Small fibre neuropathy frequently underlies the painful long-COVID syndrome.

ABSTRACT: Approximately 10% to 20% of individuals with previous SARS-CoV-2 infection may develop long-COVID syndrome, characterized by various physical and mental health issues, including pain. Previous studies suggested an association between small fibre neuropathy and pain in long-COVID cases. In this case-control study, our aim was to identify small fibre neuropathy in patients experiencing painful long-COVID syndrome. Clinical data, quantitative sensory testing, and skin biopsies were collected from 26 selected patients with painful long-COVID syndrome. We also examined 100 individuals with past COVID-19 infection, selecting 33 patients with painless long-COVID syndrome, characterized mainly by symptoms such as brain fog and fatigue, and 30 asymptomatic post-COVID-19 controls. Demographic and clinical variables were compared among these groups. Among the 26 patients with painful long-COVID syndrome, 12 had skin biopsy and/or quantitative sensory testing abnormalities compatible with small fibre neuropathy. Demographic and clinical data did not differ across patients with small fibre neuropathy, patients with painless long-COVID syndrome, and asymptomatic post-COVID-19 controls. This case-control study showed that approximately 50% of patients experiencing painful long-COVID syndrome had small fibre neuropathy. However, in our patient cohort, this specific post-COVID-19 complication was unrelated to demographic and COVID-19 clinical variables. Approximately half of our sample of patients with painful long-COVID symptoms met diagnostic criteria for small fibre neuropathy.

Autonomic Small-Fiber Pathology in Patients With Fibromyalgia.

In this clinical and skin biopsy study, we aimed to investigate whether fibromyalgia-associated small-fiber pathology (SFP), consisting of an intraepidermal nerve fiber loss, implies damage of dermal autonomic nerve fibers and how this damage is associated with autonomic symptoms that patients with fibromyalgia syndrome experience. Using skin biopsy, we investigated intraepidermal nerve fiber density, piloerector muscle, and sweat gland nerve fiber density (SGNFD) in 138 participants, that is, 58 patients with fibromyalgia syndrome, 48 healthy subjects, and 32 patients with small-fiber neuropathy. In patients with fibromyalgia-associated SFP, we also investigated how the different skin biopsy variables correlated with autonomic symptoms, as assessed with the Composite Autonomic Symptom Score 31 questionnaire. We found that in patients with fibromyalgia-associated SFP, the piloerector muscle and SGNFD were lower than that in healthy subjects. However, the autonomic small-fiber damage had no correlation with autonomic symptoms severity. In patients with SFP, the intraepidermal, piloerector muscle, and SGNFD were higher than that in patients with small-fiber neuropathy. Our clinical and skin biopsy study shows that patients with fibromyalgia have a reduction of dermal autonomic small fibers paralleling the intraepidermal nerve fiber loss, thus indicating that SFP also implies autonomic small nerve fiber damage. However, the autonomic small-fiber damage we found had no correlation with the severity of autonomic symptoms, and thus its clinical impact is still undetermined. PERSPECTIVE: In patients with fibromyalgia, SFP also affects autonomic fibers. These novel data provide additional insights into the pathophysiology of fibromyalgia syndrome, highlighting the complex role of small-fiber damage in the clinical picture of fibromyalgia.

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.

Sex differences in trigeminal neuralgia: a focus on radiological and clinical characteristics.

BACKGROUND: It is well established that trigeminal neuralgia is more prevalent in females than in males. Neurovascular compression with morphological changes of the trigeminal root represents the most recognized etiological factor. However, other factors may play a role in the framework of a multi-hit model. The primary aim of this study was to investigate sex differences in radiological and clinical characteristics of trigeminal neuralgia to better understand the multifactorial origin of this peculiar neuropathic pain condition. METHODS: In this cross-sectional study patients with a definite diagnosis of primary trigeminal neuralgia were consecutively enrolled. Each patient underwent 3T MRI with sequences dedicated to the study of neurovascular compression. Major morphological changes of the trigeminal root were quantitatively assessed. Clinical characteristics were systematically collected through a dedicated questionnaire. A logistic regression model was implemented to predict radiological and clinical characteristics based on sex. RESULTS: A total of 114 patients with classical (87) or idiopathic trigeminal neuralgia (27) were enrolled. Female sex was predictive for idiopathic trigeminal neuralgia. Male sex was predictive, among the comorbidities and clinical characteristics, for hypertension, the involvement of the left side and the second trigeminal division, alone or with the ophthalmic division. DISCUSSION: The preponderance of TN in the female sex and the association between idiopathic TN and the female sex suggest the role of additional etiological factors in the framework of a multi-hit model. The identification of clinical variables predicted by sex suggests the possibility that distinct phenotypes, with peculiar pathophysiological and therapeutic aspects, may occur in females and males.

A systematic review and meta-analysis of neuropathic pain associated with coronavirus disease 2019.

BACKGROUND AND OBJECTIVE: Neuropathic pain is an occasionally reported complication of coronavirus disease 2019 (COVID-19) that has received increased attention in scientific literature. In this systematic review and meta-analysis, we aimed to provide information on the frequency of neuropathic pain associated with COVID-19. DATABASES AND DATA TREATMENT: We systematically reviewed and analysed literature regarding neuropathic pain associated with COVID-19. Literature searches were conducted in PubMed, EMBASE and Cochrane Library databases. We considered prospective and retrospective studies published up until September 2022 (limitations included English language, full-text publications and studies including at least 10 patients). A random effects meta-analysis was performed and heterogeneity and publication bias were assessed. RESULTS: We identified 149 studies. We included 17 studies in the systematic review, and six studies reporting the frequency of neuropathic pain in the acute/subacute phase of COVID-19 in the meta-analysis. The estimated frequency of neuropathic pain ranged between 0.4 and 25%. Forest plot analysis showed that the random effect overall frequency was 10% (95% confidence interval: 5%-15%), with a high level of heterogeneity (Chi2  = 104; Tau2  = 0.004; df = 5; I2  = 95%; test for overall effect: Z = 3.584; p < 0.0005). The overall risk of bias was moderate in all studies selected, particularly due to the poor description of neuropathic pain diagnostic criteria. CONCLUSIONS: The pooled estimated frequency of neuropathic pain associated with COVID-19 should be considered with caution due to the high heterogeneity across studies and the poor description of the neuropathic pain diagnostic criteria applied. SIGNIFICANCE: Emerging evidence supports the development of neuropathic pain as a complication of COVID-19. However, longitudinal studies enrolling consecutive patients with COVID-19 that detail the diagnostic criteria for neuropathic pain are needed to better assess the frequency of this condition.

Small-fibre damage is associated with distinct sensory phenotypes in patients with fibromyalgia and small-fibre neuropathy.

BACKGROUND: In this clinical and psychophysical study, we aimed to verify whether patients with fibromyalgia with and without small-fibre pathology and patients with pure small-fibre neuropathy share common sensory phenotypes. METHODS: Using an algorithm based on quantitative sensory testing variables, we grouped 64 consecutive patients with fibromyalgia (20 with small-fibre pathology, 44 without) and 30 patients with pure small-fibre neuropathy into different sensory phenotypes: sensory loss, thermal hyperalgesia, mechanical hyperalgesia and healthy phenotypes. RESULTS: We found that the frequency of the different sensory phenotypes differed markedly between patients with fibromyalgia and patients with small-fibre neuropathy. In patients with fibromyalgia, with and without small-fibre pathology, healthy and hyperalgesia phenotypes (both thermal and mechanical) were similarly represented, whilst sensory loss and mechanical hyperalgesia phenotypes were the most frequent phenotypes in patients with small-fibre neuropathy. CONCLUSIONS: Our findings indicate that small-fibre damage is associated with distinct sensory phenotypes in patients with fibromyalgia and in patients with small-fibre neuropathy. The lack of phenotype differences between patients with fibromyalgia with and without small-fibre pathology and the relatively high frequency of the healthy phenotype in these patients highlight a complex relationship between small-fibre pathology and pain in patients with fibromyalgia.

A novel method to selectively elicit cold sensations without touch.

BACKGROUND: Thermal and tactile stimuli are transduced by different receptor classes. However, mechano- and thermo-sensitive afferents interact at spinal and supraspinal levels. Yet, most studies on responses to cooling stimuli are confounded by mechanical contact, making these interactions difficult to isolate. Methods for precise control of non-mechanical thermal stimulations remain challenging, particularly in the cold range. NEW METHOD: We developed a non-tactile, focal, temperature-controlled, multi-purpose cooling stimulator. This method controls the exposure of a target skin region to a dry-ice source. Using a thermal camera to monitor skin temperature, and adjusting the source-skin distance accordingly, we could deliver non-tactile cooling stimuli with customisable profiles, for studying different aspects of cold sensation. RESULTS: To validate our method, we measured absolute and relative thresholds for cold sensation without mechanical contact in 13 human volunteer participants, using the method of limits. We found that the absolute cold detection threshold was 32.71 oC ± 0.88 oC. This corresponded to a threshold relative to each participant's baseline skin temperature of - 1.08 oC ± 0.37 oC. COMPARISONS WITH EXISTING METHOD: Our method allows cooling stimulation without the confound of mechanical contact, in a controllable and focal manner. CONCLUSIONS: We report a non-contact cooling stimulator and accompanying control system. We used this to measure cold thresholds in the absence of confounding touch. Our method enables more targeted studies of both cold sensory pathways, and of cold-touch interactions.

Functional and morphometric assessment of small-fibre damage in late-onset hereditary transthyretin amyloidosis with polyneuropathy: the controversial relation between small-fibre-related symptoms and diagnostic test findings.

INTRODUCTION: We aimed at investigating whether functional and morphometric tests assessing small-fibre damage, ie quantitative sensory testing, Sudoscan and skin biopsy, reliably reflect neuropathic pain and autonomic symptoms in patients with late-onset hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN). METHODS: In 30 patients with late-onset ATTRv-PN, we collected quantitative sensory testing, Sudoscan and skin biopsy with assessment of intraepidermal, piloerector muscle and sweat gland nerve fibre density. We then correlated these functional and morphometric parameters with neuropathic pain and autonomic symptoms as assessed with the Neuropathic Pain Symptom Inventory (NPSI) and Composite Autonomic Symptom Score-31 (COMPASS-31). RESULTS: 50% of patients showed small-fibre damage in the form of a pure small-fibre neuropathy, 47% in the context of a mixed fibre neuropathy with small and large fibre involvement. All patients complained of at least one autonomic symptom and 60% had neuropathic pain. Whereas quantitative sensory testing and Sudoscan parameters correlated with neuropathic pain and autonomic symptoms as assessed by NPSI and COMPASS-31, intraepidermal, piloerector muscle and sweat gland nerve fibre density quantification did not. CONCLUSIONS: Our findings indicate that functional test parameters reliably reflect neuropathic pain and autonomic symptoms related to small-fibre damage. These findings might help to identify clinically useful biomarkers to assess patient follow-up.

Pain associated with COVID-19 vaccination is unrelated to skin biopsy abnormalities.

Introduction: Previous clinical observations raised the possibility that COVID-19 vaccination might trigger a small-fibre neuropathy. Objectives: In this uncontrolled observational study, we aimed to identify small fibre damage in patients complaining of generalized sensory symptoms and pain after COVID-19 vaccination. Methods: We collected clinical data, including a questionnaire for assessing autonomic symptoms (Composite Autonomic Symptom Score-31), and investigated quantitative sensory testing (QST) and skin biopsy in 15 prospectively enrolled patients with generalized sensory symptoms and pain after COVID-19 vaccination. Nine patients complaining of orthostatic intolerance also underwent cardiovascular autonomic tests. Results: We found that all patients experienced widespread pain, and most of them (11 of 15) had a fibromyalgia syndrome. All patients had normal skin biopsy findings, and in the 9 patients with orthostatic intolerance, cardiovascular autonomic tests showed normal findings. Nevertheless, 5 patients had cold and warm detection abnormalities at the QST investigation. Conclusions: In our study, most patients complaining of generalized sensory symptoms and pain after COVID-19 vaccination had clinical and diagnostic test findings compatible with a fibromyalgia syndrome. Although the abnormal QST findings we found in 5 patients might be compatible with a small-fibre neuropathy, they should be cautiously interpreted given the psychophysical characteristics of this diagnostic test. Further larger controlled studies are needed to define precisely the association between small fibre damage and COVID-19 vaccination.

IMI2-PainCare-BioPain-RCT2 protocol: a randomized, double-blind, placebo-controlled, crossover, multicenter trial in healthy subjects to investigate the effects of lacosamide, pregabalin, and tapentadol on biomarkers of pain processing observed by non-invasive neurophysiological measurements of human spinal cord and brainstem activity.

BACKGROUND: IMI2-PainCare-BioPain-RCT2 is one of four similarly designed clinical studies aiming at profiling a set of functional biomarkers of drug effects on specific compartments of the nociceptive system that could serve to accelerate the future development of analgesics. IMI2-PainCare-BioPain-RCT2 will focus on human spinal cord and brainstem activity using biomarkers derived from non-invasive neurophysiological measurements. METHODS: This is a multisite, single-dose, double-blind, randomized, placebo-controlled, 4-period, 4-way crossover, pharmacodynamic (PD) and pharmacokinetic (PK) study in healthy subjects. Neurophysiological biomarkers of spinal and brainstem activity (the RIII flexion reflex, the N13 component of somatosensory evoked potentials (SEP) and the R2 component of the blink reflex) will be recorded before and at three distinct time points after administration of three medications known to act on the nociceptive system (lacosamide, pregabalin, tapentadol), and placebo, given as a single oral dose in separate study periods. Medication effects on neurophysiological measures will be assessed in a clinically relevant hyperalgesic condition (high-frequency electrical stimulation of the skin), and in a non-sensitized normal condition. Patient-reported outcome measures (pain ratings and predictive psychological traits) will also be collected; and blood samples will be taken for pharmacokinetic modelling. A sequentially rejective multiple testing approach will be used with overall alpha error of the primary analysis split between the two primary endpoints, namely the percentage amplitude changes of the RIII area and N13 amplitude under tapentadol. Remaining treatment arm effects on RIII, N13 and R2 recovery cycle are key secondary confirmatory analyses. Complex statistical analyses and PK-PD modelling are exploratory. DISCUSSION: The RIII component of the flexion reflex is a pure nociceptive spinal reflex widely used for investigating pain processing at the spinal level. It is sensitive to different experimental pain models and to the antinociceptive activity of drugs. The N13 is mediated by large myelinated non-nociceptive fibers and reflects segmental postsynaptic response of wide dynamic range dorsal horn neurons at the level of cervical spinal cord, and it could be therefore sensitive to the action of drugs specifically targeting the dorsal horn. The R2 reflex is mediated by large myelinated non-nociceptive fibers, its circuit consists of a polysynaptic chain lying in the reticular formation of the pons and medulla. The recovery cycle of R2 is widely used for assessing brainstem excitability. For these reasons, IMI2-PainCare-BioPain-RCT2 hypothesizes that spinal and brainstem neurophysiological measures can serve as biomarkers of target engagement of analgesic drugs for future Phase 1 clinical trials. Phase 2 and 3 clinical trials could also benefit from these tools for patient stratification. TRIAL REGISTRATION: This trial was registered on 02 February 2019 in EudraCT ( 2019-000755-14 ).

The diagnostic accuracy of the small fiber neuropathy symptoms inventory questionnaire (SFN-SIQ) for identifying pure small fiber neuropathy.

A definite diagnosis of pure small fiber neuropathy (SFN) relies on specific diagnostic testing, such as skin biopsy, quantitative sensory testing (QST), and nociceptive evoked potentials, which require considerable resources that may not be widely available. Accordingly, diagnostic tools with easy implementation in non-specialist centers are warranted to identify patients who require second-level diagnostic tests. In this study, we aimed to test the accuracy of the Small Fiber Neuropathy Symptoms Inventory Questionnaire (SFN-SIQ) in diagnosing pure SFN. We enrolled 86 patients with suspected pure SFN. In these patients, we calculated the diagnostic accuracy of the SFN-SIQ using a combination of clinical examination, QST, and skin biopsy as a reference standard. We found that the SFN-SIQ showed an excellent ability to discriminate between patients with and without pure SFN, with 86% sensitivity and 70% specificity in the diagnosis of pure SFN. Our study providing the diagnostic yield of the SFN-SIQ for pure SFN diagnosis suggests that this questionnaire might be used to screen patients with suspected SFN and identify those requiring second-level diagnostic tests such as QST, skin biopsy, or nociceptive evoked potentials.

Unravelling the role of unmyelinated nerve fibres in trigeminal neuralgia with concomitant continuous pain.

OBJECTIVE: In this clinical and neurophysiological study, we aimed to test trigeminal nerve fibre function in patients with trigeminal neuralgia, with and without concomitant continuous pain. METHODS: We enrolled 65 patients with a definite diagnosis of primary trigeminal neuralgia. Patients were grouped according to whether they experienced purely paroxysmal pain (36) or also had concomitant continuous pain (29). All participants underwent trigeminal reflex testing to assess the function of large non-nociceptive myelinated fibres and laser-evoked potentials to assess the function of small myelinated Aδ and unmyelinated C fibres. Neurophysiological examiners were blinded to the affected side. RESULTS: The only neurophysiological abnormality distinguishing the two groups of patients was the side asymmetry of C fibre-related laser-evoked potential amplitude (p = 0.005), which was higher in patients with concomitant continuous pain than in patients with purely paroxysmal pain (indicative of a reduced C fibre-related laser-evoked potential amplitude in the affected side of patients with concomitant continuous pain). CONCLUSIONS: Our clinical and neurophysiological study indicates that in patients with trigeminal neuralgia concomitant continuous pain is associated with unmyelinated C fibre damage as assessed with laser-evoked potentials. SIGNIFICANCE: Our findings suggest that concomitant continuous pain is related to unmyelinated C fibre loss, possibly triggering abnormal activity in denervated trigeminal second-order neurons.

IMI2-PainCare-BioPain-RCT1: study protocol for a randomized, double-blind, placebo-controlled, crossover, multi-center trial in healthy subjects to investigate the effects of lacosamide, pregabalin, and tapentadol on biomarkers of pain processing observed by peripheral nerve excitability testing (NET).

BACKGROUND: Few new drugs have been developed for chronic pain. Drug development is challenged by uncertainty about whether the drug engages the human target sufficiently to have a meaningful pharmacodynamic effect. IMI2-PainCare-BioPain-RCT1 is one of four similarly designed studies that aim to link different functional biomarkers of drug effects on the nociceptive system that could serve to accelerate the future development of analgesics. This study focusses on biomarkers derived from nerve excitability testing (NET) using threshold tracking of the peripheral nervous system. METHODS: This is a multisite single-dose, subject and assessor-blind, randomized, placebo-controlled, 4-period, 4-way crossover, pharmacodynamic (PD), and pharmacokinetic (PK) study in healthy subjects. Biomarkers derived from NET of large sensory and motor fibers and small sensory fibers using perception threshold tracking will be obtained before and three times after administration of three medications known to act on the nociceptive system (lacosamide, pregabalin, tapentadol) and placebo, given as a single oral dose with at least 1 week apart. Motor and sensory NET will be assessed on the right wrist in a non-sensitized normal condition while perception threshold tracking will be performed bilaterally on both non-sensitized and sensitized forearm skin. Cutaneous high-frequency electrical stimulation is used to induce hyperalgesia. Blood samples will be taken for pharmacokinetic purposes and pain ratings as well as predictive psychological traits will be collected. A sequentially rejective multiple testing approach will be used with overall alpha error of the primary analysis split across the two primary outcomes: strength-duration time constant (SDTC; a measure of passive membrane properties and nodal persistent Na+ conductance) of large sensory fibers and SDTC of large motor fibers comparing lacosamide and placebo. The key secondary endpoint is the SDTC measured in small sensory fibers. Remaining treatment arm effects on key NET outcomes and PK modelling are other prespecified secondary or exploratory analyses. DISCUSSION: Measurements of NET using threshold tracking protocols are sensitive to membrane potential at the site of stimulation. Sets of useful indices of axonal excitability collectively may provide insights into the mechanisms responsible for membrane polarization, ion channel function, and activity of ionic pumps during the process of impulse conduction. IMI2-PainCare-BioPain-RCT1 hypothesizes that NET can serve as biomarkers of target engagement of analgesic drugs in this compartment of the nociceptive system for future Phase 1 clinical trials. Phase 2 and 3 clinical trials could also benefit from these tools for patient stratification. TRIAL REGISTRATION: This trial was registered 25/06/2019 in EudraCT ( 2019-000942-36 ).

The N13 spinal component of somatosensory evoked potentials is modulated by heterotopic noxious conditioning stimulation suggesting an involvement of spinal wide dynamic range neurons.

OBJECTIVES: Although somatosensory evoked potentials (SEPs) after median nerve stimulation are widely used in clinical practice, the dorsal horn generator of the N13 SEP spinal component is not clearly understood. To verify whether wide dynamic range neurons in the dorsal horn of the spinal cord are involved in the generation of the N13 SEP, we tested the effect of heterotopic noxious conditioning stimulation, which modulates wide dynamic range neurons, on N13 SEP in healthy humans. METHODS: In 12 healthy subjects, we performed the cold pressor test on the left foot as a heterotopic noxious conditioning stimulus to modulate wide dynamic range neurons. To verify the effectiveness of heterotopic noxious conditioning stimulation, we tested the pressure pain threshold at the thenar muscles of the right hand and recorded SEPs after right median nerve stimulation before, during and after the cold pressor test. RESULTS: The cold pressor test increased pressure pain threshold by 15% (p = 0.04). During the cold pressor test, the amplitude of the N13 component was significantly lower than that recorded at baseline (by 25%, p = 0.04). DISCUSSION: In this neurophysiological study in healthy humans, we showed that a heterotopic noxious conditioning stimulus significantly reduced N13 SEP amplitude. This finding suggests that the N13 SEP might be generated by the segmental postsynaptic response of dorsal horn wide dynamic range neurons.

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.

Human surrogate models of central sensitization: A critical review and practical guide.

BACKGROUND: As in other fields of medicine, development of new medications for management of neuropathic pain has been difficult since preclinical rodent models do not necessarily translate to the clinics. Aside from ongoing pain with burning or shock-like qualities, neuropathic pain is often characterized by pain hypersensitivity (hyperalgesia and allodynia), most often towards mechanical stimuli, reflecting sensitization of neural transmission. DATA TREATMENT: We therefore performed a systematic literature review (PubMed-Medline, Cochrane, WoS, ClinicalTrials) and semi-quantitative meta-analysis of human pain models that aim to induce central sensitization, and generate hyperalgesia surrounding a real or simulated injury. RESULTS: From an initial set of 1569 reports, we identified and analysed 269 studies using more than a dozen human models of sensitization. Five of these models (intradermal or topical capsaicin, low- or high-frequency electrical stimulation, thermode-induced heat-injury) were found to reliably induce secondary hyperalgesia to pinprick and have been implemented in multiple laboratories. The ability of these models to induce dynamic mechanical allodynia was however substantially lower. The proportion of subjects who developed hypersensitivity was rarely provided, giving rise to significant reporting bias. In four of these models pharmacological profiles allowed to verify similarity to some clinical conditions, and therefore may inform basic research for new drug development. CONCLUSIONS: While there is no single "optimal" model of central sensitization, the range of validated and easy-to-use procedures in humans should be able to inform preclinical researchers on helpful potential biomarkers, thereby narrowing the translation gap between basic and clinical data. SIGNIFICANCE: Being able to mimic aspects of pathological pain directly in humans has a huge potential to understand pathophysiology and provide animal research with translatable biomarkers for drug development. One group of human surrogate models has proven to have excellent predictive validity: they respond to clinically active medications and do not respond to clinically inactive medications, including some that worked in animals but failed in the clinics. They should therefore inform basic research for new drug development.

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.

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.