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Pain Mechanisms: The Basis for Optimizing Treatment

B. Eliot Cole, MD, MPA

Executive Director,

American Society of Pain Educators

Montclair, NJ 07042

www.paineducators.org

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Burden of Pain in US• Highly prevalent

– >50 million suffer from chronic pain– 25 million experience acute pain from injuries or surgery

• Undertreated– Of the ~70% of persons with cancer and significant pain: <50%

receive adequate treatment, 25% receive sufficient treatment• Disabling

– Back pain is leading cause of disability in those <45 years old• Affects sleep

– 1 in 3 adults lose >20 hours of sleep/month because of pain• Lost workdays

– Work absences total >50 million/year• Costly

– Pain costs an estimated $100 billion/year

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We Need a Mechanistic Approach to Pain

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

Improve overall patient care and outcome

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Essential Terminology of Pain

• Transduction: conversion of noxious thermal, mechanical, or chemical stimulus into electrical activity in the peripheral terminals of nociceptor sensory fibers

• Conduction: passage of action potentials from the peripheral terminal along axons to central terminal of nociceptors in the CNS

• Transmission: synaptic transfer and modulation of input from one neuron to another

• Perception: appreciation of signals arriving in higher structures a pain

• Modulation: descending inhibitory and facilitory input from the brain that modulates nociceptive transmission at the spinal cord

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How is Pain Transduced?

- Inflammatory cytokines and chemokines

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How is Pain Transmitted?

(DH)

DORSAL ROOT GANGLION (DRG)

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How is Pain Modulated?

Ascending Descending

1st order neuron

Frontal cortex (F Cx)

Hypothalamus (Hyp)

Somatosensory cortex (SS Cx)

F Cx

SS

Cx

Thalamus

SpinothalamicReticulothalamic

1

Midbrain

Medulla

SpinalCord

Hyp

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Pain Perception and Rest of Story

Nociceptive Pathways

Pain

Pain Behaviors Suffering

Tissue Factors (Endogenous Stress)

Psychosocial Factors (Exogenous Environmental Stress)

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What is Nociceptive Pain?

• Pain proportionate to degree of actual tissue damage• Sustained primarily via nociceptive system• Involves sensitization of nociceptors:

– Prostaglandins– Bradykinin– Serotonin– Histamine– Acetylcholine

• Silent nociceptors are activated by inflammation and contribute to nociception

• Can be acute or chronic• Examples: acute burns, bone fractures, other somatic and visceral

pain

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What is Somatic Pain?

• Activated by pain receptors in cutaneous or deep tissues• Usually induced by activation of nociceptors

– Cutaneous articular nociceptors– Muscular nociceptors

• Can be acute or chronic• Examples:

– Burns– Tendonitis– Arthritis– Muscle pain– Myofascial pain– Contusions of the skin

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What is Visceral Pain?

• Originates from visceral nociceptors in body organs and cavities

• Can be acute or chronic• Difficult to localize• Greater motor and autonomic involvement versus

cutaneous pain• Examples

– Myocardial ischemia from atherosclerosis– Kidney and ureteral stones– Dysmenorrhea– Irritable bowel disease

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What is Neuropathic Pain?

• Pain initiated or caused by a 1º lesion or dysfunction in the nervous system

• Lancinating, continuous burning• Accompanied by allodynia, hyperalgesia• Large unmet therapeutic need

– Mainstay treatments

• Tricyclic anti-depressants • Anticonvulsants/Antiepileptics

– Pain relief achieved in <50% of persons– Suboptimal adverse event profiles

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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

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Transition from Acute to Chronic Pain

• Sensitization– Peripheral and central

• Responsible for most continuing pain and hyperalgesia post injury

• May be the result of normal noxious stimuli from injured and inflamed tissue

• Abnormal input from injured nerves or ganglia

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How Acute Pain Become Chronic

Peripheral Sensitization• Tissue damage releases sensitizing “soup” of

cytokines & neurotransmitters• COX-mediated PGE2 release

• Sensitized nociceptors exhibit a decreased threshold for activation & increased rate of firing

• Plays an important role in central sensitization, hyperalgesia, & allodynia

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How Acute Pain Become Chronic (cont’d)

Central Sensitization• Activation

– “Wind up” of dorsal horn nociceptors

• Neuronal plasticity– Modulation– Modification: new pain-sensing fibers form

• Decreased central inhibition of pain transmission• Prime role in chronic pain, particularly

neuropathic pain

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Central Sensitization leads toSecondary Hyperalgesia

• Repeated impulse activity in C nociceptive neurons– Produces sensitization of spinothalamic tract neurons

over time• Previously subthreshold inputs reach threshold

– Initiate action potential – Increases in spontaneous activity

• Spinal and supraspinal mechanisms• Enlargement of area in periphery where stimulus will

activate neurons• N-methyl-D-aspartate (NMDA) receptor and substance P

mechanisms

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Central Sensitization “Actors”

• NMDA receptor plays a central role– NMDA receptor antagonists are antinociceptive;

limited by ubiquitous expression of these receptors• Endogenous mediators influence excitability of spinal

neurones– Prostaglandins

– Nitric oxide

– Opioids– Adrenergic agonists

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Therapeutic Inhibition of Central Sensitization

• Endogenous mediators of central sensitization:– Prostaglandins– Nitric Oxide– Opioids

– Adrenergic agonists

Influence excitability of spinal neurones

•Produce analgesia via presynaptic C-fiber neurotransmitter release AND postsynaptic hyperpolarization of 2nd order neurones

•Intrathecal morphine + α2 agonists or NSAIDs=substantial analgesic synergy

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Analgesics That Modify Pain Processes

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The Chronic Pain Armamentarium

• Nonopioids– Acetaminophen– NSAIDs– COX-2 inhibitors

• Opioids– Mu opioid antagonists– Agonist-antagonist opioids

• Adjuvant analgesics– Antidepressants– Antiepileptics – Topical agents/local

anesthetics

WHO

JC Ballantyne Oncologist 2003:8(6):567-75. © AlphaMed Press; WHO. 2005.

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Clinical Indications: Nonopioids

• Variety of acute and chronic pain types– Trauma, post-op, cancer, arthritis

• Somatic pain– Muscle and joint pain, bone/dental pain, inflammatory

pain, post-op pain

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Nonopioids: Acetaminophen

• Example– Tylenol

• Mechanism of Action– Inhibits prostaglandin production in CNS; antipyretic activity– No effect on blocking peripheral prostaglandin production; no

anti-inflammatory or antirheumatic activity• Uses

– Mild to moderate pain (eg, headache, toothache, muscular aches, backache, menstrual cramps, arthritis, cold and flu)

– Fever reduction• Common adverse events

– Liver damage and toxicity, nephrotoxicity, thrombocytopenia

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Nonopioids: NSAIDs

• Examples– Acetylated (aspirin); nonacetylated (diflunisal); acetic

acid (diclofenac); propionic acid (naproxen); fenamic acid (mefenamic acid); enolic acids (piroxicam); nonacidic (nabumetone); 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 leukatrine B4 production

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Clinical Indications: Opioids

• Most pain responds to opioids– Moderate to severe pain unresponsive to nonopioids

alone• Acute pain

– Trauma

• Breakthrough pain

• Cancer pain• Chronic, noncancer pain

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Opioids• Examples

– Morphine, hydromorphone, fentanyl, oxycodone, oxymorphone, meperidine, codeine, methadone, tramadol

• Mechanism of Action– Bind to opioid receptors in the 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

• Uses– Cancer pain; moderate to severe pain unresponsive to nonopioids

• Severe acute pain (eg, trauma, post-op); chronic pain; neuropathic pain, diabetic peripheral neuropathic pain (DPNP)

• Common adverse events– Sedation, confusion, mental clouding, respiratory depression, pruritus,

nausea and vomiting, constipation• Other

– Often combined with nonopoids to lower dose of opioids (opioid-sparing)

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Functional Status of Opioids

Full agonists Partial Agonists Agonists-Antagonists

Full Antagonists

MorphineMethadone

FentanylHydromorphone

MeperidineHydrocodoneOxycodone

OxymorphoneCodeineTramadol

Buprenorphine NalbuphinePentazocineButorphanol

NaloxoneNatrexone

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Perception

Modulation

Transduction

Transmission

OpioidsMechanism of action

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Adjuvant Analgesics: Tricyclic Antidepressants

• Examples– Amitriptyline, desipramine, doxepin, imipramine,

nortriptyline• Mechanism of action

– Reduction in action potential firing of sodium channel activity

– Inhibition of reuptake of norepinephrine and serotonin– Analgesia is independent of antidepressant function

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Adjuvant Analgesics: Selective Serotonin Reuptake Inhibitors

• Examples

– Citalopram, paroxetine, fluoxetine, sertraline

• Mechanism of action

– Selectively inhibit 5-HT reuptake without affecting norepinephrine

• Uses

– Neuropathic pain: diabetic peripheral neuropathic pain (DPNP)

– Postherpetic neuralgia (PHN)

– Cancer pain

• Common adverse events

– Anxiety, insomnia, nausea, headache, drowsiness, sexual dysfunction, withdrawal symptoms upon abrupt cessation

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Adjuvant Analgesics: Serotonin/Norepinephrine Reuptake Inhibitors

• Examples– Duloxetine and venlafaxine

• Mechanism of action– Block reuptake of 5-HT and norepinephrine

• Uses

– Neuropathic pain (eg, diabetic peripheral neuropathic pain)

• Common adverse events– Nausea, somnolence, dizziness, constipation, dry

mouth, hyperhidrosis, decreased appetite, asthenia

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Perception

Modulation

Transduction

Transmission

AntidepressantsMechanism of action

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Adjuvant Analgesics: Antiepileptics

• Examples

– Gabapentin, pregabalin, carbamazepine, phenytoin, divalproex sodium, clonazepam, levetiracetam, topiramate, lamotrigine

• Mechanism of action– Suppress neuronal hyperexcitability via

• Reducing neuronal influx of Na+ and Ca+ +

• Direct/indirect enhancement of GABA inhibitory effects

• Reduce activity of glutamate and/or blocking NMDA receptors

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Adjuvant Analgesics: Antiepileptics

• General Indications– Neuropathic pain (eg, DPNP, PHN, CRPS, HIV-

related neuropathy, phantom limb pain)– Migraine prophylaxis, musculoskeletal pain, cancer

pain, trigeminal neuralgia

• Example of some adverse events– Mental clouding, dizziness, nausea, unsteadiness,

fatigue, GI upset– Hematologic abnormalities, liver dysfunction,

hypersensitivity reactions, rash

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Mechanism of action of First-generation Antiepileptics

Anti-Epileptics

Mechanism of action

Carbamazepine •Na+-channel blocker

Phenytoin •Na+-channel blocker

Valproic Acid •Enhance synthesis and inhibit degradation of GABA

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Mechanism of action of Second-generation Antiepileptics

Anti-epileptics

Mechanism of action

Gabapentin •Binds to α2-δ subunit of voltage-gated Ca2+ channels; reduces excitatory neurotransmitter release

Pregabalin •Binds to α2-δ subunit of voltage-gated Ca2+ channels; reduces excitatory neurotransmitter release

Oxcarbazepine •Na+-channel blocker; metabolite inhibits K channels

Topiramate •Na+-channel blocker; GABA activity at receptors

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Mechanism of action of Second-generation Antiepileptics (cont’d)

Anti-Epileptics

Mechanism of action

Zonisamide •Na+-channel blocker; blocks T-type Ca channels and carbonic anhydrase

Levetiracetam •Ca2+ channel blocker; K-current rectifier, antagonizes negative allosteric GABA modulators

Lamotrigine •Na+-channel blocker; inhibits glutamate and aspartate release

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Alpha2-delta Ligands

Gabapentin• Indications:

– Postherpetic neuralgia, seizures

• Adverse events:– Dizziness– Somnolence– Nausea– Peripheral edema

Pregabalin• Indications:

– Diabetic peripheral neuropathic pain; Postherpetic neuralgia, seizures

• Adverse events:– Dizziness– Somnolence– Dry mouth– Peripheral edema

– Blurred vision– Weight gain– Abnormal thinking

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Adjuvant Analgesics: Topicals

• Examples– Lidocaine, LidoDerm 5% patch®, EMLA®, Capsaicin cream

• Mechanism of action– Block sodium channels and inhibit generation of abnormal

impulses by damaged nerves– Depletion of substance P in sensory nerve endings

• Uses– Acute and chronic pain

• Diabetic peripheral neuropathic pain, postherpetic neuralgia, cancer pain, HIV-related neuropathy, complex regional pain syndromes, arthritis

• Pain associated with medical procedures• Common adverse events

– Local allergic reactions, systemic reactions (rare); localized burning sensation

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Summary

• Today’s clinicians must possess a working knowledge of the etiology and mechanisms of pain syndromes– Understanding pain mechanisms is key to successful

pain control• Reduce the number of medications and incidence

of drug-related adverse events • A number of therapeutic options are available

– Tailoring treatment based on the individual patient and pain type can improve outcomes