Sensitization and pain - Chuyأھn Khoa Than in pain... Troels Staehelin Jensen, MD, Ph.D Dept. of Neurology

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  • Troels Staehelin Jensen, MD, Ph.D

    Dept. of Neurology &

    Danish Pain Research Center

    Aarhus University Hospital, Denmark

    Sensitization and pain: HCM city, December 2012

  • Pain transmission and modulation

    Courtesy I. Tracey 2008

    http://bp3.blogger.com/_5WwYNr2qHXQ/Rrie2NsFEXI/AAAAAAAAAew/nPASGx1o7-Q/s1600-h/Neuron+Pain.gif

  • Sensory brain Thalamus S I and S II

    Non-sensory brain DLPFC Insula Cingulate cortex Amygdala

    Pain: more than a sensory experience Sensory Affective Cognitive

    ACC

    DLPFC

    Thalamus Insula

    Amygdala

    S I

    Casey, Handb Clin Neurol , 2006

  • Pain modulation

    Nociceptive modulation: On cells, off-cells In brainstem

    Basbaum & Fields, 1984 Fields HL, 1991, 2004

     

    RVM

    PAG

    Nociceptive modulation: Noxious input activates descending control

    Jensen & Yaksh 1992

    response

    stimulus

    Increased

    facilitation

    Normal

    response

    stimulus

    Increased

    inhibition

    Normal

    Clinical pain modulation: Facilitation and inhibition

  • PAG

    Spinal

    neuron

    RVM

    LC

    Spinal

    neuron

    ParBr

    Thalamus

    Sensory Emotional

    Noxious input

    Pain

    S I

    DLPFC

    Amygdala Insula

    Cognitive

  • Following injury: Peripheral and central changes contribute to pain

    Peripheral sensitization: Amplification of signalling in nociceptive fibers that elicits pain hypersensitivity

    Central sensitization: Amplification of CNS signalling that elicits pain hypersensitivity (Woolf, Pain 2011)

  • Change in flexor reflex threshold following a 1 min burn injury to the lat. foot

    hr min hr

    Nature 1983; 306; 686-688

    Spont. activity in α-motoneuron of biceps femoris after foot injury

    Threshold for evoking response ipsi (circle) and contralat (triangel) after foot injury

    Response in a single biceps unit before and after injury First demonstration: long term consequences of noxious stimulation result from peripheral and and central changes

  • Radial nerve block

    Ulanr nerve block

    A: regions anesthetic to all modalities B: Overlapping innervation territories C: Spread of brush allodynia into radial nerve territory after capsaicin

    Extension of hyperalgesia and allodynia beyond ulnar nerve territory Positive values are areas outside ulanr nerve territory

    Sang et al. Anesthesiology 1996.

    C-nociceptor acivation evoke central sensitization: Capsaicin allodynia/hyperlgesia cross nerve territories

  • Sensitization

    Components of central sensitization: Facilitation of output persisting after a painful input Non-painful input produce output mimicking a painful stimulus Reduced inhibition, Increased facilitation

     

     

    C-fibres

    Aβ-fibres

    Normal state

    C-fibres

    Aβ-fibres

    Peripheral sensitization

    C-fibres

    Aβ-fibres

    Central sensitization

  • Capsaicin : model for peripheral and central sensitization

  • Neuronal hyperexcitability: Clinical translation

    Peripheral changes • Spontaneous activity periphery and DRG

    • Lowered threshold

    • Increased response to suprathreshold stimuli

    Clinical • Spontaneous and provoked pain

    • Hyperalgesia

    Inflammation

    Nerve injury

  • Tissue inflammation

    Ion channels Na+, K+, Ca++

    TrkA

    NGF

    Bradykinin B2

    Heat/Capsaicin/H+

    H+

    PGE2

    ATP

    ATP

    Cold

    TRPM8 P2Y

    P2X3

    EP

    ASIC

    TRPV1

    Inflammation sensitization: NGF-TrkA activate signaling pathways NGF transport to DRG: increase in: SP, TRPV1, Nav 1.XX Cytokine release ; Il-1, Il-6 ,TNF- Protons act on TRPV1 and on ASIC’s, etc

    Nerve injury

    Nerve Injury sensitization: Upregulation of ion Na+ and K+ channels and TRPV1 in non-injured fibres NGF and Cytokines increase after nerve injury Rythmic firing burst from damaged nerve fibres

    Expressed N. injury

    Nav 1.1 Non-noc cells 

    Nav 1.2 

    Nav 1.3 Expr in injury 

    Nav1.4 Heart 

    Nav1.5 Heart 

    Nav1.6 Non-noc cells 

    Nav1.7 All sens cells 

    Nav1.8 A and C cells 

    Nav1.9 In noc. C cells 

    NaX 

  • Neuronal hyperexcitability: Clinical translation

    Peripheral changes • Spontaneous activity periphery and DRG

    • Lowered threshold

    • Increased response to suprathreshold stimuli

    Clinical • Spontaneous and provoked pain

    • Hyperalgesia

    • Localized pain

    AMPA NK1

    NMDA NMDA

    NMDA

    Ca++

    Inflammation

    Nerve injury

  • Neuronal hyperexcitability: Clinical translation

    AMPA NK1

    NMDA NMDA

    NMDA

    Ca++

    Nerve injury

    Inflammation

    Central changes • Spontaneous and evoked activity

    • Recruitement of silent cells

    • Increase in receptive fields

    • Abnormal temp summation

    • Spread up and down spinal cord

    • Sensitization of brain areas

    • Neuroplastic changes

    Clinical • Spontaneous and provoked pain

    • Spread of pain to other tissues

    • Spread of pain outside injured area

    • Hyperalgesia/allodynia

    • Abnormal temporal summation

    • Aftersensations

    • Cognitive and emotional changes

  • Spinal cord

    Central sensitization following inflammation Neuronal hyperexcitability Lowering of threshold Recruitment of silent nociceptors Abnormal temporal summation (wind-up) Aftersensations Normalization when inflammation subsides

    Spinal cord Spinal cord Spinal cord

    Inflammation

  • Spinal cord Spinal cord

    Central sensitization following nerve injury Nuronal hyperexcitability Lowering of threshold Recruitment of silent nociceptors Abnormal temporal summation (wind-up) Aftersensations Maladaptive changes following continuous input

    Spinal cord

    Nerve injury

  • Chronic pain: different etiologies, common symptoms

    PHN

    Peripheral Neuropathy

    Post stroke pain

    Cancer pain

    Low back pain CRPS

    Spinal cord injury pain

  • Nociceptive Neuropathic Idiopathic

    Osteoarthritis Nerve injury Fibromyalgia

    Rheumatoid arthritis Neuropathies Whiplash syndrome

    Myositis Plexopathy Interstitial cystitis

    Tendinitis Amputation Irritable bowel

    disorder

    Colitis Trigeminal neuralgia Persistent Idiopathic

    facial pains

    Postoperative pain Postoperative pain Gulf War Syndrome

    Migraine ? MS Chronic fatigue

    syndrome

    CRPS ? Stroke

    Chronic Non-malignant types of pain: Examples

  • Characteristics

    • Sensory loss

    • Motor loss

    • Spontaneous + evoked pain

    • Allodynia/hyperalgesia

    • Specific sensory pattern

    • Aftersensations

    • Abnormal summation Nerve root damage

    1. Low back pain and radiculopathy

    • 55 yr. old M • Previously operated for L4 herniated disc • Recurrence of radicular pain after 1 yr. • Reoperated twice • Now constant burning pain in the S1 area • intermittent radicular pain and ”foot drop” gait •Pain has increased within the last month • VAS pain: 5-10

  • Causes of pain: Low back

    Definition • Pain • Muscle tension • Stifness • Below costal margin and above inf. gluteal folds

    Classification: • Specific • Non-specific Duration: • Acute pain: 3 mths Neuropathic pain LBP: • 5-37% ?

    Neurogenic mechanisms of LBP Root compression

    – Herniated disc,

    – Spinal stenosis

    – Arachnoiditis

    Peripheral nerve Lesion

    – Spinal nerve compression

    – Neuropathy

    – Nerve injury

    Lumbar plexus

    – Tumor

    – Psoas absces

    – Neuritis

  • Characteristics

    • Sensory loss in peroneal nerve territory

    • Spontaneous and evoked pain

    • Touch-evoked pain outside injured nerve territory

    • Hyperalgesia outside injured nerve territory

    Neuropathic Pain: case

    • 42 yr. old F • Tibial fracture 1996 • 1996 removal of ostesynthesis • 1998 removal of neuroma peronal nerve • Constant burning pain in malleol area • Evoked pain in lower leg and foot • VAS pain: 5-10

  • Characteristics

    • Sensory loss

    • Spont + evoked pain

    • Allodynia/hyperalgesia

    • Specific sensory pattern

    • Paroxysms

    • Aftersensations

    • Abnormal summation