76 Headache Medicine, v.3, n.2, p.76-87, Apr./May/Jun. 2012

Trigeminal neuralgia and persistent idiopathic

facial pain

A neuralgia do trigêmeo e a dor facial persistente idiopática

VIEW AND REVIEWVIEW AND REVIEW

VIEW AND REVIEW

Mark Obermann, Dagny Holle, Zaza Katsarava

Department of Neurology, University of Duisburg-Essen, Essen, Germany

Obermann M, Holle D, Katsarava Z

Trigeminal neuralgia and persistent idiopathic facial pain. Headache Medicine. 2012;3(2):76-87

ABSTRACTABSTRACT

ABSTRACT

Trigeminal neuralgia (TN) and persistent idiopathic facial

pain (PIFP) are two of the most puzzling orofacial pain

conditions and affected patients often are very difficult to

treat. TN is characterized by paroxysms of brief but crucial

pain, followed by asymptomatic periods without pain. In

some patients a constant dull background pain may persist.

This constant dull pain sometimes makes the distinction

from PIFP difficult. PIFP is defined as continuous facial

pain, typically localized in a circumscribed area of the face,

which is not accompanied by any neurological or other

lesion identified by clinical examination or clinical

investigations. The pain usually does not stay within the

usual anatomic boundaries of the trigeminal nerve

distribution and is a diagnosis of exclusion. Epidemiologic

evidence on TN and even more so on PIFP is quite scarce,

but generally both conditions are considered to be rare

diseases. The aetiology and underlying pathophysiology of

TN and more so PIFP remain unknown. Treatment is based

on only few randomized controlled clinical trials and

insufficiently evaluated surgical procedures.

eywords: eywords:

eywords: Trigeminal neuralgia; Persistent idiopathic facial

pain; Atypical facial pain; Pathophysiology; Treatment;

Differential diagnosis

RESUMORESUMO

RESUMO

A neuralgia do trigêmeo (NT) e a dor facial persistente idio-

pática (DFPI) são duas das mais intrigantes condições dolo-

rosas orofaciais, e os pacientes afetados são, frequen-

temente, muito difíceis de tratar. A NT é caracterizada por

paroxismos de dor breve mas excruciante, seguidos por

períodos assintomáticos sem dor. Em alguns pacientes, uma

dor de fundo maçante e constante pode persistir. Esta torna

difícil, às vezes, distinguir a NT da DFPI. A DPFI é definida

como uma dor facial contínua, localizada tipicamente em

uma região circunscrita da face e que não é acompanhada

por qualquer lesão – neurológica ou de outra natureza –

identificada através do exame clínico ou de investigação

complementar. A dor geralmente não permanece restrita aos

limites anatômicos da distribuição do nervo trigêmeo e é

um diagnóstico de exclusão. Evidências epidemiológicas

sobre a NT, e ainda mais sobre a DFPI, são bastante

escassas, mas usualmente ambas condições são consi-

deradas doenças raras. A etiologia e a fisiopatologia da NT

e, mais ainda, da DFPI, permanecem desconhecidas. O

tratamento é baseado em apenas uns poucos ensaios clínicos

randomizados e controlados e em procedimentos cirúrgicos

insuficientemente avaliados.

Descritores: Descritores:

Descritores: Neuralgia do trigêmeo; Dor facial persistente

idiopática; Dor facial atípica; Fisiopatologia; Tratamento;

Diagnóstico diferencial

INTRODUCTION

The prevalence of orofacial pain in the general

population was estimated between 17%-26% with 7%-

11% of those patients having been considered as

presenting a chronic condition.

(1)

The disorders that are

often summarized as orofacial pain are quite

heterogeneous and include acute and chronic pain

syndromes that often show a considerable overlap in

Headache Medicine, v.3, n.2, p.76-87, Apr./May/Jun. 2012 77

TRIGEMINAL NEURALGIA AND PERSISTENT IDIOPATHIC FACIAL PAIN

clinical presentation or present with atypical features. This

makes the differential diagnosis very difficult sometimes.

Trigeminal neuralgia (TN) and persistent idiopathic facial

pain (PIFP) are two of the most common forms of

orofacial pain assessed and treated by neurologists and

pain specialists.

(2)

DEFINITION AND CLINICAL PRESENTATION

OF TRIGEMINAL NEURALGIA

Trigeminal neuralgia (TN) is defined by the

International Headache Society (IHS) as "unilateral disorder

characterized by brief electric shock-like pains, abrupt in

onset and termination, and limited to the distribution of

one or more divisions of the trigeminal nerve".

(3)

The IHS

recommends the classification of TN in classical (essential

or idiopathic) TN and symptomatic TN ("pain

indistinguishable from that of classical TN, but caused by

a demonstrable structural lesion other than vascular

compression").

(3)

The absence of clinically evident

neurological deficit is required for the diagnosis of classical

TN. It generally starts in the second or third divisions of the

trigeminal nerve, affecting the cheek or the chin.

(3)

The

ophthalmic division alone is involved in less than 5% of

cases.

(4)

A typical TN attack lasts between less than a

second and a few seconds, but it may present in clusters

of variable intensity with up to two minutes duration. In

many cases it is followed by a brief refractory period during

which a new stimulation is not able to evoke another attack.

Between paroxysms the patient is usually pain free, but a

dull background pain may persist in some cases.

(3)

The

mechanisms associated with the development of this

persistent pain are not well understood but concomitant

background pain is associated with poor medical and

surgical outcome.

(5-7)

DEFINITION AND CLINICAL PRESENTATION

OF PERSISTENT IDIOPATHIC FACIAL PAIN

Persistent idiopathic facial pain (PIFP) was previously

termed atypical facial pain and was first introduced by

neurosurgeons in the 1920s as a distinct clinical entity.

(8)

The IHS defined it, as "a persistent facial pain that does

not have the characteristics of cranial neuralgias, presents

daily and persists for all or most of the day. The pain is

confined at onset to a limited area on one side of the

face and is deep and poorly localized".

(3)

Common sites

of onset are the nasolabial fold or the side of the chin. It

may spread to the upper or lower jaw or a wider area of

the face and neck, not following specific peripheral

neuroanatomic distributions. It is most often felt unilaterally,

but over time, in about one-third of patients the pain

becomes bilateral. The pain is often initiated by minor

surgery or injury to the face, teeth or gums, but persists

without any demonstrable cause.

(3)

Sensory loss or other

physical signs are not present and clinical investigations

are usually unremarkable. The diagnosis of PIFP is one of

exclusion and should be made only after local orofacial

disease, neurologic disorders, and related systemic

diseases are ruled out.

(9)

The IHS added a comment on

their classification that a facial pain located in the area of

the ear or temple may be associated with undiagnosed

lung cancer causing referred pain as a result of vagal

nerve involvement.

(3)

EPIDEMIOLOGY OF TRIGEMINAL NEURALGIA

TN is the most common form of cranial neuralgias

with an incidence of 4.3 per 100,000 persons per year,

with a slightly higher incidence for women (5.9/100,000)

compared to men (3.4/100,000).

(10)

The gender ratio

women to men is approximately 2:1.

(11)

The prevalence

of this relatively rare disorder has been reported to be

15.5 cases per 100,000 in the United Kingdom.

(12)

Germany the prevalence of TN is prevalence of 0.3% of

the general population.

(13)

Sjaastad et al. (2007) found

only two patients out of 1838 to fit the diagnostic criteria

for TN (0.1%) in a large Norwegian epidemiological

study (Vågå-Study).

(14)

TN can first appear at any age,

but disease onset is after the age of 40 years in over

90% of cases. The peak age is between the ages of 50

to 60 years.

(12)

The right side of the face is more often

involved that the left .

(15)

About 2% of the patients with

MS complain about symptoms identical to those of TN.

(14)

TN seldomly affects more than one member of the family,

but increased risk was reported in patients living in the

same household, suggesting disease associated

environmental factors.

(16,17)

EPIDEMIOLOGY OF PERSISTENT IDIOPATHIC

FACIAL PAIN

PIFP prevalence remains largely unclear. In general,

orofacial pain is considered to be a common problem

affecting between 17%-26% of the adult population with

increasing prevalence corresponding to increasing age.

(18)

Approximately 7%-11% of patients have chronic facial

pain in this regard.

(19)

Atypical odontalgia, often

78 Headache Medicine, v.3, n.2, p.76-87, Apr./May/Jun. 2012

OBERMANN M, HOLLE D, KATSARAVA Z

considered a subtype of PIFP and defined as a continuous

pain in the teeth or in a tooth socket after extraction in the

absence of any identifiable dental cause, occurs in 3%-

6% of patients that undergo endodontic treatment.

(20)

large population based sample reported the prevalence

of PIFP in the general population in Germany at 0.03%

[95% CI < 0.08%].

(13)

The incidence was estimated at

one patient out of 100,000 in PIFP but the authors

proposed that there might be a huge underestimation of

PIFP in their large patient population due to the lack of

diagnostic reconfirmation tests.

(21)

A gender ratio of women

compared to men of 2:1 was reported and female

hormones were suggested as a risk factor for the

development of PIFP.

(22)

AETIOLOGY AND PATHOPHYSIOLOGY OF

TRIGEMINAL NEURALGIA

Current opinion is that TN is caused by a proximal

compression of the trigeminal nerve root close to the

brainstem (root entry zone) by a tortuous or ectasic blood

vessel (artery or vein) leading to mechanical twist of nerve

fibers and secondary demyelination, probably mediated

by microvascular ischemic damages.

(23)

These changes

lower the excitability threshold of affected fibers and

promote inappropriate ephaptic propagation towards

adjacent fibers.

(24)

Thus, tactile signals coming from the

fast myelinated (A-beta) fibers can directly activate the

slow nociceptive (A-delta) fibers resulting in the high-

frequency discharges characteristic for TN. After a few

seconds these repetitive discharges spontaneously run out

and are followed by a brief period of inactivity that

resembles the refractory period observed clinically.

(2)

Demyelination and remyelination processes within the root

entry zone (i.e., 6 mm of central myelin from the brainstem;

Obersteiner-Redlich line = transition of central to

peripheral myelin of the trigeminal nerve) observed in

electronic microscopy studies might provide one

explanation for the periodicity of the syndrome.

(25,26)

Spontaneous remission of at least 6 months were

described in 50% of the cases and remissions of over one

year in 25%.

(27)

Marinkovic et al. (2007) described

trigeminal vascular pathology with immunoreactivity in TN

patients suggesting a more local concentrated

pathological origin of disease.

(23)

A recent diffusion tensor

imaging (DTI) study showed a reduced fractional

anisotropy (FA) of the trigeminal nerve in six patients with

TN on the affected side confirming tissue damage

associated with demyelination likely due to compression.

(28)

While Jannetta et al. (1967) described 88% of their

investigated patients to have a nerve vessel conflict, 6%

had MS and 6% showed a cerebellar-pontine angle

tumour,

(29)

more recent investigations demonstrated that

not all patients that were considered classical TN did have

a nerve vessel conflict (usually the superior cerebellar artery)

and that at least 25% of people without any clinical signs

of TN did show a nerve artery contact on magnetic-

resonance imaging (angio-3D-TOF).

(30)

A different study

showed that out of 220 investigated trigeminal nerves 110

(49%; 51 women, 57 men) came into contact with some

vasculature on routine MRI performed for different

reasons.

(31)

The quick pain relief following microvascular

decompression surgery in 90% of patients is a strong

indicator for the relevance of this mechanism, but lacks

explanation as to why a large percentage of patients

experience recurrence of their complaints.

(32)

It was

suggested that hyperexcitability of the compressed nerve

is necessary but alone insufficient to cause the disease, so

that a nerve-vessel conflict may represent a risk factor for

the development of TN.

(33)

Possible involvement of central

factors come more and more into focus of current

research, suggesting a central facilitation and resulting

hyperexcitability of the trigeminal system sustained by

peripheral as well as central mechanisms.

(34)

Sensitisation

of second order wide dynamic range (WDR) neurons in

lamina V of the dorsal horns and the trigeminal nerve

nuclei due to hypersensitivity of tactile A-beta fibers were

discussed as additional pathophysiological mechanism.

Since these WDR neurons receive convergent information

from tactile (A-beta) and nociceptive (A-delta and C)

fibers, their sensitization could facilitate nociceptive input

while promoting the perception of pain in response to

tactile stimuli (i.e., allodynia, trigger factors). Central

facilitation was recently demonstrated in TN patients with

additional constant dull background pain besides their

typical TN attacks using pain-related evoked potentials

(PREP) and nociceptive blink reflex (nBR).

(6)

This provides

strong evidence for the involvement of supraspinal structures

in TN. Borsook et al. (2007) reported increased fMRI

activation of a single TN patient in the primary

somatosensory cortex, insula, anterior cingulate, and

thalamus to further support supraspinal involvement.

(35)

Whether supraspinal facilitation is part of the underlying

cause of TN or merely a consequence of the disease will

need further research. While concomitant constant pain is

a predictor for poor surgical and medical outcome it is

probably not due to progressing disease or illness

duration as it is frequently observed in patients with

Headache Medicine, v.3, n.2, p.76-87, Apr./May/Jun. 2012 79

average disease duration.

(6,34)

It might be regarded as

disease variant.

AETIOLOGY AND PATHOPHYSIOLOGY OF

PERSISTENT IDIOPATHIC FACIAL PAIN

The aetiology and pathophysiology of PIFP is not

as well understood. Surgery or injury in the distribution

of the trigeminal nerve was suggested as the initiating

event as many patients attribute their pain to an

antecedent event such as dental procedure/ extraction

or other minor trauma to the face.

(36)

PIFP could represent

a neuropathic pain condition. It was suggested, that the

pain may be a consequence of deafferentation and long

term neuroplastic changes initiated by the frequently

occuring minor injuries of afferent trigeminal nerve fibers

explaining the suggested peripheral as well as central

component of this complex disease.

(2)

For many years, a psychogenic origin of PIFP was

assumed mainly based on the often observed psychiatric

comorbidities presented by patients such as depression

and anxiety disorders.

(37)

The prevalence of psychiatric

disorders in fact was shown to be increased with up to

30% of PIFP patients suffering from anxiety disorders,

16% from affective disorders, 15% from somatoform

disorders, and 6% with psychosis.

(38)

This pure

psychological concept is disputed more and more

recently with emerging evidence of measurable

neurobiological correlates for the patients' complains that

are similar to other chronic pain conditions. A recent

imaging study showed structural brain changes in regions

well known to be associated with central pain

processing.

(39)

A decrease in gray matter volume in the

anterior cingulate cortex (ACC), the temporo-insular

region, as well as the sensory-motor area projecting to

the representational area of the face were demonstrated

in patients with PIFP similar to previously described brain

alterations in primary headache disorders (i.e., tension-

type headache) and other chronic pain conditions (i.e.,

chronic back pain).

(39)

Whether these changes are due

to the PIFP pathophysiology or merely represent changes

due to chronic pain remain uncertain, but these results

support the opinion of a neurobiological origin of PIFP.

A functional imaging study with positron emmission

tomography (PET) on six patients with PIFP showed an

increased blood flow in the ACC and a decreased blood

flow in the prefrontal cortex compared to healthy controls

after application of heat pain stimuli applied to the

hand.

(40)

A similar PET study showed an increased D2

receptor density in the putamen stressing the relevance

of dopaminergic neurotransmission in the modulation

of pain perception in PIFP.

(41)

Neurophysiological testing

using blink reflex (BR) recordings and quantitative sensory

testing (QST) showed neuropathic changes and central

hyperexcitability similar to alterations described in TN

and other neuropathic causes of chronic orofacial pain.

(2)

These test results, however, were quite heterogeneous

across the investigated patients and did not show reliable

abnormalities in all investigated PIFP patients. Therefore,

authors underlined a multifactorial and heterogeneous

origin of disease in PIFP with a peripheral (i.e., nerve

injury, small-fiber neuropathy) and central component

(i.e., disturbed or disregulated pain regulation of

ascending or descending nociceptive and antinociceptive

brain centers).

(42)

Besides the neuropathy part of

suspected peripheral pathology in PIFP, a neuromuscular

component of PIFP pathology was described only

recently in a study that found an increased muscular

activity of the masseter muscles and the anterior temporal

muscles in PIFP using electromyography (EMG). This

increased activity decreased after rehabilitation with a

neuromuscular orthosis in parallel to the reduction of

individual pain perception on a visual analogue scale

(VAS) from 9.5 to 3.1.

(43)

Further research is needed to identify responsible

mechanisms and subdivide the different patho-

physiological aspects and contributing factors possibly

leading to PIFP.

DIAGNOSTICS AND DIFFERENTIAL

DIAGNOSIS

The correct clinical diagnosis is the most important

factor for sufficient treatment in both orofacial pain

conditions alike. History remains the essential tool for

diagnosis. The following six questions were proposed to

determine the correct diagnosis in orofacial pain:

(44)

1) Does the pain occur in attacks or is it constant?

2) How long are the attacks (seconds to minutes)?

3) Are the attacks electric shock like or dull, pressing

or pulsating?

4) Is the pain unilateral?

5) Is the pain confined to the distribution of a particular

branch or branches of the trigeminal nerve (ophthalmic

= V1, maxillary = V2, mandibular = V3)?

6) Are trigeminal autonomic symptoms present (e.g.,

lacrimation, rhinorrea, conjunctival injection, nasal

congestion, ptosis)?

TRIGEMINAL NEURALGIA AND PERSISTENT IDIOPATHIC FACIAL PAIN

80 Headache Medicine, v.3, n.2, p.76-87, Apr./May/Jun. 2012

Trigeminal autonomic cephalalgias (e.g., cluster

headache, SUNCT, paroxysmal hemicrania) are important

to differentiate, especially in patients with first division pain

only.

(45)

Other important differential diagnoses are

nasopharyngeal tumors and hidden dental problems

such as infections of the maxillary cavities or jaws after

previous tooth extraction as well as disorders of the

temporomandibular joint (Table 1). For correct

differentiation a thorough examination by an oral/

maxillofacial surgeon or facial pain experienced dentist

is required. The finding of septal deviation is irrelevant

and does not rule out the diagnosis.

(46)

Cranial magnetic

resonance imaging (MRI) should be performed in patients

with atypical presentation of TN and PIFP even though

data on clinical specificity or sensitivity are unavailable.

Thorough diagnostic workup is especially important in

PIFP as it is a diagnosis of exclusion. It should include a

radiologic examination of the chest, since in rare

occasions PIFP may be the presenting symptom of a lung

cancer.

(47)

In TN the main objective of special diagnostic

procedures is the differentiation of classical TN (CTN) from

symptomatic TN (STN). Clinical presentation with bilateral

TN as well as trigeminal sensory deficits are indicative of

STN, but due to low sensibility, their absence does not rule

out STN.

(32,48)

Magnetic resonance imaging detects

symptomatic causes other than nerve vessel conflict in

approximately 15% (95% CI, 11-20) of patients. Multiple

sclerosis (MS) plaques and cerebello-pontine angle

tumours are the most common findings. Blink reflex studies

and other trigeminal reflex testing has a considerably high

diagnostic value with sensitivity of 94% (95% CI, 91-97),

and specificity of 87% (95% CI, 77-93). Evoked potentials

are insufficient to separate STN from CTN.

(32,48)

The sensitivity and specificity of imaging techniques

such as MRI to detect a microvascular conflict were

reported with wide range (sensitivity 52% to 100%;

specificity 29% to 93%).

(32,48)

The usefulness of MRI in the

assessment of TN remains subject to debate. Newer

imaging techniques and MR-sequences try to fill this gab.

The combination of 3D reconstructed high-resolution

balanced fast-field echo (BFFE) images, 3D time-of-

flight (TOF) magnetic resonance (MR) angiography,

and Gd-enhanced 3D spoiled gradient recalled sequence

were able to identify 15 out of 18 CTN patients. This

clearly shows that more sophisticated techniques as well

as higher resolution of ultra-high field MRI scanners at 7

tesla may be able to revolutionize the diagnostic

possibilities for TN in the future.

(49,50)

One patient

diagnosed as PIFP with concomitant nerve vessel conflict

did not improve after decompression surgery.

(51)

MEDICAL TREATMENT

Treatment options for TN are numerous including

both medical and surgical treatment options, but mostly

restricted by low clinical evidence. The treatment options

of PIFP generally consist of medical treatment with newer

and conventional antidepressants (tricyclics and selective-

serotonin reuptake inhibitors) as well as antiepileptic drugs.

No class I or II evidence exists.

(44)

Psychological support in

terms of behavioural therapy is strongly recommended

by many authors in PIFP. In general psychological support

should be considered in all chronic pain conditions. Active

participation in support groups may help many patients

dealing better with their disease and with suggested

therapy.

(52)

OBERMANN M, HOLLE D, KATSARAVA Z

Headache Medicine, v.3, n.2, p.76-87, Apr./May/Jun. 2012 81

TRIGEMINAL NEURALGIA MEDICAL

TREATMENT

General recommendation is to start with medical

therapy and consider surgical procedures in patients that

are refractory to medical treatment.

First-line treatment optionsFirst-line treatment options

First-line treatment options

First-line therapy should be carbamazepine (CBZ;

200-1200 mg/day) and oxcarbazepine (OXC; 600-

1800 mg/day) according to current evidence based

treatment guidelines.

(32,48)

Although the evidence for CBZ

is stronger,

(53-56)

OXC has a better safety profile.

(57)

Approximately 6% to 10% of patients cannot tolerate

CBZ.

(58)

Multiple pharmacologic interactions and a

narrow therapeutic window of tolerability further limit the

use of CBZ. As the incidence of TN increases with age,

(59)

age related physiologic changes that alter pharmaco-

kinetics such as reduced hepatic and renal function,

blood flow decline, less predictable drug protein-binding

and interactions with multiple other medications required

due to concomitant illness will come more and more

into focus. Hyponatraemia is an issue with both

medications and can become a serious problem in

elderly patients.

Second line treatment optionsSecond line treatment options

Second line treatment options

Second line treatment is based on very little evidence

and includes add-on therapy with lamotrigine (400 mg/

day),

(60)

or a switch to lamotrigine, baclofen (40-80 mg/

day)

(61)

or pimozide (4-12 mg/day). Other antiepileptic

drugs have been investigated in small open-label studies.

Benefit was suggested from phenytoin, clonazepam,

gabapentin, pregabalin, topiramate and valproate, as

well as tocainide (12 mg/day).

(62)

Especially the newer

antiepileptic drugs (AED) with less interaction to other

medication and lesser side effects will be worth further

investigation. The newer AED that were tested within the

past two years were topiramate and pregabalin.

Pregabalin was tested in an open-label study including

53 patients (14 with concomitant constant facial pain) with

one year follow-up. Pregabalin (150-600 mg/day)

proved to be effective in reducing TN pain in 74% of

patients with minor efficacy reduction over the one-year

observational period. Patients without concomitant facial

pain showed better response rates (32 of 39, 82%)

compared to patients with concomitant chronic facial pain

(7 of 14, 50%, p = 0.020).

(6)

Topiramate (100-400 mg/

day) was effective in 75% of patients in a very small sample

of only eight patients.

(63)

Two small open label trials

investigated the efficacy of levetiracetam (Keppra) in the

treatment of TN and showed moderate efficacy. Both

studies concluded that randomized controlled trials of

levetiracetam will be needed to reconfirm these

findings.

(64,65)

Alternative treatment optionsAlternative treatment options

Alternative treatment options

Alternative treatment options are subcutaneous

sumatriptan and botulinum neurotoxin type A (BoNT-A)

injections. Sumatriptan and zolmitriptan showed efficacy

in controlling allodynic pain following nerve injury in an

animal model for trigeminal neuropathic pain.

(66)

A single-

blind study of subcutaneous sumatriptan compared to

placebo showed efficacy of sumatriptan on pain symptoms

in patients with TN after 15 and 30 minutes compared to

placebo. This effect lasted only 7 h on average and limits

the clinical usefulness substantially.

(67)

Several descriptions

postulated an analgesic effect of BoNT-A through local

release of anti-nociceptive neuropeptides such as

substance P, glutamate and calcitonin-gene related

peptide (CGRP) inhibiting central and possibly peripheral

sensitization.

(68)

Reports of isolated TN patients treated with

BoNT-A and a small, uncontrolled clinical trial (N = 13)

showed significant relief from symptoms after treatment

with BoNT-A.

(69)

MEDICAL TREATMENT FOR PERSISTENT

IDIOPATHIC FACIAL PAIN

Treatment of PIFP can be difficult and unsatisfactory

due to the modest knowledge of the underlying patho-

physiological mechanisms. Sufficient evidence from

randomized controlled clinical trials is scarce. Tricyclic

antidepressants (TCA) have a moderate efficacy at doses

between 25-100 mg/day.

(70)

Positive results were also

reported with selective serotonin- and serotonin-

noradrenalin reuptake inhibitors (SSNRI) fluoxetine

(71)

and

venlafaxine

(72)

(Table 2).In the fluoxetine study 178 patients

with chronic facial pain but without depression improved

in pain severity.

(71)

Venlafaxine was efficient in 30 patients

with PIFP in a randomized, double-blind, crossover

comparison study, but only twenty patients completed the

trial due to adverse events and/ or non-compliance.

(72)

single case report suggested efficacy of topiramate in PIFP

treatment.

(73)

Calcitonin did not show sufficient pain relief

in a randomized controlled trial on PIFP.

(74)

Sumatriptan

showed only a transient effect on pain score reduction but

this effect was very small so that sumatriptan was not

TRIGEMINAL NEURALGIA AND PERSISTENT IDIOPATHIC FACIAL PAIN

82 Headache Medicine, v.3, n.2, p.76-87, Apr./May/Jun. 2012

considered an appropriate therapeutic option for the

treatment of PIFP in two randomized placebo-controlled

clinical trials.

(75,76)

Hydrocodone was used successfully in

one patient and further supports a central origin of PIFP.

(46)

Kanpolat et al. showed pain relief after percutaneous

trigeminal tract and nucleus ablation, also suggesting that

central, rather than peripheral mechanisms may be the

dominant factor in this disorder.

(77)

Cognitive behavioural therapy is recommended for

the treatment of PIFP, but objective assessment of efficacy

remains unavailable.

(44)

Invasive treatment of persistent idiopathicInvasive treatment of persistent idiopathic

Invasive treatment of persistent idiopathic

facial painfacial pain

facial pain

Transcutaneous nerve stimulation (TNS) demonstrated

satisfactory analgesia in 45% (N = 20) of patients from

conventional and acupuncture-like TNS in a two-year

follow-up evaluation.

(78)

Pulsed radiofrequency (PRF)

treatment of the ganglion sphenopalatinum in patients

with different orofacial pain conditions including PIFP was

evaluated retrospectively. Out of the treated patients 21%

reported complete pain relief, and 65% experienced a

good to moderate improvement in this observational

trial.

(79)

One patient showed almost complete pain relief

from his PIFP following upper thoracic spinal cord

stimulation (SCS) for refractory angina.

(80)

SURGICAL TREATMENT

Before surgical intervention is being considered in

the treatment of TN most experts suggest at least three

adequate conventional treatments attempts with different

drugs at sufficient dosage. One of the drugs should be

carbamazepine. However, there are patients that

specifically request surgery despite sufficient pain relief by

medication, because they are concerned of disease

progression or relapse over time. Medical treatment was

patients' least favourite choice when asked what treatment

they would choose for themselves

(81)

mostly because they

were afraid of side effects. Surgery in the treatment of

TN is generally considered safe and has good efficacy.

(82)

Zakrzewska and Lopez (2003) suggested a checklist that

should be done before surgery in order to improve the

evaluation quality of surgical treatment.

(83)

Surgical treatment of PIFP is currently not

recommended. Trigeminal vascular decompression and

deep-brain stimulation of the hypothalamus were not

effective. Patients should be preserved from unnecessary

dental or surgical procedures as long as a causal

understanding of any procedure to alleviate pain is

reached.

Surgical treatment of trigeminal neuralgiaSurgical treatment of trigeminal neuralgia

Surgical treatment of trigeminal neuralgia

A lot of literature on possible interventional treatment

for medical refractory TN was presented in the past without

sufficient scientific evidence for general treatment

recommendation. Currently considered efficient are

percutaneous procedures on the Gasserian ganglion,

gamma knife surgery, and microvascular decompression.

These methods are either destructive (ablative) with

intentionally destroying the trigeminal nerve sensory

function, or non-destructive decompressive where the

normal nerve function is preserved. Gasserian ganglion

percutaneous techniques include radiofrequency

thermocoagulation (RFT), balloon compression (BC) and

percutaneous glycerol rhizolysis (PGR). Pain relief is

reported by 90% of patients following these procedures.

However, the persistence of this pain relief in many patients

does not persist with a recurrence rate of 15-32% within

the first year, after three years recurrence rate is between

36%-46%, and half of the patients have a return of

symptoms after five years post radiofrequency thermo-

coagulation. Most common side effects are sensory loss

(50%), dysesthesias (6%), anesthesia dolorosa (4%),

corneal numbness with risk of keratitis (4%). Gasserian

ganglion therapies require short acting anaesthetics, are

primarily overnight minor procedures with extremely low

mortality.

(32,48)

Gamma knife surgery severs the trigeminal nerve at

the root in the posterior fossa with a focused beam of

radiation. Sixty nine percent of patients were pain free

without additional medication after gamma knife surgery

with 52% remain pain free at three years follow-up. Pain

OBERMANN M, HOLLE D, KATSARAVA Z

Headache Medicine, v.3, n.2, p.76-87, Apr./May/Jun. 2012 83

relief may be delayed by one month and longer (mean

one month). Side effects were sensory complications in

6%, facial numbness 9%-37% which improves over time

and paresthesias 6%-13% (no anaesthesia dolorosa).

(32,48)

Quality of life improves by 88%.

(84)

The most sustained pain relief is achieved by

microvascular decompression with 90% of patients

reporting initial pain relief and over 80% remain pain

free at one year follow-up. 75% after three years and

73% after five years. However, to reach the trigeminal

nerve in the posterior fossa major surgery craniotomy is

required with corresponding complications. The average

mortality rate ranges from 0.2%-0.5%, and up to 4% of

patients suffer from major problems such as CSF leakage,

infarcts, or hematomas. Most common complication is

aseptic meningitis (11%), sensory loss (7%), and hearing

loss (10%) as long-term complication.

(32,48)

More recent investigations have focused mainly on

treatment evaluation in long-term follow-up studies.

(85,86)

and improvement of existing surgical techniques.

(87-89)

Even

thought this has been the most active field of TN research

over the past years the vast majority of studies remain on

a descriptive level making evidence based comparison

and recommendation difficult. The right timing for surgical

intervention is yet to be determined.

(81)

Some TN experts

suggest early surgical referral in patients that fail to respond

to first-line medical therapy, while others request to have

tried at least two different medical regimens including

combination therapy before considering surgery including

carbamazepine at a sufficient dose. There is no supporting

evidence for either of the two opinions. Referral for surgical

intervention seems reasonable in TN patients refractory to

medical therapy.

EXPERT COMMENTARY

For the correct diagnosis and accurate management

of TN a stepwise diagnostic and treatment approach is

mandatory. The diagnosis of TN and the distinction

between symptomatic TN and classical TN is generally

made clinically. Suspicious of STN are bilateral

involvement or sensory deficits. In STN MRI should be

considered. Blink reflex studies may also be helpful in

the distinction of STN and CTN. Carbamazepine (600-

1200 mg/day) or oxcarbazepine (600-1800 mg/day)

should be the first line therapy. It may be supplemented

with or switched to lamotrigine (200-400 mg/day),

pregabalin (150-600 mg/day), gabapentin (1800-

4200 mg/day) or topiramate (100-400 mg/day). In

case the the combination therapy is insufficient baclofen

(40-80 mg/day) can be tried. The option of surgical

intervention should be discussed early on with the patient

and reluctance in referral to surgery may be

disadvantageous to the patient after three different

medications and at least one combination therapy turned

out to provide insufficient pain relieve. The patient should

be involved in the decision on what kind of intervention

(Gasserian ganglion procedures, gamma knife surgery,

microvascular decompression) deems appropriate

regarding his own individual wishes and overall medical

condition. As a general rule of thumb the consenting

physician should remember that older patients with serious

co-morbidities should receive less invasive treatment

depending on their biological age and current medical

status.

The diagnosis of persistent idiopathic facial pain is

generally made by elimination of other causes and often

requiring multidisciplinary examination and consultation.

The underlying pathophysiological mechanisms remain

unclear and probably are a combination of peripheral

nervous and muscular as well as central and psychological

mechanisms. It may represent one end of the spectrum of

neuropathic pain when understood in broader terms to

also include subclinical neuropathies, pure small-fiber

neuropathies, or neurogenic dysfunction in the form of

deficient central top-down inhibitory control.

Pharmacological treatment with tricyclic antidepressants

and selective serotonin-noradrenalin reuptake inhibitors

may be tried. Amitriptyline (25-100 mg/day) is commonly

considered first line therapy along with venlafaxine (50-

75 mg/day) and fluoxetine (10-20 mg/day). When

pharmacological therapy fails, PRF treatment of the

ganglion sphenopalatinum may be considered. Cognitive

behavioural therapy should accompany medical therapy

if possible.

Five-year viewFive-year view

Five-year view

Continuous scientific research has worked towards a

better understanding of orofacial pain over the past

decades and provided an increased awareness of these

diverse and very disabling painful conditions in

neurologists, neurosurgeons, dentists, and primary care

physicians. More recent clinical, electrophysiological, and

imaging studies provided greater insight into the

underlying pathophysiological mechanisms and will

continue to do so in the coming years. The focus of future

research should be mainly on the central component and

the associated nociceptive and antinociceptive modulatory

TRIGEMINAL NEURALGIA AND PERSISTENT IDIOPATHIC FACIAL PAIN

84 Headache Medicine, v.3, n.2, p.76-87, Apr./May/Jun. 2012

networks that influence chronic orofacial pain conditions

like TN or PIFP. Better imaging techniques will be necessary

to untangle these networks. Controlled studies with long

term follow-up will be needed that compare surgical and

medical therapy directly with one another and determine

the optimal timing for surgical intervention. This also

includes studies that investigate second-line medical therapy

after the first-line has failed in stepwise, standardized

regimen. The development of newer, antinociceptive drugs

for the treatment of orofacial pain needs thorough

investigation toward treatment efficacy in TN as well as

PIFP.

KEY ISSUES

– Trigeminal neuralgia (TN) and persistent idiopathic

facial pain (PIFP) are rare, but excruciatingly painful

disorders mainly affecting the second and third division

of the trigeminal nerve.

– TN with concomitant, dull, less intense, but constant

facial pain is a variant of classical TN and has poor

response to medical and surgical treatment. This is

sometimes hard to distinguish from PIFP.

– Magnetic resonance imaging (MRI) and trigeminal

reflex testing are reliable to differentiate symptomatic TN

from classical TN, but no reliable test exists to confirm

PIFP.

– First-line therapy for TN is carbamazepine (CBZ;

600-1200 mg) or oxcarbazepine (OXC; 600-1800 mg).

First-line therapy for PIFP is amitriptyline (25-100 mg) as

well as fluoxetine (10-20 mg) and venlafaxine (50-75 mg).

– Lamotrigine (400 mg/day), Baclofen (40-80 mg/

day), Pimozide (4-12 mg/day) are second line treatment

options for TN.

– TN patients refractory to medical treatment should

receive early surgical therapy (percutaneous procedures on

the Gasserian ganglion, gamma knife, or microvascular

decompression). PIFP patients not responding to medical

treatment may be considered for pulsed radiofrequency

treatment (PRF) of the sphenopalatine ganglion.

– Cognitive behavioural therapy is generally

recommended as supportive treatment in PIFP patients and

may be helpful in all other chronic orofacial pain patients

as well.

REFERENCES

1. Benoliel R, Birman N, Eliav E, Sharav Y. The International

Classification of Headache Disorders: accurate diagnosis of

orofacial pain? Cephalalgia. 2008;28(7):752-62.

2. Forssell H, Tenovuo O, Silvoniemi P, Jaaskelainen SK. Differences

and similarities between atypical facial pain and trigeminal

neuropathic pain. Neurology. 2007;69(14):1451-9.

3. Headache Classification Subcommittee of the International

Headache Society. The International Classification of Headache

Disorders: 2nd Edition. Cephalalgia. 2004; 24(Suppl 1):9-

160.

4. De Simone R, Marano E, Brescia Morra V et al. A clinical

comparison of trigeminal neuralgic pain in patients with and

without underlying multiple sclerosis. Neurol Sci. 2005;26(Suppl

2):150-1.

5. Szapiro J, Jr., Sindou M, Szapiro J. Prognostic factors in

microvascular decompression for trigeminal neuralgia.

Neurosurgery. 1985;17(6):920-9.

6. Obermann M, Yoon MS, Sensen K, Maschke M, Diener HC,

Katsarava Z. Efficacy of pregabalin in the treatment of trigeminal

neuralgia. Cephalalgia. 2008;28(2):174-81.

7. Sandell T, Eide PK. Effect of microvascular decompression in

trigeminal neuralgia patients with or without constant pain.

Neurosurgery. 2008;63(1):93-99; discussion 99-100.

8. Frazier C, Russel E. Neuralgia of the face: an analysis of 754

cases with relation to pain and other sensory phenomena before

and after operation. Arch Neurol Psychiatry. 1924;11:557-63.

9. Sardella A, Demarosi F, Barbieri C, Lodi G. An up-to-date view

on persistent idiopathic facial pain. Minerva Stomatol. 2009;

58(6): 289-99.

10. Yoshimasu F, Kurland LT, Elveback LR. Tic douloureux in Rochester,

Minnesota, 1945-1969. Neurology. 1972;22(9):952-6.

11. Katusic S, Williams DB, Beard CM, Bergstralh EJ, Kurland LT.

Epidemiology and clinical features of idiopathic trigeminal

neuralgia and glossopharyngeal neuralgia: similarities and

differences, Rochester, Minnesota, 1945-1984. Neuro-

epidemiology. 1991;10(5-6):276-81.

12. MacDonald BK, Cockerell OC, Sander J, Shorvon SD. The incidence

and lifetime prevalence of neurological disorders in a prospective

community-based study in the UK. Brain. 2000; 123( Pt 4):665-

76. Comment in: Brain. 2000;123( Pt 4):663-4.

13. Mueller D, Obermann M, Yoon MS, Poitz F, Hansen N, Slomke

MA, et al. Prevalence of trigeminal neuralgia and persistent

idiopathic facial pain: a population-based study. Cephalalgia.

2011;31(15):1542-8.

14. Sjaastad O, Bakketeig LS. The rare, unilateral headaches. Vågå

study of headache epidemiology. J Headache Pain. 2007; 8(1),

19-27.

15. De Simone R, Ranieri A, Bilo L, Fiorillo C, Bonavita V. Cranial

neuralgias: from physiopathology to pharmacological treatment.

Neurol Sci. 2008;29(Suppl 1): S69-78.

16. Savica R, Laganà A, Siracusano R, Calabrò RS, Ferlazzo E,

Musolino R. Idiopathic familial trigeminal neuralgia: a case

report. Neurol Sci. 2007;28(4):196-8.

17. Smyth P, Greenough G, Stommel E. Familial trigeminal

neuralgia: case reports and review of the literature. Headache.

2003;43(8):910-5.

18. Macfarlane TV, Blinkhorn AS, Davies RM, Kincey J, Worthington

HV. Oro-facial pain in the community: prevalence and associated

impact. Community Dent Oral Epidemiol. 2002;30(1):52-60.

OBERMANN M, HOLLE D, KATSARAVA Z

Headache Medicine, v.3, n.2, p.76-87, Apr./May/Jun. 2012 85

19. McMillan AS, Wong MC, Zheng J, Lam CL. Prevalence of

orofacial pain and treatment seeking in Hong Kong Chinese. J

Orofac Pain. 2006;20(3):218-25.

20. Melis M, Lobo SL, Ceneviz C, Zawawi K, Al-Badawi E, Maloney

G, et al. Atypical odontalgia: a review of the literature. Headache.

2003;43(10):1060-74.

21. Kavuk I, Yavuz A, Cetindere U, Agelink MW, Diener HC.

Epidemiology of chronic daily headache. Eur J Med Res.

2003; 8(6): 236-40. Comment in: Eur J Med Res. 2004;9

(5):285.

22. Dao TT, LeResche L. Gender differences in pain. J Orofac Pain.

2000;14(3):169-84; discussion 184-95. Comment in: J Orofac

Pain. 2000 Summer; 14(3):165.

23. Marinkovic' S, Todorovic' V, Gibo H, Budec M, Drndarevic' N,

Pesic' D, et al. The trigeminal vasculature pathology in patients

with neuralgia. Headache. 2007;47(9):1334-9.

24. Burchiel KJ. Abnormal impulse generation in focally demyelinated

trigeminal roots. J Neurosurg. 1980;53(5):674-83.

25. Rappaport ZH, Govrin-Lippmann R, Devor M. An electron-

microscopic analysis of biopsy samples of the trigeminal root

taken during microvascular decompressive surgery. Stereotact

Funct Neurosurg. 1997;68(1-4 Pt 1):182-6.

26. Peker S, Kurtkaya O, Uzun I, Pamir MN. Microanatomy of the

central myelin-peripheral myelin transition zone of the trigeminal

nerve. Neurosurgery. 2006;59(2):354-9; discussion 354-9.

Neurosurgery. 2007; 60(3):E582; author reply E582.

27. Rushton JG, MacDonald HN. Trigeminal neuralgia; special

considerations of nonsurgical treatment. J Am Med Assoc. 1957;

165(5):437-40.

28. Herweh C, Kress B, Rasche D, Tronnier V, Tröger J, Sartor K, et

al. Loss of anisotropy in trigeminal neuralgia revealed by

diffusion tensor imaging. Neurology. 2007;68(10):776-8.

29. Jannetta PJ. Arterial compression of the trigeminal nerve at the

pons in patients with trigeminal neuralgia. J Neurosurg. 1967;

26(1) Suppl:159-62.

30. Adamczyk M, Bulski T, Sowinska J, Furmanek A, Bekiesinska-

Figatowska M. Trigeminal nerve - artery contact in people without

trigeminal neuralgia - MR study. Med Sci Monit. 2007;13 (Suppl

1):38-43.

31. Kakizawa Y, Seguchi T, Kodama K, Ogiwara T, Sasaki T, Goto T,

et al. Anatomical study of the trigeminal and facial cranial nerves

with the aid of 3.0-tesla magnetic resonance imaging. J

Neurosurg. 2008;108(3):483-90.

32. Gronseth G, Cruccu G, Alksne J, Argoff C, Brainin M, Burchiel

K, et al. Practice parameter: the diagnostic evaluation and

treatment of trigeminal neuralgia (an evidence-based review):

report of the Quality Standards Subcommittee of the American

Academy of Neurology and the European Federation of

Neurological Societies. Neurology. 2008;71(15):1183-90.

33. Hamlyn PJ, King TT. Neurovascular compression in trigeminal

neuralgia: a clinical and anatomical study. J Neurosurg. 1992;

76(6):948-54.

34. Obermann M, Yoon MS, Ese D, Maschke M, Kaube H, Diener

HC, et al. Impaired trigeminal nociceptive processing in patients

with trigeminal neuralgia. Neurology. 2007;69(9):835-41.

Comment in: Neurology. 2007;69(9):817-8.

35. Borsook D, Moulton EA, Pendse G, Morris S, Cole SH, Aiello-

Lammens M, et al. Comparison of evoked vs. spontaneous tics

in a patient with trigeminal neuralgia (tic doloureux). Mol Pain.

2007;3:34.

36. Siccoli MM, Bassetti CL, Sandor PS. Facial pain: clinical

differential diagnosis. Lancet Neurol. 2006;5(3):257-67.

37. Feinmann C, Harris M. Psychogenic facial pain. Part 1: The

clinical presentation. Br Dent J. 1984;156(5):165-8.

38. Remick RA, Blasberg B. Psychiatric aspects of atypical facial

pain. J Can Dent Assoc. 1985;51(12):913-6.

39. Schmidt-Wilcke T, Hierlmeier S, Leinisch E. Altered regional brain

morphology in patients with chronic facial pain. Headache. 2010;

50(8):1278-85.

40. Derbyshire SW, Jones AK, Devani P, Friston KJ, Feinmann C,

Harris M, et al. Cerebral responses to pain in patients with

atypical facial pain measured by positron emission tomography.

J Neurol Neurosurg Psychiatry. 1994;57(10): 1166-72.

41. Hagelberg N, Forssell H, Aalto S, Rinne JO, Scheinin H, Taiminen

T, et al. Altered dopamine D2 receptor binding in atypical facial

pain. Pain. 2003;106(1-2):43-8.

42. Jääskeläinen SK, Forssell H, Tenovuo O. Electrophysiological

testing of the trigeminofacial system: aid in the diagnosis of

atypical facial pain. Pain. 1999;80:191-200.

43. Didier H, Marchetti C, Borromeo G, Tullo V, Bussone G, Santoro

F. Persistent idiopathic facial pain: multidisciplinary approach

and assumption of comorbidity. Neurol Sci. 2010; 31(Suppl 1):

S189-95.

44. Cornelissen P, van Kleef M, Mekhail N, Day M, van Zundert J.

Evidence-based interventional pain medicine according to

clinical diagnoses. 3. Persistent idiopathic facial pain. Pain Pract.

2009;9(6):443-8.

45. Cohen AS, Matharu MS, Goadsby PJ. Short-lasting unilateral

neuralgiform headache attacks with conjunctival injection and

tearing (SUNCT) or cranial autonomic features (SUNA)--a

prospective clinical study of SUNCT and SUNA. Brain. 2006;

129(Pt 10):2746-60.

46. Evans RW, Agostoni E. Persistent idiopathic facial pain. Headache.

2006;46(8):1298-300.

47. Sarlani E, Schwartz AH, Greenspan JD, Grace EG. Facial pain as

first manifestation of lung cancer: a case of lung cancer-related

cluster headache and a review of the literature. J Orofac Pain.

2003;17(3):262-67.

48. Cruccu G, Gronseth G, Alksne J, Argoff C, Brainin M, Burchiel

K, Nurmikko T, Zakrzewska JM; American Academy of Neurology

Society; European Federation of Neurological Society. AAN-

EFNS guidelines on trigeminal neuralgia management. Eur J

Neurol. 2008;15(10):1013-28.

49. Cha J, Kim ST, Kim HJ, Choi JW, Kim HJ, Jeon P, et al. Trigeminal

neuralgia: Assessment with T2 VISTA and FLAIR VISTA fusion

imaging. Eur Radiol. 2011;21(12):2633-9.

50. Miller J, Acar F, Hamilton B, Burchiel K. Preoperative visualization

of neurovascular anatomy in trigeminal neuralgia. J Neurosurg.

2008;108(3):477-82.

51.Kuncz A, Vörös E, Barzó P, Tajti J, Milassin P, Mucsi Z, et al.

Comparison of clinical symptoms and magnetic resonance

angiographic (MRA) results in patients with trigeminal neuralgia

TRIGEMINAL NEURALGIA AND PERSISTENT IDIOPATHIC FACIAL PAIN

86 Headache Medicine, v.3, n.2, p.76-87, Apr./May/Jun. 2012

and persistent idiopathic facial pain. Medium-term outcome after

microvascular decompression of cases with positive MRA

findings. Cephalalgia. 2006;26(3): 266-76.

52. Zakrzewska JM, Jorns TP, Spatz A. Patient led conferences--who

attends, are their expectations met and do they vary in three

different countries? Eur J Pain. 2009;13(5):486-91.

53. Campbell FG, Graham JG, Zilkha KJ. Clinical trial of

carbazepine (tegretol) in trigeminal neuralgia. J Neurol

Neurosurg Psychiatry. 1966;29(3):265-7.

54. Killian JM, Fromm GH. Carbamazepine in the treatment of

neuralgia. Use of side effects. Arch Neurol. 1968;19(2):129-36.

55. Nicol CF. A four year double-blind study of tegretol in facial

pain. Headache. 1969;9(1):54-7.

56. Rockliff BW, Davis EH. Controlled sequential trials of

carbamazepine in trigeminal neuralgia. Arch Neurol. 1966;15

(2):129-36.

57. Beydoun A. Safety and efficacy of oxcarbazepine: results of

randomized, double-blind trials. Pharmacotherapy. 2000;20(8

Pt 2), 152S-8S.

58. Taylor JC, Brauer S, Espir ML. Long-term treatment of trigeminal

neuralgia with carbamazepine. Postgrad Med J. 1981;57(663),

16-8.

59. Khan OA. Gabapentin relieves trigeminal neuralgia in multiple

sclerosis patients. Neurology. 1998;51(2):611-4.

60. Zakrzewska JM, Chaudhry Z, Nurmikko TJ, Patton DW, Mullens

EL. Lamotrigine (Lamictal) in refractory trigeminal neuralgia:

results from a double-blind placebo controlled crossover trial.

Pain. 1997;73:223-30. Comments in: Pain. 1998;76(1-2):

270-1.

61. Fromm GH, Terrence CF, Chattha AS. Baclofen in the treatment

of trigeminal neuralgia: double-blind study and long-term follow-

up. Ann Neurol. 1984;15(3):240-4.

62. Lindstrom P, Lindblom U. The analgesic effect of tocainide in

trigeminal neuralgia. Pain. 1987;28(1):45-50.

63. Domingues RB, Kuster GW, Aquino CC. Treatment of trigeminal

neuralgia with low doses of topiramate. Arq Neuropsiquiatr.

2007; 65(3B):792-4.

64. Mitsikostas DD, Pantes GV, Avramidis TG, Karageorgiou KE,

Gatzonis SD, Stathis PG, et al. An observational trial to investigate

the efficacy and tolerability of levetiracetam in trigeminal

neuralgia. Headache. 2010;50(8):1371-7.

65. Jorns TP, Johnston A, Zakrzewska JM. Pilot study to evaluate the

efficacy and tolerability of levetiracetam (Keppra) in treatment of

patients with trigeminal neuralgia. Eur J Neurol. 2009;16(6),

740-4.

66. Kayser V, Aubel B, Hamon M, Bourgoin S. The antimigraine 5-

HT 1B/1D receptor agonists, sumatriptan, zolmitriptan and

dihydroergotamine, attenuate pain-related behaviour in a rat

model of trigeminal neuropathic pain. Br J Pharmacol. 2002;

137(8):1287-97.

67. Kanai A, Saito M, Hoka S. Subcutaneous sumatriptan for

refractory trigeminal neuralgia. Headache. 2006;46(4):577-

82; discussion 583-574.

68. Aoki KR. Review of a proposed mechanism for the antinociceptive

action of botulinum toxin type A. Neurotoxicology. 2005;26(5):

785-93.

69. Piovesan EJ, Teive HG, Kowacs PA, Della Coletta MV, Werneck

LC, Silberstein SD. An open study of botulinum-A toxin treatment

of trigeminal neuralgia. Neurology. 2005;65(8):1306-8.

Comment in: Neurology. 2006; 66(9):1458-9; author reply

1458-9.

70. List T, Axelsson S, Leijon G. Pharmacologic interventions in the

treatment of temporomandibular disorders, atypical facial pain,

and burning mouth syndrome. A qualitative systematic review. J

Orofac Pain. 2003;17(4):301-10.

71. Harrison S, Glover L, Maslin L, Feinmann C, Pearce S, Harris M.

A comparison of antidepressant medication alone and in

conjunction with cognitive behavioral therapy for chronic

idiopathic facial pain. In: Jensen T, Turner J, Weinsenfeld-Halin

Z, editors. Proceedings of the 8th World Congress on Pain. Vol.

8. Seattle, WA: IASP Press; 1997.

72. Forssell H, Tasmuth T, Tenovuo O, Hampf G, Kalso E. Venlafaxine

in the treatment of atypical facial pain: a randomized controlled

trial. J Orofac Pain. 2004;18(2):131-7.

73. Volcy M, Rapoport AM, Tepper SJ, Sheftell FD, Bigal ME. Persistent

idiopathic facial pain responsive to topiramate. Cephalalgia,

26. 2006;26(4):489-91.

74. Schwartz G, Galonski M, Gordon A, Shandling M, Mock D,

Tenenbaum HC. Effects of salmon calcitonin on patients with

atypical (idiopathic) facial pain: a randomized controlled trial. J

Orofac Pain. 1996;10(4): 306-15.

75. Harrison SD, Balawi SA, Feinmann C, Harris M. Atypical facial

pain: a double-blind placebo-controlled crossover pilot study

of subcutaneous sumatriptan. Eur Neuropsychopharmacol.

1997;7(2):83-8.

76. al Balawi S, Tariq M, Feinmann C. A double-blind, placebo-

controlled, crossover, study to evaluate the efficacy of

subcutaneous sumatriptan in the treatment of atypical facial pain.

Int J Neurosci. 1996;86(3-4):301-9.

77. Kanpolat Y, Savas A, Ugur HC, Bozkurt M. The trigeminal tract

and nucleus procedures in treatment of atypical facial pain. Surg

Neurol. 2005;64(Suppl 2):S96-100; discussion S100-1.

78. Eriksson MB, Sjolund BH, Sundbarg G. Pain relief from peripheral

conditioning stimulation in patients with chronic facial pain. J

Neurosurg. 1984;61(1):149-55.

79. Bayer E, Racz GB, Miles D, Heavner J. Sphenopalatine ganglion

pulsed radiofrequency treatment in 30 patients suffering from

chronic face and head pain. Pain Pract. 2005;5(3):223-7.

80. Neuman SA, Eldrige JS, Hoelzer BC. Atypical facial pain treated

with upper thoracic dorsal column stimulation. Clin J Pain. 2011;

27(6):556-8.

81. Spatz AL, Zakrzewska JM, Kay EJ. Decision analysis of medical

and surgical treatments for trigeminal neuralgia: how patient

evaluations of benefits and risks affect the utility of treatment

decisions. Pain. 2007;131(3):302-10. Comment in: Pain. 2007;

131(3):234-6.

82. Kalkanis SN, Eskandar EN, Carter BS, Barker FG 2nd.

Microvascular decompression surgery in the United States, 1996

to 2000: mortality rates, morbidity rates, and the effects of

hospital and surgeon volumes. Neurosurgery. 2003;52(6):

1251-61; discussion 1261-2.

83. Zakrzewska JM, Lopez BC. Quality of reporting in evaluations

of surgical treatment of trigeminal neuralgia: recommendations

OBERMANN M, HOLLE D, KATSARAVA Z

Headache Medicine, v.3, n.2, p.76-87, Apr./May/Jun. 2012 87

TRIGEMINAL NEURALGIA AND PERSISTENT IDIOPATHIC FACIAL PAIN

for future reports. Neurosurgery. 2003;53(1):110-20;

discussion 120-2.

84. Zakrzewska JM, Jassim S, Bulman JS. A prospective, longitudinal

study on patients with trigeminal neuralgia who underwent

radiofrequency thermocoagulation of the Gasserian ganglion.

Pain. 1999;79(1):51-8.

85. Kabatas S, Karasu A, Civelek E, Sabanci AP, Hepgul KT, Teng

YD. Microvascular decompression as a surgical management

for trigeminal neuralgia: long-term follow-up and review of

the literature. Neurosurg Rev. 2009;32(1):87-93; discussion

93-4.

86. Little AS, Shetter AG, Shetter ME, Bay C, Rogers CL. Long-term

pain response and quality of life in patients with typical trigeminal

neuralgia treated with gamma knife stereotactic radiosurgery.

Neurosurgery. 2008;63(5):915-23; discussion 923-14.

87. Sindou M, Leston JM, Decullier E, Chapuis F. Microvascular

decompression for trigeminal neuralgia: the importance of a

noncompressive technique--Kaplan-Meier analysis in a

consecutive series of 330 patients. Neurosurgery. 2008; 63(4

Suppl 2), 341-50; discussion 350-41.

88. Kanpolat Y, Kahilogullari G, Ugur HC, Elhan AH. Computed

tomography-guided percutaneous trigeminal tractotomy-

nucleotomy. Neurosurgery. 2008;63(1 Suppl 1): ONS147-53;

discussion ONS153-5.

89. Tatli M, Sindou M. Anatomoradiological landmarks for accuracy

of radiofrequency thermorhizotomy in the treatment of trigeminal

neuralgia. Neurosurgery. 2008;63(1 Suppl 1), ONS129-37;

discussion ONS137-8.

Correspondence

Mark ObermannMark Obermann

Mark Obermann

Department of Neurology, University of Duisburg-Essen,

Hufelandstr. 55, 45122

Essen, Germany

Phone: +49-201-723-84385, Fax: +49-201-723-5542,

mark.obermann@uni-due.de

Reveived: 7/20/2012

Accepted: 7/25/2012