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Concept: Peripheral neuropathy


Mutations in SCN9A have been reported in (1) congenital insensitivity to pain (CIP); (2) primary erythromelalgia; (3) paroxysmal extreme pain disorder; (4) febrile seizures and recently (5) small fibre sensory neuropathy. We sought to investigate for SCN9A mutations in a clinically well-characterised cohort of patients with CIP and erythromelalgia.

Concepts: Pain, Peripheral neuropathy, Paroxysmal extreme pain disorder


Background Androgen-deprivation therapy (ADT) has been the backbone of treatment for metastatic prostate cancer since the 1940s. We assessed whether concomitant treatment with ADT plus docetaxel would result in longer overall survival than that with ADT alone. Methods We assigned men with metastatic, hormone-sensitive prostate cancer to receive either ADT plus docetaxel (at a dose of 75 mg per square meter of body-surface area every 3 weeks for six cycles) or ADT alone. The primary objective was to test the hypothesis that the median overall survival would be 33.3% longer among patients receiving docetaxel added to ADT early during therapy than among patients receiving ADT alone. Results A total of 790 patients (median age, 63 years) underwent randomization. After a median follow-up of 28.9 months, the median overall survival was 13.6 months longer with ADT plus docetaxel (combination therapy) than with ADT alone (57.6 months vs. 44.0 months; hazard ratio for death in the combination group, 0.61; 95% confidence interval [CI], 0.47 to 0.80; P<0.001). The median time to biochemical, symptomatic, or radiographic progression was 20.2 months in the combination group, as compared with 11.7 months in the ADT-alone group (hazard ratio, 0.61; 95% CI, 0.51 to 0.72; P<0.001). The rate of a prostate-specific antigen level of less than 0.2 ng per milliliter at 12 months was 27.7% in the combination group versus 16.8% in the ADT-alone group (P<0.001). In the combination group, the rate of grade 3 or 4 febrile neutropenia was 6.2%, the rate of grade 3 or 4 infection with neutropenia was 2.3%, and the rate of grade 3 sensory neuropathy and of grade 3 motor neuropathy was 0.5%. Conclusions Six cycles of docetaxel at the beginning of ADT for metastatic prostate cancer resulted in significantly longer overall survival than that with ADT alone. (Funded by the National Cancer Institute and others; number, NCT00309985 .).

Concepts: Cancer, Metastasis, Chemotherapy, Prostate cancer, Pain, National Cancer Institute, Peripheral neuropathy, Paclitaxel


Animal and human studies indicate that electrical stimulation of DRG neurons may modulate neuropathic pain signals.ACCURATE, a pivotal, prospective, multi-center, randomized-comparative effectiveness trial, was conducted in 152 subjects diagnosed with complex regional pain syndrome (CRPS) or causalgia in the lower extremities. Subjects received neurostimulation of the DRG or dorsal column (SCS). The primary endpoint was a composite of safety and efficacy at 3 months and subjects were assessed through 12 months for long term outcomes and adverse events. The pre-defined primary composite endpoint of treatment success was met for subjects with a permanent implant who reported 50% or greater decrease in VAS from pre-implant baseline and who did not report any stimulation-related neurological deficits.No subjects reported stimulation-related neurological deficits. The percentage of subjects receiving ≥ 50% pain relief and treatment success was greater in the DRG arm (81.2%) versus the SCS arm (55.7%, p<0.001) at 3 months. Device-related and serious adverse events were not different between the 2 groups. DRG stimulation also demonstrated greater improvements in quality of life and psychological disposition. Finally, subjects using DRG stimulation reported less postural variation in paresthesia (p<0.001) and reduced extraneous stimulation in non-painful areas (p=0.014), indicating DRG stimulation provided more targeted therapy to painful parts of the lower extremities.As the largest prospective, randomized comparative effectiveness trial to date, the results show DRG stimulation provided a higher rate of treatment success with less postural variation in paresthesia intensity compared to SCS.

Concepts: Nervous system, Dorsal root ganglion, Neurology, Pain, Nociception, Suffering, Complex regional pain syndrome, Peripheral neuropathy


Chemotherapy-induced peripheral neuropathy (CIPN) is a significant problem for cancer patients, and there are limited treatment options for this often debilitating condition. Neuromodulatory interventions could be a novel modality for patients trying to manage CIPN symptoms; however, they are not yet the standard of care. This study examined whether electroencephalogram (EEG) neurofeedback (NFB) could alleviate CIPN symptoms in survivors.

Concepts: Epidemiology, Randomized controlled trial, Electroencephalography, Neurotechnology, Peripheral neuropathy, Binaural beats, Neurofeedback, Mind machine


Chemotherapy-induced neuropathic pain is a debilitating and common side effect of cancer treatment. Mitochondrial dysfunction associated with oxidative stress in peripheral nerves has been implicated in the underlying mechanism. We investigated the potential of melatonin, a potent antioxidant that preferentially acts within mitochondria, to reduce mitochondrial damage and neuropathic pain resulting from the chemotherapeutic drug paclitaxel. In vitro, paclitaxel caused a 50% reduction of mitochondrial membrane potential and metabolic rate, independent of concentration (20-100μM). Mitochondrial volume was increased dose-dependently by paclitaxel (200% increase at 100μM). These effects were prevented by co-treatment with 1μM melatonin. Paclitaxel cytotoxicity against cancer cells was not affected by co-exposure to 1μM melatonin of either the breast cancer cell line MCF-7, or the ovarian carcinoma cell line A2780. In a rat model of paclitaxel-induced painful peripheral neuropathy, pre-treatment with oral melatonin (5/10/50mg/kg), given as a daily bolus dose, was protective, dose-dependently limiting development of mechanical hypersensitivity (19/43/47% difference from paclitaxel control, respectively). Melatonin (10mg/kg/day) was similarly effective when administered continuously in drinking water (39% difference). Melatonin also reduced paclitaxel-induced elevated 8-isoprostane F2 α levels in peripheral nerves (by 22% in sciatic; 41% in saphenous) and limited paclitaxel-induced reduction of C fibre activity-dependent slowing (by 64%). Notably melatonin limited the development of mechanical hypersensitivity in both male and female animals (by 50/41%, respectively) and an additive effect was found when melatonin was given with the current treatment, duloxetine (75/62% difference, respectively). Melatonin is therefore a potential treatment to limit the development of painful neuropathy resulting from chemotherapy treatment. This article is protected by copyright. All rights reserved.

Concepts: Immune system, Cancer, Breast cancer, Metastasis, Oncology, Chemotherapy, Pain, Peripheral neuropathy


The gate control theory of pain proposes that inhibitory neurons of the spinal dorsal horn exert critical control over the relay of nociceptive signals to higher brain areas. Here we investigated how the glycinergic subpopulation of these neurons contributes to modality-specific pain and itch processing. We generated a GlyT2::Cre transgenic mouse line suitable for virus-mediated retrograde tracing studies and for spatially precise ablation, silencing, and activation of glycinergic neurons. We found that these neurons receive sensory input mainly from myelinated primary sensory neurons and that their local toxin-mediated ablation or silencing induces localized mechanical, heat, and cold hyperalgesia; spontaneous flinching behavior; and excessive licking and biting directed toward the corresponding skin territory. Conversely, local pharmacogenetic activation of the same neurons alleviated neuropathic hyperalgesia and chloroquine- and histamine-induced itch. These results establish glycinergic neurons of the spinal dorsal horn as key elements of an inhibitory pain and itch control circuit.

Concepts: Nervous system, Neuron, Action potential, Pain, Sensory system, Nociceptor, Neurotransmitter, Peripheral neuropathy


Itch-specific neurons have been sought for decades. The existence of such neurons has been doubted recently as a result of the observation that itch-mediating neurons also respond to painful stimuli. We genetically labeled and manipulated MrgprA3(+) neurons in the dorsal root ganglion (DRG) and found that they exclusively innervated the epidermis of the skin and responded to multiple pruritogens. Ablation of MrgprA3(+) neurons led to substantial reductions in scratching evoked by multiple pruritogens and occurring spontaneously under chronic itch conditions, whereas pain sensitivity remained intact. Notably, mice in which TRPV1 was exclusively expressed in MrgprA3(+) neurons exhibited itch, but not pain, behavior in response to capsaicin. Although MrgprA3(+) neurons were sensitive to noxious heat, activation of TRPV1 in these neurons by noxious heat did not alter pain behavior. These data suggest that MrgprA3 defines a specific subpopulation of DRG neurons mediating itch. Our study opens new avenues for studying itch and developing anti-pruritic therapies.

Concepts: Nervous system, Ganglion, Dorsal root ganglion, Pain, Skin, Nociception, Nociceptor, Peripheral neuropathy


The perception of fatigue is common in many disease states, however, the mechanisms of sensory muscle fatigue are not understood. In mice, rats and cats, muscle afferents signal metabolite production in skeletal muscle using a complex of ASIC, P2X and TRPV1 receptors. Endogenous muscle agonists for these receptors are combinations of protons, lactate, and ATP. Here we applied physiological concentrations of these agonists to muscle interstitium in human subjects to determine if this combination could activate sensations, and if so determined how these subjects described these sensations. Ten volunteers received infusions (0.2 ml over 30-s) containing protons, lactate and ATP under the fascia of a thumb muscle, abductor pollicis brevis (APB). Infusion of individual metabolites at maximum amounts evoked no fatigue or pain. Metabolite combinations found in resting muscles (pH 7.4+300nM ATP+1mM lactate) also evoked no sensation. The infusion of a metabolite-combination found in muscle during moderate endurance-exercise (pH 7.3+400nM ATP+5 mM lactate) produced significant fatigue sensations. Infusion of a metabolite-combination associated with vigorous exercise (pH 7.2+500nM ATP+10mM lactate) produced stronger sensations of fatigue and some ache. Higher levels of metabolites (as found with ischemic exercise) caused more ache but no additional fatigue-sensation. Thus, in a dose-dependent manner, intramuscular infusion of combinations of protons, lactate, and ATP leads to fatigue-sensation and eventually pain, probably through activation of ASIC, P2X, and TRPV1 receptors. This is the first demonstration in humans that metabolites normally produced by exercise act in combination to activate sensory neurons that signal sensations of fatigue and muscle pain.

Concepts: Metabolism, Muscle, Sensory system, Muscular system, Acetylcholine, Muscle spindle, Peripheral neuropathy, Adductor pollicis muscle


Purpose: Paclitaxel, a widely-used chemotherapeutic drug, can cause peripheral neuropathies leading to dose reductions and treatment suspensions and decreasing the quality of life of patients. It has been suggested that genetic variants altering paclitaxel pharmacokinetics increase neuropathy risk, but the major causes of inter-individual differences in susceptibility to paclitaxel toxicity remain unexplained. We carried out a whole-exome sequencing (WES) study to identify genetic susceptibility variants associated with paclitaxel neuropathy. Experimental Design: Blood samples from eight patients with severe paclitaxel-induced peripheral neuropathy were selected for WES. An independent cohort of 228 cancer patients with complete paclitaxel neuropathy data was used for variant screening by DHPLC and association analysis. HEK293 cells were used for heterologous expression and characterization of two novel CYP3A4 enzymes. Results: WES revealed two patients with rare CYP3A4 variants, a premature stop codon (CYP3A4*20 allele) and a novel missense variant (CYP3A4*25, p.P389S) causing reduced enzyme expression. Screening for CYP3A4 variants in the independent cohort revealed three additional CYP3A4*20 carriers, and two missense variants exhibiting diminished enzyme activity (CYP3A4*8 and the novel CYP3A4*27 allele, p.L475V). Relative to CYP3A4 wild-type patients, those carrying CYP3A4 variants had more severe neuropathy (2- and 1.3-fold higher risk of neuropathy for loss-of-function and missense variants, respectively, P=0.045) and higher probability of neuropathy-induced paclitaxel treatment modifications (7- and 3-fold higher risk for loss-of-function and missense variants, respectively, P=5.9x10-5). Conclusion: This is the first description of a genetic marker associated with paclitaxel treatment modifications caused by neuropathy. CYP3A4 defective variants may provide a basis for paclitaxel treatment individualization.

Concepts: DNA, Gene, Genetics, Pain, Neuropathy, Vincristine, Nonsense mutation, Peripheral neuropathy


Pedobarography is commonly employed in patients with diabetic peripheral neuropathy (DPN). However there is no evidence regarding test-retest reliability of this technique in this population, and therefore it was the purpose of the current study to address this clear gap. Dynamic plantar loading and foot geometry data were collected during barefoot gait with the EMED platform (Novel GmbH, Germany) from 10 patients with DPN over two sessions, separated by 28 days. Intra-class Correlation Coefficients (ICCs) and Coefficients of Variation (CoVs) were calculated to determine test-retest reliability. For dynamic plantar loading, reliability differed by outcome measure and foot region, with ICCs of >0.8 and CoVs of <15% observed in most cases. For dynamic foot geometry, ICCs of >0.88 and CoVs of <3% were observed for hallux angle, arch index and coefficient of spreading, while sub-arch angle was less reliable (ICC 0.76, CoV 23%). Overall, the current study observed high levels of test-retest reliability which were generally commensurate with that previously reported in healthy populations.

Concepts: Foot, Reliability, Algebra, Test-retest, Comparison of assessments, Peripheral neuropathy, Diabetic neuropathy, Gait abnormality