Expert Review of Neurotherapeutics
ISSN: 1473-7175 (Print) 1744-8360 (Online) Journal homepage: http://www.tandfonline.com/loi/iern20
Pharmacological treatment of trigeminal neuralgia Giulia Di Stefano & Andrea Truini To cite this article: Giulia Di Stefano & Andrea Truini (2017): Pharmacological treatment of trigeminal neuralgia, Expert Review of Neurotherapeutics, DOI: 10.1080/14737175.2017.1370375 To link to this article: http://dx.doi.org/10.1080/14737175.2017.1370375
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Date: 23 August 2017, At: 09:50
Publisher: Taylor & Francis Journal: Expert Review of Neurotherapeutics DOI: 10.1080/14737175.2017.1370375
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Pharmacological treatment of trigeminal neuralgia
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Department of Neurology and Psychiatry, University Sapienza, Roma
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Corresponding Author Andrea Truini,
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Sapienza University,
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Department of Neurology and Psychiatry,
Viale Università 30, 00185 Rome,
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Giulia Di Stefano, Andrea Truini
Italy
Email: [email protected]
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Abstract Introduction: Unique among the different neuropathic pain conditions, trigeminal neuralgia
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frequently has an excellent response to some selected drugs, which, on the other hand, often entail disabling side effects. Physicians should be therefore acquainted with the management of
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Areas Covered: This article, based on a systematic literature review, describes the
pharmacological options, and indicates the future perspectives for treating trigeminal neuralgia.
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The article therefore provides current, evidence-based knowledge about the pharmacological treatment of trigeminal neuralgia, and suggests a practical approach to the various drugs, including
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starting dose, titration and side effects.
Expert Commentary: Carbamazepine and oxcarbazepine are the reference standard drugs for
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treating patients with trigeminal neuralgia. They are effective in most patients. The undesired effects however cause withdrawal from treatment or a dosage reduction to an insufficient level in
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many patients. Sodium channel blockers selective for the sodium channel 1.7 (Nav1.7) receptor, currently under development, might be an alternative, better-tolerated pharmacological option in the next future.
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these drugs and the few alternative options.
Keywords: neuropathic pain, voltage gated sodium channel blockers, facial pain, trigeminal neuralgia.
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1. Introduction Trigeminal Neuralgia (TN) is characterized by unilateral paroxysmal pain most often described as
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stabbing or electric shock-like, restricted to the distribution of one or more divisions of the trigeminal nerve territory and triggered by innocuous stimuli [1]. Some patients also suffer from
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with that of the paroxysmal pain. TN with persistent pain between the paroxysms has been
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described with several definitions, including atypical TN and TN type 2; currently a widely agreed definition is TN with concomitant persistent facial pain [1]. TN has an annual incidence of three to
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five per 100.000. It is more common in women than men (age adjusted ratio: 1.74:1) and in people aged 50 to 69 years [2,3]. According to the new classification and diagnostic grading of TN issued
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by the International Association for the Study of Pain, TN is distinguished in classical, caused by vascular compression producing anatomical changes in the trigeminal nerve root, secondary, due
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to an identifiable underlying neurologic disease, and idiopathic, when even after MRI or other investigation, the aetiology of TN remains unclear [4]. The aim of this narrative review, based on a
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systematic search of relevant literature, is to provide current, evidence-based, knowledge about the pharmacological treatment of TN, and suggest a practical approach to the various drugs, including starting dose, titration and side effects. 2. Description of the search process
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persistent, dull, tingling pain between the paroxysms. The distribution of persistent pain coincides
We searched relevant papers within the PubMed, EMBASE and the Cochrane Database of Systematic Reviews, taking into account publications up to March 2017. All searches used the following synonyms for TN: trigeminal neuralgia, facial pain and tic doulourex. The primary search was supplemented by a secondary search using the bibliographies of the articles retrieved. Only full-length, original communications were accepted and the search was limited to English language publications. All retrieved articles were reviewed by title and abstract for potential relevance to this 3
topic; when the title and abstract did not clearly indicate the degree of relevance to the topic, the article itself was reviewed. To avoid selection bias, the review process was carried out independently by the two Authors; only studies independently approved by the two authors were taken into account. Inclusion criteria were the following: trials including patients with a diagnosis of primary or secondary TN and a minimum sample of 10 patients. For specific condition that had no
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top-level studies, such as in-hospital treatment for acute exacerbations, also small case series were included. Included patients suffered from unilateral paroxysmal pain, usually described as
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trigeminal territory. Exclusion criteria included duplicated patient series and experimental
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paroxysmal pain.
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3. Results
Although phenytoin has been the first drug to be used for TN with positive effects, no randomized
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controlled trials have been published [5]. Conversely four placebo-controlled trials, involving 147 patients, demonstrated the efficacy of carbamazepine (CBZ) [6-9] with a number needed to treat to
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obtain pain relief of 1.7-1.8 [5,10]. This efficacy is impaired by the tolerability, with a numberneeded to harm of 3.4 for minor and 24 for severe adverse events [11,12]. Three double-blind
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RCTs including a total of 130 patients compared Oxcarbazepine (OXC) to CBZ; only one of them however was published in extenso [15]. These studies showed that the two drugs had a comparable efficacy in reducing pain attacks [10, 13-15, 78]. However, OXC revealed greater tolerability and a lower potential for drug interaction. In a retrospective study involving 178 patients
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stabbing or electric shock-like, and restricted to the distribution of one or more divisions of the
with classical TN [16], CBZ and OXC were confirmed to be effective in virtually all patients. The initial number of responders was 98% with CBZ at a median dosage of 600 mg (range 200–1200 mg), and of 94% with OXC at a median dosage of 1200 mg (range 600–1800 mg). Among responders, 27% of patients treated with CBZ and 18% of patients treated with OXC, after a mean period of 8.6 and 13 months, incurred in adverse events that directly caused interruption of treatment or a dosage reduction to a level that was insufficient to control pain. The most frequent adverse effects involved the central nervous system, and included somnolence, dizziness and 4
unsteadiness. CBZ had a higher percentage of discontinuations for all kinds of side effect, except for sodium depletion, than OXC. Other drugs have been studied in controlled trials. A crossover study totaling 21 patients with TN compared lamotrigine to CBZ [17]. Patients were titrated to lamotrigine 400 mg and CBZ 1.200 mg. Efficacy of the medications was measured with the visual analogue scale (VAS) and a verbal rating
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scale (VRS). CBZ reduced pain in 90.5% (19/21) and lamotrigine in 62% (13/21) of the patients
using both VAS and VRS. The reported side effects were headache, dizziness and skin rash. A
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phenytoin was slightly more effective than placebo; 10/13 participants stated that lamotrigine was better or much better, compared with 8/14 on placebo, using a global evaluation [18,19].
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Baclofen, the agonist of the GABAB receptor, was superior to placebo in reducing the number of painful paroxysms in a randomized controlled trial including only ten participants [20]. An open trial
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in another 50 patients with refractory trigeminal neuralgia showed that 74% of patients were relieved of their attacks by baclofen, either alone or in combination with previously ineffective
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doses of CBZ or phenytoin. On long-term follow-up of one to five years 30% of the 60 patients was pain-free while receiving baclofen, 17% went into remission after 3 to 6 months, 22% became
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refractory to baclofen after 1 to 18 months, and 3% elected operation despite a good response to baclofen [20]. L-Baclofen was more effective compared to racemic baclofen (Lioresal) in a double-blind crossover trial in 15 patients with TN [21]. Single, low-quality, randomized controlled trials compared the three different non-antiepileptic
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crossover add-on study involving 14 patients showed that lamotrigine in combination with CBZ or
drugs tizanidine [22], tocainide [23] and pimozide [24] with CBZ. The duration of treatments was generally short: three weeks, two weeks and eight weeks [25]. Pimozide was more effective than CBZ in 48 patients, with a response rate of 100% for pimozide versus 56% for CBZ [24]. The reported side effects included central nervous system disturbances, hand tremors and memory impairment. The effect of tizanide in comparison with CBZ was tested in a very small sample of patients (12 participants, with six in each group). Three participants taking tizanidine discontinued, one because of unrelated disease and two because of intolerable pain. At the end of treatment, 5
one of five participants improved with tizanidine and four of six with CBZ. The difference was not statistically significant [22]. Tocainide was tested in 12 participants but significant side effects limited its use [23]. There are some reports about the efficacy of gabapentinoids, but they have never been adequately assessed in the treatment of TN. A small randomized controlled trial in 36 patients combining
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gabapentin with ropivacaine injection into trigger areas showed improved pain control and quality
of life [26]. Pregabalin was tested in an open-label study including 53 patients. Pregabalin (150-600
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observational studies, 65 patients with TN were treated with pregabalin in monotherapy (n = 36) or add-on (n = 29) for 12 weeks. After 12 weeks, pregabalin reduced the baseline pain intensity by
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55%, with 59% of responders (pain relief > 50%). Furthermore, pregabalin improved anxiety, depression, sleep, physical function and health state [28, 29]. However, according to the inclusion
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criteria based on DN4 questionnaire, also patients with an atypical facial might have been included in this study. In an open label crossover trial in 22 patients with refractory TN using lamotrigine and
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pregabalin together with CBZ, pregabalin showed potential anti-neuralgia properties comparable to lamotrigine. However, the level of patient’s tolerance seen with pregabalin exceeds that with
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lamotrigine [30].
Among anticonvulsants, small case series investigated the efficacy of topiramate and levetiracetam. Topiramate (100-400mg/day) reduced pain in 75% of patients, in a very small sample of only eight patients. The most frequently registered side effects were dizziness,
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mg/day) proved to be effective in reducing TN by over 50% in 74% of patient. [27]. In two
somnolence and weight loss. [31]. A pilot study investigated the efficacy and tolerability of levetiracetam in 10 patients with TN over a period of 10 weeks in an open-label prospective design. Patients were treated with up to 4000 mg daily and 40% reported an improvement of 5090% [32]. In an observational trial, totalling twenty-three patients with refractory TN, levetiracetam (3-4 g/day) for 16 weeks decreased by 62.4% the number of daily attacks [33]. Several studies assessed the efficacy of local anaesthetics. Two randomized controlled trials investigated the effect of local anaesthesia injected into trigger area. In the randomized, controlled 6
trial of Lemos et al, combining ropivacaine and gabapentin even those patients who only had ropivacaine showed short-term reduction in pain on the VAS without side effects [26]. The patients treated with the combination therapy had the best outcome and were able to use lower total daily doses of gabapentin. Although considerable effort was placed on allocation concealment and randomization, the study was only single blinded as patients knew whether they received an
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injection [26]. In a randomized, controlled trial in 45 patients combining the peripheral analgesic block with ropivacaine and CBZ, the association protocol resulted in a significant reduction in pain
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monotherapy [34]. Randomized-controlled studies tested the efficacy of lidocaine 8% in TN. In a
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randomized placebo-controlled crossed over trial including 25 patients with TN involving the second division, those given an 8% spray of lidocaine as opposed to saline had a statistically
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significant decrease in pain. Two sprays (0.1 ml of one spray twice) of intranasal lidocaine 8% significantly decreased VAS 15 minutes after treatment, whereas the placebo spray did not. The
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effect of treatment persisted for a mean of four hours without serious adverse reactions. The authors observed that 15 out of 25 subjects felt burning or stinging in the treated nostril and
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commented that this made the study difficult to blind [35]. This study showed two main limitations: it was restricted to patients with pain in the second trigeminal division and it only examined the
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response to triggering manoeuvres, whereas spontaneous pain was not tested. In a randomized, placebo-controlled, crossover study including 24 patients and severe intraoral pain the application on the painful areas of 8% lidocaine significantly reduced the NRS score of paroxysmal pain for a mean of three hours, without serious side effects [36]. A trial involving 47 participants compared
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intensity, number of daily pain crises and daily dose of CBZ intake, when compared with CBZ in
0.5% proparacaine hydrochloride eye drops with placebo, but it did not show any significant benefits [37]. Among topical treatment, capsaicin application has been investigated in two small case series. The treatment had only a mild effect [38, 39]. Two randomized controlled trials, totaling 39 patients with TN refractory to previous treatment, tested the effect of subcutaneous injection of sumatriptan 3 mg and the oral administration of 50 mg twice daily [40, 41]. Fifteen minutes after injection of sumatriptan, the baseline VAS decreased from 8.3 to 2.4 cm. At the end of oral treatment, the VAS was significantly decreased and this 7
beneficial reduction persisted a further week after treatment discontinuation. The main drawbacks of sumatriptan are the side effects related to a long-term use, including a triptan overuse headache. Six trials totaling 81 patients examined the effect of subcutaneous infiltration of botulinum toxin A (BTX-A) [42-47]. The responder rate was 85% and the pain relief lasted on average 105 days.
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Complications were mostly represented by transient facial weakness, reported in 38 patients that
disappeared in a few weeks. Some patients showed focal oedema at the sites of injection, lasting
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were treated with subcutaneous infiltration of BTX-A and 16 patients received placebo. Three months after the injection significant differences were observed in the average VAS score for
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patients treated with BTX and those who received placebo [49]. In a randomized, double-blind, placebo-controlled trial, eighty-four patients were randomized into the following groups: placebo (n
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= 28); BTX-A 25U (n = 27); BTX-A 75U (n = 29). The response rates of 25U group (70.4%) and 75U group (86.2%) were significantly higher than placebo group (32.1%) at week 8, and there was
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no significant difference between 25U and 75U groups [50]. In a randomized, single-blinded, placebo-control study carried out on 20 Egyptian patients with intractable TN, pain reduction from
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the baseline to week 12 was significant in BTX-A group; VAS scores at endpoint last observation carried forward relative to baseline for BTX-A group showed a decrease of 6.5 compared with a decrease of 0.3 for placebo [50]. An open study involving eighty-eight subjects with TN investigated the effects and safety of BTX-A during a follow-up period of 14-months. The therapeutic effect decreased gradually after 3 months, and the prevalence of effective treatment at
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about 1 week [48]. In a double-blind, randomized, placebo controlled study 20 patients with TN
14 months was 38.6%, with complete control of pain seen in 22 patients. Three patients showed swelling at injection sites and 10 patients showed facial asymmetry, both of which disappeared spontaneously without special treatment [52]. Finally, a new randomized controlled trial using BTXA in classical TN has begun and is still ongoing [53]. Acute exacerbation has been successfully treated with intravenous loading with phenytoin or fosphenytoin, but again these procedures have not been tested in controlled trials. There are three 8
reports, involving only five patients with acute, sustained exacerbations of TN, responding to intravenous infusion, with a pain relief lasting two days [55-56]. In only one double blind, randomized, crossover, placebo-controlled study totaling 20 patients with intractable TN, a single dose of intravenous lidocaine (5 mg/kg) was superior in reducing pain intensity compared to placebo during the first 24 hours after the infusion. Most common side effect was somnolence
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(reported in 32.5% of cases) [57]. There are two reports involving a total of 16 patients treated with intravenous infusion of magnesium and lidocaine [58, 59]. All the subjects experienced pain relief
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the infusion, but no severe side effects were reported. A single case of remission of TN with
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concomitant persistent facial pain after intravenous lidocaine infusion was reported. Patient remained asymptomatic for two weeks after discontinuation of lidocaine with return of mild pain
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[60]. A different approach during acute exacerbation is the ganglionic local opioid analgesia at the superior cervical ganglion, which was evaluated retrospectively in 74 patients with neuropathic
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facial pain. A clinically relevant pain reduction was observed in 73% of the patients. The proportion
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of responders (pain reduction 50%) was 59% after the first blockade [61]. Recently, the effect of a new Nav1.7 selective state-dependent, sodium channel blocker (BIIB074)
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was investigated in TN. Findings from electrophysiological studies have shown that BIIB074 preferentially inhibits high frequencies firing in nociceptive neurons [62]. Results from phase 1 studies have suggested that BIIB074 has good tolerability in healthy individuals and can be administered at therapeutic doses without lengthy titration. BIIB074 was tested in a double-blind, placebo-controlled, randomized withdrawal phase 2a trial, totaling 67 patients with classical TN
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after the combined intravenous infusion. Three patients experienced short and mild dizziness after
[63].
Forty-four patients completed open-label treatment, and 29 were randomly assigned to doubleblind treatment (15 to BIIB074 and 14 to placebo). During the double-blind phase, five (33%) patients assigned to BIIB074 versus nine (64%) assigned to placebo were classified as treatment failures. Although BIIB074 was well tolerated and no severe or serious adverse events were
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reported, the primary endpoint of treatment failure was not significantly lower in the BIIB074 group than in the placebo group. [63]. Significant treatment differences versus placebo in secondary endpoints during the double-blind phase, including time to treatment failure, number of paroxysms, average daily pain score, patient-
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and clinician-global impression of change were found. There are no placebo-controlled studies in patients with secondary TN, and the available studies
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misoprostol, a prostaglandin E1 analogue, or combination therapies in multiple-sclerosis related
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TN [64-77]. Carbamazepine was relatively effective in these patients but produced adverse effects
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causing reversible worsening of multiple sclerosis symptoms [65]. 4. Expert Commentary
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4.1 Reference standard treatment
Based on evidence [10, 78], the first line pharmacological treatment in TN is CBZ (400–1200
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mg/day) or OXC 900–1800 mg/day [Table 1]. The effectiveness of CBZ and OXC reflects primary mechanism of paroxysmal pain in TN, i.e. the focal demyelination of primary afferents near the
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entry of the trigeminal root into the pons. The focal demyelination produces ectopic excitation, ephaptic transmission and high-frequency discharges [79-81]. Recommended drugs, CBZ and OXC, block voltage-gated sodium channels in a frequency-dependent manner, stabilizing hyperexcitable neural membranes and inhibiting repetitive firing [10].
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are small, open-label trials based on CBZ, OXC, lamotrigine, gabapentin, pregabalin, topiramate,
Carbamazepine is a potent inducer of CYP3A4 and other oxidative enzyme system in the liver, and it may also increase glucuronyl-transferase activity. This inducing activity results in the acceleration of the metabolism of concurrently prescribed anticonvulsants, such as valproic acid, clonazepam, ethosuximide, lamotrigine, topiramate. The metabolism of many other drugs including tricyclic antidepressants, antipsychotics, steroid oral contraceptives, glucocorticoids, oral anticoagulants, cyclosporin, theophylline, chemotherapeutic agents and cardiovascular drugs can also be induced, leading to a number of clinically relevant drug interactions. 10
OXC, a keto-analogue of CBZ rapidly converted into its pharmacologically active 10-monohydroxy metabolite, should be preferred for the better tolerability and the decreased potential for drugs interactions [16, 82, 83]. However, given the chemical similarity of these drugs, allergic crossreactions can occur. Since spontaneous recovery in TN is rare and the condition is cyclical with periods of partial or complete remission and recurrence, it is reasonable to encourage patients to
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adjust the dosage of the drug to the frequency of attacks [10]. Before starting therapy, an accurate medical history, in order to exclude cardiac conduction abnormalities, and other possible relevant
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ensure normal renal and liver function and normal sodium level. Laboratory testing should be also
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repeated if higher doses are used and significant side-effects reported. ECG is needed when a cardiac conduction abnormality is suspected on the basis of medical history, being CBZ and OXC
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contraindicated in patients with atrioventricular block. High dosages are often necessary for sufficient pain relief, so many patients suffer from disabling side effects. Failure of the treatment
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with CBZ or OXC, most of the times, is not due to the inefficacy of the drug, but rather to undesired effects to a level that causes interruption of treatment or a dosage reduction to an insufficient level
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[16]. Common initial side effects include drowsiness, nausea, dizziness, diplopia, ataxia, elevation of transaminases and hyponatremia. Possible serious but uncommon side effects are allergic rash,
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myelosuppression, hepatotoxicity, lymphadenopathy, systemic lupus erythematosus, StevensJohnson syndrome and aplastic anaemia [84]. Females reported significantly more side effects than males, likely due to pharmacokinetic differences [83]. Worsening of pain with time and development of late resistance only occurred in a very small minority of patients [16]. In case of
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medical conditions is required [3]. During treatment laboratory testing is usually performed to
treatment failure, it may be reasonable to try both CBZ and OXC sequentially [85]. When sodium channel blockers cannot reach full dosage because of side effects, an add-on treatment combining CBZ or OXC with lamotrigine (400 mg/day) or baclofen (40-80 mg/day) might be taken into account as a reasonable next step. However, the efficacy of combination therapy in patients with TN was tested only in a few patients [18], and no high-quality studies directly compared polytherapy with monotherapy. Lamotrigine acts at voltage-sensitive sodium channels, stabilizes neural membranes and inhibits the release of excitatory neurotransmitters. The initial dose of 25 mg/day is slowly 11
increased to a target dose of 200-400 mg/day divided between two doses. Potential side effects include dizziness, nausea, blurred vision and ataxia. Approximately 7-10% of patients will report a skin rash during the first 48 weeks of therapy [86]. The dose of lamotrigine must be increased slowly in order to avoid rashes, and it is therefore not appropriate for acute management of trigeminal neuralgia. It is most effective when used for long-term control of moderate pain, such as
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in people with multiple sclerosis [87]. Baclofen is a GABAB receptor agonist and thus depresses excitatory neurotransmission. Potential side effects include lassitude, drowsiness, dizziness and
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Pimozide (4-12 mg day) is seldom used in clinical practice and poses concern about possible long-
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4.2 Pharmacological treatment for refractory TN
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term side effects such as extrapyramidal symptoms [84].
According to some clinical trials botulinum toxin injections might offers another non-surgical
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treatment option in the treatment of refractory TN. There is increasing evidence that this treatment might be efficacious in classical TN and may be offered before surgery or to those unwilling to
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undergo surgery [48]. Botulinum toxin type A (BTX-A) is a neurotoxin derived from Clostridium botulinum and its analgesic effect seems mediated by the local release of anti-nociceptive
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neuropeptides (substance P, glutamate and calcitonin-gene related peptide) inhibiting central and possibly peripheral sensitization [88]. Although several studies have assessed the efficacy of botulinum toxin in patients with TN [Table 2], currently no high-quality randomised controlled trials offers a robust support to this treatment.
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gastrointestinal discomfort. Abrupt discontinuation may cause seizures and hallucinations.
4.3 In-hospital treatment for acute exacerbations In patients who develop severe exacerbations of unremitting pain, in-hospital treatment may be necessary for titration of drugs, rehydration, management of hyponatremia and, in selected case, intravenous infusion of fosphenytoin [54-56]. Admittedly, no strong evidence is currently available to support or refute the e cacy of i.v. fosphenytoin or other i.v. medications for the acute treatment of TN. 12
4.4 Treatment of concomitant persistent facial pain While patients with TN manifesting with purely paroxysmal pain find adequate relief from CBZ and OXC, patients suffering from persistent pain between the paroxysms are more resistant to drugs. CBZ and OXC produce a frequency-dependent block of voltage-gated sodium channels and, thereby, reducing the frequency of action potential firing, effectively reduce paroxysmal pain;
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however, they have a far less positive effect on concomitant persistent pain. Gabapentinoids might be more effective in persistent than paroxysmal pain and are often tried as an add-on to
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persistent pain. No trial, however, has directly assessed the efficacy of this combination in patients with persistent pain and there is no evidence to support or refute its use in clinical practice.
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4.5 Treatment of secondary TN
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Pharmacological treatment of MS-related TN is challenging owing to the poor tolerability of the drugs and the lack of evidence-based information in the literature. There are no placebo-controlled
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studies in such patients, and the studies that do exist are small, open-label trials based on carbamazepine (CBZ), oxcarabazepine (OXC), lamotrigine, gabapentin, pregabalin, topiramate,
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misoprostol or combination therapies [10]. According to international guidelines [10], there is insufficient evidence to support or refute the effectiveness of any medication in treating pain in MSrelated TN. However, it is generally agreed that the first line therapy is pharmacological and based, as it is for classical TN, on the use of sodium-channel blockers, i.e. CBZ and OXC [81, 89]. Central nervous system demyelination however renders some patients with MS more sensitive to cognitive
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oxcarbazepine or carbamazepine in patients with the atypical form of TN with concomitant
and motor side effects, which might lead to an earlier decision for surgery. 5. Five-year view The quality of evidence for drugs useful in patients with TN is very low. Only a few randomized controlled trials have been published, usually enrolling small samples of patients. The small sample of enrolled patients also hampers the generalizability of trial results. Another problem concerning the current literature on TN treatment is the possible difficulty of an accurate diagnosis. 13
TN diagnosis relies on clinical history and examination; the inclusion of patients with a correct TN diagnosis is therefore a key point in clinical trials. Although the first line drugs, CBZ and OXC, are effective in the large majority of patients with TN, the side effects cause withdrawal from treatment in an important percentage of patients. There is consensus that OXC may have fewer side effects than CBZ, although there is a lack of RCT-based
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data to confirm this statement. These considerations therefore suggest the opportunity to develop better-tolerated drugs, such as selective channel-blockers for specific isoforms. Recently a new
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firing in nociceptive peripheral neurons, was tested in a phase 2a trial [63]. Although this study failed the primary endpoint, it provides a basis for continued investigation of BIIB074 and better
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tolerated drugs in patients in future clinical trials.
Some patients with TN also suffer from concomitant persistent facial pain. The mechanisms
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underlying this kind of pain, as opposed to paroxysmal pain, are not fully understood and the efficacy of the standard pharmacological treatment, based on sodium channel blockade, usually
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drops. Gabapentinoids, whose efficacy has already been proved in the treatment of neuropathic continuous pain due to several aetiologies, have never been systematically tested in TN patients
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with concomitant persistent facial pain. Future clinical trials addressing this issue may pave the way to improved therapeutic approaches. 6. Key issues
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Nav1.7 selective sodium channel blocker (BIIB074), that preferentially inhibits high frequencies of
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CBZ and OXC, sodium channel blockers, are the first line pharmacological treatment in TN.
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The undesired effects related to CBZ and OXC cause withdrawal from treatment in in an
important percentage of patients, thus suggesting the opportunity to develop a better tolerated drug. •
Add-on treatment with lamotrigine or baclofen should be taken into account when the full dosage of sodium channel blockers cannot be reached because of side effects.
•
Botulinum toxin injections offer a non-surgical treatment option in refractory TN. 14
Funding This paper was not funded. Declaration of interest A Truini has received grants from Mundipharma, Grunenthal, Pfier, Sigma-Tau, and Angelini. The authors have no other relevant affiliations or financial involvement with any organization or entity
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with a financial interest in or financial conflict with the subject matter or materials discussed in the
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Papers of special note have been highlighted as:
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References
** of considerable interest
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adverse symptoms in oxcarbazepine and carbamazepine in the treatment of trigeminal neuralgia and neuralgiform headaches using the Liverpool Adverse Events Profile (AEP). J Headache Pain. 2015;16:563
84. Obermann M. Treatment options in trigeminal neuralgia. Ther Adv Neurol Disord. 2010;3:107-15 85. Gomez-Arguelles JM, Dorado R, Sepulveda JM, et al. Oxcarbazepine monotherapy in carbamazepine-unresponsive trigeminal neuralgia.J Clin Neurosci. 2008;15:516-9 22
86. Wiffen PJ, Rees J. Lamotrigine for acute and chronic pain. Cochrane Database Syst Rev. 2007;18:CD006044 87. Leandri M, Lundardi G, Inglese M, et al. Lamotrigine in trigeminal neuralgia secondary to multiple sclerosis. J Neurol. 2000;247:556-8 88. Aoki KR. Review of a proposed mechanism for the antinociceptive action of botulinum toxin
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type A. Neurotoxicology. 2005;26:785793 89. Pöllmann W, Feneberg W. Current management of pain associated with multiple sclerosis.
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Figure 1. Flow chart of study selection
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CNS Drugs. 2008;22:291-24
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Carb amaz epine
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Main mechanism of action
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Drug
Voltage-gated sodium channel blocker
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Commonly used drugs for trigeminal neuralgia
Starti ng dose
Titration
Max dose
Main adverse events
Recom menda tion
200 mg
Increase 200 mg every 3 days
1200 mg (400 mg (t.i.d.)
Drowsiness, ataxia, dizziness, skin reactions, nausea, vomiting, blood dyscrasia
First line
Oxca rbaze pine
Voltage-gated sodium channel blocker
300 mg
Increase 300 mg every 3 days
1800 mg (600 mg t.i.d.)
Drowsiness, ataxia, dizziness, hyponatremia
First line
Lamo trigin e
Acting at voltage-sensitive sodium channels, stabilizes neural membranes and inhibits the release of excitatory neurotransmitters
25 mg
Increase 25 mg every 7 days
400 mg (200 mg b.i.d.)
Dizziness, nausea, blurred vision, ataxia, skin reactions
Add on therap y
24
15 mg (5 mg t.i.d)
Increase 5 mg t.i.d. every 3 days
60 mg (20 mg t.i.d)
Lassitude, drowsiness, dizziness and gastrointestinal discomfort
Add on therap y
Gaba penti n
Binding to alpha2-delta subunits of voltage-gated calcium channel
300 mg
Increase 300 mg every 3 days
3000 mg (1000 mg t.i.d.)
Drowsiness, unsteadiness, weight gain, peripheral oedema
Add on therap y
Preg abali n
Binding to alpha2-delta subunits of voltage-gated calcium channel
75 mg
Increase 75 mg every 3 days
600 mg (300 mg b.i.d. or 200 mg t.i.d.)
Drowsiness, unsteadiness, weight gain, peripheral oedema
Add on therap y
Botuli num neuro toxin type A
TRPV1 receptor block reducing local release of anti-nociceptive neuropeptides such as substance P, and CGRP
-
Mean dose: 3.22 units/cm2 subcutaneo usly
-
Transient facial weakness, focal oedema
Non surgica l option in refract ory TN
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an
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GABAB receptor agonist, depresses excitatory neurotransmission
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This table reflects the practical approach of the Authors to trigeminal neuralgia pharmacological treatment
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Baclo fen
25
Site of injection
Blindness/rando mized
R/T
Duration of effect
Shehata et al, 2013
Trigger zones
Single blind/Yes
10/2 12 weeks 0
Wu et al, 2012
Trigger zones
Double blind/Yes
15/2 5-12 weeks 2
Bohluli et al, 2011
Trigger zones
Open/No
Zúñiga et al, 2008
Trigger zones
Open/No
Türk et al, 2005
Above and below the zygomatic arch
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Study
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15/1 6 months 5
8/8
6 months
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Open/Yes
10/1 60 days 2
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R/T: Responder/Total number of patients treated with botulinum toxin
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Table 2. Trials assessing botulinum toxin injection in refractory TN
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ISSN: 1473-7175 (Print) 1744-8360 (Online) Journal homepage: http://www.tandfonline.com/loi/iern20
Pharmacological treatment of trigeminal neuralgia Giulia Di Stefano & Andrea Truini To cite this article: Giulia Di Stefano & Andrea Truini (2017): Pharmacological treatment of trigeminal neuralgia, Expert Review of Neurotherapeutics, DOI: 10.1080/14737175.2017.1370375 To link to this article: http://dx.doi.org/10.1080/14737175.2017.1370375
Accepted author version posted online: 22 Aug 2017.
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Date: 23 August 2017, At: 09:50
Publisher: Taylor & Francis Journal: Expert Review of Neurotherapeutics DOI: 10.1080/14737175.2017.1370375
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Pharmacological treatment of trigeminal neuralgia
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Department of Neurology and Psychiatry, University Sapienza, Roma
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Corresponding Author Andrea Truini,
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Sapienza University,
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Department of Neurology and Psychiatry,
Viale Università 30, 00185 Rome,
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Giulia Di Stefano, Andrea Truini
Italy
Email: [email protected]
1
Abstract Introduction: Unique among the different neuropathic pain conditions, trigeminal neuralgia
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frequently has an excellent response to some selected drugs, which, on the other hand, often entail disabling side effects. Physicians should be therefore acquainted with the management of
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Areas Covered: This article, based on a systematic literature review, describes the
pharmacological options, and indicates the future perspectives for treating trigeminal neuralgia.
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The article therefore provides current, evidence-based knowledge about the pharmacological treatment of trigeminal neuralgia, and suggests a practical approach to the various drugs, including
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starting dose, titration and side effects.
Expert Commentary: Carbamazepine and oxcarbazepine are the reference standard drugs for
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treating patients with trigeminal neuralgia. They are effective in most patients. The undesired effects however cause withdrawal from treatment or a dosage reduction to an insufficient level in
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many patients. Sodium channel blockers selective for the sodium channel 1.7 (Nav1.7) receptor, currently under development, might be an alternative, better-tolerated pharmacological option in the next future.
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these drugs and the few alternative options.
Keywords: neuropathic pain, voltage gated sodium channel blockers, facial pain, trigeminal neuralgia.
2
1. Introduction Trigeminal Neuralgia (TN) is characterized by unilateral paroxysmal pain most often described as
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stabbing or electric shock-like, restricted to the distribution of one or more divisions of the trigeminal nerve territory and triggered by innocuous stimuli [1]. Some patients also suffer from
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with that of the paroxysmal pain. TN with persistent pain between the paroxysms has been
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described with several definitions, including atypical TN and TN type 2; currently a widely agreed definition is TN with concomitant persistent facial pain [1]. TN has an annual incidence of three to
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five per 100.000. It is more common in women than men (age adjusted ratio: 1.74:1) and in people aged 50 to 69 years [2,3]. According to the new classification and diagnostic grading of TN issued
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by the International Association for the Study of Pain, TN is distinguished in classical, caused by vascular compression producing anatomical changes in the trigeminal nerve root, secondary, due
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to an identifiable underlying neurologic disease, and idiopathic, when even after MRI or other investigation, the aetiology of TN remains unclear [4]. The aim of this narrative review, based on a
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systematic search of relevant literature, is to provide current, evidence-based, knowledge about the pharmacological treatment of TN, and suggest a practical approach to the various drugs, including starting dose, titration and side effects. 2. Description of the search process
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persistent, dull, tingling pain between the paroxysms. The distribution of persistent pain coincides
We searched relevant papers within the PubMed, EMBASE and the Cochrane Database of Systematic Reviews, taking into account publications up to March 2017. All searches used the following synonyms for TN: trigeminal neuralgia, facial pain and tic doulourex. The primary search was supplemented by a secondary search using the bibliographies of the articles retrieved. Only full-length, original communications were accepted and the search was limited to English language publications. All retrieved articles were reviewed by title and abstract for potential relevance to this 3
topic; when the title and abstract did not clearly indicate the degree of relevance to the topic, the article itself was reviewed. To avoid selection bias, the review process was carried out independently by the two Authors; only studies independently approved by the two authors were taken into account. Inclusion criteria were the following: trials including patients with a diagnosis of primary or secondary TN and a minimum sample of 10 patients. For specific condition that had no
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top-level studies, such as in-hospital treatment for acute exacerbations, also small case series were included. Included patients suffered from unilateral paroxysmal pain, usually described as
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trigeminal territory. Exclusion criteria included duplicated patient series and experimental
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paroxysmal pain.
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3. Results
Although phenytoin has been the first drug to be used for TN with positive effects, no randomized
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controlled trials have been published [5]. Conversely four placebo-controlled trials, involving 147 patients, demonstrated the efficacy of carbamazepine (CBZ) [6-9] with a number needed to treat to
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obtain pain relief of 1.7-1.8 [5,10]. This efficacy is impaired by the tolerability, with a numberneeded to harm of 3.4 for minor and 24 for severe adverse events [11,12]. Three double-blind
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RCTs including a total of 130 patients compared Oxcarbazepine (OXC) to CBZ; only one of them however was published in extenso [15]. These studies showed that the two drugs had a comparable efficacy in reducing pain attacks [10, 13-15, 78]. However, OXC revealed greater tolerability and a lower potential for drug interaction. In a retrospective study involving 178 patients
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stabbing or electric shock-like, and restricted to the distribution of one or more divisions of the
with classical TN [16], CBZ and OXC were confirmed to be effective in virtually all patients. The initial number of responders was 98% with CBZ at a median dosage of 600 mg (range 200–1200 mg), and of 94% with OXC at a median dosage of 1200 mg (range 600–1800 mg). Among responders, 27% of patients treated with CBZ and 18% of patients treated with OXC, after a mean period of 8.6 and 13 months, incurred in adverse events that directly caused interruption of treatment or a dosage reduction to a level that was insufficient to control pain. The most frequent adverse effects involved the central nervous system, and included somnolence, dizziness and 4
unsteadiness. CBZ had a higher percentage of discontinuations for all kinds of side effect, except for sodium depletion, than OXC. Other drugs have been studied in controlled trials. A crossover study totaling 21 patients with TN compared lamotrigine to CBZ [17]. Patients were titrated to lamotrigine 400 mg and CBZ 1.200 mg. Efficacy of the medications was measured with the visual analogue scale (VAS) and a verbal rating
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scale (VRS). CBZ reduced pain in 90.5% (19/21) and lamotrigine in 62% (13/21) of the patients
using both VAS and VRS. The reported side effects were headache, dizziness and skin rash. A
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phenytoin was slightly more effective than placebo; 10/13 participants stated that lamotrigine was better or much better, compared with 8/14 on placebo, using a global evaluation [18,19].
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Baclofen, the agonist of the GABAB receptor, was superior to placebo in reducing the number of painful paroxysms in a randomized controlled trial including only ten participants [20]. An open trial
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in another 50 patients with refractory trigeminal neuralgia showed that 74% of patients were relieved of their attacks by baclofen, either alone or in combination with previously ineffective
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doses of CBZ or phenytoin. On long-term follow-up of one to five years 30% of the 60 patients was pain-free while receiving baclofen, 17% went into remission after 3 to 6 months, 22% became
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refractory to baclofen after 1 to 18 months, and 3% elected operation despite a good response to baclofen [20]. L-Baclofen was more effective compared to racemic baclofen (Lioresal) in a double-blind crossover trial in 15 patients with TN [21]. Single, low-quality, randomized controlled trials compared the three different non-antiepileptic
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crossover add-on study involving 14 patients showed that lamotrigine in combination with CBZ or
drugs tizanidine [22], tocainide [23] and pimozide [24] with CBZ. The duration of treatments was generally short: three weeks, two weeks and eight weeks [25]. Pimozide was more effective than CBZ in 48 patients, with a response rate of 100% for pimozide versus 56% for CBZ [24]. The reported side effects included central nervous system disturbances, hand tremors and memory impairment. The effect of tizanide in comparison with CBZ was tested in a very small sample of patients (12 participants, with six in each group). Three participants taking tizanidine discontinued, one because of unrelated disease and two because of intolerable pain. At the end of treatment, 5
one of five participants improved with tizanidine and four of six with CBZ. The difference was not statistically significant [22]. Tocainide was tested in 12 participants but significant side effects limited its use [23]. There are some reports about the efficacy of gabapentinoids, but they have never been adequately assessed in the treatment of TN. A small randomized controlled trial in 36 patients combining
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gabapentin with ropivacaine injection into trigger areas showed improved pain control and quality
of life [26]. Pregabalin was tested in an open-label study including 53 patients. Pregabalin (150-600
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observational studies, 65 patients with TN were treated with pregabalin in monotherapy (n = 36) or add-on (n = 29) for 12 weeks. After 12 weeks, pregabalin reduced the baseline pain intensity by
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55%, with 59% of responders (pain relief > 50%). Furthermore, pregabalin improved anxiety, depression, sleep, physical function and health state [28, 29]. However, according to the inclusion
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criteria based on DN4 questionnaire, also patients with an atypical facial might have been included in this study. In an open label crossover trial in 22 patients with refractory TN using lamotrigine and
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pregabalin together with CBZ, pregabalin showed potential anti-neuralgia properties comparable to lamotrigine. However, the level of patient’s tolerance seen with pregabalin exceeds that with
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lamotrigine [30].
Among anticonvulsants, small case series investigated the efficacy of topiramate and levetiracetam. Topiramate (100-400mg/day) reduced pain in 75% of patients, in a very small sample of only eight patients. The most frequently registered side effects were dizziness,
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mg/day) proved to be effective in reducing TN by over 50% in 74% of patient. [27]. In two
somnolence and weight loss. [31]. A pilot study investigated the efficacy and tolerability of levetiracetam in 10 patients with TN over a period of 10 weeks in an open-label prospective design. Patients were treated with up to 4000 mg daily and 40% reported an improvement of 5090% [32]. In an observational trial, totalling twenty-three patients with refractory TN, levetiracetam (3-4 g/day) for 16 weeks decreased by 62.4% the number of daily attacks [33]. Several studies assessed the efficacy of local anaesthetics. Two randomized controlled trials investigated the effect of local anaesthesia injected into trigger area. In the randomized, controlled 6
trial of Lemos et al, combining ropivacaine and gabapentin even those patients who only had ropivacaine showed short-term reduction in pain on the VAS without side effects [26]. The patients treated with the combination therapy had the best outcome and were able to use lower total daily doses of gabapentin. Although considerable effort was placed on allocation concealment and randomization, the study was only single blinded as patients knew whether they received an
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injection [26]. In a randomized, controlled trial in 45 patients combining the peripheral analgesic block with ropivacaine and CBZ, the association protocol resulted in a significant reduction in pain
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monotherapy [34]. Randomized-controlled studies tested the efficacy of lidocaine 8% in TN. In a
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randomized placebo-controlled crossed over trial including 25 patients with TN involving the second division, those given an 8% spray of lidocaine as opposed to saline had a statistically
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significant decrease in pain. Two sprays (0.1 ml of one spray twice) of intranasal lidocaine 8% significantly decreased VAS 15 minutes after treatment, whereas the placebo spray did not. The
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effect of treatment persisted for a mean of four hours without serious adverse reactions. The authors observed that 15 out of 25 subjects felt burning or stinging in the treated nostril and
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commented that this made the study difficult to blind [35]. This study showed two main limitations: it was restricted to patients with pain in the second trigeminal division and it only examined the
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response to triggering manoeuvres, whereas spontaneous pain was not tested. In a randomized, placebo-controlled, crossover study including 24 patients and severe intraoral pain the application on the painful areas of 8% lidocaine significantly reduced the NRS score of paroxysmal pain for a mean of three hours, without serious side effects [36]. A trial involving 47 participants compared
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intensity, number of daily pain crises and daily dose of CBZ intake, when compared with CBZ in
0.5% proparacaine hydrochloride eye drops with placebo, but it did not show any significant benefits [37]. Among topical treatment, capsaicin application has been investigated in two small case series. The treatment had only a mild effect [38, 39]. Two randomized controlled trials, totaling 39 patients with TN refractory to previous treatment, tested the effect of subcutaneous injection of sumatriptan 3 mg and the oral administration of 50 mg twice daily [40, 41]. Fifteen minutes after injection of sumatriptan, the baseline VAS decreased from 8.3 to 2.4 cm. At the end of oral treatment, the VAS was significantly decreased and this 7
beneficial reduction persisted a further week after treatment discontinuation. The main drawbacks of sumatriptan are the side effects related to a long-term use, including a triptan overuse headache. Six trials totaling 81 patients examined the effect of subcutaneous infiltration of botulinum toxin A (BTX-A) [42-47]. The responder rate was 85% and the pain relief lasted on average 105 days.
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Complications were mostly represented by transient facial weakness, reported in 38 patients that
disappeared in a few weeks. Some patients showed focal oedema at the sites of injection, lasting
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were treated with subcutaneous infiltration of BTX-A and 16 patients received placebo. Three months after the injection significant differences were observed in the average VAS score for
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patients treated with BTX and those who received placebo [49]. In a randomized, double-blind, placebo-controlled trial, eighty-four patients were randomized into the following groups: placebo (n
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= 28); BTX-A 25U (n = 27); BTX-A 75U (n = 29). The response rates of 25U group (70.4%) and 75U group (86.2%) were significantly higher than placebo group (32.1%) at week 8, and there was
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no significant difference between 25U and 75U groups [50]. In a randomized, single-blinded, placebo-control study carried out on 20 Egyptian patients with intractable TN, pain reduction from
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the baseline to week 12 was significant in BTX-A group; VAS scores at endpoint last observation carried forward relative to baseline for BTX-A group showed a decrease of 6.5 compared with a decrease of 0.3 for placebo [50]. An open study involving eighty-eight subjects with TN investigated the effects and safety of BTX-A during a follow-up period of 14-months. The therapeutic effect decreased gradually after 3 months, and the prevalence of effective treatment at
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about 1 week [48]. In a double-blind, randomized, placebo controlled study 20 patients with TN
14 months was 38.6%, with complete control of pain seen in 22 patients. Three patients showed swelling at injection sites and 10 patients showed facial asymmetry, both of which disappeared spontaneously without special treatment [52]. Finally, a new randomized controlled trial using BTXA in classical TN has begun and is still ongoing [53]. Acute exacerbation has been successfully treated with intravenous loading with phenytoin or fosphenytoin, but again these procedures have not been tested in controlled trials. There are three 8
reports, involving only five patients with acute, sustained exacerbations of TN, responding to intravenous infusion, with a pain relief lasting two days [55-56]. In only one double blind, randomized, crossover, placebo-controlled study totaling 20 patients with intractable TN, a single dose of intravenous lidocaine (5 mg/kg) was superior in reducing pain intensity compared to placebo during the first 24 hours after the infusion. Most common side effect was somnolence
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(reported in 32.5% of cases) [57]. There are two reports involving a total of 16 patients treated with intravenous infusion of magnesium and lidocaine [58, 59]. All the subjects experienced pain relief
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the infusion, but no severe side effects were reported. A single case of remission of TN with
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concomitant persistent facial pain after intravenous lidocaine infusion was reported. Patient remained asymptomatic for two weeks after discontinuation of lidocaine with return of mild pain
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[60]. A different approach during acute exacerbation is the ganglionic local opioid analgesia at the superior cervical ganglion, which was evaluated retrospectively in 74 patients with neuropathic
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facial pain. A clinically relevant pain reduction was observed in 73% of the patients. The proportion
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of responders (pain reduction 50%) was 59% after the first blockade [61]. Recently, the effect of a new Nav1.7 selective state-dependent, sodium channel blocker (BIIB074)
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was investigated in TN. Findings from electrophysiological studies have shown that BIIB074 preferentially inhibits high frequencies firing in nociceptive neurons [62]. Results from phase 1 studies have suggested that BIIB074 has good tolerability in healthy individuals and can be administered at therapeutic doses without lengthy titration. BIIB074 was tested in a double-blind, placebo-controlled, randomized withdrawal phase 2a trial, totaling 67 patients with classical TN
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after the combined intravenous infusion. Three patients experienced short and mild dizziness after
[63].
Forty-four patients completed open-label treatment, and 29 were randomly assigned to doubleblind treatment (15 to BIIB074 and 14 to placebo). During the double-blind phase, five (33%) patients assigned to BIIB074 versus nine (64%) assigned to placebo were classified as treatment failures. Although BIIB074 was well tolerated and no severe or serious adverse events were
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reported, the primary endpoint of treatment failure was not significantly lower in the BIIB074 group than in the placebo group. [63]. Significant treatment differences versus placebo in secondary endpoints during the double-blind phase, including time to treatment failure, number of paroxysms, average daily pain score, patient-
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and clinician-global impression of change were found. There are no placebo-controlled studies in patients with secondary TN, and the available studies
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misoprostol, a prostaglandin E1 analogue, or combination therapies in multiple-sclerosis related
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TN [64-77]. Carbamazepine was relatively effective in these patients but produced adverse effects
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causing reversible worsening of multiple sclerosis symptoms [65]. 4. Expert Commentary
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4.1 Reference standard treatment
Based on evidence [10, 78], the first line pharmacological treatment in TN is CBZ (400–1200
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mg/day) or OXC 900–1800 mg/day [Table 1]. The effectiveness of CBZ and OXC reflects primary mechanism of paroxysmal pain in TN, i.e. the focal demyelination of primary afferents near the
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entry of the trigeminal root into the pons. The focal demyelination produces ectopic excitation, ephaptic transmission and high-frequency discharges [79-81]. Recommended drugs, CBZ and OXC, block voltage-gated sodium channels in a frequency-dependent manner, stabilizing hyperexcitable neural membranes and inhibiting repetitive firing [10].
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are small, open-label trials based on CBZ, OXC, lamotrigine, gabapentin, pregabalin, topiramate,
Carbamazepine is a potent inducer of CYP3A4 and other oxidative enzyme system in the liver, and it may also increase glucuronyl-transferase activity. This inducing activity results in the acceleration of the metabolism of concurrently prescribed anticonvulsants, such as valproic acid, clonazepam, ethosuximide, lamotrigine, topiramate. The metabolism of many other drugs including tricyclic antidepressants, antipsychotics, steroid oral contraceptives, glucocorticoids, oral anticoagulants, cyclosporin, theophylline, chemotherapeutic agents and cardiovascular drugs can also be induced, leading to a number of clinically relevant drug interactions. 10
OXC, a keto-analogue of CBZ rapidly converted into its pharmacologically active 10-monohydroxy metabolite, should be preferred for the better tolerability and the decreased potential for drugs interactions [16, 82, 83]. However, given the chemical similarity of these drugs, allergic crossreactions can occur. Since spontaneous recovery in TN is rare and the condition is cyclical with periods of partial or complete remission and recurrence, it is reasonable to encourage patients to
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adjust the dosage of the drug to the frequency of attacks [10]. Before starting therapy, an accurate medical history, in order to exclude cardiac conduction abnormalities, and other possible relevant
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ensure normal renal and liver function and normal sodium level. Laboratory testing should be also
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repeated if higher doses are used and significant side-effects reported. ECG is needed when a cardiac conduction abnormality is suspected on the basis of medical history, being CBZ and OXC
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contraindicated in patients with atrioventricular block. High dosages are often necessary for sufficient pain relief, so many patients suffer from disabling side effects. Failure of the treatment
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with CBZ or OXC, most of the times, is not due to the inefficacy of the drug, but rather to undesired effects to a level that causes interruption of treatment or a dosage reduction to an insufficient level
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[16]. Common initial side effects include drowsiness, nausea, dizziness, diplopia, ataxia, elevation of transaminases and hyponatremia. Possible serious but uncommon side effects are allergic rash,
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myelosuppression, hepatotoxicity, lymphadenopathy, systemic lupus erythematosus, StevensJohnson syndrome and aplastic anaemia [84]. Females reported significantly more side effects than males, likely due to pharmacokinetic differences [83]. Worsening of pain with time and development of late resistance only occurred in a very small minority of patients [16]. In case of
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medical conditions is required [3]. During treatment laboratory testing is usually performed to
treatment failure, it may be reasonable to try both CBZ and OXC sequentially [85]. When sodium channel blockers cannot reach full dosage because of side effects, an add-on treatment combining CBZ or OXC with lamotrigine (400 mg/day) or baclofen (40-80 mg/day) might be taken into account as a reasonable next step. However, the efficacy of combination therapy in patients with TN was tested only in a few patients [18], and no high-quality studies directly compared polytherapy with monotherapy. Lamotrigine acts at voltage-sensitive sodium channels, stabilizes neural membranes and inhibits the release of excitatory neurotransmitters. The initial dose of 25 mg/day is slowly 11
increased to a target dose of 200-400 mg/day divided between two doses. Potential side effects include dizziness, nausea, blurred vision and ataxia. Approximately 7-10% of patients will report a skin rash during the first 48 weeks of therapy [86]. The dose of lamotrigine must be increased slowly in order to avoid rashes, and it is therefore not appropriate for acute management of trigeminal neuralgia. It is most effective when used for long-term control of moderate pain, such as
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in people with multiple sclerosis [87]. Baclofen is a GABAB receptor agonist and thus depresses excitatory neurotransmission. Potential side effects include lassitude, drowsiness, dizziness and
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Pimozide (4-12 mg day) is seldom used in clinical practice and poses concern about possible long-
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4.2 Pharmacological treatment for refractory TN
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term side effects such as extrapyramidal symptoms [84].
According to some clinical trials botulinum toxin injections might offers another non-surgical
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treatment option in the treatment of refractory TN. There is increasing evidence that this treatment might be efficacious in classical TN and may be offered before surgery or to those unwilling to
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undergo surgery [48]. Botulinum toxin type A (BTX-A) is a neurotoxin derived from Clostridium botulinum and its analgesic effect seems mediated by the local release of anti-nociceptive
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neuropeptides (substance P, glutamate and calcitonin-gene related peptide) inhibiting central and possibly peripheral sensitization [88]. Although several studies have assessed the efficacy of botulinum toxin in patients with TN [Table 2], currently no high-quality randomised controlled trials offers a robust support to this treatment.
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gastrointestinal discomfort. Abrupt discontinuation may cause seizures and hallucinations.
4.3 In-hospital treatment for acute exacerbations In patients who develop severe exacerbations of unremitting pain, in-hospital treatment may be necessary for titration of drugs, rehydration, management of hyponatremia and, in selected case, intravenous infusion of fosphenytoin [54-56]. Admittedly, no strong evidence is currently available to support or refute the e cacy of i.v. fosphenytoin or other i.v. medications for the acute treatment of TN. 12
4.4 Treatment of concomitant persistent facial pain While patients with TN manifesting with purely paroxysmal pain find adequate relief from CBZ and OXC, patients suffering from persistent pain between the paroxysms are more resistant to drugs. CBZ and OXC produce a frequency-dependent block of voltage-gated sodium channels and, thereby, reducing the frequency of action potential firing, effectively reduce paroxysmal pain;
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however, they have a far less positive effect on concomitant persistent pain. Gabapentinoids might be more effective in persistent than paroxysmal pain and are often tried as an add-on to
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persistent pain. No trial, however, has directly assessed the efficacy of this combination in patients with persistent pain and there is no evidence to support or refute its use in clinical practice.
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4.5 Treatment of secondary TN
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Pharmacological treatment of MS-related TN is challenging owing to the poor tolerability of the drugs and the lack of evidence-based information in the literature. There are no placebo-controlled
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studies in such patients, and the studies that do exist are small, open-label trials based on carbamazepine (CBZ), oxcarabazepine (OXC), lamotrigine, gabapentin, pregabalin, topiramate,
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misoprostol or combination therapies [10]. According to international guidelines [10], there is insufficient evidence to support or refute the effectiveness of any medication in treating pain in MSrelated TN. However, it is generally agreed that the first line therapy is pharmacological and based, as it is for classical TN, on the use of sodium-channel blockers, i.e. CBZ and OXC [81, 89]. Central nervous system demyelination however renders some patients with MS more sensitive to cognitive
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oxcarbazepine or carbamazepine in patients with the atypical form of TN with concomitant
and motor side effects, which might lead to an earlier decision for surgery. 5. Five-year view The quality of evidence for drugs useful in patients with TN is very low. Only a few randomized controlled trials have been published, usually enrolling small samples of patients. The small sample of enrolled patients also hampers the generalizability of trial results. Another problem concerning the current literature on TN treatment is the possible difficulty of an accurate diagnosis. 13
TN diagnosis relies on clinical history and examination; the inclusion of patients with a correct TN diagnosis is therefore a key point in clinical trials. Although the first line drugs, CBZ and OXC, are effective in the large majority of patients with TN, the side effects cause withdrawal from treatment in an important percentage of patients. There is consensus that OXC may have fewer side effects than CBZ, although there is a lack of RCT-based
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data to confirm this statement. These considerations therefore suggest the opportunity to develop better-tolerated drugs, such as selective channel-blockers for specific isoforms. Recently a new
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firing in nociceptive peripheral neurons, was tested in a phase 2a trial [63]. Although this study failed the primary endpoint, it provides a basis for continued investigation of BIIB074 and better
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tolerated drugs in patients in future clinical trials.
Some patients with TN also suffer from concomitant persistent facial pain. The mechanisms
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underlying this kind of pain, as opposed to paroxysmal pain, are not fully understood and the efficacy of the standard pharmacological treatment, based on sodium channel blockade, usually
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drops. Gabapentinoids, whose efficacy has already been proved in the treatment of neuropathic continuous pain due to several aetiologies, have never been systematically tested in TN patients
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with concomitant persistent facial pain. Future clinical trials addressing this issue may pave the way to improved therapeutic approaches. 6. Key issues
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Nav1.7 selective sodium channel blocker (BIIB074), that preferentially inhibits high frequencies of
•
CBZ and OXC, sodium channel blockers, are the first line pharmacological treatment in TN.
•
The undesired effects related to CBZ and OXC cause withdrawal from treatment in in an
important percentage of patients, thus suggesting the opportunity to develop a better tolerated drug. •
Add-on treatment with lamotrigine or baclofen should be taken into account when the full dosage of sodium channel blockers cannot be reached because of side effects.
•
Botulinum toxin injections offer a non-surgical treatment option in refractory TN. 14
Funding This paper was not funded. Declaration of interest A Truini has received grants from Mundipharma, Grunenthal, Pfier, Sigma-Tau, and Angelini. The authors have no other relevant affiliations or financial involvement with any organization or entity
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with a financial interest in or financial conflict with the subject matter or materials discussed in the
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Papers of special note have been highlighted as:
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** of considerable interest
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Carb amaz epine
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Main mechanism of action
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Drug
Voltage-gated sodium channel blocker
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Commonly used drugs for trigeminal neuralgia
Starti ng dose
Titration
Max dose
Main adverse events
Recom menda tion
200 mg
Increase 200 mg every 3 days
1200 mg (400 mg (t.i.d.)
Drowsiness, ataxia, dizziness, skin reactions, nausea, vomiting, blood dyscrasia
First line
Oxca rbaze pine
Voltage-gated sodium channel blocker
300 mg
Increase 300 mg every 3 days
1800 mg (600 mg t.i.d.)
Drowsiness, ataxia, dizziness, hyponatremia
First line
Lamo trigin e
Acting at voltage-sensitive sodium channels, stabilizes neural membranes and inhibits the release of excitatory neurotransmitters
25 mg
Increase 25 mg every 7 days
400 mg (200 mg b.i.d.)
Dizziness, nausea, blurred vision, ataxia, skin reactions
Add on therap y
24
15 mg (5 mg t.i.d)
Increase 5 mg t.i.d. every 3 days
60 mg (20 mg t.i.d)
Lassitude, drowsiness, dizziness and gastrointestinal discomfort
Add on therap y
Gaba penti n
Binding to alpha2-delta subunits of voltage-gated calcium channel
300 mg
Increase 300 mg every 3 days
3000 mg (1000 mg t.i.d.)
Drowsiness, unsteadiness, weight gain, peripheral oedema
Add on therap y
Preg abali n
Binding to alpha2-delta subunits of voltage-gated calcium channel
75 mg
Increase 75 mg every 3 days
600 mg (300 mg b.i.d. or 200 mg t.i.d.)
Drowsiness, unsteadiness, weight gain, peripheral oedema
Add on therap y
Botuli num neuro toxin type A
TRPV1 receptor block reducing local release of anti-nociceptive neuropeptides such as substance P, and CGRP
-
Mean dose: 3.22 units/cm2 subcutaneo usly
-
Transient facial weakness, focal oedema
Non surgica l option in refract ory TN
M
an
us
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ip t
GABAB receptor agonist, depresses excitatory neurotransmission
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ed
This table reflects the practical approach of the Authors to trigeminal neuralgia pharmacological treatment
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Baclo fen
25
Site of injection
Blindness/rando mized
R/T
Duration of effect
Shehata et al, 2013
Trigger zones
Single blind/Yes
10/2 12 weeks 0
Wu et al, 2012
Trigger zones
Double blind/Yes
15/2 5-12 weeks 2
Bohluli et al, 2011
Trigger zones
Open/No
Zúñiga et al, 2008
Trigger zones
Open/No
Türk et al, 2005
Above and below the zygomatic arch
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ip t
Study
an
us
15/1 6 months 5
8/8
6 months
ed
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Open/Yes
10/1 60 days 2
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R/T: Responder/Total number of patients treated with botulinum toxin
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Table 2. Trials assessing botulinum toxin injection in refractory TN
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