Trigeminal neuralgia

INTRODUCTION — Trigeminal neuralgia (TN) is characterized by recurrent brief episodes of unilateral electric shock-like pains, abrupt in onset and termination, in the distribution of one or more divisions of the fifth cranial (trigeminal) nerve that typically are triggered by innocuous stimuli [1]. An overview of TN is presented here. Other causes of facial pain are discussed separately. (See "Overview of craniofacial pain".)

ETIOLOGY AND PATHOPHYSIOLOGY

Anatomy — The trigeminal nerve (figure 1) is the sensory supply to the face and the sensory and motor supply to the muscles of mastication. It has three major divisions:

●Ophthalmic (V1)

●Maxillary (V2)

●Mandibular (V3)

The nerve starts at the midlateral surface of the pons, and its sensory ganglion (gasserian ganglion) resides in the Meckel cave in the floor of the middle cranial fossa.

Mechanisms — Compression of the trigeminal nerve root is the main mechanism of TN, but brainstem lesions account for a small proportion of cases [2].

●Compression of the trigeminal nerve root – Most cases of TN are caused by compression of the trigeminal nerve root, usually within a few millimeters of entry into the pons (the root entry zone) [3]. Compression by an aberrant loop of an artery or vein is thought to account for 80 to 90 percent of cases [3-7].

Other causes of TN via nerve compression include vestibular schwannoma (acoustic neuroma), meningioma, epidermoid or other cyst, or, rarely, a saccular aneurysm or arteriovenous malformation [8-14].

The mechanism by which compression of the nerve leads to symptoms appears to be related to demyelination in a circumscribed area around the compression [15,16]. Precisely how demyelination results in the symptoms of TN is not entirely clear. Demyelinated lesions may set up ectopic impulse generation, possibly causing ephaptic transmission. Ephaptic cross-talk between fibers mediating light touch and those involved in pain generation could account for the precipitation of painful attacks by light tactile stimulation of facial trigger zones [3]. Furthermore, alteration of afferent input may disinhibit pain pathways in the spinal trigeminal nucleus.

●Multiple sclerosis and brainstem lesions – Demyelination of one or more of the trigeminal nerve pathways may also be caused by multiple sclerosis, tumors located at the cerebellopontine angle, or other structural lesions of the brainstem. In multiple sclerosis, a plaque of demyelination typically occurs in the root entry zone of the trigeminal nerve [17,18]. In some cases, such brainstem lesions may be present years before the onset of TN symptoms, suggesting a role for chronic inflammation or central sensitization to the development of TN [19]. Vascular compression also has been noted in patients with multiple sclerosis and TN [18,20].

Tumors of the central nervous system that may present with TN include meningioma, squamous cell carcinoma, lymphoma, and schwannoma [21].

●Central sensitization – Evidence for a role of central pain mechanisms includes the presence of refractory periods after a triggered episode, trains of painful sensations after a single stimulus, and latency from the time of stimulation to the onset of pain [22]. In addition, electrophysiologic evidence of central sensitization of trigeminal nociceptive processing has been observed in some patients with TN who have concomitant chronic facial pain [23].

EPIDEMIOLOGY — TN is a rare condition that affects females more than males [21,24]. The overall prevalence of TN is <0.1 percent [25-27]. The annual incidence of TN is 4 to 13 per 100,000 people [25,28]. Despite its low incidence, TN is one of the more frequently seen neuralgias in the older adult population. The incidence increases gradually with age; most idiopathic and classic TN cases begin after age 50, although onset may occur in the second and third decades or, rarely, in children [21,29].

The male-to-female prevalence ratio of TN ranges from 1:1.5 to 1:1.7 [24,30]. This female predominance may be related to the increased longevity of females compared with males. Rare familial cases have been reported, but the vast majority of patients have sporadic disease [31,32].

Although data are not entirely consistent, hypertension may be a risk factor for the development of TN [30,33-35]. There is also some evidence that migraine is a risk factor for TN [36].

CLINICAL FEATURES — TN is defined clinically by paroxysmal, stereotyped attacks of usually intense, sharp, superficial, or stabbing pain in the distribution of one or more branches of the fifth cranial (trigeminal) nerve (figure 2).

●Trigeminal distribution – The pain of TN is strictly limited to the distribution of the trigeminal nerve. The pain most often involves the V2 and/or V3 subdivisions of the trigeminal nerve [1]. However, isolated involvement of the V1 subdivision occurs in <5 percent of patients with TN [24].

●Paroxysmal pain - The pain of TN tends to occur in paroxysms and is maximal at or near onset. Facial muscle spasms can be seen with severe pain. This finding gave rise to the older term for this disorder, tic douloureux. The pain is often described as electric, shock-like, or stabbing. It usually lasts from one to several seconds, but may occur repetitively, anywhere from 0 to more than 50 times a day [2,27,37]. A refractory period of several minutes during which a paroxysm cannot be provoked is common. Some patients with longstanding TN may have continuous dull pain that is present between paroxysms of pain. Unlike some other facial pain syndromes, TN typically does not awaken patients at night.

●Unilateral – TN is typically unilateral. Occasionally the pain is bilateral over time, though rarely on both sides simultaneously [38]. In a review of 439 patients with TN, symptoms were unilateral in 81 percent [21]. Bilateral involvement may occur in patients with TN caused by multiple sclerosis and connective tissue disorders such as Sjögren's disease, sarcoidosis, and systemic lupus erythematosus [21,39].

●Trigger zones – Nearly all patients with TN experience triggered pain [2,27,37,40,41]. Trigger zones in the distribution of the affected nerve are common and are often located near the midline. Lightly touching these zones often triggers an attack, leading patients to protect these areas [42]. Trigger zones can sometimes be demonstrated on physical examination. Other triggers of TN paroxysms include chewing, talking, brushing teeth, cold air, smiling, and/or grimacing [24,42].

●Autonomic symptoms – Autonomic symptoms, usually mild or moderate, can occur in association with attacks of TN in the V1 trigeminal distribution, including lacrimation, conjunctival injection, and rhinorrhea [24,43,44]. The presence of autonomic features, particularly when prominent or severe, is suggestive of the syndromes of short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with autonomic symptoms (SUNA). (See 'Differential diagnosis' below and "Short-lasting unilateral neuralgiform headache attacks: Clinical features and diagnosis".)

●Continuous pain – Continuous pain between attacks is present in many patients with TN. It is usually milder than the paroxysmal attacks and is typically characterized as dull or tingling, though the intensity and quality may fluctuate [27]. In a cohort of 158 patients with TN from a tertiary headache center, concomitant persistent pain was present in about one-half of patients [24].

Some reports describe patients with a history of "pretrigeminal neuralgia," a dull, continuous, aching pain in the jaw that evolves over time into TN [45-47]. This brief, milder pain is sometimes suspected to have a dental origin, and unnecessary dental procedures have been performed in some cases [48]. On the other hand, TN can be precipitated by dental procedures (eg, dental extraction), resulting in increased confusion about the precise etiology of this problem [45].

The course of TN is variable, as discussed below. (See 'Prognosis' below.)

EVALUATION AND DIAGNOSIS

Clinical diagnosis — The diagnosis of TN is based upon the characteristic clinical features described above, primarily paroxysms of pain in the distribution of the trigeminal nerve. Once the diagnosis of TN is suspected on clinical grounds, a search for secondary causes should be undertaken.

The International Classification of Headache Disorders, Third Edition (ICHD-3) diagnostic criteria for TN are as follows [1]:

●A) Recurrent paroxysms of unilateral facial pain in the distribution(s) of one or more divisions of the trigeminal nerve, with no radiation beyond, and fulfilling criteria B and C

●B) Pain has all of the following characteristics:

•Lasting from a fraction of a second to two minutes

•Severe intensity

•Electric shock-like, shooting, stabbing, or sharp in quality

●C) Precipitated by innocuous stimuli within the affected trigeminal distribution

●D) Not better accounted for by another ICHD-3 diagnosis

Determining the etiology — For all patients with suspected TN or those with recurrent attacks of pain limited to one or more divisions of the trigeminal nerve and no obvious cause, neuroimaging is necessary to help determine the mechanism (algorithm 1) [49]. Trigeminal reflex testing is not used routinely in the diagnostic evaluation of TN, but can be helpful for patients who cannot have magnetic resonance imaging (MRI) and for patients with suspected TN who have a nondiagnostic MRI [27]. (See 'Imaging' below and 'Trigeminal reflex testing' below.)

The International Classification of Headache Disorders, Third Edition (ICHD-3), defines several subtypes of TN according to the underlying cause [1]:

●Classic (or classical) TN, which develops without apparent cause other than neurovascular compression, fulfilling the ICHD-3 criteria for TN above and requiring demonstration on MRI or during surgery of neurovascular compression (not simply contact), with morphological changes in the trigeminal nerve root. The rationale is as follows. TN found to be related to compression of the trigeminal nerve by a vascular loop, as demonstrated by surgery, could be regarded as secondary by the ICHD-3, but it is not. Most patients do not have surgery, and it is often uncertain as to whether they have neurovascular contact or compression. For this reason, the ICHD-3 uses the term "classical" instead of "primary" for patients with a typical history of TN who have a presumed or demonstrated vascular source of compression as the cause.

●Secondary TN, defined as TN caused by an underlying disease. Recognized causes include multiple sclerosis, cerebellopontine angle tumor, and arteriovenous malformation. Secondary TN accounts for approximately 15 percent of cases [6,27].

●Idiopathic TN, defined as TN with neither electrophysiological tests nor MRI showing significant abnormalities. Idiopathic TN accounts for approximately 10 percent of cases [7,50].

Patients with trigeminal sensory loss or bilateral involvement are probably at higher risk of secondary TN [6]. Younger age is also probably associated with a higher risk of secondary TN. However, age is not a clinically useful predictor for distinguishing classic TN from secondary TN because there is considerable age overlap. In addition, absence of any of these clinical features (sensory loss, bilateral involvement, younger age) does not rule out a secondary cause for TN.

Imaging — As noted above, we recommend MRI with and without contrast to rule out neurovascular compression or a structural brain lesion (eg, tumor in the cerebellopontine angle, demyelinating lesions including multiple sclerosis) as the cause of TN (algorithm 1) [6,21,49,51,52]. Head computed tomography (CT) is an alternative when MRI is not an option, but MRI and magnetic resonance angiography (MRA) are much preferred because the higher resolution of MRI enables visualization of the trigeminal nerve and small adjacent lesions.

●MRI techniques – High-resolution MRI with thin cuts through the region of the trigeminal ganglion and heavy T2 weighting (eg, three-dimensional [3D] T2-weighted MRI using constructive interference in steady-state [CISS] fusion study with the addition of intravenous contrast), is optimal for visualizing the trigeminal nerve in its cisternal and cavernous segments [27,53]. 3D time-of-flight MRA is optimal for visualizing the arteries [27,54,55]. To optimize the detection of possible neurovascular contact, European guidelines recommend a combination of high-resolution sequences: 3D T2-weighted MRI, 3D T1-gadolinium contrast MRI, and 3D time-of-flight MRA [49].

●Imaging confirmation of neurovascular compression – For patients with a clinical diagnosis of TN prior to MRI, mere contact of a vessel with the trigeminal nerve on imaging is insufficient to diagnose neurovascular compression as the cause. Rather, there is a consensus that the diagnosis requires imaging confirmation of morphological changes such as dislocation, distortion, atrophy, or compression of the trigeminal nerve at its origin from the pons [1,27].

In a 2014 meta-analysis of nine blinded case-control studies, neurovascular contact of the trigeminal nerve on MRI/MRA was more frequent with symptomatic nerves compared with asymptomatic nerves (89 versus 36 percent) [7]. Anatomic change (ie, atrophy, distortion, or flattening) of the trigeminal nerve on MRI at the site of vascular contact was more frequent with symptomatic nerves (53 versus 9 percent, odds ratio 11.8, 95% CI 7.79-17.89). Trigeminal root contact alone had a sensitivity and specificity of 66 and 90 percent, respectively. When trigeminal root contact and nerve atrophy coexisted, sensitivity was lower (52 percent) but specificity was increased to 100 percent.

Trigeminal reflex testing — Although seldom used in clinical practice, trigeminal reflex testing is probably useful for distinguishing classic TN from secondary TN, while trigeminal evoked potentials are not useful for making this distinction [6,49]. Trigeminal reflex testing for TN involves side-to-side comparisons of the ophthalmic, maxillary, and mandibular divisions of the trigeminal nerve. In a guideline review of 628 patients with TN from 10 studies, trigeminal reflex testing for the diagnosis of secondary TN had a sensitivity and specificity of 94 percent and 87 percent, respectively [6,56].

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of TN includes the conditions discussed above that cause classic TN and secondary TN, mainly compression of the trigeminal nerve by a vascular loop or a nonvascular space-occupying lesion, and demyelination from multiple sclerosis in the pons or root entry zone of the trigeminal nerve.

Other causes of trigeminal distribution pain — Although less likely to be confused with TN, the differential diagnosis also includes various causes of painful trigeminal neuropathy, such as acute herpes zoster, postherpetic neuralgia, and trauma to the trigeminal nerve.

Painful trigeminal neuropathy encompasses a separate category of conditions that cause predominantly continuous or near-continuous facial pain in the distribution of the trigeminal nerve [1]. Examples include:

●Painful trigeminal neuropathy attributed to acute herpes zoster

●Trigeminal postherpetic neuropathy

●Painful post-traumatic trigeminal neuropathy

●Painful trigeminal neuropathy attributed to other disorder

●Idiopathic painful trigeminal neuropathy

Painful trigeminal neuropathy, distinct from TN, is defined as facial pain in the distribution(s) of one or more branches of the trigeminal nerve that is caused by another disorder and is indicative of neural damage [1]. Unlike TN, the pain is predominantly continuous or near continuous, and is described most often as burning or squeezing, or a pins and needles sensation. Brief paroxysms of pain may occur but are not predominant.

In most cases, painful trigeminal neuropathy can be distinguished from TN by a thorough history and examination. Of note, isolated involvement of the V1 subdivision occurs in <5 percent of patients with TN [24], while V1 is most commonly affected by postherpetic neuralgia (see "Postherpetic neuralgia"). Neuroimaging, preferably with brain magnetic resonance imaging (MRI), can discern the presence of demyelination or mass lesion as the cause of TN.

Dental causes of pain — TN may sometimes be confused with dental causes of pain. Dental pain is usually continuous, intraoral pain that is dull or throbbing, whereas classic TN is typically intermittent pain and sharp. However, classic TN is often triggered by oral manipulations such as chewing and brushing the teeth, which can suggest a dental cause and lead patients to present for dental care prior to seeking a medical evaluation. Furthermore, some patients have a phase of "pretrigeminal neuralgia" characterized by atypical symptoms (eg, jaw or tooth pain) that might mimic dental pain. (See 'Clinical features' above.)

Other causes of headache and craniofacial pain — Several uncommon causes of headache and craniofacial pain should also be considered in the differential diagnosis of TN.

●Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with autonomic symptoms (SUNA) are characterized by sudden brief attacks of severe unilateral head pain in orbital, periorbital, or temporal regions, accompanied by ipsilateral cranial autonomic symptoms. Attacks may be triggered by a number of factors, including skin contact. Given the short, stabbing nature of the attacks, the cutaneous triggering, and the association of cranial autonomic symptoms with pain in the trigeminal V1 distribution, the differentiation between SUNCT, SUNA, and TN can be difficult. Some argue that the degree of cranial autonomic features in SUNCT and SUNA is greater than in TN, while others suggest that SUNCT, SUNA, and TN are related conditions that exist on a continuum [57]. (See "Short-lasting unilateral neuralgiform headache attacks: Clinical features and diagnosis".)

●Cluster-tic syndrome is a combination of cluster headache with coexistent TN. (See "Overview of craniofacial pain", section on 'Cluster-tic syndrome'.)

●Primary stabbing headache is characterized by transient, sharp jabbing pains that occur at variable locations within trigeminal and cervical dermatomes. Most of the stabs of pain last only a few seconds and occur at irregular intervals from one to many times each day. The extratrigeminal location of some or all attacks can differentiate primary stabbing headache from TN. (See "Primary stabbing headache".)

●First bite syndrome is a paroxysmal facial pain induced by the first bite of a meal with subsequent lessening on further bites [58]. Pain can also be precipitated by smelling food. First bite syndrome can be distinguished from TN due to its association with deep parotid lesions, prior surgery that included neck dissection, and lack of cutaneous triggers.

MEDICAL TREATMENT — Pharmacologic therapy with carbamazepine or oxcarbazepine is the first-line initial treatment for most patients with classic TN (caused by neurovascular compression) and patients with idiopathic TN. Surgery is reserved for patients who are refractory to medical therapy. Although placebo-controlled trials are lacking for the treatment of secondary TN (ie, TN caused by multiple sclerosis or nonvascular compression), it is reasonable to treat the pain associated with secondary TN using the same medications that are employed in classic TN [49]. In our clinical experience, patients with secondary TN often respond well to these drugs. Treatment should also be directed at the underlying condition.

First-line therapy — For patients with TN who require pain control, we recommend initial therapy with carbamazepine or oxcarbazepine.

Carbamazepine — Carbamazepine is the best studied treatment for classic TN and is established as effective [2,6,38,59]. Side effects can be a problem but are generally manageable, particularly if low doses are prescribed initially with gradual titration.

●Efficacy – Four randomized, controlled trials with a total of 147 patients have established the effectiveness of carbamazepine (200 to 1200 mg daily) for TN [60-63]. A systematic review and practice parameter published in 2008 from the American Academy of Neurology (AAN) and European Federation of Neurological Societies (EFNS) noted that the treatment response in these trials was robust, with complete or near complete pain control attained in 58 to 100 percent of patients on carbamazepine, compared with 0 to 40 percent of patients on placebo [6]. For the outcome of important pain relief, the number needed to treat was <2. However, carbamazepine was sometimes poorly tolerated, with numbers needed to harm for minor and severe adverse events of 3 and 24, respectively.

●Dosing – The usual starting dose of carbamazepine is 100 to 200 mg twice daily. The dose can be increased gradually over weeks by increments of 200 mg as tolerated until sufficient pain relief is attained. The typical total maintenance dose is 600 to 800 mg daily, given in two divided doses for tablets and extended-release capsules, or four divided doses for oral suspension. The maximum suggested total dose for TN is 1200 mg daily.

●Adverse effects – Adverse effects of carbamazepine include nausea, vomiting, diarrhea, hyponatremia, rash, pruritus, drowsiness, dizziness, blurred or double vision, lethargy, and headache. Slow titration may minimize these effects. Carbamazepine-induced leukopenia is not uncommon, but it is usually benign. Rare but serious adverse effects of carbamazepine include agranulocytosis, aplastic anemia, Stevens-Johnson syndrome, toxic epidermal necrolysis, hepatic failure, drug reaction with eosinophilia and systemic symptoms (DRESS), dermatitis/rash, serum sickness, pancreatitis, lupus syndrome, and hypogammaglobulinemia. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Carbamazepine'.)

We suggest testing for the HLA-B*15:02 allele in genetically at-risk populations (ie, those with East or South Asian ancestry) before initiating treatment with carbamazepine. The HLA-B*15:02 allele is a genetic susceptibility marker that is associated with an increased risk of developing Stevens-Johnson syndrome and/or toxic epidermal necrolysis. If genetic testing results are positive for the presence of at least one copy of the HLA-B*15:02 allele, carbamazepine should be avoided.

Oxcarbazepine — Oxcarbazepine is an effective drug for TN and one that some experts prefer over carbamazepine, citing better tolerability and decreased risk of drug interactions [27,64,65].

●Efficacy – The 2008 AAN/EFNS practice parameter identified several randomized controlled trials that compared oxcarbazepine (600 to 1800 mg daily) with carbamazepine in 178 patients with TN [6]. In the pooled analysis, both medications were equally effective, with a >50 percent reduction of attacks achieved by 88 percent or more of patients in both treatment groups.

●Dosing – Oxcarbazepine can be started at a total dose of 600 mg daily, given in two divided doses. The dose can be increased as tolerated in 300 mg increments every third day to a total dose of 1200 to 1800 mg daily. As with carbamazepine, we suggest testing for the HLA-B*15:02 allele in genetically at-risk populations (ie, those with East Asian or South Asian ancestry) before initiating treatment with oxcarbazepine. Oxcarbazepine and carbamazepine should be avoided in patients carrying the HLA-B*15:02 allele unless the estimated benefits clearly outweigh the risks.

●Adverse effects – Adverse effects of oxcarbazepine are similar to carbamazepine and include nausea, vomiting, diarrhea, hyponatremia, rash, pruritus, drowsiness, dizziness, blurred or double vision, lethargy, and headache. Rare but serious hypersensitivity reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and multiorgan hypersensitivity, have been associated with oxcarbazepine use, usually within the first few weeks of starting the drug. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Oxcarbazepine'.)

Alternatives and adjuncts to first-line therapy — For patients with TN who are intolerant of or have contraindications to carbamazepine and oxcarbazepine, we suggest treatment with lamotrigine, gabapentin, or baclofen. Some patients who are nonresponders to first-line carbamazepine monotherapy may benefit from combination therapy with gabapentin, lamotrigine, topiramate, baclofen, or tizanidine. Nevertheless, there are no randomized controlled trials comparing monotherapy with combination therapy for TN.

Other experts advise early surgical referral for all patients who fail to respond to first-line therapy with carbamazepine or oxcarbazepine, arguing that they are unlikely to respond to alternative medications for TN [27,66]. (See 'Surgery for medically refractory TN' below.)

There is only limited evidence to support treatment alternatives for patients with TN who are unable to tolerate or do not respond to first-line medical therapy. The 2008 AAN/EFNS practice parameter concluded that baclofen, lamotrigine, and pimozide are possibly effective for TN [6]. There are weak data to support botulinum toxin injections. A subsequent (2019) systematic review from the European Academy of Neurology concluded that lamotrigine, gabapentin, botulinum toxin type A, pregabalin, baclofen, and phenytoin can be used as monotherapy or as adjuncts with first-line therapy (carbamazepine or oxcarbazepine) when first-line agents are ineffective or poorly tolerated [49]. However, the quality of supporting evidence was low to very low.

●Gabapentin – Gabapentin was shown to be possibly effective and to have fewer side effects when compared with carbamazepine in a 2016 meta-analysis of 16 randomized controlled trials (all published in Chinese). However, all studies were rated as having poor methodologic quality [67]. Nevertheless, gabapentin is an attractive choice due to its better tolerability compared with first-line agents, relative lack of drug interactions, and a low risk of hepatic or renal toxicity [49].

●Lamotrigine – In a double-blind, placebo-controlled crossover study of 14 patients with TN that was refractory to carbamazepine or phenytoin, adjunct therapy with lamotrigine (400 mg daily) was beneficial for improvement on a composite outcome index [68]. Patients continued taking either carbamazepine or phenytoin for the duration of the trial. Similarly, an open-label study found that lamotrigine was beneficial in 11 of 15 patients with TN once the 400 mg dose was reached [69]. However, the clinical utility of lamotrigine for severe pain is limited by the need to titrate the dose over many weeks, given the risk of rash and other serious adverse effects [70].

In patients who are not taking other antiseizure medications, lamotrigine is typically started at 25 mg daily for the first two weeks, and then increased to 50 mg daily for weeks 3 and 4. The dose is then titrated to effect, increasing the total daily dose by 50 mg every one to two weeks up to a maximum of 400 mg. Lamotrigine is dosed once daily as an extended-release formulation and twice daily (in divided doses) as an immediate-release formulation.

For patients taking an antiseizure medication that induces hepatic enzymes (eg, carbamazepine, phenytoin, or primidone), the initial daily dose of lamotrigine is 50 mg, titrating upward as needed to 100 mg at week 3, 200 mg at week 5, 300 mg at week 6, and 400 mg at week 7. For patients taking valproate, which inhibits hepatic enzymes, the initial daily dose of lamotrigine is 12.5 to 25 mg every other day. The titration transitions to daily dosing at subsequent intervals, with increases of 25 mg every two weeks as needed to a maximum of 200 mg daily. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Lamotrigine'.)

●Baclofen – Limited evidence from a small double-blind crossover trial suggests that baclofen is beneficial for TN [71]. Treatment with baclofen 40 to 80 mg daily resulted in a reduction in paroxysms in 7 of 10 patients with typical TN, compared with 1 of 10 who received placebo. The starting dose of baclofen is 15 mg daily given in three divided doses, with gradual titration to a maintenance dose of 50 to 60 mg per day. Sedation, dizziness, and dyspepsia can occur with treatment, and the drug should be discontinued slowly since seizures and hallucinations have been reported upon withdrawal. The utility of baclofen is limited by these adverse effects, which typically prevent a sufficient oral dose needed to achieve beneficial pain reduction [27].

●Botulinum toxin injections — Botulinum toxin injections may be beneficial for patients with TN, although data are limited. A 2016 systematic review and meta-analysis identified four small placebo-controlled randomized controlled trials with a total of 178 patients that evaluated the use of botulinum toxin A for TN [72]. The overall effect favored botulinum toxin A for the proportion of responders, defined as patients with >50 percent reduction in mean pain score from baseline to endpoint (77 percent, versus 26 percent for placebo, risk ratio 2.87, 95% CI 1.76-4.69). The paroxysm frequency per day was also reduced for patients assigned to botulinum toxin A. Small patient numbers limit the confidence in these results, and further study is required.

●Other medications – Several other drugs have shown some evidence of efficacy for TN in small, generally lower-quality controlled trials:

•Pimozide, a dopamine receptor antagonist, was more effective than carbamazepine in a randomized, double-blind crossover trial of 48 patients with refractory TN [73,74]. There were no dropouts among patients taking pimozide. However, pimozide is seldom used for TN because it has many potentially serious side effects, including sedation, arrhythmias, anticholinergic effects, acute extrapyramidal symptoms, and parkinsonism.

•Topical lidocaine given by intraoral application was more effective than placebo for pain reduction in a two-week, randomized crossover trial of 24 subjects with TN whose pain was most severe in the mouth [75]. However, blinding may have been compromised because of the bitter taste or numbness perceived by some patients when treated with lidocaine.

•Tizanidine appeared to be more effective than placebo in a small one-week trial, but patients who continued the drug in follow-up developed recurrent attacks of TN within one to three months [76].

•Tocainide was as effective as carbamazepine at two weeks in a crossover trial of 12 patients with TN [77].

Rescue therapy — Limited low-quality data suggest that intranasal or intravenous infusion of lidocaine, intravenous phenytoin or fosphenytoin, or subcutaneous injections of sumatriptan can provide analgesia for patients with TN while oral medications are titrated or during breakthrough attacks [78].

●Lidocaine – Lidocaine may be given for acute exacerbations of TN by intranasal aerosol or intravenous administration.

•Lidocaine administered intranasally or intraorally as a 2.4 percent aerosol (32 mg per dose) was reported effective in a retrospective study of 152 patients in China with severe pain from TN [79]. Pain resolution or a greater than 50 percent improvement was reported at 15 and 30 minutes in 78 and 70 percent, respectively. Adverse effects were mild including numbness, bitter taste, and burning in the affected area; no cardiovascular or other systemic adverse effects were reported. Repeat administration for pain recurrence was common and response rate was lower among patients taking high doses of carbamazepine or oxcarbazepine and those with TN symptoms affecting the ophthalmic (V1) division of the trigeminal nerve. Similar short-term benefit was reported in a small placebo-controlled trial of 25 patients with TN using intranasal lidocaine 8 percent (16 mg) [80]. Lidocaine nasal sprays are not commercially available in the United States but may be prepared by a compounding pharmacy.

•Lidocaine administered by intravenous infusion at 5 mg/kg over one hour showed some benefit for up to 24 hours after infusion in a placebo-controlled crossover trial of 20 patients [81]. Intravenous lidocaine administration requires continuous cardiac monitoring with electrocardiogram (ECG) and frequent blood pressure checks.

●Phenytoin – Phenytoin or fosphenytoin treatment has been associated with improvement in TN in case reports and small case series [82-86]. The phenytoin dose is 250 to 1000 mg given intravenously at no more than 50 mg/minute (150 mg phenytoin equivalents [PE]/minute for fosphenytoin) [82]. Alternative weight-based dosing is 15 mg/kg given over 30 to 120 minutes [82,87].

●Sumatriptan – The benefit of sumatriptan at 3 mg given by subcutaneous injection was shown in a small placebo-controlled crossover trial, with improvement persisting for a mean duration of approximately eight hours [88]. Subcutaneous sumatriptan followed by oral sumatriptan 50 mg daily for one week may provide a longer duration of analgesia [89].

●Lacosamide – In a retrospective observational study of patients with TN presenting to an emergency department, resolution of acute symptoms following an intravenous infusion of lacosamide was reported in 49 of 63 patients (78 percent) [86]. Infusion dose ranged from 50 to 400 mg; adverse effects were mild.

Duration of successful medical therapy — Periodic attempts to gradually withdraw these drugs are warranted in patients achieving relief of pain with oral medications. The key criterion for attempting a gradual wean is a sustained pain-free interval of at least six to eight weeks on medication; some authors would wait for at least six months before attempting a wean. The taper schedule varies according to the medication and dose but should be slow. The patient should be aware that the likelihood of future pain recurrence is high and would require restarting the medication.

SURGERY FOR MEDICALLY REFRACTORY TN

Choice of procedure — For patients with TN refractory to medical therapy, it is reasonable to discuss options for surgical therapy using microvascular decompression, various types of rhizotomy, or gamma knife radiosurgery [2]. The decision to have surgery and the choice among surgical options will be influenced by individual circumstances including patient preference, adverse effect profile of the available techniques, and expertise of the local center.

●Patients with classic TN - For patients with neurovascular compression confirmed by imaging (see 'Imaging' above) who are able to tolerate major surgery, we suggest microvascular decompression rather than another surgical procedure. For patients who are poor surgical candidates or prefer to avoid craniotomy, percutaneous ganglion lesion or gamma knife stereotactic radiosurgery are alternatives [90,91].

●Patients with multiple sclerosis and secondary TN – Observational data, mainly single-center case series, suggest that some patients with multiple sclerosis (MS) and TN experience at least short-term improvement with interventions including microvascular decompression [92-94], gamma knife radiosurgery [95], and percutaneous ganglion lesioning [96,97]. There is evidence that demyelinating plaque and neurovascular compression coexist in some patients with multiple sclerosis-related TN. (See 'Mechanisms' above.)

●Patients with cerebellopontine angle tumor and secondary TN – Tumor involving the cerebellopontine angle may cause TN. Most such tumors are benign; the most common ones are meningiomas, vestibular schwannomas, epidermoid cysts, and cholesteatomas. Management of these tumors is reviewed separately. (See "Management of known or presumed benign (WHO grade 1) meningioma", section on 'Large or symptomatic tumors' and "Vestibular schwannoma (acoustic neuroma)", section on 'Management' and "Uncommon brain tumors", section on 'Epidermoid cyst' and "Etiology of hearing loss in adults", section on 'Cholesteatoma' and "Cholesteatoma in children", section on 'Surgical treatment'.)

●Patients with idiopathic TN – Surgery may benefit some patients with idiopathic TN (ie, no abnormalities on magnetic resonance imaging [MRI]) but data are limited. Microvascular decompression surgery may identify vascular compression that was not evident on MRI, and if no compressive vessel is found, the surgeon can perform a partial rhizotomy sparing V1. Other strategies include radiosurgery with gamma knife or rhizotomy with radiofrequency, balloon, or glycerol.

Surgical techniques — Microvascular decompression is invasive, although the overall mortality and complication rates are low. Ablative procedures are less invasive, but recurrence may be more common. However, few surgical treatments for TN have been studied in controlled trials, and most of the evidence comes from observational studies [98]. Definitive conclusions regarding the relative effectiveness of surgical techniques for TN are precluded by the lack of studies directly comparing them [6].

●Microvascular decompression – Microvascular decompression is a major neurosurgical procedure that involves craniotomy and the removal or separation of various vascular structures, often an ectatic superior cerebellar artery, away from the trigeminal nerve [99].

Microvascular decompression appears to be the most effective surgical technique for classic TN (ie, due to neurovascular compression), although comparative randomized trials are lacking [27,49]. The 2008 Academy of Neurology (AAN) and European Federation of Neurological Societies (EFNS) practice parameter identified five studies of microvascular decompression for TN [100-104] that used independent outcome assessment [6]. The practice parameter concluded that initial pain relief was attained in 90 percent of patients, but that pain-free rates declined by one, three, and five years to 80, 75, and 73 percent, respectively. Indirect comparisons of the findings from different surgical studies suggested that microvascular decompression has a longer duration of pain control than other surgical interventions for TN. The average mortality was approximately 0.2 percent; major perioperative adverse events, such as cerebrospinal fluid leaks, infarction, or hematoma, occurred in up to 4 percent of patients, while aseptic meningitis complicated 11 percent [6]. Long-term hearing loss occurred in up to 10 percent of patients, and sensory loss occurred in 7 percent.

●Rhizotomy – Rhizotomy encompasses a number of percutaneous surgical techniques that are performed by passing a cannula through the foramen ovale under fluoroscopic or computed tomographic (CT) guidance, followed by lesioning of the trigeminal ganglion or root using one of several options [105,106]:

•Radiofrequency thermocoagulation rhizotomy, which creates a lesion by application of heat

•Mechanical balloon compression, which uses a Fogarty catheter to compress the gasserian ganglion

•Chemical (glycerol) rhizolysis, which involves the injection of 0.1 to 0.4 mL of glycerol into the trigeminal cistern

A small trial of 30 patients with TN found percutaneous radiofrequency ablation reduced pain at one month [107]. The 2008 AAN/EFNS practice parameter identified four uncontrolled case series that used independent outcome assessment of these procedures [6], including two reports of radiofrequency thermocoagulation [108,109], one report of glycerol rhizolysis [110], and one of balloon compression [111]. The AAN/EFNS found that initial pain relief was achieved in 90 percent of patients, but that pain-free rates declined by one year to 68 to 85 percent, by three years to 54 to 64 percent, and by five years to approximately 50 percent [6].

The major perioperative complication after rhizotomy procedures is meningitis, mainly aseptic, seen in 0.2 percent [6]. There is also a risk of maxillary artery injury and dural laceration overlaying Meckel cave, which could lead to oculomotor nerve injury via thermocoagulation, or inadvertent injection of glycerol into the middle cranial fossa [27]. Mortality is rare. Postoperative dysesthesia, described as a burning, heavy, or aching feeling, occurs in 12 percent [6]. Longer-term sequelae include trigeminal distribution sensory loss in nearly one-half of patients, anesthesia dolorosa in approximately 4 percent, and corneal numbness with risk of keratitis in 4 percent. The incidence of facial numbness is higher with rhizotomy procedures than with microvascular decompression or gamma knife radiosurgery.

●Radiosurgery – Gamma knife radiosurgery produces lesions with focused gamma radiation [112]. (See "Stereotactic cranial radiosurgery", section on 'Gamma Knife'.)

The therapy is aimed at the proximal trigeminal root since targeting the gasserian ganglion produced poor results [66]. The aiming of the beams is carried out with a stereotactic frame and MRI. The doses used are 70 to 90 grays (Gy). The beams cause axonal degeneration and necrosis [66]. Pain relief with gamma knife surgery occurs after a lag time of approximately one month [66,113].

The 2008 AAN/EFNS practice parameter [6] identified one randomized controlled trial of gamma knife surgery for TN that compared two different treatment regimens [114] and found no important differences. In addition, the AAN/EFNS [6] identified three case series with independent outcome assessment [115-117]. Complete pain relief at one year was found in up to 69 percent of patients, and at three years in 52 percent [6]. An earlier systematic review found that approximately 75 percent of patients reported complete relief within three months, but the proportion decreased to 50 percent by three years [118].

New or worsened facial sensory impairment occurred in 9 to 37 percent, with more bothersome sensory loss or paresthesia found in 6 to 13 percent of patients [6]. However, anesthesia dolorosa is rarely, if ever, a complication of gamma knife surgery.

Linear accelerator radiosurgery has been evaluated for the treatment of TN in retrospective case series [119,120], but no prospective studies or controlled trials are available. (See "Stereotactic cranial radiosurgery", section on 'Linac'.)

●Peripheral neurectomy – Peripheral neurectomy can be performed on the branches of the trigeminal nerve, which are the supraorbital, infraorbital, alveolar, and lingual nerves. Neurectomy is accomplished by incision, alcohol injection, radiofrequency lesioning, or cryotherapy. Cryotherapy involves freezing of the nerve using special probes, in theory to selectively destroy the pain fibers. However, the AAN/EFNS practice parameter and subsequent reviews have noted that the evidence regarding peripheral techniques for the treatment of TN is either negative or inconclusive [6,27].

Although surgical therapy for TN is generally well tolerated, a feared complication is painful post-traumatic trigeminal neuropathy (anesthesia dolorosa), a condition characterized by persistent, painful anesthesia or hypesthesia in the denervated region [1]. It can be more intolerable than the pain from classic TN itself [121]. Anesthesia dolorosa most frequently occurs as a complication of rhizotomy or thermocoagulation for TN but may also be an uncommon complication of gamma knife surgery. This risk warrants careful decision-making when considering surgical treatment for TN. (See "Overview of craniofacial pain", section on 'Painful post-traumatic trigeminal neuropathy'.)

PROGNOSIS — The course of TN is variable. Episodes may last weeks or months, followed by pain-free intervals of weeks to years, although most remissions last for only a few months [30,37]. Recurrence is common, and some patients have concomitant persistent background facial pain. Most often, the condition tends to wax and wane in severity and frequency of pain exacerbations. However, there are no pure natural history studies of TN, most likely because the severity of the pain leads to intervention [70].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Neuropathic pain".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Trigeminal neuralgia (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Symptoms – Trigeminal neuralgia (TN) is defined clinically by sudden, usually unilateral, severe, brief, stabbing or lancinating, recurrent episodes of pain in the distribution of one or more branches of the fifth cranial (trigeminal) nerve that are triggered by stimulation of the affected trigeminal division. (See 'Clinical features' above.)

●Diagnosis and evaluation – The diagnosis of TN is based upon the characteristic clinical features consisting primarily of brief paroxysms of severe pain in the distribution of the trigeminal nerve. (See 'Clinical diagnosis' above.)

For all patients with suspected TN, we recommend neuroimaging to help define the underlying cause (algorithm 1). Magnetic resonance imaging (MRI) is the preferred imaging method because of its higher resolution compared with computed tomography (CT). (See 'Determining the etiology' above.)

●Differential diagnosis – Uncommon causes of headache and craniofacial pain in the differential of TN include short-lasting unilateral neuralgiform headache attacks, cluster-tic syndrome, first bite syndrome, and primary stabbing headache. In addition, TN can sometimes be confused with dental causes of pain. Although less likely to be confused with TN, the differential diagnosis also includes various causes of painful trigeminal neuropathy, such as acute herpes zoster, postherpetic neuralgia, and trauma to the trigeminal nerve. (See 'Differential diagnosis' above.)

●Medical treatment – Pharmacologic therapy is used for initial treatment of most patients with TN. (See 'Medical treatment' above.)

•For patients with TN who require pain control, we recommend carbamazepine or oxcarbazepine as initial preventive therapy (Grade 1A). These agents have been shown effective in several placebo-controlled clinical trials. (See 'First-line therapy' above.)

•For patients with TN who are intolerant of or have contraindications to carbamazepine and oxcarbazepine, we suggest treatment with gabapentin, lamotrigine, or baclofen based on limited evidence of efficacy (Grade 2C). We add an agent from another pharmacologic class for patients with a partial response to monotherapy. Other experts advise early surgical referral for patients who fail to respond to first-line therapy. (See 'Alternatives and adjuncts to first-line therapy' above.)

Rescue therapy can provide short-term analgesia for patients with TN while oral medications are titrated or during breakthrough attacks. Available agents include intranasal or intravenous infusion of lidocaine, intravenous phenytoin or fosphenytoin, or subcutaneous injections of sumatriptan. (See 'Rescue therapy' above.)

●Surgery for medically refractory cases – For patients with TN refractory to medical therapy, it is reasonable to discuss options for surgical therapy using microvascular decompression (for TN caused by compression of the trigeminal nerve root), various types of rhizotomy, or gamma knife radiosurgery. The decision to have surgery and the choice among surgical options will be influenced by individual circumstances including patient preference, adverse effect profile of the available techniques, and expertise of the local center. (See 'Surgery for medically refractory TN' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Zahid H Bajwa, MD, who contributed to earlier versions of this topic review.