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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

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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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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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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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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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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