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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.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.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.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.Novartis.

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.

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 it may serve as a possible biomarker in self-harming adolescents. Significance The present study, for the first time, 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.

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.

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.

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.

BACKGROUND In this neurophysiological study, we aimed at verifying the nociceptive selectivity of the new, micropatterned electrode (150IDE), recently designed to generate an electric field limited to the intraepidermal free nerve endings. METHODS Using the new 150IDE, we recorded evoked potentials after stimulation of the face and hand dorsum in 22 healthy participants and in patients with exemplary conditions selectively affecting the nociceptive system. We also measured the peripheral conduction velocity at the upper arm and verified the nociceptive selectivity of 150IDE assessing the effect of a selective block of nociceptive nerve fibres of radial nerve with local anaesthetic infiltration. In healthy participants and in patients, we have also compared the 150IDE-evoked potentials with laser-evoked potentials. RESULTS In healthy participants, the 150IDE-evoked pinprick sensation and reproducible scalp potentials, with latency similar to laser-evoked potentials. The mean peripheral conduction velocity, estimated at the upper arm, was 12 m/s. The selective nociceptive fibre block of the radial nerve abolished the scalp potentials elicited by the 150IDE stimulation. In patients, the 150IDE-evoked potentials reliably detected the selective damage of the nociceptive system. CONCLUSIONS Our neurophysiological study shows that this new 150IDE provides selective information on nociceptive system. SIGNIFICANCE 150IDE is a promising new tool for investigating nociceptive system in patients with neuropathic pain.

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 Ca 2+ 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 Gd 3+ . 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.

Background: Despite being widely prescribed, relatively few controlled trials have been conducted on the class of neurotrophic/antinociceptive nutraceuticals. While performing a search in the literature, we came across an old registration study on micronized palmitoylethanolamide in patients with low back pain – sciatica by Guida and colleagues. Methods: We contacted the authors of the article and obtained all the original material, which allowed us to reanalyze the study. We assessed its clinical relevance by calculating the numbers needed to treat for pain (visual analog scale) and function (Roland-Morris Questionnaire). After excluding patients for whom the information available was insufficient, we assigned each patient to one of the five categories of increasing probability of neuropathic pain: pure lumbago, lumbago with projecting pain to surrounding regions (e.g. gluteus or groin), lumbago with projecting pain to the thigh or leg, pure sciatica and radiculopathy, and investigated any correlations (Spearman) between the improvement in pain and function with these five classes. Results: Compared with placebo, palmitoylethanolamide 600 mg/die yielded a number needed to treat of 1.7 (95% confidence interval: 1.4-2) for pain, and 1.5 (95% confidence interval: 1.4-1.7) for function. The correlation between the five categories was highly significant for pain relief (P Conclusion: Palmitoylethanolamide was extremely effective on pain and function in a large cohort of patients with low back pain – sciatica. Although, the multiple mechanisms of action of palmitoylethanolamide are ideal for mixed pain conditions such as low back pain – sciatica, the correlation between pain relief and the likelihood of neuropathic pain suggests that this drug exerts a predominant action on the neuropathic pain component.

Acetyl-L-carnitine (ALC) has shown a neuroprotective effect in patients with peripheral neuropathies of different etiologies. Preclinical studies demonstrated a central anti-nociceptive action, both in neuropathic and nociceptive pain models. The present review aims to provide the knowledge on the efficacy of ALC in patients with painful peripheral neuropathy, based on the evidence. Consistent with the PRISMA statement, authors searched PubMed, Embase and the Cochrane Database of Systematic Reviews for relevant papers, including those issued before April 2018. Two authors independently selected studies for inclusion and data extraction: only trials including patients with a diagnosis of peripheral neuropathy and involving at least 10 patients were considered for the purposes of this review. Fourteen clinical trials were revised, to provide the level of evidence for neuropathy. To assess the global efficacy of ALC in painful peripheral neuropathy, a meta-analysis of four randomized controlled trials was performed. Mean difference in pain reduction as measured on a 10-cm VAS, and 95% CIs were used for pooling continuous data from each trial. Four randomized controlled trials tested ALC in patients with neuropathy secondary to diabetes and to antiretroviral therapy for HIV. Compared to placebo, ALC produced a significant pain reduction equal to 20.2% (95% CI: 8.3%-32.1%, P

ObjectiveTo 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.MethodsWe carried out Ca2+ imaging and whole-cell patch-clamp recording.ResultsThe TRPM8 mutation enhances channel activation, increases basal current amplitude and intracellular [Ca2+] in cells carrying the mutant channel, and enhances the response to menthol.ConclusionsWe propose that Arg30Gln confers gain-of-function attributes on TRPM8, which contribute to pathogenesis of trigeminal neuralgia in patients carrying this mutation.

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

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.

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.

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.

Objectives Although pain is a common complication of the hypermobile type of Ehlers–Danlos syndrome, its underlying mechanisms are still an issue of controversy. In this psychophysical study, we aimed at testing small-fiber function and the endogenous pain inhibitory control in patients with pain due to Ehlers-Danlos syndrome. Methods In 22 patients with pain due to Ehlers-Danlos syndrome and 22 healthy participants, matched for age and sex, we tested small-fiber function using quantitative sensory testing and the endogenous pain inhibitory control using the conditioned pain modulation (CPM) protocol. As quantitative sensory testing methods, we included thermal pain and mechanical pain thresholds and the wind-up ratio. The CPM protocol consisted of two heat painful stimuli, that is, a test stimulus and a conditioning stimulus. Results All patients complained of widespread pain. Quantitative sensory testing revealed no small-fiber deficit; in the area of maximum pain, we found an increased wind-up ratio. Whereas in the healthy participants the CPM protocol showed that the test stimulus rating was significantly reduced during conditioning, in patients with pain due to hEDS, the test stimulus rating increased during conditioning. Conclusions Our psychophysical study showing that patients with pain due to hEDS have an increased wind-up ratio in the area of maximum pain and abnormal CPM protocol suggests that in this condition, pain is associated with central sensitization, possibly due to deficit of the endogenous pain inhibitory control. These data might be relevant to pharmacological treatment.

BACKGROUND We aimed at evaluating the differential involvement of large myelinated Aβ-, 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 Aβ-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 Aβ-, 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.

Objective This cross-sectional study examined, for the first time, a large cohort of patients with trigeminal neuralgia, to ascertain the occurrence of familial cases, providing a systematic description of clinical features of familial disease. Since there is evidence linking hyperexcitability of trigeminal ganglion neurons to trigeminal neuralgia, we also carried out an exploratory genetic analysis of the neuronal electrogenisome in these patients. Methods We recorded familial occurrence by systematically interviewing all patients with a definite diagnosis of classical or idiopathic trigeminal neuralgia. We found 12 occurrences of trigeminal neuralgia with positive family history out of 88 enrolled patients. Whole-exome sequencing was carried out in 11 patients. We concentrated on the genetic variants within a 173-gene panel, comprising channel genes encoding sodium, potassium, calcium, chloride, transient receptor potential channels, and gap junction channels. Gene expression profiles were based on published RNA sequencing datasets of rodent/human trigeminal ganglia tissues, with a focus on genes related to neuronal excitability. Results In patients with familial trigeminal neuralgia, pain was more often located in the right, second division. All patients reported triggers. Four patients experienced concomitant continuous pain. Whole-exome sequencing analysis within the trigeminal ganglion electrogenisome identified 41 rare variants in ion channels, consisting of variants in sodium channels (6), potassium channels (10), chloride channels (5), calcium channels (7), transient receptor potential channels (12), and gap junction channels (1). In one patient, a previously profiled gain-of-function mutation in SCN10A (Nav1.8 p.Ala1304Thr), previously reported in painful neuropathy, was found; this variant was not present in unaffected siblings. Conclusions Our results suggest that familial occurrence of trigeminal neuralgia is more common than previously considered. Although our results demonstrate variants in genes encoding voltage-gated ion channels and transient receptor potential channels within these patients, further study will be needed to determine their roles in the pathogenesis of trigeminal neuralgia.

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.

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.

Trigeminal neuralgia is a representative neuropathic facial pain condition, characterised by unilateral paroxysmal pain in the distribution territory of one or more divisions of the trigeminal nerve, triggered by innocuous stimuli. A subgroup of patients with trigeminal neuralgia [TN (previously defined as atypical TN)] also suffer from concomitant continuous pain, i.e. a background pain between the paroxysmal attacks. The aim of this review is to provide current, evidence-based, knowledge about the pharmacological treatment of typical and atypical TN, with a specific focus on drugs in development. We searched for relevant papers within PubMed, EMBASE, the Cochrane Database of Systematic Reviews and the Clinical Trials database (ClinicalTrials.gov), taking into account publications up to February 2018. Two authors independently selected studies for inclusions, data extraction, and bias assessment. Carbamazepine and oxcarbazepine are the first-choice drugs for paroxysmal pain. When sodium channel blockers cannot reach full dosage because of side effects, an add-on treatment with lamotrigine or baclofen should be considered. In patients with atypical TN, both gabapentin and antidepressants are expected to be efficacious and should be tried as an add-on to oxcarbazepine or carbamazepine. Although carbamazepine and oxcarbazepine are effective in virtually the totality of patients, they are responsible for side effects causing withdrawal from treatment in an important percentage of cases. A new, better tolerated, Nav1.7 selective state-dependent, sodium channel blocker (vixotrigine) is under development. Future trials testing the effect of combination therapy in patients with TN are needed, especially in patients with concomitant continuous pain and in TN secondary to multiple sclerosis. Electronic supplementary material The online version of this article (10.1007/s40265-018-0964-9) contains supplementary material, which is available to authorized users.

Intercostobrachial neuropathy, often resulting in neuropathic pain, is a common complication of breast cancer surgery. In this 1-year longitudinal study, we aimed at seeking information on the frequency, clinical features, and course of painless and painful intercostobrachial neuropathy. We enrolled 40 women previously undergoing breast cancer surgery. In these patients, we collected, at 3, 6 and 12 months after surgery, clinical and quantitative sensory testing (QST) variables to diagnose intercostobrachial neuropathy, DN4 questionnaire to identify neuropathic pain, Neuropathic Pain Symptom Inventory to assess the different neuropathic pain symptoms, the Beck Depression Inventory to assess depressive symptoms, and SF36 to assess quality of life and Patient Global Impression of Change. Clinical and QST examination showed an intercostobrachial neuropathy in 23 patients (57.5%). Out of the 23 patients, five experienced neuropathic pain, as assessed with clinical examination and DN4. Axillary surgery clearance was associated with an increased risk of intercostobrachial neuropathy. Whereas sensory disturbances improved during the 1-year observation, neuropathic pain did not. Nevertheless, Beck Depression Inventory, SF36, and the Patient Global Impression of Change scores significantly improved over time. Our study shows that although intercostobrachial neuropathy is a common complication of breast cancer surgery, neuropathic pain affects only a minor proportion of patients. After 1 year, sensory disturbances partially improve and have only a mild impact on mood and quality of life.

Background Dynamic Mechanical Allodynia (DMA) is a typical symptom of neuropathic pain (NP). In a recent study, the capsaicin 8% patch was noninferior to pregabalin in overall peripheral NP relief. In this study, we report the comparison of the two treatments in relieving DMA. Methods In a randomized, open-label, head-to-head, 8-week study, 488 patients with peripheral NP were treated with the capsaicin 8% patch (one application) or an optimized dose of pregabalin. Assessments included the area and intensity of DMA, and the number of patients achieving complete resolution of DMA. Results At baseline, 253 patients in the capsaicin 8% patch group and 235 patients in the pregabalin group had DMA. From baseline to end of study, the change in DMA intensity was significantly in favour of the capsaicin 8% patch versus pregabalin [-0.63 (95% CI: -1.04, -0.23; p = 0.002)]. Similarly, the capsaicin 8% patch was superior to pregabalin in reducing the area of DMA [-39.5 cm2 (95% CI: -69.1, -10.0; p = 0.009)] from baseline to end of study. Overall, a greater proportion of patients had a complete resolution of allodynia with capsaicin 8% patch treatment compared with pregabalin treatment (24.1% vs. 12.3%; p = 0.001) at end of study. Conclusion Capsaicin 8% treatment was superior to pregabalin in reducing the intensity and area of DMA, and in the number of patients with complete resolution of DMA. Significance The superiority of a topical treatment over pregabalin in relieving DMA supports the view that both peripheral and central sensitization can mediate allodynia.

Neuropathic pain is a chronic condition representing a significant burden for patients, society, and healthcare systems. The prevalence of neuropathic pain in the general population has been estimated at 7–8% and is expected to increase in the future. Neuropathic pain differs from nociceptive pain and requires a different therapeutic approach; and the management of neuropathic pain is complicated and challenging. This chapter discusses clinical practice guidelines for neuropathic pain and their usefulness in clinical practice. Funding: Pfizer, Italy.

BACKGROUND: Trigeminal neuralgia (TN) is an extremely painful condition, which can be difficult to diagnose and treat. In Europe, TN-patients are managed by many different specialities. Therefore, there is a great need for comprehensive European guidelines for management of TN. The European Academy of Neurology asked an expert panel to develop recommendations for a series of questions that are essential for daily clinical management of patients with TN.METHODS: We performed a systematic review of the literature and developed recommendations based on GRADE, where feasible, if not a good practice statement was given.RESULTS: We recommend the use of the most recent classification system, which diagnoses TN as primary TN, either classical or idiopathic depending on the degree of neurovascular contact, or as secondary TN caused by pathology other than neurovascular contact. An MRI, using a combination of three high-resolution sequences, should be performed as part of work up in TN patients, because no clinical characteristics can exclude secondary TN. If MRI is not possible, trigeminal reflexes can be used. Neurovascular contact plays an important role in primary TN, but demonstration of a neurovascular contact should not be used to confirm the diagnosis of TN. Rather, it may help to decide if and when a patient should be referred for microvascular decompression. In acute exacerbations of pain, intravenous infusion of fosphenytoin or lidocaine can be used. For long-term treatment we recommend carbamazepine or oxcarbazepine as drugs of first choice. Lamotrigine, gabapentin, botolinum toxin type A, pregabalin, baclofen and phenytoin may be used either alone or as add-on therapy. We recommend that patients should be offered surgery if pain is not sufficiently controlled medically or if medical treatment is poorly tolerated. Microvascular decompression is recommended as first-line surgery in patients with classical TN. No recommendation can be given for choice between any neuroablative treatments or between them and microvascular decompression in patients with idiopathic TN. Neuroablative treatments should be the preferred choice if MRI does not demonstrate any neurovascular contact. Treatment for patients with secondary TN should in general follow the same principles as for primary TN. In addition to medical and surgical management, we recommend that patients are offered psychological and nursing support.CONCLUSIONS: Compared with previous TN guidelines, there are important changes regarding diagnosis and imaging. These allow better characterization of patients and help in decision making regarding the planning of medical and surgical management. Recommendations on pharmacological and surgical management have been updated. There is a great need for future research on all aspects of TN, including pathophysiology and management. This article is protected by copyright. All rights reserved.

The upcoming 11th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD) of the World Health Organization (WHO) offers a unique opportunity to improve the representation of painful disorders. For this purpose, the International Association for the Study of Pain (IASP) has convened an interdisciplinary task force of pain specialists. Here, we present the case for a reclassification of nervous system lesions or diseases associated with persistent or recurrent pain for $3 months. The new classification lists the most common conditions of peripheral neuropathic pain: trigeminal neuralgia, peripheral nerve injury, painful polyneuropathy, postherpetic neuralgia, and painful radiculopathy. Conditions of central neuropathic pain include pain caused by spinal cord or brain injury, poststroke pain, and pain associated with multiple sclerosis. Diseases not explicitly mentioned in the classification are captured in residual categories of ICD-11. Conditions of chronic neuropathic pain are either insufficiently defined or missing in the current version of the ICD, despite their prevalence and clinical importance. We provide the short definitions of diagnostic entities for which we submitted more detailed content models to the WHO. Definitions and content models were established in collaboration with the Classification Committee of the IASP’s Neuropathic Pain Special Interest Group (NeuPSIG). Up to 10% of the general population experience neuropathic pain. The majority of these patients do not receive satisfactory relief with existing treatments. A precise classification of chronic neuropathic pain in ICD-11 is necessary to document this public health need and the therapeutic challenges related to chronic neuropathic pain. ispartof: PAIN vol:160 issue:1 pages:53-59 ispartof: location:United States status: published

To improve patient care and help clinical research, the Neuropathic Pain Special Interest Group of the Italian Neurological Society appointed a task force to elaborate a consensus statement on pharmacoresistant neuropathic pain. The task force included 19 experts in neuropathic pain. These experts participated in a Delphi survey consisting of three consecutive rounds of questions and a face-to-face meeting, designed to achieve a consensus definition of pharmacoresistant neuropathic pain. In the three rounds of questions, the participants identified and described the main distinguishing features of pharmacoresistance. In the face-to-face meeting the participants discussed the clinical features determining pharmacoresistance. They finally agreed that neuropathic pain is pharmacoresistant when "the patient does not reach the 50% reduction of pain or an improvement of at least 2 points in the Patient Global Impression of Change, having used all drug classes indicated as first, second, or third line in the most recent and widely agreed international guidelines, for at least 1 month after titration to the highest tolerable dose." Our consensus statement might be useful for identifying eligible patients for invasive treatments, and selecting patients in pharmacological trials, thus improving patient care and helping clinical research.

Objectives Overlapping neural system dysfunctions, mainly involving the secondary somatosensory cortex (S2), the anterior cingulate cortex (ACC) and the anterior insular cortex (AIC), seem to be related to both pain-perception abnormalities and psychotic symptoms in schizophrenia (SCZ) and bipolar disorder (BD). Laser-evoked potentials (LEPs) were used to investigate pain-perception and central pain-processing abnormalities in SCZ, bipolar I disorder (BD-I), and bipolar II disorder (BD-II), and to evaluate their relationship with history of psychosis, and social-cognitive and functional impairments. Methods Twenty patients with SCZ, 17 patients with BD-I, and 21 patients with BD-II who were all under similar pharmacological treatment underwent clinical, functional, and neuro-psychological assessment. LEPs were analyzed in patients and 19 healthy subjects (HS). LEPs elicit responses reflecting the activity of the S2 (N1 wave) and the ACC/AIC cortices (N2/P2 complex). A four-group ANOVA was conducted between patients and HS to compare pain-perceptive thresholds (PThs), N1, and N2/P2-LEP components. Results Compared to HS: (i) patients with SCZ showed pain-processing and pain-perception abnormalities, as revealed by significantly higher PTh (P

Background Patients with joint hypermobility syndrome/Ehlers–Danlos syndrome, hypermobility type (JHS/EDS-HT) commonly suffer from pain. How this hereditary connective tissue disorder causes pain remains unclear although previous studies suggested it shares similar mechanisms with neuropathic pain and fibromyalgia. Methods In this prospective study seeking information on the mechanisms underlying pain in patients with JHS/EDS-HT, we enrolled 27 consecutive patients with this connective tissue disorder. Patients underwent a detailed clinical examination, including the neuropathic pain questionnaire DN4 and the fibromyalgia rapid screening tool. As quantitative sensory testing methods, we included thermal-pain perceptive thresholds and the wind-up ratio and recorded a standard nerve conduction study to assess non-nociceptive fibres and laser-evoked potentials, assessing nociceptive fibres. Results Clinical examination and diagnostic tests disclosed no somatosensory nervous system damage. Conversely, most patients suffered from widespread pain, the fibromyalgia rapid screening tool elicited positive findings, and quantitative sensory testing showed lowered cold and heat pain thresholds and an increased wind-up ratio. Conclusions While the lack of somatosensory nervous system damage is incompatible with neuropathic pain as the mechanism underlying pain in JHS/EDS-HT, the lowered cold and heat pain thresholds and increased wind-up ratio imply that pain in JHS/EDS-HT might arise through central sensitization. Hence, this connective tissue disorder and fibromyalgia share similar pain mechanisms. What does this study add? In patients with JHS/EDS-HT, the persistent nociceptive input due to joint abnormalities probably triggers central sensitization in the dorsal horn neurons and causes widespread pain.

N-Acetylcysteine, one of the most prescribed antioxidant drugs, enhances pain threshold in rodents and humans by activating mGlu2 metabotropic glutamate receptors. Here, we assessed the analgesic activity of N-acetylcysteine in the streptozotocin model of painful diabetic neuropathy and examined the effect of N-acetylcysteine on proteins that are involved in mechanisms of nociceptive sensitization. Mice with blood glucose levels ≥250 mg/dl in response to a single intraperitoneal (i.p.) injection of streptozotocin (200 mg/kg) were used for the assessment of mechanical pain thresholds. Systemic treatment with N-acetylcysteine (100 mg/kg, i.p., either single injection or daily injections for seven days) caused analgesia in diabetic mice. N-acetylcysteine-induced analgesia was abrogated by the Sxc− inhibitors, sulfasalazine (8 mg/kg, i.p.), erastin (30 mg/kg, i.p.), and sorafenib (10 mg/kg, i.p.), or by the mGlu2/3 receptor antagonist, LY341495 (1 mg/kg, i.p.). Repeated administrations of N-acetylcysteine in diabetic mice reduced ERK1/2 phosphorylation in the dorsal region of the lumbar spinal cord. The analgesic activity of N-acetylcysteine was occluded by the MEK inhibitor, PD0325901 (25 mg/kg, i.p.), the TRPV1 channel blocker, capsazepine (40 mg/kg, i.p.), or by a cocktail of NMDA and mGlu5 metabotropic glutamate receptor antagonists (memantine, 25 mg/kg, plus MTEP, 5 mg/kg, both i.p.). These findings offer the first demonstration that N-acetylcysteine relieves pain associated with diabetic neuropathy and holds promise for the use of N-acetylcysteine as an add-on drug in diabetic patients.

Backgrounds: Patients with diabetic polyneuropathy commonly suffer from ongoing burning pain and dynamic mechanical allodynia. In this clinical and skin biopsy study, we aimed at assessing how intraepidermal regenerating nerve sprouts are associated with these two types of pain. Methods: We consecutively enrolled 85 patients with diabetic polyneuropathy. All patients underwent skin biopsy at the distal leg. Intraepidermal nerve fibres were immunostained with the anti-protein gene product 9.5 (PGP9.5) to quantify all intraepidermal nerve fibres, and the growth-associated protein 43 (GAP43) to quantify regenerating nerve sprouts. Results: We found that the GAP43-stained intraepidermal nerve fibre density and the ratio GAP43/PGP9.5 were significantly higher in patients with ongoing burning pain than in those without. The area of receiver operating characteristic (ROC) curve for the ratio GAP43/PGP9.5 was 0.74 and yielded a sensitivity and specificity for identifying ongoing burning pain of 72% and 71%, respectively. Conversely, although the density of PGP9.5 and GAP43 intraepidermal nerve fibre was higher in patients with dynamic mechanical allodynia than in those without, this difference was statistically weak and the ROC curve analysis of skin biopsy variables for this type of pain failed to reach the statistical significance. Conclusion: Our clinical and skin biopsy study showed that ongoing burning pain was strongly associated with regenerating sprouts, as assessed with GAP43 immunostaining. This finding improves our understanding on the mechanisms underlying neuropathic pain in patients with diabetic polyneuropathy and suggests that the GAP43/PGP 9.5 ratio might be used as an objective marker for ongoing burning pain due to regenerating sprouts. Significance: Our skin biopsy study showing that regenerating sprouts, as assessed with GAP43-staining, were strongly associated with ongoing burning pain, improves our knowledge on the mechanisms underlying neuropathic pain in patients with diabetes.

Peripheral neuropathic pain is among the most prevalent types of neuropathic pain. No comprehensive peripheral neuropathic pain classification system that incorporates contemporary clinical, diagnostic, biological, and psychological information exists. To address this need, this article covers the taxonomy for 4 focal or segmental peripheral neuropathic pain disorders, as part of the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership and the American Pain Society (APS) collaborative to develop a standardized, evidence-based taxonomy initiative: the ACTTION-APS Pain Taxonomy (AAPT). The disorders—postherpetic neuralgia, persistent posttraumatic neuropathic pain, complex regional pain disorder, and trigeminal neuralgia—were selected because of their clinical and clinical research relevance. The multidimensional features of the taxonomy are suitable for clinical trials and can also facilitate hypothesis-driven case-control and cohort epidemiologic studies. Perspective The AAPT peripheral neuropathic pain taxonomy subdivides the peripheral neuropathic pain disorders into those that are generalized and symmetric and those that are focal or segmental and asymmetric. In this article, we cover the focal and segmental disorders: postherpetic neuralgia, persistent posttraumatic neuropathic pain, complex regional pain disorder, and trigeminal neuralgia. The taxonomy is evidence-based and multidimensional, with the following dimensions: 1) core diagnostic criteria; 2) common features; 3) common medical and psychiatric comorbidities; 4) neurobiological, psychosocial, and functional consequences; and 5) putative neurobiological and psychosocial mechanisms, risk factors, and protective factors.

Background: Pain is a common and heterogeneous complication of multiple sclerosis (MS). In this multicenter, cross sectional study, we aimed at investigating the prevalence of pain in MS using highly specific criteria for distinguishing the different types of pain. Materials and methods: After a structured interview, in patients with pain, clinical examination and DN4 questionnaire were used for distinguishing neuropathic and nociceptive pain. In subjects with neuropathic pain, the Neuropathic Pain Symptom Inventory was used for differentiating neuropathic pain symptoms. Results: We enrolled 1249 participants (832 F, 417 M, mean age 33.9 years, mean disease duration 8 years, mean EDSS 3.2); based on clinical evaluation and DN4 score 429 patients (34.34%) were classified with pain (470 pain syndromes): 286 nociceptive pain syndromes and 184 neuropathic pain syndromes. Multivariate analysis showed that pain was associated with age, gender and disease severity and that neuropathic pain was distinctly associated with EDSS. Conclusions: Our study, providing definite information on the prevalence, characteristics and variables associated with neuropathic pain due to MS, shows that a more severe disease course is associated with a higher risk of neuropathic pain. Our findings might, therefore, provide a basis for improving the clinical management of this common MS complication.

BACKGROUND: This study aimed to describe recruitment challenges encountered during a phase IIa study of vixotrigine, a state and use-dependent Nav1.7 channel blocker, in individuals with trigeminal neuralgia.METHODS: This was an international, multicenter, placebo-controlled, randomized withdrawal study that included a 7-day run-in period, a 21-day open-label phase, and a 28-day double-blind phase in which patients (planned n = 30) were randomized to vixotrigine or placebo. Before recruitment, all antiepileptic drugs had to be stopped, except for gabapentin or pregabalin. After the trial, patients returned to their original medications. Patient recruitment was expanded beyond the original five planned (core) centers in order to meet target enrollment (total recruiting sites N = 25). Core sites contributed data related to patient identification for study participation (prescreening data). Data related to screening failures and study withdrawal were also analyzed using descriptive statistics.RESULTS: Approximately half (322/636; 50.6%) of the patients who were prescreened at core sites were considered eligible for the study and 56/322 (17.4%) were screened. Of those considered eligible, 26/322 (8.1%) enrolled in the study and 6/322 (1.9%) completed the study. In total, 125 patients were screened across all study sites and 67/125 (53.6%) were enrolled. At prescreening, reasons for noneligibility varied by site and were most commonly diagnosis change (78/314; 24.8%), age > 80 years (75/314; 23.9%), language/distance/mobility (61/314; 19.4%), and noncardiac medical problems (53/314; 16.9%). At screening, frequently cited reasons for noneligibility included failure based on electrocardiogram, insufficient pain, and diagnosis change.CONCLUSIONS: Factors contributing to recruitment challenges encountered in this study included diagnosis changes, anxiety over treatment changes, and issues relating to distance, language, and mobility. Wherever possible, future studies should be designed to address these challenges.TRIAL REGISTRATION: ClinicalTrials.gov, NCT01540630 . EudraCT, 2010-023963-16. 07 Aug 2015.

L-Acetyl-carnitine (LAC) exerts an energetic effect on nerves and muscles. Recently, preclinical experiments have demonstrated a central anti-nociceptive action.Our objective was to assess the effects of LAC on neuroprotection, pain, and function in carpal tunnel syndrome (CTS), a very frequent chronic compressive neuropathy.In a multicentre, examiner-blinded, clinical and neurophysiological 4-month study, we enrolled 82 patients and examined 120 hands with CTS of mild to moderate severity. Patients were assessed at baseline and 10, 60 and 120 days after treatment with LAC 500 mg twice daily (BID). All patients underwent a conduction study of the median nerve, the Boston Carpal Tunnel Questionnaire (BCTQ) and the Neuropathic Pain Symptom Inventory (NPSI). The primary endpoint was the sensory conduction velocity (SCV) of the median nerve.The primary endpoint was met, with significant improvement of the SCV (P 0.0001). All sensory neurophysiological measures also significantly improved. BCTQ score changed significantly (P 0.0001), with a greater improvement in the symptom component. Nine of the NPSI types of pain, particularly squeezing and pressure pain and pain evoked by pressure, showed a significant reduction (P 0.0001).Our clinical and neurophysiological study indicated that 4 months of treatment with LAC exerted a neuroprotective effect. LAC reduced pain in patients with mild and moderate CTS, a result that is possibly due to both its neuroprotective action and its central anti-nociceptive properties. Clinical Trials Registration code: EudraCT 2014-002289-62.

BACKGROUND AND PURPOSE Bibliometric searches may provide an indirect assessment of research in a field or country. The European Academy of Neurology decided to investigate how article production was developing in European countries, as an indicator of neurological vitality. METHODS We searched two databases, Scopus and PubMed, for articles published by authors belonging to neurological institutions in all European countries, the USA, Brazil, China and Japan. The search assessed production in the period between 2000 and 2015. We calculated four indicators, i.e. gross neurological product (GNP) (which includes all articles published in any indexed journal), production in top neurological journals, GNP per inhabitant and GNP per gross domestic product. RESULTS All indicators greatly increased over time. The European GNP paralleled that of the USA and was higher than those of the other countries. Restricting the search to top neurological journals showed that, since 2012, European production grew faster than that of the USA. Germany had the highest production within Europe, Switzerland had the best ratio between GNP and inhabitants, and The Netherlands had the best ratio between GNP and gross domestic product. CONCLUSIONS Although this search had several limitations, the results were so straightforward that we can conclude that European neurology is highly active in the world. Future analyses should compare neurology with other main medical disciplines.

Background In the neurophysiological assessment of patients with neuropathic pain, laser evoked potentials (LEPs), contact heat evoked potentials (CHEPs) and the evoked potentials by the intraepidermal electrical stimulation via concentric needle electrode are widely agreed as nociceptive specific responses; conversely, the nociceptive specificity of evoked potentials by surface concentric electrode (SE-PREPs) is still debated. Methods In this neurophysiological study we aimed at verifying the nociceptive specificity of SE-PREPs. We recorded LEPs, CHEPs and SE-PREPs in eleven healthy participants, before and after epidermal denervation produced by prolonged capsaicin application. We also used skin biopsy to verify the capsaicin-induced nociceptive nerve fibre loss in the epidermis. Results We found that whereas LEPs and CHEPs were suppressed after capsaicin-induced epidermal denervation, the surface concentric electrode stimulation of the same denervated skin area yielded unchanged SE-PREPs. Conclusion The suppression of LEPs and CHEPs after nociceptive nerve fibre loss in the epidermis indicates that these techniques are selectively mediated by nociceptive system. Conversely, the lack of SE-PREP changes suggests that SE-PREPs do not provide selective information on nociceptive system function. Significance Capsaicin-induced epidermal denervation abolishes laser evoked potentials (LEPs) and contact heat evoked potentials (CHEPs), but leaves unaffected pain-related evoked potentials by surface concentric electrode (SE-PREPs). These findings suggest that unlike LEPs and CHEPs, SE-PREPs are not selectively mediated by nociceptive system.

The somatosensory temporal discrimination threshold (STDT) has been used in recent years to investigate time processing of sensory information, but little is known about the physiological correlates of somatosensory temporal discrimination. The objective of this study was to investigate whether the time interval required to discriminate between two stimuli varies according to the number of stimuli in the task. We used the third-stimulus temporal discrimination threshold (ThirdDT), defined as the shortest time interval at which an individual distinguishes a third stimulus following a pair of stimuli delivered at the STDT. The STDT and ThirdDT were assessed in 31 healthy subjects. In a subgroup of 10 subjects, we evaluated the effects of the stimuli intensity on the ThirdDT. In a subgroup of 16 subjects, we evaluated the effects of S1 continuous theta-burst stimulation (S1-cTBS) on the STDT and ThirdDT. Results show that ThirdDT is shorter than STDT. We found a positive correlation between STDT and ThirdDT values. As long as the stimulus intensity was within the perceivable and painless range, it did not affect ThirdDT values. S1-cTBS significantly affected both STDT and ThirdDT, although the latter was affected to a greater extent and for a longer period of time. We conclude that the interval needed to discriminate between time-separated tactile stimuli is related to the number of stimuli used in the task. STDT and ThirdDT are encoded in S1, probably by a shared tactile temporal encoding mechanism whose performance rapidly changes during the perception process. ThirdDT is a new method to measure somatosensory temporal discrimination. NEW & NOTEWORTHY To investigate whether the time interval required to discriminate between stimuli varies according to changes in the stimulation pattern, we used the third-stimulus temporal discrimination threshold (ThirdDT). We found that the somatosensory temporal discrimination acuity varies according to the number of stimuli in the task. The ThirdDT is a new method to measure somatosensory temporal discrimination and a possible index of inhibitory activity at the S1 level.