pathophysiology of pain - columbia surgery...increased pain sensitivity gene protein affected...
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Pathophysiology of PainRamon Go MD
Assistant Professor Anesthesiology and Pain medicineNYP-CUMC
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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
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What is pain?
"an unpleasant sensory and emotional experience associated with actual or potential tissue damage”
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Anatomy of the Pain PathwayTransduction: 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.
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A closer look Transduction: Primary afferents
Skin
Spine
Nerve Fiber Function
A-beta low threshold mechanoreceptors
A-delta low threshold mechano and thermoreceptors
C high threshold thermal, mechano, and chemical receptors
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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
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Transduction: Primary afferents
Up-regulation of substance P
Enzyme activation
TRPV activation
Increased excitability of nociceptors
Activation of silent nociceptors
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Transduction: Primary afferents
Naked mole rat: Inability to convert capsaicin and acid stimulus to electrical signal
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NGF/TRKA Pathway: Activates TRPV1 ion channel allows depolarization and activation of voltage gated Na+ channels
Transduction: Primary afferents
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Transmission: Electrical stimulus is sent to the dorsal horn of the spinal cord and synapse at the 2nd order neuron
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Transmission: Electrical stimulus is sent to the dorsal horn of the spinal cord and synapse at the 2nd order neuron
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Transmission: C fiber activity increases Wide Dynamic Range Neurons firing
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Modulation: Inhibition vs amplification of signal.
Inhibitory:SerotoninNEGABA
Excitatory: EAAAchGlycinesPOxytocinCRH
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Perception: Conscious Awareness of Pain
Cortical: Somatosensory cortex, insula, and anterior cingulate cortex
Subcortical: hypothalamus, Thalamus, amygdala, hippocampus
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When the norm diverges...
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When acute pain turns to chronic...
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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
Surgical procedures and prevalence rates of developing postsurgical pain syndrome
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Allan Gottschalk, M.D., Ph.D.; Srinivasa N. Raja, M.D.
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Abnormal Transmission of Pain
Gottschalk et al 2001
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Transduction
Changes to the pain pathway in chronic pain
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
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Risk Factors for acute pain to become chronic...
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Chronic Pain
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Higher preop and postop pain scores, increases risk for CPSP
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Risk Factors for acute pain to become chronic...
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Chronic Pain
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Higher preop and postop pain scores, increases risk for CPSP
Extensive surgery, long surgical time, radiation and chemotherapy.
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Risk Factors for acute pain to become chronic...
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Chronic Pain
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Higher preop and postop pain scores, increases risk for CPSP
Extensive surgery, long surgical time, radiation and chemotherapy.
Perioperative anxiety, pain catastrophizing, excessive empathy from family.
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Risk Factors for acute pain to become chronic...
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Surgical Procedure Nerve Injured
Mastectomy Lateral pectoral, medial pectoral, intercostal
Thoracotomy Intercostal
Cesarean section Ilioinguinal, iliohypogastric
Herniorrhaphy Ilioinguinal
Higher preop and postop pain scores, increases risk for CPSP
Extensive surgery, long surgical time, radiation and chemotherapy.
Perioperative anxiety, pain catastrophizing, excessive empathy from family.
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Risk Factors for acute pain to become chronic...
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Chronic Pain
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Surgical Procedure Nerve Injured
Mastectomy Lateral pectoral, medial pectoral, intercostal
Thoracotomy Intercostal
Cesarean section Ilioinguinal, iliohypogastric
Herniorrhaphy Ilioinguinal
Higher preop and postop pain scores, increases risk for CPSP
Extensive surgery, long surgical time, radiation and chemotherapy.
Perioperative anxiety, pain catastrophizing, excessive empathy from family.
May explain ~70% of pain variability
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Genetic polymorphisms result in altered nociception
Genetics may explain 70% of variability in experiencing pain
“Man on Fire Syndrome”“No pain”
NormalPain
Perception
SCN9A Gene: Nav1.7
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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
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Summary
Normal Pain SignalingTransductionTransmissionModulationPerception
When acute becomes chronic painRates of chronic painAbnormal changes in the pain pathwayRF for acute to chronic painGenetics in pain pathway
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Thank you for you attention!