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Quantitative sensory testing (QST) has been optimized to diagnose in particular small fiber neuropathy and has been successfully used for decades. "Sensory phenotypes" have been derived from the QST data in an attempt to stratify patients with chronic pain and to gain mechanistic insights. However, studies consistently show that there is no difference in sensory phenotypes between neuropathy patients with and without pain and no successful stratification has been shown using the current version of "sensory phenotypes". Thus, after falsification of the initial hypothesis it is time to focus on more promising approaches., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Our ability to quickly detect and respond to harmful environmental stimuli is vital for our safety and survival. This inherent acute pain detection is a "gift" because it both protects our body from harm and allows healing of damaged tissues [1]. Damage to tissues from trauma or disease can result in distorted or amplified nociceptor signaling and sensitization of the spinal cord and brain (Central Nervous System; CNS) pathways to normal input from light touch mechanoreceptors. Together, these processes can result in nagging to unbearable chronic pain and extreme sensitivity to light skin touch (allodynia). Unlike acute protective pain, chronic pain and allodynia serve no useful purpose and can severely reduce the quality of life of an affected person. Chronic pain can arise from impairment to peripheral neurons, a phenomenon called "peripheral neuropathic pain." Peripheral neuropathic pain can be caused by many insults that directly affect peripheral sensory neurons, including mechanical trauma, metabolic imbalance (e.g., diabetes), autoimmune diseases, chemotherapeutic agents, viral infections (e.g., shingles). These insults cause "acquired" neuropathies such as small-fiber neuropathies, diabetic neuropathy, chemotherapy-induced peripheral neuropathy, and post herpetic neuralgia. Peripheral neuropathic pain can also be caused by genetic factors and result in hereditary neuropathies that include Charcot-Marie-Tooth disease, rare channelopathies and Fabry disease. Many acquired and hereditary neuropathies affect the skin, our largest organ and protector of nearly our entire body. Here we review how cutaneous nociception (pain perceived from the skin) is altered following diseases that affect peripheral nerves that innervate the skin. We provide an overview of how noxious stimuli are detected and encoded by molecular transducers on subtypes of cutaneous afferent endings and conveyed to the CNS. Next, we discuss several acquired and hereditary diseases and disorders that cause painful or insensate (lack of sensation) cutaneous peripheral neuropathies, the symptoms and percepts patients experience, and how cutaneous afferents and other peripheral cell types are altered in function in these disorders. We highlight exciting new research areas that implicate non-neuronal skin cells, particularly keratinocytes, in cutaneous nociception and peripheral neuropathies. Finally, we conclude with ideas for innovative new directions, areas of unmet need, and potential opportunities for novel cutaneous therapeutics that may avoid CNS side effects, as well as ideas for improved translation of mechanisms identified in preclinical models to patients., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Chemotherapy-induced neuropathy (CIN) is a major adverse effect associated with many chemotherapeutics, including bortezomib (BTZ). Several mechanisms are involved in CIN, and recently a role has been proposed for prokineticins (PKs), a chemokine family that induces proinflammatory/pro-algogen mediator release and drives the epigenetic control of genes involved in cellular differentiation. The present study evaluated the relationships between epigenetic mechanisms and PKs in a mice model of BTZ-induced painful neuropathy. To this end, spinal cord alterations of histone demethylase KDM6A, nuclear receptors PPARα/PPARγ, PK2, and pro-inflammatory cytokines IL-6 and IL-1β were assessed in neuropathic mice treated with the PK receptors (PKRs) antagonist PC1. BTZ treatment promoted a precocious upregulation of KDM6A, PPARs, and IL-6, and a delayed increase of PK2 and IL-1β. PC1 counteracted allodynia and prevented the increase of PK2 and of IL-1β in BTZ neuropathic mice. The blockade of PKRs signaling also opposed to KDM6A increase and induced an upregulation of PPAR gene transcription. These data showed the involvement of epigenetic modulatory enzymes in spinal tissue phenomena associated with BTZ painful neuropathy and underline a role of PKs in sustaining the increase of proinflammatory cytokines and in exerting an inhibitory control on the expression of PPARs through the regulation of KDM6A gene expression in the spinal cord.

Objectives: The character of upper limb disorders in computer operators is subject to debate. While nerve involvement is suggested by the presence of pain, paresthesia and subjective weakness, these symptoms are mainly interpreted as related to pathologies outside the nervous system. Findings in a previous study involving computer operators indicated peripheral nerve afflictions with specific locations in symptomatic subjects. Based on the same sample, this study addresses the relation of non-neurogenic findings to pain and neurological findings., Material and Methods: Overall, 96 computer operators scored their perceived pain in the neck, shoulder, elbow, and wrist/hand on a Visual Analogue Scale of 0-9. They underwent 2 sets of blinded physical examinations of selected non-neurogenic and neurological items, respectively. The authors analyzed correlations between the scores of each non-neuropathic finding, and a) mean pain scores for each and all regions, and b) scores for neurological patterns reflecting brachial plexopathy, median neuropathy (the elbow), and posterior interosseous neuropathy, respectively, and their combination. Kendall's rank correlation test was applied for all statistical analyses., Results: A median pain level of 1 or 0.5 was reported by 80 and 57 participants on the mouse-operating or contralateral side, respectively. Non-neurogenic and neurological findings were frequent. The mean overall pain correlated with palpation soreness of the neck insertions, and of the trapezius and supraspinatus muscles. Neck and elbow pain correlated with palpation soreness at the neck insertions and the lateral epicondyles, respectively. Significant correlations on the mouse-operating side were identified between posterior interosseous neuropathy and lateral epicondyle soreness, and between median neuropathy and any neurological pattern, and trapezius and lateral epicondyle soreness., Conclusions: Pain correlated with palpation soreness, which again correlated with the neurological patterns. Palpation soreness may be less significant as a marker of a painful disorder as it correlated no better with regional than with overall pain. The physical examination of computer operators should include a sufficient neurological assessment. Int J Occup Med Environ Health. 2021;34(5):679-91., (This work is available in Open Access model and licensed under a CC BY-NC 3.0 PL license.)

Objectives: We evaluated usefulness of peripheral nerve ultrasound (US) in detecting abnormality in painful sensory neuropathy (PSN) associated with primary Sjögren's syndrome (pSS), and associations among various clinical factors, US findings, and intraepidermal nerve fiber density (IENFD)., Methods: We conducted a retrospective, single-center, observational study of patients with pSS-PSN. US image was obtained to measure cross sectional area (CSA) of peripheral nerves and compared with matched pSS control., Results: We included 11 patients with pSS-PSN (10 women; age 70.5 ± 5.66) and 17 pSS controls (15 women; age 62.5 ± 16.7). Sural nerve CSA were significantly increased in pSS-PSN group (3.48 ± 1.0 mm 2 vs 2.05 ± 0.65 mm 2 , p  = .001). US of sural nerve showed the area under the ROC curve of 0.872 (95% CI, 0.732 - 1). Sural nerve CSA and IENFD of lower leg showed positive correlation. Compared with pSS-PSN patients with abnormal IENFD, those with normal IENFD showed significantly larger sural nerve CSA, and trends toward less systemic disease activity and small fiber impairment with sparing of large fibers., Conclusion: US was useful in discriminating pSS patients with PSN from those without. Additionally, US may disclose distinct subsets of pSS-PSN with different clinical findings and IENFD.

It is increasingly recognized that diabetic neuropathy is associated with early diabetes, prediabetes, and the metabolic syndrome. Early detection and diagnosis are important to slow progression and prevent complications. Although strict glucose control is an effective treatment in type 1 diabetes, it is less effective in type 2 diabetes. There is a growing body of literature that lifestyle interventions may be able to prevent or slow progression of neuropathy in type 2 diabetes. In addition to the typical distal symmetric polyneuropathy, there are many types of "atypical" diabetic neuropathies that are important to recognize., Competing Interests: Disclosure Dr. L. A. Zilliox have received funding from the Department of Veterans Affairs (Grant ID IK2RX001651)., (Published by Elsevier Inc.)

Objectives: To investigate the thermal pain phenotypes using QST in patients with unilateral trigeminal nerve injury and to explore whether these different thermal pain phenotypes are associated with clinical and psychophysical characteristics., Methods: This retrospective study included 84 patients diagnosed with posttraumatic trigeminal neuropathy involving inferior alveolar nerve (IAN) and lingual nerve (LN). Data on clinical characteristics, subjective symptoms including hypoesthesia, dysesthesia, and allodynia, and objective signs using thermal QST were collected and explored., Results: Three heat (heat hypoalgesia, heat hyperalgesia, and within normal range) and cold pain phenotypes (cold hypoalgesia, cold hyperalgesia, and within normal ranges) were identified, respectively. Thermal hypoalgesia was more frequently observed than thermal hyperalgesia. Heat hypoalgesia regardless of cold pain abnormalities appears to be associated with subjective negative symptoms, while thermal hyperalgesia seems to have little relationship with negative and positive symptoms. Thermal pain phenotypes were associated with loss of innocuous thermal sensation. Unlike heat pain phenotypes, cold pain phenotypes differed between IAN injury and LN injury., Conclusion: The thermal pain phenotypes identified in this study seem to be related to clinical and psychophysical findings differently. These results would be a good starting point for assessing posttraumatic trigeminal neuropathy and interpreting the thermal QST results., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. All rights reserved.)

Chemotherapy-induced peripheral neuropathy (CIPN) is a common cause of pain and poor quality of life for those undergoing treatment for cancer and those surviving cancer. Many advances have been made in the pre-clinical science; despite this, these findings have not been translated into novel preventative measures and treatments for CIPN. This review aims to give an update on the pre-clinical science, preventative measures, assessment and treatment of CIPN., Competing Interests: No competing interests were disclosed.No competing interests were disclosed.No competing interests were disclosed., (Copyright: © 2020 Gordon-Williams R and Farquhar-Smith P.)

Pain is often the initial complaint for which patients seek medical care, presenting both a diagnostic and therapeutic challenge to the primary care provider. The appreciation of pain is not merely the result of abnormal sensory stimulation causing an unpleasant sensation but rather a combination of the recognition of the somatic discomfort in association with an emotional response to that discomfort. The perception of pain and the extent of distress and disability can vary depending on previous experience, cultural background, situational factors, and comorbid psychiatric disease. Though acute pain is usually the result of tissue damage, this is not always the case, as evidenced by primary headache disorders. Chronic pain may be the result of an injury, irreversible underlying disease, or clinical conditions such as fibromyalgia for which the mechanism remains unclear. Treatment of the underlying cause will usually effect a resolution or improvement in the pain, but when the discomfort persists, a consultation with a neurologist or pain management specialist should be considered., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Diabetes is a global epidemic and more than 50% diabetic patients are also diagnosed with neuropathy, which greatly affects the quality of life of the patients. Available treatments are not always successful due to the limited efficacy and complications, such as addiction and dependency. Studies have implicated that high mobility group box1 (HMGB1) protein plays a crucial role in neuroinflammation and the development of neuropathic conditions. HMGB1 is a proinflammatory cytokine that can be released from necrotic cells in passive form or in response to inflammatory signals as an active form. HMGB1 is the ligand for the receptor for advanced glycation end products (RAGE), and toll-like receptors, (TLR)-2 and TLR4, which also indirectly activates C-X-C chemokine receptor type 4 (CXCR4). We investigated whether blocking of HMGB1 can reduce pain and inflammation in diabetic neuropathic animals to further understand the role of HMGB1 in diabetic neuropathy. Type 2 diabetic rats and mice were treated with natural inhibitor of HMGB1, glycyrrhizin (GLC) for five days/week for four weeks at a dose of 50 mg/kg per day by intraperitoneal injection. The animals were divided into three categories: naïve control, diabetic alone, diabetic with GLC treatment. All of the behavioral analyses were conducted before and after the treatment. The expression of inflammatory markers and changes in histone acetylation in the peripheral nervous system were measured by immunohistochemistry and Western blot analysis after the completion of the treatment. Our study revealed that TLR4, HMGB1, CXCR4, and Nod-like receptor protein 3 (NLRP3) levels were increased in the spinal and dorsal root ganglia (DRG) neurons of Type 2 diabetic mice and rats with painful neuropathy. GLC treatment inhibited the increases in TLR4, NLRP3, and CXCR4 expressions and improved the mechanical and thermal pain threshold in these animals. Immunohistochemical studies revealed that hyperglycemia mediated inflammation influenced HMGB1 acetylation and its release from the neurons. It also altered histone 3 acetylation in the microglial cells. The inhibition of HMGB1 by GLC prevented the release of HMGB1 as well as H3K9 acetylation. These findings indicate that the interruption of HMGB1 mediated inflammation could ameliorate diabetic neuropathy and might exhibit a unique target for the treatment.

The management of pain in persons with neurological injuries is challenging and complex. A holistic view and clinical approach are necessary when addressing pain in patients with neurological impairment because interpreting signs and symptoms and deciphering sources of pain is never a straightforward process. This problem is further magnified with the management of central pain syndromes. The best approach is to have a good understanding of the clinical characteristics commonly found in this patient population, in particular for patients with stroke, multiple sclerosis (MS), or spinal cord injury (SCI), as central pain manifests differently between these groups. This paper will focus on the history, clinical presentation, pathophysiology, assessment, and treatment of central pain in patients with these types of neurological conditions. In addition to being at risk for a decline in quality of life, patients with pain syndromes are also prone to adverse responses to treatments (e.g., opioid addiction). It is therefore important to methodically analyze the similarities and differences between patients with different pain syndromes.

The experience of pain during a severe burn is multifactorial, both in the typology of the burn and in the circumstances of its occurrence. Third-degree burns are painless as the dermis and its nociception sensors are damaged. After a severe burn, from initial management, to home care, to a long hospital stay, pain evolves with its etiology and requires specific management., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Objective: Existing pharmacologic approaches for painful diabetic neuropathy (PDN) are limited in efficacy and have side effects. We examined the feasibility, acceptability, and effects of group acupuncture for PDN., Design and Setting: We randomized patients with PDN from a public safety net hospital to 1) usual care, 2) usual care plus 12 weeks of group acupuncture once weekly, or 3) usual care plus 12 weeks of group acupuncture twice weekly., Methods: The primary outcome was change in weekly pain intensity (daily 0-10 numerical rating scale [NRS] averaged over seven days) from baseline to week 12. We also assessed health-related quality of life and related symptoms at baseline and weeks 6, 12, and 18., Results: We enrolled 40 patients with PDN (baseline pain = 5.3). Among participants randomized to acupuncture, 92% attended at least one treatment (mean treatments = 10.1). We observed no significant differences between once- vs twice-weekly acupuncture and combined those groups for the main analyses. Compared with usual care, participants randomized to acupuncture experienced greater decreases in pain during the 12-week intervention period (between-group differences from baseline = -2.06, 95% confidence interval [CI] = -3.01 to -1.10), but benefits were not maintained after acupuncture ended (baseline to week 18 = -0.61, 95% CI = -1.46 to 0.24). Quality of life improved for acupuncture participants (baseline to week 12 difference = 11.79, 95% CI = 1.92 to 21.66), but group differences were not significant compared with usual care (25.58, 95% CI = -3.90 to 55.06)., Conclusions: Group acupuncture is feasible and acceptable among linguistically and racially diverse safety net patients. Findings suggest clinically relevant reduction in pain from PDN and quality of life improvements associated with acupuncture, with no differences based on frequency., (© 2019 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Diosmetin is an O‑methylated flavone found naturally in citrus fruit, and it was identified in Amphilophium crucigerum (L.), a plant popularly used as an analgesic. This compound had different pharmacological effects and presented a chemical structure like the flavonoid eriodyctiol that exhibited antinociceptive effects by TRPV1 antagonism. However, the possible antinociceptive effect of this compound was not well documented. Thus, the goal of the present study was to evaluate the antinociceptive effect of diosmetin and its mechanism of action. The diosmetin effect on different pain models and its possible adverse effects were assessed on adult Swiss male mice (25-30 g). Mice spinal cord samples were used on calcium influx and binding assays using TRPV1 agonists. First, it was observed that the diosmetin reduced calcium influx mediated by capsaicin in synaptosomes and displace the specific binding to [ 3 H]-resiniferatoxin in membrane fractions from the spinal cord of mice. Diosmetin (0.15 to 1.5 mg/kg, intragastric, i.g.) presented antinociceptive and antiedematogenic effect in the capsaicin intraplantar test and induced antinociception in a noxious heat test (48 °C). Also, treatment with diosmetin reduced mechanical and heat hypersensitivity observed in a model of inflammatory or neuropathic pain. Acute diosmetin administration in mice did not induce locomotor or body temperature changes, or cause liver enzyme abnormalities or alter renal function. Moreover, there were no observed changes in gastrointestinal transit or induction of ulcerogenic activity after diosmetin administration. In conclusion, our results support the antinociceptive properties of diosmetin which seems to occur via TRPV1 antagonist in mice., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Chemotherapy-induced painful peripheral neuropathy (CIPN) is the most common toxicity associated with widely used chemotherapeutics. CIPN is the major cause of dose reduction or discontinuation of otherwise life-saving treatment. Unfortunately, CIPN can persist in cancer survivors, which adversely affects their quality of life. Moreover, available treatments are vastly inadequate, warranting a better understanding of the biochemical and metabolic mechanisms that occur in response to chemotherapeutics which would be critical for the development of novel therapies for CIPN. Using extracellular flux analysis, this study demonstrated that the proteasome inhibitor, bortezomib, enhanced glycolysis while suppressing oxidative phosphorylation in the sensory neurons of mice. This metabolic phenotype is known as aerobic glycolysis. Bortezomib upregulated lactate dehydrogenase A and pyruvate dehydrogenase kinase 1, which consequently enhanced the production of lactate and repressed pyruvate oxidation, respectively. Moreover, lactate dehydrogenase A- and pyruvate dehydrogenase kinase 1-driven aerobic glycolysis was associated with increased extracellular acidification, augmented calcium responses, and pain in bortezomib-induced CIPN. Remarkably, pharmacological blockade and in vivo knockdown of lactate dehydrogenase A or pyruvate dehydrogenase kinase 1 reversed the metabolic phenotype, attenuated calcium responses, and alleviated pain induced by bortezomib. Collectively, these results elucidate the mechanisms by which bortezomib induces aerobic glycolysis. Moreover, these findings establish aerobic glycolysis as a metabolic phenotype that underpins bortezomib-induced CIPN.

Background: Chemotherapy induced peripheral neuropathy (CIPN) is a painful side-effect of commonly used chemotherapeutic agents that profoundly impair the quality of life of patients as the current pharmacotherapeutic strategies are inefficient in providing adequate pain relief. Complementary and alternative medicine (CAM) therapies are preferred by patients with neuropathic pain as they experience insufficient control of pain with conventional medications. This study describes the antinociceptive effect of Tithonia tubaeformis (Jacq.) Cass. in a vincristine mouse model of established CIPN., Methods: Tithonia tubaeformis hydromethanolic extract was tested for preliminary qualitative phytochemical analysis and acute oral toxicity test in mice. The antinociceptive effect was investigated using the abdominal constriction (writhing) and tail immersion tests (25-200 mg/kg). The anti-neuropathic effect was determined in the vincristine mouse model, established by daily administration of vincristine (0.1 mg/kg/day, i.p) for consecutive 14 days. Acute treatment with Tithonia tubaeformis (100 and 200 mg/kg) and the positive control, gabapentin (75 mg/kg) was carried out on the 15th day of the last vincrsitine dose and the animals were tested for allodynia and thermal hyperalgesia at 30-120 min post extract/drug administration., Results: Vincristine produced significant temporal tactile allodynia and thermal hyperalgesia (P < 0.01 and P < 0.001 on day 7 and 14) and was maintained for the subsequent day (P < 0.001 during 30-120 min). Tithonia tubaeformis was effective in attenuating the vincristine-induced allodynia and thermal hyperalgesia at 100 mg/kg (P < 0.05, P < 0.01) and 200 mg/kg (P < 0.01, P < 0.001). Similarly, gabapentin also showed a robust antinociceptive effect in counteracting the vincristine associated behavioral alterations., Conclusions: Tithonia tubaeformis can be an effective CAM therapeutic remedy for established CIPN due to its potential antinociceptive effect in attenuating vincristine-induced neuropathy., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Introduction: Neuralgic amyotrophy (NA) is characterized by the clinical triad of pain, muscle weakness/atrophy, and sensory symptoms., Methods: We retrospectively identified children (≤18 years old) over the course of 15 years (2003-2017) at a single pediatric center., Results: We included 22 patients (8 females and 14 males, 6-18 years old); pain was the presenting manifestation in all of them. Clinical weakness involving the periscapular muscles was observed in 16 patients and scapular winging in 13 patients. Two patients had preceding viral infection. Electromyography was performed in 21 patients: sensory nerve abnormalities were detected in 5, and neurogenic changes were most commonly observed in the serratus anterior muscle. Treatment was mainly supportive, although 4 patients received immunotherapy. Persistent pain and residual motor deficits were observed in more than half of the patients at follow-up., Discussion: NA is rare in children but clinicians should be aware of this entity to avoid delays in diagnosis. In our series, presentation was similar to that seen in adults. Muscle Nerve 57: 932-936, 2018., (© 2018 Wiley Periodicals, Inc.)

Pain is a significant physical symptom that can be observed across the spectrum of hematopoietic stem cell transplant (HSCT) care. Pain assessment should include evaluation of the physical and functional components of pain. Management varies based on the type of HSCT-specific pain syndrome. Future directions for management of pain syndromes include the early integration of palliative care. The purpose of this review is to summarize various pain syndromes and management approaches in adult HSCT patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: Carpal tunnel syndrome (CTS) may develop with repetitive and forced movements of the hands and wrists. In this study, we have aimed to evaluate whether the frequency of CTS is increased amongst female hairdressers as compared with unemployed women or not. Besides, we have also analyzed whether the functionality and pain intensity levels amongst female hairdressers with CTS are different from the ones of unemployed women with CTS or not., Material and Methods: The consecutive female hairdressers and unemployed women who had referred to our electroneuromyography (ENMG) laboratory for the upper extremity nerve conduction studies were included. They were evaluated in terms of clinical and ENMG findings, socio-demographic characteristics, functionality and pain intensity levels determined with the Boston CTS Questionnaire and visual analog scale (VAS)., Results: In this study, 110 women (70 female hairdressers and 40 unemployed women) were included. The frequency of CTS among hairdressers (74.3%) was higher than the one of the unemployed control group (55%) (p = 0.032). We detected that as the time period of occupation in hairdressing increased, the risk of developing CTS also increased among hairdressers (p < 0.001). Additionally, pain intensity and functional loss levels were higher for hairdressers with CTS than those for the control group with CTS (p = 0.005, p < 0.001, p = 0.028, respectively)., Conclusions: The frequency of CTS is elevated for female hairdressers with respect to the unemployed women as in many other occupations requiring forced or repetitive hand movements. Besides, the occupational exposure in hairdressing also results in more elevated pain intensity and functional loss levels related with CTS as compared with the unemployed subjects. Int J Occup Med Environ Health 2018;31(3):333-339., (This work is available in Open Access model and licensed under a CC BY-NC 3.0 PL license.)

This chapter explores therapeutic targets and the anti-inflammatory nature of some naturally- occurring compounds and the current or potential use of these compounds in the treatment of chronic inflammatory pain states. We will review the mechanisms of chronic inflammatory pain, the molecular targets of selected natural compounds in inhibiting inflammatory pain, and the traditional and current approaches to treating pain using these compounds. Previous research on experimental as well as clinical pain will be summarized from in vitro to animal and human models. Potential areas for further research will also be discussed., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background and Purpose: The frequency of pain and cramps is uncertain in anti-myelin associated glycoprotein antibody (anti-MAG) neuropathy. Whether these symptoms may affect function/quality of life is unknown., Methods: A cross-sectional study of the prevalence, correlates and impact of pain, pain subtypes and cramps, their severity, frequency and anatomical distribution was performed for 55 clinically stable patients with anti-MAG neuropathy., Results: Pain of any type was reported by 80% of subjects. The most common subtype was paraesthesiae and dysaesthesiae (70%). Cramps were reported by >60% of patients, with lower limb cramps in all and upper limb cramps in about 20%. Cramps affected daily activities in >30% of these subjects, sleep in 60%, ability to exercise in >30%. Total pain score correlated with several Short Form 36 health-related quality of life (SF-36 HR-QoL) measures (P < 0.05), with Inflammatory Rasch-built Overall Disability Scale (I-RODS) (P = 0.006) and 10-m timed walk (P = 0.019). An independent association was ascertained with I-RODS (P = 0.002). Different pain subtypes showed multiple associations with SF-36 HR-QoL measures and/or functional scales. Upper limb cramps had multiple SF-36 HR-QoL functional correlates, with an independent association with the Overall Neuropathy Limitation Score (ONLS) (P = 0.004). Cramp severity correlated with ONLS (P = 0.04) and I-RODS (P = 0.028) and inversely with level of physiotherapy input (P = 0.009). Cramp frequency was associated with tremor score (P = 0.004) and multiple SF-36 HR-QoL subsections., Conclusions: Neuropathic pain and cramps may affect function and quality of life in anti-MAG neuropathy. Optimizing treatments of these symptoms, including by adequate levels of physiotherapy, may be beneficial in affected patients and requires further research., (© 2017 EAN.)

Neurofibromatosis type 1 (NF1) is one of the most common genetic diseases, affecting roughly 1 in 3000 individuals. As a multisystem disorder, it affects cognitive development, as well as bone, nerve and muscle constitution. Peripheral neuropathy in NF1 constitutes a potentially severe clinical complication and is associated with increased morbidity and mortality. The discovery of effective therapies for Neurofibromatosis type 1 (NF1) pain depends on mechanistic understanding that has been limited, in part, by the relative lack of availability of animal models relevant to NF1 pain. We have used intrathecal targeted editing of Nf1 in rats to provide direct evidence of a causal relationship between neurofibromin and pain responses. We demonstrated that editing of neurofibromin results in functional remodeling of peripheral nociceptors characterized by enhancement of interactions of the tetrodotoxin-sensitive (TTX-S) Na + voltage-gated sodium channel (NaV1.7) and the collapsin response mediator protein 2 (CRMP2). Collectively, these peripheral adaptations increase sensory neuron excitability and release of excitatory transmitters to the spinal dorsal horn to establish and maintain a state of central sensitization reflected by hyperalgesia to mechanical stimulation of the hindpaw. The data presented here shows that CRMP2 inhibition is sufficient to reverse the dysregulations of voltage-gated ion channels and neurotransmitter release observed after Nf1 gene editing. The concordance in normalization of ion channel dysregulation by a CRMP2-directed strategy and of hyperalgesia supports the translational targeting of CRMP2 to curb NF1-related pain.

Objective: The aim of this study was to evaluate the clinical features and functional results of patients with parosteal lipomas., Methods: A total of 12 patients (8 females and 4 males; mean age: 45 (10-62) years) with parosteal lipomas who were treated between April 1986 and April 2014, were included into the study. The medical records of the patients were reviewed to analyze the clinical features and functional results of the patients., Results: Of the 12 lipomas, 5 were localized in the proximal arm, 4 in the forearm, 1 in the distal arm, 1 in the distal thigh and 1 in the distal tibia. All patients presented with a progressive, slow-growing mass that was associated with thumb extension weakness in 1 case, and brachialgia-like symptoms in 1 case. Plain radiographs showed a juxtacortical mass in all cases and irregular ossification in 3 cases. In all cases, marginal excision was performed and no clinical recurrence was observed after a mean follow-up of 16 months., Conclusion: Parosteal lipomas are uncommon tumors that can be diagnosed with their characteristic radiological features. Parosteal lipomas occurring in the proximal radius may easily cause paralysis of the posterior interosseous nerve or muscle weakness., Level of Evidence: Level IV, Therapeutic study., (Copyright © 2017 Turkish Association of Orthopaedics and Traumatology. Production and hosting by Elsevier B.V. All rights reserved.)

Background and Purpose: This study aimed to assess the correlation between vitamin D deficiency and electrophysiological findings and pain level in patients with symptoms of carpal tunnel syndrome (CTS)., Methods: A total of 131 patients with symptoms of CTS, 70 with vitamin D deficiency and 61 without vitamin D deficiency, were included in the study. Using demographic data and findings from electrophysiological examinations, the patients were divided into two groups based on their vitamin D level (Group 1: <20 ng/ml; Group 2: ≥20 ng/ml). The Boston Carpal Tunnel Syndrome Questionnaire was used to assess their CTS- related pain level., Results: Although the rate of CTS in the patients with a low vitamin D level was found to be high, no statistically significant correlation was observed between low vitamin D level and the frequency and severity of CTS. Additionally, the pain and functional loss ratio induced by CTS was found to be higher in the group with a lower vitamin D level than in the group with normal levels., Conclusion: Low vitamin D levels may increase the severity of CTS symptoms. Treatment of vitamin D deficiency in patients with CTS can play a role in reducing pain and disability.

Neuropathy of the posterior femoral cutaneous nerve may manifest as pain and paresthesia in the skin over the inferior buttocks, posterior thigh, and popliteal region. Current treatment options include physical and oral pain therapy, perineural injections, and surgical neurectomy. Perineural steroid injections may provide short-term pain relief; however, to our knowledge, there is currently no minimally invasive denervation procedure for sustained pain relief that could serve as an alternative to surgical neurectomy. Percutaneous cryoablation of nerves is a minimally invasive technique that induces a sustained nerve conduction block through temporary freezing of the neural layers. It can result in long-lasting pain relief, but has not been described for the treatment of neuropathy-mediated PFCN pain. We report a technique of MR-guided cryoablation of the posterior femoral cutaneous nerve resulting in successful treatment of PFCN-mediated sitting pain. Cryoablation of the posterior femoral cutaneous nerve seems a promising, minimally invasive treatment option that deserves further investigation.

Aims/hypothesis: Aggressive glucose control can result in treatment induced neuropathy of diabetes (TIND) if glycemic control is achieved too quickly. The aim of the present study is to describe the 8-year follow-up data on a cohort of individuals with type 1 diabetes who developed TIND., Methods: Twenty-six individuals with type 1 diabetes and TIND were followed longitudinally for 8years with regular quantitative measurement of pain, neurological examinations and evaluation of microvascular complications. Comprehensive neurological testing was performed after TIND and 7-8years later., Results: Among the 26 individuals with TIND, 19/26 had stable glycemic control and 7/26 had unstable glycemic control in long-term follow up. Those 19/26 with stable glycemic control had improvement in neuropathy, pain and microvascular complications while the 7/26 with unstable glycemic control had significant worsening of neuropathy, pain and microvascular complications (P<0.01, all tests)., Conclusion/interpretation: TIND is a poorly understood iatrogenic complication of aggressive glycemic control, although individuals with stable glycemic control tended to improve, while those with unstable glycemic control worsened. Additional studies of TIND are required to understand potential outcomes in an era of medical 'metrics' where physician reimbursement may be tied to achievement of excessively rapid glycemic control., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Rationale: Prostacyclin-associated leg pain is a potentially debilitating adverse effect of prostacyclin therapy for patients with pulmonary arterial hypertension (PAH). However, to our knowledge, this entity has not been systematically studied., Objectives: To characterize the clinical features and metabolic risk factors for prostacyclin-associated leg pain., Methods: At one academic medical center, we assembled and analyzed a case series of patients with PAH and prostacyclin-associated leg pain., Measurements and Main Results: Over a period of 2 years, we identified 11 patients with PAH and prostacyclin-associated leg pain who agreed to participate in this study. Subjects underwent a standardized clinical evaluation, electrodiagnostic assessment, and serologic screen for metabolic causes of peripheral neuropathy. All 11 patients were female; their mean (SD) age was 50 (±9) years; their median (interquartile range) PAH duration was 56 (20-96) months; and their prostacyclin therapy duration was a median (interquartile range) of 20 (14-36) months. All patients reported leg pain beginning soon after prostacyclin initiation and varying with dose. All described a neuropathic pain in a symmetric, distal, stocking distribution. Neurologic examination revealed a sensory, small-fiber, predominantly peripheral neuropathy in seven (78%) patients. Results of autonomic reflex testing and thermoregulatory sweat testing were abnormal in 82% and 90% of patients, respectively, suggesting small-fiber neuropathy. Serologic evaluation identified a new, previously unrecognized contributor to neuropathy in eight (73%) patients, including vitamin B 12 deficiency in six (55%), uncompensated hypothyroidism in three (27%), and diabetes mellitus in one (9%)., Conclusions: Chronic prostacyclin-associated leg pain is associated with a small-fiber neuropathy. Treatable metabolic contributors (vitamin B 12 deficiency, thyroid dysfunction, or diabetes) appear to be common possible "second hits" that may be underrecognized. We recommend screening for possible metabolic contributors in patients who have otherwise unexplained leg pain in the setting of PAH and current or anticipated prostacyclin therapy.

Combined vitamin preparations in therapeutic doses are used, along with simple analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), muscle and epidural blockade, for the relief of acute pain. It is recommended to use the B vitamin preparation neuromultivit. The tablet form of this preparation contains vitamin thiamine hydrochloride (100 mg), pyridoxine hydrochloride (200 mg), cyanocobalamin (0.2 mg), and injectable form includes thiamine hydrochloride (100mg), pyridoxine hydrochloride (100 mg), cyanocobalamin (1 mg). The efficacy of neuromultivit in a two stage scheme (intramuscular injections of 2 ml daily for 5-10 days with further injections 2-3 times a week for 2-3 weeks at the initial stage and 1 tablet 3 times a day for 4 weeks at the second stage) was shown.

Introduction: Although isolated injury of the sural nerve is frequently reported, entrapment involving the lateral calcaneal branch of the sural nerve (LCSN) is very rare., Methods: We report the case of a 29-year-old man with lateral calcaneal neuropathy of the sural nerve without any history of trauma. The diagnosis was based on clinical, electrophysiologic, and radiologic studies, including ultrasonography (US) and MRI., Results: US revealed a spindle-shaped swelling in the posterior part of the sural nerve around the lateral malleolus. MRI showed a small lesion in the sural nerve close to the lesser saphenous vein around the level of the lateral malleolus. Two months after conservative management, the numbness and tingling in the lateral calcaneal region improved., Conclusions: Entrapment of the LCSN can arise from tight shoes. US is useful for evaluating the cutaneous nerve lesions that may be too small to detect by MRI. Muscle Nerve 54: 801-804, 2016., (© 2016 Wiley Periodicals, Inc.)

Background: Congenital insensitivity to pain (CIP) is a rare extreme phenotype characterised by an inability to perceive pain present from birth due to lack of, or malfunction of, nociceptors. PRDM12 has recently been identified as a new gene that can cause CIP. The full phenotype and natural history have not yet been reported., Methods: We have ascertained five adult patients and report their clinical features., Results: Based on our findings, and those of previous patients, we describe the natural history of the PRDM12-CIP disorder, and derive diagnostic and management features to guide the clinical management of patients., Conclusions: PRDM12-CIP is a distinct and diagnosable disorder, and requires specific clinical management to minimise predictable complications., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Nociception is the process of transmission of painful signals by nociceptors in the primary afferent nerve fibers, which specifically respond to noxious stimuli. These noxious stimuli are detected by nociceptors and converted into electrical signals, which are then transmitted to the spinal cord, thalamus, and the cerebral cortex, where pain is finally sensed. Transient receptor potential (TRP) ion channels have emerged as a family of evolutionarily conserved ligand-gated ion channels that function as molecular detectors of physical stimuli. Several member of this family, at least six channels from three TRP family subtypes (TRPV1-4, TRPM8, and TRPA1), are expressed in nociceptors, where they act as transducers for signals from thermal, chemical, and mechanical stimuli and play crucial roles in the generation and development of pathological pain perception. This review focuses on the increasing evidence of TRP channel involvement and contribution in nociceptive pain and the pain hypersensitivity associated with peripheral inflammation or neuropathy, and on the renewed interest in targeting TRP channels for pain relief.

Peripheral neuropathies have diverse acquired and inherited causes. The autoimmune neuropathies represent an important category where treatment is often available. There are overlapping signs and symptoms between autoimmune neuropathies and other forms. Making a diagnosis can be challenging and first assisted by electrophysiologic and sometimes pathologic sampling, with autoimmune biomarkers providing increased assistance. Here we provide a review of the autoimmune and inflammatory neuropathies, their available biomarkers, and approaches to treatment. Also discussed is new evidence to support a mechanism of autoimmune pain., (© 2016 Elsevier B.V. All rights reserved.)

The amino acid glutamate is the principal excitatory transmitter in the nervous system, including in sensory neurons that convey pain sensation from the periphery to the brain. It is now well established that a family of membrane proteins, termed vesicular glutamate transporters (VGLUTs), serve a critical function in these neurons: they incorporate glutamate into synaptic vesicles. VGLUTs have a central role both under normal neurotransmission and pathological conditions, such as neuropathic or inflammatory pain. In the present short review, we will address VGLUTs in the context of primary afferent neurons. We will focus on the role of VGLUTs in pain triggered by noxious stimuli, peripheral nerve injury, and tissue inflammation, as mostly explored in transgenic mice. The possible interplay between glutamate biosynthesis and VGLUT-dependent packaging in synaptic vesicles, and its potential impact in various pain states will be presented.

Unlabelled: Chronic neuropathic pain, the most frequent condition affecting the peripheral nervous system, remains underdiagnosed and difficult to treat. Inhaled cannabis may alleviate chronic neuropathic pain. Our objective was to synthesize the evidence on the use of inhaled cannabis for chronic neuropathic pain. We performed a systematic review and a meta-analysis of individual patient data. We registered our protocol with PROSPERO CRD42011001182. We searched in Cochrane Central, PubMed, EMBASE, and AMED. We considered all randomized controlled trials investigating chronic painful neuropathy and comparing inhaled cannabis with placebo. We pooled treatment effects following a hierarchical random-effects Bayesian responder model for the population-averaged subject-specific effect. Our evidence synthesis of individual patient data from 178 participants with 405 observed responses in 5 randomized controlled trials following patients for days to weeks provides evidence that inhaled cannabis results in short-term reductions in chronic neuropathic pain for 1 in every 5 to 6 patients treated (number needed to treat = 5.6 with a Bayesian 95% credible interval ranging between 3.4 and 14). Our inferences were insensitive to model assumptions, priors, and parameter choices. We caution that the small number of studies and participants, the short follow-up, shortcomings in allocation concealment, and considerable attrition limit the conclusions that can be drawn from the review. The Bayes factor is 332, corresponding to a posterior probability of effect of 99.7%., Perspective: This novel Bayesian meta-analysis of individual patient data from 5 randomized trials suggests that inhaled cannabis may provide short-term relief for 1 in 5 to 6 patients with neuropathic pain. Pragmatic trials are needed to evaluate the long-term benefits and risks of this treatment., (Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Unlabelled: The weight-bearing test is one method to assess pain in rodent animal models; however, the acceptance of this convenient method is limited by the low throughput data acquisition and necessity of confining the rodents to a small chamber., New Methods: We developed novel data acquisition hardware and software, data analysis software, and a conditioning protocol for an automated high throughput static weight-bearing assessment of pain. With this device, the rats voluntarily enter the weighing chamber, precluding the necessity to restrain the animals and thereby removing the potential stress-induced confounds as well as operator selection bias during data collection. We name this device the Voluntarily Accessed Static Incapacitance Chamber (VASIC)., Results: Control rats subjected to the VASIC device provided hundreds of weight-bearing data points in a single behavioral assay. Chronic constriction injury (CCI) surgery and paw pad injection of complete Freund's adjuvant (CFA) or carrageenan in rats generated hundreds of weight-bearing data during a 30 minute recording session. Rats subjected to CCI, CFA, or carrageenan demonstrated the expected bias in weight distribution favoring the un-operated leg, and the analgesic effect of i.p. morphine was demonstrated. In comparison with existing methods, brief water restriction encouraged the rats to enter the weighing chamber to access water, and an infrared detector confirmed the rat position with feet properly positioned on the footplates, triggering data collection. This allowed hands-off measurement of weight distribution data reducing operator selection bias., Conclusion: The VASIC device should enhance the hands-free parallel collection of unbiased weight-bearing data in a high throughput manner, allowing further testing of this behavioral measure as an effective assessment of pain in rodents., (Copyright © 2015. Published by Elsevier Inc.)

A 10-year-old boy was diagnosed as having the axonal form of Guillain-Barré syndrome (GBS). The patient noticed progressive weakness of the lower legs on the 1st day of illness. Intravenous immunoglobulin therapy was immediately started on the 2nd day of illness. Despite the favorable recovery of muscle weakness, he complained of severe needle-like pain in the thighs and buttocks and also painful numbness over the gastrocnemius regions. Acetaminophen and hydroxyzine therapy was ineffective for the pain control. Oral prednisolone therapy (0.7 mg/kg/day) led to drastic pain-relief with favorable improvement of the weakness. Corticosteroid therapy is not typically used in the management of GBS patients. Although GBS-associated pain frequently occurs in children, only a few reports have indicated the analgesic utility of steroids in the treatment of pediatric GBS. This observation may suggest the alternative of this therapy as for the as the limited, but potentially rapid, control of GBS-associated acute radicular pain in pediatric patients., (Copyright © 2015. Published by Elsevier B.V.)

The antiretroviral toxic neuropathy, a distal sensory polyneuropathy associated with antiretroviral treatment, is a frequently occurring neurological complication during treatment of patients with AIDS and often leads to discontinuation of antiretroviral therapy. The mechanisms by which antiretroviral drugs contribute to the development of neuropathic pain are not known. Using drugs that reduce intracellular calcium ions (Ca(2+)), we investigated the hypothesis that altered cytosolic Ca(2+) concentration contributes to the 2',3'-dideoxycytidine (ddC)-evoked painful neuropathy. Administration of ddC induced mechanical and cold allodynia, which were abolished by intrathecal administration of TMB-8, a blocker of Ca(2+) release from intracellular stores, and by ryanodine, a RyR antagonist. Treatment with the IP3R antagonist heparin prevented mechanical allodynia with no effect on thermal response. To further clarify the pathway involved, we investigated the role of HuD, a RNA binding protein involved in neuronal function. HuD silencing reverted both mechanical and cold allodynia inducing, a phenotype comparable to that of ryanodine-exposed mice. HuD binding to the RyR2 mRNA, the most abundant RyR isoform in the spinal cord, was demonstrated and RyR2 silencing prevented the ddC-induced neuropathic pain. A positive regulation of gene expression on CaMKIIα by HuD was also observed, but sequestration of CaMKIIα had no effect on ddC-induced allodynia. The present findings identify a spinal RyR2 pathway activated in response to ddC administration, involving the binding activity on RyR2 mRNA by HuD. We propose the modulation of the RyR2 pathway as a therapeutic perspective in the management of antiretroviral painful neuropathy., (Copyright © 2015 Elsevier Inc. All rights reserved.)

GABAA receptors (GABA(A)Rs) and glycine receptors are key elements of the spinal control of nociception and pain. Compromised functioning of these two transmitter systems contributes to chronic pain states. Restoring their proper function through positive allosteric modulators should constitute a rational approach to the treatment of chronic pain syndromes involving diminished inhibitory spinal pain control. Although classical benzodiazepines (i.e., full agonists at the benzodiazepine binding site of GABA(A)Rs) potentiate synaptic inhibition in spinal pain controlling circuits, they lack clinically relevant analgesic activity in humans. Recent data obtained from experiments in GABA(A)R point-mutated mice suggests dose-limiting sedative effects of classical nonspecific benzodiazepines as the underlying cause. Experiments in genetically engineered mice resistant to the sedative effects of classical benzodiazepines and studies with novel less sedating benzodiazepines have indeed shown that profound antihyperalgesia can be obtained at least in preclinical pain models. Present evidence suggests that compounds with high intrinsic activity at α2-GABA(A)R and minimal agonistic activity at α1-GABA(A)R should possess relevant antihyperalgesic activity without causing unwanted sedation. On-going preclinical studies in genetically engineered mice and clinical trials with more selective benzodiazepine site agonists should soon provide additional insights into this emerging topic., (© 2015 Elsevier Inc. All rights reserved.)

Quantitative sensory testing (QST), a set of noninvasive methods used to assess sensory and pain perception, has been used for three decades. The precision of the instruments and the uninvasiveness encouraged many QST-based trials. The developments made have benefited multiple disciplines. QST relies on analysis of an individual's response to external stimuli, reflecting the integrity of the PNS and the sensory pathway. The sensory pathway cannot be assessed in isolation from the affective and cognitive characteristics of patients or testers. Many variables potentially affect the reliability and reproducibility of QST, which after all, is designed for the testing of individuals by other individuals. Several decades of QST research have yielded exciting contributions, but the future of QST cannot be fully known.

Nucleoside reverse transcriptase inhibitors (NRTIs) are known to produce painful neuropathies and to enhance states of pain hypersensitivity produced by HIV-1 infection in patients with AIDS leading to discontinuation of antiretroviral therapy, thus limiting viral suppression strategies. The mechanisms by which NRTIs contribute to the development of neuropathic pain are not known. In the current study, we tested the hypothesis that HuD, an RNA binding protein known to be an essential promoter of neuronal differentiation and survival, might be involved in the response to NRTI-induced neuropathy. Antiretroviral neuropathy was induced by a single intraperitoneal administration of 2',3'-dideoxycytidine (ddC) in mice. HuD was physiologically expressed in the cytoplasm of the soma and in axons of neurons within DRG and spinal cord and was considerably overexpressed following ddC treatment. ddC up-regulated spinal GAP43 protein, a marker of neuroregeneration, and this increase was counteracted by HuD silencing. GAP43 and HuD colocalize in DRG and spinal dorsal horn (SDH) axons and administration of an anti-GAP43 antibody aggravated the ddC-induced axonal damage. The administration of a protein kinase C (PKC) inhibitor or the PKCγ silencing prevented both HuD and GAP43 increased expression. Conversely, treatment with the PKC activator PDBu potentiated HuD and GAP43 overexpression, demonstrating the presence of a spinal PKC-dependent HuD-GAP43 pathway activated by ddC. These results indicated that HuD recruitment and GAP43 protein increase are mechanistically linked events involved in the response to antiretroviral-induced neurodegenerative processes., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Pain is the most common complaint in the medical field and the identification of novel compounds that can effectively treat painful states without causing side effects remains a major challenge in biomedical research. The aim of the present study is to investigate the antinociceptive effect of 3-(4-fluorophenyl)-5-trifluoromethyl-1H-1-tosylpyrazole (FTosPz) in models of pathological pain in mice and compare these effects with those produced by Celecoxib. FTosPz (100-500 μmol/kg) or Celecoxib (26-260 μmol/kg) was administrated orally. The administration of either FTosPz or Celecoxib reduced the hyperalgesia but not the edema or leukocyte infiltration that was caused by Complete Freund's Adjuvant (CFA), used as an arthritis model. Oral administration of both FTosPz and Celecoxib also attenuated the postoperative hyperalgesia as well as the hyperalgesia caused by partial sciatic nerve ligation, used as a neuropathic pain model. FTosPz and Celecoxib produced antinociceptive effects without altering the locomotor activity of animals. Furthermore, FTosPz neither altered AST/ALT enzyme activity nor the urea/creatinine levels. Still, the FTosPz did not alter the COX-1 and COX-2 enzyme activities. Thus, FTosPz is an interesting prototype for the development of novel analgesic drugs., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Pain is a frequent debilitating feature reported in peripheral neuropathies with involvement of small nerve (Aδ and C) fibers. Voltage-gated sodium channels are responsible for the generation and conduction of action potentials in the peripheral nociceptive neuronal pathway where NaV 1.7, NaV 1.8, and NaV 1.9 sodium channels (encoded by SCN9A, SCN10A, and SCN11A) are preferentially expressed. The human genetic pain conditions inherited erythromelalgia and paroxysmal extreme pain disorder were the first to be linked to gain-of-function SCN9A mutations. Recent studies have expanded this spectrum with gain-of-function SCN9A mutations in patients with small fiber neuropathy and in a new syndrome of pain, dysautonomia, and small hands and small feet (acromesomelia). In addition, painful neuropathies have been recently linked to SCN10A mutations. Patch-clamp studies have shown that the effect of SCN9A mutations is dependent upon the cell-type background. The functional effects of a mutation in dorsal root ganglion (DRG) neurons and sympathetic neuron cells may differ per mutation, reflecting the pattern of expression of autonomic symptoms in patients with painful neuropathies who carry the mutation in question. Peripheral neuropathies may not always be length-dependent, as demonstrated in patients with initial facial and scalp pain symptoms with SCN9A mutations showing hyperexcitability in both trigeminal ganglion and DRG neurons. There is some evidence suggesting that gain-of-function SCN9A mutations can lead to degeneration of peripheral axons. This review will focus on the emerging role of sodium channelopathies in painful peripheral neuropathies, which could serve as a basis for novel therapeutic strategies., (© 2014 Peripheral Nerve Society.)

Although simple characterization of discomfort as cramps, heaviness, shooting pains, and so forth can be misleading, history and examination are key to accurate diagnosis. Absence of both dorsalis pedis and posterior tibial pulses strongly suggests peripheral arterial disease (PAD), and the presence of either pulse makes PAD less likely. Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) are a common cause of lower extremity myalgias. Restless legs syndrome causes nocturnal discomfort but must be distinguished from confounding“mimics." Neurologic causes of leg symptoms include lumbar spinal stenosis, radiculopathy, distal symmetric polyneuropathy, and entrapment neuropathy. Many common causes of leg discomfort can be managed conservatively., (Published by Elsevier Inc.)

Patients treated with nucleoside reverse transcriptase inhibitors (NRTIs) develop painful neuropathies that lead to discontinuation of antiretroviral therapy thus limiting viral suppression strategies. The mechanisms by which NRTIs contribute to the development of neuropathy are not known. In order to elucidate the mechanisms underlying this drug-induced neuropathy, we have characterized cellular events in the central nervous system following antiretroviral treatment. Systemic administration of the antiretroviral agent, 2',3'-dideoxycytidine (ddC) considerably increased the expression and phosphorylation of protein kinase C (PKC) γ and ɛ, enzymes highly involved in pain processes, within periaqueductal grey matter (PAG), and, to a lesser extent, within thalamus and prefrontal cortex. These events appeared in coincidence with thermal and mechanical allodynia, but PKC blockade did not prevent the antiretroviral-induced pain hypersensitivity, ruling out a major involvement of PKC in the ddC-induced nociceptive behaviour. An increased expression of GAP43, a marker of neuroregeneration, and decreased levels of ATF3, a marker of neuroregeneration, were detected in all brain areas. ddC treatment also increased the expression of HuD, a RNA-binding protein target of PKC known to stabilize GAP43 mRNA. Pharmacological blockade of PKC prevented HuD and GAP43 overexpression. Silencing of both PKCγ and HuD reduced GAP43 levels in control mice and prevented the ddC-induced GAP43 enhanced expression. Present findings illustrate the presence of a supraspinal PKC-mediated HuD-GAP43 pathway activated by ddC. Based on our results, we speculate that antiretroviral drugs may recruit the HuD-GAP43 pathway, potentially contributing to a response to the antiretroviral neuronal toxicity., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The treatment with the chemotherapeutic agent paclitaxel produces a painful peripheral neuropathy, and is associated with an acute pain syndrome in a clinically significant number of patients. However, no standard therapy has been established to manage the acute pain or the chronic neuropathic pain related to paclitaxel. In the present study, we evaluated the analgesic potential of two N-type voltage-gated calcium channel (VGCC) blockers, ω-conotoxin MVIIA and Phα1β, on acute and chronic pain induced by paclitaxel. Adult male rats were treated with four intraperitoneal injections of paclitaxel (1+1+1+1mg/kg, in alternate days) and the development of mechanical hyperalgesia was evaluated 24h (acute painful stage) or 15days (chronic painful stage) after the first paclitaxel injection. Not all animals showed mechanical hyperalgesia 24h after the first paclitaxel injection, but those that showed developed a more intense mechanical hyperalgesia at the chronic painful stage. Intrathecal administration (i.t.) of ω-conotoxin MVIIA (3-300pmol/site) or Phα1β (10-300pmol/site) reduced the mechanical hyperalgesia either at the acute or at the chronic painful stage induced by paclitaxel. When administered at the acute painful stage, ω-conotoxin MVIIA (300pmol/site, i.t.) and Phα1β (300pmol/site, i.t.) prevented the worsening of chronic mechanical hyperalgesia. Furthermore, Phα1β (30-300pmol/site, i.t.) elicited less adverse effects than ω-conotoxin MVIIA (10-300 pmol/site, i.t.). Taken together, our data evidence the involvement of N-type VGCC in pain sensitization induced by paclitaxel and point out the potential of Phα1β as a safer alternative than ω-conotoxin MVIIA to treat the pain related to paclitaxel., (© 2013.)

Background: Diabetic neuropathic cachexia is a rare and little understood variant of diabetic neuropathy. It predominantly affects men with type 2 diabetes mellitus in their sixth to seventh decades of life and is characterized by the subacute onset of a painful sensory neuropathy, rapid weight loss, and psychiatric comorbidity., Methods: We present the only female pediatric case described to date, and one of only a handful of cases reported to affect type 1 diabetics., Results: In this patient a diagnosis of diabetic neuropathic cachexia was based on the rapid onset of severe allodynic pain, polyneuropathy, and marked weight loss in the setting of poorly controlled diabetes, without evidence of end-organ disease and exclusion of other known causes of neuropathy., Conclusions: Diabetic neuropathic cachexia is a complex neuroendocrinologic disorder characterized by profound weight loss, neuropathic pain, and mood disturbance. Electrodiagnostic abnormalities were pronounced showing a moderately severe generalized sensorimotor polyneuropathy., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Gynecologic malignancies affect more than 83 000 women in the United States, each year. Because the disease involves the pelvis, many patients have side effects distal to this area in their lower extremities. The differential diagnosis of leg pain can be divided into vascular, neurologic, and musculoskeletal causes. In this review article, we address numerous etiologies of leg pain, reviewing the prevalence of disease, physical examination findings, diagnostic as well as treatment modalities.

Vincristine-induced peripheral neuropathy is a common side effect of vincristine treatment, which is accompanied by pain and can be dose-limiting. The molecular mechanisms that underlie vincristine-induced pain are not well understood. We have established an animal model to investigate pathophysiological mechanisms of vincristine-induced pain. Our previous studies have shown that the tetrodotoxin-sensitive voltage-gated sodium channel Nav1.6 in medium-diameter dorsal root ganglion (DRG) neurons contributes to the maintenance of vincristine-induced allodynia. In this study, we investigated the effects of vincristine administration on excitability in small-diameter DRG neurons and whether the tetrodotoxin-resistant (TTX-R) Nav1.8 channels contribute to mechanical allodynia. Current-clamp recordings demonstrated that small DRG neurons become hyper-excitable following vincristine treatment, with both reduced current threshold and increased firing frequency. Using voltage-clamp recordings in small DRG neurons, we now show an increase in TTX-R current density and a −7.3 mV hyperpolarizing shift in the half-maximal potential (V1/2) of activation of Nav1.8 channels in vincristine-treated animals, which likely contributes to the hyperexcitability that we observed in these neurons. Notably, vincristine treatment did not enhance excitability of small DRG neurons from Nav1.8 knockout mice, and the development of mechanical allodynia was delayed but not abrogated in these mice. Together, our data suggest that sodium channel Nav1.8 in small DRG neurons contributes to the development of vincristine-induced mechanical allodynia. [ABSTRACT FROM AUTHOR]