Etiology and Pathophysiology Etiology and Pathophysiology of Various Pain Syndromesof Various Pain Syndromes

Etiology and Pathophysiology Etiology and Pathophysiology of Various Pain Syndromesof Various Pain Syndromes

Nociception Nociception Nociception Nociception

The detection of tissue damage by The detection of tissue damage by specialized transducers connected to specialized transducers connected to A-delta and C-fibers A-delta and C-fibers

PainPainPainPain

An unpleasant sensory and emotional An unpleasant sensory and emotional experience which we primarily associate experience which we primarily associate with tissue damage or describe in terms of with tissue damage or describe in terms of such damage, or both such damage, or both

Classification of Pain NociceptionClassification of Pain NociceptionClassification of Pain NociceptionClassification of Pain Nociception

• Proportionate to the stimulation of the Proportionate to the stimulation of the nociceptornociceptor

• When acuteWhen acute– Physiologic painPhysiologic pain

– Serves a protective functionServes a protective function

– Normal painNormal pain

• Pathologic when chronicPathologic when chronic

Classification of Pain: Neuropathic PainClassification of Pain: Neuropathic PainClassification of Pain: Neuropathic PainClassification of Pain: Neuropathic Pain

• Sustained by aberrant processes in Sustained by aberrant processes in PNS or CNSPNS or CNS

• Disproportionate to the stimulation of Disproportionate to the stimulation of nociceptornociceptor

• Serves no protective functionServes no protective function

• Pathologic painPathologic pain

Classification of Pain: Mixed PainClassification of Pain: Mixed PainClassification of Pain: Mixed PainClassification of Pain: Mixed Pain

• Nociceptive componentsNociceptive components

• Neuropathic componentsNeuropathic components

• ExamplesExamples– Failed low-back-surgery syndromeFailed low-back-surgery syndrome

– Complex regional pain syndromeComplex regional pain syndrome

Classification of Pain: Idiopathic PainClassification of Pain: Idiopathic PainClassification of Pain: Idiopathic PainClassification of Pain: Idiopathic Pain

• No underlying lesion found yet, despite No underlying lesion found yet, despite investigationinvestigation

• Pain disproportionate to the degree of Pain disproportionate to the degree of clinically discernible tissue injuryclinically discernible tissue injury

Normal Central Pain Normal Central Pain MechanismsMechanisms

Normal Central Pain Normal Central Pain MechanismsMechanisms

Peripheral and Central Pathways for PainPeripheral and Central Pathways for PainPeripheral and Central Pathways for PainPeripheral and Central Pathways for Pain

Adapted with permission from Fields HL, Price DD. In: Harrington A, ed. The Placebo Effect. An InterdisciplinaryExploration. Cambridge, Mass: Harvard University Press; 1997:106.

Pain-Inhibitory and Pain-Facilitatory Pain-Inhibitory and Pain-Facilitatory Mechanisms Within the Dorsal HornMechanisms Within the Dorsal HornPain-Inhibitory and Pain-Facilitatory Pain-Inhibitory and Pain-Facilitatory Mechanisms Within the Dorsal HornMechanisms Within the Dorsal Horn

A-DELTAA-BETA C

Neuronal circuitryNeuronal circuitrywithin the dorsal horn.within the dorsal horn.Primary afferent neuronPrimary afferent neuronaxons synapse onto axons synapse onto spinothalamic neurons spinothalamic neurons and onto inhibitory and and onto inhibitory and excitatory neurons.excitatory neurons.

TO BRAIN

+ +

+_ _

+

0

STTSTTNEURONNEURON

STTSTTNEURONNEURON

Rating of First and Second Pain IntensityRating of First and Second Pain IntensityRating of First and Second Pain IntensityRating of First and Second Pain Intensity

Adapted with permission from Cooper BY, et al. Adapted with permission from Cooper BY, et al. Pain.Pain. 1986;24:103 1986;24:103 andand from Lee KH, et al. In: Fields HL, from Lee KH, et al. In: Fields HL, Dubner R, Cervero F, eds. Dubner R, Cervero F, eds. Proceedings of the Fourth World Congress on Pain.Proceedings of the Fourth World Congress on Pain. New York, NY: Raven Press; New York, NY: Raven Press; 1985:204.1985:204.

Adapted with permission from Cooper BY, et al. Adapted with permission from Cooper BY, et al. Pain.Pain. 1986;24:103 1986;24:103 andand from Lee KH, et al. In: Fields HL, from Lee KH, et al. In: Fields HL, Dubner R, Cervero F, eds. Dubner R, Cervero F, eds. Proceedings of the Fourth World Congress on Pain.Proceedings of the Fourth World Congress on Pain. New York, NY: Raven Press; New York, NY: Raven Press; 1985:204.1985:204.

Mechanisms ofMechanisms ofPathologic PainPathologic PainMechanisms ofMechanisms ofPathologic PainPathologic Pain

Mechanisms of Pathologic Pain: Mechanisms of Pathologic Pain: General ConsiderationsGeneral Considerations

Mechanisms of Pathologic Pain: Mechanisms of Pathologic Pain: General ConsiderationsGeneral Considerations

• Pain-processing mechanisms function Pain-processing mechanisms function abnormallyabnormally– Examples: neuropathic pain syndromesExamples: neuropathic pain syndromes

• Nociception is sustained by chronic injuryNociception is sustained by chronic injury– Example: arthritisExample: arthritis

Mechanisms of Pathophysiologic Pain: Mechanisms of Pathophysiologic Pain: Peripheral ProcessesPeripheral Processes

Mechanisms of Pathophysiologic Pain: Mechanisms of Pathophysiologic Pain: Peripheral ProcessesPeripheral Processes

•   Injured or diseased nerve(s)Injured or diseased nerve(s)

• Growth of axonal sproutsGrowth of axonal sprouts

• Formation of ectopic fociFormation of ectopic foci

Mechanisms of Pathophysiologic Pain: Mechanisms of Pathophysiologic Pain: Central Sensitization ProcessesCentral Sensitization Processes

Mechanisms of Pathophysiologic Pain: Mechanisms of Pathophysiologic Pain: Central Sensitization ProcessesCentral Sensitization Processes

• Repeated impulse activity in C nociceptive Repeated impulse activity in C nociceptive neurons produces sensitization of STT neurons neurons produces sensitization of STT neurons over timeover time

• Sensitization of STT neurons leads toSensitization of STT neurons leads to– Increased spontaneous impulse activity Increased spontaneous impulse activity

– Enhanced responses to impulses in nociceptive and Enhanced responses to impulses in nociceptive and non-nociceptive primary afferentsnon-nociceptive primary afferents

• Causes hyperalgesia, allodynia, and spontaneous Causes hyperalgesia, allodynia, and spontaneous painpain

Temporal summation of second pain (second pain summation is a result of repeated input from C-fiber).

Temporal summation of responses of a dorsal horn (STT) neuron to repeated C-fiber stimulation and the effects of the NMDA-receptor antagonist ketamine.

Reproduced with permission from Price DD, et al. In: Fields HL, Liebeskind JC, eds. Pharmacological Approaches to the Treatment of Chronic Pain: New Concepts and Critical Issues. Seattle, Wash: IASP Press; 1994:66.

Mechanism of Central Sensitization Associated Mechanism of Central Sensitization Associated With Tonic C Nociceptor InputWith Tonic C Nociceptor Input

Mechanism of Central Sensitization Associated Mechanism of Central Sensitization Associated With Tonic C Nociceptor InputWith Tonic C Nociceptor Input

Enhanced postsynaptic effects by NMDA-receptor sensitization

Tonic activity in C nociceptors

A-DELTAA-BETA

TO BRAIN

+ +

+_ _

+

0

STTSTTNEURONNEURON

STTSTTNEURONNEURON

+

+++ +

C

Intracellular Intracellular Mechanisms Mechanisms of of SensitizationSensitization

Intracellular Intracellular Mechanisms Mechanisms of of SensitizationSensitization

Reproduced with permission from Mao J, et al. Pain. 1995;61:361.

Enhanced postsynaptic effects by NMDA-receptor sensitization

Tonic activity in C nociceptors

A-DELTAA-BETA

TO BRAIN

+ +

+_ _

+

0

STTSTTNEURONNEURON

STTSTTNEURONNEURON

+++ +

Loss of Inhibitory ILoss of Inhibitory Interneuron Functionnterneuron FunctionLoss of Inhibitory ILoss of Inhibitory Interneuron Functionnterneuron Function

C

Brain-to-Spinal-Cord Brain-to-Spinal-Cord Modulation of PainModulation of Pain

Brain-to-Spinal-Cord Brain-to-Spinal-Cord Modulation of PainModulation of Pain

Adapted with permission from Fields HL, Price DD. In: Harrington A, ed. The Placebo Effect. An InterdisciplinaryExploration. Cambridge, Mass: Harvard University Press; 1997:108.

cellcell

Mechanisms of Neuropathic Pain Mechanisms of Neuropathic Pain Mechanisms of Neuropathic Pain Mechanisms of Neuropathic Pain

• Noninflammatory statesNoninflammatory states

• Inflammatory statesInflammatory states

Pathophysiology of Neuropathic PainPathophysiology of Neuropathic PainPathophysiology of Neuropathic PainPathophysiology of Neuropathic Pain

• Ectopic activity in the peripheral pathways, Ectopic activity in the peripheral pathways, including axons and DRGincluding axons and DRG

• CNS mechanismsCNS mechanisms

Radicular and Discogenic Neuropathic Pain Radicular and Discogenic Neuropathic Pain Mechanisms Mechanisms

Radicular and Discogenic Neuropathic Pain Radicular and Discogenic Neuropathic Pain Mechanisms Mechanisms

• Ectopic activity of the nerve root Ectopic activity of the nerve root nervi nervorum nervi nervorum

• Sensitization and ectopic activity of the Sensitization and ectopic activity of the nociceptors innervating spinal periosteal nociceptors innervating spinal periosteal structures, ie, annuli and ligamentsstructures, ie, annuli and ligaments

• Possible role of abnormal nociceptors overgrown Possible role of abnormal nociceptors overgrown within the intradiscal space, postsurgical within the intradiscal space, postsurgical epidural scars, degenerated facet jointsepidural scars, degenerated facet joints

• CNS sensitization and reorganizationCNS sensitization and reorganization

Neuropathic Pain: Central Mechanisms Neuropathic Pain: Central Mechanisms Neuropathic Pain: Central Mechanisms Neuropathic Pain: Central Mechanisms

Peripheral neuropathic events can be Peripheral neuropathic events can be complicated by temporary or long-term complicated by temporary or long-term CNS changes, such as CNS changes, such as central sensitizationcentral sensitization and then and then reorganizationreorganization of the pain of the pain pathways at the dorsal horn levelpathways at the dorsal horn level

Neuropathic Pain and SMPNeuropathic Pain and SMPNeuropathic Pain and SMPNeuropathic Pain and SMP

• Some neuropathic pains are sustained, at least in Some neuropathic pains are sustained, at least in part, by sympathetic efferent activitypart, by sympathetic efferent activity– SMP SMP

• Expression of alpha-adrenergic receptors on Expression of alpha-adrenergic receptors on injured C-fibers may be a relevant mechanism of injured C-fibers may be a relevant mechanism of SMP, but others are possible SMP, but others are possible

• Clinical findings consistent with CRPS signal an Clinical findings consistent with CRPS signal an increased likelihood of SMPincreased likelihood of SMP

Central sensitization

Central sensitization

Peripheral sensitizationPeripheral sensitization

CNS CNS

PNSPNS

CNScentralnervous system

CNScentralnervous system

“Healthy” nociceptors“Healthy” nociceptors

NormaltransmissionNormaltransmission

Central reorganization Central reorganization

AbnormalnociceptorsAbnormalnociceptors

Physiologic statePhysiologic state

Nociceptive Pain Nociceptive Pain Neuropathic Pain Neuropathic Pain

PNSperipheral nervous system

PNSperipheral nervous system

Pathologic Pathologic statestatePathologic Pathologic statestate

Pappagallo M. 2001.

Nociceptive PainNociceptive PainNociceptive PainNociceptive Pain

• Sensitization and activation of “healthy” Sensitization and activation of “healthy” nociceptor endings and recruitment of nociceptor endings and recruitment of “silent” nociceptors“silent” nociceptors

• ““Soup” of inflammatory algogenic agents, Soup” of inflammatory algogenic agents, such as protons, prostaglandins, such as protons, prostaglandins, bradykinin, serotonin, adenosine, bradykinin, serotonin, adenosine, histamine, cytokineshistamine, cytokines

Low Back Pain and Sciatica: Nociceptive/ Low Back Pain and Sciatica: Nociceptive/ Inflammatory Pain MechanismsInflammatory Pain Mechanisms

Low Back Pain and Sciatica: Nociceptive/ Low Back Pain and Sciatica: Nociceptive/ Inflammatory Pain MechanismsInflammatory Pain Mechanisms

• Activation and sensitization of the nerve Activation and sensitization of the nerve root root nervi nervorumnervi nervorum from root from root compression/traction compression/traction

• Sensitization of the nociceptors of the Sensitization of the nociceptors of the annulus fibrosus, periosteal spinal annulus fibrosus, periosteal spinal structures, and ligaments, due to acute structures, and ligaments, due to acute inflammation, eg, status post traumainflammation, eg, status post trauma

• Hyperalgesia (deep spinal and dermatomal) Hyperalgesia (deep spinal and dermatomal) due to central sensitizationdue to central sensitization

Fibromyalgia Syndrome: Fibromyalgia Syndrome: PathophysiologyPathophysiology

Fibromyalgia Syndrome: Fibromyalgia Syndrome: PathophysiologyPathophysiology

• Central-nervous-system abnormalitiesCentral-nervous-system abnormalities

• Muscle pathologyMuscle pathology

• PsychopathologyPsychopathology

• Genetic predispositionGenetic predisposition

Myofascial Pain Syndrome: Myofascial Pain Syndrome: PathophysiologyPathophysiology

Myofascial Pain Syndrome: Myofascial Pain Syndrome: PathophysiologyPathophysiology

• Current pathophysiologic knowledge relies Current pathophysiologic knowledge relies significantly on clinical examinationsignificantly on clinical examination

• Histologic studies of trigger points have not been Histologic studies of trigger points have not been particularly helpfulparticularly helpful

• Local ischemic factors due to prolonged muscle Local ischemic factors due to prolonged muscle contraction may play a role in the development of contraction may play a role in the development of the painthe pain

• Denervation supersensitivity has been suggested Denervation supersensitivity has been suggested by some to be the causeby some to be the cause

Pathophysiology of Pain: ConclusionPathophysiology of Pain: ConclusionPathophysiology of Pain: ConclusionPathophysiology of Pain: Conclusion

• Neuronal plasticityNeuronal plasticity– Nociceptor, spinal cord, brainNociceptor, spinal cord, brain

• Pain-facilitatory and pathophysiologic Pain-facilitatory and pathophysiologic mechanismsmechanisms– Wind-up phenomenonWind-up phenomenon

– Central sensitizationCentral sensitization

• Modulating mechanismsModulating mechanisms– AscendingAscending

– DescendingDescending