1 Introduction
Trigeminal neuralgia (TN) is a representative neuropathic facial pain condition, characterised by unilateral paroxysmal pain described as stabbing or electric shock-like, in the distribution territory of one or more divisions of the trigeminal nerve and triggered by innocuous stimuli [
1].
According to the new classification and diagnostic grading of TN issued by the International Association for the Study of Pain (IASP), TN is distinguished in three diagnostic categories—classical, caused by vascular compression producing anatomical changes in the trigeminal nerve root—secondary, due to an identifiable underlying neurologic disease,—idiopathic, when even after MRI or other investigation, the aetiology of TN remains unclear (Table
1) [
2].
Table 1
Trigeminal neuralgia diagnostic criteria
IASP criteria |
Definition | TN is orofacial pain restricted to one or more divisions of the trigeminal nerve. With the exception of TN caused by MS, the pain affects one side of the face. It is abrupt in onset and typically lasts only a few seconds (2 min at maximum). Patients may report their pain as arising spontaneously, but these pain paroxysms can always be triggered by innocuous mechanical stimuli or movements. Patients usually do not experience pain between paroxysms. If they do report additional continuous pain, in the same distribution and in the same periods as the paroxysmal pain, they are considered to have TN with continuous pain |
Classification | Classical TN: caused by vascular compression of the trigeminal nerve root resulting in morphological changes of the root |
Secondary TN: caused by major neurological disease, e.g. a tumor of the cerebellopontine angle or MS |
Idiopathic TN: no apparent cause |
ICHD criteria |
Criteria | A. At least three attacks of unilateral facial pain fulfilling criteria B and C |
B. Occurring in one or more divisions of the trigeminal nerve, with no radiation beyond the trigeminal distribution |
C. Pain has at least three of the following four characteristics: 1. recurring in paroxysmal attacks lasting from a fraction of a second to 2 min 2. severe intensity 3. electric shock-like, shooting, stabbing or sharp in quality 4. precipitated by innocuous stimuli to the affected side of the face |
D. No clinically evident neurological deficit |
E. Not better accounted for by another ICHD-3 diagnosis |
Classification | 13.1.1.1 Classical TN (classical TN, purely paroxysmal; classical TN with concomitant continuous pain) |
| 13.1.1.2 Secondary TN (TN attributed to MS; TN attributed to space-occupying lesion; TN attributed to other cause |
| 13.1.1.3 Idiopathic TN (idiopathic TN, purely paroxysmal; idiopathic TN with concomitant continuous pain |
Regardless of the aetiology, the primary mechanism of paroxysmal pain is the same, i.e. a focal demyelination of primary trigeminal afferents near the entry of the trigeminal root into the pons, making the axons hyper-excitable and increasing the susceptibility to ectopic excitation, ephaptic transmission, and high-frequency discharges [
3‐
5].
TN has an annual incidence of three to five per 100,000. It is more common in women than men (age adjusted ratio: 1.74:1) and in people aged 50–69 years [
6,
7].
In virtually the entire population of patients with TN, at least one trigger capable of provoking a paroxysm can be identified. In a recent study, provocation of paroxysmal pain by various trigger manoeuvres was reported by 136 of the 140 patients. The most frequent manoeuvres were gentle touching of the face and talking. Trigger zones were predominantly reported in the perioral and nasal region and were variable in size [
8]. These data are coherent with the use of trigger factor as an essential diagnostic feature for a clinically established diagnosis of TN [
2]. Patients with TN may suffer from different types of pain, ranging from single attacks to a series of prolonged attacks, and it was suggested that these pain characteristics can vary over time [
9].
Traditionally, autonomic symptoms such as tearing and rhinorrhoea have not been associated with TN. However, it is now known that a large proportion of TN patients have autonomic symptoms [
10].
A subgroup of patients with TN also suffer from concomitant continuous pain (CCP), described as dull, burning or aching [
11]. This condition has been described with several definitions, including atypical TN and TN type 2; the International Headache Society Classification (ICHD) [
1] defined this relatively uncommon type of TN as TN with concomitant continuous facial pain. The presence of continuous pain is not related to aetiology and may occur in idiopathic, classic, or secondary TN. Background pain distribution coincides with that of the paroxysmal pain, and fluctuations of its intensity parallel in time those of the paroxysmal pain [
12,
13]. A prevalence three times higher in women than in men was reported [
11]. In a cohort of 158 patients with TN, continuous pain developed within a mean period of 1.5 years since the disease onset, thus suggesting that this kind of pain is not a consequence of a long duration of stabbing pain [
11]. The mechanisms underlying continuous pain, as opposed to paroxysmal pain, are not fully understood, with implications for treatment. There is the evidence that continuous and paroxysmal pain may improve differently after microvascular decompression, thus supporting the hypothesis that the mechanisms responsible for the two pain components may be different [
14‐
17]. Central mechanisms [
18] and progressive root damage due to compression [
19] have been proposed as possible factors.
Carbamazepine (CBZ) and oxcarbazepine (OXC) are the first-choice medical treatment in TN. They have the same mechanism of action, the blockade of voltage gated sodium channel in a frequency dependent manner, resulting in the stabilization of hyperexcited neural membranes and in the inhibition of repetitive firing. In patients with purely paroxysmal pain, CBZ and OXC are effective in virtually the entire patient population. However, they produce side effects to a level that cause interruption of treatment or a dosage reduction in 23% of patients [
20], making necessary the development of new, more selective sodium channel blockers. Conversely in patients with CCP, the efficacy of CBZ and OXC may drop, thus suggesting the opportunity to test the efficacy of different drug categories. A wide range of drugs has been investigated in TN, but the scientific literature highlighted the need of high quality clinical trials in TN [
21].
The aim of this review, based on a systematic search of relevant literature, is to provide current, evidence-based, knowledge about the pharmacological treatment of typical and atypical TN, with a specific focus on drugs in development, such as botulinum toxin A and new, more selective sodium channel blockers.
2 Search Process
We searched for relevant papers within the PubMed, EMBASE and the Cochrane Database of Systematic Reviews, taking into account publications up to February 2018. All searches used the following synonyms for TN: trigeminal neuralgia and tic douloureux. The primary search was supplemented by a secondary search using the bibliographies of the retrieved articles. Only full-length, original communications including open-label studies were considered, and the search was limited to English language publications. Clinical trials database (ClinicalTrial.gov) has been checked in order to include in the analysis studies currently in progress. The review process was carried out independently by two reviewers and only publications independently approved by the two authors were taken into account (Supplementary Material 1). The authors independently assessed the quality of the individual trials during data extraction. Inclusion criteria were the following: trials including patients with a diagnosis of typical or atypical TN, including classical, idiopathic and secondary TN, and a minimum sample of 10 patients.
4 Drugs in Secondary Trigeminal Neuralgia
No randomised controlled trials were found in patients with secondary TN. The existing studies based on CBZ, OXC, eslicarbazepine, lamotrigine, gabapentin, pregabalin, topiramate and misoprostol have an open label design and include small sample of patients with multiple sclerosis (MS) [
47,
64‐
78]. Only few studies provided details about the type of MS and the TN diagnostic criteria [
78]. One study used a VAS and recorded both intensity and number of attacks [
75,
78]. These case series reported the potential efficacy of lamotrigine as monotherapy or in association with gabapentin or CBZ, topiramate and gabapentin. Three studies reported the efficacy of misoprostol (a prostaglandin-E1-analogue) in a total of 27 patients with TN secondary to MS [
74‐
76]. According to the international guidelines [
22], there is insufficient evidence to support or refute the effectiveness of any medication in treating pain in TN secondary to MS.
6 Expert Opinion
Based on evidence [
22], CBZ (400–1200 mg/day) and OXC (900–1800 mg/day) are the first-choice medical treatment in TN. OXC should be preferred for better tolerability and the decreased potential for drugs interactions. These drugs are effective in most patients and the development of late resistance only occurred in a very small minority of patients. However, the side effects cause withdrawal from treatment in an important percentage of patients [
20]. Common initial side effects include drowsiness, nausea, dizziness, diplopia, ataxia and elevation of transaminases. Hyponatraemia occurs in 6–8% of patients; sodium levels are dose related and should be monitored during the treatment, especially when high dosage is used. Patients treated with diuretics may be more susceptible to developing sodium depletion [
14]. The addition of sodium chloride capsules can be helpful in patients with persistent hyponatremia. Serious but uncommon side effects include allergic rash, hepatotoxicity, lymphadenopathy, systemic lupus erythematosus, Stevens–Johnson syndrome and aplastic anaemia. Specific contraindications are cardiac conduction problems or severe arrhythmias.
In a prospective, observational, exploratory survey of 161 patients with idiopathic TN, females treated with CBZ or OXC reported significantly more side effects than males [
79]. Pharmacokinetic and pharmacodynamic differences are likely to be the reason for gender differences in reporting side effects.
The consumers’ views on treatments used for TN was investigated by using a self-administered questionnaire distributed to 133 patients and 21 clinicians attending national support group meetings in the USA and UK [
80]. All patients reported at least one side effect. The clinicians underestimated the number of side effects, but both groups agreed that drowsiness and cognitive impairment were the most disliked side effects.
A prospective study investigated the risk and genetic association of OXC-induced cutaneous adverse reactions, including Stevens–Johnson syndrome/toxic epidermal necrolysis, in Asian populations. The authors found that HLA-B*15:02 was significantly associated with OXC-Stevens-Johnson syndrome in Chinese and Thai populations [
81].
CBZ is a potent inducer of CYP3A4 and other oxidative enzyme systems in the liver, and it may also increase glucuronyl transferase activity, leading to a number of clinically relevant drug interactions. OXC, a keto-analogue of CBZ, rapidly converted into its pharmacologically active metabolite, should be preferred for the better tolerability and the decreased potential for drugs interactions.
A recent meta-analysis investigating the teratogenic effects of different antiepileptic drugs showed that children exposed to CBZ were at a higher risk of malformation than children born to women without, and women with untreated epilepsy [
82].
Vixotrigine, a new sodium channel blocker that is selective for the Nav1.7 receptor is under development and has promise of efficacy without inducing side effects related to CNS depression [
21].
Lamotrigine is considered a second-line treatment in patients with TN. Potential side effects of lamotrigine include dizziness, nausea, blurred vision and ataxia. Approximately 7–10% of patients will report a skin rash during the first 48 weeks of therapy [
32]. The dose of lamotrigine must be increased slowly in order to avoid skin rash.
In patients with refractory TN, or in the event of withdrawal due to side effects, surgery should at least be proposed and discussed with the patient.
In refractory TN, BTX-A is a promising alternative treatment option that might spare the need for surgical interventions [
83]. Although it is reasonable that BTX-A primarily acts on constant pain, to our knowledge, no study has reported the effects of injections in a subgroup of patients with CCP until now.
During acute exacerbation, in-hospital treatment may be necessary for rehydration, management of hyponatraemia, titration of drugs, and, in selected case, lidocaine or fosphenytoin intravenous infusion, under specialist supervision and cardiac monitoring. Intravenous loading of fosphenytoin was reported in case series but no randomised controlled trials have been conducted until now [
7,
84‐
86].
The first-line therapy in secondary TN is based on sodium channel blockers. In patients with MS-related TN, gabapentin, lamotrigine and topiramate represent other therapeutic options, but the quality of evidence is poor. In this patient category pharmacological treatment may potentiate some of the MS symptoms with a high dropout rate. Expert consensus suggests that baclofen may be useful in patients with MS who develop TN. Such patients are often taking baclofen already to reduce spasticity and may achieve control of symptoms without having to add CBZ. The main side effects of baclofen are transient sedation and loss of muscle tone. Abrupt discontinuation may cause seizures and hallucinations [
87].
In patients with TN, CCP is associated with poor medical and surgical outcome. In this condition, both calcium channel blockers (gabapentin and pregabalin) and antidepressants may be efficacious and should be tried as an add-on to OXC or CBZ. However, randomised, controlled, double-blinded trials are still lacking.