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

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: <6 wks • Subacute. 6 wks -3mths • Chronic: >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

• Mood and sleep cognitive changes

Neuropathic Pain case

2. Neuropathic pain

History and symptoms

• 31 yr old Female

• 1998: removal of melanoma

• 1999: exploration f. neurinoma

• Const. pricking pain in scar

• Abnormal cold sensation on back

• Light clothes on back is painful

Findings • sensory loss

• Spontaneous pain

• evoked pain

• Pinprick hyperalgesia

• dynamic allodynia

• Cold allodynia

• Static hyperalgesia

• Temp summation

• Aftersensations

0 3 0 6 0 9 0 1 2 0 1 5 0 1 8 0 2 1 0 2 4 0

0

2 0

4 0

6 0

8 0

1 0 0

VAS

2.0 Hz

0.2 Hz

Aftersensation

Sec

Pain after herniotomy

Reduced sensitivity

Increased sensitivity

Ilioinguinal N

Genitofemoral N

Iliohyogastric N

60-yr M, healthy; Fulltime worker as a work manager; Is active in sport

2003: Inguinal herniotomy uncomplicated , but immediately after operation he had pain in the groin

Constant pain: VAS: 2

Pain on movement : VAS:7

Wake up 1-2 times during night because of pain

Can't do sports, Works only part-time. Can't walk with his dog. Has put on 5 kg.

Surgical procedures CABG Cranofacial surgery Amputation Hernia Nerve lysis Mastectomy Thoracotomy Vascular graft SNB and LND Hip arthroplasty Hysterectomy Cholecystectomy?

Postoperative Pain: Epidemiology

Surgical procedure

Incidence of pain (%)

Severe pain (%)

Limb amputation 30–50 5–10

Breast surgery (mastectomy)

30–40 5–10

Inguinal hernia repair

10 2–4

Thoracotomy 30–40 ~10 ?

Coronary bypass 30–50 5–10

Caesarean section 10 ~4

Hip arthroplasty 20 <5

Craniofacial surgery

5

Lymp node dissection

34 <12

Post Stroke Pain: 3 days after stoke: L. pricking pain; Cold allodynia 3 yrs after stroke: Constant pain L. face, arm, trunc Deep burning, pricking pain VAS pain intensity: 8

Acute MR – DWI CTC Day 2

Stroke 48 yr, F. sudden L. hemiparesis Gaze palsy, L hemiparalysis L. sensory loss DWI lesion R. hemisphere Thrombolysis Day 2 large MCI infarction

CPSP

• Pain in area of sensory abnormality • Pain area: Fraction of sensory loss • Sensory loss and hypersensitivity. • Loss of input to thalamus Pain in

corresponding body territory

Reticular N

Anterior

Lateral Medial

stroke

Sensory loss Pain

Spinal cord injury (SCI) Etiology

• Sports and leisure activities

• Assaults

• Transport activities

• Falls

• Other traumatic causes

• Nontraumatic causes

Consequences

• Paresis

• Bladder, bowel and sexual dysfunction

• Autonomic changes

• Spasticity

• Sensory changes and pain

Neuropathic pain following SCI

At-level

Below-level

Other

Bryce et al. Spinal Cord 2011 Epub

Within the dermatome of the

neurological level and three

dermatomes below this level

More than three dermatomes

below the neurological level

but may extend to the “at-

level” region

Neuropathic pain unrelated

or indirectly related to the

SCI

Classification Neuropathic pain at level

Neuropathic pain below level

Musculoskeletal pain

Visceral pain

Spinal cord injury pain

STT neurons

Spinal

lesion

Propriospinal system

Spinal cord

Finnerup unpublished obs

Finnerup et al. 2003

Sensory disturbance

after spinal lesion

Pain Localisation

after spinal lesion

SCI: Sensory function

Brush allodynia Pinprick hyperalgesia

Cold allodynia Cold allodynia

Dorsal column

Postion, vibration

Spinothalamic tract

Touch, pinprick,

temperature

Classification Neuropathic pain at level Neuropathic pain below level

STT

Spinal lesion

Propriospinal system

Spinal cord

Mechanism SCI pain at and below level •Deafferentation •Spinothalamic loss necessary •Spinothalamic loss not sufficient •Hyperexcitability at injury level •Grey matter loss above injury level

Central sensitization after nerve injury: Injury triggers sensitization in spinal cord (homo- and hetero-synaptic) Spinal sensitization involves a series of mechanisms and substances Spinal sensitization spreads to the brain Brain activation: areas controlling sensation, emotions, cognition Changed descending control

Locations: Periperal nerves Spinal cord Brainstem Thalamus Cortical/Subcortical

Conclusion: Sensitization

Thanks to all collaborators at DPRC: Birgitte Brandsborg, Erisela Querama, Lene Vase, Lone Nikolajsen, Anders D Kristensen, Hanne Gottrup, Nanna Finnerup, Cathrine Baastrup, Henriette Klit, Lise Gormsen, Astrid Terkelsen, Annette T. Møller, Helle O. Andersen, Camilla Maersk-Møller, Anne Hansen, Lene Christensen, Casper Skau-Madsen, Kaare Brinck, Paal Karlsson