mechanical Allodynia

central sensitization acute phase

src

pERK

NMDA

PKC

Tyr

S/T

AMPA

Activity

Glutamate

S/T

Ca2+

PKA

mGluR

Sub P

IP3

NK1

Central Terminal

Central Sensitization - Acute Phase

COX-2

Insensitive

cox 2 induction in the spinal cord inflammation
COX-2 Induction in the Spinal Cord - Inflammation

12 Hrs

24 Hrs

48 Hrs

Naïve

tRNA

2 Hrs

4 Hrs

6 Hrs

1 Hr

COX-2

b-actin

cox 2 is not induced in the spinal cord by peripheral nerve injury

Sham

12 h

24 h

72 h

7 d

Cox2

b-Actin

97

88

115

100

112

Cox2 band

intensity

Cox-2 is not induced in the Spinal Cord by Peripheral Nerve Injury
central sensitization late phase inflammation

Primary sensory neuron

central terminal

+

Nociceptive dorsal

horn neuron

EP

+

EP/IP

+

COX-2

PGE2

Glycine receptor

Inhibitory

interneuron

EP

Central Sensitization Late Phase (Inflammation)

COX-2

Sensitive

slide22

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

slide23

1

2

3

A

B

C

Etiology

Mechanism

Symptom

slide24

1

2

3

A

B

C

Etiology

Mechanism

Symptom

slide25

Need to differentiate Analgesic

and Anti-hypersensitivity drugs

Temporal and Intensity characteristics

of pain do not reflect mechanisms and may

not be useful predictors of analgesic action

Pain Mechanisms and Drug Mechanisms

may provide the most useful input for

determining Indication and Efficacy

slide26

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 empirical

clinical data on efficacy

Are there global analgesics?