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Neurobiology of Pain : Clinical application

Neurobiology of Pain : Clinical application. Kongkiat Kulkantrakorn, MD. Neurology division, Faculty of Medicine Thammasat University. The beginning and the end of pain. Unrelieved Pain. USA Survey 1999: “40% 0f Chronic (moderate to severe) pain pts. reported that their pain is

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Neurobiology of Pain : Clinical application

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  1. Neurobiology of Pain :Clinical application Kongkiat Kulkantrakorn, MD. Neurology division, Faculty of Medicine Thammasat University

  2. The beginning and the end of pain

  3. Unrelieved Pain USA Survey 1999: “40% 0f Chronic (moderate to severe) pain pts. reported that their pain is “Out of Control” and “They had not found adequate relief” despite advanced in new pain medications

  4. Inadequate pain control due to • Attitude of doctor, nurse, and patient • Fear of narcotic usage • Knowledge deficits • Laws and regulations

  5. Components Motivational-Affective: Emotional Sensory-Discriminative Nociception Awareness of the stimulation of nociceptors by a noxious stimulus Subjective response to nociceptive input to brain PAIN

  6. Achieve pain controlEarlier is better

  7. Perceptual categories • Pricking (First pain) • Quality: Sharp • Temporal: Initial pain sensation; Brief • PNS axons: Aδ fibers • CNS pathway: Somatosensory to thalamus & cortex • Burning (Second pain) • Qualities: Dull; Aching; Unpleasant • Temporal: Later, more long-lasting pain sensation • PNS axons: C fibers • CNS: Reticular formation; Periaqueductal gray; Hypothalamus; Central thalamus

  8. What is a Nociceptor? • A number of receptors/channels that sense damage • VR1 vanilloid receptor family - capsaicin/ATP • ASICs - respond to low pH/mechanical? • P2X receptors - respond to ATP • Chemical sensors - prostaglandins, 5HT, Bk etc - peripheral sensitization & inflammation

  9. capsaicin ATP mechanical? COX1 COX2 DRG heat H+ cold warm ATP PGs C-fibre VRs TRPs P2X ASICs EPs Na+, K+, Ca2+ channels sensitize, activate

  10. SENSATIONS INPUTS REFLEXES

  11. INFLAMMATION/NOCICEPTIVE Peripheral Sensitization Central Sensitization Damaged Zone ALLODYNIA HYPERALGESIA Sensitization and activation COX1 - COX2 BK2 - BK1 PGs, H+ CNS ATP NGF C-fibre blood vessel SP, CGRP Transmitter release - neuronal excitability BK 5HT Vasodilation+plasma extravasation

  12. NEUROPATHY Central Sensitization HYPERALGESIA ALLODYNIA Sympathetic sprouting Ectopic activity Nerve Injury Neurochemical alterations CNS Na+ channels Transmitter release Ephaptic transmission

  13. Multiple mediators at the site of injury J Pain 2000;1:344.

  14. Ca++ Na+ Increase Na+ influx Increase Ca++ influx C-fiber a2 5-HT3 d m 5-HT2 Glu GABAB SP SP Glu m d a2 NMDA AMPA GABAB GABAA 5-HT3 5-HT2 Dorsal horn

  15. Skin Naive 6h 12h Peripheral Sensitization Tissue damage Macrophage IL1b, IL6TNFa Mast cell Cox-2 PGS AA PG COX-2 Sensitive TRPV1 EP/IP H+ Ca2+ PKC PKA (SNS/SNS2) Primary sensory neuron peripheral terminal There are both prostanoid and non-prostanoid sensitizers

  16. Spontaneous pain Allodynia Tissue damage Hyperalgesia PERIPHERAL ACTIVITY CENTRAL SENSITIZATION Decreased threshold to peripheral stimuli Increased spontaneous activity Nerve damage Expansion of receptive field

  17. 10 8 6 4 2 0 Hyperalgesia Normal Pain Response Pain Intensity Allodynia Stimulus Intensity Pain Sensitization Injury Gottschalk and Smith. Am Fam Physician. 2001.

  18. Pain perception: Located in Thalamus & Cortex • Psychophysical features • Components: Location; Intensity; Character; Duration • Location: 1° & 2° somatosensory cortex • Affective features • Components: Unpleasantness & Rejection • Location: Limbic cortex (Cingulate & Insula) • Ascending pathway: Dorsal horn; Parabrachial nucleus; Amygdala

  19. Monoamines & GABA after Nerve Injury Midbrain 5-HT 5HT1 inhibitory 5HT2 & 3 excitatory Brainstem • Spinal transmission can • also be modulated from • supraspinal mechanisms • Use a wide range of • neurotransmitters Noradrenaline a2-adrenergic Rs inhibitory Spinal cord GABA Tonic inhibition, GABAA/B

  20. Analgesic classification 1. Narcotics no ceiling effect except partial agonists and mixed agonist -antagonist 2. Non-narcotics NSAIDs/Coxibs ceiling effect 3. Adjuvant analgesic or coanalgesics tricyclic antidepressants antiepileptics steroids bisphosphonates

  21. Analgesic ladders Strong - opioid + Non - opioid + Adjuvant Weak - opioid + Non - opioid + Adjuvant ความปวดจากมะเร็ง Pain persisting or increasing Pain persisting or increasing Non - opioid + Adjuvant ความปวดเฉียบพลัน

  22. Opioid NSAIDs, COX-2 inhibitors, regional blocks, α2-agonist Multimodal Analgesia A N E X A M P L E Potentiation •  doses of each analgesic • Improved anti-nociception due to synergistic/additive effects • May  severity of side effects of each drug Adapted from Kehlet H, Dahl JB. Anesth Analg., 1993;77:1048–1056.

  23. Clinical application

  24. Pharmacology • Around the clock dosing vs PRN dosing • Development of new drugs, preparation • COX-2 inhibitors • Tramadol • Long acting opioids • Opioid receptors • Pharmacogenomics • Variable responses

  25. NSAIDS/COX II inhibitor

  26. Acetaminophen, Clonidine

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