This document discusses orofacial pain and neuropathic pain. It provides information on differential diagnoses for orofacial pain and summarizes a study on oral and maxillofacial surgery in patients with chronic orofacial pain. The document also discusses the challenges in diagnosing and treating neuropathic pain, highlighting evidence that neuropathic pain results from complex peripheral and central mechanisms in the nervous system.

1. 1
Orofacial pain
- a neuropathic
pain syndrome?

2. 2
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

3. 3
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

4. 4
Dental pain

5. 5
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.

6. 6
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

7. 7
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

8. 8
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

9. 9
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

10. 10
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

11. 11
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.

12. 12
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

13. 13
Thermo test
Heat pain tolerance
Heat pain
Neutral
Cold
Cold pain
Heat
Patients respond
to standardized thermal
stimuli

14. 14
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.

15. 15
Phenotypic mapping:
 Standardised QST protocol to determine
the mechanisms and design a
mechanism-based treatment
German Research Network on
Neuropathic Pain, Baron R 2006

16. 16
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

17. 17
Neuropathic pain
based on
complex mechanisms!
Central and peripheral mechanisms

18. 18
Animal pain research
- nerve injury models provide new
insight to the mechanisms

19. 19
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

20. 20

21. 21
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 α2δ-1 channel subunits (gabapentin?)
 Na 1.3 channels
 Bradykinin (BK B1) and capsaicin (TRPV1) receptors
 Future therapy: Specific sodium channel blockers?

22. 22
Ion channels and
receptors are
translocated to intact
neurons
 Na channels
 TRPV1 (vanilloid)
 adrenoceptors
Baron R 2006

23. 23
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

24. 24

25. 25
Evidence for
activated glia
cells
 Astrocytes in spinal
cord activated after
sciatic nerve damage
Garrison et al 1991

26. 26
A close interplay
Glutamate

27. 27
Marchand F et al Nature 2005

28. 28
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 α antagonists (Embrel®)?

29. 29
Marchand F et al Nature 2005

30. 30
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)?

31. 31
Marchand F et al Nature 2005
LPS
Naloxone

32. 32
Glia activation - neurodestructive or
neuroprotective?

33. 33
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

34. 34
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

35. 35
At the time being
Keep the surgerions away!
Cognitive interventions
Symptomatic treatment?