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:

Stimulating Mediators Sensitising Mediators
H+ Prostaglandins
K+ Leukotrienes
ACh Substance P
Histamine Neurokinin A
5-HT Calcitonin GRP
Bradykinin

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 DRG
      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 DRG
      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 interneurones 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 presynaptically 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 synpases 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 atropy
    • Decreased neurotransmitter production

References

  1. Peck TE, Hill SA. Pharmacology for Anaesthesia and Intensive Care. 4th Ed. Cambridge University Press. 2014.
  2. Schug SA, Palmer GM, Scott DA, Halliwell R, Trinca J. Acute Pain Management: Scientific Evidence. 4th Ed. 2015. Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine.
  3. Chambers D, Huang C, Matthews G. Basic Physiology for Anaesthetists. Cambridge University Press. 2015.
  4. Kam P, Power I. Principles of Physiology for the Anaesthetist. 3rd Ed. Hodder Education. 2012.
  5. Merskey H, Bogduk N. Classification of Chronic Pain. 2nd Ed. 1994. IASP Task Force on Taxonomy. IASP Press, Seattle.
  6. Halaszynski T. Influences of the Aging Process on Acute Perioperative Pain Management in Elderly and Cognitively Impaired Patients. The Ochsner Journal. 2013;13(2):228-247.
  7. Melzack R, Wall PD. Pain mechanisms: a new theory. Science. 1965. 19;150(3699):971-9.
  8. Gibson S. Pathophysiology of Pain.
Last updated 2017-09-22

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