# Presentation: 949369

## Pain - Basic Science Implications for Analgesia & Analgesics

**Pain - Basic Science Implications for Analgesia & Analgesics**

*Neural Plasticity Research Group*
*Department of Anesthesia and Critical Care*
*Massachusetts General Hospital and**Harvard Medical School*

**Clifford J. Woolf**

## Is there a basis for the

**separation of pain**
**on the basis of**
** ****Chronicity**
** ****Intensity**
** ****Mechanisms**

## Pain Chronicity

**Acute**
**Chronic**
**Persistence or Recruitment**
** **

## Pain Chronicity

**Acute ****	****- Transient / Recurrent ****	****	**
**	****	****- Reversible**
**Chronic****	****- Long lasting/Reversible**
**	****	****- Persistent / Irreversible**** **

## Pain Intensity

**Mild**
**Moderate**
**Severe**
**Continuum or Discrete**
**Stimulus or Response**

## Pain Mechanism

**Pain Mechanism**

**Etiological Factors**
*inflammation/tissue damage/nerve lesions*

**Pain Sydromes**
*post-operative/arthritic/back pain/neuropathic*

## Multiple Pain Mechanisms

** ****Nociception**
** ****Peripheral sensitization**
** ****Central sensitization**
** ****Ectopic excitability**
** ****Decreased inhibition/**
**  ****Structural reorganization**

## Multiple Pain Symptoms

** ****Spontaneous Pain**
**	****	****Superficial/Deep**
**	****	****Continuous/Intermittent**
** ****Evoked Pain**
**	****	****Thermal/Mechanical**
**	****	****Allodynia**
**	****	****Hyperalgesia**

## Role of COX-2

**selective/specific**
**inhibitors**

## Nociception

**Noxious**
**stimulus**

**Transduction****	****Conduction****	****	****Transmission**

***primary sensory neuron******	******        central neuron***

**Modulation**

**Nociception**

**“****Ouch” Pain**

***	******	******Nociceptor Activators***

**Heat**
**H****+**

**VR1 **
**ASIC     TRPV3**

**Bradykinin**

**B1/B2**

**DRASIC/mDEG**

**Mechanical**

**generator potential**
**action potentials**

**Nociception – Transduction**

**Cold**

**CRM1**

**COX-2 Insensitive**

## Transmission/Modulation

**Afferent Central ****Terminal**** **

**Glutamate**

**Sub P**

**Activity**

**NK1**

**mGluR**

**NMDA**

**AMPA**

**VGCC**

**GABA****A**
**Adensosine**
**Opiate**
**CB1**

**Dorsal Horn **
**Neuron**

**Transmission/Modulation**

**COX-2**
**Insensitive**

## Nociception is not COX-2Sensitive

## Peripheral Sensitization

**Innocuous/Noxious**
**stimulus**

**Reduced Transduction Threshold**

***primary sensory neuron******	******        central neuron***

**Peripheral Sensitization**

**Primary hyperalgesia**
**Primary heat allodynia**

**Inflammation**

## Peripheral Sensitization

**There are prostanoid and non-prostanoid sensitizers**

**Peripheral Sensitization**

**PKC**

**PKA**

**(SNS/SNS2**)

**VR1**

**Ca****2+**

** **

***PG***

***EP/IP***

***AA***

***Cox-2***

***PGS***

**Primary sensory neuron**
**peripheral terminal**

**Tissue **
**damage**

**Macrophage**

**Mast **
**cell**

**IL1********, IL6****TNF******

**H****+**

**COX-2**
**Sensitive**

## Central Sensitization

**Noxious**
**stimulus**

**Increased Pain Responsiveness**

***primary sensory neuron******	******        central neuron***

**Central Sensitization**

**Secondary hyperalgesia**
**Tactile allodynia**

**Irritants**
**Tissue damage**
**Inflammation**

## Central Sensitization – Central Pain Hypersensitivity

**Weak ****synapse**

***innocuous ******stimulus***

***non-painful ******sensation***

***innocuous ******stimulus***

***painful ******sensation***

**Increased ****synaptic ****strength**

**A******** fibre mechanoreceptor**

**Central Sensitization – ****Central Pain Hypersensitivity**

## Central Sensitization - Acute Phase

**Central Sensitization - Acute Phase**

**COX-2**
**Insensitive**

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

**tRNA**

**Naïve**

**1 Hr**

**2 Hrs**

**4 Hrs**

**6 Hrs**

**24 Hrs**

**12 Hrs**

**48 Hrs**

**COX-2**

******-actin**

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

## Cox-2 is not induced in the Spinal Cord by Peripheral Nerve Injury

## Central Sensitization Late Phase (Inflammation)

**Central Sensitization Late Phase (Inflammation)**

**COX-2**
**Sensitive**

## 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**

##  A 

** ****A **

** ****B **

** ****C **

**Etiology**

**Mechanism**

**Symptom**

##  A 

** ****A **

** ****B **

** ****C **

**Etiology**

**Mechanism**

**Symptom**

## 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****  **

## 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?**