Pain

Describe the physiology of pain, including the pathways and mediators

Key definitions:

• Pain
  Pain is an "unpleasant sensory or emotional experience associated with actual or potential tissue damage, or described in such terms." Pain can be broadly classified by:
  • Aetiology
    • Nociceptive pain
      Stimulation of nociceptors by noxious stimuli.
    • Visceral pain
    • Neuropathic pain
      Nervous system dysfunction.
  • Duration
    • Acute pain
      Pain due to symptoms of current pathology.
    • Chronic pain
      Pain occurring after the pathological process has resolved.

• Hyperalgesia
  Increased response to a normally painful stimulus.
  • Primary hyperalgesia
    Local reduction in pain threshold.
  • Secondary hyperalgesia
    Hyperalgesia away from the site of injury due to alteration in spinal cord signaling.

• Allodynia
  Painful response to a normally painless stimuli. Occurs due to pathological synapse between second-order neurones in the spinal cord.

• Anaesthesia dolorosa
  Pain in an area which is anaesthetised.

Peripheral Nociception

Nociceptors are receptors which respond to a noxious stimulus. Nociceptors:

• Can be stimulated or sensitised by:
  • Chemical signals
    See table.
  • Mechanical signals
    • Shear stress
  • Thermal signals
    • Hot nociceptors activate above 43°C
    • Cold nociceptors activate below 26°C
• Stimulation initiates a nervous impulse
• Sensitisation increases a receptors sensitivity to a stimulating mediator

Key chemical stimulating and sensitising mediators include:

Nociceptors

Impulses are conducted by two types of primary afferent fibres:

• Aδ fibres:
  • Small (~2-5μm diameter)
  • Myelinated
  • Conduct sharp pain at up to 40m.s^-1
  • Mediate initial reflex responses to acute pain
  • Synapse in laminae I in the dorsal horn
    Substance P is the neurotransmitter at the NK1 receptor.
• C fibres:
  • <2μm diameter
  • Unmyelinated
  • Conduct dull pain at 2m.s^-1
  • Synapse in laminae II in the dorsal horn
    Substance P is the neurotransmitter at the NK1 receptor.

Pain Pathway and Site of Action of Analgesics

The response to a painful stimulus requires a cascade of processes:

• Activation of nociceptors
  Membrane depolarisation in response to stimulus. If the stimulus is great enough to reach the threshold potential, an action potential is generated.
  • NSAIDS reduce nociceptor mediated inflammation
  • Opiates act on peripheral MOP receptors
  • Local anaesthetics prevent signal propagation
• Synapse in the dorsal horn
  Input from both Aδ and C fibres, and descending interneurons.
  • Descending inhibitory input reduces nociceptive transmission
    Basis of "gate control" theory. Descending input increased with:
    • Touch
      Aβ 'touch' fibres stimulate inhibitory interneurons in the dorsal horn, 'closing the gate' by increasing descending inhibition and prevent signals from peripheral C fibres from rising to the thalamus.
    • Arousal
    • Opioid receptors
      Particularly MOP (pre- and post-synaptically).
      • Opioids act pre-synaptically to reduce Substance P and glutamine release.
    • α₂ receptors
      Clonidine, tricyclic antidepressants, noradrenaline-reuptake inhibitors, and endogenous catecholamines.
    • Gabapentin and pregabalin inhibit presynaptic neurotransmitter release
  • Wide dynamic range neurones
    Receive afferent input from chemical, thermal, and mechanoreceptors.
    • Typically more difficult to stimulate
    • Important in wind-up
      Mediated by NMDA agonism.
      • Ketamine reduces windup and central sensitisation
    • Lead to secondary hyperalgesia
    • Lead to allodynia
      Via additional synapses to sensory neurones in lamina III and IV.
    • Interneuron synapses with a second-order neurones fibre
      These secondary afferents:
  • Cross within 1-2 vertebral segments and ascends in the spinothalamic tract
  • Receives input from descending fibres
  • Opioids act post-synaptically to hyperpolarise second-order neurones

• Reflex arc

• Higher centres
  Pain perception occurs in the somatosensory cortex.

Neuropathic Pain

Pain due to a lesion of the somatosensory system, rather than a stimulus itself. Neuropathic pain is divided into:

• Central neuropathic pain
  From CNS injury, e.g. spinal cord injury, CVA, multiple sclerosis.
• Peripheral neuropathic pain
  Damage from:
  • Diabetes
    Ischaemia of Schwann cells causes demyelination, causing the exposed axon to generate action potentials inappropriately.
  • Trauma
    Transected axons may regrow with endings that spontaneously fire or that have altered threshold potentials.

Mechanisms of Neuropathic Pain

• Neuroma
  Healing of damaged nerves leads to neuroma formation. Neuromas:
  • Are more sensitive to painful stimuli
  • Cause spontaneous pain
  • May sprout and innervate local tissues
    Movement of these tissues may lead to pain.
• Windup
• Phantom limb pain
  Neurons damaged in removal of a limb develop additional synapses, leading to phantom sensations.

Features of Neuropathic Pain

Neuropathic pain is associated with:

• Injury or disease that causes nerve injury
• Burning or electrical quality
• Reduced or absent sensation
• Poor response to typical analgesia

Chronic Regional Pain Syndrome

Damage to the SNS can lead to abnormalities in autonomic function:

• Change in temperature due to vasomotor dysfunction
• Altered sweating
• Reduced hair growth
• Osteoporosis
• Hyperalgesia and allodynia

Pain in the Elderly

Nervous System Changes:

• Peripheral Nervous System
  • Nerve deterioration
  • Decreased myelination
  • Decreased conduction velocity
  • Reduced range and speed of ANS responses
  • Increased resting sympathetic tone
• Central Nervous System
  • Decreased pain perception
  • Increased sensitivity to anaesthetic and analgesics
    Reach ceiling effects more rapidly.
  • Degeneration of myelin
    Subsequent cognitive dysfunction due to neuronal circuit dysfunction.
  • Generalised atrophy
  • Decreased neurotransmitter production

References

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3. Chambers D, Huang C, Matthews G. Basic Physiology for Anaesthetists. Cambridge University Press. 2015.
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8. Gibson S. Pathophysiology of Pain.