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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 “Out of Control” and “They had not found adequate relief” despite advanced in new pain medications Inadequate pain control due to Attitude of doctor, nurse, and patient Fear of narcotic usage Knowledge deficits Laws and regulations PAIN Subjective response to nociceptive input to brain Components Motivational-Affective: Emotional Sensory-Discriminative Nociception Awareness of the stimulation of nociceptors by a noxious stimulus Achieve pain control Earlier is better 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 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 ATP capsaicin heat mechanical? COX1 COX2 H+ cold PGs warm ATP VRs ASICs EPs TRPs P2X Na+, K+, Ca2+ channels DRG sensitize, activate C-fibre SENSATIONS SP & CGRP peripheral endings dorsal root ganlgia I I Io I Ii III low intensity non-noxious stimuli high intensity noxious stimuli heavily myelinated fast conducting thinly myelinated intermediate conducting unmyelinated slow conducting IV A WDR A VI C X V II INPUTS V I II IX REFLEXES V INFLAMMATION/NOCICEPTIVE Peripheral Sensitization Central Sensitization Damaged Zone ALLODYNIA HYPERALGESIA Sensitization and activation COX1 - COX2 BK2 - BK1 PGs, H+ CNS ATP NGF blood vessel C-fibre SP, CGRP BK 5HT Vasodilation+plasma extravasation Transmitter release - neuronal excitability NEUROPATHY Ectopic activity Central Sensitization HYPERALGESIA ALLODYNIA Sympathetic sprouting Nerve Injury Neurochemical alterations CNS Na+ channels Ephaptic transmission Transmitter release Multiple mediators at the site of injury J Pain 2000;1:344. C-fiber a2 m SP Ca++ m Increase Ca++ influx 5-HT3 Glu SP 5-HT2 GABAB Glu Na+ a2 NMDA AMPA GABAB GABAA 5-HT3 5-HT2 Increase Na+ influx Dorsal horn Peripheral Sensitization Macrophage Skin Mast cell 6h 12h PGS TRPV1 Tissue damage Cox-2 AA PG EP/IP H+ IL1, IL6 TNFa Ca2+ COX-2 Sensitive PKC PKA (SNS/SNS2) Primary sensory neuron peripheral terminal There are both prostanoid and non-prostanoid sensitizers Tissue damage Hyperalgesia PERIPHERAL ACTIVITY Nerve damage Spontaneous pain Allodynia CENTRAL SENSITIZATION Decreased threshold to peripheral stimuli Increased Expansion of spontaneous activity receptive field Pain Sensitization 10 Hyperalgesia Normal Pain Response Pain Intensity 8 6 4 Injury Allodynia 2 0 Stimulus Intensity Gottschalk and Smith. Am Fam Physician. 2001. 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 Monoamines & GABA after Nerve Injury Midbrain Brainstem • Spinal transmission can also be modulated from supraspinal mechanisms 5-HT 5HT1 inhibitory 5HT2 & 3 excitatory Noradrenaline a2-adrenergic Rs inhibitory • Use a wide range of neurotransmitters Spinal cord GABA Tonic inhibition, GABAA/B 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 Analgesic ladders ความปวดจากมะเร็ง Pain persisting or increasing Non - opioid + Adjuvant Pain persisting or increasing Strong - opioid + Non - opioid + Adjuvant Weak - opioid + Non - opioid + Adjuvant ความปวดเฉียบพลัน Multimodal Analgesia AN E XAM PLE Opioid doses of each analgesic Improved anti-nociception Potentiation due to synergistic/ additive effects May severity of side effects NSAIDs, COX-2 inhibitors, regional blocks, α2-agonist of each drug Adapted from Kehlet H, Dahl JB. Anesth Analg., 1993;77:1048–1056. Clinical application 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 NSAIDS/COX II inhibitor Acetaminophen, Clonidine