Orofacial pain a neuropathic pain syndrome

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Orofacial pain - a neuropathic pain syndrome?
Gunnvald Kvarstein gunnvald.kvarstein_at_rikshospital
et.no
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Which specialist should treat facial pain?

• Challenge to medical and dental professions.
• The patients have multiple diagnoses, requiring
  management by multiple disciplines
• Neurology
• Otolaryngology
• Dentistry
• Psychiatry

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Differential diagnosis

• Atypical facial pain
• Trigeminal neuralgia (primary or secondary?)
• Horton's syndrome (cluster headache)
• Temporomandibular disorders
• Dental pain
• Sinusitis
• Cancer
• Cervical pain
• Myofascial pain

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Dental pain
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Atypical odontalgia--a form of neuropathic pain
that emulates dental pain

• Overtreatment - numerous invasive procedures
  and unnecessary treatment.
• Dental extraction, injection or even the
  placement of a crown represents a tissue trauma
  and deafferentation.
• A small percentage have a genetic predisposition
  to deafferentation pain.

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Oral and maxillofacial surgery in patients with
chronic orofacial pain.

• Pupulation 120 patients
• Diagnoses
• myofascial pain (50)
• atypical facial neuralgia (40),
• depression (30)
• TMJ synovitis (14)
• TMJ osteoarthritis (12)
• trigeminal neuralgia (10)
• TMJ fibrosis (2)
• History of previous oral and maxillofacial
  surgical procedures (32).
• Israel HA 2003

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Oral and maxillofacial surgery in patients with
chronic orofacial pain.

• Procedures performed
• endodontics (30)
• extractions (27),
• apicoectomies (12)
• temporomandibular joint (TMJ) surgery (6),
• neurolysis (5)
• orthognathic surgery (3)
• debridement of bone cavities (2)
• Surgery exacerbated pain in 55 of those operated
• Israel HA 2003

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Oral and maxillofacial surgery in patients with
chronic orofacial pain

• Treatment recommendations
• medications (91) TCA, anticonculsants, opioids?
  
• physical therapy (36)
• psychiatric management (30)
• trigger injections (15)
• oral appliances (13) (local anesthesia,
  capsaicain)
• biofeedback (13)
• acupuncture (8) TENS?
• surgery (4)
• Botox injections (1)
• Israel HA 2003

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Oral and maxillofacial surgery in patients with
chronic orofacial pain

• Misdiagnosis and multiple failed treatments were
  common, and lead to sequelae, with delay of
  necessary treatment in 5
• Surgery, may exacerbate the pain,
• Surgery must be based on a specific diagnosis
  that is amenable to surgical therapy
• Israel HA 2003

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What is neuropathic pain (NP)?

• Neuropathic pain initiated by a lesion or disease
  affecting parts of the nervous system that
  normally transmits pain related signals

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Some characteristics of NP

• The symptoms
• Both stimulus independent and stimulus dependent
  pain
• A delayed onset, but remain after healing
• My change over time
• Heterogeneous mechanisms not explained by a
  single etiology or a specific lesion
• Difficult to treat, limited effect of TCA,
  anticonvulsants and opioids.

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From simple sensory testing to Quantitative
sensory testing (QST )

• Touch and Pin prik
• Cold/heat
• Pressure and vibration
• Thermorollers (200C and 450C)
• Von Frey hairs (standardized mechanical stimuli)
• Hypo-/hyper- phenomena?
• Temporal summation (response to repeated
  stimulation

Thermorollers
Von Frey hair Nylon filaments
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Thermo test
Heat pain tolerance
Heat pain
Heat
Neutral
Cold
Cold pain
Patients respond to standardized thermal stimuli
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Diagnostic dilemma

• A specific symptom can reflect different
  pathophysiological mechanisms
• To predict the underlying mechanism, we need a
  wider symptom profile and a battery of sensory
  stimuli.

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Phenotypic mapping

• Standardised QST protocol to determine the
  mechanisms and design a mechanism-based treatment
  
• German Research Network on Neuropathic
  Pain, Baron R 2006

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• A standardized mapping of symptoms and signs
• - to determine the mechanisms (target)
• - to optimize therapy
• Baron R.
• Mechanisms of Disease ..
• Nat Clin Pract Neurol 2006

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Neuropathic pain based oncomplex mechanisms!
Central and peripheral mechanisms
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Animal pain research- nerve injury models
provide new insight to the mechanisms
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Mechanisms after a nerve injury

• Peripherally
• Nerve sprouting and neuroma
• DRG
• Sprouting of sympathetic fibres
• Increased gene expression of ion-channels,
  transmittors and receptors
• .
• Decreased expression of opioid receptors.
• Dorsal horn
• Loss of inhibitory (GABA) interneurons
  (apoptosis)
• Impaired central inhibition and increased central
  fascilitation

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New insight

• Decreased function of unmyelinated fibres
• Downregulation of
• Nav1.8 channels
• Bradykinin- (B2), substance P- and opioid-
  receptors
• Increased function of myelinated fibres
• Upregulation of
• Ca a2d-1 channel subunits (gabapentin?)
• Na 1.3 channels
• Bradykinin (BK B1) and capsaicin (TRPV1)
  receptors
• Future therapy Specific sodium channel blockers?

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• Ion channels and receptors are translocated to
  intact neurons
• Na channels
• TRPV1 (vanilloid)
• adrenoceptors
• Baron R 2006

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Lysophosphatidic acid (LPA)

• A small phospholipid
• After tissue and nerve injury release from
  activated platelets, damaged nerve cells (cancer
  cells)
• LPA activate LPA receptors (DRG) leading to
  demyelinisation and allodynia
• In knockout mice (no LPA1 reseptor) or after
  pretreatment with antidot (AS ODN) no
  demyelinisation or allodynia

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Evidence for activated glia cells

• Astrocytes in spinal cord activated after sciatic
  nerve damage
• Garrison et al 1991

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A close interplay
Glutamate
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Marchand F et al Nature 2005
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Are the activated glica cells neurodestructive?

• Proinflammatory mediators lead to NP and
  allodynia
• Antagonists of TLR4 (stopping cytokine
  production) reverses NP
• Blocking glia activation a target for therapy?
• Fluorocitrate, minicyclin, propentofylline
• IL 1 beta and TNF a antagonists (Embrel)?

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Marchand F et al Nature 2005
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Opioids activate glia cells

• TLR (toll like receptors) recognise opioids and
  release neuroexitatory pro-inflammatory cytokines
• This counteracts opioid analgesia
• Prevention of glial cell activation
• enhances opioid analgesia
• prevents opioid tolerance, depencence, withdrawal
  and respiratory depression!
• Therapeutic target?
• TLR antagonists (LPS- R/S naloxone)?

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LPS
Naloxone
Marchand F et al Nature 2005
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Glia activation - neurodestructive or
neuroprotective?
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Glia cell activation neuroprotective?

• Remove cell debris which prevents proinflammatory
  activation
• Provide antiinflammatory cytokines IL2, IL4, and
  IL 10
• Is blocking glial activation beneficial?
• A neuroprotective activation the new target?
• Cannabinoids (CB2) receptors on glial cells
• Intrathecal administration IL-4 and IL 10
  suppresses chronic pain

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Gene implantation the future treatment?

• Implantation of cytokine genes may provide
  prolonged production
• Genes enter the cell by endocytosis of a viral
  vector

Milligan 2009
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At the time being

• Keep the surgerions away!
• Cognitive interventions
• Symptomatic treatment?