Pathophysiology of Pain. Ramon Go MD Assistant Professor Anesthesiology and Pain medicine NYP-CUMC
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1 Pathophysiology of Pain Ramon Go MD Assistant Professor Anesthesiology and Pain medicine NYP-CUMC
2 Learning Objectives Anatomic pathway of nociception Discuss the multiple target sites of pharmacological agents Learn risk factors for the development of chronic pain Utilize information to treat pain at multiple target sites
3 What is pain? "an unpleasant sensory and emotional experience associated with actual or potential tissue damage
4 Anatomy of the Pain Pathway Transduction: Conversion of a noxious stimuli (chemical, mechanical, or thermal) into electrical energy Transmission: Electrical stimulus is sent to the dorsal horn of the spinal cord and synapse at the 2nd order neuron Modulation: Inhibition vs amplification of signal (facilitated by EAA) Perception: Conscious awareness of pain as a culmination of previous processes in the context of the individuals experiences.
5 A closer look Transduction: Primary afferents Skin Spine Nerve Fiber A-beta A-delta C Function low threshold mechanoreceptors low threshold mechano and thermoreceptors high threshold thermal, mechano, and chemical receptors
6 Transduction: Primary afferents Inflammatory Soup Mast cells and Neutrophils: ATP, bradykinin, PGE2, Na+, H+, serotonin COX-2 activation Macrophage: NGF, IL-6, TNFa C-fibers: CGRP, Substance P, neurokinin
7 Transduction: Primary afferents Up-regulation of substance P Enzyme activation TRPV activation Increased excitability of nociceptors Activation of silent nociceptors
8 Transduction: Primary afferents Naked mole rat: Inability to convert capsaicin and acid stimulus to electrical signal
9 Transduction: Primary afferents NGF/TRKA Pathway: Activates TRPV1 ion channel allows depolarization and activation of voltage gated Na+ channels
10 Transmission: Electrical stimulus is sent to the dorsal horn of the spinal cord and synapse at the 2nd order neuron
11 Transmission: Electrical stimulus is sent to the dorsal horn of the spinal cord and synapse at the 2nd order neuron
12 Transmission: C fiber activity increases Wide Dynamic Range Neurons firing
13 Modulation: Inhibition vs amplification of signal. Excitatory: EAA Ach Glycine sp Oxytocin CRH Inhibitory: Serotonin NE GABA
14 Perception: Conscious Awareness of Pain Cortical: Somatosensory cortex, insula, and anterior cingulate cortex Subcortical: hypothalamus, Thalamus, amygdala, hippocampus
15 When the norm diverges...
16 When acute pain turns to chronic...
17 Surgical procedures and prevalence rates of developing postsurgical pain syndrome Procedure Prevalence Breast Surgery 22 35% Thoracotomy 11 52% Cholecystectomy 21% Limb Amputation 5 50% Hip 7 13% Laparoscopic Hernia Repair 15% at nine months
18 Allan Gottschalk, M.D., Ph.D.; Srinivasa N. Raja, M.D.
19 Abnormal Transmission of Pain Gottschalk et al 2001
20 Changes to the pain pathway in chronic pain Transduction Transmission Modulation Perception Sustained increase in nociceptors. Activation of TRPV1-R Increase in sp and CGRP NMDA-R activation Wind-up WDR-Neurons sprout abnormal connections Activation of glial cells Central sensitization Decreased inhibition vs Increased amplification Loss of pain filtering Increased release of pain transmitters Gray matter decrease (reversible) Increased connections: Medial Prefrontal Cortex (mpfc) and Nucleus Accumbens
21 Risk Factors for acute pain to become chronic... Higher preop and postop pain scores, increases risk for CPSP Chronic Pain
22 Risk Factors for acute pain to become chronic... Extensive surgery, long surgical time, radiation and chemotherapy. Higher preop and postop pain scores, increases risk for CPSP Chronic Pain
23 Risk Factors for acute pain to become chronic... Extensive surgery, long surgical time, radiation and chemotherapy. Higher preop and postop pain scores, increases risk for CPSP Chronic Pain Perioperative anxiety, pain catastrophizing, excessive empathy from family.
24 Risk Factors for acute pain to become chronic... Extensive surgery, long surgical time, radiation and chemotherapy. Higher preop and postop pain scores, increases risk for CPSP Chronic Pain Perioperative anxiety, pain catastrophizing, excessive empathy from family. Surgical Procedure Mastectomy Nerve Injured Lateral pectoral, medial pectoral, intercostal Thoracotomy Intercostal Cesarean section Ilioinguinal, iliohypogastric Herniorrhaphy Ilioinguinal
25 Risk Factors for acute pain to become chronic... Extensive surgery, long surgical time, radiation and chemotherapy. Higher preop and postop pain scores, increases risk for CPSP Chronic Pain Perioperative anxiety, pain catastrophizing, excessive empathy from family. May explain ~70% of pain variability Surgical Procedure Mastectomy Nerve Injured Lateral pectoral, medial pectoral, intercostal Thoracotomy Intercostal Cesarean section Ilioinguinal, iliohypogastric Herniorrhaphy Ilioinguinal
26 Genetic polymorphisms result in altered nociception Genetics may explain 70% of variability in experiencing pain SCN9A Gene: Nav1.7 No pain Normal Pain Perception Man on Fire Syndrome
27 Increased Pain Sensitivity Gene Protein affected Phenotype KCNS1 Voltage gated potassium ion channel Increase sciatica pain and phantom limb pain SCN9A Voltage gated sodium ion channel Chronic burning pain, phantom limb pain ADRB2 Beta-2-adrenergic receptor Risk for widespread body pain IL6 Interleukin 6 Pain from endometriosis CACNG2 Voltage-gated calcium ion channel Post mastectomy pain HTR2A Serotonin receptor Increased post-surgical pain Decreased Pain Sensitivity Gene Protein affected Phenotype COMT Catechol-O-methyltransferase Decreased or increased pain perception OPRM1 OPRM1: opioid receptor mu 1 Decreased pain perception TRPV1 Transient receptor potential vanilloid 1 Decreased thermal pain sensitivity MC1R Melanocortin 1 receptor Decreased pain perception GCH1 GTP cyclohydrolase Decreased post-surgical pain CACNA2D3 Voltage-gated calcium ion channel Decreased thermal pain sensitivity
28 Summary Normal Pain Signaling Transduction Transmission Modulation Perception When acute becomes chronic pain Rates of chronic pain Abnormal changes in the pain pathway RF for acute to chronic pain Genetics in pain pathway
29 Thank you for you attention!
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