Chronic pain in children:pathophysiology

Guy Hans

Definition of chronic pain?

• “An unpleasant sensory and emotionalexperience associated with actual or potentialtissue damage, and lasts beyond the normal time for healing.”

• “Chronic pain in children is the result of adynamic integration of biological processes, psychological factors, and sociocultural context considered within a developmental trajectory.”

• Chronic pain in children…

• … clinical reality or rather an exceptional condition?

Physiology of acute pain

The BIOMEDICAL Model

• Pain as a sensory event reflecting underlying disease or tissue damage

Physiological method of protection↓

Body is warned against further tissue damage↓

React in a proper manner⇓

SURVIVAL

Transmission of nociceptive signal

Jane W. Ball and Ruth C. BindlerChild Health Nursing: Partnering with Children & Families

© 2006 by Pearson Education, Inc.Upper Saddle River, New Jersey 07458

All rights reserved.

Presence of pain complaints

damage ≠ to painpain ≠ to lesioning

Pain without lesion/tissue damage is possible:

Kidd, Urban. Br J Anaesthesia 2001;87(1).

Development of chronic pain

Chronic Pain

Hyperalgesia Allodynia

The Role of Plasticity in Chronic Pain

Injury

Acute Pain

Healing With PlasticityNormal Healing

Pain Relief

Adapted from Marcus DM. Am Fam Physician. 2000;61:1331-1338.

With Permission. Woolf,2000.

Consequences of central sensitization

Risk factors of central sensitization …

Gate Control Theory

Melzack R. In: Cousins MJ, Bridenbaugh PO, eds. Neural Blockade in Clinical Anesthesia and Management of Pain. 3rd ed. Philadelphia, Penn: Lippincott Williams & Wilkins; 1998.

Milan MJ, Progress in Neurobiology 66, 2002.

Hyperalgesia Sensitization

pain threshold threshold for response

pain to suprathreshold response to stimuli suprathreshold stimuli

Spontaneous pain Spontaneous activity

SENSITIZING ‘SOUP’Hydrogen Ions Histamine Purines

Noradrenaline Potassium Cytokines

Bradykinin Prostaglandins NGF

Leukotrienes 5-HT Neuropeptides

Tissue Damage

Woolf, Chong. Anesth. Analgesia (77), 1993.

Peripheral Sensitization

Inflammation Sympathetic Terminals

SKIN

Peripheral Sensitization

PeripheralNerve

Terminal

Pressure ?

Plasma ExtravasationVasodilation

Heat 5-HT3 PGE2Bradykinin

VR1 5-HT3 EP B1/B2

IL1ß

MastCell

Macrophage

(PKC)

TNF-αIL-6LIF

IL1-R TrkAH+

PKCTTXr

(SNS/SNS2)

Sub P

Gene Regulation

TTXr

TTXs

H+

P2X ASIC

Adapted from Woolf CJ, et al. Science. 2000;288:1765-1768.

TissueDamage

ATPNGF

H1

Histamine

Ca2+

PKA

With permission. Jensen TS et al. Acta Anaesth Scand, 45, 2001.

Mechanisms of nociceptive central pain1. Autosensitization of receptors

2. Ectopic firing of DRG cells

3. Calcium-induced molecular cascades from excess glutamate

4. Phenotypic change of A-β cells and DRG

5. Changes in gene expression of sodium channels and neuropeptides

6. Anatomic changes at dorsal horn

Schwarzman et al. Neurological Review, 58, 2001.

Neuropathic Pain Is Defined as…

…Pain caused by a lesion or dysfunction of the nervous system1

• Nerve sensitization or damage can be located in the peripheral or central nervous system1

• Manifests with sensory symptoms and signs2

• May have both positive and negative sensory and motor symptoms and signs2

1. Merskey H, Bogduk N, eds. Classification of Chronic Pain. 2nd ed. Seattle, WA: IASP Press; 1994.2. Backonja MM. Anesth Analg. 2003;97:785-790.

Examples of Peripheral vs. Central Sensitization

Adapted from Woolf CJ, Mannion RJ. Lancet. 1999;353:1959-1964.

Sensory function after nerve injury with spontaneous firing along axon

No Stimulus Pain

SensationNociceptorDorsal Horn

Neuron

To Brain

Central sensitization occurs as a result of increased nociceptor drive or disinhibition after nerve injury, leading to exaggerated dorsal horn response

Disinhibition

Innocuous or Noxious Stimulus

Dorsal Horn Neuron

To Brain

Increased Nociceptor Drive

Innocuous Stimulus

Dorsal Horn Neuron

Inhibitory Input Is Downregulated

Persistent Pain as a Disease Entity:

• Increase peripheral input: increase DH firing

• Increase firing: increased NMDA, Ca, PKC, Nitric Oxide

• Increase PKC, Ca: genetic changes

• Increase NO: decreased GABA neurons

• Increase Neurotrophins: sprouting

Cousins, MJ, 2009 AAPM

Apkarian AV, et al. J of Neuroscience, 24(46), 2004.

Price DD. Science 2000.

Price DD. Science. 2000;288:1769-1772.

Price DD. Science. 2000;288:1769-1772.

“Pain Matrix”

Moseley GL. Man Ther. 2003;8(3):130-140.

“Pain Matrix”

• Anterior cingulate cortex (ACC)

• Insular cortex (IC)

• Thalamus

• Sensorimotor cortex (SSI, SSII)

• Cerebellum

Moseley GL. Man Ther. 2003;8(3):130-140.

Petrovic P, et al. Science 2002;295:1737-1740.

Petrovic P, et al. Science. 2002;295:1737-1740.

INJURY SYMPTOMSTissue Damage

Nerve Damage

HyperalgesiaSpontaneous

Pain Allodynia

PERIPHERAL ACTIVITY

CENTRAL

SENSITIZATION

Decreased threshold to

peripheral stimuli Expansion ofReceptive field

IncreasedSpontaneous

activity

Tracey, 2008