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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
