Pain

• Sensory System


  Transmit sensory information into the spinal cord and to sensory areas of the brain
• Sensory Receptors


  • Mechanoreceptors
  • Thermoreceptors
  • Chemoreceptors
  • Proprioceptors
  • Nociceptors
• Pain


  Subjective response to a noxious stimulus
• Sensation


  Nociceptors, Free nerve endings
• Acute Pain


  Less than 3 months
• Chronic Pain


  More than 3 months
• Acute Pain


  • Physiological response that warns us of danger
  • Nociception – Normal processing of pain and the responses to noxious stimuli that are damaging or potentially damaging to normal tissue
• Inflammatory Pain


  • Tissue damage
  • Release of inflammatory mediators such as prostaglandins and bradykinin
  • Increase the sensitivity of nociceptors to noxious stimuli
  • Hyperalgesia – Hypersensitivity to a noxious stimulus
  • Allodynia – Pain that results from a non-noxious stimulus (low threshold mechanoreceptors and thermoreceptors)
  • NSAIDs reduce production of prostaglandins
• Neuropathic Pain


  • Caused by damage or injury to the nociceptive nerves – peripherally or centrally
  • The pain is usually described as a burning sensation and affected areas are often sensitive to touch
• Nociceptors


  • Free nerve endings in the skin
  • Act as molecular transducer to depolarize these neurons
  • Blocked by local anaesthetics
• TRPV1


  • Transient receptors potential cation channel vanilloid (TRPV1) receptors
  • Cation channels, activation results in sodium influx
  • Activated by noxious heat, also low pH
  • Leads to painful, burning sensation
  • Sensitised by inflammatory agents
  • Antagonists block TRPV1 activity, thus reducing pain
• TRPM8


  • TPR subfamily M
  • Cation channel
  • Sodium influx in response to cold
  • Upregulated in patients with painful bladder syndrome
  • May be a target in prostate cancer
• ENaC / Degenerin Family


  • Activated by mechanical stimuli
• ASIC


  • Acid Sensing Ion Channel
  • Belongs to same family as ENaC
  • Sodium channel activated by protons – acid
  • Mamba venom is made up of mostly of dendrotoxins (dendrotoxin k, -1, -3 & -7)
  • Mambalgins – Potent analgesic as strong as morphine without most side effects, block acid sensing ion channels
• The Pain Pathway


  • Perception of paid throughout the body arises when neural signals transmitted to specific higher order brain areas
  • Cingulate Cortex – Mediated emotional component of pain
  • Opiates decrease pain by modulating the descending the pain pathway in a complex manner
• Pain Transmission in Spinal Cord

  • Nociceptive axons synapse with second order neurons in lamina I, ii & V of the dorsal horn in spinal cord
  • For moderate pain, axons release glutamate with fast action
  • Stronger pain – axons release glutamate and substance P (and ATP) with slower sustained actions
  • Local inhibitory interneurons release GABA and glycine
  • Descending pain controls fibres release opioids to inhibit pain
• Noradrenergic & Serotonergic


  • Antidepressant – Tricyclics
  • Treatment of neuropathic pain
  • Amitriptyline, Doxepin, Imipramine – Inhibit reuptake of norepinephrine and serotonin
• Analgesic Ladder


  • Non-opioid analgesics (e.g. aspirin, paracetamol, NSAIDs)
  • Mild opioids (e.g. codeine) with or without non opioid
  • Strong opioids with or without non opioid, useful for moderate to severe pain
  • Neuropathic Pain – Antidepressants (5-HT), Anticonvulsants (Carbamazepine – NaCh & GABA-R0, Gabapentin & Pregabalin (GABA), Ketamine (NMDA Receptors)
• Opioids


  Encompasses all drugs that act on opioid receptors - Synthetic, Semi Synthetic, or Naturally occurring
• Opiate


  Subset of opiates that are either derived directly from poppy or synthesised from one
• Opiates


  • Opium
  • Morphine
  • Codeine
• Semi-Synthetic Opioids


  • Heroin
  • Hydrocodone
  • Hydromorphone
  • Oxycodone
  • Oxymorphone
  • Buprenorphine
• Synthetic Opioids


  • Fentanyl
  • Methadone
  • Tramadol
• Opioid Receptors


  • Endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociception
  • G Protein-Coupled Receptors with Opioids as Ligands
  • Mu m opioid receptor (MOR) – activated by morphine, b endorphin and enkephalins
  • Delta d opioid receptors (DOR) activated by enkephalins and b endorphin
  • Kappa k opioid receptor (KOR) activated by dynorphin
• Receptor Activation


  • Opens K+ channels – makes neurons less excitable
  • Inhibits Ca2+ channels – decreases neurotransmitter release
• Opiates


  • Act on many places in the brain and nervous system
  • Addiction
  • Reward centre of the brain – dopamine
  • Opiates can change the brain stem an area that controls automatic body functions and depress breathing
  • Opiates can change the limbic system which controls emotions to increase feelings of pleasure
  • Opiates can block pain messages transmitted by the spinal cord from the body
• Peripheral Effects of Opioids

  • Decreased propulsive peristaltic waves in GI Motility
  • Increased tone and amplitude of contraction of ureter, response quite variable
  • Inhibit urinary voiding reflex, catheterisation may be required
• Diamorphine (Heroin)


  • Very lipid soluble
  • Pass through BBB readily so fast onset
  • Within body rapidly deacetylated to morphine
• Codeine


  • 20% analgesic efficiency to morphine
  • Mainly used as oral analgesic
  • Mild type of pain
  • Cause constipation
  • Has antitussive activity so often used in cough mixtures
• Nalorphine


  • Opioid antagonist
  • High first pass metabolism so has to been given by injection
  • Use for reversing respiratory depression, haemorrhagic shock
• Naloxone


  • Opioid antagonist
  • Orally active and longer acting
  • Used in treatment for opioid addiction
• Pethidine


  • Virtually identical to morphine but tends to cause restlessness rather than sedation
  • Additional anti-muscarinic action (dry mouth and blurred vision)
  • Partly N-demethylated in liver to norpethidine which has hallucinogenic and convulsant effect
  • Preferred to morphine for analgesia during labour because it is shorter acting
• Methadone


  • Main difference from morphine is oral efficiency and considerably longer duration of action
  • Used in treatment of opioid addiction