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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

B.J. Sessle

The Complexity and Multidimensionality of Pain

B.J. Sessle

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B.J. Sessle

• 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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B.J. Sessle

From TIME 2006

Anatomical Chart Co.,2006

CNS MECHANSIMS

B.J. Sessle

- 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’

B.J. Sessle

Superficialskin

mucosa

Deepjoint

muscletooth pulp

dura/vessels

Most trigeminocervical nociceptive neurons have extensive convergent afferent inputs

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B.J. Sessle

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

B.J. Sessle

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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B.J. Sessle

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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B.J. Sessle

• 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