Neuropathic Pain










T
here are four types of pain: nociceptive pain, inammatory
pain, neuropathic pain, and dysfunctional pain
1
(Fig 6-1). These
four types of pain can be divided into two broad groups:
healthy protective pain and chronic dysfunctional pain. Protective
pain includes both acute nociceptive pain and inammatory pain.
Nociceptive pain is a process of transduction and transmission to
the sensory cortex whereby pain is registered in the region of tissue
where the noxious stimulation has occurred, thereby warning the
individual to limit the damage. Inammatory pain is pain following
tissue damage whereby peripheral and central mechanisms cause
Key Points
Clinicians need to recognize and understand that not all
“toothaches” are of odontogenic origin.
Episodic or continuous neuropathic pains may present
with symptoms that mimic odontogenic pain, but these
may require medical or surgical intervention instead of rou-
tine dental intervention. Repeated surgery and prescrip-
tion of antibiotics are not indicated for neuropathic pain.
Clinicians should have an understanding of neuropathic
processes to avoid misdirected or incomplete treatment.
Clinicians should have an understanding of the role of rou-
tine anesthetic and surgical techniques in the causation of
neuropathic pain.
Referral to other health care providers should be a consid-
eration when patients present with complex and confus-
ing symptoms.
Management of neuropathic pain often requires a multi-
dimensional and multidisciplinary approach, and early rec-
ognition and treatment of posttraumatic neuropathy may
prevent chronic pain.
Neuropathic
Pain
6

91
Neuropathic Pain
sensitization of the damaged tissue and the
nearby undamaged tissues. This pain thereby
serves a protective purpose in helping facili-
tate tissue repair.
Chronic pain is a process where the brain
continues to overlay pain in a body region
when the tissues are healed. This type of pain
no longer serves a protective purpose as do
the two healthy pain types. Chronic pain can
either be due to nerve damage (neuropathic
pain) or to pathology of the pain system (dys-
functional pain), which may be caused by am-
plication of pain signals in the central nervous
system (CNS) and can share some of the signs
Fig 6-1 Differing types of pain. Reproduced with permission from Woolf.
1
Noxious stimuli
Heat
Cold
Intense mechanical force
Chemical irritants
Adaptive, high-threshold pain
Early warning system (protective)
Adaptive, low-threshold pain
Tenderness promotes
repair (protective)
Maladaptive, low-threshold pain
Disease state of nervous system
Normal peripheral
tissue and nerves
Peripheral
inammation
Positive
symptoms
Abnormal
central processing
Abnormal
central processing
Peripheral
nerve damage
Nociceptor
sensory neuron
Pain
Autonomic response
Withdrawal reex
Spontaneous pain
Pain hypersensitivity
Spontaneous pain
Pain hypersensitivity
Spontaneous pain
Pain hypersensitivity
Spinal cord
Injury
Stroke
A Nociceptive pain
B Inammatory pain
C Pathologic pain
Inammation
Macrophage
Mast cell
Neutrophil
Granulocyte
Tissue damage
Neuropathic pain
Neural lesion
Positive and negative
symptoms
Dysfunctional pain
No neural lesion
No inammation
Positive symptoms

92
Neuropathic Pain
6
of neuropathic pain, including wind-up, hyper-
algesia, and allodynia.
2
Neuropathic pain is dened as pain that
arises from injury, disease, or dysfunction
of the peripheral or CNS, as compared with
somatic pain, which occurs in response to
noxious stimulation of normal neural recep-
tors.
3
Neuropathic pain is generally classied
according to the agent of insult and anatomi-
cal distribution of the pain. Based on temporal
features, neuropathic pain can be episodic or
continuous and can be peripherally gener-
ated or centrally mediated. Often, both cen-
tral and peripheral sensitization play a role in
the continuation or persistence of the condi-
tion. Patients experiencing neuropathic pain
may complain of a combination of spontane-
ous (stimulus-independent) or touch-evoked
(stimulus-dependent) pain.
4
Sensory signs
and symptoms characteristically accompany
neuropathic pain. These signs may be either
positive, meaning gain in function (eg, hyper-
algesia or allodynia to mechanical or thermal
stimuli); negative, meaning loss of function
(eg, numbness); or a combination of both,
such as dysesthesia.
5
The clinical presentation
of neuropathic pain can be dependent on its
origin and the initial insult that caused it.
6
Throughout this chapter, the codes from
the third edition of the International Headache
Society’s Classication of Headache disor-
ders, third edition, beta version (ICHD)
7
and
The International Classication of Diseases,
Tenth Edition (ICD-10) are presented for each
disorder.
Neuralgia
Head and neck pains are mediated by afferent
bers in the trigeminal nerve, nervus interme-
dius, glossopharyngeal and vagus nerves, and
upper cervical roots via the occipital nerves.
Neuralgia can result when these nerves are
stimulated by compression, distortion, other
forms of irritation, or lesions in the peripheral
or central pathways. A common characteristic
of this pain is a paroxysmal (very short-lasting),
sharp, stabbing, or electric shock–like qual-
ity felt in the area innervated by the involved
nerve and hence the so-called neuralgia. The
pain is often triggered by mild and innocuous
stimuli (allodynia). Neuralgia is named ac-
cording to the nerve involved, with the most
common type being trigeminal neuralgia (TN).
Other neuralgias include glossopharyngeal and
nervus intermedius (geniculate).
Trigeminal neuralgia (ICHD 13.1; ICD-10
G50.0)
TN, also known as tic douloureux, is a pain-
ful condition affecting the face in the distribu-
tion of one or more divisions of the trigeminal
nerve unilaterally. The condition is character-
ized by brief (paroxysmal) electric shock–like
or lancinating pains that are typically precipi-
tated by nonpainful stimuli, such as washing
or lightly touching the face, shaving, talking,
or brushing the teeth. The pain may also be
spontaneous in nature. The paroxysmal pains
are usually severe, with a duration of seconds
to a few minutes. Frequently, there is a refrac-
tory period following a paroxysm in which an
outburst cannot be provoked. Sometimes, sev-
eral paroxysms will occur in succession and
fuse, with the patient describing a longer du-
ration of pain. In addition, some patients who
have frequent attacks of pain will describe
a longer-lasting burning sensation in the same
distribution.
The condition is marked by remission peri-
ods lasting days to years during which minimal
or no pain is noted. The pain-free intervals usu-
ally become shorter and the exacerbations in-
tensify as the neuralgia progresses.
8–10
Attacks
usually occur during waking hours but may also
awaken the patient from sleep.
11,12
Clinically,
there do not appear to be any neurologic de-
cits.
7
Very occasionally, attacks can be accom-
panied by autonomic features, but this is not
typical.
13
The second and third divisions of the
93
Neuralgia
trigeminal nerve are most commonly affected;
the rst division is affected in only 1% to 2%
of patients. The right side of the face is more
often involved than the left; it was hypothesized
that the nerve on the right side would be more
often subject to entrapment because the right
side foramen and ovale and foramen rotundum
are smaller than the left.
14
The pain does not
cross the midline of the face, although the con-
dition may affect the face bilaterally in as many
as 3% to 5% of patients. The neurologic exami-
nation is normal.
7
The average age of onset is
approximately 50 years, and the prevalence has
been estimated to be 107.5 men per million and
200.2 women per million.
15
The term trigeminal neuralgia is a broad
term that can be misinterpreted and unknow-
ingly misused. The ICHD uses the overarching
term classical trigeminal neuralgia (ICHD 13.1.1)
to explain that this is TN with no cause identi-
ed other than neurovascular compression of
the trigeminal nerve in the area of the dorsal
root entry zone.
7
The alternate diagnosis in the
IHCD TN grouping (13.1) is painful trigeminal
neuropathy (13.1.2), which accounts for some
conditions that might mimic the signs and
symptoms of classic TN and would have previ-
ously been known as symptomatic or second-
ary TN in the previous ICHD (second edition).
16
However, it must be noted that many condi-
tions in this group may produce continuous
neuropathic pain as opposed to episodic neu-
ropathic pain and therefore were probably not
best grouped under the overarching category
of TN in the current ICHD. Notwithstanding,
continuous neuropathic pain conditions may
occasionally produce some overlapping symp-
toms with TN. This may be claried with further
research and revised in the next edition of the
ICHD. TN may also be more accurately consid-
ered a secondary neuropathy because it is di-
agnosed in relation to vascular compression of
the trigeminal nerves dorsal root entry zone.
The ICHD divides classic TN into two sub-
types: paroxysmal classic TN (13.1.1.1) and
classic TN with concomitant persistent facial
pain (13.1.1.2) (Box 6-1). This is because a sig-
nicant proportion of classic TN patients de-
scribe brief paroxysmal attacks superimposed
on a dull background pain. In a recent study,
30% of patients with typical short-duration at-
tacks reported a persistent background pain in
addition to the paroxysmal pain.
17
The same
study highlighted a subgroup of patients who
report attacks lasting more than 2 minutes (ac-
cording to ICHD criteria, classic TN has a cut-
off at 2 minutes); the authors speculated that
these patients may be reporting the paroxysm
of neuralgic pain and the after pain as one. Pre-
vious studies have suggested a correlation be-
tween attack duration and disease duration.
18,19
In previous classications of TN, there had
been a dened entity of pretrigeminal neural-
gia, but this is now subsumed into the two
categories of classic TN in the ICHD. However,
practitioners should still be aware that it may
be possible for patients to present for several
months in an almost “prodromal” phase of dull
continuous toothache before developing symp-
toms consistent with classic TN or classic TN
with concomitant persistent facial pain.
20–22
Successful management of pretrigeminal neu-
ralgia is possible with similar medications as
used for classic TN.
21
Any of the presentations of TN discussed
here can present a challenge to the clinicians
diagnostic process because they may mimic
odontogenic pain, depending on the state of
the dentition and the clarity of the patient’s
history. This might cause clinicians to be led
away from a diagnosis of TN. The opposite is
also true in that many other conditions can also
mimic TN, including painful trigeminal neuropa-
thies arising from demyelination (eg, multiple
sclerosis [MS]), space-occupying lesions (cen-
trally or peripherally) or trauma, dental pain,
and trigeminal autonomic cephalalgias. Accord-
ing to the ICHD, pathology producing painful
neuropathic symptoms that mimic TN are now
classied in a group listed as painful TN (ICHD
13.1.2) as opposed to their previous classica-
tion as symptomatic or secondary TN.

94
Neuropathic Pain
6
Pathogenesis
The pathogenesis of classic TN is not com-
pletely understood, but there are many hy-
potheses. Classic TN has been investigated as
a result of demyelination, the loss of the insu-
lating myelin sheath that separates individual
nerve bers. The cause of the demyelination
is most frequently compression of the trigemi-
nal nerve root close to its entry into the pons
by overlying blood vessels.
23
This compression
and resultant deformation of the trigeminal
nerve root and some of its insulating myelin are
thought to allow for spontaneous and ectop ic
nerve ring with ephaptic cross-talk among
adjacent bers (cross-stimulation of C-bers).
24
This hypothesis may account for the presenta-
tion of innocuous stimuli, resulting in sponta-
neous perception of pain. Some researchers
have reported familial TN, suggesting that
there are genetic traits that are autosomal
dominant. For instance, Charcot-Marie-Tooth
disease is an autosomal-dominant sensory
motor type I neuropathy that is associated
with peripheral demyelination and can there-
fore produce TN-like symptoms.
25
Although there appears to be a strong as-
sociation between demyelination and TN, de-
myelination theories alone do not account for
many of the characteristics of this particular
neuropathy. Devor et al
26
proposed the igni-
tion hypothesis, which takes the demyelination
theories one or more steps further. The ignition
hypothesis attempts to explain the following
phenomena:
Triggering: How a trigger stimulus such
as light touch can cause severe pain that
long outlasts the stimulus.
Box 6-1 Summary of presenting features of classic TN purely paroxysmal and classic TN
with concomitant facial pain as dened by the ICHD
7
Classic TN purely paroxysmal
At least three attacks of unilateral facial
pain occurring in one or more of the
trigeminal nerve dermatomes.
Pain must have at least three of the
following characteristics:
Recurring attacks of a paroxysmal
nature (duration of attack: from less
than 1 second to up to 2 minutes)
Severe intensity
Character/quality: electric shock,
shooting, stabbing, or sharp
Triggered by innocuous stimuli to
face (some can be spontaneous,
but there must be at least three
triggered by innocuous stimuli)
No clinically evident neurologic deficit.
No persistent pain between attacks.
Not better accounted for by another
ICHD diagnosis.
Classic TN with concomitant facial pain
Recurrent attacks fulfilling criteria for
classic TN purely paroxysmal.
Between paroxysms of pain, there is a
persistent pain of moderate intensity
in the affected dermatome.
This group of conditions was
previously known as atypical TN or TN
type 2.
95
Neuralgia
Amplication: How the innocuous stim-
ulus results in a spreading response far
beyond the area innervated by the origi-
nally stimulated nerve bers.
Stop mechanism: How the pain re-
sponse is sustained for a period of time
and then actually stops itself.
Rappaport and Devor
27
explained 13 out
of 14 key features of TN based on neuronal
abnormalities related to nerve injury. In most
cases, this injury is related to nerve root com-
pression, but other forms of injury may apply.
Nerves that are injured become hyperexcitable
and therefore may re with little or no stimu-
lus. These so-called ectopic pacemaker sites
may actually be at points of demyelination or at
the ends of severed nerves.
26
Some sites may
re continuously at a low level and produce a
dull, background, burning pain, and others may
require only the slightest stimulation to pro-
duce a long-lasting burst of impulses that re-
sult in severe pain lasting long beyond the ini-
tial stimulus.
28
Nerve bers may recruit other
adjacent bers and so on, causing short-lasting
shooting pain from one point to another.
27
Once ignited, there can be further amplica-
tion of the pain by ephaptic transmission or
electrical cross-talk between nerve bers at
a site of injury or compression, whereby the
adjacent nerve bers have lost their insulating
neural sheaths, allowing direct “short circuit”
stimulation.
29
The stop mechanism can be ex-
plained by hyperpolarization of the neuron. This
stops the burst, and until the ionic imbalance
returns to its prestimulation levels, the nerve
ber can no longer be stimulated.
26
Not only is
the burst of pain stopped, but it also cannot be
triggered again for a period of time. This period
is called the refractory period.
In the majority of patients who have under-
gone surgical treatment for TN, microvascular
compression of the trigeminal nerve root was
identied. These patients mostly responded well
to microvascular decompression (MVD) surgery.
Compressive damage of trigeminal ganglion
has been found in patients as well.
30
If no
pathologic factor other than vascular compres-
sion is identiable, the neuralgia is classied
as classic TN, previously known as primary or
idiopathic TN. The vast majority (> 85%) of TN
patients are diagnosed with classic TN. If the
neuralgia is caused by a veriable lesion such
as a tumor, epidermoid cyst (eg, acoustic neu-
rilemoma or meningioma), cholesteatoma, oste-
oma, aneurysms, or vascular malformations, it
is not classied as TN, but as either painful tri-
geminal neuropathy attributed to space-
occupying lesion (ICHD 13.1.2.5) or painful tri-
geminal neuropathy attributed to other disorder
(ICHD 13.1.2.6).
31
Classic TN must therefore
also be differentiated from other extracranial
causes of facial pain, including local dental dis-
orders, sinus disease, head and neck neo-
plasms, and infections and headache (or facial
pain) associated with a temporomandibular
disorder (TMD) (ICHD 11.7). Additionally, three
other pain conditions that have to be consid-
ered in the differential diagnosis are short-lasting
unilateral neuralgiform headache attacks with
conjunctival injection and tearing (SUNCT; ICHD
3.3), short-lasting unilateral neuralgiform head-
ache attacks with cranial autonomic features
(SUNA; ICHD 3.3) and primary stabbing head-
ache (ICHD 4.7). These three conditions pre-
dominantly affect the rst division of the trigem-
inal nerve in contrast to classic TN, which mostly
involves the second and third divisions. Imaging
studies of the head and brain may be indicated
as part of identifying other causes of the pain.
Treatment
The treatment for classic TN can be divided
into two modalities: medical and surgical.
Medical management
Carbamazepine is the most effective medica-
tion for classic TN with a number to treat of
1.9 (95% condence interval: 1.6 to 2.5) for >
50% pain relief.
32
The initial response to carba-
mazepine is good (70%) but drops dramatically
(20%) after 5 to 16 years of use.
33
The start-

96
Neuropathic Pain
6
ing dosage is 100 mg/day, and then the dos-
age is increased by 100 mg every 2 weeks to
a maximum of 1,200 mg/day in a divided-dose
regimen. A benecial effect is often apparent
within hours to a couple of days after starting
this medication. The most common side effects
include drowsiness, dizziness, unsteadiness,
nausea, and anorexia. These are often transient
and can be reduced by starting with a low dose
and increasing the dose slowly. Aplastic ane-
mia is a rare side effect, while a transient eleva-
tion in liver enzymes may occur in 5% to 10%
of patients, and transient leukopenia may mani-
fest in 5% of patients (persistent in 2%). There-
fore, patients taking this drug need to have
their blood levels carefully monitored for these
potential complications. One suggested proto-
col for monitoring for the side effects of carba-
mazepine is given by Reisner and Pettengill
34
:
Perform a complete (full) blood count
(CBC) and urea and electrolytes (U&E)
preadministration and every 2 to 4 weeks
for the rst 3 months. If the total white
cell count decreases, then stop usage
(this is most likely in the rst 3 months).
Perform liver function tests at baseline
and then every 6 weeks. If they are nor-
mal for two intervals, then discontinue
the tests.
After close monitoring over the rst 3
months, consider checking CBC and U&E
every 3 months or twice per year.
The other rare complication of carba-
mazepine use in a Caucasian population is
Stevens-Johnson syndrome (SJS) or toxic
epidermal necrosis (TEN) (0.01% to 0.06%
incidence). SJS and TEN are differentiated
by the extent of skin detachment, with < 10%
body surface involvement for SJS and > 30%
for TEN. There is a strong association be-
tween a human leucocyte antigen (HLA) al-
lele HLA-B*15:02 and carbamazepine-induced
SJS. Only 1% to 2% of Caucasians are genetic
carriers of this allele as opposed to Han Chi-
nese or Thai (Southeast Asian) populations,
where 15% of the population are carriers. This
results in a much greater risk of SJS in this
population, and HLA screening has shown
to be cost-effective and is recommended for
these populations prior to prescription of car-
bamazepine by both the US Food and Drug
Administration in the United States and the
Medicines Healthcare Regulatory Authority in
the United Kingdom.
35–37
Sustained or slow-release preparations of
carbamazepine have improved compliance and
reduce the sedating side effects of the drug. A
recent Cochrane Database systematic review
of the efcacy of carbamazepine for the treat-
ment of classic TN revealed only ve placebo
and three active randomized controlled trials
(RCTs). The numbers in the studies that could
be evaluated were small but showed that
there is evidence that carbamazepine is effec-
tive in the treatment of TN.
32
Oxcarbazepine, a keto-analog of carbamaze-
pine, may be equally effective in the treatment
of TN.
38,39
Oxcarbazepine can be begun at 150
mg twice daily, increasing the daily dose as
tolerated up to 300 to 600 mg twice daily with
a maximum dose of 2,400 mg/day. The side
effect prole of oxcarbazepine is less severe
than that of carbamazepine; however, hypo-
natremia occurs more frequently when using
oxcarbazepine.
40
Oxcarbazepine is now be-
coming the most likely second drug of choice
after carbamazepine and may replace it as the
rst-choice drug as new evidence emerges.
41
Alternatives to oxcarbazepine include aug-
menting carbamazepine through the use of
baclofen, which has a synergistic effect when
coprescribed with carbamazepine.
42
Following
this, the next best alternative is lamotrigine,
which has been validated for refractory cases,
especially in TN due to MS, with doses be-
tween 100 and 400 mg daily.
42–44
Side effects
may include diplopia, dizziness, headache, and
gastrointestinal symptoms. Dermatologic re-
actions, including SJS, occur in around 0.1%
of patients and often present within 2 to 9
97
Neuralgia
weeks of beginning treatment, so lamotrigine
should be discontinued as soon as possible at
the rst sign of any form of rash.
43
Other anticonvulsants lack sufcient evi-
dence to trial them as rst- or second-line med-
ications in the absence of specic indications:
Phenytoin has been prescribed for the
treatment of TN. However, long-term
success was achieved in only 25% of
cases when used alone. The combination
of phenytoin and baclofen appears to be
more effective.
45,46
Common side effects
are drowsiness, dizziness, and gastroin-
testinal symptoms.
Gabapentin may be an alternative treat-
ment. Compared with carbamazepine and
phenytoin, gabapentin has minimal side
effects and is better tolerated by older
patients.
47,48
However, there are no RCTs
specically investigating the efcacy of
phenytoin or gabapentin for TN.
49,50
Pregabalin, an antiepileptic drug struc-
turally related to gabapentin, has shown
to be efcacious in the treatment of TN
in an open-label study and according to
patient-reported outcomes.
51,52
Topiramate has shown initial promise,
and in a meta-analysis comparing topi-
ramate with carbamazepine, it was re-
ported that there seemed to be no dif-
ferences in the overall effectiveness and
tolerability between these two medi-
cations in the treatment of classic TN;
however, a favorable effect of topiramate
was present after a 2-month duration.
53–55
Topiramate can be begun at 25 mg once
daily, increasing it slowly by 25 mg every
2 weeks, towards a daily dosage of 100 to
400 mg divided twice daily. Side effects
include weight loss, somnolence, anxi-
ety, psychomotor disturbance, urinary/
renal calculi, and glaucoma.
Cochrane database systematic reviews
con cluded that there is insufcient evidence
from RCTs to advocate the use of nonseizure
medications, including tizanidine, tocainide,
proparacaine hydrochloride, pimozide, clomip-
ramine, and amitriptyline, for the treatment
of TN. Overall, the methodologic quality of
the studies was considered poor, and side ef-
fects associated with the medications were
common.
56
Surgical management
A number of peripheral and central surgical
procedures have been suggested as manage-
ment techniques for TN.
41
Peripheral surgical
techniques include neurectomy, cryotherapy,
and alcohol injection. Surgical techniques
aimed at the trigeminal (gasserian) ganglion
often aim to disrupt or destroy nervous tis-
sue and include radiofrequency thermoco-
agulation, percutaneous glycerol rhizotomy,
and percutaneous balloon microcompression.
The central surgical techniques include MVD
and stereotactic radiosurgery (gamma knife)
surgery.
Neurectomy is a peripheral ablative proce-
dure in which the offending trigeminal nerve
branch is avulsed under local or general an-
esthesia. Success rates for neurectomy are
conicting (50% to 64%) and involve relatively
small series with short-term follow-up.
57
Com-
mon side effects are hypoesthesias and par-
esthesias, and pain recurrence is frequent.
58,59
Cryotherapy is a peripheral ablative proce-
dure in which the offending trigeminal branch
is frozen under general or local anesthesia. A
specially designed probe allows the procedure
to be performed without surgical exposure of
the nerve.
60
Generally, the effects of cryother-
apy are short lasting (6 to 12 months), although
longer pain relief has been reported.
60–62
Side
effects may include dysesthesia and/or sen-
sory decits.
Alcohol injections are performed under
local anesthesia. After the affected branch of
the trigeminal nerve is anesthetized, a small
amount of absolute alcohol is deposited. Com-
pared with neurectomy and radiofrequency

98
Neuropathic Pain
6
thermocoagulation, alcohol blocks result in
a higher percentage of recurrence but fewer
side effects.
58
Side effects typically include
hypoesthesia, paresthesia, and dysesthesia
as well as the potential for tissue brosis, re-
activation of herpes zoster, and bony necro-
sis.
57
Duration of pain relief is generally less
than 1 year.
63
However, the procedure can be
repeated without impact on the extent or du-
ration of pain relief.
63
Because of the risk of
developing neuropathic pain, peripheral proce-
dures should really only be used for patients
with signicant medical comorbidities that
would make other surgical treatments or man-
agement techniques unsafe.
57
Three types of trigeminal ganglion proce-
dures are available for treatment of TN. Per-
cutaneous radiofrequency thermocoagulation
and percutaneous glycerol rhizotomy are neu-
rosurgical procedures in which a uoroscopi-
cally guided needle is inserted through the
foramen ovale of the patient under sedation.
After careful manipulation of the needle and
feedback from the patient, the selected nerve
bers are destroyed by thermal lesioning or
by injection of anhydrous glycerol.
64–66
Cor-
neal numbness and masseter weakness are
the most common complications of radiofre-
quency thermocoagulation (10% to 12%).
67
Corneal numbness and dysesthesia are the
most common complications of percutaneous
glycerol rhizotomy (8% each).
67
Percutaneous balloon microcompression
is a neurosurgical procedure in which the tri-
geminal nerve is compressed by inating a
tiny balloon in the area of the involved nerve
bers.
68,69
The needle placement is similar to
that of the other two procedures. Reports
show high rates of immediate pain relief with
balloon compression (91% to 100%), and the
recurrence rates at 12 to 18 months were low
(2.5% to 5%).
70–72
A retrospective study with
an average follow-up time of almost 11 years
reported 19% recurrence within a 5-year period
and 32% recurrence over a 20-year period.
73
Side effects of this procedure include numb-
ness and dysesthesia, the severity of which
may be related to the amount of compression
applied.
70
Transient masseter weakness is re-
ported with high frequency.
74
Other complica-
tions include arterial and cranial nerve injuries.
An alternative to rhizotomy is MVD of the
trigeminal ganglion and dorsal root, rst de-
scribed in 1952 by Taarnhøj
75
in Denmark and
by Love
76
in the United States. Jannetta
77
re-
ned and popularized this procedure, which in-
volves a postauricular craniotomy into the pos-
terior fossa, allowing its exploration. The cortex
is carefully lifted, exposing the root entry zone
of the trigeminal nerve while the offending
vessel or lesion responsible for compressing
the nerve root is located. The superior cerebel-
lar artery is the most common offending ves-
sel. The vessel is carefully dissected from the
trigeminal nerve, and a separator (often some
form of sponge) is placed between the struc-
tures, often resulting in immediate success. Al-
though MVD appears to have great long-term
success in terms of duration of effect and de-
creased neuropathic adverse effects, a major
surgical procedure is required, along with its
accompanying morbidity (0.3% to 3%) and
mortality.
78
Patient selection is therefore ex-
tremely important. Relatively young, healthy
patients are the best candidates.
The identication and then selection of pa-
tients with sufciently signicant vascular con-
tact for MVD procedures is also problematic.
In a recent prospective study from the Danish
Headache Centre, 135 patients with classic TN
were assessed by high-quality blinded mag-
netic resonance imaging (MRI).
79
These inves-
tigators found that on both the symptomatic
and asymptomatic sides (89% and 78%, re-
spectively), some form of contact between the
adjacent vasculature and trigeminal dorsal root
entry zone was common. However, severe dis-
placement or atrophy of the trigeminal nerve
occurred more often on the symptomatic side.
A minimally invasive method to treat TN is
stereotactic neurosurgery (gamma knife sur-
gery). Precisely focused radiation of 40 to 90

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There are four types of pain: nociceptive pain, inammatory pain, neuropathic pain, and dysfunctional pain1 (Fig 6-1). These four types of pain can be divided into two broad groups: healthy protective pain and chronic dysfunctional pain. Protective pain includes both acute nociceptive pain and inammatory pain. Nociceptive pain is a process of transduction and transmission to the sensory cortex whereby pain is registered in the region of tissue where the noxious stimulation has occurred, thereby warning the individual to limit the damage. Inammatory pain is pain following tissue damage whereby peripheral and central mechanisms cause Key Points◊ Clinicians need to recognize and understand that not all “toothaches” are of odontogenic origin.◊ Episodic or continuous neuropathic pains may present with symptoms that mimic odontogenic pain, but these may require medical or surgical intervention instead of rou-tine dental intervention. Repeated surgery and prescrip-tion of antibiotics are not indicated for neuropathic pain.◊ Clinicians should have an understanding of neuropathic processes to avoid misdirected or incomplete treatment. ◊ Clinicians should have an understanding of the role of rou-tine anesthetic and surgical techniques in the causation of neuropathic pain.◊ Referral to other health care providers should be a consid-eration when patients present with complex and confus-ing symptoms. ◊ Management of neuropathic pain often requires a multi-dimensional and multidisciplinary approach, and early rec-ognition and treatment of posttraumatic neuropathy may prevent chronic pain. Neuropathic Pain6 91Neuropathic Painsensitization of the damaged tissue and the nearby undamaged tissues. This pain thereby serves a protective purpose in helping facili-tate tissue repair.Chronic pain is a process where the brain continues to overlay pain in a body region when the tissues are healed. This type of pain no longer serves a protective purpose as do the two healthy pain types. Chronic pain can either be due to nerve damage (neuropathic pain) or to pathology of the pain system (dys-functional pain), which may be caused by am-plication of pain signals in the central nervous system (CNS) and can share some of the signs Fig 6-1 Differing types of pain. Reproduced with permission from Woolf.1Noxious stimuliHeatColdIntense mechanical forceChemical irritantsAdaptive, high-threshold painEarly warning system (protective)Adaptive, low-threshold painTenderness promotes repair (protective)Maladaptive, low-threshold painDisease state of nervous systemNormal peripheraltissue and nervesPeripheral inammationPositive symptomsAbnormalcentral processingAbnormalcentral processingPeripheralnerve damageNociceptorsensory neuronPainAutonomic responseWithdrawal reexSpontaneous painPain hypersensitivitySpontaneous painPain hypersensitivitySpontaneous painPain hypersensitivitySpinal cordInjuryStrokeA Nociceptive painB Inammatory painC Pathologic painInammationMacrophageMast cellNeutrophilGranulocyteTissue damageNeuropathic painNeural lesionPositive and negative symptomsDysfunctional painNo neural lesionNo inammationPositive symptoms 92Neuropathic Pain6of neuropathic pain, including wind-up, hyper-algesia, and allodynia.2Neuropathic pain is dened as pain that arises from injury, disease, or dysfunction of the peripheral or CNS, as compared with somatic pain, which occurs in response to noxious stimulation of normal neural recep-tors.3 Neuropathic pain is generally classied according to the agent of insult and anatomi-cal distribution of the pain. Based on temporal features, neuropathic pain can be episodic or continuous and can be peripherally gener-ated or centrally mediated. Often, both cen-tral and peripheral sensitization play a role in the continuation or persistence of the condi-tion. Patients experiencing neuropathic pain may complain of a combination of spontane-ous (stimulus-independent) or touch-evoked (stimulus-dependent) pain.4 Sensory signs and symptoms characteristically accompany neuropathic pain. These signs may be either positive, meaning gain in function (eg, hyper-algesia or allodynia to mechanical or thermal stimuli); negative, meaning loss of function (eg, numbness); or a combination of both, such as dysesthesia.5 The clinical presentation of neuropathic pain can be dependent on its origin and the initial insult that caused it.6 Throughout this chapter, the codes from the third edition of the International Headache Society’s Classication of Headache disor-ders, third edition, beta version (ICHD)7 and The International Classication of Diseases, Tenth Edition (ICD-10) are presented for each disorder.NeuralgiaHead and neck pains are mediated by afferent bers in the trigeminal nerve, nervus interme-dius, glossopharyngeal and vagus nerves, and upper cervical roots via the occipital nerves. Neuralgia can result when these nerves are stimulated by compression, distortion, other forms of irritation, or lesions in the peripheral or central pathways. A common characteristic of this pain is a paroxysmal (very short-lasting), sharp, stabbing, or electric shock–like qual-ity felt in the area innervated by the involved nerve and hence the so-called neuralgia. The pain is often triggered by mild and innocuous stimuli (allodynia). Neuralgia is named ac-cording to the nerve involved, with the most common type being trigeminal neuralgia (TN). Other neuralgias include glossopharyngeal and nervus intermedius (geniculate).Trigeminal neuralgia (ICHD 13.1; ICD-10 G50.0)TN, also known as tic douloureux, is a pain-ful condition affecting the face in the distribu-tion of one or more divisions of the trigeminal nerve unilaterally. The condition is character-ized by brief (paroxysmal) electric shock–like or lancinating pains that are typically precipi-tated by nonpainful stimuli, such as washing or lightly touching the face, shaving, talking, or brushing the teeth. The pain may also be spontaneous in nature. The paroxysmal pains are usually severe, with a duration of seconds to a few minutes. Frequently, there is a refrac-tory period following a paroxysm in which an outburst cannot be provoked. Sometimes, sev-eral paroxysms will occur in succession and fuse, with the patient describing a longer du-ration of pain. In addition, some patients who have frequent attacks of pain will describe a longer-lasting burning sensation in the same distribution.The condition is marked by remission peri-ods lasting days to years during which minimal or no pain is noted. The pain-free intervals usu-ally become shorter and the exacerbations in-tensify as the neuralgia progresses.8–10 Attacks usually occur during waking hours but may also awaken the patient from sleep.11,12 Clinically, there do not appear to be any neurologic de-cits.7 Very occasionally, attacks can be accom-panied by autonomic features, but this is not typical.13 The second and third divisions of the 93Neuralgiatrigeminal nerve are most commonly affected; the rst division is affected in only 1% to 2% of patients. The right side of the face is more often involved than the left; it was hypothesized that the nerve on the right side would be more often subject to entrapment because the right side foramen and ovale and foramen rotundum are smaller than the left.14 The pain does not cross the midline of the face, although the con-dition may affect the face bilaterally in as many as 3% to 5% of patients. The neurologic exami-nation is normal.7 The average age of onset is approximately 50 years, and the prevalence has been estimated to be 107.5 men per million and 200.2 women per million.15 The term trigeminal neuralgia is a broad term that can be misinterpreted and unknow-ingly misused. The ICHD uses the overarching term classical trigeminal neuralgia (ICHD 13.1.1) to explain that this is TN with no cause identi-ed other than neurovascular compression of the trigeminal nerve in the area of the dorsal root entry zone.7 The alternate diagnosis in the IHCD TN grouping (13.1) is painful trigeminal neuropathy (13.1.2), which accounts for some conditions that might mimic the signs and symptoms of classic TN and would have previ-ously been known as symptomatic or second-ary TN in the previous ICHD (second edition).16 However, it must be noted that many condi-tions in this group may produce continuous neuropathic pain as opposed to episodic neu-ropathic pain and therefore were probably not best grouped under the overarching category of TN in the current ICHD. Notwithstanding, continuous neuropathic pain conditions may occasionally produce some overlapping symp-toms with TN. This may be claried with further research and revised in the next edition of the ICHD. TN may also be more accurately consid-ered a secondary neuropathy because it is di-agnosed in relation to vascular compression of the trigeminal nerve’s dorsal root entry zone.The ICHD divides classic TN into two sub-types: paroxysmal classic TN (13.1.1.1) and classic TN with concomitant persistent facial pain (13.1.1.2) (Box 6-1). This is because a sig-nicant proportion of classic TN patients de-scribe brief paroxysmal attacks superimposed on a dull background pain. In a recent study, 30% of patients with typical short-duration at-tacks reported a persistent background pain in addition to the paroxysmal pain.17 The same study highlighted a subgroup of patients who report attacks lasting more than 2 minutes (ac-cording to ICHD criteria, classic TN has a cut-off at 2 minutes); the authors speculated that these patients may be reporting the paroxysm of neuralgic pain and the after pain as one. Pre-vious studies have suggested a correlation be-tween attack duration and disease duration.18,19In previous classications of TN, there had been a dened entity of pretrigeminal neural-gia, but this is now subsumed into the two categories of classic TN in the ICHD. However, practitioners should still be aware that it may be possible for patients to present for several months in an almost “prodromal” phase of dull continuous toothache before developing symp-toms consistent with classic TN or classic TN with concomitant persistent facial pain.20–22 Successful management of pretrigeminal neu-ralgia is possible with similar medications as used for classic TN.21 Any of the presentations of TN discussed here can present a challenge to the clinician’s diagnostic process because they may mimic odontogenic pain, depending on the state of the dentition and the clarity of the patient’s history. This might cause clinicians to be led away from a diagnosis of TN. The opposite is also true in that many other conditions can also mimic TN, including painful trigeminal neuropa-thies arising from demyelination (eg, multiple sclerosis [MS]), space-occupying lesions (cen-trally or peripherally) or trauma, dental pain, and trigeminal autonomic cephalalgias. Accord-ing to the ICHD, pathology producing painful neuropathic symptoms that mimic TN are now classied in a group listed as painful TN (ICHD 13.1.2) as opposed to their previous classica-tion as symptomatic or secondary TN. 94Neuropathic Pain6Pathogenesis The pathogenesis of classic TN is not com-pletely understood, but there are many hy-potheses. Classic TN has been investigated as a result of demyelination, the loss of the insu-lating myelin sheath that separates individual nerve bers. The cause of the demyelination is most frequently compression of the trigemi-nal nerve root close to its entry into the pons by overlying blood vessels.23 This compression and resultant deformation of the trigeminal nerve root and some of its insulating myelin are thought to allow for spontaneous and ectop ic nerve ring with ephaptic cross-talk among adjacent bers (cross-stimulation of C-bers).24 This hypothesis may account for the presenta-tion of innocuous stimuli, resulting in sponta-neous perception of pain. Some researchers have reported familial TN, suggesting that there are genetic traits that are autosomal dominant. For instance, Charcot-Marie-Tooth disease is an autosomal-dominant sensory motor type I neuropathy that is associated with peripheral demyelination and can there-fore produce TN-like symptoms.25Although there appears to be a strong as-sociation between demyelination and TN, de-myelination theories alone do not account for many of the characteristics of this particular neuropathy. Devor et al26 proposed the igni-tion hypothesis, which takes the demyelination theories one or more steps further. The ignition hypothesis attempts to explain the following phenomena:• Triggering: How a trigger stimulus such as light touch can cause severe pain that long outlasts the stimulus.Box 6-1 Summary of presenting features of classic TN purely paroxysmal and classic TN with concomitant facial pain as dened by the ICHD7Classic TN purely paroxysmal • At least three attacks of unilateral facial pain occurring in one or more of the trigeminal nerve dermatomes.• Pain must have at least three of the following characteristics: – Recurring attacks of a paroxysmal nature (duration of attack: from less than 1 second to up to 2 minutes) – Severe intensity – Character/quality: electric shock, shooting, stabbing, or sharp – Triggered by innocuous stimuli to face (some can be spontaneous, but there must be at least three triggered by innocuous stimuli)• No clinically evident neurologic deficit.• No persistent pain between attacks.• Not better accounted for by another ICHD diagnosis.Classic TN with concomitant facial pain• Recurrent attacks fulfilling criteria for classic TN purely paroxysmal. • Between paroxysms of pain, there is a persistent pain of moderate intensity in the affected dermatome.• This group of conditions was previously known as atypical TN or TN type 2. 95Neuralgia• Amplication: How the innocuous stim-ulus results in a spreading response far beyond the area innervated by the origi-nally stimulated nerve bers.• Stop mechanism: How the pain re-sponse is sustained for a period of time and then actually stops itself.Rappaport and Devor27 explained 13 out of 14 key features of TN based on neuronal abnormalities related to nerve injury. In most cases, this injury is related to nerve root com-pression, but other forms of injury may apply. Nerves that are injured become hyperexcitable and therefore may re with little or no stimu-lus. These so-called ectopic pacemaker sites may actually be at points of demyelination or at the ends of severed nerves.26 Some sites may re continuously at a low level and produce a dull, background, burning pain, and others may require only the slightest stimulation to pro-duce a long-lasting burst of impulses that re-sult in severe pain lasting long beyond the ini-tial stimulus.28 Nerve bers may recruit other adjacent bers and so on, causing short-lasting shooting pain from one point to another.27 Once ignited, there can be further amplica-tion of the pain by ephaptic transmission or electrical cross-talk between nerve bers at a site of injury or compression, whereby the adjacent nerve bers have lost their insulating neural sheaths, allowing direct “short circuit” stimulation.29 The stop mechanism can be ex-plained by hyperpolarization of the neuron. This stops the burst, and until the ionic imbalance returns to its prestimulation levels, the nerve ber can no longer be stimulated.26 Not only is the burst of pain stopped, but it also cannot be triggered again for a period of time. This period is called the refractory period.In the majority of patients who have under-gone surgical treatment for TN, microvascular compression of the trigeminal nerve root was identied. These patients mostly responded well to microvascular decompression (MVD) surgery. Compressive damage of trigeminal ganglion has been found in patients as well.30 If no pathologic factor other than vascular compres-sion is identiable, the neuralgia is classied as classic TN, previously known as primary or idiopathic TN. The vast majority (> 85%) of TN patients are diagnosed with classic TN. If the neuralgia is caused by a veriable lesion such as a tumor, epidermoid cyst (eg, acoustic neu-rilemoma or meningioma), cholesteatoma, oste-oma, aneurysms, or vascular malformations, it is not classied as TN, but as either painful tri-geminal neuropathy attributed to space- occupying lesion (ICHD 13.1.2.5) or painful tri-geminal neuropathy attributed to other disorder (ICHD 13.1.2.6).31 Classic TN must therefore also be differentiated from other extracranial causes of facial pain, including local dental dis-orders, sinus disease, head and neck neo-plasms, and infections and headache (or facial pain) associated with a temporomandibular disorder (TMD) (ICHD 11.7). Additionally, three other pain conditions that have to be consid-ered in the differential diagnosis are short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT; ICHD 3.3), short-lasting unilateral neuralgiform head-ache attacks with cranial autonomic features (SUNA; ICHD 3.3) and primary stabbing head-ache (ICHD 4.7). These three conditions pre-dominantly affect the rst division of the trigem-inal nerve in contrast to classic TN, which mostly involves the second and third divisions. Imaging studies of the head and brain may be indicated as part of identifying other causes of the pain. TreatmentThe treatment for classic TN can be divided into two modalities: medical and surgical. Medical managementCarbamazepine is the most effective medica-tion for classic TN with a number to treat of 1.9 (95% condence interval: 1.6 to 2.5) for > 50% pain relief.32 The initial response to carba-mazepine is good (70%) but drops dramatically (20%) after 5 to 16 years of use.33 The start- 96Neuropathic Pain6ing dosage is 100 mg/day, and then the dos-age is increased by 100 mg every 2 weeks to a maximum of 1,200 mg/day in a divided-dose regimen. A benecial effect is often apparent within hours to a couple of days after starting this medication. The most common side effects include drowsiness, dizziness, unsteadiness, nausea, and anorexia. These are often transient and can be reduced by starting with a low dose and increasing the dose slowly. Aplastic ane-mia is a rare side effect, while a transient eleva-tion in liver enzymes may occur in 5% to 10% of patients, and transient leukopenia may mani-fest in 5% of patients (persistent in 2%). There-fore, patients taking this drug need to have their blood levels carefully monitored for these potential complications. One suggested proto-col for monitoring for the side effects of carba-mazepine is given by Reisner and Pettengill34:• Perform a complete (full) blood count (CBC) and urea and electrolytes (U&E) preadministration and every 2 to 4 weeks for the rst 3 months. If the total white cell count decreases, then stop usage (this is most likely in the rst 3 months).• Perform liver function tests at baseline and then every 6 weeks. If they are nor-mal for two intervals, then discontinue the tests. • After close monitoring over the rst 3 months, consider checking CBC and U&E every 3 months or twice per year.The other rare complication of carba-mazepine use in a Caucasian population is Stevens-Johnson syndrome (SJS) or toxic epidermal necrosis (TEN) (0.01% to 0.06% incidence). SJS and TEN are differentiated by the extent of skin detachment, with < 10% body surface involvement for SJS and > 30% for TEN. There is a strong association be-tween a human leucocyte antigen (HLA) al-lele HLA-B*15:02 and carbamazepine-induced SJS. Only 1% to 2% of Caucasians are genetic carriers of this allele as opposed to Han Chi-nese or Thai (Southeast Asian) populations, where 15% of the population are carriers. This results in a much greater risk of SJS in this population, and HLA screening has shown to be cost-effective and is recommended for these populations prior to prescription of car-bamazepine by both the US Food and Drug Administration in the United States and the Medicines Healthcare Regulatory Authority in the United Kingdom.35–37Sustained or slow-release preparations of carbamazepine have improved compliance and reduce the sedating side effects of the drug. A recent Cochrane Database systematic review of the efcacy of carbamazepine for the treat-ment of classic TN revealed only ve placebo and three active randomized controlled trials (RCTs). The numbers in the studies that could be evaluated were small but showed that there is evidence that carbamazepine is effec-tive in the treatment of TN.32Oxcarbazepine, a keto-analog of carbamaze-pine, may be equally effective in the treatment of TN.38,39 Oxcarbazepine can be begun at 150 mg twice daily, increasing the daily dose as tolerated up to 300 to 600 mg twice daily with a maximum dose of 2,400 mg/day. The side effect prole of oxcarbazepine is less severe than that of carbamazepine; however, hypo-natremia occurs more frequently when using oxcarbazepine.40 Oxcarbazepine is now be-coming the most likely second drug of choice after carbamazepine and may replace it as the rst-choice drug as new evidence emerges.41Alternatives to oxcarbazepine include aug-menting carbamazepine through the use of baclofen, which has a synergistic effect when coprescribed with carbamazepine.42 Following this, the next best alternative is lamotrigine, which has been validated for refractory cases, especially in TN due to MS, with doses be-tween 100 and 400 mg daily.42–44 Side effects may include diplopia, dizziness, headache, and gastrointestinal symptoms. Dermatologic re-actions, including SJS, occur in around 0.1% of patients and often present within 2 to 9 97Neuralgiaweeks of beginning treatment, so lamotrigine should be discontinued as soon as possible at the rst sign of any form of rash.43Other anticonvulsants lack sufcient evi-dence to trial them as rst- or second-line med-ications in the absence of specic indications:• Phenytoin has been prescribed for the treatment of TN. However, long-term success was achieved in only 25% of cases when used alone. The combination of phenytoin and baclofen appears to be more effective.45,46 Common side effects are drowsiness, dizziness, and gastroin-testinal symptoms.• Gabapentin may be an alternative treat-ment. Compared with carbamazepine and phenytoin, gabapentin has minimal side effects and is better tolerated by older patients.47,48 However, there are no RCTs specically investigating the efcacy of phenytoin or gabapentin for TN.49,50 • Pregabalin, an antiepileptic drug struc-turally related to gabapentin, has shown to be efcacious in the treatment of TN in an open-label study and according to patient-reported outcomes.51,52 • Topiramate has shown initial promise, and in a meta-analysis comparing topi-ramate with carbamazepine, it was re-ported that there seemed to be no dif-ferences in the overall effectiveness and tolerability between these two medi-cations in the treatment of classic TN; however, a favorable effect of topiramate was present after a 2-month duration.53–55 Topiramate can be begun at 25 mg once daily, increasing it slowly by 25 mg every 2 weeks, towards a daily dosage of 100 to 400 mg divided twice daily. Side effects include weight loss, somnolence, anxi-ety, psychomotor disturbance, urinary/ renal calculi, and glaucoma. Cochrane database systematic reviews con cluded that there is insufcient evidence from RCTs to advocate the use of nonseizure medications, including tizanidine, tocainide, proparacaine hydrochloride, pimozide, clomip-ramine, and amitriptyline, for the treatment of TN. Overall, the methodologic quality of the studies was considered poor, and side ef-fects associated with the medications were common.56 Surgical management A number of peripheral and central surgical procedures have been suggested as manage-ment techniques for TN.41 Peripheral surgical techniques include neurectomy, cryotherapy, and alcohol injection. Surgical techniques aimed at the trigeminal (gasserian) ganglion often aim to disrupt or destroy nervous tis-sue and include radiofrequency thermoco-agulation, percutaneous glycerol rhizotomy, and percutaneous balloon microcompression. The central surgical techniques include MVD and stereotactic radiosurgery (gamma knife) surgery. Neurectomy is a peripheral ablative proce-dure in which the offending trigeminal nerve branch is avulsed under local or general an-esthesia. Success rates for neurectomy are conicting (50% to 64%) and involve relatively small series with short-term follow-up.57 Com-mon side effects are hypoesthesias and par-esthesias, and pain recurrence is frequent.58,59 Cryotherapy is a peripheral ablative proce-dure in which the offending trigeminal branch is frozen under general or local anesthesia. A specially designed probe allows the procedure to be performed without surgical exposure of the nerve.60 Generally, the effects of cryother-apy are short lasting (6 to 12 months), although longer pain relief has been reported.60–62 Side effects may include dysesthesia and/or sen-sory decits. Alcohol injections are performed under local anesthesia. After the affected branch of the trigeminal nerve is anesthetized, a small amount of absolute alcohol is deposited. Com-pared with neurectomy and radiofrequency 98Neuropathic Pain6thermocoagulation, alcohol blocks result in a higher percentage of recurrence but fewer side effects.58 Side effects typically include hypoesthesia, paresthesia, and dysesthesia as well as the potential for tissue brosis, re-activation of herpes zoster, and bony necro-sis.57 Duration of pain relief is generally less than 1 year.63 However, the procedure can be repeated without impact on the extent or du-ration of pain relief.63 Because of the risk of developing neuropathic pain, peripheral proce-dures should really only be used for patients with signicant medical comorbidities that would make other surgical treatments or man-agement techniques unsafe.57 Three types of trigeminal ganglion proce-dures are available for treatment of TN. Per-cutaneous radiofrequency thermocoagulation and percutaneous glycerol rhizotomy are neu-rosurgical procedures in which a uoroscopi-cally guided needle is inserted through the foramen ovale of the patient under sedation. After careful manipulation of the needle and feedback from the patient, the selected nerve bers are destroyed by thermal lesioning or by injection of anhydrous glycerol.64–66 Cor-neal numbness and masseter weakness are the most common complications of radiofre-quency thermocoagulation (10% to 12%).67 Corneal numbness and dysesthesia are the most common complications of percutaneous glycerol rhizotomy (8% each).67 Percutaneous balloon microcompression is a neurosurgical procedure in which the tri-geminal nerve is compressed by inating a tiny balloon in the area of the involved nerve bers.68,69 The needle placement is similar to that of the other two procedures. Reports show high rates of immediate pain relief with balloon compression (91% to 100%), and the recurrence rates at 12 to 18 months were low (2.5% to 5%).70–72 A retrospective study with an average follow-up time of almost 11 years reported 19% recurrence within a 5-year period and 32% recurrence over a 20-year period.73 Side effects of this procedure include numb-ness and dysesthesia, the severity of which may be related to the amount of compression applied.70 Transient masseter weakness is re-ported with high frequency.74 Other complica-tions include arterial and cranial nerve injuries. An alternative to rhizotomy is MVD of the trigeminal ganglion and dorsal root, rst de-scribed in 1952 by Taarnhøj75 in Denmark and by Love76 in the United States. Jannetta77 re-ned and popularized this procedure, which in-volves a postauricular craniotomy into the pos-terior fossa, allowing its exploration. The cortex is carefully lifted, exposing the root entry zone of the trigeminal nerve while the offending vessel or lesion responsible for compressing the nerve root is located. The superior cerebel-lar artery is the most common offending ves-sel. The vessel is carefully dissected from the trigeminal nerve, and a separator (often some form of sponge) is placed between the struc-tures, often resulting in immediate success. Al-though MVD appears to have great long-term success in terms of duration of effect and de-creased neuropathic adverse effects, a major surgical procedure is required, along with its accompanying morbidity (0.3% to 3%) and mortality.78 Patient selection is therefore ex-tremely important. Relatively young, healthy patients are the best candidates.The identication and then selection of pa-tients with sufciently signicant vascular con-tact for MVD procedures is also problematic. In a recent prospective study from the Danish Headache Centre, 135 patients with classic TN were assessed by high-quality blinded mag-netic resonance imaging (MRI).79 These inves-tigators found that on both the symptomatic and asymptomatic sides (89% and 78%, re-spectively), some form of contact between the adjacent vasculature and trigeminal dorsal root entry zone was common. However, severe dis-placement or atrophy of the trigeminal nerve occurred more often on the symptomatic side.A minimally invasive method to treat TN is stereotactic neurosurgery (gamma knife sur-gery). Precisely focused radiation of 40 to 90 99NeuralgiaGy emitted from 201 photo beams is applied to the trigeminal root entry zone in the posterior fossa. Compared with other procedures, onset of pain relief is delayed.80 Reports of pain re-lief vary from 61% to 92%, while recurrence rates vary from 10% to 27%.80–83 Dysesthesia is the most prominent side effect related to stereotactic radiosurgery (9%), and this ap-pears inversely related with pain control.67,84–86 Repeat surgeries seem to be as efcacious as initial surgeries.84–87 Safety and efcacy of the procedure after more than one repeat surgery have not yet been denitively established, and repeat surgery should be used selectively be-cause limited data are available on the effects of cumulative radiation dose.88,89 Furthermore, data are also lacking on which patients to treat with a repeat surgery and, when treated with a repeat surgery, which target to aim for and with which dose.90 From the limited data avail-able, results may suggest that those who de-veloped facial numbness following the rst surgery along with a good pain response are more likely to benet from a second surgery, if required.87,91 There are no RCTs comparing different types of surgeries or comparing surgeries with medications for TN. A thorough systematic re-view including only high-quality studies with actuarial data evaluated the treatment efcacy of radiofrequency thermocoagulation, per-cutaneous glycerol rhizotomy, percutaneous balloon compression, and stereotactic radio-surgery.67 This review revealed that, whereas radiofrequency thermocoagulation showed the longest pain relief, the complications, though transient, were also the most frequent. Ra-diofrequency thermocoagulation and percu-taneous glycerol rhizotomy yielded higher percentages of complete pain relief at 6, 12, and 24 months than stereotactic radiosurgery. However, the pain-relieving effects of glycerol rhizotomy rapidly declined after 2 years. It has been reported that MVD and balloon com-pression have the best prospects to improve the quality of the patient’s life. Percutaneous glycerol rhizotomy and radiofrequency ther-mocoagulation also yielded favorable results, whereas medications were the least likely to improve the patient’s quality of life.92 A sys-tematic review concluded that there is a pau-city of high-quality evidence for the efcacy of most neurosurgical procedures (no studies of MVD met inclusion criteria). All the surgical techniques examined in the review produced variable pain relief, but several also resulted in sensory side effects.93The American Academy of Neurology and the European Federation of Neurological So-cieties have all published guidelines regarding TN management (medical and surgical), and the International Association for the Study of Pain (IASP) neuropathic pain special interest group has also published a review of interven-tional management in neuropathic pain.94,95 The IASP review concluded that, on the basis of the current evidence, either peripheral pro-cedures are ineffective or there is a lack of evidence of their effectiveness. On the basis of the current literature, there is inconclusive, low-quality evidence for recommending MVD, radiofrequency or glycerol rhizotomy, balloon compression, or stereotactic radiosurgery; however, consideration should be given to using these in the face of classic TN refractory to medical management because patients would seem to benet from them. The choice between these surgical strategies is based on a level of certainty of diagnosis of TN, socio-demographics, patient preference, patient’s gen-eral health, local expertise, and the presence or absence of vascular compression on MRI. Glossopharyngeal neuralgia (ICHD 13.2; ICD-10 G52.1) Glossopharyngeal neuralgia (ICHD 13.2) is sim-ilar in character to TN but is present in the distri-bution of the glossopharyngeal nerve and may be present in the distribution of the auricular and pharyngeal branches of the vagus nerve. The pain is typically severe; transient; stabbing 100Neuropathic Pain6or burning; and located in the ear, base of the tongue, tonsillar fossa, or beneath the angle of the jaw. Estimates of its incidence are fraught with methodologic difculty but are thought to be about 0.7/100,000 per annum with little sex differentiation.96 The pain is unilateral, al-though 1% to 2% of patients may experience asynchronous bilateral pain. The paroxysms of pain usually last seconds to 2 minutes and are provoked by swallowing, chewing, talking, or yawning. There may also be concomitant vagal symptoms given the neuroanatomy of the glossopharyngeal and vagus nerves. Glos-sopharyngeal neuralgia may relapse and remit like TN.97 The co-occurrence of TN and glosso-pharyngeal neuralgia is common and expected to occur in 10% to 12% of glossopharyngeal neuralgia patients.97 The neurologic examina-tion is normal. The pathophysiology is thought to be similar to that of idiopathic TN. The evaluation of a patient with glossopha-ryngeal neuralgia should include an MRI scan with contrast to exclude a glossopharyngeal neuralgia secondary to other pathology either centrally or peripherally arising from such pa-thology as posterior fossa tumors, fusiform (dolichoectatic) vertebral or basilar arterial pa-thology, vascular anomalies, infection affecting the course of the glossopharyngeal nerve pe-ripherally, and nasopharyngeal tumors. Effective treatment can often be accomplished with the same anticonvulsant medications used for the treatment of TN, such as carbamazepine, oxcar-bazepine, baclofen, phenytoin, and lamotrigine either alone or in combination.38,98 Surgical pro-cedures include intracranial sectioning of the glossopharyngeal nerve and the upper rootlets of the vagus nerve and MVD of the glossopha-ryngeal nerve or gamma knife surgery.99,100Nervus intermedius neuralgia (ICHD 13.3; ICD-10 G51.9)Nervus intermedius neuralgia is a rare condi-tion that is characterized by unilateral parox-ysms of pain felt in the depth of the ear and lasting seconds or minutes. An alternative term used for this condition is geniculate neu-ralgia because the cell bodies of the sensory afferents are located in the geniculate gan-glion. There is often a trigger zone in the poste-rior wall of the auditory canal. Disorders of lac-rimation, salivation, and taste are sometimes present. Nervus intermedius neuralgia is now subclassied in the ICHD into classic (13.3.1) and secondary nervus intermedius neuropa-thy (13.3.2, previously known as Ramsay Hunt Syndrome) attributed to acute herpes zoster with the former having no apparent cause and the latter requiring evidence of causation by herpes zoster and facial paresis. The evidence for causation by herpes zoster includes a vesic-ular eruption in the ear and/or oral mucosa that was preceded by pain less than a week before the eruption.6,16,101,102 Medications used for TN may be trialed. Surgical section of the nervus intermedius or chorda tympani may relieve the pain. Local ear disorders must be ruled out.Painful Trigeminal Neuropathies (ICHD 13.1.2)A large amount of work has occurred to try and develop a more accurate diagnostic classica-tion of trigeminal neuropathies. Some of the work in painful posttraumatic trigeminal neu-ropathies (PPTTNs) has been at slight cross purposes with other research in the area, and efforts are underway to clarify the situation through organizations such as INfORM (pre-viously known as the International Research Diagnostic Criteria for TMDs [RDC/TMD Con-sortium Network]), the American Academy of Orofacial Pain (AAOP), and the IASP’s special interest group in orofacial pain. Readers should keep abreast of changes in the next few years as the eld is currently in a state of ux due to the confusing nomenclature in the literature, which presents difculties from taxonomic and ontologic perspectives. 101Painful Trigeminal NeuropathiesNumb chin syndromePrior to discussing the various subtypes of painful trigeminal neuropathies, it is pertinent to mention and clarify a predominantly non-painful condition whose denition and use seems to have gained favor in recent years. This increase in use is presumably, and un-derstandably, because of its desirable facilita-tory function in teaching as a simple heuristic, but its use has no real taxonomic or ontologic basis. The condition is numb chin syndrome, which is essentially a mental or inferior alveo-lar nerve sensory neuropathy. Features of this syndrome are anesthesia, paresthesia, and—very occasionally—dysesthesia in the men-tal dermatome.103 Mental neuropathy can be caused by a variety of events, disorders, or dis-eases, including dental procedures (eg, local anesthesia, implants, surgical endodontics) and pathologies (eg, odontogenic infection or neoplasia in close proximity to the nerve).104–111The presence of signs and symptoms of numb chin syndrome should not be consid-ered lighthearted in the absence of odonto-genic causes because they can be related to local or systemic malignant neoplastic condi-tions.112–114 In recent years, numerous case re-ports have been published indicating a wide variety of underlying causes, including but not limited to MS, use of antiresorptive medica-tions (bisphosphonates), vagal and hypoglos-sal paralysis, leukemic vasculitis, non-Hodgkin lymphoma, B-cell lymphoma, and other meta-static cancers. Under these circumstances, im-mediate referral to the relevant medical prac-titioner is paramount. Signs and symptoms of numbness should not be dismissed because they play an important part in ensuring health professionals are aware of its potential red ag status. It does not however constitute a diag-nosis, and because it is rarely painful, it does not really t into the current ICHD unless it is painful and/or is due to either a systemic cause or a traumatic cause. Painful peripheral sensory neuropathiesExpanding the discussion regarding numb chin syndrome, if a wider perspective of pain-ful peripheral sensory neuropathies (PPSNs) affecting the whole body is taken, it is pos-sible to consider PPSNs to be either primary or secondary (as has been seen in the preced-ing discussion of numb chin syndrome).115 If PPSNs are primary, they are neuropathic pain prior to any active intervention; in the trigemi-nal system, this would include conditions pre-viously known as pretrigeminal neuralgia and phantom tooth pain, which are now hypotheti-cally and conceptually considered (in part) as persistent dentoalveolar pain disorder (PDAP) and/or PPTTN (see later section). This type of primary PPSN can be difcult to diagnose be-cause it is poorly understood, but it must be excluded prior to dental treatment because it may represent half of all cases of persistent tooth pain.116,117Secondary PPSNs may be due to a vari-ety of disorders including hereditary sensory neuropathies (eg, Fabry disease), multifocal lesions of the peripheral nervous system (eg, polyarteritis nodosa causing mononeuritis multiplex), and generalized lesions of the pe-ripheral nervous system (eg, polyneuropathies such as diabetes mellitus). Lesions of the CNS (eg, spinal cord injury) and complex neuro-pathic disorders (eg, complex regional pain syndrome [CRPS] types 1 and 2) may also give rise to neuropathic pain. The most common conditions causing secondary painful trigemi-nal neuropathies include the following:• PPTTN• Painful trigeminal neuropathy attributed to acute herpes zoster • Postherpetic trigeminal neuropathy• Painful trigeminal neuropathy attributed to MS plaque 102Neuropathic Pain6PPTTN (ICHD 13.1.2.3)PPTTN was previously classied as anesthe-sia dolorosa in the second edition of the ICHD (13.18.1) as a painful area of anesthesia or dys-esthesia in the trigeminal nerve distribution. It can arise following peripheral or central (neu-rosurgical) damage to the trigeminal nerve, ganglion, or nuclear complex, such as that occurring in some neurosurgical management strategies for TN. As a type of deafferentation pain, PPTTN is feared most with rhizotomies, but a review revealed a low incidence rate of PPTTN (less than 2%) after radiofrequency thermocoagulation and glycerol injections.67 Balloon microcompression, MVD, and gamma knife surgery have not typically been associ-ated with the development of PPTTN.71,81,118–120 In addition to the characteristic pain, a feature of this condition is decreased sensitivity to pain and temperature in one or more divisions of the trigeminal nerve. Accordingly, central pain results from lesions that affect the tri-geminothalamic pathways. Very few studies are available with regard to the treatment of anesthesia dolorosa. Therefore, treatment re-mains anecdotal and usually consists of tricy-clic antidepressants and anticonvulsants. Mi-crosurgical repair has shown to be effective in only one out of seven patients.121 Dorsal root entry zone lesioning has shown some promise in the treatment of anesthesia dolorosa, as has sensory thalamic neurostimulation.122,123What was previously known as atypical odontalgia has been subsumed into PPTTN or PDAP because of the emerging opinion that atypical odontalgia is likely, at least in part, to be neuropathic in origin.124 The use of PPTTN or PDAP to label cases previously known as atypical odontalgia is dependent on which classication system one feels is more robust. In essence, the disorders previously grouped under atypical odontalgia are likely to be char-acterized by124–127:• Persistent pain in a dened area of the dentoalveolus for more than 4 months, which can oscillate in intensity• Pain characteristics that may include dull aching or burning, worsening pain with changes in barometric pressure, pain or pressure feeling deep within the bone, prickly or itching feelings, difculty in com-municating nature or character of pain• Potentially presenting more frequently in females than in males (proposed 3:1)• Usually following a deafferentation injury (eg, extraction or extirpation)• Equivocal response to local anesthesia• More frequent presentations in anterior teeth and in the maxillaThis group of conditions produces a collo-quial phantom tooth pain. This pain may occur in situations of extirpation and root canal treat-ment of the tooth that is still in situ despite no demonstrable failure of the root canal treat-ment or through extraction of the tooth and ongoing pain despite demonstrable clinical and radiographic healing. Given the likely neu-ropathic nature of PPTTN and PDAP, manage-ment of a diagnosed deafferentation phantom tooth pain (ie, PPTTN or PDAP) follows the same principles of either topical or systemic neuromodulation covered later in this section.Recent advances in this group’s diagnosis include the use of quantitative sensory test-ing (QST) and/or qualitative sensory testing (QualST) and the development of a self-report screening instrument.128–130 QST has shown to be reliable intraorally and highlighted ob-jective somatosensory differences between patients suffering from atypical odontalgia and control groups.131,132 QST is, however, a time-consuming and equipment-dependent process, given its uses. There are 13 tests to examine Aδ, Aβ, and C-ber function and tem-poral summation (wind-up), and therefore it is not suited for routine everyday clinical prac-tice. QualST is an abbreviated form of QST that achieves results comparable with QST 103Painful Trigeminal Neuropathiesusing simpler equipment available in all clini-cal facilities: cotton wool, ice-cold spatula, and dental probe or explorer.128,129 The ipsilateral af-fected side is tested for sensory loss or gain compared with the contralateral side. Sensory loss or gain on the ipsilateral side is one indi-cation that PPTTN or PDAP may be present. It is also possible to examine wind-up using QualST, and a good description of both QST and QualST has been previously reported.133 A self-report screening instrument consisting of 13 questions has also demonstrated pre-liminary promise during pilot testing.130 This screening instrument concentrates on the key features of PPTTN and PDAP within the patient’s complaint as described earlier. It is currently under review and will be published in open access shortly.Risk factors for any postsurgical neuropathyPrevention of chronic postsurgical pain with or without neuropathy may be possible. Risk factors evident in diseases and disorders af-fecting other areas of the body may translate to the orofacial region. Considerations for iden-tication of risk factors may include some of the following134,135:Perform preoperative screening for unusual presentations of pain before and after surgery. Neuropathic pain can develop slowly over time, so clinicians should always be cognizant of its putative diagnosis. There are validated di-agnostic screening tools available to help with neuropathic pain, although to date the sensi-tivity and specicity of these instruments are deemed low when used with orofacial neu-ropathies.136,137 The screening tools include the following: • Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) or its self-reported version (S-LANSS) • Neuropathic Pain Questionnaire (NPQ)• Douleur Neuropathique en 4 (DN4)• painDETECT• ID-Pain Perform preoperative screening for patient-specic factors such as the following:• Genetics: Haplotype for catecholamine- O-methyltransferase• Preceding pain: Intensity and chronicity• Psychosocial factors: Anxiety, depres-sion, fear avoidance, self-efcacy, work, physical levels of activity, somatization, anxiety, catastrophizing• Younger age: Increased risk of neuro-pathic pain following breast surgery and herniorrhaphy• Older age: Increased risk of neuropathic pain following other surgery• Female sex: Increased risk of neuro-pathic pain134Surgical risk factors may be potentially modiable. They include the duration and ex-tent of surgical procedure and technique (eg, tension due to retraction of tissues) and level of reported perioperative pain intensity. Modi-cations to account for these risk factors may include:• Multimodal management of severe acute postsurgical pain• Minimal access surgery• Intraoperative use of local anesthesia when patient is undergoing general anestheticAssessmentAs is commonplace in assessing orofacial pain, the clinician must conduct a holistic evaluation of the patient’s pain history, the functional im-pact, and psychologic consequences of the pain. The area of neuropathy must be quali-ed within the dermatome distribution of the damaged sensory nerve.138 The ipsilateral and contralateral unaffected dermatome should be subject to at least a basic mechanosen-sory examination recording for the following whether there is sensory gain or loss: Assess the patient’s response to light tough (eg, cot- 104Neuropathic Pain6ton wool), painful stimuli (eg, sharp probe or explorer), and thermal challenge (eg, cold spat-ula). Visual inspection and palpation should be used to examine for any autonomic changes in color, temperature, sweating, and swell-ing. Elicited mechanical and thermal allodynia and/or hyperalgesia will reinforce diagnosis of neuropathic pain when there is hyperesthesia rather than a hypoesthetic nerve injury (anes-thesia or paresthesia). There is a role for judicious use of investiga-tions as determined by the presenting patient, their history, and the examination ndings. These investigations may include: • Hematologic tests to exclude systemic causes of neuropathy, including CBC, thyroid function tests, C-reactive protein, autoantibody screen, erythrocyte sedi-mentation rate, creatinine, alanine trans-aminase, vitamin B12, ferritin, folate, and serum protein immunoelectrophoresis.• HbA1c to assess for risk of diabetes or level of glycemic control in patients known to have diabetes.139 • Imaging of varying forms such as plain lms, computed tomography (CT), or MRI. Most often, local imaging (eg, cone beam CT) or plain lms would be indi-cated if there is a denite history of local damage (eg, mandibular third molar re-moval or implant placement), but an MRI scan may be indicated if centrally medi-ated sensory neuropathy is suspected. Management of posttraumatic neuropathic pain A recent Cochrane review140 concluded that there is a lack of high-quality trials to investi-gate the effectiveness of all forms of manage-ment for iatrogenic inferior alveolar and lingual nerve injuries. Thus, management of posttrau-matic neuropathic pain is mainly extrapolated from other types of nerve pain. Most patients present with chronic neuro-pathic pain mixed with numbness and altered sensation.138 The pain the patient is experienc-ing must be assessed and include the related functional and psychologic impact.141 These aspects must then be managed alongside the pain using psychologic interventions if the pa-tient accepts the important role that psycho-logic therapies have in managing neuropathic pain. For most patients, it is necessary to use multiple strategies that are tailored to the indi-vidual patient’s complaint.142The mechanism of injury drives the decision making in and timing of the management of trigeminal nerve injuries. Surgery is urgently indicated for posttraumatic neuropathy related to third molar, implant, or endodontic surgery within 30 hours and rarely up to 3 months but not later.142 Broad principles for surgical ap-proaches are to immediately repair if nerve section is known and to remove an implant within 24 hours of placement if compression by an implant is thought to be the cause. Sur-gery is not indicated to explore inferior alveolar nerve injuries older than 4 weeks. Exploratory surgery for lingual nerve injuries must occur within 3 months after injury.143–145 Immediate pharmacologic therapy may be indicated along-side surgery for acute sensory nerve injuries. Early management with a corticosteroid taper for 5 to 7 days followed or replaced by 3 weeks of NSAIDs may help reduce the chance of neu-ropathy following injury.146–148 If a painful trigem-inal nerve injury has been delayed in its pre-sentation to the consulting clinician, or is not associated with a clear-cut macroscopic trauma amenable to surgery (eg, in PPTTN and PDAP), then there may be indications for different phar-macologic therapy. Considerations in the case of delayed painful presentations include topical and systemic pharmacotherapeutic agents:Topical agents for pain: Topical lidocaine 5% (12 hours on and 12 hours off) should be applied to facial skin away from mucous membranes and eyes.149 Other compounded off-label topical uses of systemic neuromodu-latory agents are also available.150 Practitioners should be aware of recent concerns about the 105Painful Trigeminal Neuropathieslack of preclinical safety studies for such topi-cal medications.151Botulinum toxin: There is a recent report of two cases using botulinum toxin for PPTTN.152Systemic agents for pain: There are guidelines for the medical management of neuropathic pain in adults.153–156 The medications used may include selective serotonin-norepinephrine reuptake inhibitors (SSNRIs; duloxetine and venlafaxine), tricyclic antidepressants (amitrip-tyline or nortriptyline), or anticonvulsants (pre-gabalin or gabapentin).Postsurgical neuropathic pain is rare and not well recognized in the eld of dentistry. Current management strategies are based on evidence from other neuropathic conditions. Thus, research is needed to provide sufcient evidence with regard to assessment and man-agement of posttraumatic trigeminal nerve injuries.157Painful trigeminal neuropathy attributed to acute herpes zoster (ICHD 13.1.2.1)Chicken pox is caused by the varicella zoster virus. Following the initial infection with the varicella zoster virus, the virus remains dor-mant in the cell bodies of sensory nerves and may reactivate many years later. This type of reactivation is known as herpes zoster (or shingles in laymen’s terms). The incidence rate of herpes zoster is an estimated 0.03% to 0.05%. Herpes zoster largely affects elderly patients or those with impaired immunity. Symptoms of herpes zoster generally include itching, numbness, or a tingly sensation in the affected dermatome, followed by blisters and pain. Most people heal without sequela in about 3 to 4 weeks, but in a small percent-age of people (28.2 to 42 out of 100,000), persistent sensory disturbances or pain may occur.158 There are now vaccines available to help decrease or prevent herpes zoster in peo-ple over the age of 50 years.159Management of the acute pain of painful tri-geminal neuropathy attributed to acute herpes zoster will be determined by consideration of a number of factors: degree of symptoms, pres-ence of lesions on face or eye, age and immu-nologic status of the host, and other comor-bidities. Antiviral, corticosteroid, and tricyclic antidepressant medications have all been sug-gested to try and help manage the acute pain and reduce the risk of postherpetic neuropa-thy.160 Cochrane reviews, however, cast doubt on the roles of both antiviral and corticosteroid medications in helping prevent postherpetic neuropathy, but they are thought to be ben-ecial in the management of the acute pain of painful trigeminal neuropathy attributed to acute herpes zoster.161,162 Because of the im-munosuppressive effect of corticosteroids, they should not be given without antivirals.Postherpetic trigeminal neuropathy (ICHD 13.1.2.2; ICD-10 B02.22)Most people heal completely from an episode of herpes zoster within 3 to 4 weeks without any persisting sequelae. However, some peo-ple may have irreversible damage to the skin and sensory disturbances. Whereas persisting or recurrent pain is infrequent in the general population, postherpetic trigeminal neuropathy (previously known as postherpetic neuralgia) may affect 50% to 75% of the older popula-tion who have had herpes zoster, and its inci-dence varies from 28.2 per 100,000 persons to 42 per 100,000 persons, depending on the country of study.158,163 The ICHD describes postherpetic trigeminal neuropathy as unilat-eral pain developing in temporal relationship to an acute herpes zoster infection that affected one or more branches of the trigeminal nerve and lasting for 3 months or more. The pain usu-ally has a burning character, but there may be superimposed brief, stabbing exacerbations of pain. Postherpetic trigeminal neuropathy may be accompanied by hyperalgesia and al-lodynia or by profound sensory loss and anes- 106Neuropathic Pain6thesia dolorosa.164 Risk factors for developing postherpetic trigeminal neuropathy include female sex, older age, experience of a pro-drome, severe rash, and severe pain.165The pathophysiology of postherpetic tri-geminal neuropathic pain is still largely un-known, but peripheral and central mechanisms have been suggested. Cell destruction at the level of the dorsal horn and loss of cutane-ous nerve endings have been implicated.166,167 Baron164 proposed three different types of postherpetic trigeminal neuropathies: one based on peripheral and central sensitization, one based on predominant degeneration of nociceptive neurons, and one mainly based on skin deafferentation. Depending on the type of underlying mechanism, different symptoms may prevail, and different treatment modali-ties might be more successful. The existence, value, and implications of this differentiation must be further evaluated. According to a recent systematic review, the anticonvulsants gabapentin (1,800 mg and 3,600 mg per day) and pregabalin (150 to 600 mg per day) show satisfactory pain relief, as does the tricyclic antidepressant amitriptyline (25 to 150 mg per day).156 Topical lidocaine has also been advocated for treatment of posther-petic trigeminal neuropathy. To date, there are not enough data to support the use of the newer antidepressants in postherpetic trigemi-nal neuropathy, but if the conventional medi-cations fail or produce too many side effects, a trial of these medications may be indicated. The efcacy of opioids in postherpetic trigemi-nal neuropathy is as yet uncertain.168Painful trigeminal neuropathy attributed to MS plaque (ICHD 13.1.2.4)Pain can be a common problem in those suf-fering from MS. The pathophysiology of the pain can be due to either central or peripheral pathology and is often dependent on plaque location. Migraine-type headaches can develop as a consequence of MS or its treatment (ie, interferon).169 MS is known for its association with the development of TN, and this is likely to be due to the long-term damage to the tri-geminal nerve root entry zone.MS increases the risk of developing TN by a factor of 20.170 The nature of TN in MS does not usually differ from classic TN other than being more frequently bilateral. Bilateral TN (14% to 31% in MS) or TN in a young patient may be indicative of underlying MS.171,172 TN will pre-cede MS in only 0.3% of patients.173 Interest-ingly, only a minority of patients with MS show vascular compression of the trigeminal nerve root. Decompression procedures on these few specic patients often relieve the neuralgia-like symptoms.174 Management of this type of pain is the same as that of TN. Burning mouth syndrome (ICHD 13.10; ICD-10 K14.6)Burning mouth syndrome (BMS) is dened as “a distinctive nosologic entity characterized by unremitting oral burning or similar pain in the absence of detectable oral mucosal changes” that can last at least 4 to 6 months.6,175 Pri-mary or idiopathic BMS (pBMS) has no known cause, so exclusion of causes of secondary burning mouth symptoms is essential to make a diagnosis of pBMS. The array of local and sys-temic conditions that may produce BMS-like symptoms are listed in Box 6-2.175pBMS is a poorly understood pain condition that is most probably neuropathic with both peripheral and central components. Reported prevalence rates of burning mouth symptoms in general populations vary from 0.7% to 15%, with variation likely based on whether a study was a survey or a clinical assessment, the pop-ulation assessed, and the geographic location under study.180–183 Burning mouth symptoms appear most commonly in postmenopausal women—12.2% in the 50-to-69-year age group—and are extremely rare in both men and women under the age of 30 years.180 107Painful Trigeminal NeuropathiesThe condition has also been known as stomatodynia, glossodynia, or stomatopyrosis and is characterized by a burning sensation in the mucosa despite the absence of clinical ex-amination ndings; pBMS would also have no abnormalities identied in laboratory testing or imaging. The burning pain commonly presents with a bilateral symmetric distribution, with the most frequently affected areas including the anterior two-thirds, dorsum, and lateral borders of the tongue; the anterior hard palate; and the mu-cosa of the lower lip; it often occurs in more than one oral site.184,185 Onset often appears to be spontaneous in around 50% of patients; however, 17% to 33% of patients may attribute the onset of pain with an upper respiratory tract infection, a previous dental procedure, or med-ication use (including antibiotics).183,186 Others report that onset of symptoms occurred fol-lowing traumatic life stressors.186 Symptoms may be continuously present for signicant periods of time (months to years) without ces-sation or remission, and only a small number (3% of patients within 5 years of onset) dem-onstrate complete remission.187 Burning is usually a constant daily phenomenon, and around one-third of patients experience symp-toms both day and night.180,184 Most patients report minimal symptoms on awakening, after which the symptoms crescendo through the day toward the evening. A large proportion of patients experience intensication of the burn-ing related to presence of personal stressors and fatigue or eating acidic, hot, or spicy foods. Equally, however, a proportion report reduction Box 6-2 Local and systemic factors thought to be potentially causative for secondary BMS176,177Local factors• Alcohol-based mouthwash• Allergy (serum IgE and patch test for dental materials patient is exposed to)• Chewing tobacco use• Ciguatera neurotoxin exposure178• Dehydration, mouth breathing, or nasal obstruction• Gastric reflux179• Infection (bacterial, fungal, viral)• Mechanical (trauma or reduced tongue space from poorly fitting prostheses)• Oral lesions: erosive lichen planus; geographic tongue; leukoplakia, neoplasia, pemphigoid; pemphigus; vesiculobullous conditions• Parafunctional habits• Stomatitis: allergy-induced, aphthous, radiation-induced• Xerostomia (salivary flow rate) Systemic factors• Autoimmune conditions (Sjögren syndrome)• Endocrine: diabetes mellitus (HbA1c), hypothyroidism (thyroid function tests), menopause• Helicobacter pylori (antibodies to H pylori)• Medication (eg, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, antiretrovirals, psychotropic, anticholinergic, clonazepam, chemotherapeutic agents) • Neuropathy: nutritional neuropathy (check serum ferritin, vitamins B1, B6, B12, folate, and zinc); peripheral neuropathy due to systemic disease (eg, HIV, sarcoidosis, MS) Ig, immunoglobulin.Examinations should reect those undertaken for peripheral neuropathies and conditions listed earlier in the chapter. If any of the factors listed above are discovered to contribute to the burning mouth symptoms, then a diagnosis of secondary BMS should be made. 108Neuropathic Pain6or alleviation of burning through oral intake or stimulation and distraction.188pBMS is associated with many possible fac-tors including anxiety, depression, and person-ality disorders, particularly in postmenopausal women, but it is unclear if pain initiates the psychologic disorder or vice versa.175,180,189,190 Approximately 21% of pBMS patients pre-sent with signicant psychologic distress, but pBMS patients show no evidence of signi-cant clinical depression, anxiety, and somati-zation.191 Moreover, pBMS patients report less interference in their daily activities than other chronic pain patients.191 There are various regional and local phe-nomena that have been associated with pBMS. These include reduced parotid gland function and altered salivary composition.192,193 pBMS patients generally exhibit greater vaso-reactivity, suggesting involvement of the auto-nomic nervous system.194 Evidence supports two theories: a neuropathic imbalance be-tween the gustatory and sensory systems or a peripheral and/or central sensory neuropathy. A role for some form of neuropathy in pBMS seems likely given that varying somatosensory changes (gain or loss) have repeatedly been identied in patients with pBMS.195,196It is thought that inhibitory inuences be-tween the gustatory and sensory systems help to maintain a sensory balance in the tongue. Hypothetically, therefore, disruption in this equilibrium through altered chorda tym-pani dysfunction could then lead to lingual nerve hyperfunction and a neuropathic-based burning sensation. The role of an imbalance between the gustatory (chorda tympani or glossopharyngeal) and sensory systems (lin-gual or glossopharyngeal) is uncertain, espe-cially given that grey matter changes are pres-ent in the pain matrix of those with BMS as opposed to dysgeusia, but there are data sup-porting interplay between sensory and gusta-tory trigeminal pathways.197–199 Further studies are needed to elucidate this complex and puta-tive relationship.pBMS may result not only from hyperactiv-ity of the sensory component of the trigeminal nerve following loss of central inhibition but also from damage to the chorda tympani.200–203 This damage results in reduced inhibition of the trigeminal nerve that in turn leads to an intensied response to oral irritants and even-tually to neuropathic pain. The exact mecha-nisms and interactions, however, are obscure, and the evidence is unclear.A sensory neuropathy is suggested by nd-ings that the sensory threshold in the tongue was signicantly higher in patients than in con-trols.204,205 pBMS patients have a signicantly lower density of epithelial nerve bers in the anterior two-thirds of the tongue, with some correlation to symptom duration.206,207 Ex-perimental evidence suggests the existence of several diagnostic BMS-neuropathy sub-groups, including peripheral neuropathy and centrally mediated pain.198,208–212 Studies ex-amining the identication of a predominantly peripherally driven BMS as opposed to a pre-dominantly centrally driven BMS have used a lingual block to make this determination. They have demonstrated that topical medication, specifically clonazepam, is more effective in those with a peripherally driven BMS and that its therapeutic effect may be mediated by γ-aminobutyric acid A (GABAA) receptors pres-ent on peripheral afferents in the tongue.213,214Management options for pBMS are limited because of the incomplete understanding of the etiology and pathophysiologic pro-cesses for this disorder. Current treatment approaches include the following, which can be combined215: • Cognitive behavioral approaches • Topical management using analgesics, anxiolytics, artificial sweeteners, and low-level laser therapy • Systemic management using antidepres-sants, anticonvulsants, and atypical anal-gesics or antipsychotics 109Central Neuropathic PainOne of the most intensively investigated pharmacologic agents for BMS is clonazepam, for which there are meta-analysis data sup-porting its efcacy both systemically and topi-cally.216 A recent clinical evidence update sug-gests that cognitive behavioral therapy is likely to be benecial and that there is a trade-off be-tween risks and benets with the use of clon-azepam, given its potential for dependency.217 The same review suggests that α-lipoic acid, benzydamine hydrochloride, selective sero-tonin reuptake inhibitors (SSRIs), and tricyclic antidepressants are of unknown effectiveness.Central Neuropathic Pain (ICHD 13.12)This new category in the ICHD is subdivided into central neuropathic pain attributed to MS and central poststroke pain (CPSP).Central neuropathic pain attributed to MS (ICHD 13.12.1)Pain is a frequent symptom in MS and may have a variety of potential mechanisms, includ-ing pain resulting from the disease process, but also pain as a result of the disability.218 Any lesion from the spinal dorsal horn or spi-nal trigeminal nucleus to the cerebral cortex can cause central neuropathic pain attributed to MS.Neuropathic pain in MS shares the generic features of neuropathic pain as previously de-scribed. This pain may be episodic or constant, although constant pain is more typical. With the exception of some of the stereotyped man-ifestations (such as TN, optic neuritis, or painful tonic spasms), the clinical features of the neu-ropathic pain in MS are often not specic for site of lesion or the underlying pathology. An-ecdotally, central neuropathic pain affecting the face and head attributed to MS is much less frequent than TN. Diagnostic pointers for cen-tral neuropathic pain attributed to MS include evidence of CNS disease, distribution of pain (sometimes regional or cranial nerve or occa-sionally root), and the presence of other neu-rologic symptoms or signs (mostly sensory). Central poststroke pain (ICHD 13.12.2; ICD-10 G89.0)CPSP is characterized by unilateral facial or head pain, dysesthesia, and impaired sensa-tion to pinprick and temperature that occurs within 6 months of a stroke and is not due to a lesion of the trigeminal nerve (with imaging demonstrating a lesion in an appropriate site). CPSP is attributed to a lesion somewhere along the spinothalamic pathway and by de-nition is the result of a vascular lesion (eg, ischemic or hemorrhagic infarction). The pain is not limited to the facial and cranial area; similar symptoms may be experienced in the entire half of the body contralateral to the infarction (such as after a thalamic stroke). Similar pain can be produced by lesions that involve the as-cending pain pathways elsewhere in the CNS, and the term central pain is used to indicate such involvement.Few RCTs investigating treatment modali-ties for CPSP have been performed. A 2006 systematic review identied amitriptyline and lamotrigine as the most effective medications, followed by mexiletine and phenytoin.219 Car-bamazepine did not appear effective, whereas gabapentin, although promising, was not stud-ied sufciently. This review also indicated that intravenous ketamine, propofol, and lidocaine might be helpful for short-term treatment. Invasive procedures may have a place when pharmacologic management fails. The avail-able data are mostly anecdotal but suggest that deep brain stimulation and cortical stimu-lation may be helpful.220 110Neuropathic Pain6Neurodegenerative Diseases as Causes for Central PainThere is a growing awareness that neuropathic pain can be an important feature of neurode-generative conditions.221 This has been per-haps best dened in Parkinson disease, a de-generative neurologic disorder with motor and nonmotor features. Pain is a common symp-tom in patients with Parkinson disease.222 This includes primary pain (ie, central pain arising from the CNS) and secondary pain (eg, pain arising from the musculoskeletal system). Central pain in Parkinson disease is estimated to have a prevalence of 10% to 12%.222 Cen-tral pain is recognized in a number of different areas including the mouth, rectum, vagina, ab-domen, chest, and testes. Fil et al222 have re-viewed pain in Parkinson disease and propose that it might result from pathologic changes in structures involved in the nociceptive system. In some patients, this pain might respond to dopaminergic therapy, but conventional anal-gesics and tricyclic antidepressants are recom-mended otherwise.Tolosa-Hunt syndrome (ICHD 13.7; ICD-10 H51.9)Tolosa-Hunt syndrome is characterized by epi-sodes of orbital pain accompanied by paralysis of one or more of cranial nerves III, IV, or VI. One or more of these nerves will contain le-sions caused by granulomatous inammation of superior orbital ssure, cavernous sinus, or orbit as demonstrated by MRI or biopsy. As with any painful ophthalmoplegia, other differ-ential diagnoses should be considered, includ-ing vasculitis or vascular, neurologic, inamma-tory, inltrative, or space-occupying processes, such as pseudotumor of the orbit, temporal arteritis, and ophthalmoplegic migraine.223 Epi-sodes are said to have a duration of 8 weeks in untreated patients; patients experience relief of pain within 72 hours of initiation of corti-costeroid therapy. If suspected, referral to an ophthalmologist is suggested.CRPS (no ICHD category; ICD-10 G90.50) CRPS is a term that has been coined to re-place two different disorders of the autonomic nervous system. CRPS 1 has been proposed to replace the term reex sympathetic dystro-phy (ICD-10 G90.59), and CRPS 2 has been proposed to replace the term causalgia, also described as mononeuritis (ICD-10 G58.9). The replacements have not been widely accepted, and the older terms are still frequently used. According to the IASP, CRPS is character-ized by persistent, often burning pain accom-panied by allodynia and hyperalgesia and at some point accompanied by swelling, changes in blood ow, and/or abnormal sudomotor ac-tivity.6 In CRPS 1, the symptoms occur after a mild injury and are disproportionate to the ini-tiating event, whereas in CRPS 2, there is evi-dence of nerve damage preceding the persis-tent pain. A 2007 revision to the IASP criteria has been proposed.224 The criteria include four symptom categories, of which at least three must be reported and at least two must be present at the time of evaluation. The four cat-egories consist of sensory, vasomotor, sudo-motor/edema, and motor/trophic changes. The distinction between CRPS 1 and CRPS 2 was maintained, and a third diagnosis, CRPS not otherwise specied, was added for patients not fully meeting the criteria. The pathophysiology of CRPS remains un-clear, and it may be peripherally or centrally mediated and of neuropathic, inammatory, or immunologic origin.225 Estimates of the incidence of CRPS range between 5 and 26 cases per 100,000 persons.226,227 Women are aficted about three times more often than men.227 CRPS is typically found in the upper or lower extremities, with the upper extremities more often involved than the lower extremi-ties, and it is not generally described as oc-curring in the head and neck. A review of the 111Neurodegenerative Diseases as Causes for Central Painavailable literature between 1947 and 2000 identied only 13 cases with head and neck involvement.228 The typical features, such as loss of function and skin atrophy, were rarely seen, and therefore the diagnoses in most of these cases were debatable. In some cases of CRPS, the peripheral noci-ceptors become sensitive to adrenergic stimu-lation. In those cases, any increase in activity of the sympathetic nervous system is likely to increase the pain experience. Increased levels of emotional stress and even visual or auditory stimuli can markedly increase the pain inten-sity. Typically, this pain is responsive to sym-pathetic blockade, and in such cases, the term sympathetically maintained pain is appropriate. Studies trying to resolve which features (eg, mechanical allodynia, cold allodynia) might pre-dict a favorable response to sympathetic block-ade have shown contrasting results.229–231 High anxiety levels, litigation, and disability may be related to poor treatment response to a sym-pathetic blockade.231 Treatment of CRPS generally includes phys-ical rehabilitation, psychologic interventions, and pharmacologic management.225,232 Few RCTs with adequate sample sizes are available with regard to the treatment of CRPS, and no particular pharmacologic or intervention strat-egy appears to stand out. Therefore, at this time, pharmacologic treatment should follow the treatment paradigms for neuropathic pain. In the case of sympathetically maintained pain, a series of sympathetic blocks is indicated.233 Persistent idiopathic facial pain (ICHD 13.11; ICD-10 G50.9)This category has historically been referred to as atypical facial pain. It is a term that when applied essentially means that no absolute mechanism or characteristics can be deter-mined that allow the presenting pain to be assigned to any other diagnostic category. It may or may not belong in a neuropathic pain classication given the wide variation in its pre-sentation as only some of this continuum rep-resents potential neuropathy.234 The incidence of persistent idiopathic facial pain is estimated at 4.4 per 100,000 person-years, and lifetime prevalence is estimated at 0.03% with a pre-dilection for presenting in middle-aged to older women.195,235,236The current ICHD suggests that persistent idiopathic facial pain can only be diagnosed when pain is present for more than 3 months, occurring daily with episodes of pain lasting for greater than 2 hours, in a poorly localized man-ner, and following an unrecognized dermatome pattern. Its character is described as a dull ach-ing, nagging quality, but it can have acute ex-acerbations, with one of the aggravators being stress. It may present with psychiatric comor-bidity and signicant psychosocial disability. Prior to the diagnosis, all other local or systemic causes and intracranial causes (eg, intracranial mass lesions) must be excluded. This may re-quire additional assessment by an otorhinolar-yngologist and/or a neurologist. In the process of evaluating potential other types of underlying pathology, hematologic and imaging investiga-tions may be necessary, including an MRI of the head and/or face to exclude intra- and extracra-nial causes of the pain. QST may also be of ben-et to determine if there are any neuropathic elements contributing to the overall pain picture of persistent idiopathic facial pain.195Because there are no RCTs that include large samples of patients with persistent id-iopathic facial pain, treatment typically relies on therapies proven successful in studies for other persistent orofacial pains predominantly using cognitive behavioral therapy and/or any of the following therapeutic agents: tricyclic antidepressants, SSNRIs, gabapentin, and pregabalin.237,238 Occlusal dysesthesia (phantom bite/occlusion)Patients with occlusal dysesthesia (OD) pre sent with a primary complaint of an uncomfortable 112Neuropathic Pain6and/or incorrect occlusion, usually accompa-nied by emotional distress.239,240 Even though this is largely unveriable, OD patients are con-vinced of the validity of their complaints and the belief that mechanical and/or surgical dental interventions will accomplish correction.239 Re-peated and failed treatments by clinicians serve to reinforce the patient’s potentially hypervigi-lant state in respect to the occlusion and/or that something is seriously wrong with the occlu-sion.241–245 Clinicians often pursue a course of multiple occlusal readjustment appointments, which usually results in increasingly distressing symptomatology reported by the patient. Reas-surances that the patient suffers from no oc-clusal problems usually induce further distress. The onset of OD can occur at any stage of dental treatment. However, patients typically associate the origin of phantom bite syndrome with the construction of extensive dental pros-theses.246 OD is observed in all age groups with no clear sex predilection; adolescents undergoing orthodontic treatment may also experience OD.239,247 OD is usually painless; when pain accompanies OD in patients with a history of extractions or multiple surgical inter-ventions, an additional diagnosis of peripheral painful traumatic trigeminal neuropathy should be considered. Patients with OD may describe the need for repositioning of the mandible (often protrusion) to obtain some relief. Fur-ther complaints may include the feeling that the tongue is too big or disturbed sensations in the gingiva.240 Whether OD is a neuropathic disorder is de-batable. Originally, patients with OD were con-sidered to be suffering from a form of mono-symptomatic hypochondriacal psychosis, which is an uncommon psychiatric disorder character-ized by a single delusion as the sole symp-tom.239,248 Although OD cases are often charac-terized by a number of psychosocial disorders, current thinking links the initiating pathophysiol-ogy to physical components.246,249,250 The rst possibility is occlusal hyperawareness or iatro-genic dysproprioception.251 Following changes in the dental occlusion, it is necessary to adapt to or relearn new jaw movements and proprio-ception. Patients with OD suffer because they are unable to adapt to even small changes in the dental occlusion. Additionally, patients with OD may become distressed by the lack of familiar-ity of their own bite. This is based on the theory that the sensation derived through tooth con-tact acts as a self-identier.240,248 In other words, when placing one’s teeth together, one con-rms the “self.” A further possibility is that when tissue damage (apicoectomies, extrac-tions, implants) has formed part of the initiation of OD, the pathophysiology may be due to neu-ropathic mechanisms, as occurs in traumatic neuropathy.240 Peripheral painful traumatic neu-ropathy may present with disturbed propriocep-tion, allodynia, and pain, explaining the symptoma-tology of OD.18 In many ways, it is similar to the “phantom pain” described by amputees—hence the original term phantom bite. Pain in OD may arise from comorbid trau-matic neuropathy, and this should be treated accordingly. Comorbidity of OD with TMDs has been reported, and although successful therapy of the TMD does not alleviate symp-toms of OD, it improves the patient’s quality of life.246,252 Treatment of OD itself is difcult—any further attempts to “equilibrate” the occlu-sion or grind down specic areas that bother the patient will usually lead to no improvement or worsening of symptoms.253 Based on case reports, the use of acrylic guards does not re-lieve OD symptoms.246 In a small case series, the use of milnacipran, an SSNRI, improved OD symptoms in ve out of six patients.254 A psychiatric consultation or a psychologic as-sessment is a specic consideration. A com-bined approach beginning with a behavioral medicine consultation and initiation of SSNRI therapy is recommended. 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