Chronic Pain as a

Disease State

Perry G. Fine, MDProfessor of Anesthesiology

Pain Research Center

School of Medicine

University of Utah

Salt Lake City, Utah

Disease

An impairment of health or condition of abnormal functioning.

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Adapted from: Loeser J, et al. Bonica's Management of Pain. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins. 2001;241-254.

Nociception

Pain Perception

Suffering

Pain Behavior

The Complex Nature of Pain

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Therapeutic Approaches to Pain as a

Disease State

Pharmacotherapy

Opioids, nonopioids,

adjuvant analgesics

Interventional

Approaches

Injections,

neurostimulation

Psychological

Support

Psychotherapy,

group support

Lifestyle Change

Exercise, weight

loss

Complementary

and Alternative

Medicine

Massage,

supplements

Physical Medicine

and Rehabilitation

Assistive devices,

electrotherapy

Fine PG, et al. J Support Oncol. 2004;2(suppl 4):5-22; Portenoy RK, et al. In: Lowinson JH, et al, eds. Substance Abuse: A Comprehensive Textbook. 4th ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 2005:863-903.

Physiology of Pain Perception

• Transduction

• Transmission

• Modulation

• Perception

• Interpretation

• Behavior

Injury

Descending Pathway

PeripheralNerve

Dorsal Root

Ganglion

C-Fiber

A-β Fiber

A-δ Fiber

AscendingPathways

DH

Brain

Spinal Cord

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DH = dorsal horn.

A. Nociceptive Pain

B. Inflammatory Pain

C. Neuropathic Pain

D. Noninflammatory/Nonneuropathic Pain

Noxious

Peripheral

Stimuli

Peripheral nerve damage

No known tissue or nerve damage

Abnormal central processing

Multiple mechanisms

Brain

Brain

Brain

Brain

Inflammation

Multiple Types of Pain

1. Adapted from: Woolf CJ. Ann Intern Med. 2004;140:441-451. 2. Chong MS, Bajwa ZH. J Pain Symptom Manage. 2003;25:S4-S11.

• Patients may experience multiple pain states simultaneously2

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Neuroplasticity in Pain Processing1,2

1. Woolf CJ, Salter MW. Science. 2000;288:1765-1769. 2. Basbaum AI, Jessell TM.Principles of Neural Science. 4th ed. New York, NY:

McGraw-Hill. 2000;473-490. 3. Cervero F, Laird JM. Pain. 1996;68:13-23.

Stimulus Intensity

100

Injury Normal

Allodynia

Hyperalgesia3

80

60

40

20

0Innocuous Noxious

Pain

Sen

sati

on

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Neuroplasticity in Spinal Cord Processing: Central Sensitization

• Definition: Heightened dorsal horn excitability due to increased peripheral nociceptor activity

• Features of central sensitization1:

− Reduced threshold for dorsal horn neuron activation

− Increased receptive field of dorsal horn neurons

− Increased response of dorsal horn neurons to painful stimuli

• Potential mechanisms implicated in central sensitization:

− NMDA-receptor activation1

− Altered gene expression in dorsal horn neurons1

− Decreased inhibition2

− Microglial activation3

− Thalamic and somatosensory cortex changes4

NMDA = N-methyl-D-aspartic acid.

1. Mannion RJ, Woolf CJ. Clin J Pain. 2000;16:S144-S156. 2. Ossipov MH, et al. Ann N Y Acad Sci. 2000;909:12-24.

3. Wieseler-Frank J, et al. Neurosignals. 2005;14:166-174. 4. Guilbaud G, et al. Exp Brain Res. 1992;92:227-245.

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ACC = anterior cingulate cortex. PFC = prefrontal cortex.

Brain image courtesy of ATI.

Apkarian AV, et al. Eur J Pain. 2005;9:463-484.

PFCSomatosensory Cortex

ThalamusACC

Insular Cortex

Brain Regions Involved in Pain Processing

Amygdala

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Allodynia Activates Some of the Regions in the Pain Circuit

S1, S2 = primary, secondary somatosensory cortices.

Moisset X, Bouhassira D. Neuroimage. 2007;37:S80-S88. Baliki MN, et al. Curr Pain Headache Rep. 2007;11:171-177.

Thalamus

S1

S2

InsulaACC

PFC

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Neuroplasticity: Neural Reorganization

Modulation

Axotomy

CTB = cholera toxin B.

Photo courtesy of Professor S.B. McMahon.

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C fiber

terminals in

laminae I/II

Aβ fiber

terminals in

laminae III-VI

The Role of Microglia

• The Journal of Neuroscience, February 28, 2007, 27(9):2357-2368; doi:10.1523/JNEUROSCI.0138-07.2007This Article Neurobiology of DiseaseExtracellular Signal-Regulated Kinase-Regulated Microglia–Neuron Signaling by Prostaglandin E2 Contributes to Pain after Spinal Cord Injury

• Peng Zhao, Stephen G. Waxman, and Bryan C. Hains

• We recently showed that microglia become activated after experimental SCI and dynamically maintain hyperresponsiveness of spinal cord nociceptive neurons and pain-related behaviors.

Block et al. Nature Reviews Neuroscience 8, 57–69 (January 2007) | doi:10.1038/nrn2038

Brain Changes with Chronic Pain

CBP = chronic back pain.

Baliki MN, et al. J Neurosci. 2008;28:1398-1403.

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Dorsal

Horn

BRAIN

The Current Analgesic Formulary

Descending Modulation

Peripheral

Sensitization

Central Sensitization

PNS

Local anesthetics

Topical analgesics

Anticonvulsants

Tricyclic antidepressants

Opioids

Anticonvulsants

Opioids

NMDA-receptor antagonists

Tricyclic/SNRI antidepressants

Anticonvulsants

Opioids

Tricyclic/SNRI antidepressants

Dual mechanism opioid/mono-

amine uptake inhbitorsSPINAL

CORDCNS

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PNS = peripheral nervous system. SNRI = serotonin-norepinephrine reuptake inhibitor.

Peripheral Nociceptor Hyperexcitability and Sensitization

Mechanisms Symptoms Targets

Hyperexcitability

Ectopic impulse generation;

oscillations in dorsal root

ganglion

Spontaneous pain (shooting) Sodium channels

Sensitization: Inflammation within nerves

Cytokine releaseSpontaneous pain

(ongoing)Cytokines

Sensitization: Reduced activation threshold

Reduced threshold to heat or

coldHeat allodynia or cold allodynia

TRPV1 receptor or TRPM8

receptor

Reduced threshold to

mechanical stimuliStatic mechanical allodynia ASIC receptor

Reduced threshold to histamine

or norepinephrine

Sympathetically maintained

pain

Histamine H1 receptors or α

receptors

ASIC = acid-sensing ion channel. TCA = tricyclic antidepressant. TNF- α = tumor necrosis factor- α. TRPM8 = transient receptor potential cation channel,

subfamily M, member 8. TRPV1 = transient receptor potential vanilloid 1.

Adapted from: Baron R. Nat Clin Pract Neurol. 2006;2:95-106. Mendell JR, Sahenk Z. N Engl J Med. 2003;348:1243-1255. Woolf CJ, Mannion RJ.

Lancet. 1999;353:1959-1964.

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GABA-ergic or opioidergic

interneurons decreased

Spontaneous pain (ongoing),

dynamic mechanical allodynia,

punctate mechanical hyperalgesia

Amplification of C-fiber input,

gating of Aβ-fiber and Aδ-fiber

input

Spontaneous pain (ongoing),

dynamic mechanical

allodynia, punctate

mechanical hyperalgesia

Central Dorsal Horn Hyperexcitability

Mechanisms Symptoms Targets

Central sensitization, increased synaptic transmission

Amplification of C-fiber input,

gating of Aβ-fiber and Aδ-fiber

input

Spontaneous pain (ongoing),

dynamic mechanical allodynia,

punctate mechanical

hyperalgesia

µ receptors, calcium channels

(α2-δ), NMDA-receptors, NK1

receptors, sodium channels,

intracellular cascades

Intraspinal inhibitory interneurons decreased

GABA-ergic or opioidergic

interneurons decreased

Spontaneous pain (ongoing),

dynamic mechanical allodynia,

punctate mechanical

hyperalgesia

GABAB receptors or µ receptors

Changes in supraspinal descending modulation

Inhibitory control (5-HT,

noradrenaline) decreased

Spontaneous pain (ongoing),

dynamic mechanical allodynia,

punctate mechanical

hyperalgesia

5-HT receptors, α2 receptors

α2 = alpha 2 adrenergic receptor. GABAB = gamma-aminobutyric acid receptor – subtype B. NK-1 = neurokinin. 5-HT = 5-hydroxytryptamine

(serotonin) receptor.

Adapted from: Baron R. Nat Clin Pract Neurol. 2006;2:95-106. Mendell JR, Sahenk Z. N Engl J Med. 2003;348:1243-1255. Woolf CJ, Mannion

RJ. Lancet. 1999;353:1959-1964.

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Pain as a Disease

“When we wish to perfect our senses, neuroplasticity is a blessing; when it works in the service of pain, plasticity can be a curse”

―Norman Doidge, MD

Doidge N. The Brain That Changes Itself: Stories of Personal Triumph from the Frontiers of Brain Science. New York, NY. Viking Press. 2007;177-195.

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