Keywords
anticonvulsants - facial pain - neuromodulation - pulsed radiofrequency - trigeminal
neuralgia
Introduction
Trigeminal neuralgia (TN) is a chronic facial pain condition that affects one or more
divisions of the trigeminal nerve (5th cranial nerve), which carries sensation from
face to brain. This nerve has three major branches: the ophthalmic nerve (V1), the
maxillary nerve (V2), and the mandibular nerve (V3). Any single or multiple branches
can contribute to the cause of the pain. The mandibular branch is the most frequently
affected division.[1] Pain occurs in areas supplied by the trigeminal nerve, including the cheek, jaw,
teeth, gums, lips, or less often in the eyes and forehead. Pain is usually localized
in the territory of the affected branch; however, it may migrate to other branches
over time. The International Association for Study of Pain (IASP) has defined TN as
“sudden, usually unilateral, severe, brief, stabbing, recurrent episodes of pain in
the distribution of one or more branches of the trigeminal nerve.”[2] A variety of triggers such as shaving, chewing, drinking, talking, smiling, brushing
the teeth, washing the face, and encountering a breeze may initiate the pain of TN.
Usually, pain resolves completely between the attacks. It usually does not occur when
the person is asleep. Rapid spreading to other division, bilateral involvement, or
simultaneous involvement of other nerve suggests a secondary disease such as multiple
sclerosis (MS) or expanding cranial tumor. It is one of the most painful conditions
and can result in depression and suicidal tendencies.[3]
Demographics
TN is a fairly common condition, with an incidence rate of 5.7 per 100,000 women and
2.5 per 100,000 men. The usual age range is around 50 to 70 years. TN is uncommon
in young adults and rare in children.[4]
Types of Trigeminal Neuralgia
Types of Trigeminal Neuralgia
There are two varieties of TN: type 1 (classical TN) and type 2 (atypical TN). Occurrence
of pain in type 1 is intermittent as described earlier. In type 2, the pain is constant
with less severity and is described as burning or pricking, rather than a shock. A
subset of patients can progress from type 1 to type 2 TN over time; thus, both types
may coexist in the same person. A more recent and simple classification of TN has
categorized TN into three types for simplicity of treatment options: possible TN,
classical TN, and idiopathic TN ([Fig. 1]).[5]
Fig. 1 New classification and diagnostic flowchart of trigeminal neuralgia (TN).
Etiopathogenesis
The exact etiology of TN is unknown, but mostly it is due to due to loss of the myelin
around the trigeminal nerve. This may occur due to compression from a blood vessel
(mostly superior cerebellar artery) at the root entry zone (REZ) near the foramen
ovale. Other causes include multiple sclerosis, stroke, trauma, tumor, and arteriovenous
malformation. There is evidence that TN precedes MS in patients. According to the
American Society of Neurology, the pain felt in MS in young patients is mostly due
to TN. Neuroimaging and surgical evidence suggests that neurovascular compression
might act in concert with the pontine plaque through a double-crush mechanism.[6] Established knowledge postulates that TN secondary to MS is associated with a pontine
demyelinating plaque. The role of the pontine demyelinating plaque is also supported
by functional neuroimaging studies showing that in patients with classical and idiopathic
TN, tensor abnormalities are located in the cisternal and REZ segments of the trigeminal
nerve, whereas in patients with TN secondary to MS the abnormalities are located in
the pontine tract of the trigeminal nerve.[7]
Theories Described for Trigeminal Neuralgia
Theories Described for Trigeminal Neuralgia
Trigeminal Convergence Projection Theory
The continuous nociceptive inputs that are received from the head and neck converge
in the spinal trigeminal nucleus. The neurotransmitters released from the nucleus
excite the second-order neurons which gives rise to a type of chronic neuropathic
pain.[8]
Bioresonance Hypothesis
This is a new hypothesis which proposes that if the vibration frequency of a structure
near the trigeminal nerve becomes close to its natural frequency, the resonance of
the trigeminal nerve occurs. This can cause abnormal transmission and results in pain.[9]
Ignition Hypothesis
Injury to the trigeminal afferent neurons in the REZ makes the axons hyperexcitable
and leads to synchronized discharge activity.[10]
Diagnosis
The diagnosis of TN is essentially clinical. Although such patients do not have any
neurological deficit, quantitative sensory testing have shown subtle sensory abnormalities
which may not be detected in routine clinical examination. Magnetic resonance imaging
(MRI) is aimed to detect changes in trigeminal root and any neurovascular conflict,
and to rule out secondary pathology. MRI sequences augmented by a three-dimensional
gradient echo sequence such as fast inflow with steady-state precession (constructive
interference in steady-state [CISS] sequence) or intravenous gadolinium–diethylene
triamine pentaacetic acid (DTPA) can also improve visualization of the vascular compression
around the trigeminal nerve root.[11]
Treatment
The anticonvulsant drug carbamazepine is the drug of choice in TN. The second drug
of choice is oxcarbazepine.[12]In a comparison between these two drugs, efficacy is very similar but tolerability
is better with oxcarbazepine. Other drugs such as baclofen, lamotrigine, clonazepam,
topiramate, phenytoin, gabapentin, pregabalin, and sodium valproate can be used. Polytherapy
is useful when patients are unable to tolerate higher doses of carbamazepine.[13] Opioids are considered ineffective against TN and, thus, should not be prescribed.
A multidisciplinary approach using antidepressants and antianxiety drugs such as amitriptyline
and duloxetine is needed for the management of emotional status. Acupuncture can be
an option in the treatment of idiopathic TN due to its analgesic effect in both idiopathic
TN and secondary myofascial pain associated with it.[14]
Peripheral nerve blocks using local anesthetic along with absolute alcohol or glycerol
is also very effective in reducing pain.[13]
[15] If nerve blocks are administered appropriately, patient may feel asymptomatic for
few months to even years.[16] It also reduces the number and doses of drugs. Small studies have shown that botulinum
toxin type A (BTX-A) injections may reduce pain from TN in people who are no longer
helped by medications.[17] A recent meta-analysis showed a pooled reduction of pain by –3.009 points on a 0
to 10 verbal rating scale (95% confidence interval [CI], p < 0.001) after treatment with BTX-A and confirmed moderate efficacy.[18] However, more research needs to be done before this treatment is widely used for
this condition.
Surgery is normally recommended only after medication has proved ineffective, or if
side effects of medication are intolerable. Microvascular decompression is surgical
treatment of choice in TN resistant to medical management, particularly, in young
individuals.[19] Patients with significant medical comorbidities are generally advised to undergo
gamma knife radiosurgery, percutaneous balloon compression, glycerol rhizotomy, and
radiofrequency thermocoagulation procedures. Partial sensory root sectioning is indicated
in negative vessel explorations during surgery and large intraneural vein.[20] Endoscopic technique can be used alone for vascular decompression or as an adjuvant
to microscope.[21]
Recent Advances in Treatment Modalities
Recent Advances in Treatment Modalities
After extensive literature search from popular databases like PubMed, Embase, Scopus,
and Google Scholar, articles depicting newer treatment modalities were identified
in the last 10 years. The keywords for search were “trigeminal neuralgia,” “new modalities,”
and “future therapy.” Those newer modalities which showed promising results in prospective
randomized controlled trials and case-control studies were extracted and synthesized
in this review. Data from recent meta-analysis were taken in case of certain treatment
modalities that showed promising results.
Recent Advances in Pharmacological Therapy
Recent Advances in Pharmacological Therapy
The constant search for new drugs have led to the development of few recent medications
that act via novel pathways for reducing the electrical activity of the already excited
nerve.
-
Vixotrigine: Vixotrigine is a novel sodium channel blocker that preferentially targets higher
frequencies and suppresses seizures or noxious stimuli. In an open-labeled study,
vixotrigine 150 mg administered thrice daily in patients with TN was compared with
placebo and showed successful pain relief in the final week of therapy.[22] The drug was administered for 21 days. There was a reduction in the number of paroxysms
by 60% compared with only 12% in placebo, and pain severity decreased by 55% compared
with placebo. The treatment failure rate was 33% with this new drug and no serious
adverse event was noted. A multicentric prospective phase III randomized controlled
trial is already underway and its results will throw further light on this drug.[23]
-
Eslicarbazepine: It is a third-generation antiepileptic drug belonging to the dibenzepine group.
The drug targets the voltage-gated sodium channels and is currently approved as adjunct
therapy for focal seizures. In a recent open-labeled trial, eslicarbazepine was administered
in a dose of 200 to 1200 mg/day in patients suffering from TN. Around 88.9% patients
had good pain relief but there was high incidence of side effects to the tune of 71%.[24]
-
Sumatriptan: It is a 5-hydroxytyptamine receptor (1A/B/C) receptor blocker agonist. It has been
used extensively in migraine and cluster headaches with good pain relief efficacy.
The drug inhibits vasodilation and demyelination near the inflamed trigeminal nerve
root. The drug comes in a formulation of tablets, nasal spray, or injections. Two
randomized controlled trials tested the effect of subcutaneous injection of sumatriptan
3 mg and the oral administration of 50 mg twice daily. Fifteen minutes after injection
of sumatriptan, the baseline pain scores decreased.[25]
[26] After oral treatment, the visual analog score for pain also decreased significantly,
and this effect persisted after treatment discontinuation for a week. The main side
effect like dizziness and rebound headaches are common for which there is lack of
adherence to therapy.
-
Intranasal carbon dioxide (CO2): CO2 has always been considered a pain modulator in hyperactive neurons. Recent studies
have shown that CO2 is a nociceptive modulator of afferent active trigeminal neurons based on the hypothesis
that CO2 causes a decreased mucosal pH and that in turn activates the nociceptive effect of
primary trigeminal afferent neurons.[27] A controlled, randomized, parallel-group study investigated the effects of intranasal
CO2 on the transient receptor potential cation channel subfamily V member 1 (TRPV1)–mediated
experimental trigeminal pain in healthy volunteers. Only mild modulatory effect of
intranasal insufflation of CO2 at flow rates of 1 L/min was found, but the clinical utility seemed limited since
changes in pain ratings were therapeutically irrelevant.[28] Hence, another phase 2 placebo-controlled trial was undertaken in which CO2 and placebo were administered in TN patients for 1 minute. All patients received
three doses of CO2 and placebo each, and it was found that CO2 had improved effect on VAS scores. The trial is underway and its results are yet
to be published (ClinicalTrials.gov identifier: NCT02473016).[29]
-
Calcium channel blockers (CCBs): Usually, in patients with continuous pain mediated by other pathophysiological mechanisms,
a monotherapy with sodium channel blocker is not sufficient to control pain and other
drugs are usually needed. CCBs and antidepressants have been advocated in the treatment
of trigeminal neuralgia in patients not relieved by monotherapy with sodium channel
blockers.[30] Thus, apart from few case reports or cohort studies there is very little evidence
on management of continuous pain and more studies with CCBs are warranted.
-
Miscellaneous drugs: Various other medications like topical capsaicin, lignocaine, misoprostol, and intranasal
lignocaine are available but their widespread use is not advocated at present. Misoprostol,
a prostaglandin E1 analogue, showed efficacy in TN. Few studies reported the efficacy
of misoprostol in a total of 27 patients with TN secondary to multiple sclerosis.[31] However, there is insufficient evidence to support or refute the use of this drug
in TN.
Recent Advances in Nonpharmacological Therapy
Recent Advances in Nonpharmacological Therapy
Nowadays apart from conventional RFA, new modalities utilizing reinforced RF doses
for short periods called pulsed RF and other attenuated laser therapy are gaining
importance. The list below enumerates the novel new therapeutic modalities.
-
Pulsed radiofrequency (PRF): PRF uses brief pulses of higher frequency alternate current to produce the same voltage
or even higher fluctuations than during conventional radiofrequency (RF) treatment.
PRF does not produce thermal lesions but there are microdamages within axonal microfilament
and microtubules, especially in the pain-carrying C fibers.[32] Recent studies have shown that combination of both PRF and RF lesioning (RFL) has
similar results in achieving a pain relief with lesser side effects than RFL alone.[33] There is also less number of complications like anesthesia dolorosa and hyperesthesia
with PRF. To achieve better results, PRF and RFL should be used in tandem rather than
using these modalities separately.
-
Ozone injection around gasserian ganglion (OIAGG): Some newer studies have explored the role of OIAGG. In a multicentric retrospective
study, the authors injected an ozone–oxygen mixture gas at a concentration of 30 μg/mL
into the area around the gasserian ganglion performed under C-arm X-ray guidance.
The results showed that pain relief rates at posttreatment, 6 months, 1 year, and
2 years after the procedure were 88.35%, 86.87%, 84.46%, and 83.30%, respectively
(p < 0.05).[34] A regression analysis found out that preoperative structural nerve damage was associated
with less clinical effect or poor outcome. The study confirmed that OIAGG is a safe
and effective modality for pain management in refractory TN.
-
Cryotherapy: To overcome the drawbacks of conventional cryotherapy such as incomplete pain relief
and recurrence, few modifications have been suggested. These include (a) the use of
a curved cryoprobe, (b) maintaining optimal temperature and pressure throughout the
surgical procedure, (c) scoring of the epineurium, (d) application of petroleum jelly
around the nerve before the introduction of the cryoprobe, and (e) delivery of three
cycles of 3-minute freezing and 5-minute thawing to each nerve.[35]
In a study, Bansal et al showed that a closed curved cryoprobe tip when used with
nitrous oxide at a temperature of–98°C and a pressure of 70 kg/cm or 100 psi provided
excellent analgesia. Almost 48.97% patients had pain-free interval of 36 to 40 months.
The side effect was loss of fine and crude sensation over face for 6 to 24 months.[36]
-
Neuromodulation: It is a new prospect in the management of TN patients, targeting either neural stimulation
or inhibition to restore normal neurological function. Various neuromodulation techniques
have been recently explored for the management of TN. These include transcranial magnetic
stimulation, motor cortex stimulation, deep brain stimulation, spinal cord stimulation,
transcutaneous electrical nerve stimulation, and peripheral nerve stimulation. A recent
study is underway to establish the feasibility of using transcranial magnetic stimulation
(TMS) for chronic orofacial pain in the interim period before surgery. Participants
were randomized to either receive TMS or sham-TMS (a nontherapeutic TMS coil which
sounds and feels similar to normal TMS), or standard treatment during the weeks of
wait time before surgery. The sham TMS is a subtherapeutic level of magnetic stimulation
which makes the same sound as normal TMS and causes a similar tingling of the skin.
All study patients were asked to fill out an online survey about pain during different
time points of the study. The complete results are not yet available, but preliminary
results indicate that TMS, when applied to the head for a few minutes, has been shown
to reduce pain in people with chronic orofacial pain of TN (ClinicalTrials.gov identifier:
NCT04120129).[37] Few studies have been conducted based on these techniques with variable success
rate.[38]
[39]
-
Low level laser therapy (LLLT): LLLT uses a single wavelength light source and works on the principle that irradiation
with monochromatic light may affect cell function.[40]This technique involves irradiation of the region of interest followed by laser puncture
at predetermined points along the course of the nerve. In a recent systematic review
(8 randomized controlled trials, 2 prospective studies, and 3 case series) which evaluated
the efficacy of LLLT for the therapeutic management of neuropathic orofacial pain,
Pedro et al found a reduction in pain intensity in all studies (most of them significant).[41] However, more quality studies assessing all outcome measures of chronic pain are
warranted.
-
Carbon dioxide laser: A CO2 laser is used to ablate the peripheral nerve in patients with drug refractory TN.
Recently, it has been shown to reduce the pain scores in TN and persistence of pain
relief till 12 months.[42] The authors ablated peripheral nerves using low-power defocused mode; however, there
was prolonged paresthesia of the affected nerves with this technique.
-
Neural prolotherapy: Neural prolotherapy has been described in relation to the management of TN. It is
also known as perineural injection therapy (PIT) and is one of the latest advancements
in regenerative medicine. First described by Dr. Paul Pybus and Dr. Roger Wyburn-Mason,
PIT targets neurogenic inflammation in subcutaneous nerves that potentially generates
pain.[43]The technique involves injection of hypertonic dextrose saline with local anesthetics
at the trigger points and usually requires multiple sittings.[44]
-
Nerve combing: Nerve combing, also called internal neurolysis, is a kind of surgical strategy that
splits the branches of trigeminal nerve longitudinally using a special fiber knife
based on preoperative pain locations and intraoperative finding. Jie et al studied
60 patients who achieved good pain relief following nerve combing.[45] Nerve combing has a much higher pain relief rate in patients without vascular compression
than those with vascular compression.
-
Complimentary medicine: Apart from standard conventional therapy there are several complimentary therapies
that aid in pain relief of TN. These include standard acupuncture, electroacupuncture,
and spinal regulation therapies.[14] Other modalities of complimentary medicine include sound therapy; low-intensity
and low-frequency acoustic ultrasound patch; and vitamin B, C, and biofeedback.
Precautions in the Wake of COVID-19 Pandemic
Precautions in the Wake of COVID-19 Pandemic
In the wake of the coronavirus disease 2019 (COVID-19) pandemic, certain precautions
need to be taken while managing cases of TN. The standard operating protocols involve
consultations in the outpatient department for those who are suffering from excruciating
pain and not controlled with optimum dose of medications. Most of the patients with
mild to moderate pain were treated with medicines and tele-consultations, which have
become the norm in COVID-19 era. Most of the patients who are suffering from unbearable
pain after maximal medication are advised for less invasive peripheral nerve blocks
which can be done as a daycare procedure without the use of sedation or general anesthesia.
The latest guidelines of European Society of Regional Anesthesia (ESRA) recommend
that peripheral nerve blocks are non–aerosol-generating procedures and should be preferred
than other invasive procedures.[46] They have highlighted few precautions that need to be taken prior to such procedures:
-
Body temperature screening to be done and if temperature is more than 37.5°C then
he/she should be directed to the flu clinic.
-
Rapid antigen testing or preferably RTPCR COVID-19 testing of all the patients before
shifting to operation theatre complex.
-
Don appropriate personal protective equipment before doing the procedure, take extra
time to doff, and use an observer.
-
All patients should wear proper universal precautions like surgical gown, mask, and
gloves.
-
Ensure the use of plastic covers to protect ultrasound equipment.
-
Use minimal supplemental oxygen needed to maintain saturation.
-
Keep a high threshold for repeated blocks, as this may potentiate complications and
increase exposure time.
Conclusion
There is a huge clinical burden of TN in our society. The age of presentation varies
and hence there is a wide array of treatment options available. The treatment options
need to be catered according to the age of the patient and the mode and type of presentation.
The treatment modalities range from standard medical therapy and peripheral blocks
to surgical procedures. Newer and novel techniques have arrived that show promising
results. However, large randomized controlled trials are required for the validation
of such techniques. The best technique should be simple, noninvasive, and achieved
in a single setting with few recurrences, and provide long-term pain relief.