trigeminal neuralgia thesis

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Trigeminal neuralgia thesis

A systematic review of the management of trigeminal neuralgia in patients with multiple sclerosis. World Neurosurg ; : — Kerr FW. Pathology of trigeminal neuralgia: light and electron microscopic observations. J Neurosurg ; 26 : — Jannetta PJ. Gross mesoscopic description of the human trigeminal nerve and ganglion. Arterial compression of the trigeminal nerve at the pons in patients with trigeminal neuralgia.

Zakrzewska JM, Akram H. Neurosurgical interventions for the treatment of classical trigeminal neuralgia. Trigeminal neuralgia: a comparison of the results of percutaneous rhizotomy and microvascular decompression. Can J Neurol Sci ; 8 : — Structural magnetic resonance imaging can identify trigeminal system abnormalities in classical trigeminal neuralgia.

Front Neuroanat ; 10 : Magnetic resonance imaging contribution for diagnosing symptomatic neurovascular contact in classical trigeminal neuralgia: a blinded case-control study and meta-analysis. Pathological findings associated with trigeminal neuralgia caused by vascular compression. Neurosurgery ; 35 : —, discussion Central demyelination of the Vth nerve root in trigeminal neuralgia associated with vascular compression. Brain Pathol ; 8 : 1—11, discussion 11— Mechanism of trigeminal neuralgia: an ultrastructural analysis of trigeminal root specimens obtained during microvascular decompression surgery.

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Clin J Pain ; 18 : 4— Rappaport ZH, Devor M. Trigeminal neuralgia: the role of self-sustaining discharge in the trigeminal ganglion. Pain ; 56 : — Changes in the expression of voltage-gated sodium channels Nav1. Neuroreport ; 27 : — The expression of voltage-gated sodium channels in trigeminal nerve following chronic constriction injury in rats. Int J Neurosci ; : — Abnormal expression of voltage-gated sodium channels Nav1.

Neuroscience ; : — No association of polymorphisms in Nav1. Pain Med ; 20 : — A gain-of-function mutation in Nav1. Mol Med ; 22 : — KCNQ channels in nociceptive cold-sensing trigeminal ganglion neurons as therapeutic targets for treating orofacial cold hyperalgesia. Mol Pain ; 11 : Role of KCNQ2 channels in orofacial cold sensitivity: KCNQ2 upregulation in trigeminal ganglion neurons after infraorbital nerve chronic constrictive injury.

Neurosci Lett ; : 84— Activation of expressed KCNQ potassium currents and native neuronal M-type potassium currents by the anti-convulsant drug retigabine. J Neurosci ; 21 : — Potassium channels. Mechanisms of action of antiepileptic drugs. West Islip: Professional Communications, Inc, , pp. Altered brain structure and function associated with sensory and affective components of classic trigeminal neuralgia.

Spatial-temporal signature of resting-state BOLD signals in classic trigeminal neuralgia. J Pain Res ; 10 : — Gray matter volume reduction reflects chronic pain in trigeminal neuralgia. Neuroimage ; 74 : — Functional brain imaging of trigeminal neuralgia. Eur J Pain ; 15 : — Frequency-specific alterations in cortical rhythms and functional connectivity in trigeminal neuralgia. Brain Imaging Behav ; 13 : — Biswal BB. Resting state fMRI: a personal history. Neuroimage ; 62 : — Logothetis NK.

What we can do and what we cannot do with fMRI. Nature ; : — J Neurosci Methods ; : — Jiang L, Zuo XN. Regional homogeneity: a multimodal, multiscale neuroimaging marker of the human connectome. Neuroscientist ; 22 : — Application of amplitude of lowfrequency fluctuation to altered spontaneous neuronal activity in classical trigeminal neuralgia patients: a restingstate functional MRI study.

Mol Med Rep ; 20 : — Altered spontaneous brain activity in patients with classical trigeminal neuralgia using regional homogeneity: a resting-state functional MRI study. Pain Pract ; 19 : — Altered brain network centrality in patients with trigeminal neuralgia: a resting-state fMRI study. Acta Radiol ; 61 : 67— Cheshire WP. Trigeminal neuralgia: for one nerve a multitude of treatments.

Expert Rev Neurother ; 7 : — Trigeminal neuralgia — diagnosis and treatment. European Academy of Neurology guideline on trigeminal neuralgia. Eur J Neurol ; 26 : — Food and Drug Administration. Public meeting on neuropathic pain associated with peripheral neuropathy patient-focused drug development, www. Evidence-based interventional pain medicine according to clinical diagnoses. Cluster headache. Pain Pract ; 9 : — Maan JS, Saadabadi A. Al-Quliti KW. Update on neuropathic pain treatment for trigeminal neuralgia.

The pharmacological and surgical options. Neurosciences Riyadh ; 20 : — Mol Pharmacol ; 51 : — Kuo CC. Mol Pharmacol ; 54 : — Anesthesiology ; : — J Biol Chem ; : 20— J Biol Chem ; : — J Gen Physiol ; : 95— Eslicarbazepine acetate for the treatment of focal epilepsy: an update on its proposed mechanisms of action.

Pharmacol Res Perspect ; 3 : e Eslicarbazepine and the enhancement of slow inactivation of voltage-gated sodium channels: a comparison with carbamazepine, oxcarbazepine and lacosamide. Neuropharmacology ; 89 : — Carbamazepine and topiramate modulation of transient and persistent sodium currents studied in HEK cells expressing the Na v 1. Epilepsia ; 48 : — Mutation of sodium channel SCN3A in a patient with cryptogenic pediatric partial epilepsy.

Neurosci Lett ; : 65— Properties of human brain sodium channel alpha-subunits expressed in HEK cells and their modulation by carbamazepine, phenytoin and lamotrigine. Br J Pharmacol ; : — Compact myelin dictates the differential targeting of two sodium channel isoforms in the same axon. Neuron ; 30 : 91— Lorincz A, Nusser Z. Cell-type-dependent molecular composition of the axon initial segment. J Neurosci ; 28 : — A comprehensive approach to identifying repurposed drugs to treat SCN8A epilepsy.

Epilepsia ; 59 : — Jo S, Bean BP. Sidedness of carbamazepine accessibility to voltage-gated sodium channels. Mol Pharmacol ; 85 : — Inhibition of Navbeta4 peptide-mediated resurgent sodium currents in Nav1. Mol Pharmacol ; 80 : — SCN9A epileptic encephalopathy mutations display a gain-of-function phenotype and distinct sensitivity to oxcarbazepine. Neurosci Bull ; 36 : 11— Oxcarbazepine: mechanisms of action. Epilepsia ; 35 : S5—S9.

Schmidt D, Elger CE. What is the evidence that oxcarbazepine and carbamazepine are distinctly different antiepileptic drugs? Epilepsy Behav ; 5 : — Abou-Khalil BW. Oxcarbazepine and carbamazepine: expected and unexpected differences and similarities. Epilepsy Curr ; 7 : 74— Pharmacol Ther ; : 42— Electrophysiological properties of mutant Nav1. J Neurosci ; 24 : — Gain-of-function mutation in Nav1. Brain ; : — Gain of function Na V 1. Ann Neurol ; 71 : 26— A novel Nav1.

Ann Neurol ; 65 : — Phenytoin and carbamazepine: differential inhibition of sodium currents in small cells from adult rat dorsal root ganglia. Neurosci Lett ; : 95— Heterologous expression and functional analysis of rat Nav1. Neuropharmacology ; 46 : — Eur J Pharmacol ; : — A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Anesthesiology ; 94 : — Carbamazepine interacts with a slow inactivation state of NaV1.

Neurosci Lett ; : — Korean J Physiol Pharmacol ; 22 : — Modulated anticonvulsant block of sodium channels in nerve and muscle. Eur J Pharmacol ; 88 : 1—9. Efficacy loss of the anticonvulsant carbamazepine in mice lacking sodium channel beta subunits via paradoxical effects on persistent sodium currents. Deseure K, Hans GH. Differential drug effects on spontaneous and evoked pain behavior in a model of trigeminal neuropathic pain.

B vitamins relieve neuropathic pain behaviors induced by infraorbital nerve constriction in rats. Life Sci ; 91 : — Pharmacological studies on a rat model of trigeminal neuropathic pain: baclofen, but not carbamazepine, morphine or tricyclic antidepressants, attenuates the allodynia-like behaviour.

Pain ; 79 : — Compression of the trigeminal ganglion produces prolonged nociceptive behavior in rats. Eur J Pain ; 13 : — A novel trigeminal neuropathic pain model: compression of the trigeminal nerve root produces prolonged nociception in rats. Prog Neuropsychopharmacol Biol Psychiatry ; 38 : — Pharmacokinetics, brain distribution and plasma protein binding of carbamazepine and nine derivatives: new set of data for predictive in silico ADME models.

Epilepsy Res ; : 37— Antiepileptic drugs in critically ill patients. Crit Care ; 22 : Long-term safety and tolerability of oxcarbazepine in painful diabetic neuropathy. Acta Neurol Scand ; : — Eur J Neurol ; 15 : — Controlled sequential trials of carbamazepine in trigeminal neuralgia. Arch Neurol ; 15 : — Clinical trial of carbazepine tegretol in trigeminal neuralgia.

J Neurol Neurosurg Psychiatry ; 29 : — Carbamazepine for chronic neuropathic pain and fibromyalgia in adults. Di Stefano G, Truini A. Pharmacological treatment of trigeminal neuralgia. Expert Rev Neurother ; 17 : — Beydoun A. Safety and efficacy of oxcarbazepine: results of randomized, double-blind trials. Pharmacotherapy ; 20 : S—S. Natural history and outcome of outpatients with classical trigeminal neuralgia treated with carbamazepine or oxcarbazepine in a tertiary centre for neuropathic pain.

J Headache Pain ; 15 : Carbamazepine for acute and chronic pain in adults. Adverse effects of anti-epileptics in trigeminal neuralgiform pain. Bialer M. Why are antiepileptic drugs used for nonepileptic conditions? Epilepsia ; 53 : 26— Sills GJ. The mechanisms of action of gabapentin and pregabalin. Curr Opin Pharmacol ; 6 : — Patel R, Dickenson AH.

Mechanisms of the gabapentinoids and alpha 2 delta-1 calcium channel subunit in neuropathic pain. Pharmacol Res Perspect ; 4 : e Identification of the alpha2-delta-1 subunit of voltage-dependent calcium channels as a molecular target for pain mediating the analgesic actions of pregabalin. Pharmacology and mechanism of action of pregabalin: the calcium channel alpha2-delta alpha2-delta subunit as a target for antiepileptic drug discovery. Epilepsy Res ; 73 : — The increased trafficking of the calcium channel subunit alpha2delta-1 to presynaptic terminals in neuropathic pain is inhibited by the alpha2delta ligand pregabalin.

J Neurosci ; 29 : — Gabapentin suppresses ectopic nerve discharges and reverses allodynia in neuropathic rats. J Pharmacol Exp Ther ; : — Gabapentin selectively reduces persistent sodium current in injured type-A dorsal root ganglion neurons. Pain ; : 48— The anti-allodynic gabapentinoids: myths, paradoxes, and acute effects.

Neuroscientist ; 23 : 40— Antidepressants and gabapentinoids in neuropathic pain: mechanistic insights. Calcium channel alpha2delta1 proteins mediate trigeminal neuropathic pain states associated with aberrant excitatory synaptogenesis. Rogawski MA, Loscher W. The neurobiology of antiepileptic drugs. Nat Rev Neurosci ; 5 : — Bergouignan M. Rev Neurol Paris ; 98 : — Phenytoin and carbamazepine in trigeminal neuralgia: marketing-based versus evidence-based treatment.

A systematic review of rescue analgesic strategies in acute exacerbations of primary trigeminal neuralgia. Br J Anaesth ; : e—e Voltage-gated sodium channels as therapeutic targets in epilepsy and other neurological disorders. Lancet Neurol ; 9 : — Molecular model of anticonvulsant drug binding to the voltage-gated sodium channel inner pore. Mol Pharmacol ; 78 : — Mechanism of sodium channel block by local anesthetics, antiarrhythmics, and anticonvulsants.

J Gen Physiol ; : — Cell Physiol Biochem ; 44 : — Neocortical potassium currents are enhanced by the antiepileptic drug lamotrigine. Epilepsia ; 43 : — Clinically significant pharmacokinetic drug interactions with carbamazepine. An update. Clin Pharmacokinet ; 31 : — Role of inhibitory mechanisms in trigeminal neuralgia. Neurology ; 31 : — Effect of baclofen enantiomorphs on the spinal trigeminal nucleus and steric similarities of carbamazepine. Pharmacology ; 27 : 85— Baclofen in the treatment of trigeminal neuralgia: double-blind study and long-term follow-up.

Ann Neurol ; 15 : — Baclofen in trigeminal neuralgia: its effect on the spinal trigeminal nucleus: a pilot study. Arch Neurol ; 37 : — Efficacy of baclofen in trigeminal neuralgia and some other painful conditions.

A clinical trial. Eur Neurol ; 23 : 51— Treatment of trigeminal neuralgia: use of baclofen in combination with carbamazepine. Clin Pharm ; 4 : 93— Baclofen in trigeminal neuralgia — a clinical trial. Indian J Dent Res ; 1 : — A clinical study on comparative evaluation of the effectiveness of carbamazepine and combination of carbamazepine with baclofen or capsaicin in the management of trigeminal neuralgia.

Niger J Surg ; 24 : 95— Efficacy and safety of oral baclofen in the management of spasticity: a rationale for intrathecal baclofen. J Rehabil Med ; 49 : — Ghanavatian S, Derian A. Treasure Island: StatPearls, Botulinum toxin A might be an alternative or adjunct therapy for the treatment of trigeminal and postherpetic neuralgia. J Evid Based Dent Pract ; 17 : — Botulinum toxin-A for the treatment of neuralgia: a systematic review and meta-analysis. J Pain Res ; 11 : — Botulinum toxin type A as an alternative way to treat trigeminal neuralgia: a systematic review.

Neurol Neurochir Pol ; 53 : — Botulinum toxin as a pain killer: players and actions in antinociception. Toxins Basel ; 7 : — Regulation of calcitonin gene-related peptide secretion from trigeminal nerve cells by botulinum toxin type A: implications for migraine therapy. Headache ; 44 : 35—42, discussion 42— Activation of TRPV1 mediates calcitonin gene-related peptide release, which excites trigeminal sensory neurons and is attenuated by a retargeted botulinum toxin with anti-nociceptive potential.

Neurobiol Dis ; 48 : — Behavioral and immunohistochemical evidence for central antinociceptive activity of botulinum toxin A. Central antinociceptive activity of peripherally applied botulinum toxin type A in lab rat model of trigeminal neuralgia.

Springerplus ; 5 : Practice parameter: the diagnostic evaluation and treatment of trigeminal neuralgia an evidence-based review : report of the Quality Standards Subcommittee of the American Academy of Neurology and the European Federation of Neurological Societies. Neurology ; 71 : — Fully endoscopic microvascular decompression for trigeminal neuralgia: technique review and early outcomes. Neurosurg Focus ; 37 : E Percutaneous treatments for trigeminal neuralgia.

Neurosurg Clin N Am ; 25 : — Sade B, Lee JH. Microvascular decompression for trigeminal neuralgia. Rev Neurol ; 61 : — Assessment of efficacy and safety of eslicarbazepine acetate for the treatment of trigeminal neuralgia. Eur J Pain ; 22 : — Efficacy and safety of eslicarbazepine acetate as add-on treatment in patients with focal-onset seizures: integrated analysis of pooled data from double-blind phase III clinical studies.

Epilepsia ; 54 : 98— Epilepsy Res ; : — Owen RT. Eslicarbazepine acetate: a novel agent for the adjunctive treatment of epilepsy. Drugs Today ; 46 : 23— Massot A, Gimenez-Arnau A. Cutaneous adverse drug reaction type erythema multiforme major induced by eslicarbazepine. J Pharmacol Pharmacother ; 5 : — Seizure ; 47 : 81— The aims of this paper are to describe the implementation and practical organization of this cross-speciality management program with particular emphasis on the collaboration between the specialties.

Furthermore, we aim to report the flow of patients during the first 2 years after implementation of this practice. It is the overall aim to create scientific awareness of TN management and to inspire discussions about how TN ideally should be handled in clinical practice.

It was established in and has since then received and treated headache and TN patients from all over Denmark. This led to meetings with consultants from the Departments of Neuroradiology and Neurosurgery, to discuss how work-up, treatment and research could be optimized. Patients were referred to DHC directly from general practitioners, private neurologists or hospital departments. Patients referred directly to the Department of Neurosurgery were re-directed to DHC for MRI and pre-surgical evaluation of diagnosis and medical treatment.

The accelerated work-up and treatment program is outlined in Fig. Algorithm of the accelerated work-up and treatment program. The three specialties involved in the work-up, diagnosis and treatment collaborate closely to secure a seamless patient path. Due to lack of resources the general waiting time for headache patients at DHC is up to 2 years. We therefore find it necessary to prioritize patients with the most severe or potential serious disorders such as TN, cluster headache and idiopathic intracranial hypertension.

The aim was to see TN patients within 2—6 weeks after referral. As to patients re-directed from the Department of Neurosurgery the aim was to book their first out-patient visit within 2—4 weeks. At the first out-patient visit the previous diagnosis and treatment were re-evaluated. Categorical and quantitative variables were systematically collected in a semi-structured interview, designed for this TN management program.

The interviewing clinician paid special attention to onset, periodicity, localization, character, intensity and frequency of pain and accompanying autonomic symptoms, to ensure correct diagnose. The patients were systematically questioned about previous treatments related to TN including; efficacy, duration, dosage and side effects of medical treatment and previous neurosurgical intervention.

The clinical examination included full routine clinical and neurological examination with special emphasis on trigeminal sensory function. A cotton swap and pin was used to examine touch and pinprick respectively, in all three branches of the trigeminal nerve. Examination of the intraoral sensory function of the mucosa of the cheeks and on either side of the tongue was tested with a cotton swap.

Evaluation of the corneal reflex was also done systematically with a cotton swap. The majority of patients had already been thoroughly examined by a dentist to exclude odontogenic causes of pain. If not, patients were referred to their own dentist if this was considered relevant.

At the first out-patient visit, thorough oral and written information about the disease, its causes and potential medical and neurosurgical treatments were given. The written information was developed in collaboration between the involved neurologists and neurosurgeons. After the first visit patients were referred to a 3. The neuroradiologist described the MRI blinded to pain side. The aim was to perform the MRI within 4 weeks after the first out-patient visit.

Medical treatment was adjusted at fixed out-patient visits at 3 and 9 months after the first visit and thereafter according to need. Phone consultations with trained headache nurses at DHC could also be booked and the nurses could book additional consultations with the doctors, if needed.

Patients were followed for at least 2 years in order to optimize medical treatment and the need for referral to neurosurgical treatment was continuously evaluated. At each follow-up visit at DHC the treating neurologist performed a semi-structured interview, recording whether the patient was in remission, type and dose of medical treatment and its effects and side effects. Patients were treated according to the international guidelines developed by the American Academy of Neurology and the European Federation of Neurological Societies [ 13 ].

First choice medical treatment was carbamazepine titrated to a dose sufficient to relieve pain or the maximum tolerated dose. Second choice was oxcarbazepine titrated in the same manner. If there was a response to carbamazepine or oxcarbazepine but unacceptable side effects at high doses, we used add-on treatments where first choice was gabapentin, then pregabalin and lamotrigine in sufficient and tolerable dosages. Only one combination treatment was tried and if the side effects to even low doses of carbamazepine or oxcarbazepine were unacceptable, we used gabapentin, pregabalin or lamotrigine, as monotherapy or in combination.

After pain freedom or insignificant pain for at least 1 month we encouraged patients to taper medication by one or half a tablet every seven to 14 days. In case of severe pain exacerbation that could not be controlled with oral treatments patients were admitted to in-patient treatment to optimize medical treatment.

In severe cases patients were treated with intravenous loading of fosphenytoin. We defined failed medical treatment as lack of efficacy or intolerable side effects to carbamazepine, oxcarbazepine and to a combination of the best of these drugs and gabapentin, pregabalin or lamotrigine. In such case neurosurgical treatment was suggested to the patient. Oral and written information about the efficacy and potential complications for each type of surgical intervention was given by the treating neurologist.

Preferably, a close relative or a friend should accompany the patient during oral information. This was weighed against the expected chance of a successful outcome of surgery and the potential surgical complications. Indication for surgery and its efficacy and potential complications were also discussed with the patient by the neurosurgeon, who was responsible for the final decision about surgery.

Microvascular decompression was first choice surgical treatment when a neurovascular contact was demonstrated on the MRI and there were no contraindications to open neurosurgery. Second choice was percutaneous balloon compression. If neither microvascular decompression nor balloon compression did have effect percutaneous glycerol blockade was offered as third choice. Patients that were treated with microvascular decompression were routinely seen in the outpatient clinic at the Department of Neurosurgery 3 months after surgery.

All neurosurgical treated patients were routinely seen in the outpatient clinic at DHC at standardized visits 3, 6, 12 and 24 months postoperatively to evaluate efficacy, complications, patient satisfaction and the need for medical treatment after surgery. To evaluate the feasibility of the implemented management program and the patient flow the first 2 years we describe the referral pattern of TN patients from May to April We evaluated the waiting time of referral and work-up and whether and when the patient was referred to neurosurgery within this period.

Patients who had been treated at DHC before May were excluded as were patients with communication barriers and patients who for some reason did not enter the accelerated program. Continuous data are summarized by descriptive statistics. SAS 9. Thus, patients were diagnosed with TN in the inclusion period. Hereof patients entered the accelerated treatment program. Flowchart of included patients. Inclusion period lasted from May to April The median waiting time for the first out-patient visit was 42 days, range 6 to days.

For subsequent 3. Data from 21 patients were not included in the analysis as 13 patients had their protocol MRI done before their first out-patient visit and 8 patients did not have MRI performed according to the special protocol. Twenty-five of the TN patients, who entered the program, were initially re-directed to DHC from the department of neurosurgery. The three patients that were not operated continued medical treatment and follow-up at DHC.

Eighty-four patients were not referred to neurosurgery but continued medical treatment at DHC. The remaining 6 patients had tolerable pain and preferred to be without medicine. Data was missing in three patients. The median time of the third medical follow up was days after the first outpatient visit.

None were treated with intravenous fosphenytoin. Scientific data were collected on all the included patients. This data collection has made it possible to describe demographics of the included patients in this paper as well as the clinical characteristics and neuroanatomical abnormalities of our patient population, which so-far has resulted in five publications [ 11 , 12 , 14 — 16 ]. The most important experiences from the implementation of the described cross-speciality TN management program were that it proved to be feasible to standardize the referral pathway and work-up, that the program ensured acceptable waiting times, and that early high-quality MRI ensured correct diagnosis and a standardized basis before decision-making on impending surgery.

Moreover, the referral of the subgroup of patients in need for surgery was not unacceptably prolonged and the management program ensured continuous evaluation of pharmacological and surgical management, and provides the basis for scientific research. The described program has also facilitated centralization of expertise in TN and a close collaboration between the involved neurological, neurosurgical and neuroradiological departments ensures a higher volume of TN patients per clinician.

The importance of this is supported by Kalkanis et al. Because TN is one of the most painful diseases known to mankind a short waiting time for out-patient work-up and treatment is important. Early diagnosis will save some TN patients from unnecessary dental treatments [ 16 ] and years of suboptimal medical treatment.

Median waiting time for the first out-patient visit was 42 and 37 days for subsequent MRI, which we consider acceptable in a public health care system. It is our clinical experience that the waiting time for first out-patient visit has been reduced significantly since implementation. Likewise it is our clinical experience that the waiting time has been lower and the quality of the MRI description higher after implementation of the program. The specific TN protocol for the 3.

Prior to the implementation of the program we did not register waiting time or patient satisfaction specifically for TN patients, so we cannot provide scientific documentation for improvement of these parameters after implementation of the program.

However, with the described structured and accelerated manner of referral we demonstrate a relatively short and acceptable waiting time for diagnosis and imaging. The median time from the first out-patient visit at DHC to referral to neurosurgery was approximately 2 months for all patients but only 20 days for patients who were initially referred to neurosurgery and then re-directed to DHC for pre-surgical evaluation.

This delay must be considered acceptable given that the patients on average had suffered from TN for 7 years and considering that even among those initially referred for surgery and then re-directed to DHC for pre-surgical evaluation, half could be sufficiently controlled be medical management. Thus, the accelerated work-up and treatment program ensures that patients with medically intractable pain are quickly referred to neurosurgery.

In addition, for the patients who were initially referred to neurosurgery, who could be controlled on medical treatment, the re-direction to DHC reduced their waiting time for optimization of medical treatment and ensured that these patients did not undergo neurosurgery with its potential complications. With the limited scientific evidence regarding efficacy of medical treatment [ 18 — 20 ], there is no single answer as to how many medications should be tried out before a TN patient is deemed medically refractory and surgery should be considered.

Moreover, there is a lack of well-designed neurosurgical studies using independent evaluators of the efficacy and complications of microvascular decompression [ 21 , 22 ], which makes the decision process even more challenging. The international guidelines [ 13 ] on TN treatment recommend carbamazepine and oxcarbazepine as first line treatment based on clinical studies [ 5 , 6 , 23 , 24 ].

Other drugs used to treat TN have not been investigated to the same extent but some smaller studies showed promising results using pregabalin [ 25 ], lamotrigine [ 26 ], baclofen [ 27 ] and gabapentin [ 28 ]. Based on our clinical experience we agree with the international treatment guidelines although we find that referral for neurosurgery after failed monotherapy may be too hasty and we in general try out a combination treatment before referral to surgery.

Unfortunately, the scientific support for combination treatment is sparse and there are no published studies directly comparing monotherapy with polytherapy [ 29 ]. We suggest that follow up on medical treatment should remain in the hands of experts until the condition is stable and the patient is familiar with the program of titrating up and tapering of medication according to the level of pain and side effects.

We suggest that 2 years of follow up is appropriate, but this depends on the resources of the clinic and the health care system. The described structured management program has made it possible to prospectively collect scientific data, which so far has resulted in five publications, while several other manuscripts are in preparation.

This is an important advantage of the systematic approach to patient management, since there is a huge need for scientific research in TN both with respect to controlled drug trials as well as to determine the optimal time for referral to surgery, i. To meet this need for evidence we are currently prospectively following a large representative population of TN patients at DHC to document efficacy, side effects, complications and patient satisfaction after medical and surgical treatment in an open label design.

The outlined management program is not based on scientific evidence but on clinical experience which is a limitation. Although the presented data are not evidence based, we consider it important to describe our management program due to the lack of prior reports on how to structure TN management in clinical practice. We suggest this description of the management as a starting point from which to make adjustments, start discussions and collect scientific evidence on treatment efficacy and patient satisfaction.

According to initial feedback from patients and clinicians, the newly implemented accelerated cross-speciality management program represents an improvement of our TN management by means of an acceptable waiting time, fast diagnosis and high-quality neuroimaging by specialists and standardized treatment and information to patients.

We demonstrate that a formal collaboration across medical, diagnostic and surgical specialties is feasible at a regional and national level. Furthermore, we show that enrolment in a structured management program like this does not hold patients with medically intractable pain back for unacceptably long time before referral to neurosurgery and that the medical treatment is properly tested before impending neurosurgery.

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In any case, this effect may contribute to its analgesic effect in TN. Several other mechanisms have been proposed to underlie gabapentinoid analgesia, such as suppression of spinal N-methyl-d-aspartic acid receptors via a coagonist binding site, activation of potassium channels leading to neuronal hyperpolarization and inhibition of descending serotonergic facilitation of nociceptive processing, and finally, activation of descending inhibitory noradrenergic input to the dorsal horn for review, see Alles and Smith and Kremer et al.

Indeed, an upregulation has already been reported in certain experimental conditions and may predict a better response to these drugs. Lamotrigine and phenytoin are effective in pain states by virtue of the same selective blocking properties of high-frequency action potential firing that account for their antiseizure activity. In fact, phenytoin was the first drug introduced for the treatment of TN in , and in the following decades evidence accumulated regarding its effectiveness in TN pain management for review, see Keppel Hesselink and Schatman Its use, as well of its prodrug fosphenytoin, is still recommended in the treatment of refractory TN or in acute exacerbations of pain.

Compared with CBZ, it has three-fold higher affinity for depolarized channels, but CBZ binds to them at a five-fold faster rate for review, see Mantegazza et al. It has been suggested that all three anticonvulsants i. There is currently a weak recommendation for lamotrigine as add-on or monotherapy for TN pain management, but unlike phenytoin, it is not recommended for acute pain exacerbations, since doses must be escalated slowly in order to avoid rashes.

Phenytoin is reported to reduce plasma CBZ concentrations to a clinically significant extent probably by stimulating CYP3A4, while lamotrigine metabolism is accelerated by CBZ due to its ability to induce the same isoform of cytochrome P enzyme. Preclinical observations suggest that baclofen resembles CBZ and phenytoin in its ability to depress excitatory transmission and facilitate segmental inhibition in the trigeminal nucleus.

It has long been a mainstay in the management of spasticity of several origins. It induces analgesia possibly by presynaptic inhibition of neurotransmitter release from the central endings of primary nociceptors in the spinal cord and by stimulating inhibitory neuronal signals in the postsynaptic neurons. As baclofen does not easily penetrate the blood-barrier, its intrathecal use has been indicated to control spasticity in refractory patients or those who experience intolerable side effects with oral use.

Surgical procedures are indicated for patients with incapacitating symptoms of TN, refractory or recurrent TN or in case of intolerable adverse effects related to medication. These procedures include microvascular decompression, gamma knife radiosurgery, and percutaneous techniques, such as glycerol rhizotomy, radiofrequency thermocoagulation, and percutaneous balloon compression.

Advances in the pharmacological treatment of TN include the assessment of an extended-release formulation of OXC termed eslicarbazepine and evaluation of a new selective Nav1. Eslicarbazepine is the active metabolite of OXC and was approved in Europe in and in by the FDA and Health Canada as an adjunctive therapy in adults with partial-onset seizures. Eslicarbazepine has been shown to interact selectively with the inactive state of VGSCs through altered slow inactivation, as opposed to the effects on fast inactivation associated with CBZ and OXC.

In addition, eslicarbazepine effectively inhibited Cav3. Vixotrigine was first discovered in and the target indications included depression, bipolar mood disorder, and substance disorders. It was formerly named raxatrigine and was considered a selective Nav1. Subsequently, the compound was stated to be a selective Nav1. Vixotrigine has been considered a state- and use-dependent Nav1. In a clinical paper that discusses the experimental design to assess vixotrigine efficacy in TN patients, its preclinical profile is described as the compound having selectivity for Nav1.

This enhanced ability of a sodium channel blocker to discriminate between the resting and inactivated channels compared to CBZ may provide a better safety profile and tolerability during systematic administration. Results from a phase 2a study indicated that vixotrigine can be administered at therapeutic doses without titration and has shown good tolerability. During this open-label phase, 23 patients withdrew mainly due to lack of efficacy 18 patients.

Thus, 44 patients were eligible for the open-label phase which showed that treatment failure was not significantly different between placebo- and vixotrigine-treated groups, but significant treatment differences were found in time to treatment failure, number of paroxysms, average daily pain score, and assessments of overall function and quality of life. The drug was well tolerated, headache, and dizziness being the most frequent adverse events.

The conclusion regarding efficacy is limited by challenges in the realization of TN clinical studies, but the results encourage moving forward to a phase 3 study, which is currently in progress ClinicalTrials. The drug has been also evaluated in individuals with IEM, the first Nav1. It is noteworthy that other small molecules and peptide-derived Nav channels blockers are under development by different pharmaceutical companies and may represent perspectives for TN pain control.

Another potential target to be explored in TN is the Kv7. A study conducted in the rat model of infraorbital nerve constriction showed that Kv7. Small clinical studies suggest that flupirtine effectively reduces chronic musculoskeletal pain, migraine and neuralgias, among other types of pain, but, to our knowledge, its efficacy in TN patients has never been investigated.

This assumption is based mainly in preclinical data showing that CGRP plays a role in trigeminal afferent sensitization and CGRP receptor blockade results in antinociceptive effects in different models of trigeminal neuropathic pain. Likewise, there are some reports indicating elevated CGRP levels in blood, cerebrospinal fluid, and plasma of TN patients. A summary of pharmacological profiles and therapeutic indications of the drugs mentioned earlier are presented in Table 3.

Mechanism of action and half-life profile for new pharmacological approaches to trigeminal neuralgia. Although TN is considered a rare condition, it dramatically reduces the quality of life of affected individuals not only due to pain attacks but also to other disease-associated comorbidities, such as anxiety and depression.

In fact, it is probable that the prevalence of TN in the general populations is underestimated, as studies in this condition are very challenging and population aging is increasing. Likewise, the two main TN-related comorbidities, that is, anxiety and depression, are often underdiagnosed and undertreated and just recently have gained attention.

Thus, a better understanding of the pathophysiology is necessary for the improvement of current therapies or development of innovative pharmacological treatments. The authors would like to acknowledge Brooke Belanger Hotchkiss Brain Institute, University of Calgary for her contribution to the production and graphic design of Figure 1. Gerald W. National Center for Biotechnology Information , U. Journal List Mol Pain v. Mol Pain. Published online Jan Eder Gambeta , 1 Juliana G.

Chichorro , 2 and Gerald W. Zamponi 1. Juliana G. Author information Article notes Copyright and License information Disclaimer. Email: ac. Email: rb. This article has been cited by other articles in PMC. Short abstract The trigeminal nerve V is the fifth and largest of all cranial nerves, and it is responsible for detecting sensory stimuli that arise from the craniofacial area.

Keywords: Facial pain, carbamazepine, oxcarbazepine, sodium channel, Nav1. Basic organization of the trigeminal system Sensory information from the craniofacial region is conveyed by the trigeminal sensory system, which is composed of peripheral structures, such as the trigeminal nerve V and trigeminal ganglia TG , and central structures, such as the trigeminal brainstem sensory nuclear complex VBSNC.

Open in a separate window. Figure 1. Trigeminal neuralgia: Definition and classification Trigeminal neuralgia TN is the most common form of craniofacial neuropathic pain and is considered the cause of one of the most severe types of pain that a person can experience. Pharmacological treatment: Carbamazepine mechanisms of action and effectiveness TN treatment is initially pharmacological in the form of monotherapy; however, combined therapy with different drugs may be used when the efficacy of monotherapy is low.

In vivo effects Along with in vitro studies, several in vivo studies already demonstrated the effectiveness of CBZ and OXC in animal models of pain. Table 1. Table 2. Mechanism of action of other therapeutic treatments used for trigeminal neuralgia. Additional pharmacological perspectives Advances in the pharmacological treatment of TN include the assessment of an extended-release formulation of OXC termed eslicarbazepine and evaluation of a new selective Nav1.

Table 3. Concluding remarks Although TN is considered a rare condition, it dramatically reduces the quality of life of affected individuals not only due to pain attacks but also to other disease-associated comorbidities, such as anxiety and depression. Acknowledgments The authors would like to acknowledge Brooke Belanger Hotchkiss Brain Institute, University of Calgary for her contribution to the production and graphic design of Figure 1. References 1. Sessle BJ. Mechanisms of oral somatosensory and motor functions and their clinical correlates.

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The median time of the third medical follow up was days after the first outpatient visit. None were treated with intravenous fosphenytoin. Scientific data were collected on all the included patients. This data collection has made it possible to describe demographics of the included patients in this paper as well as the clinical characteristics and neuroanatomical abnormalities of our patient population, which so-far has resulted in five publications [ 11 , 12 , 14 — 16 ].

The most important experiences from the implementation of the described cross-speciality TN management program were that it proved to be feasible to standardize the referral pathway and work-up, that the program ensured acceptable waiting times, and that early high-quality MRI ensured correct diagnosis and a standardized basis before decision-making on impending surgery.

Moreover, the referral of the subgroup of patients in need for surgery was not unacceptably prolonged and the management program ensured continuous evaluation of pharmacological and surgical management, and provides the basis for scientific research.

The described program has also facilitated centralization of expertise in TN and a close collaboration between the involved neurological, neurosurgical and neuroradiological departments ensures a higher volume of TN patients per clinician. The importance of this is supported by Kalkanis et al. Because TN is one of the most painful diseases known to mankind a short waiting time for out-patient work-up and treatment is important.

Early diagnosis will save some TN patients from unnecessary dental treatments [ 16 ] and years of suboptimal medical treatment. Median waiting time for the first out-patient visit was 42 and 37 days for subsequent MRI, which we consider acceptable in a public health care system.

It is our clinical experience that the waiting time for first out-patient visit has been reduced significantly since implementation. Likewise it is our clinical experience that the waiting time has been lower and the quality of the MRI description higher after implementation of the program.

The specific TN protocol for the 3. Prior to the implementation of the program we did not register waiting time or patient satisfaction specifically for TN patients, so we cannot provide scientific documentation for improvement of these parameters after implementation of the program.

However, with the described structured and accelerated manner of referral we demonstrate a relatively short and acceptable waiting time for diagnosis and imaging. The median time from the first out-patient visit at DHC to referral to neurosurgery was approximately 2 months for all patients but only 20 days for patients who were initially referred to neurosurgery and then re-directed to DHC for pre-surgical evaluation. This delay must be considered acceptable given that the patients on average had suffered from TN for 7 years and considering that even among those initially referred for surgery and then re-directed to DHC for pre-surgical evaluation, half could be sufficiently controlled be medical management.

Thus, the accelerated work-up and treatment program ensures that patients with medically intractable pain are quickly referred to neurosurgery. In addition, for the patients who were initially referred to neurosurgery, who could be controlled on medical treatment, the re-direction to DHC reduced their waiting time for optimization of medical treatment and ensured that these patients did not undergo neurosurgery with its potential complications.

With the limited scientific evidence regarding efficacy of medical treatment [ 18 — 20 ], there is no single answer as to how many medications should be tried out before a TN patient is deemed medically refractory and surgery should be considered.

Moreover, there is a lack of well-designed neurosurgical studies using independent evaluators of the efficacy and complications of microvascular decompression [ 21 , 22 ], which makes the decision process even more challenging. The international guidelines [ 13 ] on TN treatment recommend carbamazepine and oxcarbazepine as first line treatment based on clinical studies [ 5 , 6 , 23 , 24 ]. Other drugs used to treat TN have not been investigated to the same extent but some smaller studies showed promising results using pregabalin [ 25 ], lamotrigine [ 26 ], baclofen [ 27 ] and gabapentin [ 28 ].

Based on our clinical experience we agree with the international treatment guidelines although we find that referral for neurosurgery after failed monotherapy may be too hasty and we in general try out a combination treatment before referral to surgery. Unfortunately, the scientific support for combination treatment is sparse and there are no published studies directly comparing monotherapy with polytherapy [ 29 ].

We suggest that follow up on medical treatment should remain in the hands of experts until the condition is stable and the patient is familiar with the program of titrating up and tapering of medication according to the level of pain and side effects. We suggest that 2 years of follow up is appropriate, but this depends on the resources of the clinic and the health care system.

The described structured management program has made it possible to prospectively collect scientific data, which so far has resulted in five publications, while several other manuscripts are in preparation. This is an important advantage of the systematic approach to patient management, since there is a huge need for scientific research in TN both with respect to controlled drug trials as well as to determine the optimal time for referral to surgery, i.

To meet this need for evidence we are currently prospectively following a large representative population of TN patients at DHC to document efficacy, side effects, complications and patient satisfaction after medical and surgical treatment in an open label design. The outlined management program is not based on scientific evidence but on clinical experience which is a limitation.

Although the presented data are not evidence based, we consider it important to describe our management program due to the lack of prior reports on how to structure TN management in clinical practice. We suggest this description of the management as a starting point from which to make adjustments, start discussions and collect scientific evidence on treatment efficacy and patient satisfaction. According to initial feedback from patients and clinicians, the newly implemented accelerated cross-speciality management program represents an improvement of our TN management by means of an acceptable waiting time, fast diagnosis and high-quality neuroimaging by specialists and standardized treatment and information to patients.

We demonstrate that a formal collaboration across medical, diagnostic and surgical specialties is feasible at a regional and national level. Furthermore, we show that enrolment in a structured management program like this does not hold patients with medically intractable pain back for unacceptably long time before referral to neurosurgery and that the medical treatment is properly tested before impending neurosurgery.

In our opinion, this is crucial to secure a high quality of TN management. We encourage other centres to publish their experiences with structured management programs in TN and to collect scientific evidence for the efficacy and side effects of medical and surgical treatment. Cephalalgia — Article Google Scholar.

Rasmussen P Facial pain. A prospective survey of patients with a view of: character of the attacks, onset, course, and character of pain. Acta Neurochir Wien —8. Cephalalgia —8. PubMed Article Google Scholar. Spatz AL, Zakrzewska JM, Kay EJ Decision analysis of medical and surgical treatments for trigeminal neuralgia: how patient evaluations of benefits and risks affect the utility of treatment decisions. Pain — ArchNeurol — CAS Google Scholar. Nicol CF A four year double blind study of Tegretol in facial pain.

Headache Apr — Sindou M, Leston J, Decullier E, Chapuis F Microvascular decompression for primary trigeminal neuralgia: long-term effectiveness and prognostic factors in a series of consecutive patients with clear-cut neurovascular conflicts who underwent pure decompression. JNeurosurg — NEnglJMed — Varagunam M, Hutchings A, Black N Relationship between patient-reported outcomes of elective surgery and hospital and consultant volume.

Med Care —6. PubMed Google Scholar. Cephalalgia 24 Suppl — Brain in press:. Maarbjerg S, Wolfram F, Gozalov A, Olesen J, Bendtsen L Association between neurovascular contact and clinical characteristics in classical trigeminal neuralgia: a prospective clinical study using 3.

Google Scholar. EurJNeurol — Headache — Neurosurgery — Di Stefano G, La Cesa S, Truini A, Cruccu G Natural history and outcome of outpatients with classical trigeminal neuralgia treated with carbamazepine or oxcarbazepine in a tertiary centre for neuropathic pain.

J Headache Pain —5. Zakrzewska JM, Akram H Neurosurgical interventions for the treatment of classical trigeminal neuralgia. CochraneDatabaseSystRev — Zakrzewska JM, Lopez BC Quality of reporting in evaluations of surgical treatment of trigeminal neuralgia: recommendations for future reports.

J Neurol Neurosurg Psychiatry —7. Beydoun A Safety and efficacy of oxcarbazepine: results of randomized, double-blind trials. Pharmacotherapy S—8. AnnNeurol —4. Cheshire WP Defining the role for gabapentin in the treatment of trigeminal neuralgia: a retrospective study. J Pain — Br J Anaesth — Download references. We thank Professor Jes Olesen for his valuable contributions to the conceivement of the management program. The funding sources had no role in the study.

You can also search for this author in PubMed Google Scholar. Correspondence to Lars Bendtsen. TH participated in the design of the study. SM and TH drafted the manuscript and collected and analyzed the data. All authors read and approved the final manuscript. Reprints and Permissions. Heinskou, T. Trigeminal neuralgia — a coherent cross-specialty management program.

J Headache Pain 16, 66 Download citation. Received : 22 May Accepted : 01 July Published : 17 July Skip to main content. Search all BMC articles Search. Download PDF. Abstract Background Optimal management of patients with classical trigeminal neuralgia TN requires specific treatment programs and close collaboration between medical, radiological and surgical specialties.

Results From May to April , patients entered the accelerated program. Conclusion The described cross-speciality management program proved to be feasible and to have acceptable waiting times for referral and highly specialized work-up of TN patients in a public tertiary referral centre for headache and facial pain. Full size image. Discussion The most important experiences from the implementation of the described cross-speciality TN management program were that it proved to be feasible to standardize the referral pathway and work-up, that the program ensured acceptable waiting times, and that early high-quality MRI ensured correct diagnosis and a standardized basis before decision-making on impending surgery.

Reduction of waiting time Because TN is one of the most painful diseases known to mankind a short waiting time for out-patient work-up and treatment is important. When are the medical intractable patients referred to neurosurgery? Mono- or combination therapy The international guidelines [ 13 ] on TN treatment recommend carbamazepine and oxcarbazepine as first line treatment based on clinical studies [ 5 , 6 , 23 , 24 ].

Collection of scientific data and methodological considerations The described structured management program has made it possible to prospectively collect scientific data, which so far has resulted in five publications, while several other manuscripts are in preparation. Conclusions According to initial feedback from patients and clinicians, the newly implemented accelerated cross-speciality management program represents an improvement of our TN management by means of an acceptable waiting time, fast diagnosis and high-quality neuroimaging by specialists and standardized treatment and information to patients.

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Trigeminal neuralgia thesis Brain in press:. Toxins Basel ; 8 : J Neurosci ; 29 : — Vixotrigine has been considered a state- and thesis statement keywords Nav1. Figure 1. We evaluated the waiting time of referral and work-up and whether and when the patient was referred to neurosurgery within this period. Subsequently, the compound was stated to be a selective Nav1.
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Custom book review writing for hire for mba Likewise it is our clinical experience that the waiting time has been lower and the quality of the MRI description higher after implementation of the program. Pharmacological treatment: Carbamazepine mechanisms of action and effectiveness TN treatment is initially pharmacological in the form of monotherapy; however, combined therapy with different drugs may be trigeminal neuralgia thesis when the efficacy of monotherapy is low. References 1. Trigeminal neuralgia versus atypical facial pain. Front Neuroanat ; 10 : Management of TN should be based on scientific evidence and clinical experience and be handled by experts as TN can be difficult to diagnose and treatment can cause troublesome side effects and complications [ 4 — 8 ].
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