neuropathic pain syndrome

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?