2016A13 Outline the physiological mechanisms of progression from acute to chronic pain
and how drugs may alter this progression.



·         Intro: chronic pain

·         Peripheral sensitization

·         Dorsal horn sensitization

·         Higher processing


Intro: chronic pain


·   Chronic pain: > 3 months

·   Initial insult resolved


·   Hyperalgaesia: hurts more than should

·   Allodynia: hurts when shouldn’t

·   Neuropathic pain: hurts due to nerve damage

·   Phantom pain: hurts after body part removed

Risk factors

·   Surgical: nerve injury e.g. amputation, breast, thoracotomy -> ↑dorsal horn activation

·   Patient: depression, psychosocial stressors -> altered cortical processing

·   Pain character: neuropathic, phantom -> ↑dorsal horn activation


Peripheral sensitization:

Inflammation -> nociception

·   Inflamed tissue and WBC release NGF, neurturin etc

·   ↑nociceptive receptor activation and expression

Nociception -> inflammation

·   Nociceptor releases substance P, VIP etc

·   Mast cell degranulation

·   Vasodilatation, capillary leak

·   WBC chemotaxis, differentiation

·   *note vicious cycle*

Nerve injury -> nociception

·   Spontaneous abnormal discharge -> neuropathic pain

·   ? Altered receptor function


·   Anti-inflammation: NSAID

·   Inhibit bradykinin-sensitive nociceptors: paracetamol

(both less effective in chronic pain)

·   Nerve injury: no effective peripheral agent exists yet


Dorsal horn sensitization:

Gain of function WDR neurons

·   Inflamed tissue, injured nerve -> ↑ NMDA activation

·   Brief: ↑receptor irritability -> “wind-up”

·   Persistent: synaptic reinforcement -> “long term potentiation”

·   Mechanism: NMDA -> 2nd messenger and altered gene expression

o  Early: ↑c-Fos, COX-2

o  Late: ↑NK1, TrkB

Gain of function of excitatory neurons

·   Inhibition of VDKC -> ↑excitability

Loss of function of inhibitory neurons

·   (Don’t know the cause)

Abnormal new connections

·   e.g. Aβ 1° afferents -> nociceptive specific 2° afferents

·   Touch becomes painful

Effects on chronic pain

·   Hyperalgaesia

·   Allodynia

·   Expansion of receptive field


·   Regional anaesthetic: inhibit pre-synaptic VDNaC

·   Neuraxial anaesthetic: inhibit VDNaC at dorsal horn, spinal nerve root (very effective)

·   Monoamine reuptake inhibitors: ↓pre-synaptic activity

·   NMDA antagonists: ↓ post-synaptic activity, sensitisation, reinforcement (very effective)

·   Antagonists at pre-synaptic VdCC α2δ subunit: ↓pre-synaptic activity

·   Opioids: inhibit 1° afferent (less effective for chronic pain)


Higher processing:


·   ↑Production of CCL21 -> ↑PGE2 production by microglia -> sensitisation
-> hyperalgaesia, allodyania

Cerebral cortex

·   Psychiatric illness increases risk of chronic pain

·   Mechanism poorly understood

·   Anti-depressants may help (e.g. SSRI – fluoxetine)