Introduction to Orofacial Pain










1
O
rofacial pain refers to pain associated with the hard and soft
tissues of the head, face, and neck. These tissues, whether
skin, blood vessels, teeth, glands, or muscles, send impulses
through the trigeminal nerve to be interpreted as pain by the brain
circuits that are primarily responsible for the processing that con-
trols complex behavior.
1
The complaint of orofacial pain encom-
passes a diagnostic range from neurogenic, musculoskeletal, and
Key Points
Orofacial pain remains a prevalent and debilitating condi-
tion with signicant social and economic impacts.
Many of the risk factors associated with a temporoman-
dibular disorder (TMD) involve mechanical, chemical, or
environmental stressors that increase the likelihood of
developing and maintaining a chronic pathologic state.
TMDs are not caused by a single gene mutation but are
a result of changes in the expression of many genes that
contribute to the pathology and nature of the pain.
Sensitization and activation of trigeminal nerves and the
subsequent development of peripheral and central sen-
sitization are key pathophysiologic events that lead to al-
lodynia and hyperalgesia.
A decade of discovery from the Orofacial Pain: Prospec-
tive Evaluation and Risk Assessment (OPPERA) study
helped to clarify specic risk factors and genes implicated
in the development of a TMD.
Given the complex nature of orofacial pain conditions,
treatment should involve multiple modalities including
pharmaceuticals, physical therapy, behavioral modica-
tions, diet, and exercises that emphasize proper breathing
and increasing exibility.
Introduction to
Orofacial Pain

2
Introduction to Orofacial Pain
1
psychophysiologic pathology to headaches,
cancer, infection, autoimmune phenomenon,
and tissue trauma. Evaluation and manage-
ment of orofacial pain requires collaboration
among all elds of medicine because pain has
the potential to arise from multiple trigeminal
receptive elds.
The quest to better manage pain problems
involving the trigeminal system such as TMDs
and headaches has led to the establishment of
orofacial pain as a discipline in the eld of den-
tistry. There are residency training programs in
orofacial pain, board certication processes,
and increasing cooperation among advocacy
groups, universities, professional organiza-
tions, and federal agencies. A huge step in
the recognition of orofacial pain as a discipline
in dentistry occurred in 2009 when the Com-
mission on Dental Accreditation (CODA) ap-
proved orofacial pain as an area of advanced
education. Since 2011, several programs in
the United States have received accreditation
from CODA. Furthermore, the International
Association for the Study of Pain developed a
core curriculum on this subject for all health
care professionals in a clear acknowledgment
of the need for orofacial pain as a component
of professional education.
2
This revised edition is a collaborative effort
derived from reviews of refereed literature
spanning the spectrum of conditions that are
at the root of orofacial pain. It is intended for
health care professionals who evaluate and
treat patients with orofacial pain and face the
daunting task of keeping up with the literature
in the rapidly emerging arena of pain manage-
ment in clinical practice.
The Health Care Professional’s
Responsibility in Orofacial Pain
It is every clinicians responsibility to remain
unbiased during evaluation and differential di-
agnosis. Orofacial pain complaints involve di-
verse, complex physiologic interrelationships,
and all clinicians must be able to judge when
their diagnostic acumen requires consultation;
otherwise, treatment may not target the ap-
propriate source.
The clinicians responsibility is threefold.
First, the clinician must combine a current
working knowledge of the clinical science of
orofacial pain with an ability to obtain a com-
plete relevant history from the patient. Appro-
priate questions must be asked, answers must
be analyzed, and ndings must be synthesized
into an initial differential diagnosis. Second,
the clinician must perform a thorough clinical
assessment, including a physical examina-
tion and indicated laboratory testing, imaging
studies, neurologic testing, and consultations.
Accurate diagnosis may require insight from
other health care professionals. Third, the clini-
cian must be able to explain to the patient all
ndings as well as the details of the treatment
plan, which must be consistent with standards
of care based on scientic literature. When the
scope of care falls beyond individual expertise,
an interdisciplinary team approach may be de-
veloped. The clinician should discuss appropri-
ate referral options with the patient.
Epidemiology of Orofacial Pain
Pain is a common experience that has profound
societal effects. Results from a cross-sectional
Internet-based survey found that the weighted
point prevalence of chronic pain was 30.7% in
adults in the United States.
3
This prevalence
was greater in women and increased with
age.
3
Based on results obtained from the 2012
National Health Interview Survey, the National
Center for Complimentary and Integrative
Health from the National Institutes of Health
(NIH) reports that nearly 50 million American
adults suffer from signicant chronic or severe
pain. Not surprisingly, the study found that in-
dividuals in more severe pain required more
health care services and experienced greater
disability when compared with individuals re-
3
porting lower levels of pain. About half of the
individuals in the worst pain still reported their
overall health as good or better, while both sex
(women) and ethnicity (non-Hispanics) were
associated with a higher frequency of report-
ing painful conditions. Findings from this report
highlight the need for a better appreciation of
the subjective nature of pain and the challenge
of personalizing the treatment to achieve a
successful outcome for each pain patient.
Chronic pain costs the United States bil-
lions of dollars annually due to loss of work,
decreased productivity, disability compensa-
tion, and expenses for health care services
including more emergency room visits, higher
medication costs, and greater psychologic
treatment expense.
4
Chronic pain is economi-
cally costly because it requires medical inter-
vention and makes it more difcult to treat
other ailments. The cost of pain is actually es-
timated to be greater than the annual costs of
heart disease, cancer, and diabetes.
5
Lipton et al
6
surveyed 45,711 American
households and reported that nearly 22% of
the general population had experienced at least
one of ve types of orofacial pain in the past
6 months. The most common type of orofacial
pain was toothache, reported by 12.2% of the
population. Temporomandibular joint (TMJ)
pain was reported by 5.3%, with face or cheek
pain being reported by 1.4%. Orofacial pain sel-
dom appears to be an isolated complaint. More
than 81% of patients reporting to an orofacial
pain center had pain sources apart from the
trigeminal system, but few patients mention
these other pain sources.
7, 8
Conditions that
seem to coexist with TMDs include bromyal-
gia (FM), chronic fatigue syndrome, headache,
panic disorder, gastroesophageal reux disor-
der, irritable bowel syndrome (IBS), multiple
chemical sensitivity, and posttraumatic stress
disorder.
9,10
Symptoms of such comorbid con-
ditions differentiate orofacial pain patients
from those who seek routine dental care.
11
If
the true pain sources are not revealed during
the evaluation, the prognosis may be adversely
affected by the continued barrage of brain cir-
cuits as the result of chronic nociception.
Results have been published from the
OPPERA study funded by the National Institute
of Dental and Craniofacial Research (NIDCR)
to identify risk factors involved in the initia-
tion and maintenance of TMDs and to develop
treatments for managing TMD-associated
pain. The major objectives of this longitudinal,
multidisciplinary study were to determine psy-
chologic and physiologic risk factors, clinical
characteristics, and associated genetic and
cellular mechanisms that inuence the de-
velopment of TMDs. Based on ndings from
these studies, the investigators presented a
model that includes genetic, physiologic, and
environmental factors that increase the risk
for an individual to experience TMD pathol-
ogy (Fig 1-1). More recently, NIDCR funded an
additional study, OPPERA II, with the goal of
further investigating risk factors for the devel-
opment of TMDs and understanding their re-
lationship with often-reported comorbid pain
conditions including IBS, headache, and lower
back pain. A summary of the major ndings
from a decade of research from the OPPERA
studies has recently been published.
12,13
Those
individuals seeking more information from the
OPPERA studies are encouraged to visit the
Journal of Pain website.
Importantly, both the US Congress and
NIH now recognize coexisting pain condi-
tions characterized by a set of disorders that
include, but should not be limited to, TMDs,
FM, vulvodynia, IBS, interstitial cystitis/pain-
ful bladder syndrome, endometriosis, chronic
tension-type headache, migraine headache,
myalgic encephalomyelitis/chronic fatigue syn-
drome, and chronic lower back pain.
14
Taken
together, these conditions are gradually being
referred to as chronic overlapping pain condi-
tions. The discussion of these overlapping pain
conditions produced by the Chronic Pain Re-
search Alliance can be found at their website.
Epidemiology of Orofacial Pain

4
Introduction to Orofacial Pain
1
Pain constructs
Pain is dened as “an unpleasant sensory and
emotional experience associated with actual or
potential tissue damage, or described in terms
of such damage.
15
Nociceptors are polymo-
dal, high-threshold nerve endings that send
impulses in response to damaged tissue on
fast-conducting Aδ bers and slow-conducting
C-bers to the central nervous system (CNS).
Although pain is an interpretation of nocicep-
tion, many orofacial pain patients lack apparent
tissue damage, and anatomical changes such
as TMJ disc displacement without reduction
do not predict continuing pain.
16,17
About 25% of free nerve endings in skeletal
muscle that transmit impulses to the CNS on
Aδ bers and C-bers are chemo- and mecha-
noreceptive but not nociceptive.
18
Some of
these low-threshold receptors, called metabo-
receptors, appear to be uniquely stimulated
by the metabolic products generated during
muscle activity, while others sense the relative
distension of post–capillary bed venules.
19–21
These receptors display background activity at
rest, accelerate impulse transmission as be-
havior intensity increases, and may affect the
same central modulatory systems as nocicep-
tion.
21–24
The CNS uses this input to coordinate
respiratory and cardiovascular changes during
dynamic muscle behavior.
19,21–23
Future consid-
eration of the role of these receptors in pain
etiology may help us better understand pain
conditions in which there is no apparent tissue
damage.
Anatomical and Physiologic
Considerations of Orofacial Pain
Orofacial pain may be dened as pain and dys-
function affecting motor and sensory transmis-
sion in the trigeminal nerve system.
25
From a
sensory perspective, the trigeminal system
Fig 1-1 Overview of major factors that contribute to development of TMD pathology and the associated genes.
(Reprinted with permission from Slade et al.
12
)
Neuro-
endocrine
function
Persistent TMD
Transient TMD
Subclinical signs and symptoms
Somatization
Stress
response
Depression
Anxiety
Mood
High psychologic
distress
Painful
TMD
High state of pain
amplication
Autonomic
function
Impaired
pain
regulation
Pro-
inammatory
state
Xp11.23 12q11.2 9q34.3 11q23 5q31-q32 5q31-32 6q24-q25 1p13.1 22q11.21
Cannabinoid
receptors
Serotonin
receptor
GAD65
MAO NMDA
CREB1 GR
CACNA1A
DREAM POMC
NET
BONF NGF Prodynorphin Interleukins
COMTIKK
Na+, K+
ATPase
Adrenergic
receptors
Opioid
receptors
Dopamine
receptors
Serotonin
transporter
Environmental
Contributions
Physical environment
e
g, trauma, infection
Social environment
eg, life stressors
Culture
e
g, health beliefs
Demographics
5
oversees the efcacy and tissue integrity of
the highly integrative orofacial behaviors that
are controlled by cranial nerves and modulated
by the autonomic nervous system (ANS) and
the greater limbic system.
26
Orofacial nerves
transmit information about pressure (touch),
position, temperature, and potential pain to
the trigeminal nuclei, which have extensive
bidirectional connections throughout the
brain.
27–29
These trigeminal connections affect
the sensory, motor, and autonomic-endocrine
changes that occur during orofacial behaviors,
and orofacial pain may result when these be-
haviors are impaired. The next sections briey
discuss peripheral and central trigeminal neu-
roanatomy to explain how the trigeminal sys-
tem affects physiology and pain.
Neuroanatomy of the orofacial structures
Cranial nerves are extensions of the brain that
directly or indirectly innervate tissues involved
with the trigeminal system.
4
The specialized
neurons of the olfactory, optic, and vestibulo-
cochlear nerves that send smell, sight, sound,
and balance information to the CNS do not
travel through the trigeminal nuclei. However,
nerves associated with the nose, eye, and ear
tissues do transmit proprioceptive, pressure,
and potential pain impulses into the trigeminal
nuclei. A comprehensive orofacial pain evalua-
tion should include a basic assessment of the
function of all cranial nerves (see chapter 2).
Five of these nerves (V, VII, IX, X, and XII) are
reviewed here.
Trigeminal nerve
The trigeminal nerve, which provides sensory
innervation to most of the head and face, is
the primary nerve involved in TMDs, migraine,
sinus, pulpal, and periodontal pathology. It is
the largest cranial nerve and consists of three
peripheral divisions: the ophthalmic, maxillary,
and mandibular.
30–33
These branches receive
sensory input that is conveyed on rst-order
neurons through the trigeminal ganglion,
where most neuronal cell bodies are located.
Although these neurons enter the ganglion on
three branches, they exit in one large sensory
root that enters the brainstem at the level
of the pons before reaching the trigeminal
nuclei.
34
Ophthalmic branch (V1). This branch of
the trigeminal nerve leaves the skull through
the superior orbital ssure and transmits sen-
sory information from the scalp and forehead,
upper eyelid, conjunctiva and cornea of the
eye, nose (including the tip of the nose), nasal
mucosa, frontal sinuses and parts of the me-
ninges (the dura and blood vessels), and deep
structures in these regions. It also carries post-
ganglionic parasympathetic motor bers to the
glands and sympathetic bers to the pupillary
dilator muscles.
34
Maxillary branch (V2). This branch exits
the skull at the foramen rotundum. It has a sen-
sory function for the lower eyelid and cheek;
the nares and upper lip; the maxillary teeth and
gingiva; the nasal mucosa; the palate and roof
of the pharynx; the maxillary, ethmoid, and
sphenoid sinuses; and parts of the meninges.
Near its origin, it divides to form the middle
meningeal nerve, which supplies the middle
meningeal artery and part of dura mater. The
terminal V2 branches—the anterior and greater
palatine nerves and the superior, middle, and
anterior alveolar nerves—innervate the soft
palate, uvula, hard palate, maxillary gingiva and
teeth, and mucous membranes of the cheek.
34
Mandibular branch (V3). This branch
leaves the skull through the foramen ovale and
functions in both sensory and motor transmis-
sion. V3 carries sensory information from the
lower lip, mandibular teeth and gingiva, oor of
the mouth, anterior two-thirds of the tongue,
the chin and jaw (except the angle of the jaw,
which is supplied by C2 and C3), parts of the
external ear, parts of the meninges, and deep
structures. The auriculotemporal nerve is a
branch of V3 that innervates most of the TMJ.
The motor nuclei use V3 to provide motor -
bers to the muscles of mastication (ie, mas-
Anatomical and Physiologic Considerations of Orofacial Pain

Introduction to Orofacial Pain
1
6
seter, temporalis, medial pterygoid, lateral
pterygoid, anterior digastric, and mylohyoid)
as well as the tensor veli palatini involved with
Eustachian tube function and the tensor tym-
pani, which attaches to the malleus bone in the
eardrum.
34
Trigeminal sensory nuclei. The trigeminal
sensory nuclei lay in bilateral columns on ei-
ther side of the brainstem. They originate in
the midbrain and terminate in the dorsal horn
of the cervical spinal cord (Fig 1-2). All touch,
position, and temperature sensory input from
the face is sent to the trigeminal nuclei, as is
potential pain input from the face, head, and
neck.
4
They are, in a rostrocaudal orientation,
the mesencephalic nucleus, the main sensory
nucleus, and the spinal trigeminal nucleus.
The mesencephalic nucleus, which is
more a ganglion than a nucleus, houses the
cell bodies of the proprioceptive neurons that
convey input from the apical periodontal liga-
ment and the muscle bers that contract dur-
ing the jaw-closing reex. These proprioceptive
neurons and possibly the blink reex nerves
represent the only peripheral nerves with cell
bodies located within the CNS.
4,35
The neu-
rons are monosynaptic and pass through the
mesencephalic nucleus to synapse in the tri-
geminal motor nuclei located medially to the
much larger main sensory nucleus. The main
sensory nucleus receives the facial proprio-
ceptive and pressure input for orofacial be-
haviors (eg, chewing, kissing, smiling, and
light touch) other than the jaw-closing reex.
Fig 1-2 Sensory pathways and motor response to referred pain. The rst-order neurons from a pain site in
facial lamina 5 and from the pain source in the C4 receptive eld each converge on lamina 5 of the subnucleus
caudalis and excite the same second-order neurons. As these second-order neurons ascend, they arborize
with the subnucleus oralis and subnucleus interpolaris (not shown) and many reticular formation structures
before synapsing with third-order neurons in the thalamus. The third-order neurons are thalamo-cortico-basal
ganglia-limbic circuits that interpret pain and generate the descending motor and pain modulatory reactions
to pain interpretation. The descending motor neurons also arborize with reticular formation locations and
connect, via interneurons, to the trigeminal motor nucleus and to all cranial nerve motor nuclei. Note that
trigeminal input is never analyzed in isolation because primary sensory and spinal thalamic tract input is also
constantly presented to the brain for analysis. RF, reticular formation structure; SNO, subnucleus oralis; STT,
spinal thalamic tract.
5
C2
Limbic
hypothalamus
RF
Thalamus
Basal
ganglia
Pain
source
Pain
site
Pain
Motor
cortices
Sensory
cortices
Primary
senses
Other
cranial nerve
motor nuclei
Interneurons
STT
SNO
1
st
2
nd
3
rd
C3
C4
C4
C2-C3
4
3
2
1
7
These neurons have their cell bodies in the
trigeminal ganglion and synapse in the main
sensory nucleus, where input is conveyed to
the motor nuclei by arrays of small interneu-
rons.
4
The spinal trigeminal nucleus consists
of three subnuclei: subnucleus oralis, sub-
nucleus interpolaris, and subnucleus caudalis.
Subnucleus oralis and subnucleus interpolaris
receive some peripheral nociceptive bers, but
they mostly receive temperature information
on Aδ bers and touch impulses on Aβ bers
from the periphery and convey this input via
interneurons to the motor nuclei.
4
In response
to nociceptor activation, neuropeptides and
other inammatory agents are released in the
spinal trigeminal nucleus and can cause excita-
tion of neurons and glial cells. This promotes
development of central sensitization, allodynia,
and hyperalgesia, which are physiologic events
associated with acute and chronic pain.
36,37
The subnucleus caudalis is the main ter-
minus for most slow rst-order neurons that
convey potential pain from trigeminal receptive
elds. Figure 1-2 illustrates the onion peel”
somatotropic organization of the face (areas 1
to 5) and the corresponding laminae (1 to 5)
in the subnucleus caudalis, where rst-order
nociceptive neurons terminate regardless of
their division of origin.
4
For instance, A- and
C-ber neurons from area 5 in the face all syn-
apse with second-order nociceptive neurons in
the most caudal aspect of the subnucleus cau-
dalis, lamina 5, whether they start in V1, V2,
or V3. Such convergence means that a dural
blood vessel, masseter muscle, or a tooth or
tongue nociceptive afferent could excite the
same second-order neurons.
This convergence, the anatomical basis for
referred pain, is not just a facial phenomenon.
Cervical spine nociceptive afferents also syn-
apse in the subnucleus caudalis, meaning that
trapezius or sternocleidomastoid nociceptive
afferents can excite second-order neurons
that also receive input from facial tissues.
28,29,38
Recent ndings from the OPPERA study have
provided evidence that pain in the neck and
shoulder muscles is highly correlated with
both acute and chronic TMDs. Thus, this type
of neuronal organization may help to explain
the high prevalence of comorbid pain condi-
tions associated with tissues in the head and
face (eg, headache and sinusitis, headache
and TMDs). Another construct to consider is
that all of the CNS structures affected by tri-
geminal nociceptive input are also contacted
by second-order neurons from the dorsal horn
of the spinal cord.
15
Therefore, potential pain
input from regions outside trigeminal receptive
elds may excite CNS structures that commu-
nicate with trigeminal nuclei and modulate
their functions.
Facial nerve
The seventh cranial nerve is a mixed nerve
that has ve branches (temporal, zygomatic,
buccal, mandibular, and cervical) that course
through the parotid gland but do not innervate
the gland. Its main function is motor control of
most of the muscles of facial expression and
the stapedius muscle of the middle ear. The
facial nerve supplies parasympathetic bers to
the sublingual and submandibular glands via
the chorda tympani and to the lacrimal gland
via the pterygopalatine ganglion. In addition,
it conveys taste sensations from the anterior
two-thirds of the tongue to the solitary tract
nucleus and transmits cutaneous sensation
from the skin in and around the earlobe via the
intermediate nerve.
34
Glossopharyngeal nerve
The ninth cranial nerve is a mixed nerve com-
prising somatic, visceral, and motor bers. It
conveys sensory information from the pos-
terior third of the tongue, tonsils, pharynx,
middle ear, and carotid body. Taste sensation
from the posterior third of the tongue as well
as carotid body baroreceptor and chemorecep-
tor information are transmitted to the solitary
tract nucleus. Nociceptive input from the ear is
sent to the spinal trigeminal nucleus. From the
inferior salivatory nucleus, the glossopharyn-
Anatomical and Physiologic Considerations of Orofacial Pain

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1Orofacial pain refers to pain associated with the hard and soft tissues of the head, face, and neck. These tissues, whether skin, blood vessels, teeth, glands, or muscles, send impulses through the trigeminal nerve to be interpreted as pain by the brain circuits that are primarily responsible for the processing that con-trols complex behavior.1 The complaint of orofacial pain encom-passes a diagnostic range from neurogenic, musculoskeletal, and Key Points◊ Orofacial pain remains a prevalent and debilitating condi-tion with signicant social and economic impacts.◊ Many of the risk factors associated with a temporoman-dibular disorder (TMD) involve mechanical, chemical, or environmental stressors that increase the likelihood of developing and maintaining a chronic pathologic state.◊ TMDs are not caused by a single gene mutation but are a result of changes in the expression of many genes that contribute to the pathology and nature of the pain.◊ Sensitization and activation of trigeminal nerves and the subsequent development of peripheral and central sen-sitization are key pathophysiologic events that lead to al-lodynia and hyperalgesia.◊ A decade of discovery from the Orofacial Pain: Prospec-tive Evaluation and Risk Assessment (OPPERA) study helped to clarify specic risk factors and genes implicated in the development of a TMD. ◊ Given the complex nature of orofacial pain conditions, treatment should involve multiple modalities including pharmaceuticals, physical therapy, behavioral modica-tions, diet, and exercises that emphasize proper breathing and increasing exibility.Introduction to Orofacial Pain 2Introduction to Orofacial Pain1psychophysiologic pathology to headaches, cancer, infection, autoimmune phenomenon, and tissue trauma. Evaluation and manage-ment of orofacial pain requires collaboration among all elds of medicine because pain has the potential to arise from multiple trigeminal receptive elds.The quest to better manage pain problems involving the trigeminal system such as TMDs and headaches has led to the establishment of orofacial pain as a discipline in the eld of den-tistry. There are residency training programs in orofacial pain, board certication processes, and increasing cooperation among advocacy groups, universities, professional organiza-tions, and federal agencies. A huge step in the recognition of orofacial pain as a discipline in dentistry occurred in 2009 when the Com-mission on Dental Accreditation (CODA) ap-proved orofacial pain as an area of advanced education. Since 2011, several programs in the United States have received accreditation from CODA. Furthermore, the International Association for the Study of Pain developed a core curriculum on this subject for all health care professionals in a clear acknowledgment of the need for orofacial pain as a component of professional education.2 This revised edition is a collaborative effort derived from reviews of refereed literature spanning the spectrum of conditions that are at the root of orofacial pain. It is intended for health care professionals who evaluate and treat patients with orofacial pain and face the daunting task of keeping up with the literature in the rapidly emerging arena of pain manage-ment in clinical practice. The Health Care Professional’s Responsibility in Orofacial PainIt is every clinician’s responsibility to remain unbiased during evaluation and differential di-agnosis. Orofacial pain complaints involve di-verse, complex physiologic interrelationships, and all clinicians must be able to judge when their diagnostic acumen requires consultation; otherwise, treatment may not target the ap-propriate source. The clinician’s responsibility is threefold. First, the clinician must combine a current working knowledge of the clinical science of orofacial pain with an ability to obtain a com-plete relevant history from the patient. Appro-priate questions must be asked, answers must be analyzed, and ndings must be synthesized into an initial differential diagnosis. Second, the clinician must perform a thorough clinical assessment, including a physical examina-tion and indicated laboratory testing, imaging studies, neurologic testing, and consultations. Accurate diagnosis may require insight from other health care professionals. Third, the clini-cian must be able to explain to the patient all ndings as well as the details of the treatment plan, which must be consistent with standards of care based on scientic literature. When the scope of care falls beyond individual expertise, an interdisciplinary team approach may be de-veloped. The clinician should discuss appropri-ate referral options with the patient.Epidemiology of Orofacial PainPain is a common experience that has profound societal effects. Results from a cross-sectional Internet-based survey found that the weighted point prevalence of chronic pain was 30.7% in adults in the United States.3 This prevalence was greater in women and increased with age.3 Based on results obtained from the 2012 National Health Interview Survey, the National Center for Complimentary and Integrative Health from the National Institutes of Health (NIH) reports that nearly 50 million American adults suffer from signicant chronic or severe pain. Not surprisingly, the study found that in-dividuals in more severe pain required more health care services and experienced greater disability when compared with individuals re- 3porting lower levels of pain. About half of the individuals in the worst pain still reported their overall health as good or better, while both sex (women) and ethnicity (non-Hispanics) were associated with a higher frequency of report-ing painful conditions. Findings from this report highlight the need for a better appreciation of the subjective nature of pain and the challenge of personalizing the treatment to achieve a successful outcome for each pain patient. Chronic pain costs the United States bil-lions of dollars annually due to loss of work, decreased productivity, disability compensa-tion, and expenses for health care services including more emergency room visits, higher medication costs, and greater psychologic treatment expense.4 Chronic pain is economi-cally costly because it requires medical inter-vention and makes it more difcult to treat other ailments. The cost of pain is actually es-timated to be greater than the annual costs of heart disease, cancer, and diabetes.5 Lipton et al6 surveyed 45,711 American households and reported that nearly 22% of the general population had experienced at least one of ve types of orofacial pain in the past 6 months. The most common type of orofacial pain was toothache, reported by 12.2% of the population. Temporomandibular joint (TMJ) pain was reported by 5.3%, with face or cheek pain being reported by 1.4%. Orofacial pain sel-dom appears to be an isolated complaint. More than 81% of patients reporting to an orofacial pain center had pain sources apart from the trigeminal system, but few patients mention these other pain sources.7, 8 Conditions that seem to coexist with TMDs include bromyal-gia (FM), chronic fatigue syndrome, headache, panic disorder, gastroesophageal reux disor-der, irritable bowel syndrome (IBS), multiple chemical sensitivity, and posttraumatic stress disorder.9,10 Symptoms of such comorbid con-ditions differentiate orofacial pain patients from those who seek routine dental care.11 If the true pain sources are not revealed during the evaluation, the prognosis may be adversely affected by the continued barrage of brain cir-cuits as the result of chronic nociception.Results have been published from the OPPERA study funded by the National Institute of Dental and Craniofacial Research (NIDCR) to identify risk factors involved in the initia-tion and maintenance of TMDs and to develop treatments for managing TMD-associated pain. The major objectives of this longitudinal, multidisciplinary study were to determine psy-chologic and physiologic risk factors, clinical characteristics, and associated genetic and cellular mechanisms that inuence the de-velopment of TMDs. Based on ndings from these studies, the investigators presented a model that includes genetic, physiologic, and environmental factors that increase the risk for an individual to experience TMD pathol-ogy (Fig 1-1). More recently, NIDCR funded an additional study, OPPERA II, with the goal of further investigating risk factors for the devel-opment of TMDs and understanding their re-lationship with often-reported comorbid pain conditions including IBS, headache, and lower back pain. A summary of the major ndings from a decade of research from the OPPERA studies has recently been published.12,13 Those individuals seeking more information from the OPPERA studies are encouraged to visit the Journal of Pain website.Importantly, both the US Congress and NIH now recognize coexisting pain condi-tions characterized by a set of disorders that include, but should not be limited to, TMDs, FM, vulvodynia, IBS, interstitial cystitis/pain-ful bladder syndrome, endometriosis, chronic tension-type headache, migraine headache, myalgic encephalomyelitis/chronic fatigue syn-drome, and chronic lower back pain.14 Taken together, these conditions are gradually being referred to as chronic overlapping pain condi-tions. The discussion of these overlapping pain conditions produced by the Chronic Pain Re-search Alliance can be found at their website.Epidemiology of Orofacial Pain 4Introduction to Orofacial Pain1Pain constructs Pain is dened as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”15 Nociceptors are polymo-dal, high-threshold nerve endings that send impulses in response to damaged tissue on fast-conducting Aδ bers and slow-conducting C-bers to the central nervous system (CNS). Although pain is an interpretation of nocicep-tion, many orofacial pain patients lack apparent tissue damage, and anatomical changes such as TMJ disc displacement without reduction do not predict continuing pain.16,17 About 25% of free nerve endings in skeletal muscle that transmit impulses to the CNS on Aδ bers and C-bers are chemo- and mecha-noreceptive but not nociceptive.18 Some of these low-threshold receptors, called metabo-receptors, appear to be uniquely stimulated by the metabolic products generated during muscle activity, while others sense the relative distension of post–capillary bed venules.19–21 These receptors display background activity at rest, accelerate impulse transmission as be-havior intensity increases, and may affect the same central modulatory systems as nocicep-tion.21–24 The CNS uses this input to coordinate respiratory and cardiovascular changes during dynamic muscle behavior.19,21–23 Future consid-eration of the role of these receptors in pain etiology may help us better understand pain conditions in which there is no apparent tissue damage.Anatomical and Physiologic Considerations of Orofacial PainOrofacial pain may be dened as pain and dys-function affecting motor and sensory transmis-sion in the trigeminal nerve system.25 From a sensory perspective, the trigeminal system Fig 1-1 Overview of major factors that contribute to development of TMD pathology and the associated genes. (Reprinted with permission from Slade et al.12)Neuro-endocrinefunctionPersistent TMDTransient TMDSubclinical signs and symptomsSomatizationStressresponseDepressionAnxietyMoodHigh psychologicdistressPainfulTMDHigh state of painamplicationAutonomicfunctionImpairedpainregulationPro-inammatorystateXp11.23 12q11.2 9q34.3 11q23 5q31-q32 5q31-32 6q24-q25 1p13.1 22q11.21CannabinoidreceptorsSerotoninreceptorGAD65MAO NMDACREB1 GRCACNA1ADREAM POMC NETBONF NGF Prodynorphin InterleukinsCOMTIKKNa+, K+ATPaseAdrenergicreceptorsOpioidreceptorsDopaminereceptorsSerotonintransporterEnvironmentalContributionsPhysical environment• eg, trauma, infectionSocial environment• eg, life stressorsCulture• eg, health beliefsDemographics 5oversees the efcacy and tissue integrity of the highly integrative orofacial behaviors that are controlled by cranial nerves and modulated by the autonomic nervous system (ANS) and the greater limbic system.26 Orofacial nerves transmit information about pressure (touch), position, temperature, and potential pain to the trigeminal nuclei, which have extensive bidirectional connections throughout the brain.27–29 These trigeminal connections affect the sensory, motor, and autonomic-endocrine changes that occur during orofacial behaviors, and orofacial pain may result when these be-haviors are impaired. The next sections briey discuss peripheral and central trigeminal neu-roanatomy to explain how the trigeminal sys-tem affects physiology and pain. Neuroanatomy of the orofacial structuresCranial nerves are extensions of the brain that directly or indirectly innervate tissues involved with the trigeminal system.4 The specialized neurons of the olfactory, optic, and vestibulo-cochlear nerves that send smell, sight, sound, and balance information to the CNS do not travel through the trigeminal nuclei. However, nerves associated with the nose, eye, and ear tissues do transmit proprioceptive, pressure, and potential pain impulses into the trigeminal nuclei. A comprehensive orofacial pain evalua-tion should include a basic assessment of the function of all cranial nerves (see chapter 2). Five of these nerves (V, VII, IX, X, and XII) are reviewed here.Trigeminal nerveThe trigeminal nerve, which provides sensory innervation to most of the head and face, is the primary nerve involved in TMDs, migraine, sinus, pulpal, and periodontal pathology. It is the largest cranial nerve and consists of three peripheral divisions: the ophthalmic, maxillary, and mandibular.30–33 These branches receive sensory input that is conveyed on rst-order neurons through the trigeminal ganglion, where most neuronal cell bodies are located. Although these neurons enter the ganglion on three branches, they exit in one large sensory root that enters the brainstem at the level of the pons before reaching the trigeminal nuclei.34 Ophthalmic branch (V1). This branch of the trigeminal nerve leaves the skull through the superior orbital ssure and transmits sen-sory information from the scalp and forehead, upper eyelid, conjunctiva and cornea of the eye, nose (including the tip of the nose), nasal mucosa, frontal sinuses and parts of the me-ninges (the dura and blood vessels), and deep structures in these regions. It also carries post-ganglionic parasympathetic motor bers to the glands and sympathetic bers to the pupillary dilator muscles.34Maxillary branch (V2). This branch exits the skull at the foramen rotundum. It has a sen-sory function for the lower eyelid and cheek; the nares and upper lip; the maxillary teeth and gingiva; the nasal mucosa; the palate and roof of the pharynx; the maxillary, ethmoid, and sphenoid sinuses; and parts of the meninges. Near its origin, it divides to form the middle meningeal nerve, which supplies the middle meningeal artery and part of dura mater. The terminal V2 branches—the anterior and greater palatine nerves and the superior, middle, and anterior alveolar nerves—innervate the soft palate, uvula, hard palate, maxillary gingiva and teeth, and mucous membranes of the cheek.34Mandibular branch (V3). This branch leaves the skull through the foramen ovale and functions in both sensory and motor transmis-sion. V3 carries sensory information from the lower lip, mandibular teeth and gingiva, oor of the mouth, anterior two-thirds of the tongue, the chin and jaw (except the angle of the jaw, which is supplied by C2 and C3), parts of the external ear, parts of the meninges, and deep structures. The auriculotemporal nerve is a branch of V3 that innervates most of the TMJ. The motor nuclei use V3 to provide motor -bers to the muscles of mastication (ie, mas-Anatomical and Physiologic Considerations of Orofacial Pain Introduction to Orofacial Pain16seter, temporalis, medial pterygoid, lateral pterygoid, anterior digastric, and mylohyoid) as well as the tensor veli palatini involved with Eustachian tube function and the tensor tym-pani, which attaches to the malleus bone in the eardrum.34Trigeminal sensory nuclei. The trigeminal sensory nuclei lay in bilateral columns on ei-ther side of the brainstem. They originate in the midbrain and terminate in the dorsal horn of the cervical spinal cord (Fig 1-2). All touch, position, and temperature sensory input from the face is sent to the trigeminal nuclei, as is potential pain input from the face, head, and neck.4 They are, in a rostrocaudal orientation, the mesencephalic nucleus, the main sensory nucleus, and the spinal trigeminal nucleus.The mesencephalic nucleus, which is more a ganglion than a nucleus, houses the cell bodies of the proprioceptive neurons that convey input from the apical periodontal liga-ment and the muscle bers that contract dur-ing the jaw-closing reex. These proprioceptive neurons and possibly the blink reex nerves represent the only peripheral nerves with cell bodies located within the CNS.4,35 The neu-rons are monosynaptic and pass through the mesencephalic nucleus to synapse in the tri-geminal motor nuclei located medially to the much larger main sensory nucleus. The main sensory nucleus receives the facial proprio-ceptive and pressure input for orofacial be-haviors (eg, chewing, kissing, smiling, and light touch) other than the jaw-closing reex. Fig 1-2 Sensory pathways and motor response to referred pain. The rst-order neurons from a pain site in facial lamina 5 and from the pain source in the C4 receptive eld each converge on lamina 5 of the subnucleus caudalis and excite the same second-order neurons. As these second-order neurons ascend, they arborize with the subnucleus oralis and subnucleus interpolaris (not shown) and many reticular formation structures before synapsing with third-order neurons in the thalamus. The third-order neurons are thalamo-cortico-basal ganglia-limbic circuits that interpret pain and generate the descending motor and pain modulatory reactions to pain interpretation. The descending motor neurons also arborize with reticular formation locations and connect, via interneurons, to the trigeminal motor nucleus and to all cranial nerve motor nuclei. Note that trigeminal input is never analyzed in isolation because primary sensory and spinal thalamic tract input is also constantly presented to the brain for analysis. RF, reticular formation structure; SNO, subnucleus oralis; STT, spinal thalamic tract.5C2LimbichypothalamusRF ThalamusBasalgangliaPainsourcePainsitePainMotorcorticesSensorycorticesPrimarysensesOthercranial nervemotor nucleiInterneuronsSTTSNO1st2nd3rdC3C4C4C2-C34321 7These neurons have their cell bodies in the trigeminal ganglion and synapse in the main sensory nucleus, where input is conveyed to the motor nuclei by arrays of small interneu-rons.4 The spinal trigeminal nucleus consists of three subnuclei: subnucleus oralis, sub-nucleus interpolaris, and subnucleus caudalis. Subnucleus oralis and subnucleus interpolaris receive some peripheral nociceptive bers, but they mostly receive temperature information on Aδ bers and touch impulses on Aβ bers from the periphery and convey this input via interneurons to the motor nuclei.4 In response to nociceptor activation, neuropeptides and other inammatory agents are released in the spinal trigeminal nucleus and can cause excita-tion of neurons and glial cells. This promotes development of central sensitization, allodynia, and hyperalgesia, which are physiologic events associated with acute and chronic pain.36,37 The subnucleus caudalis is the main ter-minus for most slow rst-order neurons that convey potential pain from trigeminal receptive elds. Figure 1-2 illustrates the “onion peel” somatotropic organization of the face (areas 1 to 5) and the corresponding laminae (1 to 5) in the subnucleus caudalis, where rst-order nociceptive neurons terminate regardless of their division of origin.4 For instance, A- and C-ber neurons from area 5 in the face all syn-apse with second-order nociceptive neurons in the most caudal aspect of the subnucleus cau-dalis, lamina 5, whether they start in V1, V2, or V3. Such convergence means that a dural blood vessel, masseter muscle, or a tooth or tongue nociceptive afferent could excite the same second-order neurons. This convergence, the anatomical basis for referred pain, is not just a facial phenomenon. Cervical spine nociceptive afferents also syn-apse in the subnucleus caudalis, meaning that trapezius or sternocleidomastoid nociceptive afferents can excite second-order neurons that also receive input from facial tissues.28,29,38 Recent ndings from the OPPERA study have provided evidence that pain in the neck and shoulder muscles is highly correlated with both acute and chronic TMDs. Thus, this type of neuronal organization may help to explain the high prevalence of comorbid pain condi-tions associated with tissues in the head and face (eg, headache and sinusitis, headache and TMDs). Another construct to consider is that all of the CNS structures affected by tri-geminal nociceptive input are also contacted by second-order neurons from the dorsal horn of the spinal cord.15 Therefore, potential pain input from regions outside trigeminal receptive elds may excite CNS structures that commu-nicate with trigeminal nuclei and modulate their functions.Facial nerve The seventh cranial nerve is a mixed nerve that has ve branches (temporal, zygomatic, buccal, mandibular, and cervical) that course through the parotid gland but do not innervate the gland. Its main function is motor control of most of the muscles of facial expression and the stapedius muscle of the middle ear. The facial nerve supplies parasympathetic bers to the sublingual and submandibular glands via the chorda tympani and to the lacrimal gland via the pterygopalatine ganglion. In addition, it conveys taste sensations from the anterior two-thirds of the tongue to the solitary tract nucleus and transmits cutaneous sensation from the skin in and around the earlobe via the intermediate nerve.34Glossopharyngeal nerveThe ninth cranial nerve is a mixed nerve com-prising somatic, visceral, and motor bers. It conveys sensory information from the pos-terior third of the tongue, tonsils, pharynx, middle ear, and carotid body. Taste sensation from the posterior third of the tongue as well as carotid body baroreceptor and chemorecep-tor information are transmitted to the solitary tract nucleus. Nociceptive input from the ear is sent to the spinal trigeminal nucleus. From the inferior salivatory nucleus, the glossopharyn-Anatomical and Physiologic Considerations of Orofacial Pain 8Introduction to Orofacial Pain1geal nerve delivers parasympathetic control to the parotid and mucous glands throughout the oral cavity, while motor bers from the nucleus ambiguous project to the stylopharyn-geus muscle and upper pharyngeal muscles. An altered gag reex indicates glossopharyn-geal nerve damage.34 Vagus nerveThe tenth cranial nerve originates in the brain-stem and extends to the abdomen and inner-vates virtually all organs from the neck to the transverse colon except the adrenal glands. It supplies visceral afferent bers to the mucous membranes of the pharynx, larynx, bronchi, lungs, heart, esophagus, stomach, intestines, and kidneys, and it distributes efferent or para-sympathetic bers to the heart, esophagus, stomach, trachea, bronchi, biliary tract, and most of the intestine. The vagus nerve also af-fects motor control of the voluntary muscles of the larynx, pharynx, and palate and carries so-matic sensory bers that terminate in the skin of the posterior surface of the external ear and the external acoustic meatus.34 Through these connections, the vagus affects activities as var-ied as respiration, cardiac function, sweating, digestion, peristalsis, hearing, and speech.Spinal accessory nerveThe eleventh cranial nerve innervates the cer-vical muscles, the sternocleidomastoid and trapezius, which are coactivated during mas-ticatory behaviors. Like the trigeminal motor nucleus, the accessory motor nuclei are rich in norepinephrine receptors, which can facilitate vigilant behaviors.39 Nociceptive afferents from the cervical muscles converge onto the spinal trigeminal nucleus. It is notable that cervical myofascial pain seems to be prominent in pa-tients with orofacial pain.Upper cervical nervesSpinal nerves C1 to C4 and possibly C5 are important considerations in orofacial pain be-cause their sensory bers converge onto the trigeminal subnucleus caudalis.28,29,38 As C1 to C4 leave the spine, they combine to form the cervical plexus, which yields cutaneous, muscular, and mixed branches. C1 forms the suboccipital nerve that supplies motor control to the muscles of the suboccipital triangle. The cutaneous branches are the lesser oc-cipital (C2, C3), the greater auricular (C2, C3), the transverse cervical (C2, C3), and the su-praclavicular (C3, C4). These nerves innervate the back of the head and neck, the auricle and external acoustic meatus, the anterior neck and angle of the mandible and the shoulders, and the upper thoracic region. The muscular branch—the ansa cervicalis—innervates the sternohyoid, the sternothyroid, and the omo-hyoid muscles and is composed of a superior root (C1, C2) and an inferior root (C2, C3). The mixed branch is the phrenic nerve (C3, C4, and C5), which innervates the diaphragm.34 Autonomic nervous systemThe ANS, which is commonly viewed as a largely involuntary motor system, is composed of three peripheral divisions—the sympathetic, parasympathetic, and enteric—that function to maintain homeostasis.34 The peripheral ANS is controlled by the central ANS, which com-prises cortical, limbic, and reticular formation structures and nuclei.39 Stimuli that activate the central ANS induce increased sympathetic activity initially in the brainstem and then in the periphery.39,40 The sympathetic system is involved in vigilance, energy expenditure, and the ight-or-ght response, while the role of the parasympathetic system is to counterbal-ance sympathetic arousal with rest-and-digest actions.41 The sympathetic and parasympa-thetic systems have preganglionic neurons that originate in different parts of the CNS and postganglionic neurons that deliver impulses to target tissues. Preganglionic neurons re-lease acetylcholine at the autonomic ganglia. The postganglionic sympathetic neurons re-lease the primary neurotransmitters norepi- 9nephrine and epinephrine, while parasympa-thetic neurons are cholinergic and therefore secrete acetylcholine at the target sites.The enteric system provides local sensory and motor bers to the gastrointestinal tract, the pancreas, and the gallbladder. This system can function autonomously but is regulated by CNS reexes. Its control of gastrointestinal vascular tone, motility, secretions, and uid transport plays a vital role in homeostasis. Persistent sympathetic arousal that impairs parasympathetic function and leads to distur-bances of the enteric system may be related to orofacial pain because functional disorders of visceral organs controlled by the ANS seem to be common comorbid conditions.9,11,41Sympathetic input to the orofacial re-gion. Sympathetic preganglionic neurons originate in the spinal cord. Their cell bodies are found in the intermediolateral gray matter at the level of the T12 and L1 to L3 vertebrae. They exit the spinal cord via the ventral horn at the segmental level where their cell bodies are located, but they can synapse with any of the sympathetic ganglia in the bilateral paraverte-bral chains. The superior portion of the sympa-thetic chain contains four cervical ganglia. In a rostrocaudal orientation, they are the superior cervical, middle cervical, intermediate cervical, and stellate ganglia. Postganglionic bers leav-ing these sympathetic ganglia transmit motor input to the blood vessels in the head and neck, various glands, and the eyes. The skin of the face and scalp receive sympathetic in-nervation from the superior cervical ganglia via plexuses extending along the branches of the external carotid artery.34,41Parasympathetic input to the orofacial region. Parasympathetic preganglionic neu-rons originate in the brainstem nuclei, where their cell bodies are located, or in the lateral gray columns of the sacral spinal cord (S2 to S4). Cranial nerves III, VII, IX, X, and the splanchnic nerve in the pelvic region carry para-sympathetic preganglionic neurons, which are considerably longer than the postganglionic bers because ganglia are generally located close to or embedded in the target organ.Neurophysiology of Orofacial PainOrofacial pain pathwaysNociceptive impulses generated by potential or actual tissue damage are just one of the types of input that are continually assessed and evaluated throughout the various levels within the CNS. The senses (smell, sight, hearing, touch, and taste) alert the brain to stimuli through thalamic-amygdala and thalamic-cortical-amygdala circuits, and those data streams are analyzed and compared with what the brain already knows to sequence ef-cient behavior.42,43 Ongoing proprioceptive, nociceptive, thermoreceptive, baroreceptive, chemoreceptive, and vestibular inputs tell the brain how effectively its tissues are conduct-ing responses and enables the brain to make ongoing behavioral adjustments aimed at maintaining efciency. Nociception provides the brain an opportunity to interpret pain and make behavioral adjustments to avoid further potentially damaging stimuli.44 First-order nociceptive nerves, whether they synapse in the spinal trigeminal nucleus or in the dorsal horn, excite the same type of second-order neurons that respond to noci-ceptive signals as well as a variety of sensory stimuli and are therefore called wide-dynamic range neurons. These neurons conduct no-ciception and other sensations through the brainstem and display varying degrees of ar-borization with structures throughout the re-ticular formation where baseline physiologic processes are controlled before reaching the third-order neurons in the thalamus (see Fig 1-2).4,45–47 Second-order neurons, stimulated by the faster-conducting Aδ bers that release glutamate, arborize less than those receiving impulses from the slower-conducting C-bers that release a wide variety of neurotransmit-Neurophysiology of Orofacial Pain 10Introduction to Orofacial Pain1ters.4,48,49 Thus, information from Aδ bers al-lows for a much faster nocifensive response (ie, reflex response) than that elicited by C-ber input, which is important in maintain-ing persistent pain and coordinating reparative and behavioral responses.With sufcient temporal and/or spatial sum-mation, third-order circuits, which start in the thalamus and connect the sensory cortex with the basal ganglia and the limbic system, inter-pret nociceptive input.1,4 This is how pain is perceived.1,4 Even when pain is felt, it is some-times difcult to locate the actual source. Sites of cutaneous stimuli are easier to recognize than stimuli from the muscles and visceral organs because the dermis has more noci-ceptive free nerve endings than deep tissues to assess integument integrity.4 In response to pain interpretation, multilevel behavioral responses are coordinated, and descending motor commands are created. Whether noci-ception is delivered to the CNS through the spinothalamic tract or the trigeminal thalamic tract, pain perception evokes ANS-modulated cranial nerve responses.4,50,51 Because the tis-sues under cranial nerve control will continue to excite the trigeminal nociceptive pathways, an orofacial pain prognosis may be poor if on-going pain sources beyond the trigeminal re-ceptive elds cannot be controlled.Nociception and pain modulationOrganisms need to be able to recognize and avoid pathologic pain to prevent potential tis-sue damage; however, normal daily activities should not be signicantly altered by transient physiologic pain. Therefore, nociception has a biphasic effect in the CNS. Low-intensity no-ciceptive impulses are facilitated rst through the CNS and then by stimulation of the cor-tex and a variety of brainstem regions, while inhibition may be facilitated via activation of the rostral ventromedial medulla and the peri-aqueductal gray regions.52,53 If nociception is relatively minor, inhibitory mechanisms will minimize the impact of transient nociceptive barrages in the CNS that affect cognitive func-tion and task performance. Simultaneously, low-intensity nociception via second-order neuron arborization stimulates reticular forma-tion structures to coordinate adjustments in motor and vascular behavior.51 Because of net inhibition, such adjustments can occur almost below the level of consciousness, and efcient behavior will continue. In addition, data from human and animal studies support a role for diffuse noxious inhibitory controls (DNICs) in modulating response to painful stimuli.54,55 This occurs at the level of the spinal cord and is mediated when some neurons are strongly inhibited in response to a nociceptive stimulus applied to any part of the body, distinct from their excitatory receptive elds. For example, stimulation in more remote areas of the body is reported to induce inhibitory reex move-ments in the jaw and tongue in response to noxious craniofacial stimulation.56,57 Thus, the inhibitory effects of DNIC are observed in noci-ceptive neurons and wide-dynamic range neu-rons in the spinal trigeminal nucleus as well as in sensorimotor behavioral responses involv-ing the spinal trigeminal nucleus.58–61 Because the term DNIC, although still widely used, describes a specic inhibitory mechanism at the lower brainstem level, a group of clinicians and basic scientists has proposed a new term that could be used for psychophysical testing in humans. This new term, conditioned pain modulation, can be used to describe the neu-ronal mechanism where pain inhibits pain at all levels in the CNS.62,63 Importantly, dysfunction of these inhibitory control mechanisms is likely to be involved in promoting and maintaining chronic orofacial pain. Of clinical relevance, dysfunction in DNIC may make those individu-als more likely to progress to a chronic pain state following tissue injury or infection in the orofacial region.When nociception persists to excite third-order neurons and pain is realized, the brain’s inhibitory capacity, stimulation- 11produced analgesia (SPA), must work harder to counteract facilitation. By both noradrenergic and serotonergic pathways, SPA inhibits noci-ceptive transmission at many sites but initially where rst- and second-order neurons syn-apse in the spinal trigeminal nucleus or in the dorsal horn.4 This descending inhibition is me-diated by endogenous opioids, γ-aminobutyric acid (GABA), and various inhibitory amino acids that are located in the periaqueductal gray. These same inhibitory compounds are re-leased when stressors induce anxiety, fear, or depression.64 Brain circuits that interpret pain and direct descending inhibition also send sig-nals to direct alterations in motor behavior and ANS functions. These descending commands reach structures throughout the reticular for-mation and, by vast pools of interneurons, affect all cranial nerve motor nuclei and alter behavior in response to pain (Fig 1-3).65–67 Al-ternative motor pathways are recruited, and protective changes in respiration and cardio-vascular mechanisms are engaged.68 In the case of trigeminal motor activity, premotor in-terneurons deliver messages to the main sen-sory nucleus, the subnucleus oralis, and the subnucleus interpolaris, which, through inter-neurons, alter motor neuron sequencing in the motor nuclei. These same nuclei mediate the minor motor adjustments when net inhibition minimizes minor nociceptive volley intrusion on circuits where pain is perceived.45–47 SensitizationWith persistent nociception, excitation can exceed inhibitory capacity, and a spectrum of neuroplastic changes occurs, rst peripherally and then centrally. These changes are called peripheral and central sensitization. The fol-lowing changes are characteristic of neuronal Fig 1-3 Sensitization. First-order nociceptive neurons from facial lamina 5 transmitted via V1 and C4 converge onto lamina 5 of the subnucleus caudalis. The pain sources are not controlled, summation exceeds descend-ing inhibition, and progressive levels of central sensitization occur, rst at the subnucleus caudalis and then at the ipsilateral subnucleus oralis, where Aβ bers are carried on the V3 synapse. With continued summation, sensitization occurs at higher brain sites and at the contralateral subnucleus oralis. Nonpainful thermal and tactile inputs are experienced as painful (allodynia) or a more intense pain is felt (hyperalgesia) because of the effects of central sensitization. RF, reticular formation structure; SN, subnucleus.55C2Basal gangliaCortexC.V1V3AβInterneuronsSensitization1stC3C4C4C2-C344332211TrigeminalganglionDescendingfacilitationAllodyniahyperalgesiaThalamusLimbicHypothalamusRFMensencephalicMain sensoryMotorSN oralisSN interpolarisSN caudalis (1-5)Neurophysiology of Orofacial Pain 121Introduction to Orofacial Painsensitization: nerve thresholds are lowered, receptive elds are enlarged, gene expression is changed, and pain is persistent and evoked by nonpainful stimuli.48–50 In the transition from acute to chronic pain, nociceptive neurons can change the type and level of expression of receptors and ion channels, leading to the development of a primed state.69 In the primed state, lower levels of inammatory mediators are required to generate nociception, and sen-sitizing agents can become stimulatory agents. The transformation of nociceptors to the prime state is implicated in persistent pain condi-tions. High-threshold peripheral nociceptors do not re unless exposed to noxious stimuli. However, repeated stimulation can quite rap-idly reduce ring thresholds by the actions of a variety of inammatory molecules acting on various receptors. The antidromic release of neurogenic inammatory compounds by peri-vascular afferents at the location of the pain also enhances peripheral nociceptor sensitization. This increase in the transmission frequency of noxious action potentials to second-order neurons is called long-term potentiation and, if persistent, leads to central sensitization.48,49 The development of sensitization is a time- and intensity-dependent progression. Initially, low-intensity nociceptive volleys carried on Aδ neurons release glutamate and activate postsynaptic α-amino-3-hydroxy-5-methyl-4- isoxazole-propionic acid (AMPA) receptors in the spinal trigeminal nucleus or dorsal horn. Higher-intensity stimuli induce C-bers to re-lease neuropeptides and other inammatory mediators that cause changes in the expres-sion and activity of neuronal receptors and ion channels that result in lower activation thresh-olds in second-order neurons.70,71In nonpainful states, Aβ bers release only glutamate and deliver tactile sensations to the subnucleus oralis and subnucleus interpolaris or dorsal horn lamina 3 and 4. These tactile sensations are important for coordination of motor behaviors. As central sensitization de-velops, the thresholds where second-order neurons arborize to the subnucleus oralis and subnucleus interpolaris are lowered, and Aβ bers can begin to sprout axons into the adja-cent nociceptive lamina.36,37,55,72 As a result of this structural reorganization in the CNS, non-painful stimuli that converge onto a sensitized CNS will be interpreted as painful (see Fig 1-3).73 Reduction of inhibition and reorganiza-tion of synaptic connectivity are other mecha-nisms by which Aβ bers may be recruited to mediate pain. Patients thus suffer allodynia (pain induced by stimuli that normally would not be perceived as painful), pain exacerba-tions, and hyperalgesia (an exaggerated pain response to painful stimuli).4 In acute pain states such as posttraumatic wounds, these mechanisms are vital to help avoid contact that would slow wound heal-ing; survivability of the species improves as a result. However, in chronic pain states with glial cell activation augmenting CNS cytokine release, maintenance of central sensitization requires minimal nociceptive input.4,73,74 Un-derstanding central sensitization is essential to pain practice because it explains light-touch pain symptoms that once were considered psychosomatic. Sensitization may also affect symptoms associated with a variety of diagno-ses such as migraine, gastroesophageal reux disease, IBS, and FM, which are often comor-bid with facial pain.50,75,76 It is vital to abort acute pain and eliminate pain sources as quickly as possible because once central sensitization is rmly established, it becomes exceedingly dif-cult to diminish with current pharmacologic and nonpharmacologic therapies. Pain in the head and face, which can be very severe and debilitating, often involves activation of the trigeminal ganglion nerves and the development of peripheral and cen-tral sensitization. The craniofacial symptoms can manifest as acute or transient conditions such as toothaches and headaches, or they can transform into more chronic conditions such as migraine, rhinosinusitis, TMDs, or trigeminal neuralgia. It is well established that peripheral 13tissue injury or in ammation leads to excitation of trigeminal nerves, resulting in the release of in ammatory molecules in the periphery and within the CNS at the level of the spinal trigeminal nucleus. Calcitonin gene-relatedpeptide (CGRP), which is an abundant neuro-peptide in trigeminal ganglion neurons, is impli-cated in the underlying pathology of diseases involving trigeminal nerve activation given its ability to promote neurogenic in ammation as well as peripheral and central sensitization (Fig 1-4).77–79 However, peripheral tissue injury or in ammation also leads to increased interac-tions between neuronal cell bodies and satel-lite glial cells within the trigeminal ganglion.80These cell-to-cell interactions, which involve the transfer of key regulatory mediators via channels or gap junctions as well as paracrine signaling, are thought to play an important role in the induction and maintenance of peripheral sensitization of trigeminal nociceptive neurons. Under normal conditions, neuron-glia interac-tions in the trigeminal ganglia are involved in information processing, neuroprotection, and regulation of neuronal activity including the basal rate of spontaneous  ring and threshold of activation to maintain homeostasis. While a transient increase in neuron-glia communica-tion is associated with an acute response to in ammatory signals, stable gap junctions are formed between trigeminal neurons and satel-lite glia in response to sustained in ammation that is implicated in TMDs.81 Specialized glial cells found in the CNS, namely astrocytes and microglia, perform functions similar to satellite glia.82 Astrocytes are the most abundant type of cell found in the CNS and perform a diverse array of im-portant functions, including regulation of neu-ronal development, synaptic coupling, repair, and even nutritional support. In addition, as-trocytes monitor and control the concentration Fig 1-4 CGRP involvement in promoting peripheral and central sensitization of trigeminal nociceptive neurons. In response to tissue injury or ischemia, in ammatory mediators cause activation of primary nociceptive neu-rons and subsequent CGRP release (1) in peripheral tissues to promote neurogenic in ammation from the cell body in the ganglion to facilitate development of an in ammatory loop and cross-excitation, and (2) in the spinal trigeminal nucleus to cause activation of second-order neurons and glial cells, resulting in hyperalgesia and allodynia. While CGRP release in the peripheral tissue and ganglion initiate and sustain peripheral sensi-tization of primary trigeminal neurons, elevated CGRP levels in the upper spinal cord promote development of central sensitization via activation of astrocytes and microglia. (Reprinted with permission from Durham.79)Tissue injuryischemiaIn ammatorymediatorsActivation/sensitizationof primary neuronsPeripheraltissueHyperalgesiaallodyniaCGRP releaseIn ammatory loopcross-excitationCGRP releaseActivation/sensitizationof second-order neuronsand glial cellsCGRP releaseNeurogenicin ammationSatellitegliaSpinaltrigeminalnucleusTrigeminal ganglion neuronNeuronalcell bodyNeurophysiology of Orofacial Pain 14Introduction to Orofacial Pain1of ions, neurotransmitters, and metabolites, as well as water movement, and thus play a key role in modulating the excitability state of neurons both in the brain and the spinal cord.83 The other prominent glial cells in the CNS are the microglia that function as immune cells to remove cellular debris and dead cells; they also release inammatory mediators to pro-mote healing.84,85 Glial cells are responsible for regulating the extracellular environment around neurons and hence neuronal activities, and their importance in regard to the underly-ing pathology of many inammatory diseases is now becoming recognized. Thus, glial cells have emerged as important cellular targets for therapeutic intervention given their role in pro-moting peripheral and central sensitization and persistent pain.86Heterotopic painA common phenomenon associated with oro-facial pain that may confuse both patients and clinicians is heterotopic pain. When reporting chief complaints, patients often describe the site where they feel the pain, which may dif-fer from the actual pain source.87 For treatment to be effective, clinicians must determine the sources of pain. Primary pain is that which occurs at the source, as is often the case in acute injury or infection.87 Primary pain is not a difcult problem to diagnose and treat when other pain sources are absent, but diagnostic difculties may be presented when the source of pain is not located in the region of pain per-ception. Such pain is said to be heterotopic. In the spinal system, heterotopic pain commonly involves impulses projected along a common nerve distribution.87 For instance, in the L4 dis-tribution, a patient may feel pain in the big toe when the source is a hip muscle impingement or foraminal stenosis. Projected nerve pain also occurs in the trigeminal system. A good exam-ple is the pain related to trigeminal neuralgia, which is felt throughout the peripheral distribu-tion of the affected nerve. Another diagnostic challenge is referred pain, in which the pain is felt at a location served by one nerve but the source of nociception arrives at the subnucleus caudalis on a different nerve (see Fig 1-3). A common example is temple pain in the V1 dis-tribution caused by trapezius input delivered to the subnucleus caudalis on C4.88 The neuroanatomical basis for referred pain is provided by the convergence of multiple sensory nerves carrying input to the trigemi-nal spinal nuclei from cutaneous and deep tis-sues located throughout the head and neck. As opposed to dermatomal projected pain in the spinal system, primary nociceptive afferents from tissues served by V1, V2, V3, C2, C3, and C4 can excite some of the same second-order neurons in the spinal trigeminal nucleus. In ad-dition, rst-order nociceptive neurons carried by C5, C6, and C7 and cranial nerves VII, IX, and X can synapse in the spinal trigeminal nu-cleus as well as the paratrigeminal nuclei.4,28,29 Further, data clearly show that trigeminal second-order neurons converge on multiple brainstem locations involved in motor, ANS, and hypothalamic-pituitary-adrenal (HPA) activity.28,29 Convergence explains how intracranial, neck, shoulder, or throat nociception may excite the second-order neurons that receive input from facial structures. This convergence of input from tissues controlled by multiple motor nerves and delivered by multiple different sensory nerves to trigeminal nuclei helps to illustrate the impor-tant role of the trigeminal system in integrating nocifensive behaviors involving head, neck, and shoulder tissues. Because nociceptive affer-ents from the cervical muscles converge in the spinal trigeminal nucleus, the same location as trigeminal nociceptors, it is not surprising that cervical myofascial pain appears to be a promi-nent orofacial pain problem. As important as convergence of peripheral afferents is to understanding orofacial behav-iors and referred pain, it is perhaps even more signicant to appreciate descending conver-gence from cortical, limbic, hypothalamic, and ANS regions into the vast interneuronal pools of the brainstem. These interneurons not only 15reach the trigeminal motor nuclei through the spinal trigeminal nucleus; they also simulta-neously convey directives to the other cranial nerve motor nuclei.65–67 When pain is felt, the CNS adapts, trying to minimize continued noci-ceptive barrages by altering patterns of move-ment involving the highly integrative behaviors controlled by the cranial nerves.55 For example, the CNS restricts jaw movement in response to pain in the sternocleidomastoid, resulting in reduced jaw range of motion or cocontraction. The muscles of the jaw, tongue, face, throat, and neck work synergistically to execute multi-ple orofacial functions, but pain in these areas alters the movements.26 Neck or shoulder pain may result in impaired jaw or neck movement just as a sore tooth alters chewing and swal-lowing or a severe headache compels retreat from light and sound, but these sources will also contribute to central sensitization. While convergence is the anatomical construct for re-ferred pain, sensitization with its allodynic and hyperalgesic responses underlies the neuro-physiologic changes that make it challenging to diagnose and treat persistent pain involving the trigeminal system. The Biopsychosocial Model: Allostasis and the Emotional Motor System Mind/body dualism is a concept that views the mind and mental phenomena as nonphysi-cal, something apart from the body. This con-cept has existed since 1641, but many physi-cians and patients still believe that disease and pain must be the result of a detectable physical malady or injury.4 A mechanistic or biomedical model of medicine discounts the effects of the mind and society on disease processes. It views pain as the result of tissue damage, and if such organic disease or injury cannot be detected, then pain is explained as psychosomatic. Engel89 challenged the traditional biomedi-cal model of disease as shortsighted in its assumptions that correcting the somatic pa-rameters of disease dened the scope of phy-sicians’ responsibilities and that the psychoso-cial elements of human malfunction lie outside the responsibility and authority of medicine. After rejecting the biomedical approach that all clinicians need to do to resolve pain is to nd and repair the offending tissues, Engel devel-oped the biopsychosocial model. This model views biologic, psychologic, and sociologic issues as body systems just like the muscu-loskeletal or cardiovascular systems, with no separation of mind and body. Pain arises as a symptom that results from the combination of biologic, psychologic, and sociologic factors that continuously affect all individuals, and no two people experience the same spectrum of factors. Psychologic and sociologic differences are why equal degrees of nociception, a mea-surable biologic parameter, can produce vastly different pain and behavioral responses. The biopsychosocial model also makes a distinction between (1) disease associated with demonstrable pathology and (2) illness in which poor health is perceived but biologic parameters do not show disease pathology. As science evolves, imaging techniques and biologic and genetic markers continue to be discovered that show the adverse effects of psychologic and sociologic issues on physiol-ogy, thus redening disease.90–92 The mecha-nisms for central sensitization or the modica-tion of neuroendocrine parameters that have been found to characterize abuse victims, who often suffer from many comorbid illnesses, are examples of science revealing markers for conditions previously considered as lacking biologic basis.93,94 Another theory that considers chronic pain a multidimensional experience is the neuro-matrix theory put forth by Dr Melzack.95 This novel theory of pain associated with persistent pain syndromes, which are often characterized by severe pain with little or no discernible in-The Biopsychosocial Model: Allostasis and the Emotional Motor System 16Introduction to Orofacial Pain1jury or pathology as well as chronic psycho-logic or physical stress, provides a new con-ceptual framework to examine orofacial pain conditions. In this model, pain is perceived in response to activation of perceptual, homeo-static, and behavioral programs after injury, pa-thology, or chronic stress, rather than directly only by sensory input evoked by injury, inam-mation, or other pathologic events. Thus, al-though the neural pattern that produces pain is primarily established by genetics and modi-ed by sensory experience, the output pattern is determined by multiple inuences including neural-hormonal mechanisms of stress. Allostasis is the adaptation of neural, neu-roendocrine, and immune mechanisms in the face of stressors. Allostatic load refers to the physiologic changes that continued stressors produce as organisms attempt to maintain homeostasis. The changes in HPA axis func-tion and brain cytokine activities that underlie cardiac disease and diabetes are examples of allostatic load.96,97 Allostasis intersects with the controversial concept known as the emo-tional motor system. The emotional motor system maintains that thoughts and emotions create neuroendocrine-mediated motor re-sponses.98,99 When an organism hears, sees, or smells, its limbic system (amygdala and hip-pocampus) acquires primary sensory stimuli and compares their relevance with prior knowl-edge in a matter of 15 to 30 milliseconds to help sequence dynamic behavior.42 Input analy-sis and the emotional motor system facilitation of autonomic and cranial nerve motor behavior involve the full spectrum of brain neurochemis-try and endocrine function.43,100Two scenarios not uncommon in orofacial pain practice illustrate how sociologic experi-ence may alter supraspinal physiology and pain experience. Consider an excessively worried patient who awakes with neck pain, the same initial complaint reported by his uncle who died from cancer, or a headache patient experienc-ing a panic attack when a smell rekindled the fear physiology associated with an assault 7 years earlier. For these patients, investigating only acute biomedical parameters may not help and may even contribute to a deepening state of illness as the pathologic processes continue without recognition and treatment. These are patients for whom the biopsychosocial approach may prevent increased allostatic load. Taking sufcient time to obtain a thorough history and to explain the physiologic effects as they relate to psychosocial problems can help patients con-trol factors that affect illness symptoms. Although there is an increasing awareness of the need to assess all three systems out-lined by Engel, many barriers described in a 2005 study prevent its widespread utiliza-tion.101 The study found that physicians and residents avoided approaching psychosocial issues because of inadequate training, lack of time, insufcient monetary incentive, and a large cultural ethos that favors “quick xes.”101 The Research Diagnostic Criteria for TMDs (RDC/TMD) represent an attempt to apply both biologic (Axis I) and psychosocial (Axis II) factors to better understand a patient’s condi-tion.102,103 However, the RDC/TMD have met resistance because Axis I fails to account for how referred pain and central sensitization affect physical ndings, and Axis II is per-ceived by many as indicating that TMDs are psychosomatic despite evidence of disease. Yet, a 5-year follow-up study showed that in the 49% of TMD patients whose pain remit-ted, baseline psychologic measures were the same as found in the general population.104 Of the remaining 51%, the 14% who experi-enced high pain improvement had improved psychologic parameters but minimal change in physical ndings. In the 37% who did not get better, neither psychologic nor physical nd-ings improved. Such data, which suggest that psychologic issues affect prognosis, demand that the physiology of psychosocial parameters be better addressed. Otherwise, advances in managing chronic orofacial pain problems and the conditions that may be comorbid with fa-cial pain complaints may not be achieved. 17Although a great deal of effort is dedicated to understanding genetic predisposition for disease, it is equally if not more important to realize that environmental stressors alter the expression of genetic codes and behav-ior. An animal model has shown that placing an identical twin in a harsher environment causes downregulation of GABA receptors and increases locus coeruleus (noradrenergic) modulated stress behaviors.105 It is important to understand that each individual will interpret nociception differently, depending on the inu-ence of cognitive processes on pain percep-tion and allostatic adaptations in response to its lifetime experiences. A TMD is not caused by a single gene mutation but is a result of changes in the ex-pression of many genes that contribute to the pathology and pain characteristic of this preva-lent medical condition. As documented in the OPPERA study, many of the risk factors asso-ciated with TMDs involve mechanical, chemi-cal, or environmental stressors that increase the likelihood of developing and maintaining a chronic pathologic state.106,107 Epigenetics is an emerging area of research that focuses on understanding the impact of environmental factors on the global expression of genes and thus overall health.108 Epigenetics determines how changes in one’s diet; the quantity and quality of sleep; and the amount of exercise, tobacco use, and exposure to drugs and toxins inuence the packaging of DNA.109–111 Thus, epi-genetic changes ultimately control genes that can either protect from or render one more susceptible to disease progression.109–111Suering and Pain: Comorbid Conditions Suffering and pain are different. Though the term is notably absent in most medical diction-aries, Fordyce112 dened suffering as the nega-tive emotional or psychologic state that occurs in response to or in anticipation of nociception, while pain was dened as perceived nocicep-tion. But suffering is not exclusive to pain, as it also characterizes sadness, sorrow, and grief. Anticipation of intense and protracted pain, sadness, or grief does affect the intensity of suffering. Moral and societal premises such as secondary gain also inuence how much suf-fering an individual may demonstrate. Regard-ing sadness, time may improve some wounds. But in the case of pain from uncontrolled eti-ology, sensitization of the anterior cingulate cortex with limbic system and endocrine modulation may make suffering a progressive experience to the individual and those who are touched by that person’s struggle.113 Acute pain, a biologic adaptive pain, is as-sociated with quick onset and short duration. It may be very intense as in postsurgical pain, but the cause-and-effect relationship is usu-ally apparent and the stimuli are not repeated. Central sensitization is induced only as a pro-tective element to protect wound sites. As tis-sues heal, pain reduces, sensitization resolves, and duration of suffering is short.Acute and chronic pain can be distinguished by the duration of pain; acute pain can be-come chronic pain if it lasts longer than 3 to 6 months, or the time it would take connec-tive tissue to heal. Chronic pain is persistent pain that becomes part of the patient’s daily routine. It is resistant to medical treatment be-cause of neuroplastic changes throughout the CNS and in primary nociceptors.69,114 Chronic pain may present with psychopathology such as depression, but this is not always the case.4 What seems to be true in patients with chronic pain is persistent central sensitization and an increased possibility of comorbid conditions. Although conditions like conversion disorders may exist, the links between stressor effects on the CNS and the digestive, respiratory, mus-culoskeletal, cardiovascular, endocrine, and im-mune systems are redening what used to be called somatoform disorders.91,115–118 Chronic nociception, unrelenting stressors, or horric experiences as in posttraumatic stress disor-Suering and Pain: Comorbid Conditions 18Introduction to Orofacial Pain1der can all cause central sensitization, sympa-thetic upregulation, and endocrine abnormali-ties, which may explain why conditions such as headaches, TMDs, IBS, gastroesophageal reux disease, and FM are so prevalent in chronic pain states.119–121 The role of the clinician is changing as sci-ence claries how CNS dysfunction caused by uncontrolled inflammatory processes and chronic stressors leads to a maladap-tive chronic pain state that affects all the major physiologic systems. The fast-paced, ever-changing nature of society unfortunately creates an environment in which people ex-perience the ght-or-ight response multiple times on a daily basis. This lifestyle promotes a state of hyperexcitability characterized by mental exhaustion and a feeling of helpless-ness that favors sympathetic drive and sup-presses parasympathetic function. Practition-ers must see the patient’s whole story, not just the portion seen through the biomedical model. For example, exposure to violence is a common experience, and in patients with chronic pain, exposure to abuse may be three-fold greater than that experienced in the gen-eral population.122 Patients may not always reveal these experiences given the cultural taboos associated with abuse or the repres-sion induced by the sheer horror of the abuse or another catastrophic event. Clinicians must be aware that severe pain and comorbid condi-tions due to maladaptive CNS function may be the only indications of psychosocial distress. It is often a delicate subject to approach, but if pain improvement is to be achieved, clinicians must rst recognize patients with problematic psychosocial histories and then refer them to skilled therapists. A primary goal of the health care provider should be to prevent the transition from an acute episodic disease that is reversible with common pharmaceutical and behavioral treat-ments to a chronic pain state that is not eas-ily altered and is often comorbid with anxiety, depression, and IBS. The risk factors for this transition need to be evaluated and reduced. In particular, the patient should be encouraged to incorporate activities that naturally evoke a parasympathetic response such as walking, swimming, yoga, tai chi, Pilates, meditation, or mindfulness training. These exercises empha-size proper breathing and increasing exibility, and incorporating them into the patient’s daily routine will reduce the negative effect of key risk factors and help to empower the patient to become an active participant in the manage-ment of his or her disease. Chronic Orofacial Pain Disorders: TMDs and Comorbid ConditionsThe 1996 NIH Technology Assessment Confer-ence dened a TMD as “a collection of medical and dental conditions affecting the [TMJ] and/or the muscles of mastication, as well as con-tiguous tissue components.”123 This denition was similar to that published in the third edition of Orofacial Pain: Guidelines for Assessment, Diagnosis, and Management (Quintessence, 1996), which referred to contiguous tissue components as “associated structures.” It is not yet clear what constitutes contiguous tis-sue components for TMDs, and this question strongly inuenced the NIH conference’s major conclusions: “diagnostic classications for TMD are awed as they were based on signs and symptoms and not etiology; etiology was not known, no consensus on what or when to treat existed, and no therapies had proven ef-cacy although behavioral approaches offered the best outcomes with the least risks.” The consensus on TMD etiology and the scope of signs and symptoms has not been achieved, but research on TMDs has provided informa-tion that may help with patient care. Many if not most patients with a TMD will recover with no or minimal care.16,17 A minor-ity of TMD problems become chronic, and of those that do, one-third seemed to resolve over an 8- to 10-year period.124,125 TMD patients 19who signicantly improve may have mini-mal psychologic issues, while patients with chronic TMDs, like those with chronic muscu-loskeletal pain, have psychologic comorbidity similar to other chronic pain patients.104,126–129 Chronic TMD pain, like headache and most other chronic pains, is more prevalent among women, especially when multiple symptoms are present.130–133 It is well known that women with orofacial pain displayed more medi-cal problems than female controls.11 Over a 12-month period, 73% of adults experienced headache, 56% had back pain, 46% had stom-ach pain, and 27% had dental pain.133,134 These ndings coincide with data suggesting that preexisting headache or back, abdominal, or chest pain were better predictors than depres-sion for the onset of facial pain experienced by 12% of the population.135 More than 81% of patients with facial pain also report pain in regions below the head.7, 8 TMD patients fre-quently have symptoms of FM, chronic fatigue syndrome, headaches, panic disorder, gastro-esophageal reux disease, IBS, multiple chem-ical sensitivity, posttraumatic stress disorder, and interstitial cystitis.9 Unfortunately, TMD patients may avoid care when symptoms carry psychosomatic stigma.136 Heart rate variability is a measure of the beat-to-beat time interval that reects the CNS control of the ANS tone.137 Low heart rate variability, when the beat-to-beat time interval becomes inexible, occurs when high sympa-thetic tone impedes parasympathetic (vagal) dampening of cardiac activity.138 Low heart rate variability is a common nding for condi-tions such as cardiovascular disease, diabetes, depression, anxiety, cognitive problems, IBS, gastroesophageal reux disease, posttrau-matic stress disorder, migraine, FM, and sleep apnea.139 High heart rate variability, when parasympathetic control modulates a variable beat-to-beat time interval, is associated with health and improved cognitive capacity.140,141 TMD patients have been differentiated from controls by pain, anxiety, depression, sleep disturbance, and measures of ANS reactivity, and behavioral therapies have been shown to treat these conditions more successfully than traditional dental therapies.142–144 Orofacial pain patients with TMDs and other comorbid condi-tions such as headaches, gastroesophageal re-ux disease, and FM demonstrated low heart rate variability when subjected to stressors compared with controls. Three months after patients were exposed to self-regulation skills aimed at controlling stress, associated jaw, neck, and breathing behaviors and pain scores improved, and measures of heart rate vari-ability no longer differentiated patients from pain-free controls. The improved heart rate variability scores correlated with decreased pain interference scores, suggesting enhanced self-efcacy in the face of stressors. Patients with orofacial pain report a high degree of exposure to traumatic events and signicant disability.120,121 In the past, disabling chronic pain was attributed to the failure of cop-ing skills related to personality type.145,146 The heart rate variability study data suggest that, for some orofacial pain patients with multiple comorbid conditions, specic self-regulation skills may enable patients to cope with pre-viously unrecognized and therefore uncon-trolled physiologic disturbances associated with the pain. Acceptance of a biopsychoso-cial approach by the patient may largely be de-pendent on his or her previous psychosocial experiences.147 Persistent elevation of sympathetic tone and impaired parasympathetic tone may be responsible for many comorbid conditions that affect orofacial pain patients. Heart rate vari-ability is a noninvasive measurable parameter that may track the physiology of ANS prob-lems in patients with trigeminal pain and shed light on its cause.148 Reducing upregulated sympathetic activation, which may drive an out-of-control emotional motor system, may reduce central sensitization that underlies the refractory nature of the spectrum of conditions seen in orofacial pain practice.Chronic Orofacial Pain Disorders: TMDs and Comorbid Conditions 20Introduction to Orofacial Pain1Headache and orofacial pain disorders Recurrent headache may occur in as many as 80% of TMD patients compared with a 20% to 23% occurrence rate in a general popula-tion.149–153 One-third of the population has been estimated to suffer from severe head-ache at some point in their life, a lifetime in-cidence similar to the 34% rate estimated for TMDs, but only 5% to 10% of North Ameri-cans have sought medical advice for severe headache.135,154,155 Although earlier studies have shown associations between TMDs and headache, causal interrelationships have not been demonstrated.131,151,156–159 However, in a study in which 61% of orofacial pain patients had headache complaints and 38% fullled the criteria for migraine, higher migraine dis-ability assessment (MIDAS) scores correlated with masticatory and cervical myalgia but not with the presence or absence of intracapsular TMJ problems.160 More recently, an associa-tion of sleep bruxism and painful TMDs was reported to greatly increase the risk for the development of episodic migraine, episodic tension-type headache, and especially for chronic migraine.161 Interestingly, in women experiencing both TMDs and migraine, the migraine condition only signicantly improved when both conditions were treated. Further-more, women suffering from migraine are likely to have more muscular and articular TMDs, which supports the notion that both disorders are clinically associated.162 This also highlights the importance of physical therapy assessment in the multidisciplinary team ap-proach to managing complex pain patients.162 Headaches and TMDs are major complaints associated with trigeminal pain, leading to sig-nicant suffering and absenteeism from work or school.134,163 Traumatic stressors may play a signicant role in this suffering and pain.120,121 The head and neck muscles are responsible for orienting organisms to collect primary sensory input and executing orofacial behaviors. Ac-cording to the myalgia correlation, these mus-cles may affect the overwhelming input that might contribute to the states of ANS dysfunc-tion and central sensitization that characterize headache and other comorbidities.50,160,164–167Data are emerging from human genetic linkage analysis and association studies sup-porting the notion that mutations in genes in-volved in modulation of the nervous system predispose individuals to a hyperexcitable ner-vous system and thus play an important role in the initiation and maintenance of chronic pain.168 The genes responsible for regulat-ing neurotransmission in both the ascending and descending nociceptive pathways seem to be the ones augmented in all the chronic pain conditions examined thus far, including TMDs and migraine. For example, mutations have been identied in ion channels and recep-tors on neurons and glial cells that are associ-ated with increased neuronal excitability and an enhanced sensitized state of nociceptors. Collectively, results from these studies have begun to provide a clearer understanding of how genetic variants inuenced by environ-mental factors lead to the development of multifactorial pathologic conditions that share overlapping etiologies. There is clearly a need for more specic treatment options for the di-verse array of chronic pain conditions. Findings from these genetic studies may help to direct development of more personalized strategies for managing chronic pain patients, including pharmacologic and nonpharmacologic meth-ods. Finally, it should be noted that there are several novel therapeutic approaches that are showing efcacy in the treatment of migraine, including monoclonal antibodies that target CGRP, vagal nerve stimulation, and the use of cannabinoids.169–171 Given the underlying patho-logic nature of orofacial pain conditions, these therapies are likely to be useful in relieving pain associated with TMDs, neuropathic pain, and other diseases involving sensitization and activation of trigeminal nociceptive neurons. 21ReferencesReferences1. Groenewegen HJ, Uylings HB. The prefrontal cortex and the integration of sensory, limbic and autonomic information. Prog Brain Res 2000;126:3–28.2. Charlton JE, International Association for the Study of Pain. Core Curriculum for Professional Education in Pain. Seattle: IASP, 2005.3. Johannes CB, Le TK, Zhou X, Johnston JA, Dworkin RH. The prevalence of chronic pain in United States adults: Results of an Internet-based survey. J Pain 2010;11: 1230–1239.4. 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