Female sex is a risk factor for painful diabetic peripheral neuropathy: the EURODIAB prospective diabetes complications study.

AIMS/HYPOTHESIS: While the risk factors for diabetic peripheral neuropathy (DPN) are now well recognised, the risk factors for painful DPN remain unknown. We performed analysis of the EURODIAB Prospective Complications Study data to elucidate the incidence and risk factors of painful DPN. METHODS: The EURODIAB Prospective Complications Study recruited 3250 participants with type 1 diabetes who were followed up for 7.3±0.6 (mean ± SD) years. To evaluate DPN, a standardised protocol was used, including clinical assessment, quantitative sensory testing and autonomic function tests. Painful DPN (defined as painful neuropathic symptoms in the legs in participants with confirmed DPN) was assessed at baseline and follow-up. RESULTS: At baseline, 234 (25.2%) out of 927 participants with DPN had painful DPN. At follow-up, incident DPN developed in 276 (23.5%) of 1172 participants. Of these, 41 (14.9%) had incident painful DPN. Most of the participants who developed incident painful DPN were female (73% vs 48% painless DPN p=0.003) and this remained significant after adjustment for duration of diabetes and HbA1c (OR 2.69 [95% CI 1.41, 6.23], p=0.004). The proportion of participants with macro- or microalbuminuria was lower in those with painful DPN compared with painless DPN (15% vs 34%, p=0.02), and this association remained after adjusting for HbA1c, diabetes duration and sex (p=0.03). CONCLUSIONS/INTERPRETATION: In this first prospective study to investigate the risk factors for painful DPN, we definitively demonstrate that female sex is a risk factor for painful DPN. Additionally, there is less evidence of diabetic nephropathy in incident painful, compared with painless, DPN. Thus, painful DPN is not driven by cardiometabolic factors traditionally associated with microvascular disease. Sex differences may therefore play an important role in the pathophysiology of neuropathic pain in diabetes. Future studies need to look at psychosocial, genetic and other factors in the development of painful DPN.

Considerations When Using Gabapentinoids to Treat Trigeminal Neuralgia: A Review.

Despite the exemplary efficacy of voltage-gated sodium channel blockers as a first-line treatment of trigeminal neuralgia, the pharmacological management of this excruciating facial pain condition remains a major issue, as these first-line drugs produce intolerable side effects in a significant portion of patients. In addition, in patients with concomitant continuous pain, the efficacy of these drugs may drop, thus suggesting the opportunity to test the efficacy of different drug categories. The aim of this review is to provide current, evidence-based, knowledge about the use of gabapentin and other α2δ ligands in patients with trigeminal neuralgia. We searched for relevant papers within PubMed, EMBASE, the Cochrane Database of Systematic Reviews and the Clinical Trials database (ClinicalTrials.gov), considering publications up to April 2023. Two authors independently selected studies for inclusion and data extraction. The efficacy of α2δ ligands, gabapentin and pregabalin, has been assessed in seven controlled or open-label studies. Despite the low quality of evidence, the favorable tolerability profile and the possible action on concomitant continuous pain make this drug category of interest for future trials in trigeminal neuralgia.

Pain-motor integration in chronic pain: A neurophysiological study.

OBJECTIVE: Chronic pain may lead to functional changes in several brain regions, including the primary motor cortex (M1). Our neurophysiological study aimed to probe M1 plasticity, through a non-invasive transcranial magnetic stimulation protocol, in a cohort of patients with chronic pain. METHODS: Twenty patients with chronic pain (age ± SD: 62.9 ± 9.9) and 20 age- and sex-matched healthy controls (age ± SD: 59.6 ± 15.8) were recruited. Standardized scales were used for the evaluation of pain severity. Neurophysiological measures included laser-evoked potentials (LEPs) and motor-evoked potentials (MEPs) collected at baseline and over 60 minutes following a standardized Laser-paired associative stimulation (Laser-PAS) protocol. RESULTS: LEPs and MEPs were comparable in patients with chronic pain and controls. The pain threshold was lower in patients than in controls. Laser-PAS elicited decreased responses in patients with chronic pain. The response to Laser-PAS was similar in subgroups of patients with different chronic pain phenotypes. CONCLUSIONS: M1 plasticity, as tested by Laser-PAS, is altered in patients with chronic pain, possibly reflecting abnormal pain-motor integration processes. SIGNIFICANCE: Chronic pain is associated with a disorder of M1 plasticity raising from abnormal pain-motor integration.

Joint European Academy of Neurology-European Pain Federation-Neuropathic Pain Special Interest Group of the International Association for the Study of Pain guidelines on neuropathic pain assessment.

BACKGROUND AND PURPOSE: In these guidelines, we aimed to develop evidence-based recommendations for the use of screening questionnaires and diagnostic tests in patients with neuropathic pain (NeP). METHODS: We systematically reviewed studies providing information on the sensitivity and specificity of screening questionnaires, and quantitative sensory testing, neurophysiology, skin biopsy, and corneal confocal microscopy. We also analysed how functional neuroimaging, peripheral nerve blocks, and genetic testing might provide useful information in diagnosing NeP. RESULTS: Of the screening questionnaires, Douleur Neuropathique en 4 Questions (DN4), I-DN4 (self-administered DN4), and Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) received a strong recommendation, and S-LANSS (self-administered LANSS) and PainDETECT weak recommendations for their use in the diagnostic pathway for patients with possible NeP. We devised a strong recommendation for the use of skin biopsy and a weak recommendation for quantitative sensory testing and nociceptive evoked potentials in the NeP diagnosis. Trigeminal reflex testing received a strong recommendation in diagnosing secondary trigeminal neuralgia. Although many studies support the usefulness of corneal confocal microscopy in diagnosing peripheral neuropathy, no study specifically investigated the diagnostic accuracy of this technique in patients with NeP. Functional neuroimaging and peripheral nerve blocks are helpful in disclosing pathophysiology and/or predicting outcomes, but current literature does not support their use for diagnosing NeP. Genetic testing may be considered at specialist centres, in selected cases. CONCLUSIONS: These recommendations provide evidence-based clinical practice guidelines for NeP diagnosis. Due to the poor-to-moderate quality of evidence identified by this review, future large-scale, well-designed, multicentre studies assessing the accuracy of diagnostic tests for NeP are needed.

Safety and efficacy of erenumab in patients with trigeminal neuralgia in Denmark: a double-blind, randomised, placebo-controlled, proof-of-concept study.

BACKGROUND: Trigeminal neuralgia is a severe facial pain disorder that is difficult to treat. Erenumab, a monoclonal antibody against the calcitonin gene-related peptide (CGRP) receptor, has proven efficacy in migraine. Erenumab modulates sensory processing in peripheral trigeminal pain pathways in mice and was reported to be effective for patients with trigeminal neuralgia in open-label studies. We aimed to evaluate the efficacy of erenumab in patients with trigeminal neuralgia. METHODS: We did a randomised, double-blind, placebo-controlled trial in adults (aged 18-85 years) with idiopathic or classic trigeminal neuralgia as defined by the 3rd edition of the International Classification of Headache Disorders. The trial was based at the Danish Headache Center, Copenhagen University Hospital. Eligible participants had no clinically significant cerebrovascular or cardiovascular disease, had self-reported pain intensity of at least 4 on the 11-point Numeric Rating Scale (0=no pain, 10=worst pain imaginable), and had at least three daily pain paroxysms. After a 1-week pre-screening period, patients entered a 4-week baseline period. Participants who met pain inclusion criteria at the end of the baseline period were randomly assigned (1:1) to receive subcutaneous injections of either erenumab 140 mg or placebo and entered the 4-week follow-up period. Randomisation was done in blocks of 10 using a computer-generated schedule by a third-party company. Participants and assessors were masked to treatment allocation, and erenumab and placebo were packed in identical prefilled syringes. The primary outcome was the number of responders, defined as patients who had a reduction of at least 30% in mean average daily pain intensity during the follow-up period compared with during the baseline period, analysed in the intention-to-treat population. This trial is registered with the European Union Drug Regulating Authorities Clinical Trials Database, EudraCT number 2019-000848-95. FINDINGS: We assessed 860 patients for suitability and excluded 741 between Oct 28, 2019, and Sept 13, 2021. 119 participants entered a 1-week pre-screening period and 26 were excluded, 93 participants entered a 4-week baseline period with 13 excluded before randomisation, and 80 participants were randomly assigned to erenumab 140 mg (n=40) or placebo (n=40). There was no difference between groups in the number of responders at 4 weeks in the intention-to-treat population (14 [35%] of 40 with erenumab vs 18 [45%] of 40 with placebo; estimated effect size -10% [95% CI -31 to 11]; p=0·36). 20 (50%) of 40 participants reported adverse events in each group. The most common adverse events were constipation (28%) and headache (10%) in the erenumab group, and headache (13%), constipation (10%), and abdominal pain (10%) in the placebo group. INTERPRETATION: Erenumab did not reduce pain intensity compared with placebo in patients with trigeminal neuralgia and CGRP probably does not have an important role in paroxysmal pain. Well tolerated, effective treatments in trigeminal neuralgia are still needed. FUNDING: Novartis.

A TRPM7 mutation linked to familial trigeminal neuralgia: Omega current and hyperexcitability of trigeminal ganglion neurons.

Trigeminal neuralgia (TN) is a unique pain disorder characterized by intense paroxysmal facial pain within areas innervated by the trigeminal nerve. Although most cases of TN are sporadic, familial clusters of TN suggest that genetic factors may contribute to this disorder. Whole-exome sequencing in patients with TN reporting positive family history demonstrated a spectrum of variants of ion channels including TRP channels. Here, we used patch-clamp analysis and Ca2+ and Na+ imaging to assess a rare variant in the TRPM7 channel, p.Ala931Thr, within transmembrane domain 3, identified in a man suffering from unilateral TN. We showed that A931T produced an abnormal inward current carried by Na+ and insensitive to the pore blocker Gd3+. Hypothesizing that replacement of the hydrophobic alanine at position 931 with the more polar threonine destabilizes a hydrophobic ring, near the voltage sensor domain, we performed alanine substitutions of F971 and W972 and obtained results suggesting a role of A931-W972 hydrophobic interaction in S3-S4 hydrophobic cleft stability. Finally, we transfected trigeminal ganglion neurons with A931T channels and observed that expression of this TRPM7 variant lowers current threshold and resting membrane potential, and increases evoked firing activity in TG neurons. Our results support the notion that the TRPM7-A931T mutation located in the S3 segment at the interface with the transmembrane region S4, generates an omega current that carries Na+ influx in physiological conditions. A931T produces hyperexcitability and a sustained Na+ influx in trigeminal ganglion neurons that may underlie pain in this kindred with trigeminal neuralgia.

Dissecting pain processing in adolescents with Non-Suicidal Self Injury: Could suicide risk lurk among the electrodes?

BACKGROUND: Although non-suicidal self-injury (NSSI) disorder is highly prevalent in adolescents, its relationship with pain system function and suicidality is still controversial. The present study was designed to assess the function of the nociceptive afferent pathways and the endogenous pain modulation in adolescent patients with NSSI and to longitudinally register any suicide attempt, describe its frequency and find a possible association between suicide, neurophysiological measures and psychological measures. METHODS: We enrolled 30 adolescents suffering from NSSI and 20 age- and gender-matched healthy controls. Patients underwent a comprehensive psychological evaluation. Each participant underwent thermal pain thresholds of the quantitative sensory testing, laser-evoked potential recording to study the ascending nociceptive pathway and the conditioned pain modulation testing to test the endogenous pain modulation. RESULTS: We found that patients with NSSI had a reduced amplitude of the N2 component of laser-evoked potentials and an abnormal conditioned pain modulation. The amplitude of the N2 was associated with suicidal risk. CONCLUSIONS: The deficit of the endogenous pain modulation likely depends on a saturation due to continuous pain solicitation. The strong association of a reduced amplitude of the N2 component with suicide suggests that it may serve as a possible biomarker in self-harming adolescents. SIGNIFICANCE: The present study identifies the N2 component of laser-evoked potentials as a possible neurophysiological biomarker of suicidal risk in patients with non-suicidal self-injury, therefore, raising the possibility for a non-invasive test to identify subjects at higher risk of suicide among self-harming patients.

Trigeminal Neuralgia TRPM8 Mutation: Enhanced Activation, Basal [Ca2+]i and Menthol Response.

OBJECTIVE: To assess the functional effects of a variant, c.89 G > A (p.Arg30Gln), in the transient receptor potential melastatin 8 (TRPM8) cold-sensing, nonselective cation channel, which we have previously identified in a patient with familial trigeminal neuralgia. METHODS: We carried out Ca2+ imaging and whole-cell patch-clamp recording. RESULTS: The TRPM8 mutation enhances channel activation, increases basal current amplitude and intracellular [Ca2+] in cells carrying the mutant channel, and enhances the response to menthol. CONCLUSIONS: We propose that Arg30Gln confers gain-of-function attributes on TRPM8, which contribute to pathogenesis of trigeminal neuralgia in patients carrying this mutation.

Pharmacotherapeutic Options for Managing Neuropathic Pain: A Systematic Review and Meta-Analysis.

Despite an increasing number of available therapies, the treatment of neuropathic pain remains a major issue. Systematic reviews and meta-analyses indicate that only a minority of patients with neuropathic pain have an adequate response to pharmacological treatment and that most drugs have dose-limiting side effects. We conducted a systematic review and meta-analysis of randomised controlled trials published in the last five years. We searched for relevant papers within PubMed, EMBASE, the Cochrane Database of Systematic Reviews, and the Clinical Trials database (ClinicalTrials.gov). Two authors independently selected studies for inclusion, data extraction, and bias assessment. We identified 39 randomised controlled trials and included 16 in the meta-analysis. Trial outcomes were generally modest even for first-line drugs such as tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitors, and gabapentinoids. Many drugs acting on new pain targets are currently under development. Clinical data are currently available for sodium channel isoform-specific antagonists, anti-nerve growth factor molecules, and fatty acid amide hydrolase inhibitors.

Real-world effectiveness and tolerability of carbamazepine and oxcarbazepine in 354 patients with trigeminal neuralgia.

BACKGROUND: It is widely agreed that carbamazepine and oxcarbazepine are highly effective in the long-term treatment of trigeminal neuralgia. However, the tolerability of these drugs across the different aetiologies of trigeminal neuralgia is still undetermined. METHODS: In this retrospective, real-world study, we assessed the effectiveness and tolerability of carbamazepine and oxcarbazepine in a large cohort of patients with classical (254 patients), secondary (60 patients) and idiopathic (40 patients) trigeminal neuralgia. We analysed data using a propensity score analysis to account for selection bias; frequencies of side effects associated with carbamazepine and oxcarbazepine were calculated by adjusting data with the inverse probability of treatment weighting. RESULTS: The initial proportion of responders was 88.3% with carbamazepine, and 90.9% with oxcarbazepine. The number of refractory patients was significantly higher in idiopathic (15%) and secondary forms (27%) than in classical trigeminal neuralgia (6%; p < .05). In 53 patients treated with carbamazepine (29.6%) and in 22 treated with oxcarbazepine (12.6%), major side effects caused treatment interruption or dosage reduction to an unsatisfactory level. Side effects occurred more frequently in patients treated with carbamazepine (43.6%) than with oxcarbazepine (30.3%, p < .0001). The frequency of treatment discontinuation was higher in patients with secondary and idiopathic forms than in those with classical trigeminal neuralgia (p < .05). CONCLUSIONS: Our real-world study shows that carbamazepine and oxcarbazepine are effective in most patients with trigeminal neuralgia; nevertheless, side effects are still a major issue, particularly in patients with secondary and idiopathic trigeminal neuralgia. SIGNIFICANCE: Although carbamazepine and oxcarbazepine are effective in most patients with trigeminal neuralgia, their side effects are still a major issue, thus necessitating the development of better-tolerated drugs.

Differential involvement of myelinated and unmyelinated nerve fibers in painful diabetic polyneuropathy.

BACKGROUND: We aimed at evaluating the differential involvement of large myelinated Aß-, small myelinated Aδ-, and unmyelinated C-fibers in patients with diabetic polyneuropathy and how they contribute to neuropathic pain. METHODS: We collected clinical and diagnostic test variables in 133 consecutive patients with diabetic polyneuropathy. All patients underwent Aß-fiber mediated nerve conduction study, Aδ-fiber mediated laser-evoked potentials and skin biopsy mainly assessing unmyelinated C-fibers. RESULTS: Pure large-fiber and small-fiber polyneuropathy were relatively uncommon; conversely mixed-fiber polyneuropathy was the most common type of diabetic polyneuropathy (74%). The frequency of neuropathic pain was similar in the three different polyneuropathies. Ongoing burning pain and dynamic mechanical allodynia were similarly associated with specific small-fiber related variables. CONCLUSIONS: Diabetic polyneuropathy mainly manifests as a mixed-fiber polyneuropathy, simultaneously involving Aß-, Aδ-, and C-fibers. In most patients, neuropathic pain is distinctly associated with small-fiber damage. The evidence that the frequency of neuropathic pain does not differ across pure large-, pure small-, and mixed-fiber polyneuropathy, raises the possibility that in patients with pure large-fiber polyneuropathy nociceptive nerve terminal involvement might be undetected by standard diagnostic techniques.

Painful stimulation increases spontaneous blink rate in healthy subjects.

Spontaneous blink rate is considered a biomarker of central dopaminergic activity. Recent evidence suggests that the central dopaminergic system plays a role in nociception. In the present study, we aimed to investigate whether pain modulates spontaneous blink rate in healthy subjects. We enrolled 15 participants. Spontaneous blink rate was quantified with an optoelectronic system before and after: (1) a painful laser stimulation, and (2) an acoustic startling stimulation. In control experiments, we investigated whether laser stimulation effects depended on stimulation intensity and whether laser stimulation induced any changes in the blink reflex recovery cycle. Finally, we investigated any relationship between spontaneous blink rate modification and pain modulation effect during the cold pressor test. Laser, but not acoustic, stimulation increased spontaneous blink rate. This effect was independent of stimulation intensity and negatively correlated with pain perception. No changes in trigeminal-facial reflex circuit excitability were elicited by laser stimulation. The cold pressor test also induced an increased spontaneous blink rate. Our study provides evidence on the role of dopamine in nociception and suggests that dopaminergic activity may be involved in pain modulation. These findings lay the groundwork for further investigations in patients with pathological conditions characterized by dopaminergic deficit and pain.

Efficacy and Safety of Low Doses of Trazodone in Patients Affected by Painful Diabetic Neuropathy and Treated with Gabapentin: A Randomized Controlled Pilot Study.

BACKGROUND: Painful diabetic neuropathy is an important therapeutic challenge as the efficacy of analgesic drugs in this setting is still unsatisfactory. Monotherapy with available treatments is often not sufficient and a combination of drugs is necessary. Trazodone (TRZ) is a compound with a multi-modal mechanism of action, being a serotonin-2 antagonist/reuptake inhibitor developed and approved for the treatment of depression in several countries. Previous clinical trials suggest a possible beneficial effect of low doses of trazodone for the treatment of patients affected by painful diabetic neuropathy. OBJECTIVE: This phase II study was designed to collect data on the efficacy and safety of low doses of TRZ combined with gabapentin after 8 weeks of treatment in patients affected by painful diabetic neuropathy. METHODS: This was a randomized, double-blind, placebo-controlled, multi-center, international, prospective study. Male and female diabetic patients aged 18-75 years and affected by painful diabetic neuropathy were eligible for enrollment. Subjects were randomized (1:1:1 ratio) to TRZ30 (10 mg three times daily for 8 weeks) or TRZ60 (20 mg three times daily for 8 weeks) or placebo. Gabapentin as background therapy was administered in open-label conditions to all patients. The primary endpoint was the change from baseline of the Brief Pain Inventory Short Form item 5 to week 8. Secondary endpoints included the other Brief Pain Inventory Short Form items, and the assessment of anxiety, sleep, quality of life, patient's improvement, and safety. RESULTS: One hundred and forty-one patients were included in the intention-to-treat population: 43 allocated to the TRZ30 group, 50 to the TRZ60 group, and 48 to the placebo group. After 8 weeks, the mean changes of Brief Pain Inventory Short Form item 5 from baseline were - 3.1, - 2.6, and - 2.5 in the TRZ30, TRZ60, and placebo groups, respectively. No statistically significant differences between groups were seen. Nevertheless, a better trend was observed for TRZ30 vs placebo (95% confidence interval - 1.30, 0.15; p = 0.1179), on top of the background effect of gabapentin administered to all study groups. 62.8% of patients achieved a ≥ 50% reduction in the TRZ30 group, 54% in the TRZ60 group, and 45.8% in the placebo group. At the same time, a statistically significant improvement was observed in Brief Pain Inventory Short Form item 6 for TRZ30 vs placebo (95% confidence interval - 1.54, - 0.07; p = 0.0314). No serious adverse event occurred during the trial and the most frequent treatment-emergent adverse events involved nervous system, QT prolongation, and gastrointestinal disorders. CONCLUSIONS: All treatment groups showed a clinically meaningful pain improvement; nevertheless, patients in the TRZ30 treatment group reported better efficacy outcomes. This finding suggests that low doses of TRZ could be useful for treating painful diabetic neuropathy, and support further adequately powered confirmatory trials investigating the efficacy of TRZ. CLINICAL TRIAL REGISTRATION: NCT03202979, date of registration: 29/06/2017.

Small-fibre pathology has no impact on somatosensory system function in patients with fibromyalgia.

We aimed to investigate whether small-fibre pathology, a common skin biopsy finding in patients with fibromyalgia, implies clinically important abnormalities of somatosensory system function and verify whether it is associated with voltage-gated sodium channel variants. In 57 consecutively enrolled patients with fibromyalgia, we used skin biopsy to distinguish patients with and without small-fibre pathology. In all patients, we assessed somatosensory system function using quantitative sensory testing (QST) and laser-evoked potentials and investigated voltage-gated sodium channel genotyping. We then compared these variables in patients with and without small-fibre pathology. We found that clinical measures, QST, and laser-evoked potential variables did not differ between patients with and without small-fibre pathology. In most patients with small-fibre pathology, QST and laser-evoked potential variables fell within normative ranges commonly used in clinical practice. Of the 57 patients, one patient without small-fibre pathology and 2 patients with small-fibre pathology had rare variants of voltage-gated sodium channels, namely SCN11A, SCN9A, and SCN1A variants. The SCN9A variant, found in a patient with small-fibre pathology, was an already profiled gain-of-function mutation, previously reported in small-fibre neuropathy. Our findings suggest that small-fibre pathology has a negligible impact on somatosensory system function in fibromyalgia. The genetic analysis suggests that patients with rare small-fibre neuropathy due to voltage-gated sodium channel variants may be misdiagnosed as patients with fibromyalgia.

Advances in diagnosis, classification, pathophysiology, and management of trigeminal neuralgia.

Trigeminal neuralgia is a very painful neurological condition with severe, stimulus-evoked, short-lasting stabbing pain attacks in the face. The past decade has offered new insights into trigeminal neuralgia symptomatology, pathophysiology, and treatment, leading to a change in the classification of the condition. An accurate diagnosis is crucial because neuroimaging interpretation and clinical management differ among the various forms of facial pain. MRI using specific sequences should be a part of the diagnostic workup to detect a possible neurovascular contact and exclude secondary causes. Demonstration of a neurovascular contact should not be used to confirm a diagnosis but rather to facilitate surgical decision making. Carbamazepine and oxcarbazepine are drugs of first choice for long-term treatment, whereas microvascular decompression is the first-line surgery in medically refractory patients. Advances in neuroimaging techniques and animal models will provide further insight into the causes of trigeminal neuralgia and its pathophysiology. Development of more efficacious treatment options is highly warranted.

Conduction velocity of the cold spinal pathway in healthy humans.

OBJECTIVES: We aimed to investigate the conduction velocity of the cold spinal pathway in healthy humans. METHODS: Using a cold stimulator consisting of micro-Peltier elements that was able to produce steep cooling ramps up to -300°C/s, we recorded cold-evoked potentials after stimulation of the dorsal midline at C5, T2, T6 and T10 vertebral levels and calculated the conduction velocity of the cold spinal pathway. In all participants, we used laser stimulation to deliver painful heat (Aδ-fibres-mediated) and warm (C-fibres-mediated) stimuli to the same sites in order to compare the conduction velocity of the cold spinal pathway with that of the nociceptive and warm spinal pathways. RESULTS: Cold stimulation evoked large-amplitude vertex potentials from all stimulation sites. The mean conduction velocity of the cold spinal pathway was 12.0 m/s, which did not differ from that of the nociceptive spinal pathway (10.5 m/s). The mean conduction velocity of the warm spinal pathway was 2.0 m/s. DISCUSSION: This study provides previously unreported findings regarding cold spinal pathway conduction velocity in humans that may be useful in the assessment of spinal cord lesions as well as in intraoperative monitoring during spinal surgery. SIGNIFICANCE: This neurophysiological study provides previously unreported findings on cold spinal pathway conduction velocity in healthy humans. Cold-evoked potentials may represent an alternative to laser-evoked potential recording, useful to assess spinothalamic tract in patients with spinal cord lesions and monitor patients during spinal surgery.

Concomitant continuous pain in patients with trigeminal neuralgia is associated with trigeminal nerve root atrophy.

INTRODUCTION: Trigeminal neuralgia is an exemplary neuropathic pain condition characterized by paroxysmal electric-shock-like pain. However, up to 50% of patients also experiences concomitant continuous pain. In this neuroimaging study, we aimed to identify the specific anatomical features of trigeminal nerve root in patients with concomitant continuous pain. METHODS: We enrolled 73 patients with a definitive diagnosis of classical and idiopathic trigeminal neuralgia and 40 healthy participants. The diagnosis of trigeminal neuralgia was independently confirmed by two clinicians. Patients were grouped as patients with purely paroxysmal pain (45 patients) and patients also with concomitant continuous pain (28 patients). All participants underwent a structured clinical examination and a 3T MRI with sequences dedicated to the anatomical study of the trigeminal nerve root, including volumetric study. Images analysis was independently performed by two investigators, blinded to any clinical data. RESULTS: In most patients with concomitant continuous pain, this type of pain, described as burning, throbbing or aching, manifested at the disease onset. Demographic and clinical variables did not differ between the two groups of patients; the frequency of neurovascular compression and nerve dislocation were similar. Conversely, trigeminal nerve root atrophy was more severe in patients with concomitant continuous pain than in those with purely paroxysmal pain (p = 0.006). CONCLUSIONS: Our clinical and neuroimaging study found that in patients with trigeminal neuralgia, concomitant continuous pain was associated with trigeminal nerve root atrophy, therefore suggesting that this type of pain is likely related to axonal loss and abnormal activity in denervated trigeminal second-order neurons.

Capsaicin 8% dermal patch in clinical practice: an expert opinion.

INTRODUCTION: Neuropathic pain (NP) is caused by a lesion or disease of the somatosensory system, which can severely impact patients' quality of life. The current-approved treatments for NP comprise of both centrally acting agents and topical drugs, including capsaicin 8% dermal patches, which is approved for the treatment of peripheral NP. AREAS COVERED: The authors summarize literature data regarding capsaicin use in patients who suffer from NP and discuss the clinical applications of this topical approach. EXPERT OPINION: Overall, the capsaicin 8% dermal patch is as effective in reducing pain intensity as other centrally active agents (i.e. pregabalin). Some studies have also reported fewer systemic side effects, a faster onset of action and superior treatment satisfaction compared with systemic agents. In our opinion, capsaicin 8% dermal patches also present additional advantages, such as a good systemic tolerability, the scarcity of adverse events, the possibility to combine it with other agents, and a good cost-effective profile. It is important to note that, as the mechanism of action of capsaicin 8% is the 'defunctionalization' of small afferent fibers through interaction with TRPV1 receptors, the peripheral expression of this receptor on nociceptor fibers, is crucial to predict patient's response to treatment.

Pharmacotherapeutic Options for Managing Pain in Multiple Sclerosis.

Pain is a major matter for patients with multiple sclerosis; treatment response is frequently inadequate, with a significant impact on quality of life. The estimated prevalence of pain in multiple sclerosis ranges widely (26-86%), and different subtypes of pain, mediated by specific pathophysiological mechanisms, are described. The aim of this narrative review, performed using a systematic search methodology, was to provide current, evidence-based, knowledge about the pharmacological treatment of the different kinds of pain in multiple sclerosis. We searched for relevant papers within PubMed, EMBASE, the Cochrane Database of Systematic Reviews, and the Clinical Trials database (ClinicalTrials.gov), considering publications up to November 2019. Two authors independently selected studies for inclusion, data extraction, and bias assessment. A total of 27 randomized controlled trials were identified, but in only a few cases, patients with different pain qualities were stratified. Following a mechanism-based approach, treatment of paroxysmal pain and painful tonic spasms should be based on sodium-channel blockers, whereas treatment of ongoing extremity pain should be based on gabapentinoids and antidepressants.