what have the past 40 years of research into ......6 b.j. sessle zhang et al, 2010, 2011 cortical...
TRANSCRIPT
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B.J. Sessle
Barry J. Sessle
Professor, Faculties of Dentistry and MedicineUniversity of Toronto
Canada
WHAT HAVE THE PAST 40 YEARS OF
RESEARCH INTO CRANIOFACIAL PAIN
MECHANISMS TOLD US ABOUT
CRANIOFACIAL PAIN STATES AND
THEIR MANAGEMENT?
AHS 2017
B.J. Sessle
DISCLOSURES
Pfizer Canada..Research grant, 2009-2011
Lilly Canada..Cymbalta National Advisory Board, 2009–11
Pfizer Canada..Neuropathic Research Grant Review Committee, 2010-12
Canadian Institutes of Health Research
Canadian Foundation for Innovation
US National Institutes of Health
B.J. Sessle
Over the 40 years of his clinical and academic life, Steven Graff-Radford was committed to improving the diagnosis and treatment of craniofacial pain states. His many lectures and publications drew particular attention to the importance of
research into pain mechanisms for the development of successful therapeutic approaches for headaches and other forms of craniofacial pain. This inaugural Steven Graff-Radford lecture highlights many of the research-based advances in our knowledge of craniofacial pain mechanisms over the past 40 years that have helped improve clinical
understanding and management of craniofacial pain states.
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B.J. Sessle
Primary afferent mechanisms, including peripheral sensitization and modulatory processes.
Central nociceptive pathways and mechanisms, including central sensitization and modulatory processes.
The relevance of these mechanisms to the Diagnosis and Management of craniofacial pain states.
OVERVIEW
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The Complexity and Multidimensionality of Pain
B.J. Sessle
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• Various chemical mediators influence the excitability of cranio-facial nociceptive afferents and are involved in the pain-inducing effects of noxious stimulation and also in peripheral sensitization which may contribute to hyperalgesia, allodynia and pain spread.
• A sex difference exists in some nociceptive afferents’ responses (eg, to glutamate) that may contribute to sex differences in pain.
• Several therapeutic approaches exert their analgesic effects by targeting these processes , eg, NSAIDs, LA patches, PHN vaccines.
OVERVIEW OF FINDINGS & CLINICAL SIGNIFICANCE
Meyer et al, 2006
B.J. Sessle
The peripheral sensitization of the peripheral nociceptive afferent endings is associated with their increased excitability and sensitivity to subsequent stimuli:
- Decreased activation threshold- Increased responsiveness
as well as- Involvement of adjacent afferents
which are implicated,respectively, in
- Allodynia- Hyperalgesia- Pain spread
Peripheral Sensitization
Dubner, Iwata et al, 2014
B.J. Sessle From Strassman et al, 1996
Example of peripheral sensitization, in a dural afferent
‘inflammatory soup’
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From TIME 2006
Anatomical Chart Co.,2006
CNS MECHANSIMS
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- Primary afferents, with cell
bodies in trigeminal ganglion
- Trigeminal brainstem sensory
nuclear complex (and C1-2)
- Other brainstem areas,
e.g reticular formation (RF)
- Ventroposterior thalamus
- Other thalamic areas
- Cerebral cortex,
e.g. somatosensory area, anterior cingulate gyrus
Craniofacial Nociceptive Pathways
Subnucleus Caudalis a.k.a. ‘medullary dorsal horn’
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Superficialskin
mucosa
Deepjoint
muscletooth pulp
dura/vessels
Most trigeminocervical nociceptive neurons have extensive convergent afferent inputs
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Burstein et al, 2000
Clinical Significance: Referred Pain/Allodynia
Convergent excitatory facial and dural inputs to nociceptive trigeminocervical neurons
Note analogies in coding of stimulus properties
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RF area(cm2)
Proestrus
DiestrusMale
Okamoto et al, 2003
Sex differences and sensitivity to light and hypothalamic modulation are also features of some trigeminocervical neurons
Katagiri et al, 2013
Light evokes neuronal responses
that can be reduced by application to
posterior hypothalamus of GABAa
antagonist BMI
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Modulation of neurons also evident in animal model
of trigeminal autonomic cephalgias
Akerman & Goadsby, 2015
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B.J. SessleZhang et al, 2010, 2011
Cortical spreading depression induced by cortical stimuli
produces facilitation of trigeminocervical neuronal activity
B.J. Sessle
From Price
From Hargreaves & Goodis, 2002
Trigeminal Subnucleus Caudalis
(aka Medullary Dorsal Horn)
These findings in animal models have been complemented by correlated findings in human experimental pain models
(eg, SEPs, MRI, QST)
Craniofacial nociceptive transmission is modulated by intrinsic CNS processes
B.J. Sessle
DBS-Induced Analgesia
AnalgesicDrugs
Acupuncture-Induced Analgesia
From M. Meldrum/ Purdue Pharma
Placebo Analgesia
Colloca&Benedetti,NatureNeurosci,2005
Stress/Anxiety/Depression
Disturbed Sleep
Sex Differences in Pain
Cognitive
BehaviouralTherapy
Andreashorn -
https://commons.wikimedia.org/w/index.php?curid=40251125
Relevance of these modulatory mechanisms, or
alterations in them, to clinical features of pain and its control
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B.J. Sessle From C. Woolf
Many of these modulatory mechanisms are Inhibitory, but some may be associated with ‘amplification’ of pain
Neuroplasticity, and ‘Central Sensitization’
From Science July 16,2004
B.J. Sessle
Trigeminal nociceptive neurons can undergo neuroplastic changes
(‘central sensitization’) following acute injury or inflammation
Mustard oil to pulp induces NMDA-dependent central sensitization (eg,
increase in receptive field size and responses of nociceptive neurons).
Acute Pulpitis
trigeminal subnucleus caudalis
Central sensitization of nociceptive neurons is also evident at higher CNS levels of the trigeminal system
(eg, thalamus, sensorimotor cortex), consistent with correlated findings in human experimental pain models
B.J. Sessle
From Burstein et al, 1998
Central sensitization can also be induced by dural stimulation
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B.J. Sessle Moayedi et al, 2011, 2012
TMD
Pain
Youseff et al, 2014
Functional and structural changes also occur in CNS of patients with chronic craniofacial pain (HA, TMD, PTN)
May, 2008
B.J. Sessle
- Receptive field expansion
(Pain spread and referral)
- Increased suprathreshold
responsiveness
(Hyperalgesia)
- Decreased activation threshold
(Allodynia)
Central Sensitization is reflected in neuroplastic changes
in central nociceptive neurones, that is, the pain ‘pathways’ are not hard-wired but are ‘plastic’.
These changes have clinical correlates:
central sensitization
Deepjoint
muscletooth pulp
dura/vessels
Superficialskin
mucosa
B.J. Sessle
Central Sensitization is reflected in neuroplastic changes
in central nociceptive neurones, that is, the pain ‘pathways’ are not hard-wired but are ‘plastic’.
These changes have clinical correlates:
Superficialskin
mucosa
Deepjoint
muscletooth pulp
dura/vesselscentral sensitization
- Although normally reversible, maintenance of these neuroplastic changes may set up a prolonged central hyperexcitable state leading to the development of a chronic pain state
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B.J. Sessle
Central Sensitization is reflected in neuroplastic changes
in central nociceptive neurones, that is, the pain ‘pathways’ are not hard-wired but are ‘plastic’.
These changes have clinical correlates:
Superficialskin
mucosa
Deepjoint
muscle
tooth pulpdura/vessels
central sensitization
- Since central sensitization is induced by nociceptive afferent inputs, therapeutic approachesthat reduce nociceptive inputs may decrease the likelihood of itsdevelopment
- Although normally reversible, maintenance of these neuroplastic changes may set up a prolonged central hyperexcitable state leading to the development of a chronic pain state
B.J. Sessle
- Although normally reversible, maintenance of these neuroplastic changes may set up a prolonged central hyperexcitable state leading to the development of a chronic pain state
Central Sensitization is reflected in neuroplastic changes
in central nociceptive neurones, that is, the pain ‘pathways’ are not hard-wired but are ‘plastic’.
These changes have clinical correlates:
Superficialskin
mucosa
Deepjoint
muscletooth pulp
dura/vesselscentral sensitization
- The involvement of several centrally acting chemical mediators, and glia, also provides therapeutic targets for the control of central sensitization and pain
NMDASP
OPIOIDSGABA
5-HT
B.J. Sessle
From Goadsby et al, 2002
Central sensitization as well as peripheral sensitization may contribute
to many craniofacial pain states (e.g. migraine)
and both processes may be modulated by 5-HT-related drugs
Burstein et al, 2003
Early triptan treatment most effective in blocking development of trigeminal central sensitization
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Other drugs effective for pain relief in humans also suppress
trigeminal central sensitization and associated pain behaviour
Cao et al,J. Pain,2013
Pregabalin attenuates
nociceptive behaviour and trigeminal central
sensitization following
trigeminal nerve injury
These new findings
support the clinical use of pregabalin in
craniofacial neuropathic
pain conditions
Trigeminal neuropathic pain model
B.J. SessleTsuboi et al, 2011
Glial cells are important in trigeminal central sensitization occurring in acute or chronic craniofacial inflammatory or nerve injury states
Chronic Pulpitis
GFAP
GS
B.J. Sessle
FA blocks astrocyte Krebs cycle function, and SB203580 blocks p38 MAPK
activity in microglia; both interfere with caudalis central sensitization
Blockade of brainstem glial cell function overcomes trigeminal central sensitization
Acute Pulpitis
Glial cell inhibition also blocks trigeminal central sensitization and nociceptive behaviour in chronic craniofacial pain models
Chiang et al, 2007
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• Findings in human studies (e.g. TMD OPPERA study of
Maixner et al) have documented several genetic risk
factors for clinical, psychological and sensory phenotypes
related to pain onset.
• Recent studies in animal models of craniofacial pain have
shown that genetic factors (as well as environmental
factors) influence expression of trigeminal central
sensitization and associated pain behavior (Varathan, Cherkas &
Sessle, 2013).
Genetic as well as environmental factors also influence trigeminal central sensitization and pain behaviour
B.J. Sessle
• Some of these peripheral processes represent therapeutic targets for several current therapeutic approaches.
• A better understanding of these peripheral processes is crucial for the development of new peripherally based approaches to control pain without CNS side effects.
• Various chemical mediators and receptor mechanisms have been shown to be involved in the peripheral processes of craniofacial pain. These include peripheral sensitization that may contribute to allodynia, hyperalgesia,
and pain spread occurring in many craniofacial pain states.
• Many new insights into craniofacial pain mechanisms have resulted from clinical and experimental studies in animals as
well as humans over the last 40 years, and have led to improved understanding of craniofacial pain and its control.
SUMMARY
B.J. Sessle
• The neurons and CNS pathways that signal acute craniofacial pain have been identified. They have properties that can explain many of the clinical features of craniofacial pain states and their modulation by “psychological” factors
and several therapeutic approaches.
• Neuroplastic changes reflected in central sensitization of these nociceptive neurons can result from peripheral injury or inflammation, and represent an important factor in several chronic craniofacial pain states and their management.
• Trigeminal central sensitization is regulated by genetic factors, and this regulation may contribute to differences between individuals in the development and maintenance of
chronic craniofacial pain states and in their response to specific treatment approaches.
SUMMARY
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B.J. Sessle
• The plastic capacity of both glia and neurons in the craniofacial nociceptive system represents a crucial target for the development of novel therapeutic approaches to manage craniofacial pain states.
• Glia have been discovered to play a crucial role in pain states and may offer a novel therapeutic target for control of trigeminal central sensitization and other neuroplastic
changes occurring in craniofacial pain states.
SUMMARY
B.J. Sessle
In the insightful words of Steven Graff-Radford….
“the key to successful headache and pain therapy is research
aimed at prevention and mimimizing the plastic changes
triggering chronic pain.”
• The plastic capacity of both glia and neurons in the craniofacial nociceptive system represents a crucial target for the development of novel therapeutic approaches to manage craniofacial pain states.
Romero-Reyes & Graff-Radford, 2007
• Glia have been discovered to play a crucial role in pain states and may offer a novel therapeutic target for control of trigeminal central sensitization and other neuroplastic
changes occurring in craniofacial pain states.
SUMMARY
B.J. Sessle
Collaborators
B. Cai P. Cherkas
C.Y. Chiang J.O. Dostrovsky P. Fiorentino B. Hu
J.W. Hu D. Lam
C. Tambeli C.-M. Tsai
X.-M. Yu V. Varathan
L. Arendt-Nielsen, M. Bakke, B. Cairns, K. Iwata, S.J. Park, P. Svensson, H. Vernon, K. Wang, A. Woda, S. Zhang
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B.J. Sessle
THANK YOU!
B.J. Sessle
REFERENCES
• Sessle, BJ. J. Orofacial Pain 13: 238-245, 1999
• Sessle, BJ. Crit.Rev.Oral.Biol.& Med.11: 57-91, 2000.
• Sessle, BJ, Lavigne, GJ, Lund, JP & Dubner R (Eds). ‘OROFACIAL PAIN : FROM BASIC SCIENCE TO CLINICAL MANAGEMENT’, 2nd edition, Quintessence, IL, 2008
• Chiang, CY et al. The Neuroscientist 17: 303-320, 2011.
• Dubner, R, Ren, K & Sessle, BJ. In: ‘TREATMENT OF TMDs’, Eds. C. Greene & D. Laskin. Quintessence, IL, 2013.
• Sessle, BJ. (Ed) ‘OROFACIAL PAIN. Recent Advances in Assessment, Management, and Understanding of Mechanisms’,IASP Press, Washington DC, 2014.
• Chichirro, J, Porreca, F & Sessle, B. Cephalalgia 37: 613-626, 2017.
B.J. Sessle