RARE DISEASE
Trigeminal neuralgia
Trigeminal neuralgia
Trigeminal neuralgia
Drug discovery
7
drugs
With orphan designations
Overview
Trigeminal neuralgia (TN) is a chronic neuropathic disorder characterized by sudden, severe, unilateral facial pain described as electric shock-like or lancinating attacks. Episodes are typically triggered by innocuous stimuli (e.g., chewing, light touch) and classified as classic (vascular nerve compression), secondary (underlying pathology like multiple sclerosis), or idiopathic. Diagnosis is clinical after excluding dental causes, with MRI often used to identify neurovascular conflict or structural lesions [1][5][11]. Multidisciplinary management prioritizes rapid pain control and tailored interventions.
Population
Predominantly affects adults >50 years, with a female-to-male ratio of ~3:2 [1][9][16].
Incidence: 4.7–23.1/100,000 person-years, rising with age [9][17][19]. Lifetime prevalence ~0.3% [1][7].
Strongly associated with hypertension, multiple sclerosis (relative risk 20.0), and cerebrovascular anomalies [9][11][12].
Burden
Debilitating impact on quality of life: 30–50% develop depression/anxiety; 8% report suicidal ideation [9][12][18].
Frequent healthcare utilization due to misdiagnosis, medication side effects, or recurrent surgeries [9][18].
Remission periods shorten over time, with 30–50% recurrence post-surgery within 5–10 years [6][8][14].
Therapies
First-line: Carbamazepine or oxcarbazepine (50–90% efficacy) [1][5][6]. Second-line agents include lamotrigine, gabapentin, or baclofen [1][5][18].
Refractory cases: Microvascular decompression (MVD) for classic TN (62–89% long-term remission) [1][8][11]; stereotactic radiosurgery or percutaneous rhizotomy for high-risk patients [2][6][8].
Adjuncts: Botulinum toxin injections or neuromodulation for medication-resistant pain [3][5][18].
Categories: rare neurological diseases
Research Papers
3,893 drug discovery papers about Trigeminal neuralgia, with 3 first-in-class and 17 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
3,893 drug discovery papers about Trigeminal neuralgia, with 3 first-in-class and 17 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-27 | Fixed-dose combination of poorly water-soluble drugs, indomethacin and carbamazepine, formulated as a multi-composed amorphous solid dispersion: a potential therapy for HC-tic (part 1).
Hemicrania continua-trigeminal neuralgia is a rare, but severe pain syndrome treated with a combination of indomethacin and carbamazepine. Combination therapy is often associated with high pill burden, which reduces patient compliance and compromises therapeutic outcomes. Fixed-dose combinations, which combine multiple drugs into a single formulation, address the issue of high pill burden by reducing the number of pills patients need to take, thereby improving patient compliance. However, both drugs exhibit poor aqueous solubility, which limits their oral bioavailability. To overcome this limitation, various formulation strategies have been developed, including amorphous solid dispersions (ASDs). This study aimed to address both challenges by developing multi-composed ASDs (MC-ASDs) containing indomethacin and carbamazepine dispersed within a single polymer matrix (PVPVA, PVP, or HPMC).The MC-ASDs as well as the corresponding binary ASDs were prepared by spray drying and characterized using modulated differential scanning calorimetry, X-ray powder diffraction and Fourier transform infrared spectroscopy. In vitro dissolution behaviour was evaluated using a USP II apparatus with a pH-shift method simulating gastrointestinal conditions, while physical stability was assessed for one month under stress conditions. MC-ASDs containing PVPVA and HPMC outperformed the crystalline counterparts and, for carbamazepine, even the binary ASDs. Furthermore, the MC-ASDs exhibited good physical stability. Overall, multi-composed ASDs represent a promising approach for the development of fixed-dose combinations of poorly water-soluble drugs.
2026-09-22 | Dose rate matters: comparative outcomes of high and low dose rate LINAC stereotactic radiosurgery in trigeminal neuralgia.
To evaluate the impact of dose rate on clinical outcomes in patients undergoing linear accelerator stereotactic radiosurgery (linac SRS) for trigeminal neuralgia (TN). We analyzed outcomes of 134 frame-based linac SRS treatments for TN performed at our institution. Twenty-one treatments were excluded for not meeting the inclusion criteria. Each treatment was performed by the same clinical team and consisted of 40 Gy prescribed to the 50 % isodose line with maximum point dose of 80 Gy, targeting the proximal trigeminal nerve root. All included treatments were delivered using a dose rate of 800 monitor units (MU) per minute or 2400 MU⋅min-1, corresponding to approximately 4 Gy⋅min-1 and 12 Gy⋅min-1. Clinical outcomes were assessed using the Barrow Neurological Institute pain intensity and facial numbness scales. Both univariate and multivariate analysis of patient demographics on clinical outcomes were performed using age, comorbidity with multiple sclerosis, time between diagnosis and treatment, previous procedures, and dose rate. Biologically effective dose (BED) was calculated and compared between each dose rate cohort. Furthermore, a comprehensive review of the dosimetric consistency of all plans was performed to assess potential effects on clinical outcomes. Kaplan-Meier analysis and log-rank statistics indicated a statistically significant improvement in pain relief for patients treated with the higher dose rate (p = 0.002). Cox proportional hazards modelling identified dose rate as the only statistically significant hazard, with a hazard ratio of 3.43 (95 % CI = [1.33, 8.84], p = 0.011). All dosimetric consistency tests confirmed comparable treatment delivery across and within cohorts, and a Mann-Whitney U test analysis of the BED between dose rate groups confirmed a statistically significantly higher BED in the 2400 MU⋅min-1 group (p < 0.05). Higher dose rates using cone and frame-based linac-SRS for TN are associated with improved patient outcomes.
2026-09-18 | Hydrogen: a review of the effects and underlying mechanisms in oral diseases.
Oral diseases can affect the quality of life of patients and cause secondary systemic diseases, thereby harming systemic health. Hydrogen has been shown to exhibit anti-oxidant stress, anti-inflammatory and anti-apoptosis and other effects, indicating its therapeutic significance for many kinds of diseases. Hydrogen administered through different methods can effectively reduce plaque biofilm formation, resist oxidative stress, inhibit the inflammatory response, and promote tissue repair and regeneration. This review summarizes the primary strategies for and research on hydrogen therapy, as well as the application of hydrogen in oral diseases such as dental caries, periodontitis, peri-implantitis, oral mucosal diseases, jaw diseases, oral and maxillofacial tumors, and trigeminal neuralgia. We highlight the regulatory effects of hydrogen on the functional states and interactions of common oral disease pathogens and various cells, including immune cells, osteoblast-associated cells, osteoclasts, and fibroblasts, and summarize the involved signaling pathways. In addition, this paper discusses the problems and shortcomings of the existing research, and highlights the directions for future development to provide the basis and support for future investigations into the mechanisms through which hydrogen exerts antioxidant stress and anti-inflammatory activity, promotes mucosal healing, enhances bone regeneration, as well as alleviates neuropathic pain.
2026-09-04 | Clinical outcomes of linear accelerator-based stereotactic radiosurgery for trigeminal neuralgia.
Trigeminal neuralgia (TN) is a severely disabling facial pain disorder. When medical treatment fails, stereotactic radiosurgery (SRS) is an established option. The Gamma Knife is widely used but not always available. This study assessed the efficacy and safety of linear accelerator (LINAC)-based SRS, a more accessible alternative, for the management of classical or idiopathic TN. We conducted a retrospective review of 30 consecutive patients treated between January 2017 and April 2022 in a single oncology center. All patients received SRS delivered with a LINAC targeting the retrogasserian portion of the trigeminal nerve with doses of 80-90 Gy. Demographic, clinical, and treatment variables were collected. Pain outcomes were evaluated using the Barrow Neurological Institute pain scale. The mean age was 57.2 years, with a female predominance. The mandibular branch was the most frequently involved division. Pain relief was achieved in 90% of patients, with a mean onset at 3.1 months. Complete pain relief was obtained in 60% of cases. Pain recurrence occurred in 30% (9/30) of patients within 2-24 months; three benefited from repeat radiosurgery. Adverse effects were mild, mainly facial hypoesthesia and ocular irritation, with no hearing impairment or dry eye. LINAC -based SRS is an effective and safe option for refractory TN. Its accessibility makes it a valuable alternative to Gamma Knife, particularly in centers without dedicated neurosurgical platforms and in low- and middle-income countries.
2026-09-03 | The cerebrospinal fluid-contacting nucleus CGRP-RAMP1-PKA signaling pathway mediates trigeminal neuralgia and its mechanism.
Trigeminal neuralgia (TN) is prevalent form of neuropathic pain (NP). Its regulatory circuits and mechanisms remain unclear. The authors' previous work demonstrated that the cerebrospinal fluid-contacting nucleus (CSF-contacting nucleus) participates in the regulation of NP induced by sciatic nerve injury via the brain-CSF circuit. However, whether it mediates NP caused by trigeminal nerve injury has not been reported. This study used viral retrograde tracing to examine neural projections between the CSF-contacting nucleus and the trigeminal ganglion (TG). Neuronal activity in TN model was assessed using immunofluorescence, and chemogenetic tools were used to test its role in pain behavior. Local calcitonin gene-related peptide (CGRP)-RAMP1-PKA signaling changes and their modulation were analyzed for effects on TN. Retrograde tracing confirmed neural projections between the CSF-contacting nucleus and the TG. In TN model rats, elevated c-Fos expression indicated its activation. Chemogenetic activation induced hyperalgesia in normal rats, whereas its inhibition reduced pain in TN rats. Molecular analyses revealed upregulation of CGRP, RAMP1, and components of the PKA pathway within the nucleus. Pathway inhibition via RAMP1 knockdown or olcegepant administration attenuated pain, with knockdown effect being reversible by cAMP. This study reveals that the CSF-contacting nucleus is activated during TN and participates in central pain regulation through its local CGRP-RAMP1-PKA signaling pathway. Intervening in this pathway effectively modulates pain behavior, suggesting that this nucleus and its signaling system may represent novel therapeutic targets for treating TN. These findings provide experimental evidence for understanding the central mechanisms of TN and developing analgesic strategies.
proteins
2026-08-11 | Botulinum toxin type A attenuates trigeminal neuralgia-like pain by suppressing CGRP release and modulating NaV1.7-associated signaling.
Trigeminal neuralgia (TN) is a disabling facial pain disorder, and current treatments remain insufficient for a substantial proportion of patients. Botulinum toxin type A (BoNT/A) has shown therapeutic benefit in TN, but its peripheral analgesic mechanisms remain incompletely understood. We aimed to determine whether BoNT/A alleviates TN-like pain by modulating the calcitonin gene-related peptide (CGRP)-extracellular signal-regulated kinase (ERK)-NaV1.7 pathway in trigeminal ganglion neurons. TN-like pain was induced in mice by chronic constriction injury of the infraorbital nerve (CCI-ION). On postoperative day 14, BoNT/A (10 U) or saline was injected intradermally into the whisker pad. Evoked and spontaneous pain-like behaviors were assessed using von Frey testing, the Ugo Basile facial pain test, and spontaneous scratching recordings; anxiety-like behavior was evaluated using the elevated plus maze. Myelin pathology was examined by Luxol fast blue staining and transmission electron microscopy. CGRP, NaV1.7/NaV1.8, and ERK/MAPK signaling were examined in trigeminal ganglion neurons using immunofluorescence, Western blotting, RT-qPCR, ELISA, calcium-influx assays, and whole-cell patch-clamp recordings. Olcegepant and PD98059 were used to interrogate CGRP receptor- and ERK-dependent mechanisms. BoNT/A significantly attenuated CCI-ION-induced mechanical allodynia, increasing the facial withdrawal threshold from 0.11 to 1.29 g, and reducing spontaneous pain-like behaviors. BoNT/A also improved anxiety-like behavioral measures in CCI-ION mice. Histological and ultrastructural analyses shown partial amelioration of myelin pathology, accompanied by increased myelin basic protein expression and a lower g-ratio. Mechanistically, BoNT/A reduced CGRP-associated activity in TRPV1-positive trigeminal ganglion neurons, accompanied by lower serum CGRP levels and attenuated capsaicin-evoked calcium influx. These changes were associated with a preferential reduction in NaV1.7 membrane localization, without a comparable reduction in NaV1.8, and with a marked decrease in sodium current density, with peak sodium current reduced by 78.6%. Pharmacological inhibition of CGRP receptors or ERK phosphorylation reproduced the effects of BoNT/A on NaV1.7 membrane localization. These findings suggest that BoNT/A alleviates CCI-ION-induced TN-like pain, at least in part, by suppressing CGRP-dependent ERK activation and subsequent NaV1.7 membrane recruitment in trigeminal ganglion neurons. The CGRP-ERK-NaV1.7 pathway may represent a peripheral mechanism of BoNT/A-mediated analgesia and a potential target for neuropathic facial pain. Not applicable.
2026-06-25 | Botulinumtoxin Type-A (BoNTA) in the Management of Refractory Trigeminal Neuralgia: An Expert-Opinion, Practice-Oriented Narrative Review on Behalf of the GRASP Study Group.
Trigeminal neuralgia (TN) ranks among the most excruciating neuropathic pain syndromes, characterized clinically by multiple daily episodes of unilateral, paroxysmal, electric shock-like facial pain. The daily activities and quality of life of affected patients are profoundly diminished. First-line pharmacological agents, such as carbamazepine and oxcarbazepine, provide initial relief for many patients. However, a significant proportion eventually develops refractory symptoms or experience intolerable adverse effects, leading to the discontinuation of traditional oral medications. For these patients with complex clinical phenotypes who fail to respond or are intolerant to these therapies, alternative pharmacological strategies are required before considering invasive surgical procedures. Over the past two decades, botulinumtoxin type-A (BoNTA) has become an effective and safe, minimally invasive therapeutic option for refractory TN. This review provides a practical framework for BoNTA use in the clinical setting of refractory TN. To connect the pathophysiological background with clinical patient care, we summarize the current understanding of TN pathophysiology, the proposed mechanisms by which BoNTA exerts its antinociceptive effects and the evolving clinical evidence supporting its efficacy and safety. We also critically examine dosing protocols, injection techniques, long-term outcomes and the integration of BoNTA into the management algorithm of refractory TN.
2026-05-27 | Effects of IncobotulinumtoxinA in the Infraorbital Nerve Chronic Constriction Injury Model of Trigeminal Pain in Rats.
Background/Objectives: Trigeminal neuralgia (TN) is a debilitating neurological condition characterized by recurrent, severe pain linked to peripheral and central sensitization within trigeminal pathways. Current pharmacologic treatments are limited by inadequate efficacy or dose-limiting side effects, and botulinum neurotoxin type A (BoNT/A) has emerged as a viable option. However, its potential use in the management of TN is hampered by methodological limitations in existing studies and a lack of pivotal clinical trials. This study investigated the efficacy, optimal treatment site, preventive utility, and duration of effect of incobotulinumtoxinA (Inco/A), a BoNT/A, in a model of TN. Methods: An infraorbital nerve chronic constriction injury model was used to induce mechanical allodynia in male Sprague-Dawley rats, reproducing the trigeminal sensitization seen in TN. The effects of subcutaneous Inco/A (1, 2, and 4 U) were measured using the mechanical sensitivity (von Frey) test to evaluate the dose response, effect of injection location, potential preventive nature of treatment, and duration of benefit. Results: Inco/A produced a robust, dose-dependent reduction in mechanical allodynia, predominantly via a local mechanism of action. Both preventive and therapeutic administration of Inco/A was efficacious, with significant reduction in allodynia even when administered up to 28 days before nerve injury. The anti-allodynic effect persisted up to 56 days post-injection. Conclusions: Inco/A is highly effective in alleviating mechanical allodynia in a validated rat model of TN. The findings highlight Inco/A as a promising candidate for clinical translation in TN and related neuropathic pain syndromes and support systematic investigation in well-controlled human trials.
2026-04-09 | Medical management of refractory trigeminal neuralgia.
First- and second-line medical and surgical therapies for trigeminal neuralgia (TN) may have limited efficacy or tolerability in some individuals. In addition, even when these therapies are initially successful, efficacy frequently wanes over time. This narrative review presents medication options for intractable trigeminal neuralgia with a focus on new and upcoming therapies. Lacosamide, eslicarbazepine, and botulinum toxin are increasingly used for intractable TN, with recent studies demonstrating efficacy. Basimglurant and vixotrigine (BIIB074) are investigational agents currently or recently studied for treatment of TN. Intravenous (i.v.) sodium channel blockers, i.v. magnesium, multiple formulations of lidocaine, and sumatriptan can be used for acute treatment of intractable TN. Multiple medical therapies exist for treatment of intractable TN, with newer options demonstrating efficacy in recent studies. Investigational agents are currently being studied as potential future options for management of intractable TN.
2026-01-24 | Rabies Virus Glycoprotein-Decorated Liposomes in Thermosensitive Nasal Spray Gels: Facilitating Retrograde Neural Transport for Targeted Trigeminal Neuralgia Therapy.
Clinical management of trigeminal neuralgia (TN) is hindered by poor neural bioavailability and systemic toxicity of oral drugs. While the nasal route offers a direct pathway to target the trigeminal nerve, rapid mucociliary clearance and competition from systemic absorption limit its effectiveness. To address these limitations, this study aimed to develop a biomimetic nasal gel system for targeted drug delivery to the trigeminal nerve. Inspired by the neurotropism of rabies virus, we engineered a thermoresponsive nasal spray gel (OMRLP@NSG). The system utilizes rabies virus glycoprotein (RVG)-modified liposomes coloaded with oxcarbazepine and mecobalamin. The liposomal formulation was specifically chosen to enhance drug stability, facilitate mucosal penetration, and provide a platform for neuron-specific targeting via RVG modification. Upon nasal administration, the OMRLP@NSG transitions from spray to gel, enhancing nasal distribution, mucosal adhesion, and neuron-specific targeting. Pharmacokinetics demonstrated a 3 h earlier Tmax and 537.25% higher relative bioavailability in trigeminal nerves versus oral Trileptal. OMRLP@NSG at 1/10th the Trileptal dose achieved comparable trigeminal nerve exposure while reducing off-target site concentrations by 74.18∼92.00% (plasma, brain, liver). Pharmacodynamics showed that the OMRLP@NSG significantly alleviated TN pain in rats, increasing the pain threshold by 3.92-fold over Trileptal. It also normalized the expression of pain-related neuropeptides (substance P and β-endorphin) to 112.05 and 98.81% of normal levels, respectively. Mechanistically, it suppressed P2 × 7R/NLRP3 inflammasome activation, downregulating IL-1β and TNF-α, thereby reducing neuronal damage and promoting remyelination. Additionally, long-term toxicity studies confirmed the favorable in vivo biosafety. This strategy transcends conventional systemic administration paradigms by resolving the tripartite challenge of spatial control, temporal retention, and cellular precision, thereby addressing the critical clinical demand for effective nose-to-brain delivery in trigeminal neuralgia.
cell therapies
2026-09-07 | Endovascular transverse sinus stenting for pressure-dependent trigeminal neuralgia: illustrative case.
Trigeminal neuralgia (TN) is most commonly attributed to neurovascular compression at the trigeminal root entry zone. However, a subset of patients present without clear compressive pathology or with refractoriness to standard therapies, suggesting alternative mechanisms. Emerging evidence implicates intracranial pressure (ICP) dysregulation and venous outflow obstruction as potential contributors to a pressure-dependent form of TN, although this association remains incompletely defined. The authors report the case of a 33-year-old female with medically refractory TN and no radiographic evidence of classical neurovascular compression. Imaging demonstrated features suggestive of intracranial hypertension and severe right transverse sinus stenosis with contralateral sinus hypoplasia. Lumbar puncture revealed elevated opening pressure with transient symptom relief. Cerebral venography confirmed a significant transstenotic pressure gradient. Following endovascular transverse sinus stenting, there was immediate and sustained resolution of facial pain, with discontinuation of all medications and durable improvement at follow-up. TN may, in selected patients, represent a pressure-dependent disorder related to intracranial hypertension and venous outflow obstruction rather than isolated arterial compression. Recognition of this phenotype is important, as ICP-targeted therapies, including venous sinus stenting (VSS), may provide effective treatment in appropriately selected patients. However, current evidence remains limited, and careful diagnostic and hemodynamic evaluation is essential before considering VSS. https://thejns.org/doi/10.3171/CASE26456.
2026-02-03 | Short-term infraorbital nerve electrical stimulation for herpes zoster herpetic trigeminal maxillary division neuralgia: A case report.
Herpetic neuralgia of the maxillary division of the trigeminal nerve is a rare clinical condition characterized by unilaterally distributed burning pain with clustered blister-like lesions. Peripheral nerve stimulation, an effective neuromodulation technique, has demonstrated significant efficacy in treating herpetic neuralgia. However, the application of peripheral nerve stimulation to herpes zoster (HZ) of the maxillary division of the trigeminal nerve is still limited. This study reports a case of HZ trigeminal neuralgia maxillary division neuralgia treated with a short-term infraorbital nerve stimulation guided by digital subtraction angiography (DSA) with satisfactory results. The patient, a 77-year-old male, was admitted to the hospital with "left-sided facial pain with herpes for 1 month." On examination, the left side of the face showed an incompletely dislodged crust and hyperpigmented scar, and the lesion was confined to the infraorbital innervation area. It did not cross the midline of the face, with a positive trigger pain test. Pain assessment: Numerical Rating Scale (NRS) 7 to 8, nocturnal eruptive pain episodes 3 to 4 times/night, Pittsburgh Sleep Quality Index 19 to 20. Herpes zoster neuralgia of the maxillary division of the trigeminal nerve. DSA-guided short-term infraorbital nerve electrical stimulation placement. After a short-term infraorbital nerve stimulation, the patient experienced significant relief of pain symptoms and complete healing of the skin lesions. The NRS score decreased from 7 to 8 before treatment to 2 to 3, and the nocturnal eruption pain disappeared, significantly improving sleep quality. Postoperative follow-up at 1 and 3 months showed that the NRS score decreased to 1 to 2, the Pittsburgh Sleep Quality Index showed a progressive decrease, and sleep quality improved. Our findings suggest that DSA-guided short-term infraorbital nerve electrical stimulation offers a new option for treating pain in patients with HZ herpetic trigeminal maxillary division neuralgia when commonly used clinical treatments are ineffective.
2026-01-24 | The use of cellular therapies for trigeminal neuralgia: a systematic review of behavioral and molecular outcomes.
Trigeminal neuralgia (TN) is a neuropathic pain disorder characterized by severe orofacial pain. The underlying pathophysiological nuances remain under study, and their understanding is key to developing new and more effective therapies for this debilitating disease. The field of cellular therapies for neurological diseases is continuously evolving. This systematic review was performed after the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We sought studies on the preclinical and clinical uses of cellular therapies for trigeminal neuralgia. We included 8 studies encompassing 1 clinical and 7 preclinical applications. Of the preclinical studies, four used Stem Cells from Human Exfoliated Deciduous Teeth (SHED), two used Olfactory Ensheathing Cells (OECs), and one used Bone Marrow Mesenchymal Stem Cells (BMSCs). All preclinical studies showed a statistically significant behavioral improvement in groups receiving cellular therapies compared to controls (p < 0.05), with either local or systemic delivery. In addition, cellular therapies have the potential to mitigate TN by promoting myelin repair, reducing neuroinflammation, and modulating pain-related pathways. The only clinical report in the literature described the incidental use of Adipose-Derived Stem Cells (ADSCs) during a facial cosmetic procedure in a 60-year-old female with a long history of TN, who remained pain-free at 2-year follow-up. These findings highlight the promising role of cellular therapies in the treatment of TN, demonstrating significant behavioral and molecular benefits in preclinical models and a compelling clinical case. Further rigorous clinical studies are necessary to establish their safety, efficacy, and long-term therapeutic impact.
2026-01-14 | Peripheral Nerve Stimulation Is Effective in the Management of Trigeminal Pain: A Systematic Review and meta-analysis.
Trigeminal Neuralgia (TN) patients usually experience severe facial pain, leading to a significant reduction in quality of life. To evaluate the effect of peripheral nerve stimulation (PNS) on pain relief in patients with TN. The databases of EMBASE, WEB OF SCIENCE, and PUBMED were searched from inception to 2024 for clinical trials of PNS for TN. The inclusion criteria consisted of any study using PNS to treat TN and reporting outcomes of pain intensity. Risk of bias was assessed using Revised Cochrane Risk of Bias 2.0 and Methodological Index of Non-Randomised Studies (MINORS) tool. Meta-analysis was conducted with RevMan 5.3 and publication bias was evaluated via Egger's test through STATA17. We identified 1,574 citations, and included 9 trials comprising 112 participants. In terms of efficacy, PNS was associated with significant pain relief compared to baseline (MD, -6.23 cm [95% CI, -7.20 to -5.26 cm], P < 0.05, I2 = 89%), with the reduction closely approaching the minimal important difference (MID) threshold of 6.25 cm. Subgroup analysis showed that patients with baseline pain scores ≥ 8 experienced greater pain relief (N = 52, MD, -7.06 cm [95% CI, -8.30 to -5.82 cm], I2 = 87%, p = 0.02) compared to patients with pain scores < 8(N = 60, MD, -4.75 cm [95% CI, -6.22 to -3.28 cm], I2 = 89%) . The meta-analysis results showed PNS leads to a statistically and clinically significant improvement in pain. PNS may be a promising approach in the management of TN.
2026-01-12 | Sphenopalatine ganglion block in orofacial pain and headache disorders: A review of case reports.
To review and synthesize published case reports on the use of sphenopalatine ganglion (SPG) block in orofacial and headache disorders, focusing on techniques and clinical outcomes. A review of 55 case reports and series extracted data on 29 papers, including diagnoses, SPG block technique, anesthetic or drug, outcomes, and adverse effects. SPG block was reported in trigeminal neuralgia and neuropathies, burning mouth syndrome, non-specified facial pain, autonomic cephalalgias, migraine, tension type headache, COVID related headache and acute cephalalgias. The most frequently used technique was intranasal with cotton tip applicators, with lidocaine 2-10% as the most common agent. Most reports document relief, but long-term data is not available. Neurogenic pain conditions and migraine showed superior therapeutic responses to the SPG block procedure. SPG block appears effective and safe, though higher-level evidence is still needed.
antibodies
2026-09-24 | Cytotoxic Lesion of the Corpus Callosum After Hospital-Administered Intravenous Fentanyl for Trigeminal Neuralgia: A Case Report and Focused Review.
Fentanyl-associated neurotoxicity is increasingly recognized across illicit, inhalational, transdermal, pediatric, and delayed posthypoxic exposures, but isolated splenial CLOCC after hospital-administered intravenous fentanyl has not been well characterized. This is a single-patient case report with a focused review of fentanyl-associated neurotoxic syndromes and proposed mechanisms. A 41-year-old woman with trigeminal neuralgia presented with severe facial pain. After droperidol, metoclopramide, and metamizole failed to control symptoms, intravenous fentanyl (75 μg) was administered. Soon afterward, she developed dizziness, nausea, vomiting, left-sided paresthesias, hypoesthesia, and mild weakness. Initial computed tomography was unrevealing, and cerebrospinal fluid findings were normal. Brain magnetic resonance imaging (MRI) obtained 8 days later showed a 6-mm midline splenial lesion that was hyperintense on T2-weighted and FLAIR sequences, restricted on diffusion-weighted imaging, and nonenhancing, consistent with CLOCC. Follow-up MRI showed complete radiologic resolution, but serial assessments documented persistent deficits in the left upper and lower extremities, including impaired fine motor control, dysdiadochokinesia, arm and leg weakness, foot drag, and gait imbalance; somatosensory-evoked potentials showed mild dysfunction of the left lower-extremity pathway. Review of comparable fentanyl-associated cases shows a spectrum ranging from isolated callosal injury to diffuse, cerebellar, and delayed leukoencephalopathic phenotypes. This case expands the neuroimaging spectrum of fentanyl-associated brain injury and supports a toxic-metabolic pathogenesis in which splenial CLOCC may represent a focal manifestation of broader opioid-related white-matter vulnerability.
2026-09-07 | NEUROPHYSIOLOGICAL BASIS OF PSYCHOSOMATIC DISORDERS IN TRIGEMINAL NEURALGIA
Trigeminal neuralgia (TN) is one of the most severe forms of neuropathic facial pain and is characterized by recurrent, short-lasting, unilateral episodes of electric shock-like pain in the distribution of the trigeminal nerve.(1-3)Despite the predominantly neurological nature of the disorder, chronic and recurrent pain may significantly affect the patient's emotional state, sleep, social activity, and overall quality of life.(6-7) Psychosomatic manifestations, particularly anxiety, depressive symptoms, sleep disturbances, and autonomic dysfunction, may further contribute to the persistence and exacerbation of pain.(8-9-10)
2026-04-20 | HLA genotype testing for carbamazepine, oxcarbazepine and eslicarbazepine: A guideline developed by the UK Centre of Excellence in Regulatory Science and Innovation in Pharmacogenomics (CERSI-PGx).
Carbamazepine is licensed in the United Kingdom for the treatment of epilepsy, bipolar disorder and trigeminal neuralgia. The related compounds oxcarbazepine and eslicarbazepine are licensed for the treatment of epilepsy. These drugs can cause immune-mediated hypersensitivity reactions, which typically affect the skin, and can be of variable severity. The liver and other organ systems can also be affected. The HLA alleles, HLA-B*15:02, HLA-B*15:11 and HLA-A*31:01, are known predisposing factors for these hypersensitivity reactions. Any treatment-naïve patient, regardless of ancestry or indication for treatment, who is about to be prescribed carbamazepine, oxcarbazepine or eslicarbazepine, or has been on these drugs for less than 3 months, should undergo pharmacogenetic testing to identify all clinically relevant HLA alleles to reduce the risk of hypersensitivity reactions. Carbamazepine, oxcarbazepine and eslicarbazepine should be avoided in HLA-B*15:02-positive patients. These drugs should also be avoided in patients positive for HLA-A*31:01 or HLA-B*15:11 if an alternative is possible. Where it is not possible to use an alternative, treatment should only be commenced after careful consideration of the benefits and risks, with increased monitoring and advising patients on appropriate action to take if a skin rash occurs. Our guideline is compatible with other international pharmacogenetics prescribing guidelines. This guideline is grounded in the latest evidence but cannot account for all individual factors relevant to patient care. Therefore, prescribers must conduct a thorough assessment of each patient's risk-benefit profile, ensuring that therapy is optimised to maximise benefits whilst minimising potential harms.
2026-03-19 | Phosphoproteomics uncovers a neuroimmune perspective on trigeminal neuralgia: sexually dimorphic regulatory networks linking calcium channels to the complement cascade.
Trigeminal neuralgia (TN) is a neuropathic pain disorder with a marked female predominance. While transcriptional changes in TN are documented, the translational and post-translational landscapes-specifically protein abundance and phosphorylation states-within the trigeminal ganglion (TG) remain largely unexplored. Understanding these layers is essential to deciphering the mechanisms behind the disease's sexual dimorphism. we utilized the chronic infraorbital nerve ligation (CION) method via an intraoral approach model in male and female Sprague-Dawley rats. Mechanical allodynia was confirmed via behavioral testing. On postoperative day 7, trigeminal ganglia were harvested to capture the somatic molecular response. We performed an integrated analysis using TMT-based quantitative proteomics and phosphoproteomics. Bioinformatics tools were employed to map differentially expressed proteins (DEPs), kinase-substrate relationships, and protein-protein interaction (PPI) networks. The study quantified 5,820 proteins and 8,830 phosphopeptides. (1) A striking divergence was observed in pathological pathways. Females exhibited a robust neuroimmune signature characterized by the specific upregulation of complement components (C1QA, C1QC) and Kininogen (KNG1). In contrast, males showed alterations primarily in lipid metabolism and synaptic vesicle cycles. (2) Phosphoproteomics identified the MAPK signaling pathway as a shared mechanism. Specifically, phosphorylation of HSPB1 at Ser86 (pS86-HSPB1)-a target of the MAPKAPK2/3 cascade-was significantly elevated, linking stress signaling to cytoskeletal reorganization. (3) PPI analysis highlighted voltage-gated calcium channel subunits as central hubs connecting these sex-specific modules, validating the relevance of calcium channel modulation in TN management. This study presents the first dual-omics atlas of the injured trigeminal ganglion. We identify a female-specific "Complement-Kininogen" axis and a conserved "MAPK-HSPB1" phosphorylation pathway as key drivers of TN. These findings provide a molecular explanation for the clinical gender bias and suggest that therapeutic strategies may need to be sex-stratified, with complement inhibition holding particular potential for female patients.
2026-01-24 | Causal interplay between trigeminal neuralgia and systemic inflammatory markers: A bidirectional Mendelian randomization study.
Trigeminal neuralgia (TN) is a debilitating neuropathic pain disorder with profound impacts on quality of life. Although alterations in circulating inflammatory proteins have been reported, observational findings remain inconsistent and are vulnerable to confounding and reverse causation. Whether these immune changes are causal or merely downstream consequences of TN remains uncertain, underscoring the need for robust causal inference methods. We conducted a bidirectional 2-sample Mendelian randomization (MR) analysis to investigate the causal relationships between circulating inflammatory proteins and TN. Genetic instruments for 91 proteins and TN were obtained from large-scale publicly available genome-wide association studies. Five complementary MR estimators were applied - inverse-variance weighting (IVW), MR-Egger, weighted median, weighted mode, and simple mode - and sensitivity analyses were performed to evaluate heterogeneity, pleiotropy, and robustness. Forward MR identified 5 proteins significantly associated with TN risk: eotaxin (IVW odds ratio [OR] = 0.834, 95% CI = 0.711-0.977, P = .025); C-X-C motif chemokine ligand 5 [CXCL5]; IVW OR = 0.841, 95% CI = 0.726-0.974, P = .021); IL-20RA (IVW OR = 1.317, 95% CI = 1.032-1.679, P = .027); interleukin-6 (IVW OR = 1.343, 95% CI = 1.059-1.704, P = .015); and neurturin (IVW OR = 1.190, 95% CI = 1.004-1.410, P = .044). Reverse MR indicated that TN causally influenced 5 immune traits: eotaxin (OR = 0.39, 95% CI = 0.19-0.80, P = .010); CXCL5 (OR = 0.32, 95% CI = 0.11-0.91, P = .032); IL-20RA (OR = 2.07, 95% CI = 1.11-3.84, P = .022); interleukin-15 receptor α (OR = 0.28, 95% CI = 0.08-0.99, P = .048); and transforming growth factor-α (OR = 0.44, 95% CI = 0.23-0.83, P = .011). Notably, eotaxin, CXCL5, and IL-20RA showed bidirectional associations with TN. All signals were consistent across complementary estimators and sensitivity analyses, with no evidence of heterogeneity or horizontal pleiotropy (all P > .05). Our genetic evidence demonstrates a close coupling between the circulating inflammatory network and TN, providing testable leads for biomarker development and immunomodulatory strategies in TN.
other
2026-03-13 | A Tac1-Expressing Brainstem Pathway Underlies the Pathogenesis of Trigeminal Neuralgia.
Trigeminal neuralgia (TN) is widely recognized to be one of the most severe pain disorders, severely affects the life quality of patients. However, the neuronal mechanisms underlying TN pathogenesis remain largely unknown. Here, we identify a periphery-to-brain neural circuit that governs TN development in mice. Tachykinin 1 (Tac1)-expressing parabrachial nucleus (PBNTac1) neurons show heightened stimulus-evoked responses, and chemogenetic inhibition of these neurons effectively prevents TN development. Furthermore, PBNTac1 neurons receive projections from the caudal part of the spinal trigeminal nucleus (Sp5C), and PBN-projecting Sp5C neurons are essential for TN-induced pain hypersensitivity. Remarkably, PBN-projecting Sp5C neurons predominantly express Tac1, and knockdown Tac1 gene in these neurons significantly attenuates TN-induced pain hypersensitivity. Through retrograde viral tracing and electrophysiological recordings, we demonstrate that Tac1-expressing Sp5C neurons directly relay signals from the trigeminal ganglion (TG) to the PBN. Collectively, our findings unveil a critical TG-Sp5CTac1-PBNTac1 pathway that drives the TN pathogenesis.
2026-02-20 | Nr4a1 regulates microglia overactivation-mediated neuroinflammation to ameliorate cognitive impairment in trigeminal neuralgia rats.
BACKGROUND: Cognitive impairment affects prognosis and quality of life in patients with trigeminal neuralgia (TN). Modulating hippocampal microglial activation is a promising approach for addressing TN-related cognitive deficits. Nuclear receptor subfamily 4 group A member 1 (Nr4a1) is involved in hippocampal-dependent cognition and microglial homeostasis. However, its role in trigeminal neuralgia-associated cognitive dysfunction remains unclear. We aimed to investigate the role of Nr4a1 in regulating neuroinflammation mediated by microglial hyperactivation, and to establish the relationship between the resulting synaptic plasticity impairment and cognitive dysfunction. METHODS: A TN rat model was established using chronic constriction injury of the distal infraorbital nerve. Cognitive function and hippocampal microglial activation were evaluated over time. Transcriptomic sequencing was performed to identify differentially expressed genes related to microglial activation. Nr4a1 was overexpressed in hippocampal microglia using adeno-associated virus and lentivirus in TN rats and BV2 cells, respectively. Multi-omics analyses, co-immunoprecipitation, and mass spectrometry were used for mechanistic assessments. RESULTS: Here, we observed that TN rats exhibited time-dependent cognitive impairment accompanied by excessive activation of hippocampal microglia and significant downregulation of Nr4a1 expression. Nr4a1 overexpression suppresses excessive activation of microglia and the neuroinflammation they mediate. These effects correlate with restored neuronal autophagy, enhanced synaptic plasticity, and improved cognitive function in TN rats. Mechanistically, we first revealed aberrant alterations in the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway through multi-omics sequencing. Furthermore, we identified Nr4a1 primarily targeting Akt2 among the Akt isoforms in the rat hippocampus. Restoring Nr4a1 expression reversed PI3K/Akt2 signaling downregulation in vivo and in vitro, whereas PI3K/Akt2 signaling pharmacological inhibition abrogated Nr4a1 overexpression-mediated benefits. CONCLUSION: Collectively, Nr4a1 may suppress excessive microglial activation by restoring the PI3K/Akt2 signaling pathway to alleviate neuroinflammation, thereby improving neuronal autophagy and synaptic plasticity. Our findings provide a deeper theoretical basis and molecular target for future TN-related cognitive impairment treatment.
2025-12-26 | Cerebellar neurocan gene expression is a common pathogenic factor of trigeminal neuralgia and depression.
BACKGROUND: Trigeminal neuralgia (TN) is a severe neuropathic pain disorder characterized by sudden, electric shock-like facial pain. It frequently co-occurs with depression and these conditions often exacerbate each other. However, their shared pathogenic mechanisms remain poorly understood METHODS: In this study, neuroimaging data were integrated with whole-genome sequencing data to identify common genetic risk factors. Initially, single nucleotide polymorphisms (SNPs) associated with both conditions were identified through whole-genome analysis. Gene-tissue associations were then elucidated using the S-PrediXcan and summary data-based Mendelian Randomization (SMR) methods. These findings were further validated through neuroimaging analysis and animal experiments. RESULTS: Whole-genome analysis identified SNPs shared by TN and depression. The neurocan (NCAN) gene was significantly associated with both disorders and showed a cerebellum-specific expression pattern. Neuroimaging revealed significant differences in brain function and structure between TN and depression patients, primarily localized in the temporal lobe, frontal lobe, and cerebellum. Animal experiments corroborated these findings, showing that elevated cerebellar NCAN expression is closely linked to the onset and progression of both TN and depression. CONCLUSIONS: The study identifies the NCAN gene and cerebellar dysfunction as shared potential pathogenic factors between TN and depression. These findings provide new insights into the common mechanisms underlying these comorbid conditions and suggest potential implications for developing targeted therapeutic strategies.
2025-12-16 | USP19 restores mitochondrial function in neurons by deubiquitinating FUS to alleviate trigeminal neuralgia.
Deubiquitinating enzymes of the ubiquitin-specific peptidase (USP) family have been increasingly recognized for their roles in modulating neuropathic pain. In this study, bioinformatic analysis identified USP19 as a downregulated gene in trigeminal neuralgia (TN). Using a mouse model of TN induced by foramen lacerum impingement of the trigeminal nerve (FLIT), we demonstrated that adeno-associated virus-mediated overexpression of USP19 in the cerebral cortex significantly alleviated anxiety-like and pain-like behaviors. USP19 overexpression promoted deubiquitination and stabilization of fused in sarcoma (FUS), as confirmed by Western blotting, actinomycin D treatment, and ubiquitination assays. In HT22 and SH-SY5Y cells exposed to lipopolysaccharide to induce mitochondrial dysfunction, USP19 restored mitochondrial membrane potential, reduced mitochondrial reactive oxygen species, suppressed DRP1 phosphorylation, and upregulated CYTB and ND4 levels. These effects were reversed by FUS knockdown, both in vitro and in vivo. Moreover, FUS silencing abolished USP19-mediated improvements in NAD⁺/NADH ratio and mitochondrial function, as well as its analgesic and anxiolytic benefits in TN mice. These findings suggest that USP19 alleviates TN by enhancing FUS deubiquitination and preserving mitochondrial integrity in neurons. This study reveals a novel USP19/FUS signaling axis in the regulation of mitochondrial homeostasis and provides a promising therapeutic target for the treatment of TN.
2025-10-11 | Reprogramming activated astrocytes into GABAergic neurons to treat trigeminal neuralgia.
Trigeminal neuralgia (TN) is the most common type of cranial neuralgia. Currently, there remains a significant gap in the availability of effective and safe treatment options in clinical practice. Transdifferentiation of proliferating activated astrocytes into inhibitory neurons is a potential therapeutic strategy for central nervous system diseases. GABAergic neurons are one of the most type of prevalent inhibitory neurons. This study aims to reprogram proliferating astrocytes in the spinal trigeminal subnucleus caudalis (SpVc) into GABAergic neurons, could improve neuronal excitation-inhibition balance, alleviate pain, which serve as a potential treatment for trigeminal neuralgia. A chronic constriction injury of the distal infraorbital nerve (CCI-dION) was induced in the infraorbital branch of the trigeminal nerve to create a rat model of TN. Adeno-associated viruses were used to overexpress transcription factors Sox2 and Mash1 in astrocytes. The changes in astrocytes and GABAergic neurons in the SpVc region were detected by immunofluorescence, Western blotting, qPCR, and electron microscopy. The mechanical pain threshold testing was used to assess rat TN. In the SpVc region of CCI-dION rats, astrocytes showed proliferation and activation, and the number of GABAergic neurons decreased significantly. Overexpressing Sox2 and Mash1 in astrocytes led to a significant transdifferentiation into GABAergic neurons, which - improved the mechanical pain threshold in CCI-dION rats. Furthermore, fluorocitrate-mediated astrocyte deactivation abolished both the neuronal reprogramming and the analgesic effects, underscoring the essential role of astrocytes in this process. These findings suggest that overexpressing Sox2 and Mash1 in astrocytes led to a significant transdifferentiation into GABAergic neurons, which significantly improved the mechanical pain threshold in CCI-dION rats. Thus, this approach has the potential to provide a new treatment for TN.
small molecules
2026-09-27 | Fixed-dose combination of poorly water-soluble drugs, indomethacin and carbamazepine, formulated as a multi-composed amorphous solid dispersion: a potential therapy for HC-tic (part 1).
Hemicrania continua-trigeminal neuralgia is a rare, but severe pain syndrome treated with a combination of indomethacin and carbamazepine. Combination therapy is often associated with high pill burden, which reduces patient compliance and compromises therapeutic outcomes. Fixed-dose combinations, which combine multiple drugs into a single formulation, address the issue of high pill burden by reducing the number of pills patients need to take, thereby improving patient compliance. However, both drugs exhibit poor aqueous solubility, which limits their oral bioavailability. To overcome this limitation, various formulation strategies have been developed, including amorphous solid dispersions (ASDs). This study aimed to address both challenges by developing multi-composed ASDs (MC-ASDs) containing indomethacin and carbamazepine dispersed within a single polymer matrix (PVPVA, PVP, or HPMC).The MC-ASDs as well as the corresponding binary ASDs were prepared by spray drying and characterized using modulated differential scanning calorimetry, X-ray powder diffraction and Fourier transform infrared spectroscopy. In vitro dissolution behaviour was evaluated using a USP II apparatus with a pH-shift method simulating gastrointestinal conditions, while physical stability was assessed for one month under stress conditions. MC-ASDs containing PVPVA and HPMC outperformed the crystalline counterparts and, for carbamazepine, even the binary ASDs. Furthermore, the MC-ASDs exhibited good physical stability. Overall, multi-composed ASDs represent a promising approach for the development of fixed-dose combinations of poorly water-soluble drugs.
2026-09-22 | Dose rate matters: comparative outcomes of high and low dose rate LINAC stereotactic radiosurgery in trigeminal neuralgia.
To evaluate the impact of dose rate on clinical outcomes in patients undergoing linear accelerator stereotactic radiosurgery (linac SRS) for trigeminal neuralgia (TN). We analyzed outcomes of 134 frame-based linac SRS treatments for TN performed at our institution. Twenty-one treatments were excluded for not meeting the inclusion criteria. Each treatment was performed by the same clinical team and consisted of 40 Gy prescribed to the 50 % isodose line with maximum point dose of 80 Gy, targeting the proximal trigeminal nerve root. All included treatments were delivered using a dose rate of 800 monitor units (MU) per minute or 2400 MU⋅min-1, corresponding to approximately 4 Gy⋅min-1 and 12 Gy⋅min-1. Clinical outcomes were assessed using the Barrow Neurological Institute pain intensity and facial numbness scales. Both univariate and multivariate analysis of patient demographics on clinical outcomes were performed using age, comorbidity with multiple sclerosis, time between diagnosis and treatment, previous procedures, and dose rate. Biologically effective dose (BED) was calculated and compared between each dose rate cohort. Furthermore, a comprehensive review of the dosimetric consistency of all plans was performed to assess potential effects on clinical outcomes. Kaplan-Meier analysis and log-rank statistics indicated a statistically significant improvement in pain relief for patients treated with the higher dose rate (p = 0.002). Cox proportional hazards modelling identified dose rate as the only statistically significant hazard, with a hazard ratio of 3.43 (95 % CI = [1.33, 8.84], p = 0.011). All dosimetric consistency tests confirmed comparable treatment delivery across and within cohorts, and a Mann-Whitney U test analysis of the BED between dose rate groups confirmed a statistically significantly higher BED in the 2400 MU⋅min-1 group (p < 0.05). Higher dose rates using cone and frame-based linac-SRS for TN are associated with improved patient outcomes.
2026-09-18 | Hydrogen: a review of the effects and underlying mechanisms in oral diseases.
Oral diseases can affect the quality of life of patients and cause secondary systemic diseases, thereby harming systemic health. Hydrogen has been shown to exhibit anti-oxidant stress, anti-inflammatory and anti-apoptosis and other effects, indicating its therapeutic significance for many kinds of diseases. Hydrogen administered through different methods can effectively reduce plaque biofilm formation, resist oxidative stress, inhibit the inflammatory response, and promote tissue repair and regeneration. This review summarizes the primary strategies for and research on hydrogen therapy, as well as the application of hydrogen in oral diseases such as dental caries, periodontitis, peri-implantitis, oral mucosal diseases, jaw diseases, oral and maxillofacial tumors, and trigeminal neuralgia. We highlight the regulatory effects of hydrogen on the functional states and interactions of common oral disease pathogens and various cells, including immune cells, osteoblast-associated cells, osteoclasts, and fibroblasts, and summarize the involved signaling pathways. In addition, this paper discusses the problems and shortcomings of the existing research, and highlights the directions for future development to provide the basis and support for future investigations into the mechanisms through which hydrogen exerts antioxidant stress and anti-inflammatory activity, promotes mucosal healing, enhances bone regeneration, as well as alleviates neuropathic pain.
2026-09-04 | Clinical outcomes of linear accelerator-based stereotactic radiosurgery for trigeminal neuralgia.
Trigeminal neuralgia (TN) is a severely disabling facial pain disorder. When medical treatment fails, stereotactic radiosurgery (SRS) is an established option. The Gamma Knife is widely used but not always available. This study assessed the efficacy and safety of linear accelerator (LINAC)-based SRS, a more accessible alternative, for the management of classical or idiopathic TN. We conducted a retrospective review of 30 consecutive patients treated between January 2017 and April 2022 in a single oncology center. All patients received SRS delivered with a LINAC targeting the retrogasserian portion of the trigeminal nerve with doses of 80-90 Gy. Demographic, clinical, and treatment variables were collected. Pain outcomes were evaluated using the Barrow Neurological Institute pain scale. The mean age was 57.2 years, with a female predominance. The mandibular branch was the most frequently involved division. Pain relief was achieved in 90% of patients, with a mean onset at 3.1 months. Complete pain relief was obtained in 60% of cases. Pain recurrence occurred in 30% (9/30) of patients within 2-24 months; three benefited from repeat radiosurgery. Adverse effects were mild, mainly facial hypoesthesia and ocular irritation, with no hearing impairment or dry eye. LINAC -based SRS is an effective and safe option for refractory TN. Its accessibility makes it a valuable alternative to Gamma Knife, particularly in centers without dedicated neurosurgical platforms and in low- and middle-income countries.
2026-09-03 | The cerebrospinal fluid-contacting nucleus CGRP-RAMP1-PKA signaling pathway mediates trigeminal neuralgia and its mechanism.
Trigeminal neuralgia (TN) is prevalent form of neuropathic pain (NP). Its regulatory circuits and mechanisms remain unclear. The authors' previous work demonstrated that the cerebrospinal fluid-contacting nucleus (CSF-contacting nucleus) participates in the regulation of NP induced by sciatic nerve injury via the brain-CSF circuit. However, whether it mediates NP caused by trigeminal nerve injury has not been reported. This study used viral retrograde tracing to examine neural projections between the CSF-contacting nucleus and the trigeminal ganglion (TG). Neuronal activity in TN model was assessed using immunofluorescence, and chemogenetic tools were used to test its role in pain behavior. Local calcitonin gene-related peptide (CGRP)-RAMP1-PKA signaling changes and their modulation were analyzed for effects on TN. Retrograde tracing confirmed neural projections between the CSF-contacting nucleus and the TG. In TN model rats, elevated c-Fos expression indicated its activation. Chemogenetic activation induced hyperalgesia in normal rats, whereas its inhibition reduced pain in TN rats. Molecular analyses revealed upregulation of CGRP, RAMP1, and components of the PKA pathway within the nucleus. Pathway inhibition via RAMP1 knockdown or olcegepant administration attenuated pain, with knockdown effect being reversible by cAMP. This study reveals that the CSF-contacting nucleus is activated during TN and participates in central pain regulation through its local CGRP-RAMP1-PKA signaling pathway. Intervening in this pathway effectively modulates pain behavior, suggesting that this nucleus and its signaling system may represent novel therapeutic targets for treating TN. These findings provide experimental evidence for understanding the central mechanisms of TN and developing analgesic strategies.
proteins
2026-08-11 | Botulinum toxin type A attenuates trigeminal neuralgia-like pain by suppressing CGRP release and modulating NaV1.7-associated signaling.
Trigeminal neuralgia (TN) is a disabling facial pain disorder, and current treatments remain insufficient for a substantial proportion of patients. Botulinum toxin type A (BoNT/A) has shown therapeutic benefit in TN, but its peripheral analgesic mechanisms remain incompletely understood. We aimed to determine whether BoNT/A alleviates TN-like pain by modulating the calcitonin gene-related peptide (CGRP)-extracellular signal-regulated kinase (ERK)-NaV1.7 pathway in trigeminal ganglion neurons. TN-like pain was induced in mice by chronic constriction injury of the infraorbital nerve (CCI-ION). On postoperative day 14, BoNT/A (10 U) or saline was injected intradermally into the whisker pad. Evoked and spontaneous pain-like behaviors were assessed using von Frey testing, the Ugo Basile facial pain test, and spontaneous scratching recordings; anxiety-like behavior was evaluated using the elevated plus maze. Myelin pathology was examined by Luxol fast blue staining and transmission electron microscopy. CGRP, NaV1.7/NaV1.8, and ERK/MAPK signaling were examined in trigeminal ganglion neurons using immunofluorescence, Western blotting, RT-qPCR, ELISA, calcium-influx assays, and whole-cell patch-clamp recordings. Olcegepant and PD98059 were used to interrogate CGRP receptor- and ERK-dependent mechanisms. BoNT/A significantly attenuated CCI-ION-induced mechanical allodynia, increasing the facial withdrawal threshold from 0.11 to 1.29 g, and reducing spontaneous pain-like behaviors. BoNT/A also improved anxiety-like behavioral measures in CCI-ION mice. Histological and ultrastructural analyses shown partial amelioration of myelin pathology, accompanied by increased myelin basic protein expression and a lower g-ratio. Mechanistically, BoNT/A reduced CGRP-associated activity in TRPV1-positive trigeminal ganglion neurons, accompanied by lower serum CGRP levels and attenuated capsaicin-evoked calcium influx. These changes were associated with a preferential reduction in NaV1.7 membrane localization, without a comparable reduction in NaV1.8, and with a marked decrease in sodium current density, with peak sodium current reduced by 78.6%. Pharmacological inhibition of CGRP receptors or ERK phosphorylation reproduced the effects of BoNT/A on NaV1.7 membrane localization. These findings suggest that BoNT/A alleviates CCI-ION-induced TN-like pain, at least in part, by suppressing CGRP-dependent ERK activation and subsequent NaV1.7 membrane recruitment in trigeminal ganglion neurons. The CGRP-ERK-NaV1.7 pathway may represent a peripheral mechanism of BoNT/A-mediated analgesia and a potential target for neuropathic facial pain. Not applicable.
2026-06-25 | Botulinumtoxin Type-A (BoNTA) in the Management of Refractory Trigeminal Neuralgia: An Expert-Opinion, Practice-Oriented Narrative Review on Behalf of the GRASP Study Group.
Trigeminal neuralgia (TN) ranks among the most excruciating neuropathic pain syndromes, characterized clinically by multiple daily episodes of unilateral, paroxysmal, electric shock-like facial pain. The daily activities and quality of life of affected patients are profoundly diminished. First-line pharmacological agents, such as carbamazepine and oxcarbazepine, provide initial relief for many patients. However, a significant proportion eventually develops refractory symptoms or experience intolerable adverse effects, leading to the discontinuation of traditional oral medications. For these patients with complex clinical phenotypes who fail to respond or are intolerant to these therapies, alternative pharmacological strategies are required before considering invasive surgical procedures. Over the past two decades, botulinumtoxin type-A (BoNTA) has become an effective and safe, minimally invasive therapeutic option for refractory TN. This review provides a practical framework for BoNTA use in the clinical setting of refractory TN. To connect the pathophysiological background with clinical patient care, we summarize the current understanding of TN pathophysiology, the proposed mechanisms by which BoNTA exerts its antinociceptive effects and the evolving clinical evidence supporting its efficacy and safety. We also critically examine dosing protocols, injection techniques, long-term outcomes and the integration of BoNTA into the management algorithm of refractory TN.
2026-05-27 | Effects of IncobotulinumtoxinA in the Infraorbital Nerve Chronic Constriction Injury Model of Trigeminal Pain in Rats.
Background/Objectives: Trigeminal neuralgia (TN) is a debilitating neurological condition characterized by recurrent, severe pain linked to peripheral and central sensitization within trigeminal pathways. Current pharmacologic treatments are limited by inadequate efficacy or dose-limiting side effects, and botulinum neurotoxin type A (BoNT/A) has emerged as a viable option. However, its potential use in the management of TN is hampered by methodological limitations in existing studies and a lack of pivotal clinical trials. This study investigated the efficacy, optimal treatment site, preventive utility, and duration of effect of incobotulinumtoxinA (Inco/A), a BoNT/A, in a model of TN. Methods: An infraorbital nerve chronic constriction injury model was used to induce mechanical allodynia in male Sprague-Dawley rats, reproducing the trigeminal sensitization seen in TN. The effects of subcutaneous Inco/A (1, 2, and 4 U) were measured using the mechanical sensitivity (von Frey) test to evaluate the dose response, effect of injection location, potential preventive nature of treatment, and duration of benefit. Results: Inco/A produced a robust, dose-dependent reduction in mechanical allodynia, predominantly via a local mechanism of action. Both preventive and therapeutic administration of Inco/A was efficacious, with significant reduction in allodynia even when administered up to 28 days before nerve injury. The anti-allodynic effect persisted up to 56 days post-injection. Conclusions: Inco/A is highly effective in alleviating mechanical allodynia in a validated rat model of TN. The findings highlight Inco/A as a promising candidate for clinical translation in TN and related neuropathic pain syndromes and support systematic investigation in well-controlled human trials.
2026-04-09 | Medical management of refractory trigeminal neuralgia.
First- and second-line medical and surgical therapies for trigeminal neuralgia (TN) may have limited efficacy or tolerability in some individuals. In addition, even when these therapies are initially successful, efficacy frequently wanes over time. This narrative review presents medication options for intractable trigeminal neuralgia with a focus on new and upcoming therapies. Lacosamide, eslicarbazepine, and botulinum toxin are increasingly used for intractable TN, with recent studies demonstrating efficacy. Basimglurant and vixotrigine (BIIB074) are investigational agents currently or recently studied for treatment of TN. Intravenous (i.v.) sodium channel blockers, i.v. magnesium, multiple formulations of lidocaine, and sumatriptan can be used for acute treatment of intractable TN. Multiple medical therapies exist for treatment of intractable TN, with newer options demonstrating efficacy in recent studies. Investigational agents are currently being studied as potential future options for management of intractable TN.
2026-01-24 | Rabies Virus Glycoprotein-Decorated Liposomes in Thermosensitive Nasal Spray Gels: Facilitating Retrograde Neural Transport for Targeted Trigeminal Neuralgia Therapy.
Clinical management of trigeminal neuralgia (TN) is hindered by poor neural bioavailability and systemic toxicity of oral drugs. While the nasal route offers a direct pathway to target the trigeminal nerve, rapid mucociliary clearance and competition from systemic absorption limit its effectiveness. To address these limitations, this study aimed to develop a biomimetic nasal gel system for targeted drug delivery to the trigeminal nerve. Inspired by the neurotropism of rabies virus, we engineered a thermoresponsive nasal spray gel (OMRLP@NSG). The system utilizes rabies virus glycoprotein (RVG)-modified liposomes coloaded with oxcarbazepine and mecobalamin. The liposomal formulation was specifically chosen to enhance drug stability, facilitate mucosal penetration, and provide a platform for neuron-specific targeting via RVG modification. Upon nasal administration, the OMRLP@NSG transitions from spray to gel, enhancing nasal distribution, mucosal adhesion, and neuron-specific targeting. Pharmacokinetics demonstrated a 3 h earlier Tmax and 537.25% higher relative bioavailability in trigeminal nerves versus oral Trileptal. OMRLP@NSG at 1/10th the Trileptal dose achieved comparable trigeminal nerve exposure while reducing off-target site concentrations by 74.18∼92.00% (plasma, brain, liver). Pharmacodynamics showed that the OMRLP@NSG significantly alleviated TN pain in rats, increasing the pain threshold by 3.92-fold over Trileptal. It also normalized the expression of pain-related neuropeptides (substance P and β-endorphin) to 112.05 and 98.81% of normal levels, respectively. Mechanistically, it suppressed P2 × 7R/NLRP3 inflammasome activation, downregulating IL-1β and TNF-α, thereby reducing neuronal damage and promoting remyelination. Additionally, long-term toxicity studies confirmed the favorable in vivo biosafety. This strategy transcends conventional systemic administration paradigms by resolving the tripartite challenge of spatial control, temporal retention, and cellular precision, thereby addressing the critical clinical demand for effective nose-to-brain delivery in trigeminal neuralgia.
cell therapies
2026-09-07 | Endovascular transverse sinus stenting for pressure-dependent trigeminal neuralgia: illustrative case.
Trigeminal neuralgia (TN) is most commonly attributed to neurovascular compression at the trigeminal root entry zone. However, a subset of patients present without clear compressive pathology or with refractoriness to standard therapies, suggesting alternative mechanisms. Emerging evidence implicates intracranial pressure (ICP) dysregulation and venous outflow obstruction as potential contributors to a pressure-dependent form of TN, although this association remains incompletely defined. The authors report the case of a 33-year-old female with medically refractory TN and no radiographic evidence of classical neurovascular compression. Imaging demonstrated features suggestive of intracranial hypertension and severe right transverse sinus stenosis with contralateral sinus hypoplasia. Lumbar puncture revealed elevated opening pressure with transient symptom relief. Cerebral venography confirmed a significant transstenotic pressure gradient. Following endovascular transverse sinus stenting, there was immediate and sustained resolution of facial pain, with discontinuation of all medications and durable improvement at follow-up. TN may, in selected patients, represent a pressure-dependent disorder related to intracranial hypertension and venous outflow obstruction rather than isolated arterial compression. Recognition of this phenotype is important, as ICP-targeted therapies, including venous sinus stenting (VSS), may provide effective treatment in appropriately selected patients. However, current evidence remains limited, and careful diagnostic and hemodynamic evaluation is essential before considering VSS. https://thejns.org/doi/10.3171/CASE26456.
2026-02-03 | Short-term infraorbital nerve electrical stimulation for herpes zoster herpetic trigeminal maxillary division neuralgia: A case report.
Herpetic neuralgia of the maxillary division of the trigeminal nerve is a rare clinical condition characterized by unilaterally distributed burning pain with clustered blister-like lesions. Peripheral nerve stimulation, an effective neuromodulation technique, has demonstrated significant efficacy in treating herpetic neuralgia. However, the application of peripheral nerve stimulation to herpes zoster (HZ) of the maxillary division of the trigeminal nerve is still limited. This study reports a case of HZ trigeminal neuralgia maxillary division neuralgia treated with a short-term infraorbital nerve stimulation guided by digital subtraction angiography (DSA) with satisfactory results. The patient, a 77-year-old male, was admitted to the hospital with "left-sided facial pain with herpes for 1 month." On examination, the left side of the face showed an incompletely dislodged crust and hyperpigmented scar, and the lesion was confined to the infraorbital innervation area. It did not cross the midline of the face, with a positive trigger pain test. Pain assessment: Numerical Rating Scale (NRS) 7 to 8, nocturnal eruptive pain episodes 3 to 4 times/night, Pittsburgh Sleep Quality Index 19 to 20. Herpes zoster neuralgia of the maxillary division of the trigeminal nerve. DSA-guided short-term infraorbital nerve electrical stimulation placement. After a short-term infraorbital nerve stimulation, the patient experienced significant relief of pain symptoms and complete healing of the skin lesions. The NRS score decreased from 7 to 8 before treatment to 2 to 3, and the nocturnal eruption pain disappeared, significantly improving sleep quality. Postoperative follow-up at 1 and 3 months showed that the NRS score decreased to 1 to 2, the Pittsburgh Sleep Quality Index showed a progressive decrease, and sleep quality improved. Our findings suggest that DSA-guided short-term infraorbital nerve electrical stimulation offers a new option for treating pain in patients with HZ herpetic trigeminal maxillary division neuralgia when commonly used clinical treatments are ineffective.
2026-01-24 | The use of cellular therapies for trigeminal neuralgia: a systematic review of behavioral and molecular outcomes.
Trigeminal neuralgia (TN) is a neuropathic pain disorder characterized by severe orofacial pain. The underlying pathophysiological nuances remain under study, and their understanding is key to developing new and more effective therapies for this debilitating disease. The field of cellular therapies for neurological diseases is continuously evolving. This systematic review was performed after the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We sought studies on the preclinical and clinical uses of cellular therapies for trigeminal neuralgia. We included 8 studies encompassing 1 clinical and 7 preclinical applications. Of the preclinical studies, four used Stem Cells from Human Exfoliated Deciduous Teeth (SHED), two used Olfactory Ensheathing Cells (OECs), and one used Bone Marrow Mesenchymal Stem Cells (BMSCs). All preclinical studies showed a statistically significant behavioral improvement in groups receiving cellular therapies compared to controls (p < 0.05), with either local or systemic delivery. In addition, cellular therapies have the potential to mitigate TN by promoting myelin repair, reducing neuroinflammation, and modulating pain-related pathways. The only clinical report in the literature described the incidental use of Adipose-Derived Stem Cells (ADSCs) during a facial cosmetic procedure in a 60-year-old female with a long history of TN, who remained pain-free at 2-year follow-up. These findings highlight the promising role of cellular therapies in the treatment of TN, demonstrating significant behavioral and molecular benefits in preclinical models and a compelling clinical case. Further rigorous clinical studies are necessary to establish their safety, efficacy, and long-term therapeutic impact.
2026-01-14 | Peripheral Nerve Stimulation Is Effective in the Management of Trigeminal Pain: A Systematic Review and meta-analysis.
Trigeminal Neuralgia (TN) patients usually experience severe facial pain, leading to a significant reduction in quality of life. To evaluate the effect of peripheral nerve stimulation (PNS) on pain relief in patients with TN. The databases of EMBASE, WEB OF SCIENCE, and PUBMED were searched from inception to 2024 for clinical trials of PNS for TN. The inclusion criteria consisted of any study using PNS to treat TN and reporting outcomes of pain intensity. Risk of bias was assessed using Revised Cochrane Risk of Bias 2.0 and Methodological Index of Non-Randomised Studies (MINORS) tool. Meta-analysis was conducted with RevMan 5.3 and publication bias was evaluated via Egger's test through STATA17. We identified 1,574 citations, and included 9 trials comprising 112 participants. In terms of efficacy, PNS was associated with significant pain relief compared to baseline (MD, -6.23 cm [95% CI, -7.20 to -5.26 cm], P < 0.05, I2 = 89%), with the reduction closely approaching the minimal important difference (MID) threshold of 6.25 cm. Subgroup analysis showed that patients with baseline pain scores ≥ 8 experienced greater pain relief (N = 52, MD, -7.06 cm [95% CI, -8.30 to -5.82 cm], I2 = 87%, p = 0.02) compared to patients with pain scores < 8(N = 60, MD, -4.75 cm [95% CI, -6.22 to -3.28 cm], I2 = 89%) . The meta-analysis results showed PNS leads to a statistically and clinically significant improvement in pain. PNS may be a promising approach in the management of TN.
2026-01-12 | Sphenopalatine ganglion block in orofacial pain and headache disorders: A review of case reports.
To review and synthesize published case reports on the use of sphenopalatine ganglion (SPG) block in orofacial and headache disorders, focusing on techniques and clinical outcomes. A review of 55 case reports and series extracted data on 29 papers, including diagnoses, SPG block technique, anesthetic or drug, outcomes, and adverse effects. SPG block was reported in trigeminal neuralgia and neuropathies, burning mouth syndrome, non-specified facial pain, autonomic cephalalgias, migraine, tension type headache, COVID related headache and acute cephalalgias. The most frequently used technique was intranasal with cotton tip applicators, with lidocaine 2-10% as the most common agent. Most reports document relief, but long-term data is not available. Neurogenic pain conditions and migraine showed superior therapeutic responses to the SPG block procedure. SPG block appears effective and safe, though higher-level evidence is still needed.
antibodies
2026-09-24 | Cytotoxic Lesion of the Corpus Callosum After Hospital-Administered Intravenous Fentanyl for Trigeminal Neuralgia: A Case Report and Focused Review.
Fentanyl-associated neurotoxicity is increasingly recognized across illicit, inhalational, transdermal, pediatric, and delayed posthypoxic exposures, but isolated splenial CLOCC after hospital-administered intravenous fentanyl has not been well characterized. This is a single-patient case report with a focused review of fentanyl-associated neurotoxic syndromes and proposed mechanisms. A 41-year-old woman with trigeminal neuralgia presented with severe facial pain. After droperidol, metoclopramide, and metamizole failed to control symptoms, intravenous fentanyl (75 μg) was administered. Soon afterward, she developed dizziness, nausea, vomiting, left-sided paresthesias, hypoesthesia, and mild weakness. Initial computed tomography was unrevealing, and cerebrospinal fluid findings were normal. Brain magnetic resonance imaging (MRI) obtained 8 days later showed a 6-mm midline splenial lesion that was hyperintense on T2-weighted and FLAIR sequences, restricted on diffusion-weighted imaging, and nonenhancing, consistent with CLOCC. Follow-up MRI showed complete radiologic resolution, but serial assessments documented persistent deficits in the left upper and lower extremities, including impaired fine motor control, dysdiadochokinesia, arm and leg weakness, foot drag, and gait imbalance; somatosensory-evoked potentials showed mild dysfunction of the left lower-extremity pathway. Review of comparable fentanyl-associated cases shows a spectrum ranging from isolated callosal injury to diffuse, cerebellar, and delayed leukoencephalopathic phenotypes. This case expands the neuroimaging spectrum of fentanyl-associated brain injury and supports a toxic-metabolic pathogenesis in which splenial CLOCC may represent a focal manifestation of broader opioid-related white-matter vulnerability.
2026-09-07 | NEUROPHYSIOLOGICAL BASIS OF PSYCHOSOMATIC DISORDERS IN TRIGEMINAL NEURALGIA
Trigeminal neuralgia (TN) is one of the most severe forms of neuropathic facial pain and is characterized by recurrent, short-lasting, unilateral episodes of electric shock-like pain in the distribution of the trigeminal nerve.(1-3)Despite the predominantly neurological nature of the disorder, chronic and recurrent pain may significantly affect the patient's emotional state, sleep, social activity, and overall quality of life.(6-7) Psychosomatic manifestations, particularly anxiety, depressive symptoms, sleep disturbances, and autonomic dysfunction, may further contribute to the persistence and exacerbation of pain.(8-9-10)
2026-04-20 | HLA genotype testing for carbamazepine, oxcarbazepine and eslicarbazepine: A guideline developed by the UK Centre of Excellence in Regulatory Science and Innovation in Pharmacogenomics (CERSI-PGx).
Carbamazepine is licensed in the United Kingdom for the treatment of epilepsy, bipolar disorder and trigeminal neuralgia. The related compounds oxcarbazepine and eslicarbazepine are licensed for the treatment of epilepsy. These drugs can cause immune-mediated hypersensitivity reactions, which typically affect the skin, and can be of variable severity. The liver and other organ systems can also be affected. The HLA alleles, HLA-B*15:02, HLA-B*15:11 and HLA-A*31:01, are known predisposing factors for these hypersensitivity reactions. Any treatment-naïve patient, regardless of ancestry or indication for treatment, who is about to be prescribed carbamazepine, oxcarbazepine or eslicarbazepine, or has been on these drugs for less than 3 months, should undergo pharmacogenetic testing to identify all clinically relevant HLA alleles to reduce the risk of hypersensitivity reactions. Carbamazepine, oxcarbazepine and eslicarbazepine should be avoided in HLA-B*15:02-positive patients. These drugs should also be avoided in patients positive for HLA-A*31:01 or HLA-B*15:11 if an alternative is possible. Where it is not possible to use an alternative, treatment should only be commenced after careful consideration of the benefits and risks, with increased monitoring and advising patients on appropriate action to take if a skin rash occurs. Our guideline is compatible with other international pharmacogenetics prescribing guidelines. This guideline is grounded in the latest evidence but cannot account for all individual factors relevant to patient care. Therefore, prescribers must conduct a thorough assessment of each patient's risk-benefit profile, ensuring that therapy is optimised to maximise benefits whilst minimising potential harms.
2026-03-19 | Phosphoproteomics uncovers a neuroimmune perspective on trigeminal neuralgia: sexually dimorphic regulatory networks linking calcium channels to the complement cascade.
Trigeminal neuralgia (TN) is a neuropathic pain disorder with a marked female predominance. While transcriptional changes in TN are documented, the translational and post-translational landscapes-specifically protein abundance and phosphorylation states-within the trigeminal ganglion (TG) remain largely unexplored. Understanding these layers is essential to deciphering the mechanisms behind the disease's sexual dimorphism. we utilized the chronic infraorbital nerve ligation (CION) method via an intraoral approach model in male and female Sprague-Dawley rats. Mechanical allodynia was confirmed via behavioral testing. On postoperative day 7, trigeminal ganglia were harvested to capture the somatic molecular response. We performed an integrated analysis using TMT-based quantitative proteomics and phosphoproteomics. Bioinformatics tools were employed to map differentially expressed proteins (DEPs), kinase-substrate relationships, and protein-protein interaction (PPI) networks. The study quantified 5,820 proteins and 8,830 phosphopeptides. (1) A striking divergence was observed in pathological pathways. Females exhibited a robust neuroimmune signature characterized by the specific upregulation of complement components (C1QA, C1QC) and Kininogen (KNG1). In contrast, males showed alterations primarily in lipid metabolism and synaptic vesicle cycles. (2) Phosphoproteomics identified the MAPK signaling pathway as a shared mechanism. Specifically, phosphorylation of HSPB1 at Ser86 (pS86-HSPB1)-a target of the MAPKAPK2/3 cascade-was significantly elevated, linking stress signaling to cytoskeletal reorganization. (3) PPI analysis highlighted voltage-gated calcium channel subunits as central hubs connecting these sex-specific modules, validating the relevance of calcium channel modulation in TN management. This study presents the first dual-omics atlas of the injured trigeminal ganglion. We identify a female-specific "Complement-Kininogen" axis and a conserved "MAPK-HSPB1" phosphorylation pathway as key drivers of TN. These findings provide a molecular explanation for the clinical gender bias and suggest that therapeutic strategies may need to be sex-stratified, with complement inhibition holding particular potential for female patients.
2026-01-24 | Causal interplay between trigeminal neuralgia and systemic inflammatory markers: A bidirectional Mendelian randomization study.
Trigeminal neuralgia (TN) is a debilitating neuropathic pain disorder with profound impacts on quality of life. Although alterations in circulating inflammatory proteins have been reported, observational findings remain inconsistent and are vulnerable to confounding and reverse causation. Whether these immune changes are causal or merely downstream consequences of TN remains uncertain, underscoring the need for robust causal inference methods. We conducted a bidirectional 2-sample Mendelian randomization (MR) analysis to investigate the causal relationships between circulating inflammatory proteins and TN. Genetic instruments for 91 proteins and TN were obtained from large-scale publicly available genome-wide association studies. Five complementary MR estimators were applied - inverse-variance weighting (IVW), MR-Egger, weighted median, weighted mode, and simple mode - and sensitivity analyses were performed to evaluate heterogeneity, pleiotropy, and robustness. Forward MR identified 5 proteins significantly associated with TN risk: eotaxin (IVW odds ratio [OR] = 0.834, 95% CI = 0.711-0.977, P = .025); C-X-C motif chemokine ligand 5 [CXCL5]; IVW OR = 0.841, 95% CI = 0.726-0.974, P = .021); IL-20RA (IVW OR = 1.317, 95% CI = 1.032-1.679, P = .027); interleukin-6 (IVW OR = 1.343, 95% CI = 1.059-1.704, P = .015); and neurturin (IVW OR = 1.190, 95% CI = 1.004-1.410, P = .044). Reverse MR indicated that TN causally influenced 5 immune traits: eotaxin (OR = 0.39, 95% CI = 0.19-0.80, P = .010); CXCL5 (OR = 0.32, 95% CI = 0.11-0.91, P = .032); IL-20RA (OR = 2.07, 95% CI = 1.11-3.84, P = .022); interleukin-15 receptor α (OR = 0.28, 95% CI = 0.08-0.99, P = .048); and transforming growth factor-α (OR = 0.44, 95% CI = 0.23-0.83, P = .011). Notably, eotaxin, CXCL5, and IL-20RA showed bidirectional associations with TN. All signals were consistent across complementary estimators and sensitivity analyses, with no evidence of heterogeneity or horizontal pleiotropy (all P > .05). Our genetic evidence demonstrates a close coupling between the circulating inflammatory network and TN, providing testable leads for biomarker development and immunomodulatory strategies in TN.
other
2026-03-13 | A Tac1-Expressing Brainstem Pathway Underlies the Pathogenesis of Trigeminal Neuralgia.
Trigeminal neuralgia (TN) is widely recognized to be one of the most severe pain disorders, severely affects the life quality of patients. However, the neuronal mechanisms underlying TN pathogenesis remain largely unknown. Here, we identify a periphery-to-brain neural circuit that governs TN development in mice. Tachykinin 1 (Tac1)-expressing parabrachial nucleus (PBNTac1) neurons show heightened stimulus-evoked responses, and chemogenetic inhibition of these neurons effectively prevents TN development. Furthermore, PBNTac1 neurons receive projections from the caudal part of the spinal trigeminal nucleus (Sp5C), and PBN-projecting Sp5C neurons are essential for TN-induced pain hypersensitivity. Remarkably, PBN-projecting Sp5C neurons predominantly express Tac1, and knockdown Tac1 gene in these neurons significantly attenuates TN-induced pain hypersensitivity. Through retrograde viral tracing and electrophysiological recordings, we demonstrate that Tac1-expressing Sp5C neurons directly relay signals from the trigeminal ganglion (TG) to the PBN. Collectively, our findings unveil a critical TG-Sp5CTac1-PBNTac1 pathway that drives the TN pathogenesis.
2026-02-20 | Nr4a1 regulates microglia overactivation-mediated neuroinflammation to ameliorate cognitive impairment in trigeminal neuralgia rats.
BACKGROUND: Cognitive impairment affects prognosis and quality of life in patients with trigeminal neuralgia (TN). Modulating hippocampal microglial activation is a promising approach for addressing TN-related cognitive deficits. Nuclear receptor subfamily 4 group A member 1 (Nr4a1) is involved in hippocampal-dependent cognition and microglial homeostasis. However, its role in trigeminal neuralgia-associated cognitive dysfunction remains unclear. We aimed to investigate the role of Nr4a1 in regulating neuroinflammation mediated by microglial hyperactivation, and to establish the relationship between the resulting synaptic plasticity impairment and cognitive dysfunction. METHODS: A TN rat model was established using chronic constriction injury of the distal infraorbital nerve. Cognitive function and hippocampal microglial activation were evaluated over time. Transcriptomic sequencing was performed to identify differentially expressed genes related to microglial activation. Nr4a1 was overexpressed in hippocampal microglia using adeno-associated virus and lentivirus in TN rats and BV2 cells, respectively. Multi-omics analyses, co-immunoprecipitation, and mass spectrometry were used for mechanistic assessments. RESULTS: Here, we observed that TN rats exhibited time-dependent cognitive impairment accompanied by excessive activation of hippocampal microglia and significant downregulation of Nr4a1 expression. Nr4a1 overexpression suppresses excessive activation of microglia and the neuroinflammation they mediate. These effects correlate with restored neuronal autophagy, enhanced synaptic plasticity, and improved cognitive function in TN rats. Mechanistically, we first revealed aberrant alterations in the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway through multi-omics sequencing. Furthermore, we identified Nr4a1 primarily targeting Akt2 among the Akt isoforms in the rat hippocampus. Restoring Nr4a1 expression reversed PI3K/Akt2 signaling downregulation in vivo and in vitro, whereas PI3K/Akt2 signaling pharmacological inhibition abrogated Nr4a1 overexpression-mediated benefits. CONCLUSION: Collectively, Nr4a1 may suppress excessive microglial activation by restoring the PI3K/Akt2 signaling pathway to alleviate neuroinflammation, thereby improving neuronal autophagy and synaptic plasticity. Our findings provide a deeper theoretical basis and molecular target for future TN-related cognitive impairment treatment.
2025-12-26 | Cerebellar neurocan gene expression is a common pathogenic factor of trigeminal neuralgia and depression.
BACKGROUND: Trigeminal neuralgia (TN) is a severe neuropathic pain disorder characterized by sudden, electric shock-like facial pain. It frequently co-occurs with depression and these conditions often exacerbate each other. However, their shared pathogenic mechanisms remain poorly understood METHODS: In this study, neuroimaging data were integrated with whole-genome sequencing data to identify common genetic risk factors. Initially, single nucleotide polymorphisms (SNPs) associated with both conditions were identified through whole-genome analysis. Gene-tissue associations were then elucidated using the S-PrediXcan and summary data-based Mendelian Randomization (SMR) methods. These findings were further validated through neuroimaging analysis and animal experiments. RESULTS: Whole-genome analysis identified SNPs shared by TN and depression. The neurocan (NCAN) gene was significantly associated with both disorders and showed a cerebellum-specific expression pattern. Neuroimaging revealed significant differences in brain function and structure between TN and depression patients, primarily localized in the temporal lobe, frontal lobe, and cerebellum. Animal experiments corroborated these findings, showing that elevated cerebellar NCAN expression is closely linked to the onset and progression of both TN and depression. CONCLUSIONS: The study identifies the NCAN gene and cerebellar dysfunction as shared potential pathogenic factors between TN and depression. These findings provide new insights into the common mechanisms underlying these comorbid conditions and suggest potential implications for developing targeted therapeutic strategies.
2025-12-16 | USP19 restores mitochondrial function in neurons by deubiquitinating FUS to alleviate trigeminal neuralgia.
Deubiquitinating enzymes of the ubiquitin-specific peptidase (USP) family have been increasingly recognized for their roles in modulating neuropathic pain. In this study, bioinformatic analysis identified USP19 as a downregulated gene in trigeminal neuralgia (TN). Using a mouse model of TN induced by foramen lacerum impingement of the trigeminal nerve (FLIT), we demonstrated that adeno-associated virus-mediated overexpression of USP19 in the cerebral cortex significantly alleviated anxiety-like and pain-like behaviors. USP19 overexpression promoted deubiquitination and stabilization of fused in sarcoma (FUS), as confirmed by Western blotting, actinomycin D treatment, and ubiquitination assays. In HT22 and SH-SY5Y cells exposed to lipopolysaccharide to induce mitochondrial dysfunction, USP19 restored mitochondrial membrane potential, reduced mitochondrial reactive oxygen species, suppressed DRP1 phosphorylation, and upregulated CYTB and ND4 levels. These effects were reversed by FUS knockdown, both in vitro and in vivo. Moreover, FUS silencing abolished USP19-mediated improvements in NAD⁺/NADH ratio and mitochondrial function, as well as its analgesic and anxiolytic benefits in TN mice. These findings suggest that USP19 alleviates TN by enhancing FUS deubiquitination and preserving mitochondrial integrity in neurons. This study reveals a novel USP19/FUS signaling axis in the regulation of mitochondrial homeostasis and provides a promising therapeutic target for the treatment of TN.
2025-10-11 | Reprogramming activated astrocytes into GABAergic neurons to treat trigeminal neuralgia.
Trigeminal neuralgia (TN) is the most common type of cranial neuralgia. Currently, there remains a significant gap in the availability of effective and safe treatment options in clinical practice. Transdifferentiation of proliferating activated astrocytes into inhibitory neurons is a potential therapeutic strategy for central nervous system diseases. GABAergic neurons are one of the most type of prevalent inhibitory neurons. This study aims to reprogram proliferating astrocytes in the spinal trigeminal subnucleus caudalis (SpVc) into GABAergic neurons, could improve neuronal excitation-inhibition balance, alleviate pain, which serve as a potential treatment for trigeminal neuralgia. A chronic constriction injury of the distal infraorbital nerve (CCI-dION) was induced in the infraorbital branch of the trigeminal nerve to create a rat model of TN. Adeno-associated viruses were used to overexpress transcription factors Sox2 and Mash1 in astrocytes. The changes in astrocytes and GABAergic neurons in the SpVc region were detected by immunofluorescence, Western blotting, qPCR, and electron microscopy. The mechanical pain threshold testing was used to assess rat TN. In the SpVc region of CCI-dION rats, astrocytes showed proliferation and activation, and the number of GABAergic neurons decreased significantly. Overexpressing Sox2 and Mash1 in astrocytes led to a significant transdifferentiation into GABAergic neurons, which - improved the mechanical pain threshold in CCI-dION rats. Furthermore, fluorocitrate-mediated astrocyte deactivation abolished both the neuronal reprogramming and the analgesic effects, underscoring the essential role of astrocytes in this process. These findings suggest that overexpressing Sox2 and Mash1 in astrocytes led to a significant transdifferentiation into GABAergic neurons, which significantly improved the mechanical pain threshold in CCI-dION rats. Thus, this approach has the potential to provide a new treatment for TN.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
7 orphan drug designations for Trigeminal neuralgia.
7 orphan drug designations for Trigeminal neuralgia.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
trimeprazine tartrate | small molecules | FDA | — | Undaunted Bio, Inc. |
A potent negative allosteric modulator (NAM) of human alpha5-GABAA receptor | small molecules | FDA | Shanghai SIMR Biotechnology Co., Ltd. | |
carbon dioxide | small molecules | FDA | Capnia, Inc. | |
vixotrigine | small molecules | FDA | Biogen, Inc. | |
dehydrated alcohol | small molecules | FDA | — | Luitpold Pharmaceuticals, Inc. |
L-baclofen | small molecules | FDA | — | Osmotica Pharmaceutical Corp. |
L-baclofen | small molecules | FDA | — | Fromm, Gerhard M.D. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.