Medical Management of Trigeminal Neuralgia
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.315996
Source of Support: None, Conflict of Interest: None
Keywords: Botulinum toxin A, pharmacotherapy, resistant trigeminal neuralgia, second-line drugs, trigeminal neuralgia
Trigeminal neuralgia (TN) is a painful condition characterized by unilateral, brief, paroxysms of “stabbing” pain or “electric shock-like” sensation over the face along the area supplied by one or more divisions of the trigeminal nerve., The incidence of TN in the European population is around 12.6–27 per 100,000 person-years and prevalence is 0.16%–0.3%.,,, The exact incidence and prevalence of TN in India are not known, but the condition is regularly seen in all parts of the country. It occurs more commonly in women than men (F:M––1.74:1)., The age at disease onset is around 53–57 years.,
As per the International Association for the Study of Pain (IASP) and the International Headache Society (ICHD) Classifications, TN is classified into three types: Classical, secondary, and idiopathic.,, Classical TN patients are those with a vascular loop, often at the root entry zone, secondary TN results due to diseases like multiple sclerosis (MS) or tumors, and idiopathic TN are those cases without either of the above. The classical and idiopathic cases are further subdivided into two subgroups: Those with purely paroxysmal pain and those with concomitant continuous pain (CCP).,,
TN is a distressing illness, often affecting the quality of life., The painful paroxysms can vary from a few to over a hundred attacks per day. These paroxysms can also occur in sleep, leading to nocturnal awakenings. Sometimes, the disease can be severe enough to provoke depression and suicidal tendencies in the affected individuals.,
We reviewed the available literature on TN in clinical databases including PubMed, Google Scholar, and the Cochrane Database of Systematic Reviews with a specific focus on the pharmacological treatment and newer drugs under development for the treatment of TN.
The pathological changes in TN occur at the root entry zone, which is the transition zone between the peripheral and central myelination., Structural pathologies like tumors, vascular compression, and MS lead to abnormal demyelination as seen in biopsy samples.,, The proposed mechanism for spontaneous pain is hyperexcitability of neuronal membranes of the demyelinated fibers. Trigger evoked pain seems to occur due to ephaptic transmission between the affected fibers., For patients without any identifiable structural cause, an abnormal gain of function mutations in the voltage-gated sodium channels like NaV 1.3, 1.6, 1.7, and 1.8 is postulated., A genetic basis is hypothesized in familial clusters, though large-scale studies are not available to support this theory.,,
The first-line drugs for the treatment of TN comprise antiepileptics like carbamazepine (CBZ) and oxcarbazepine (OXC)., These drugs block the voltage-sensitive sodium channels, in a frequency-dependent manner, which prevents the high-frequency repetitive firing of neurons. Hence, both these drugs are effective in patients with paroxysms but have a limited role in patients who have continuous pain.,
[Table 1] depicts selected randomized control trials (RCTs) for drugs used for the treatment of TN. A systematic review assessing the efficacy and safety of CBZ in neuropathic pain (including TN) found three placebo-controlled trials and two trials comparing CBZ with pimozide and tocainide in over 183 patients with TN.,,,,, The number needed to treat (NNT) for pain relief with CBZ is around 1.7–1.8., Although CBZ causes an 80% reduction in painful paroxysms with initial therapy, tachyphylaxis soon occurs due to auto-induction., Adverse events are a major limiting factor for CBZ, with a number needed to harm being between 3.4 and 24., The common side effects are dizziness, drowsiness, nausea, vertigo, ataxia, diplopia, and hepatotoxicity. Cardiotoxicity and higher incidence of drug-drug interactions further poses a problem in the elderly with TN., Caution is also advised for the rare occurrence of adverse events like myelosuppression and allergic rash. Individuals with HLA-B1502 are more susceptible to Steven Johnson syndrome and toxic epidermal necrolysis after therapy with CBZ.
Oxcarbazepine, a pro-drug of CBZ, has lesser side effects and lower drug-drug interactions. Three RCTs comparing OXC with CBZ (none placebo-controlled) have shown a robust efficacy with OXC.,
The preferred choice of therapy between CBZ and OXC needs to be tailored on an individual basis. Some centers prefer OXC over CBZ as the initial choice of therapy., OXC may be tried if there is no significant benefit with CBZ, and the reverse also stands true. Major concerns with OXC include excessive central nervous system depression or dose-related hyponatremia. If a drug reaction or severe toxicity occurs with CBZ, OXC should be avoided. The dosage of drugs may be adjusted by the patients depending on pain relief and side effects.,, Painful nocturnal awakenings may be reduced by a nighttime dose covering the sleeping hours as well. [Table 2] depicts the posology of selected drugs for preventive therapy in TN.
A proportion of cases (30%) are initially resistant to the first-line drugs. Drugs like lamotrigine, gabapentin, pregabalin, and baclofen can be used either as monotherapy or in combination with CBZ/OXC when there is no improvement despite adequate tolerable doses of CBZ/OXC or occurrence of undesirable side effects.,,
LTG acts on the voltage-sensitive sodium channels, stabilizing the membrane and inhibiting the release of excitatory neurotransmitters., LTG was found to be slightly more effective (in combination with CBZ or phenytoin) than placebo in a double-blind crossover RCT carried over two weeks in each treatment arm. Another study compared LTG (400 mg) to CBZ (1200 mg), with pain relief in over 62% of patients with LTG and 90% with CBZ. Dose-dependent side effects like headache, skin rash, and dizziness limit the use of doses higher than 400 mg. Caution is advised for severe allergic reactions.,
Gabapentin and pregabalin
Gabapentin and pregabalin act by blocking the α2δ auxiliary subunit of voltage-gated calcium channels and thus reduce the hyperexcitability of neurons. A metanalysis of 16 RCTs from multiple centers in China, involving 1156 patients, analyzed the efficacy of gabapentin versus CBZ. There was a similar response to either drug. However, only five of these studies were truly randomized and variability in results and methodological quality was noted. The side effects of gabapentin are vertigo, somnolence, nausea, and fatigue. Gabapentin can be used in patients who cannot tolerate CBZ/OXC or as an add-on drug.,,, There are no RCTs on the use of pregabalin in TN. There are two open-label studies and two observational studies, involving a total of 140 patients, comparing the efficacy of pregabalin as monotherapy or an add-on therapy (with LTG and CBZ), which showed comparable efficacy.,,,
Baclofen is an agonist of the GABAB receptor which suppresses the release of excitatory neurotransmitters. A small RCT with ten patients compared baclofen to placebo in reducing painful paroxysm with favorable results in seven patients (70%). Baclofen may be used as an add-on therapy if there is a poor response to CBZ/OXC.,
Alternative drugs (anti-epileptics)
Antiepileptics like phenytoin, topiramate, levetiracetam, and eslicarbazepine have been used as alternative drugs in case of poor/non-responders to first-line and/or second-line drugs. There is weak evidence regarding the efficacy of these drugs.
Phenytoin acts by blocking the voltage-gated sodium channels. Although it was the first drug that proved efficacious in TN, its use became limited due to dose-related side effects. There are no RCTs on the use of phenytoin as a chronic therapy in TN. A systematic review on rescue drugs in acute TN, however, found phenytoin and its pro-drug (fosphenytoin) to be effective. There is one study of eight patients which showed modest efficacy with topiramate. Topiramate (100-400 mg/day) may be considered in refractory TN, failing conventional drugs.
Levetiracetam and esclicarbazepine are the newer anti-epileptics tried in TN. Eslicarbazepine (the active metabolite of OXC) causes slow inactivation of the sodium channels, contrary to CBZ/OXC which cause fast inactivation of these channels.,, Open-label studies, comprising of small numbers of study participants, showed around 40% efficacy with levetiracetam (up to 4 g) and 88.9% with eslicarbazepine (200 mg to 1200 mg).,
Alternative drugs (non-antiepileptics)
Drugs like pimozide, tocainide, tizanidine, misoprostol, sumatriptan, and capsaicin have been given in non-responder patients. A systematic review analyzed various RCTs on non-antiepileptic drugs, for TN. Three RCTs recruited 80 participants, and compared the drugs such as pimozide, tocainide, and tizanidine, with CBZ.,, Pimozide showed better results compared to CBZ in a double-blind, cross-over RCT comprising 68 participants. However, pimozide may cause side effects like tremors and memory disturbances. Tizanidine, a centrally acting alpha-receptor agonist showed mild benefit in a small number of participants, with recurrence of symptoms three months after discontinuation. Tocainide, an anti-arrhythmic agent which blocks the sodium channels, has not shown any significant pain relief in a single double-blind cross-over RCT. Besides, bothersome side effects limit its use in clinical practice. Misoprostol, a prostaglandin E1 analog, showed good efficacy in patients with TN secondary to MS, in three studies involving a small number of participants. It can be tried in refractory TN secondary to MS.
Sumatriptan is a 5-HT1A/1B/1D receptor agonist which acts by inhibiting vasodilation and inflammation near the demyelinated trigeminal root. Sumatriptan in injectable and oral forms has been tested for pain relief in TN by two RCTs comprising a total of 29 participants., Favorable results were obtained as measured by a decrease in pain scores without severe adverse events. However, overuse headache is a major drawback of triptan therapy.
Botulinum toxin A (BoNT-A) and local anesthetics
BoNT-A is an exotoxin produced by Clostridium botulinum, which blocks the TRPV1 receptor of unmyelinated C fibers. It also inhibits the release of acetylcholine, nociceptive neuropeptides like substance P, glutamate, and calcitonin gene-related peptide (CGRP) at the presynaptic terminals. The muscle relaxant effects of BoNT-A seem to be unrelated to the pain relief mechanisms in TN., A recent systematic review analyzed ten RCTs comprising of 390 participants treated with BoNT-A and compared its efficacy and safety with placebo. Pooled results of these trials show a favorable result in improvement of pain scores for three months post-BoNT-A therapy. The NNT of BoNT-A for 50% pain relief compared to placebo ranged from 1.2-3.3 in four of these studies. The dosage of BoNT-A ranged from 25 U to 300 U administered by either subcutaneous, submucosal, or intradermal routes. The side effects post-therapy were comparable in either group., These included transient facial weakness, edema, and hematoma at the injection site. The current role of BoNT-A is as an add-on therapy for the treatment of TN. Large-scale studies however need to be conducted for more robust evidence.,
Local anesthetic injections at trigger areas like ropivacaine or lidocaine are tried in TN patients not responding to oral therapy. Two RCTs studied the effects of combined therapy with local ropivacaine and CBZ or gabapentin., Ropivacaine with CBZ showed improved outcomes in pain relief in 45 participants as compared to CBZ monotherapy. The combination of topical ropivacaine with gabapentin was also safe and effective with a significant reduction in pain scores after 7 and 28 days. Topical lidocaine (8%) was compared to placebo in two RCTs that recruited 49 patients., Lidocaine as a local spray over affected areas showed significant pain relief compared to placebo. However, the evidence generated from these studies is not robust enough to support the routine use of such topical agents.
Vixotrigine is a newer selective sodium channel blocker that blocks the NaV 1.7 receptor., The NaV 1.7 is preferentially expressed in the nociceptive neurons and occurs outside the brain. The results of the phase 1 trial in TN were promising suggesting good tolerability. This facilitated a phase 2A study including 67 patients with classical and idiopathic TN., Vixotrigine was used in a dose of 150 mg thrice a day for a treatment phase of 28 days. The number of paroxysms was reduced by 60% in the treatment group and 12% in the placebo group. The pain severity decreased by 55% with vixotrigine and 18% with placebo. Vixotrigine met both primary and secondary treatment outcomes, though the results were not statistically significant. It was well tolerated without any serious adverse events. Two double-blind randomized withdrawal phase 3 studies are presently underway to evaluate the efficacy and safety of vixotrigine compared with placebo (NCT03070132 and NCT03637387).,
Rimegepant is a highly selective CGRP receptor antagonist approved for the treatment of acute migraine. Preclinical studies suggest that blockage of CGRP receptor has antinociceptive properties.,,, A single-center, double-blind, crossover, phase two trial (NCT03941834) in the United States is currently recruiting participants with treatment-refractory TN for evaluation of the efficacy of rimegepant compared with placebo.
Choice of therapy
Acute treatment for severe exacerbations
Acute exacerbation of TN is characterized by very frequent attacks leading to dehydration due to poor oral intake and anorexia., The treatment of such attacks is usually hospitalization with rapid correction of dehydration and intravenous drugs to abate the attack followed by titration of the oral drugs. A systematic review identified 17 studies on acute rescue drugs in severe TN, comprising of three RCTs (total of 69 participants with classical TN) comparing intravenous lidocaine with placebo and one RCT (comprising 24 participants) with sumatriptan compared to placebo. Intravenous lidocaine (5 mg/kg over 60 min) was tested for efficacy in acute exacerbation. There were favorable results in pain relief compared to placebo, the limiting side effect being somnolence. Sumatriptan administered subcutaneously decreased pain scores from 8.3 to 2.4. Phenytoin or fosphenytoin has been tried for quick relief intravenously in isolated case reports. There are no RCTs testing these drugs for acute TN. Intravenous fosphenytoin and lidocaine may be used in acute exacerbations of pain (weak recommendation). As per the systematic review by Moore and colleagues, local anesthetics (lidocaine), anticonvulsants (phenytoin or fosphenytoin), serotonin agonist, and sumatriptan may be beneficial in the management of exacerbations. [Figure 1] depicts a simplified algorithm for the medical management of TN.
For patients with classical or idiopathic TN, CBZ and OXC are effective as first-line drugs as a chronic therapy, especially for early TN [Table 2]. Baclofen, lamotrigine, and pimozide are possibly effective. Topical ophthalmic anesthetic agents are probably ineffective for controlling pain. Alternative drugs need to be considered if the first-line drugs are not well tolerated or become ineffective with prolonged therapy. The second-line drugs include LTG, baclofen, gabapentin, and pregabalin used either as monotherapy or combined with CBZ/OXC. In selected patients, BoNT-A can be used where initial drug therapy fails, though strong evidence is lacking. Several add-on drugs are available; however, the use of such agents has to be tailored to individual requirements.
A multidisciplinary approach is necessary while managing patients. Patients need to be educated regarding titration of dosage as per pain severity and side effects. The changes in dosage (increment or decrement) needs to be gradual over several days. While surgical intervention is considered for the resistant patients with idiopathic as well as classical TN, its type and timing need to be decided on an individual basis.
The treatment for secondary TN follows the same general principles as for classical/idiopathic TN., The first-line therapy in secondary TN is still CBZ/OXC. The available literature on the use of alternative drugs for secondary TN (including patients with MS) comprises of small, open-label trials comparing LTG, gabapentin, topiramate, and misoprostol in patients of TN with MS. Drugs like gabapentin, LTG, topiramate, and baclofen may be useful in patients with TN secondary to MS.
Elderly patients usually have multiple co-morbidities and are generally on polypharmacy for their treatment. This poses a problem for drug-drug interactions with CBZ/OXC. A recent systematic review analyzed 18 studies (comprising six studies on anti-epileptics and 12 studies on non-epileptic drugs) in a total of 521 patients. LTG (as an add-on to CBZ) was found to be an effective and safer option with pain relief in 67% of patients. Amongst the non-epileptic drugs, baclofen showed promising results compared to placebo (in a small number of patients); while tizanidine, pimozide, topical anesthetics, and BoNT-A had either no significant beneficial effect or severe adverse events. The first-line drugs still remain CBZ/OXC, with a cautious slow escalation of dosage.,
CBZ/OXC is very effective in reducing painful paroxysms. A prospective study comprising of 158 participants with TN with CCP showed poor results with CBZ/OXC therapy. Drugs like gabapentin and pregabalin seem to be more effective in TN with CCP as compared to surgical options. However, there are no RCTs assessing the efficacy of drugs in TN with CCP.,
Refractory TN refers to a state with no-response to either CBZ/OXC, or a patient having specific contraindications to the drug, or an inability to reach the therapeutic dosage because of excessive adverse effects. About 50% of cases develop treatment resistance to oral drugs over the subsequent years of therapy. A systematic analysis of 12 studies on drugs for refractory TN analyzed various drugs used as monotherapy or as add-on therapy. LTG was noted to be effective as an add-on, while others like gabapentin, pregabalin, topiramate, and levetiracetam did not show significant pain relief. Topical drugs too failed to show good results. BoNT-A showed excellent results (85% response rate compared to placebo) in two RCTs., BoNT-A may be a good presurgical option; however, strong evidence is still lacking.,
CBZ is considered the gold standard for the initial therapy of TN. The first-line drugs for TN (irrespective of the age group or type) are CBZ and OXC. With time, the beneficial effects of CBZ/OXC may wane off. Combination therapy with second-line or other drugs may become necessary with subsequent years of therapy or with poor response to CBZ/OXC or if adverse events occur. In patients unresponsive to CBZ/OXC, add-on therapy with LTG or surgery may be considered. Medical treatment for TN in the elderly is challenging due to comorbidities and safety concerns due to potential drug-drug interactions. BoNT-A may be a useful presurgical option prior to referral for surgical or radiologic interventions. Patients should be offered surgical options if there is a poor response or a poor tolerance of medical therapy.
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[Table 1], [Table 2]