1.
Orofacial pain - a neuropathic pain syndrome? dr shabeel pn [email_address] www.hi-dentfinishingschool.blogspot.com

2.
Which specialist should treat facial pain? <ul><li>Challenge to medical and dental professions…. </li></ul><ul><li>The patients have multiple diagnoses, requiring management by multiple disciplines </li></ul><ul><ul><li>Neurology </li></ul></ul><ul><ul><li>Otolaryngology </li></ul></ul><ul><ul><li>Dentistry </li></ul></ul><ul><ul><li>Psychiatry </li></ul></ul>

3.
Differential diagnosis <ul><li>Atypical facial pain </li></ul><ul><li>Trigeminal neuralgia (primary or secondary?) </li></ul><ul><li>Horton's syndrome (cluster headache) </li></ul><ul><li>Temporomandibular disorders </li></ul><ul><li>Dental pain </li></ul><ul><li>Sinusitis </li></ul><ul><li>Cancer </li></ul><ul><li>Cervical pain </li></ul><ul><li>Myofascial pain </li></ul>

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Dental pain

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Atypical odontalgia--a form of neuropathic pain that emulates dental pain <ul><li>Overtreatment - numerous invasive procedures and unnecessary treatment. </li></ul><ul><li>Dental extraction, injection or even the placement of a crown represents a tissue trauma and deafferentation. </li></ul><ul><li>A small percentage have a genetic predisposition to deafferentation pain. </li></ul>

6.
Oral and maxillofacial surgery in patients with chronic orofacial pain. <ul><li>Pupulation: 120 patients </li></ul><ul><li>Diagnoses: </li></ul><ul><ul><li>myofascial pain (50%) </li></ul></ul><ul><ul><li>atypical facial neuralgia (40%), </li></ul></ul><ul><ul><li>depression (30%) </li></ul></ul><ul><ul><li>TMJ synovitis (14%) </li></ul></ul><ul><ul><li>TMJ osteoarthritis (12%) </li></ul></ul><ul><ul><li>trigeminal neuralgia (10%) </li></ul></ul><ul><ul><li>TMJ fibrosis (2%) </li></ul></ul><ul><li>History of previous oral and maxillofacial surgical procedures (32%). </li></ul><ul><ul><li>Israel HA 2003 </li></ul></ul>

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Oral and maxillofacial surgery in patients with chronic orofacial pain. <ul><li>Procedures performed </li></ul><ul><ul><li>endodontics (30%) </li></ul></ul><ul><ul><li>extractions (27%), </li></ul></ul><ul><ul><li>apicoectomies (12%) </li></ul></ul><ul><ul><li>temporomandibular joint (TMJ) surgery (6%), </li></ul></ul><ul><ul><li>neurolysis (5%) </li></ul></ul><ul><ul><li>orthognathic surgery (3%) </li></ul></ul><ul><ul><li>debridement of bone cavities (2%) </li></ul></ul><ul><ul><li>Surgery exacerbated pain in 55% of those operated </li></ul></ul><ul><ul><li>Israel HA 2003 </li></ul></ul>

8.
Oral and maxillofacial surgery in patients with chronic orofacial pain <ul><li>Treatment recommendations: </li></ul><ul><ul><li>medications (91%): TCA, anticonculsants, opioids? </li></ul></ul><ul><ul><li>physical therapy (36%) </li></ul></ul><ul><ul><li>psychiatric management (30%) </li></ul></ul><ul><ul><li>trigger injections (15%) </li></ul></ul><ul><ul><li>oral appliances (13%) (local anesthesia, capsaicain) </li></ul></ul><ul><ul><li>biofeedback (13%) </li></ul></ul><ul><ul><li>acupuncture (8%) TENS? </li></ul></ul><ul><ul><li>surgery (4%) </li></ul></ul><ul><ul><li>Botox injections (1%) </li></ul></ul><ul><ul><li>Israel HA 2003 </li></ul></ul>

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Oral and maxillofacial surgery in patients with chronic orofacial pain <ul><li>Misdiagnosis and multiple failed treatments were common, and lead to sequelae, with delay of necessary treatment in 5% </li></ul><ul><li>Surgery, may exacerbate the pain, </li></ul><ul><li>Surgery must be based on a specific diagnosis that is amenable to surgical therapy </li></ul><ul><ul><li>Israel HA 2003 </li></ul></ul>

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What is neuropathic pain (NP)? <ul><li>Neuropathic pain initiated by a lesion or disease affecting parts of the nervous system that normally transmits pain related signals </li></ul>

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

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From simple sensory testing to Quantitative sensory testing (QST ) <ul><li>Touch and Pin prik </li></ul><ul><li>Cold/heat </li></ul><ul><li>Pressure and vibration </li></ul><ul><li>Thermorollers (20 0 C and 45 0 C) </li></ul><ul><li>Von Frey hairs (standardized mechanical stimuli) </li></ul><ul><li>Hypo-/hyper- phenomena? </li></ul><ul><li>Temporal summation (response to repeated stimulation </li></ul>Thermorollers ” Von Frey hair” – Nylon filaments

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Thermo test Heat pain tolerance Heat pain Neutral Cold Cold pain Heat Patients respond to standardized thermal stimuli

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Diagnostic dilemma: <ul><li>A specific symptom can reflect different pathophysiological mechanisms </li></ul><ul><li>To predict the underlying mechanism, we need a wider symptom profile and a battery of sensory stimuli. </li></ul>

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Phenotypic mapping: <ul><li>Standardised QST protocol to determine the mechanisms and design a mechanism-based treatment </li></ul><ul><li>German Research Network on Neuropathic Pain, Baron R 2006 </li></ul>

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

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Neuropathic pain based on complex 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: <ul><li>Peripherally </li></ul><ul><li>Nerve sprouting and neuroma </li></ul><ul><li>DRG: </li></ul><ul><li>Sprouting of sympathetic fibres </li></ul><ul><li>Increased gene expression of ion-channels, transmittors and receptors </li></ul><ul><li>. </li></ul><ul><li>Decreased expression of opioid receptors. </li></ul><ul><li>Dorsal horn </li></ul><ul><li>Loss of inhibitory (GABA) interneurons (apoptosis) </li></ul><ul><li>Impaired central inhibition and increased central fascilitation </li></ul>

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New insight: <ul><li>Decreased function of unmyelinated fibres </li></ul><ul><li>Downregulation of: </li></ul><ul><ul><li>Na v 1.8 channels </li></ul></ul><ul><ul><li>Bradykinin- (B2), substance P- and opioid- receptors </li></ul></ul><ul><li>Increased function of m yelinated fibres </li></ul><ul><li>Upregulation of: </li></ul><ul><ul><li>Ca α 2 δ -1 channel subunits (gabapentin?) </li></ul></ul><ul><ul><li>Na 1.3 channels </li></ul></ul><ul><ul><li>Bradykinin (BK B1) and capsaicin (TRPV1) receptors </li></ul></ul><ul><li>Future therapy: Specific sodium channel blockers? </li></ul>

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<ul><li>Ion channels and receptors are translocated to intact neurons </li></ul><ul><ul><li>Na channels </li></ul></ul><ul><ul><li>TRPV1 (vanilloid) </li></ul></ul><ul><ul><li>adrenoceptors </li></ul></ul><ul><li>Baron R 2006 </li></ul>

23.
Lysophosphatidic acid (LPA) <ul><li>A small phospholipid </li></ul><ul><li>After tissue and nerve injury release from activated platelets, damaged nerve cells (cancer cells) </li></ul><ul><li>LPA activate LPA receptors (DRG) leading to demyelinisation and allodynia </li></ul><ul><li>In knockout mice (no LPA1 reseptor) or after pretreatment with ”antidot” (AS ODN) no demyelinisation or allodynia </li></ul>

25.
Evidence for activated glia cells <ul><li>Astrocytes in spinal cord activated after sciatic nerve damage </li></ul><ul><li>Garrison et al 1991 </li></ul>

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A close interplay Glutamate

27.
Marchand F et al Nature 2005

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Are the activated glica cells neurodestructive? <ul><li>Proinflammatory mediators lead to NP and allodynia: </li></ul><ul><li>Antagonists of TLR4 (stopping cytokine production) reverses NP </li></ul><ul><li>Blocking glia activation a target for therapy? </li></ul><ul><ul><li>Fluorocitrate, minicyclin, propentofylline </li></ul></ul><ul><ul><li>IL 1 beta and TNF α antagonists (Embrel ® )? </li></ul></ul>

29.
Marchand F et al Nature 2005

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Opioids activate glia cells <ul><li>TLR (toll like receptors) recognise opioids and release neuroexitatory pro-inflammatory cytokines </li></ul><ul><ul><li>This counteracts opioid analgesia </li></ul></ul><ul><li>Prevention of glial cell activation: </li></ul><ul><ul><li>enhances opioid analgesia </li></ul></ul><ul><ul><li>prevents opioid tolerance, depencence, withdrawal and respiratory depression! </li></ul></ul><ul><li>Therapeutic target? </li></ul><ul><ul><li>TLR antagonists (LPS- R/S; naloxone)? </li></ul></ul>

31.
Marchand F et al Nature 2005 <ul><ul><li>LPS </li></ul></ul><ul><ul><li>Naloxone </li></ul></ul>

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Glia activation - neurodestructive or neuroprotective?

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

34.
Gene implantation – the future treatment? <ul><li>Implantation of ”cytokine” genes may provide prolonged production </li></ul><ul><li>Genes enter the cell by endocytosis of a viral vector </li></ul>Milligan 2009

35.
At the time being <ul><li>Keep the surgerions away! </li></ul><ul><li>Cognitive interventions </li></ul><ul><li>Symptomatic treatment? </li></ul>