Neuropathic Patients Research Articles

Spinal cord stimulation modulates descending pain inhibition and temporal summation of pricking pain in patients with neuropathic pain

Spinal cord stimulation (SCS) is an established treatment option for patients with refractory chronic pain conditions. While effects of SCS on dorsal horn neuronal circuitries are intensively studied, current knowledge on the impact of SCS on descending pain pathways is scarce and relies on preclinical data. We aimed to address this topic and hypothesized a significant effect of SCS on descending pain modulation. In light of current efforts to determine the sensitivity of "static" versus "dynamic" somatosensory parameters to characterize pathophysiological pain conditions, all SCS patients were carefully investigated using both classes of somatosensory outcome parameters. Descending pain pathways were investigated by using a "Cold Pressor Test." This test enables to evaluate the efficacy of conditioned pain modulation (CPM) at the individual level. CPM efficacy was assessed in eight neuropathic pain patients (age 55.5±10.6) during the two conditions stimulator "ON" and "OFF." The impact of SCS on "static" and "dynamic" somatosensory parameters was explored by using a quantitative sensory testing (QST) battery. CPM efficacy on pressure pain sensitivity was nearly absent during "OFF" (- 1.2±5.6% facilitation), but increased significantly to 16.3±3.4% inhibition during "ON" (p = 0.03). While most "static" nociceptive QST parameters, represented by mechanical/thermal pain thresholds, exhibited only small effects of SCS (p > 0.05), the wind-up ratio was strongly reduced to within the normal range during "ON" (p = 0.04; Cohen's d = 1.0). Dynamic mechanical allodynia was abolished in six of seven patients. Our study provides first human evidence for an impact of SCS on descending pain pathways in the dorsolateral funiculus and emphasizes the significance of "dynamic" pain measures like "CPM"-efficacy and "temporal summation" to evaluate SCS treatment effects. Future prospective studies may use these measures of nociceptive processing to predict SCS therapy response.

Stratification of neuropathic pain patients: the road to mechanism-based therapy?

It has been demonstrated that within one pain entity, patients may report highly heterogenic sensory signs and symptoms. Although mechanism might differ fundamentally between those patients, yet the treatment recommendations are uniform throughout all phenotypes. Therefore, the introduction of new stratification tools could pave the way to an individualized pain treatment. In the past, retrospective stratifications of patients successfully identified responders to certain pharmacological treatments. This indicated predictive validity and reliability of this classification tool in those patient subgroups. Further on, these observations have been confirmed in prospective studies. This review focusses on recent achievements in neuropathic pain and suggests a promising implementation of an individualized pharmacological therapy in the future.

Electrochemical Skin Conductance as a Marker of Painful Oxaliplatin-Induced Peripheral Neuropathy.

Purpose Oxaliplatin is a platinum compound widely used in gastrointestinal cancer treatment but produces dose-limiting peripheral neuropathy. New insights into oxaliplatin-induced peripheral neuropathy (OIPN) assessment are needed to detect more effectively this condition. In this context, we conducted Canaloxa study, a prospective preliminary clinical trial that aimed to investigate how Electrochemical Skin Conductance (ESC), a parameter used in small fiber neuropathy assessment, could be helpful in OIPN diagnosis. Methods Cancer patients treated for at least three months with oxaliplatin and suffering from clinically OIPN were included. Electrochemical Skin Conductance, thermal thresholds, and neuropathic pain were assessed in all included patients. Results During one year, 36 patients were included. The main result was the correlation between ESC and Neuropathic Pain Symptom Inventory score for hands (rho value = -0.69, p < 0.0001) and feet (rho value = -0.79, p < 0.0001). ESC values were lower in neuropathic patients with painful symptoms than in ones without painful symptoms (p = 0.0003 and p < 0.0001 for hands and feet, respectively). No correlation was observed between ESC and thermal thresholds. Conclusion These preliminary data suggest that ESC could be a useful objective marker of painful oxaliplatin-induced neuropathy and could complement the use of subjective clinical scales. This study was prospectively registered on clinicaltrials.gov (NCT02827916) before patient recruitment has begun.

SIGMA-1 Receptor Gene Variants Affect the Somatosensory Phenotype in Neuropathic Pain Patients

Pain sensitivity is characterized by interindividual variability, determined by factors including genetic variation of nociceptive receptors and pathways. The sigma-1 receptor (SIGMAR1) is involved in pain modulation especially under pre-sensitized conditions. However, the contribution of SIGMAR1 genetic variants to pain generation and sensitivity is unknown yet. This study aimed to identify effects of 5 SIGMAR1 variants on the somatosensory phenotype of neuropathic pain patients (n = 228) characterized by standardized quantitative sensory testing. Principal component analysis revealed that the SIGMAR1 variants −297G>T (rs10814130) and 5A>C (rs1800866) significantly lowered thermal detection and heat/pressure nociception in particular in neuropathic pain patients with mainly preserved somatosensory function. Compared to wild-type, the variant allele −297T was associated with loss of warm detection (P = .049), lower heat-pain sensitivity (P = .027) and wind-up ratio (P = .023) as well as increased paradoxical heat sensation (P = .020). Likewise for 5A>C the strongest genotype-associated differences observed were reduced peripheral (less heat hyperalgesia; P = .026) and central sensitization (lower mechanical pain sensitivity; P = .026) in variant compared to wild-type carriers. This study indicates lack of association of SIGMAR1 −297G>T and 5A>C genetic variants to susceptibility to develop chronic pain, but significant modulation of somatosensory function in neuropathic pain patients. PerspectiveThis article presents the first study indicating a modulation of somatosensory function in neuropathic pain patients by selected genetic variants in SIGMAR1. As our findings could contribute to the explanation of interindividual differences in drug response they might help to improve the treatment of neuropathic pain.

Targeting the Nav1.8 ion channel engenders sex-specific responses in lysophosphatidic acid-induced joint neuropathy.

Joint neuropathic pain occurs in a subset of arthritis patients, and lysophosphatidic acid (LPA) has been implicated as a mediator of joint neuropathy. The mechanism by which LPA promotes neuropathic pain is unknown but may be related to altered signalling of the voltage-gated sodium channel Nav1.8 located on nociceptors. Because arthritis and neuropathic pain are more prevalent in females, this study aimed to explore potential sex differences in the development of LPA-induced joint neuropathy and whether Nav1.8 played a role in the associated neuropathic pain. Joint neuropathy was induced in male and female Wistar rats (179-284 g) by intra-articular injection of 50-µg LPA. Pain behaviour was assessed over 21 days using von Frey hair algesiometry. On day 21, electrophysiological recordings of joint primary afferents were conducted to measure peripheral sensitisation. Saphenous nerve morphology and expression of the nerve-damage marker ATF3 and Nav1.8 in ipsilateral dorsal root ganglions were compared on the basis of sex. The analgesic properties of the selective Nav1.8 antagonist A-803467 was determined in pain behaviour and electrophysiology experiments. Females developed more severe mechanical allodynia than males after LPA treatment. Lysophosphatidic acid caused more pronounced demyelination of the saphenous nerve in females, but no sex differences were observed in the expression of ATF3 or Nav1.8 in dorsal root ganglion neurones. Blockade of Nav1.8 channels with A-803467 resulted in a decrease in joint mechanosensitivity and secondary allodynia with females exhibiting a greater response. These findings suggest that LPA has sex-specific effects on joint neuropathy and Nav1.8 gating, which should be considered when treating neuropathic arthritis patients.

Prevalence of central and peripheral neuropathic pain in patients attending pain clinics in Spain: factors related to intensity of pain and quality of life.

BackgroundThe objective of the study was to estimate the prevalence of pure central neuropathic pain (CNP) and peripheral neuropathic pain (PNP) among patients attending pain clinics in Spain. The study also aimed to analyze factors associated with pain intensity and quality of life (QoL).MethodsA cross-sectional study was performed including 53 patients with pure CNP and 281 with pure PNP attending in 104 pain clinics in Spain. The revised grading system proposed in 2008 to determine a definite, probable or possible diagnosis of NP was used. Pain features, psychological variables and QoL were assessed. Descriptive, bivariate and multivariate analyses were performed.ResultsThe prevalence of pure CNP and PNP amongst neuropathic pain patients was 2.4% (95% CI: 1.7;3.1) and 12.9% (95% CI: 1.5;14.3), respectively. Comorbid anxiety, depression or sleep disorders were high in both groups, but higher in CNP patients (51.1%, 71.4%, respectively). Pain intensity in PNP patients was associated with the presence of depression and sleep disturbances. However, in CNP patients, it was related with pain in the lower limbs. The impairment of QoL was greater in CNP patients than in PNP patients; pain location, presence of depression and sleep disturbance were the factors that most negatively affected QoL. Among PNP patients, women and those with higher pain intensity had worse QoL.ConclusionPain intensity and QoL are affected by different factors in patients suffering from CNP or PNP. Identifying these factors could serve to guide therapeutic strategies and improve the QoL of patients.

Neuropathy following spinal nerve injury shares features with the irritable nociceptor phenotype: A back-translational study of oxcarbazepine.

BackgroundThe term ‘irritable nociceptor’ was coined to describe neuropathic patients characterized by evoked hypersensitivity and preservation of primary afferent fibres. Oxcarbazepine is largely ineffectual in an overall patient population, but has clear efficacy in a subgroup with the irritable nociceptor profile. We examine whether neuropathy in rats induced by spinal nerve injury shares overlapping pharmacological sensitivity with the irritable nociceptor phenotype using drugs that target sodium channels.Methods In vivo electrophysiology was performed in anaesthetized spinal nerve ligated (SNL) and sham‐operated rats to record from wide dynamic range (WDR) neurones in the ventral posterolateral thalamus (VPL) and dorsal horn.ResultsIn neuropathic rats, spontaneous activity in the VPL was substantially attenuated by spinal lidocaine, an effect that was absent in sham rats. The former measure was in part dependent on ongoing peripheral activity as intraplantar lidocaine also reduced aberrant spontaneous thalamic firing. Systemic oxcarbazepine had no effect on wind‐up of dorsal horn neurones in sham and SNL rats. However, in SNL rats, oxcarbazepine markedly inhibited punctate mechanical‐, dynamic brush‐ and cold‐evoked neuronal responses in the VPL and dorsal horn, with minimal effects on heat‐evoked responses. In addition, oxcarbazepine inhibited spontaneous activity in the VPL. Intraplantar injection of the active metabolite licarbazepine replicated the effects of systemic oxcarbazepine, supporting a peripheral locus of action.ConclusionsWe provide evidence that ongoing activity in primary afferent fibres drives spontaneous thalamic firing after spinal nerve injury and that oxcarbazepine through a peripheral mechanism exhibits modality‐selective inhibitory effects on sensory neuronal processing.SignificanceThe inhibitory effects of lidocaine and oxcarbazepine in this rat model of neuropathy resemble the clinical observations in the irritable nociceptor patient subgroup and support a mechanism‐based rationale for bench‐to‐bedside translation when screening novel drugs.

Tinnitus and neuropathic pain share a common neural substrate in the form of specific brain connectivity and microstate profiles

Tinnitus and neuropathic pain share similar pathophysiological, clinical, and treatment characteristics. In this EEG study, a group of tinnitus (n = 100) and neuropathic pain (n = 100) patients are compared to each other and to a healthy control group (n = 100). Spectral analysis demonstrates gamma band activity within the primary auditory and somatosensory cortices in patients with tinnitus and neuropathic pain, respectively. A conjunction analysis further demonstrates an overlap of tinnitus and pain related activity in the anterior and posterior cingulate cortex as well as in the dorsolateral prefrontal cortex in comparison to healthy controls. Further analysis reveals that similar states characterize tinnitus and neuropathic pain patients, two of which differ from the healthy group and two of which are shared. Both pain and tinnitus patients spend half of the time in one specific microstate. Seed-based functional connectivity with the source within the predominant microstate shows delta, alpha1, and gamma lagged phase synchronization overlap with multiple brain areas between pain and tinnitus. These data suggest that auditory and somatosensory phantom perceptions share an overlapping brain network with common activation and connectivity patterns and are differentiated by specific sensory cortex gamma activation.

KIF1Bβ mutations detected in hereditary neuropathy impair IGF1R transport and axon growth.

KIF1Bβ is a kinesin-3 family anterograde motor protein essential for neuronal development, viability, and function. KIF1Bβ mutations have previously been reported in a limited number of pedigrees of Charcot-Marie-Tooth disease type 2A (CMT2A) neuropathy. However, the gene responsible for CMT2A is still controversial, and the mechanism of pathogenesis remains elusive. In this study, we show that the receptor tyrosine kinase IGF1R is a new direct binding partner of KIF1Bβ, and its binding and transport is specifically impaired by the Y1087C mutation of KIF1Bβ, which we detected in hereditary neuropathic patients. The axonal outgrowth and IGF-I signaling of Kif1b-/- neurons were significantly impaired, consistent with decreased surface IGF1R expression. The complementary capacity of KIF1Bβ-Y1087C of these phenotypes was significantly impaired, but the binding capacity to synaptic vesicle precursors was not affected. These data have supported the relevance of KIF1Bβ in IGF1R transport, which may give new clue to the neuropathic pathogenesis.

Do fragments and glycosylated isoforms of alpha-1-antitrypsin in CSF mirror spinal pathophysiological mechanisms in chronic peripheral neuropathic pain? An exploratory, discovery phase study

BackgroundPost-translational modifications (PTMs) generate a tremendous protein diversity from the ~ 20,000 protein-coding genes of the human genome. In chronic pain conditions, exposure to pathological processes in the central nervous system could lead to disease-specific PTMs detectable in the cerebrospinal fluid (CSF). In a previous hypothesis-generating study, we reported that seven out of 260 CSF proteins highly discriminated between neuropathic pain patients and healthy controls: one isoform of angiotensinogen (AG), two isoforms of alpha-1-antitrypsin (AT), three isoforms of haptoglobin (HG), and one isoform of pigment epithelium-derived factor (PEDF). The present study had three aims: (1) To examine the multivariate inter-correlations between all identified isoforms of these seven proteins; (2) Based on the results of the first aim, to characterize PTMs in a subset of interesting proteins; (3) To regress clinical pain data using the 260 proteins as predictors, thereby testing the hypothesis that the above-mentioned seven discriminating proteins and/or the characterized isoforms/fragments of aim (2) would be among the proteins having the highest predictive power for clinical pain data.MethodsCSF samples from 11 neuropathic pain patients and 11 healthy controls were used for biochemical analysis of protein isoforms. PTM characterization was performed using enzymatic reaction assay and mass spectrometry. Multivariate data analysis (principal component analysis and orthogonal partial least square regression) was applied on the quantified protein isoforms.ResultsWe identified 5 isoforms of AG, 18 isoforms of AT, 5 isoforms of HG, and 5 isoforms of PEDF. Fragments and glycosylated isoforms of AT were studied in depth. When regressing the pain intensity data of patients, three isoforms of AT, two isoforms of PEDF, and one isoform of angiotensinogen “reappeared” as major results, i.e., they were major findings both when comparing patients with healthy controls and when regressing pain intensity in patients.ConclusionsAltered levels of fragments and/or glycosylated isoforms of alpha-1-antitrypsin might mirror pathophysiological processes in the spinal cord of neuropathic pain patients. In particular, we suggest that a putative disease-specific combination of the levels of two different N-truncated fragments of alpha-1-antitrypsin might be interesting for future CSF and/or plasma biomarker investigations in chronic neuropathic pain.

Salivary beta-endorphin and substance P are not biomarkers of neuropathic chronic pain propensity

ObjectiveThe pathophysiology of chronic pain is complex, with most of our knowledge being derived from preclinical studies. The search for biomarkers mirroring the pathophysiology of chronic pain is ongoing, and there is an increasing interest in saliva as a diagnostic tool. Given what is known about salivary substance P and salivary gland innervation, we hypothesized that salivary substance P and/or beta-endorphin might reflect the basal activity of these neuropeptides in the central nervous system, thereby perhaps mirroring a general propensity to chronic pain. Based on this overall hypothesis, our aim was to compare salivary levels of these neuropeptides in chronic neuropathic pain patients with healthy controls. An additional aim was to relate salivary levels to plasma levels. Materials and methodsWe compared salivary concentrations of beta-endorphin and substance P in 14 chronic neuropathic pain patients with concentrations in 18 healthy controls using a Luminex technology kit. Salivary-to-plasma quotients were also calculated. ResultsWe found no significant difference between the groups' salivary concentrations of substance P and beta-endorphin. No correlation was found between salivary and plasma concentrations of each neuropeptide, which we hypothesize might point to local production of beta-endorphin and/or substance P in the salivary glands. Given high substance P salivary-to-plasma quotients, such a local production seems more likely for substance P than for beta-endorphin. ConclusionsPropensity to neuropathic chronic pain was not substantiated by our analysis of salivary levels of substance P and/or beta-endorphin. However, we report salivary-to-plasma quotients that give potentially important physiological insight about these neuropeptides.

Pharmacological target therapy of neuropathic pain and patient-reported outcomes in patients with chronic low back pain in Korea: Results from the NLBP Outcomes Research.

A number of studies have demonstrated an association of neuropathic pain and chronic low back pain (CLBP), but the outcome difference in each medical management is poorly understood. This study is aimed to investigate treatment patterns of neuropathic pain in CLBP patients and to explore patient-reported outcomes (PROs) including quality of life (QoL) and functional disability by treatment patterns.Data were extracted from the neuropathic low back pain (NLBP) outcomes research. It was a multicenter and cross-sectional study in which 1200 patients were enrolled at 27 general hospitals, from 2014 to 2015. Of total, 478 patients classified as neuropathic pain were used for this subgroup analysis. The patients were divided into 2 groups according to treatment patterns (with vs. without the targeted therapy [TT] of neuropathic pain). Demographic and clinical features were collected by chart reviews and PROs were measured by patient's survey. QoL was assessed by EuroQoL 5-dimension (EQ-5D) questionnaire. Functional disability was measured by the Quebec Back Pain Disability Scale (QBPDS). Multiple linear regression analyses were conducted to compare the PROs between TT group and non-targeted therapy (nTT) group.Among the NLBP patients (mean age 63years, female 62%), EQ-5D index, EuroQoL-Visual Analog Scale (EQ-VAS), and QBPDS Scores (mean ± standard deviation) were 0.40 ± 0.28, 54.98 ± 19.98, and 46.03 ± 21.24, respectively. Only 142 (29.7%) patients had pharmacological TT of neuropathic pain. Univariate analyses revealed no significant mean differences between TT group and nTT group in the EQ-5D index (0.41 ± 0.27 and 0.39 ± 0.28), EQ-VAS (56.43 ± 18.17 and 54.37 ± 20.69), and QBPDS (45.31 ± 21.32 and 46.31 ± 21.24). After adjustment with covariates, TT group had higher scores of EQ-5D index (β = 0.07; P < 0.01) and EQ-VAS (β = 4.59; P < 0.05) than the nTT group. The TT group's QBPDS score was lower than the nTT group, although its statistical significance still has not been reached (β = −4.13; P = 0.07).We found that considerable proportion of the NLBP patients remains untreated or undertreated. Although TT group had significantly better QoL than nTT group, only 29.7% of NLBP patients had pharmacological TT. Therefore, clinicians should consider using TT for better QoL of neuropathic pain patients.

Prevalence of chronic pain with or without neuropathic characteristics in France using the capture-recapture method: a population-based study.

Capture-recapture methods are increasingly used to determine the prevalence of numerous chronic conditions but have never been used in the context of chronic pain (CP). This study sought to provide up-to-date estimates of the prevalence of people experiencing CP ± neuropathic characteristics in France using the capture-recapture method. In 2013 to 2015, 3 data sources were used: the French prescription drug database (D-list), the national hospital discharge database (H-list), and the French pain center database (P-list). Patients aged 18 years and older treated with analgesic drugs for ≥6 months (D-list) or with a diagnosis of CP ± neuropathic characteristics (H- and P-lists) were included. Two successive capture-recapture analyses were conducted, with log-linear regression for each analysis performed. A total of 63,557 and 9852 distinct cases of CP and chronic neuropathic pain were captured, respectively. The estimated prevalence of CP and chronic neuropathic pain in the adults ranged from 27.2% (95% confidence interval: 26.1-28.4) to 32.7% (26.0-43.3) and from 5.55% (2.89-19.0) to 7.30% (6.40-8.41), respectively. Most patients were female, median ages were 67 (55-80) and 63 (51-76) years for chronic and neuropathic pain, respectively. The analgesic drugs most frequently used in CP patients were paracetamol (62.1%), weak opioids (39.7%), and nonsteroidal anti-inflammatory drugs (32.7%), whereas in neuropathic pain patients, anticonvulsants (45.3%), tricyclic antidepressants (18.1%), and serotonin-norepinephrine reuptake inhibitors (13.3%) were more frequently used. This first electronic health record-based study on CP using the capture-recapture method revealed a high prevalence of CP, with a significant proportion of neuropathic pain patients.

Quantitative Assessment of Type-1 Collagen in Charcot Neuroarthropathy with Use of Harmonic Generation and Multiphoton Microscopy

Category: Diabetes Introduction/Purpose: Diabetic Charcot neuroarthropathy is characterized by rapid loss of bone with accompanied disruption to the surrounding joints and is often in the absence of trauma or infection. Previous research has demonstrated neuropeptide release and osteoclast activation in addition to increased collagen turnover. Currently, there is limited understanding on the impact of the disease on type-1 collagen within the joint synovium. The purpose of this study was to analyze qualitative and quantitative differences in type-1 collagen between diabetic, neuropathic patient controls and those with Charcot neuroarthropathy. Methods: A prospective case-control study using routinely discarded surgical waste synovial tissue from diabetic, neuropathic patients with and without Charcot. The tissue was prepared in the laboratory for analysis. Microscopy was performed using multiphoton excitation fluorescence (MPEF) and second harmonic generation (SHG) microscopy techniques, utilizing a mode locked femto-second i: Sapphire Tsunami (Spectra-Physics, Mountain View, CA) synchronously pumped by a Millenia Xs J (Spectra-Physics) diode-pumped solid state laser. Qualitative and quantitative microscopic analysis was performed on Charcot specimens and controls. A statistical analysis was performed to detect a quantitative difference in type-1 collagen. Results: An analysis was performed on 8 samples; 4 neuropathic controls and 4 Charcot neuroarthropathy samples. There was a statistically significant difference between the amount, the quality and organization of type-1 collagen (p&lt;0.0001). The Charcot group had significantly less type-1 collagen when compared to the control (p&lt;0.0001). Qualitative analysis was performed using a mean intensity value. The control group’s mean intensity was 2561.4 nm while the Charcot group’s was 884.1 nm. The Charcot group had a significantly smaller mean intensity indicating poorer quality of collagen (p&lt;0.0001). Orientation index was used to assess the organization of type-1 collagen in the synovium. A smaller orientation index signifies an increase in disorganization. The Charcot group had a significantly smaller orientation index of 16.5 compared to the control group’s 27.8 (p&lt;0.0001). Conclusion: Charcot neuroarthropathy leads to significant abnormalities in type-1 collagen within the joint synovium when compared to the diabetic controls. Further research will determine if these differences are attributable to neuropeptide release and osteoclastic activation.

Comparison of Cognitive Function, Depression, and Sleep Quality among Type 2 Diabetes Mellitus Patients With and Without Diabetic Neuropathy

Diabetic neuropathy is one of the most common complication of diabetes mellitus. Many studies had reported that type 2 diabetes mellitus increases the risk of cognitive impairement,depression and sleep impairement in patients with diabetes mellitus. The main objective of the study is to determine whether any significant impairement in cognition function, sleep quality and depression status exist among diabetic neuropathy patients compared to patients with type 2 diabetes mellitus alone. A prospective observational study was conducted in a tertiary care teaching hospital. Patients who satisfied both inclusion and exclusion criteria were included in the study. A total of 59 type 2 diabetes mellitus patients with neuropathy and 55 patients with out neuropathy were enrolled in to the study after obtaining written informed consent. Cognitive status was assessed with the help of MOCA questionnaire. Sleep quality was assessed by using pittsburgh sleep quality index questionnare and depression, by using PHQ-9 questionnaire. The diabetic neuropathic patients showed a significant impairement in cognitive status (P value 0.003), sleep quality (P value 0.000) and depression status (p value 0.000). The study concluded that diabetic neuropathy increases the risk of cognitive impairement, impairement in sleep quality and depression in type 2 diabetes mellitus patients. Disclosure C. Radhakrishnan: None. R.R. Cr: None. S. K: None. A. Ut: None.

Short-term incubation of gabapentin or pregabalin does not affect chemically induced injury in neuronal cell models in vitro.

PurposeGabapentinoids are currently the mainstay of pharmacological treatments for patients with neuropathic pain. Little is known about the effects of this therapy on the integrity of neuronal networks, especially in patients with an already-damaged nervous system. Since gabapentinoids can worsen cognitive functions and recent studies have shown alterations in the brains of patients with neuropathic pain, it may be possible that these drugs have neurotoxic effects.MethodsRat clonal PC12 pheochromocytoma (autonomic) and primary sensory dorsal-root ganglion (DRG) neurons from newborn Wistar rats were employed for this study. To mimic neuronal damage, cells were exposed to cytotoxins using either hydrogen peroxide (H2O2) or vincristine.ResultsNo direct cytotoxic effects were observed after incubating PC12 cells for 24 hours with increasing concentrations of gabapentin or pregabalin using MTT cytotoxicity assays. Even a 7-day incubation did not cause cellular damage. Furthermore, in preinjured PC12 and DRG neurons, neither gabapentin nor pregabalin prevented or enhanced the cytotoxic effects of H2O2 or vincristine after incubation for 24 hours and 7 days, respectively. Cell morphology and integrity of the cytoskeleton assessed by employing immunostaining of cytoskeletal proteins (α-tubulin, neurofilament L) remained intact and were not altered by gabapentinoids.ConclusionBased on these results, gabapentinoids are unlikely to be neurotoxic in cultured autonomic (PC12) and sensory DRG cells, even when cells are preinjured. These results are of high clinical relevance, as it seems unlikely that the morphological changes recently observed in the brains of neuropathic pain patients are caused or worsened by gabapentinoids.

Phenytoin Cream for the Treatment for Neuropathic Pain: Case Series.

BACKGROUND: Neuropathic pain can be disabling, and is often difficult to treat. Within a year, over half of all patients stop taking their prescribed neuropathic pain medication, which is most probably due to side effects or disappointing analgesic results. Therefore, new therapies are needed to alleviate neuropathic pain. As such, topical analgesics could be a new inroad in the treatment of neuropathic pain. In 2014, we developed a new topical formulation containing either phenytoin or sodium phenytoin. After optimization of the formulation, we were able to reach a 10% concentration and combine phenytoin with other co-analgesics in the same base cream. OBJECTIVE: To describe a series of 70 neuropathic pain patients who were treated with phenytoin cream. MATERIAL AND METHODS: Cases treated with phenytoin 5% or 10% creams were gathered. The mean onset of pain relief, the duration of effect, and reduction in pain intensity measured on the 11-point numerical rating scale (NRS) were all studied. A single-blind response test with phenytoin 10% and placebo creams was conducted on 12 patients in order to select responders prior to prescribing the active cream. Plasma phenytoin concentrations were measured in 16 patients. RESULTS: Nine patients applied phenytoin 5% cream, and 61 patients used phenytoin 10% cream. After grouping the effects of all of the patients, the mean onset of pain relief was 16.3 min (SD: 14.8), the mean duration of analgesia was 8.1 h (SD: 9.1), and the mean pain reduction on the NRS was 61.2% (SD: 25.0). The mean pain reduction on the NRS while using phenytoin cream was statistically significant compared with the baseline, with a reduction of 4.5 (CI: 4.0 to 5.0, p < 0.01). The 12 patients on whom a single-blind response test was performed experienced a statistically significant reduction in pain in the area where the phenytoin 10% cream was applied in comparison to the area where the placebo cream was applied (p < 0.01). Thirty minutes after the test application, the mean pain reduction on the NRS in the areas where the phenytoin 10% cream and the placebo cream were applied was 3.3 (CI: 2.3 to 4.4, p < 0.01) and 1.1 (CI: 0.4 to 1.9, p < 0.05), respectively. In all 16 patients, the phenytoin plasma levels were below the limit of detection. So far, no systemic side effects were reported. Two patients only reported local side effects: a transient burning aggravation and skin rash. CONCLUSION: In this case series, the phenytoin cream had reduced neuropathic pain considerably, with a fast onset of analgesic effect.

Skin temperature of the foot: comparing transthyretin Familial Amyloid Polyneuropathy and Diabetic Foot patients

Skin temperature regulation is dependent on the autonomic nervous system function, which may be impaired in patients with neuropathy. Literature reporting thermographic assessment of patients with established diagnosis of Diabetic Foot (DF) is scarce, but this information is completely absent in patients suffering from Transthyretin Familial Amyloid Polyneuropathy (TTR-FAP). The aim of this study is to compare skin temperature distribution in patients with DF and TTR-FAP. Thermograms of the dorsal and plantar surfaces of twelve neuropathic patients, six with DF and six with TTR-FAP, were assessed and compared. Skin temperature was significantly higher in the diabetic foot group, in both regions of interest. Thermal symmetry values were high, but similar in both groups. The bias between the right and left foot was smaller, with smaller limits of agreement in TTR-FAP patients, suggesting a lower agreement between the temperature of the right and left feet in DF patients.

Tuning in C-nociceptors to reveal mechanisms in chronic neuropathic pain.

Develop and validate a low-intensity sinusoidal electrical stimulation paradigm to preferentially activate C-fibers in human skin. Sinusoidal transcutaneous stimulation (4Hz) was assessed psychophysically in healthy volunteers (n = 14) and neuropathic pain patients (n = 9). Pursuing laser Doppler imaging and single nociceptor recordings in vivo in humans (microneurography) and pigs confirmed the activation of "silent" C-nociceptors. Synchronized C-fiber compound action potentials were evoked in isolated human nerve fascicles in vitro. Live cell imaging of L4 dorsal root ganglia in anesthetized mice verified the recruitment of small-diameter neurons during transcutaneous 4-Hz stimulation of the hindpaw (0.4mA). Transcutaneous sinusoidal current (0.05-0.4mA, 4Hz) activated "polymodal" C-fibers (50% at ∼0.03mA) and "silent" nociceptors (50% at ∼0.04mA), intensities substantially lower than that required with transcutaneous 1-ms rectangular pulses ("polymodal" ∼3mA, "silent" ∼50mA). The stimulation induced delayed burning (nonpulsating) pain and a pronounced axon-reflex erythema, both indicative of C-nociceptor activation. Pain ratings to repetitive stimulation (1 minute, 4Hz) adapted in healthy volunteers by Numeric Rating Scale (NRS) -3 and nonpainful skin sites of neuropathic pain patients by NRS -0.5, whereas pain even increased in painful neuropathic skin by approximately NRS +2. Sinusoidal electrical stimulation at 4Hz enables preferential activation of C-nociceptors in pig and human skin that accommodates during ongoing (1-minute) stimulation. Absence of such accommodation in neuropathic pain patients suggest axonal hyperexcitability that could be predictive of alterations in peripheral nociceptor encoding and offer a potential therapeutic entry point for topical analgesic treatment. Ann Neurol 2018;83:945-957.

PSY2 - Pregabalin use on Diabetic Neuropathy Patients and the Risk of Heart Failure

Pregabalin is widely used in neuropathic pain patients (including diabetic neuropathy) as a first-line agent. However, there are concerns regarding its cardiovascular safety, especially the risk of heart failure (HF). Moreover, diabetes is a risk factor for HF. Therefore, it is critical to assess whether pregabalin increases the risk of HF in diabetic neuropathy patients. We conducted a retrospective cohort study in a commercially insured population using IMS LifeLink PharMetrics Plus™ data. Patients with a diagnosis of diabetic neuropathy and receiving any one of the first-line medications – pregabalin, duloxetine, gabapentin or amitriptyline – between June 01 2006 and April 30 2015 were included in the study. Patients were required to be enrolled 6 months prior to the therapy initiation (index date). Primary comparison was between users of pregabalin and users of duloxetine. The outcome was defined as emergency department visit or inpatient hospitalization for HF within 90 days of index date. All covariates were gathered 6 months prior to index date and included in a cox proportion-hazards regression model. The final sample consisted of 2950 patients for the primary comparison. We found no difference in the risk of HF with pregabalin compared to duloxetine (hazard ratio of 1.319, 95% CI 0.445-3.912). Secondary analyses yielded similar results that pregabalin has no higher risk of HF compared to either amitriptyline or gabapentin (hazard ratio of 0.532, 95% CI 0.219-1.294; hazard ratio of 0.599, 95% CI 0.336-1.069, respectively) Our results showed no increase of HF risk in diabetic neuropathy patients who used pregabalin.