pain pathways made simple pathways made...meperidine, codeine, methadone, tramadol mechanism of...
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Pain Pathways Made Simple
David M Glick, DC, DAAPM, CPE
Disclosures !Nothing to Disclose
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Learning Objectives!Differentiate between nociceptive and
neuropathic pain!Describe the process of pain transmission! Identify the specific pain pathways that can
be acted upon by common pharmacotherapy classes
Classification of Pain!Good pain vs. Bad Pain
Clinical Pearl
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Good Pain!Nociceptive Pain: Purposeful Pain! Eudynia - being pain linked to normal tissue function or
damage !Non-maldynic Pain!Adaptive
Bad Pain!Neuropathic Pain: Non-purposeful Pain! Maldynia - pain linked to disorder, illness or damage ! i.e may be abnormal, unfamiliar pain, assumed to be caused by
dysfunction in PNS or CNS
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Pain Mechanisms
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General Anatomy of Pain
! Adapted from Von Hehn CA, Baron R, Woolf CJ. Deconstructing the neuropathic pain phenotype to reveal neural mechanisms. Neuron. 2012; 23;73(4):638-652.
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Pain Roadmap:Peripheral and Central Nervous System Landmarks
1. Gardner EP, et al. In: Kandel E, et al, eds. Principles of Neural Science. 4th ed. McGraw-Hill Medical; 2000; chapters 21-23.
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Common Types of Pain!"#$#%&'$(%)&*$+
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Nociceptive vs Neuropathic PainNociceptive vs Neuropathic Pain
1. Portenoy RK, Kanner RM. In: Portenoy RK, et al, eds. Pain Management: Theory and Practice. Philadelphia, PA: FA Davis Company;1996:4. 2. Galer BS, Dworkin RH. A Clinical Guide to Neuropathic Pain. Minneapolis, MN: McGraw-Hill Companies Inc; 2000:8-9.
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Pain Pathway Steps
Adapted from Scholtz J, Woolf CJ, Nat Neuroscience, 2002,5:1062-1067
PAG = periaqueductal greyRVM = rostral ventromedial medulla
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Transduction: Processing at Peripheral Nerve Endings
! Conversion of mechanical, thermal or chemical stimuli into an electric charge
! Involves! receptors activated
directly by stimuli! injury/inflammatory
response
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How is Pain Transduced?
! Nociception! Mechanical! Thermal! Chemical
! Mediators! Prostaglandins! Leukotrienes! Substance P! Histamine! Bradykinin! Serotonin! Hydroxyacids! Reactive oxygen species! Inflammatory cytokines and chemokines
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ConductionDORSAL ROOT
GANGLION (DRG)! "#$%&"'(#$)(*+&,-.-)/0#*)+0(*102)$#"(".+'#0-)'#)'3.)-+($1,)"#0%)4%#0-1,)3#0$5)1,#$6)'3.)+.0(+3.01,)$.07.8
Primary Nociception!A-delta fibers!Small receptive fields! Thermal & mechanical!Myelinated!Rapidly conducting
" 10-30 m/sec! Large diameter
! C-fibers!Broad receptive fields!Polymodal!Unmyelinated!Slower conducting
" .5-2.0 m/sec!Cross sensitized!Small diameter
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Peripheral Pain Nociceptors
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Transmission & Modulation
! Adapted from Von Hehn CA, Baron R, Woolf CJ. Deconstructing the neuropathic pain phenotype to reveal neural mechanisms. Neuron. 2012; 23;73(4):638-652.
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How is Pain Conducted and Transmitted?
! Excitatory Transmitters! Substance P! Calcitonin gene related peptide! Aspartate, Glutamate
DORSAL ROOT GANGLION (DRG)
! Inhibitory Transmitters (Descending Inhibitory Pathways)! GABA! Glycine! Somatostatin! !2 "#$%&'('
DORSAL ROOT GANGLION (DRG)GANGLION (DRG)
Role of Neuronal Plasticity in Pain! Nervous system changes in
! Neuronal structure! Connections between neurons! Quantity/properties of neurotransmitters, receptors, ion channels
! Decreases body’s pain inhibitory systems (Increased Pain)! Injury, inflammation, and disease are culprits! Produces short-term and permanent changes! Pivotal to the development of hypersensitivity of inflammatory pain
! Enables NS to modify its function according to different conditions or demands placed upon it.
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How Acute Pain Becomes Chronic!Peripheral Sensitization! Tissue damage releases sensitizing “soup” of cytokines &
neurotransmitters! COX-mediated PGE2 release! Sensitized nociceptors exhibiting a decreased threshold for activation &
increased rate of firing!Central Sensitization –Resulting from noxious input to the spinal cord ! Resulting in hyperalgesia, & allodynia
Definitions
!Hyperalgesia! Lowered threshold to different
types of noxious stimuli
!Allodynia!Painful response to what should
normally be non-painful stimuli
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Neuroplasticity in Pain Processing
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Neuroplasticity in Peripheral Pain Transmission
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Peripheral Sensitization
Central Sensitization
! Activation! “Wind up” of dorsal horn nociceptors
! Modulation! Excitatory/Inhibitory neurotransmitters
! Decreased central inhibition of pain transmission! NE/5HT
Prime role in chronic pain, particularly neuropathic pain
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Definitions!Wind Up
!Causes long-term changes in nociceptive neurons, which become hyperexcitable such that they respond to lower stimuli" NMDA-type glutamate receptors play an
important role in this process 1,2,3,4 !Prolonged opening of the ion channels enables
greater influx of calcium and sodium across the post-synaptic membrane and greater excitation of nociceptive neurons 2,3
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Central Sensitization
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Dorsal Horn of the Spinal Cord Serves as a Relay Station in Pain Processing 1,2
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Neuroplasticity: Cross Talk
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Central Sensitization:Neuroplasticity in Spinal Cord Processing
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Brain Regions Involved in Pain Processing
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Analgesics That Modify Pain Processes
! Perception! Parenteral opiods! !2 agonists! General anesthetics
! Conduction! Local anesthetics
" Peripheral nerve, plexus, epidural block
! Transmission/Modulation! Spinal opiods! !2 agonists! NMDA receptor antagonistis! NSAIDs! NO inhibitors! K+ channel openers
! Transduction! NSAIDs! Antihistamines! Membrane stabilizing agents! Local anesthetic cream! Opiods! Bradykinin & Serotonin antagonists
Pharmacological Targets in Pain
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The Chronic Pain ArmamentariumNonopioids
! Acetaminophen! NSAIDs! COX-2 inhibitors
Opioids! Mu-opioid agonists! Mixed Agonist-antagonists
Adjuvant analgesics! Antidepressants! Anticonvulsants ! Topical agents/local anesthetics
WHO
JC Ballantyne Oncologist 2003:8(6):567-75. © AlphaMed Press; WHO. 2005.
VA DoD Stepped Pain Care Model
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Common Pharmacologic Therapies!Acetaminophen!NSAIDS!Antiepileptics!TCAs !SNRIs !Topicals!Muscle Relaxants!Opioids
Muscle Relaxants
Nonopioids: AcetaminophenExample!Acetaminophen
Mechanism of Action! Inhibits prostaglandin production in CNS;
antipyretic activity!No effect on blocking peripheral prostaglandin production; no anti-
inflammatory or antirheumatic activity
FDA Warning! Potential severe liver damage if over-used! Stevens-Johnson Syndrome & toxic epidermal necrolysis
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Nonopioids: NSAIDsExamples!Acetylated (aspirin); nonacetylated (diflunisal);
acetic acid (diclofenac); propionic acid (naproxen); fenamic acid (mefenamic acid); enolicacids (piroxicam); nonacidic (nabumetone); ibuprofen, selective COX-2s (celecoxib)
Mechanism of Action!Exhibit both peripheral and central effects;
antiinflammatory and analgesic effects! Inhibition of cyclooxygenase and prostaglandin
production! Inhibition of leukotriene B4 production!Lipoxins (signaling resolution of inflammation)
OpioidsExamples!Morphine, hydromorphone, fentanyl, oxycodone, oxymorphone,
meperidine, codeine, methadone, tramadolMechanism of Action!Bind to opioid receptors in the central nervous system (CNS) to
inhibit transmission of nociceptive input from periphery to spinal cord!Activate descending pathways that modulate transmission in spinal
cord!Alter limbic system activity; modify sensory and affective pain
aspects
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Overview of Descending Pain Inhibitory Pathways and Modulation of Pain Response
Modulation of Central Sensitization by 5-HT & NE Descending Pathways
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Mechanism of Action - Opioids
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>4/)(0'."#*2>5)(4$/.'$#()+9/++/")6'9"*,0($/")()*'.%)$#(0'+%)+/$/?($/")
3%#/4;%#52:#()+9/++/")'()*4%#/4;%#(0'+%)+/$/?($/")
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<#(/)+$%92=%+.%)*/)1'9"*,0($/")
>4/)(0'."#*2>5)(4$/.'$#()+9/++/")6'9"*,0($/")()*'.%)$#(0'+%)+/$/?($/")
3%#/4;%#52:#()+9/++/")'()*4%#/4;%#(0'+%)+/$/?($/")4%#/4;%#(0'+%)+/$/?($/")
Adjuvant Analgesics: Tricyclic AntidepressantsExamples!Amitriptyline, desipramine, doxepin, imipramine, nortriptyline
Mechanism of action!Reduction in action potential firing of sodium channel activity! Inhibition of reuptake of NE and 5-HT!Analgesia is independent of antidepressant function!High side effect profile (tolerability),
" cardiotoxic (overdose)
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TCAs and SNRIs Pharmacological Properties
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SSRIs (Selective Serotonin Reuptake Inhibitors)
Examples!Citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline
Mechanism of action!Selectively inhibit 5-HT reuptake without affecting NE
Therefore, no pain relief expected!
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Serotonin ! International Union of Pure and Applied Chemistry nomenclature! 5-Hydroxytryptamine (5-HT)!monoamine neurotransmitter, biochemically derived from tryptophan! receptors are a group of G protein-coupled receptors (GPCRs) and
ligand-gated ion channels (LGICs) found in the central and peripheralnervous systems
Serotonin/5-HT Receptors
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Serotonin/5-HT Receptors! 5-HT1a (Blood Ves/CNS)
! Addiction ! Aggression! Anxiety! Appetite! BP! Cardiovascular function! Emesis! Heart Rate! Impulsivity! Memory! Mood ! Nausea! Nociception! Penile Erection! Pupil Dilatation
! 5-HT5a & 5-HT6 (CNS)! Locomotion! Sleep! Anxiety! Cognition! Learning! Memory! Mood
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! 5 -HT1a (cont)! Respiration! Sexual Behavior ! Sleep! Sociability! Thermoregulation
SNRIs (Serotonin/Noradrenaline Reuptake Inhibitors)
Examples!duloxetine, milnacipran, and venlafaxine
Mechanism of action!Block reuptake of 5-HT and NA
" (better tolerated, lower tendency for drug-drug interactions, better overdose safety)
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Modulation of Central Sensitization by 5-HT & NE Descending Pathways
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Site of Action - SNRIs
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Adjuvant Analgesics: AntiepilepticsExamples!Gabapentin, pregabalin*, carbamazepine, phenytoin, divalproex
sodium, clonazepam, levetiracetam, topiramate, lamotrigineMechanism of action!Suppress neuronal hyperexcitability via
" Reducing neuronal influx of sodium (Na+) and calcium (Ca+ +)" Direct/indirect enhancement of GABA inhibitory effects" Reduce activity of glutamate and/or blocking
NMDA receptors" Binds the !2" subunit of voltage gated Ca+ channels, inhibit NT release
Site of Action - Antiepileptics
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Adjuvant Analgesics: TopicalsExamples! Lidocaine Patch 5% , eutectic, mixture of lidocaine and prilocaine! capsaicin cream/patch!Diclofenac (cream/liquid/gel/patch)
Mechanism of action!Block sodium channels and inhibit generation of abnormal impulses by
damaged nerves!Depletion of peripheral small fibers and therefore Substance P release
from sensory nerve endings! Target local inflammatory response
Muscle Relaxants ! Decrease tone of skeletal muscles! Subclasses !Neuromuscular blockers" Act at the neuromuscular junction"Often used in surgery to cause temporary
paralysis!Spasmolytics" Centrally acting
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Muscle Relaxants - Spasmolytics! Enhancing the level of inhibition
! mimicking or enhancing the actions of endogenous inhibitory substances, such as GABA
! Reducing the level of excitation.! Common examples
! cyclobenzaprine (TCA) methocarbamol, carisoprodol, tizanadine (!-2 agonist), baclofen (GABA agonist), orphenadrine (diphenhydramine)
! Common adverse effects! sedation, lethargy & confusion (cyclobenzaprine),
dependence (carisopradol)
Case Study! 54 year-old with three year history of neck, shoulder and upper extremity pain
following a lifting injury! Current Medications
" Fluoxetine" Milnacipran" Gabapentin" Clonazepam" Alprazolam" Methocarbamol" Tapentadol" Acetaminophen and propoxyphene " Zolpidem " Diclofenac topical" Acetaminophen
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Importance for Understanding Pain Mechanisms
! Allow for rational rather than empirical approach to pain control
! Foster the development of diagnostic tools to identify specific pain mechanisms
! Facilitate pharmacotherapies that act on specific pain pathways and mechanisms
! Reduce the number of pharmacotherapies and incidence of drug-related adverse events (rationale polypharmacy)
! Enhances use of non-pharmacologic treatments! Improve overall patient care and outcome
! Tailoring treatment based on the individual patient and pain type
! Do not forget to look for the spear