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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, weaimed 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 associatedwith COVID-19. Literature searches were conducted in PubMed, EMBASE and Cochrane Library databases. We consideredprospective and retrospective studies published up until September 2022 (limitations included English language, full-textpublications and studies including at least 10 patients). A random effects meta-analysis was performed and heterogeneityand publication bias were assessed.Results: We identified 149 studies. We included 17 studies in the systematic review, and six studies reporting the frequencyof neuropathic pain in the acute/ subacute phase of COVID-19 in the meta-analysis. The estimated frequency of neuropathicpain ranged between 0.4 and 25%. Forest plot analysis showed that the random effect overall frequency was 10% (95%confidence interval: 515%), with a high level of heterogeneity (Chi2 = 104; Tau2 = 0.004; df = 5; I2 = 95%; test for overalleffect: Z = 3.584; p < 0.0005). The overall risk of bias was moderate in all studies selected, particularly due to the poordescription of neuropathic pain diagnostic criteria.Conclusions: The pooled estimated frequency of neuropathic pain associated with COVID-19 should be considered withcaution due to the high heterogeneity across studies and the poor description of the neuropathic pain diagnostic criteriaapplied.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 areneeded to better assess the frequency of this condition.

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.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.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.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.

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.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.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).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.Our findings suggest that concomitant continuous pain is related to unmyelinated C fibre loss, possibly triggering abnormal activity in denervated trigeminal second-order neurons.

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.

Aims: The aim of this study was to assess patient perspectives and experiences of the impact of neuropathic pain, painful diabetic neuropathy (pDPN) diagnosis and treatment, and the patient-healthcare professional (HCP) relationship.Methods: We conducted a quantitative online survey in Germany, the Netherlands, Spain, and the UK among adults with diabetes who responded "yes" to at least four of ten questions of in the Douleur Neuropathique en 4 Questions (DN4) questionnaire.Results: Of 3626 respondents, 576 met the eligibility criteria. Daily pain was rated as moderate or severe by 79 % of respondents. Most participants reported a negative impact of their pain on sleep (74 %), mood (71 %), exercise (69 %), concentration (64 %) and daily activities (62 %), and 75 % of those in employment had missed work because of their pain in the past year. Overall, 22 % of respondents avoided discussing pain with their HCP, 50 % had not received formal pDPN diagnosis, and 56 % had not used prescribed pain medications. Although two-thirds (67 %) of respondents reported feeling satisfied or very satisfied with treatment, 82 % of these patients still experienced daily moderate or severe pain.Conclusions: Neuropathic pain in people with diabetes affects daily life and remains underdiagnosed and undertreated in clinical practice.

This chapter presents the case of a woman with burning pain of the lower legs and lightheadedness when standing up from a sitting position who had normal neurological examination and electromyography. Hence, she was told that pain was “in her head,” but a psychiatrist stated that she did not suffer from a psychiatric condition. She was ultimately diagnosed with small fiber neuropathy based on complementary investigations, including laser evoked potentials and skin punch biopsy. This case illustrates the importance of an in-depth assessment of patients with chronic pain and shows the place of complementary investigations. The fact that pain was limited to the lower limbs and described as neuropathic should orient toward a neurological lesion.

This chapter presents the case of an old woman who suffers from facial pain characterized by intense attacks, limited to the right side of the face, involving the cheek, upper and lower lips, and the underlying gums, lasting fractions of a seconds, and sometimes occurring in bursts. Her clinical picture is typical of trigeminal neuralgia. Diagnosis is clinical, but a magnetic resonance imaging scan or complete trigeminal reflex testing is mandatory to exclude major neurological diseases. First-line therapy is medical and includes carbamazepine or oxcarbazepine. If the occurrence of side effects prevents the patient from reaching the effective dosage, a neurosurgical referral should be considered.

This chapter presents the case of a woman who initially developed pain involving the lower limbs, compatible with sensory neuropathy (specifically small fiber neuropathy), and now reports pain “all over the body,” associated with multiple other symptoms, fulfilling criteria for fibromyalgia. Fibromyalgia may classically develop in the context of rheumatological diseases, such as chronic arthritis or spondylosis, but also in relation with stress, sleep disorders, past traumatic events, or any focal painful injury. Fibromyalgia may also be associated with painful (small fiber) neuropathy, but it is unclear whether the neuropathy is a trigger or may cause the pain and associated symptoms in fibromyalgia syndrome. Therapeutic management should be based on the clinical phenotype and include mainly therapeutic education, physical reconditioning, and cognitive–behavior therapy.

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.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.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 (ChiThe 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.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.

Study of intraepidermal nerve fiber density (IENFD) by skin biopsy represents a promising tool in the evaluation of patients with ATTRv polyneuropathy (ATTRv-PN). Herein, we retrospectively analyze intraepidermal innervation and quantitative sensory test (QST) data from an Italian cohort of Italian ATTRv-PN patients and asymptomatic carriers aimed to provide insights into early nerve pathological and functional changes in this disease. IENFD and QST data of 14 ATTRv-PN patients and 14 asymptomatic carriers were retrospectively analyzed together with clinical and paraclinical data such as disease stage and severity, neuropathic pain scales, and sural SNAP amplitude. Given an estimated time to the predicted age of onset of symptomatic disease of 20.27 + / − 7.9 years, small nerve fiber loss seems to be unexpectedly early in carriers. Moreover, carriers showed skin denervation at the proximal (thigh) site, suggesting a non-length-dependent neuropathic process. IENFD at ankle correlated with disease severity and other paraclinical variables such as sural nerve potential amplitude and QST parameters. Patients at earlier stages of the disease did not show significant differences in ankle IENFD compared with asymptomatic carriers, but significant differences in terms of QST parameters, small fiber neuropathy symptoms, and neuropathic pain. Skin biopsy can disclose an early non-length-dependent small fiber loss in ATTRv-PN and, together with QST, could provide a useful insight disease onset and progression.

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.

Diabetic neuropathy is among the most frequent complications of both type 1 (T1DM) and type 2 diabetes (T2DM) and commonly manifests as a distal symmetrical polyneuropathy (DSPN). Despite evidence that T1DM- and T2DM-related DSPN are separate entities, most of our knowledge on diabetic DSPN derives from studies focused on type 2 diabetes. This systematic review provides an overview of current evidence on DSPN in T1DM, including its epidemiological, pathophysiological and clinical features, along with principal diagnostic tests findings. This review included 182 clinical and preclinical studies. The results indicate that DSPN is a less frequent complication in T1DM compared with T2DM and that distinctive pathophysiological mechanisms underlie T1DM-related DSPN development, with hyperglycemia as a major determinant. T1DM-related DSPN more frequently manifests with non-painful than painful symptoms, with lower neuropathic pain prevalence compared with T2DM-associated DSPN. The overt clinical picture seems characterized by a higher prevalence of large fiber-related clinical signs (e.g., ankle reflexes reduction and vibration hypoesthesia) and to a lesser extent small fiber damage (e.g., thermal or pinprick hypoesthesia). These findings as a whole suggest that large fibers impairment plays a dominant role in the clinical picture of symptomatic T1DM-related DSPN. Nevertheless, small fiber diagnostic testing shows high diagnostic accuracy in detecting early nerve damage and may be an appropriate diagnostic tool for disease monitoring and screening.

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). 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). 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. 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.

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 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).

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.

Introduction Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) remains a diagnostic challenge due to clinical, neurophysiological, and laboratory findings suggestive of other diagnoses, particularly chronic inflammatory demyelinating polyneuropathy (CIDP). In this cross-sectional prospective study, we aimed to investigate the utility of high-resolution ultrasonography of peripheral nerves as a diagnostic tool to differentiate ATTRv-PN from CIDP. Methods In 11 treatment-naive patients with genetically confirmed late-onset ATTRv-PN and 25 patients with CIDP, we collected clinical, electrodiagnostic, and high-resolution ultrasonography data of the peripheral nerves. In each patient, we used high-resolution ultrasonography to assess 26 nerve sites. Results Of the 11 patients with ATTRv-PN, two had electrodiagnostic study data compatible with a CIDP diagnosis. High-resolution ultrasonography showed that the cross-sectional area of the brachial plexus, median nerve at the axilla, arm, and forearm, ulnar nerve at the forearm, and peroneal nerve at the popliteal fossa were significantly smaller in the 11 ATTRv-PN patients than in CIDP patients. However, in the two patients with electrodiagnostic study data compatible with a CIDP diagnosis, high-resolution nerve ultrasonography data were comparable to those in patients with CIDP. Conclusion Although high-resolution ultrasonography of peripheral nerves provides reliable information in patients with ATTRv-PN, its usefulness as a standalone diagnostic tool to differentiate ATTRv-PN from CIDP might be limited.

Laser evoked potentials (LEPs) – the EEG response to temporally-discrete thermal stimuli – are commonly used in experimental pain studies in humans. Such stimuli selectively activate nociceptors and produce EEG features which correlate with pain intensity. The rodent LEP has been proposed to be a translational biomarker of nociception and pain, however its validity has been questioned because of reported differences in the classes of nociceptive fibres mediating the response. Here we use a machine learning, trial by trial analysis approach on wavelet-denoised LEPs generated by stimulation of the plantar hindpaw of rats. The LEP amplitude was more strongly related to behavioural response than to laser stimulus energy. A simple decision tree classifier using LEP features was able to predict behavioural responses with 73% accuracy. An examination of the features used by the classifier showed that mutually exclusive short and long latency LEP peaks were clearly seen in single-trial data, yet were not evident in grand average data pooled from multiple trials. This bimodal distribution of LEP latencies was mirrored in the paw withdrawal latencies which were preceded and predicted by the LEP responses. The proportion of short latency events was increased after intradermal application of high dose capsaicin (to defunctionalise TRPV1 expressing nociceptors), suggesting they were mediated by Aδ-fibres (specifically AMH-I). These findings demonstrate that both C- and Aδ-fibres contribute to rodent LEPs and concomitant behavioural responses, providing a real-time assay of specific fibre function in conscious animals. Single-trial analysis approaches can improve the utility of LEPs as a translatable biomarker of pain.

Background IMI2-PainCare-BioPain-RCT3 is one of four similarly designed clinical studies aiming at profiling a set of functional biomarkers of drug effects on the nociceptive system that could serve to accelerate the future development of analgesics, by providing a quantitative understanding between drug exposure and effects of the drug on nociceptive signal processing in human volunteers. IMI2-PainCare-BioPain-RCT3 will focus on biomarkers derived from non-invasive electroencephalographic (EEG) measures of brain activity. 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. Biomarkers derived from scalp EEG measurements (laser-evoked brain potentials [LEPs], pinprick-evoked brain potentials [PEPs], resting EEG) 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 in separate study periods. Medication effects will be assessed concurrently in a non-sensitized normal condition and a clinically relevant hyperalgesic condition (high-frequency electrical stimulation of the skin). Patient-reported outcomes will also be collected. A sequentially rejective multiple testing approach will be used with overall alpha error of the primary analysis split between LEP and PEP under tapentadol. Remaining treatment arm effects on LEP or PEP or effects on EEG are key secondary confirmatory analyses. Complex statistical analyses and PK-PD modeling are exploratory. Discussion LEPs and PEPs are brain responses related to the selective activation of thermonociceptors and mechanonociceptors. Their amplitudes are dependent on the responsiveness of these nociceptors and the state of the pathways relaying nociceptive input at the level of the spinal cord and brain. The magnitude of resting EEG oscillations is sensitive to changes in brain network function, and some modulations of oscillation magnitude can relate to perceived pain intensity, variations in vigilance, and attentional states. These oscillations can also be affected by analgesic drugs acting on the central nervous system. For these reasons, IMI2-PainCare-BioPain-RCT3 hypothesizes that EEG-derived 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 25/06/2019 in EudraCT (2019%2D%2D001204-37).

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.

In Parkinson's disease (PD), pain represents a significant issue in terms of prevalence, clinical features, and treatment. Painful manifestations not strictly related to the disease are often amplified by the motor dysfunction. On the other hand, typical pain problems may specifically concern this vulnerable population. In turn, pain may have a deep impact on patients' health-related quality of life. However, pain treatment in PD remains an unmet need as only about half of patients with pain use analgesics and pain is often managed by simply increasing doses of PD medications. In this complex scenario, pain treatments should follow multimodal approaches through a careful combination of pharmacological agents with non-pharmacological strategies, depending on the type of pain and the clinical context. A multidisciplinary approach involving medical specialists from different disciplines could be a winning strategy to address the issue. This work is aimed to provide practical suggestions useful for different types of clinicians and care professionals for pain management in this vulnerable population.

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

There is an urgent need for analgesics with improved efficacy, especially in neuropathic and other chronic pain conditions. Unfortunately, in recent decades, many candidate analgesics have failed in clinical phase II or III trials despite promising preclinical results. Translational assessment tools to verify engagement of pharmacological targets and actions on compartments of the nociceptive system are missing in both rodents and humans. Through the Innovative Medicines Initiative of the European Union and EFPIA, a consortium of researchers from academia and the pharmaceutical industry was established to identify and validate a set of functional biomarkers to assess drug-induced effects on nociceptive processing at peripheral, spinal and supraspinal levels using electrophysiological and functional neuroimaging techniques. Here, we report the results of a systematic literature search for pharmacological probes that allow for validation of these biomarkers. Of 26 candidate substances, only 7 met the inclusion criteria: evidence for nociceptive system modulation, tolerability, availability in oral form for human use and absence of active metabolites. Based on pharmacokinetic characteristics, three were selected for a set of crossover studies in rodents and healthy humans. All currently available probes act on more than one compartment of the nociceptive system. Once validated, biomarkers of nociceptive signal processing, combined with a pharmacometric modelling, will enable a more rational approach to selecting dose ranges and verifying target engagement. Combined with advances in classification of chronic pain conditions, these biomarkers are expected to accelerate analgesic drug development.

The diagnosis of a cranial neuralgia or neuropathy is clinical and rests on a detailed oral history. A working diagnosis can be obtained using eight yes-or-no questions. Clinical examination apart from sensory testing serves to rule out other facial pain conditions. Magnetic resonance imaging is essential as an aetiological investigation but requires use of specific imaging paradigms that allow visualization of the affected cranial nerve, surrounding blood vessels, and respective root entry zones to detect neurovascular compression. Only magnetic resonance imaging is capable of showing strategically placed brain lesions, such as multiple sclerosis plaques or solitary pontine lesions. Neurophysiological testing employing trigeminal reflexes reveals response abnormalities in practically all cases of secondary trigeminal neuralgia. As important as searching for a clinical diagnosis is assessment of the impact of the pain on the patient’s mood, functionality, and quality of life requires dedicated attention. Use of validated psychometric questionnaires will greatly facilitate this.

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

Objective: In this neurophysiological study in healthy humans, we assessed how central sensitization induced by either high-frequency stimulation (HFS) or topical capsaicin application modulates features of the RIII reflex response. The ability of these stimuli to engage the endogenous pain modulatory system was also tested. Methods: In 26 healthy participants we elicited an RIII reflex using suprathreshold stimulation of the sural nerve. Subsequently HFS or capsaicin were applied to the foot and the RIII reflex repeated after 15 minutes. Contact heating of the volar forearm served as the heterotopic test stimulus to probe activation of the endogenous pain modulatory system. Results: HFS significantly reduced the pain threshold by 29% and the RIII reflex threshold by 20%. Capsaicin significantly reduced the pain threshold by 17% and the RIII reflex threshold by 18%. Both HFS and capsaicin left RIII reflex size unaffected. Numerical Rating Scale (NRS) pain scores elicited by the heterotopic noxious heat stimulus were unaffected by capsaicin and slightly increased by HFS. Conclusions: HFS and capsaicin similarly modulated the pain threshold and RIII reflex threshold, without a concomitant inhibitory effect of the endogenous pain modulatory system. Significance: Our neurophysiological study supports the use of the RIII reflex in investigating central sensitization in humans. &nbsp

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.

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.