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A 64-year-old woman presented to an academic medical centre with postoperative left ischial pain following a left total hip replacement. Her pain was exacerbated by sitting down and with forward flexion of the spine, and the pain radiated from the left ischial tuberosity to the left perineum, groin and medial thigh. An ischial bursa injection was performed, but only resulted in 1 day of excellent pain relief. A diagnosis of inferior cluneal neuralgia was then made. Subsequent inferior cluneal nerve radiofrequency ablation was performed, and provided sustained 50% relief in pain. The patient had a concomitant sensation of ‘ball like’ pressure at her rectum which was determined to be due to levator ani syndrome. She was prescribed pelvic floor physical therapy and botulinum toxin injection, which resulted in further notable improvement of her symptoms.

Background Herpes zoster presents as clustered blisters on one side of the body, accompanied by nerve pain. This is caused by reactivation of the varicella zoster virus, and it occurs primarily in people with weakened immunity. Tumor and chemotherapy drugs can impair the patient's immune function, induce herpes zoster and prolong the course of disease.In these patients, skin changes can last for months and blisters can recur and cause serious complications such as postherpetic neuralgia.Acupuncture is a common alternative therapy for herpes zoster in East Asia. Case presentation We report a case of an elderly male patient with widespread herpes zoster in the trunk after non-Hodgkin's lymphoma chemotherapy. The patient had received conventional treatment with valaciclovir and mecobalamin within 24 hours of symptom onset. Because neither the clustered blisters nor the nerve pain were improved a week later, acupuncture and related techniques were applied. These included electro-acupuncture, surrounding acupuncture, fire acupuncture, and cupping. The patient recovered 20 days after the herpes zoster attack, and there were no adverse reactions during the treatment process. Conclusions This case suggests that acupuncture and related techniques are effective interventions for this condition.This case report is innovative because it shows that acupuncture as an adjuvant treatment can improve the skin lesions in patients with HZ after tumour chemotherapy, relieve pain, and shorten the course of HZ.

Central pain after stroke due to brainstem infarction is very rare. Treatment is difficult and specific guidelines are lacking. This is the report of a 61-year-old female patient who, after a posterolateral left medulla oblongata insult with incomplete Wallenberg syndrome, subsequently developed a burning and tingling pain in the contralateral leg and a burning and shooting pain in the ipsilateral face in trigeminal branches 1 and 2. More than 3 years of therapy with amitriptyline, gabapentin, pregabalin and various grade II and III opioids was ineffective or showed intolerable side effects. The administration of tetrahydrocannabinol and cannabidiol as an oromucosal spray in a 1:1 ratio improved the pain situation and quality of life quickly and permanently. The encouraging results in the present case may suggest that treatment with medical cannabis should be considered in similar cases when standard therapies are insufficient.

Pain is a complex phenomenon that is usually unpleasant and aversive. It can range widely in intensity, quality, and duration and has diverse pathophysiologic mechanisms and meanings. Voltage-gated sodium and calcium channels are essential to transmitting painful stimuli from the periphery until the dorsal horn of the spinal cord. Thus, blocking voltage-gated calcium channels (VGCCs) can effectively control pain refractory to treatments currently used in the clinic, such as cancer and neuropathic pain. VGCCs blockers isolated of cobra Naja naja kaouthia (α-cobratoxin), spider Agelenopsis aperta (ω-Agatoxin IVA), spider Phoneutria nigriventer (PhTx3.3, PhTx3.4, PhTx3.5, PhTx3.6), spider Hysterocrates gigas (SNX-482), cone snails Conus geographus (GVIA), Conus magus (MVIIA or ziconotide), Conus catus (CVID, CVIE and CVIF), Conus striatus (SO- 3), Conus fulmen (FVIA), Conus moncuri (MoVIA and MoVIB), Conus regularis (RsXXIVA), Conus eburneus (Eu1.6), Conus victoriae (Vc1.1.), Conus regius (RgIA), and spider Ornithoctonus huwena (huwentoxin-I and huwentoxin-XVI) venoms caused antinociceptive effects in different acute and chronic pain models. Currently, ziconotide is the only clinical used N-type VGCCs blocker peptide for chronic intractable pain. However, ziconotide causes different adverse effects, and the intrathecal route of administration also impairs its use in a more significant number of patients. In this sense, peptides isolated from animal venoms or their synthetic forms that act by modulating or blocking VGCCs channels seem to be a relevant prototype for developing new analgesics efficacious and well tolerated by patients.

Funding Information: Source(s) of financial support: The study was supported by State funding for University‐level health research (TYH 2013311, Y122417012, and Y102218018), the Signe and Ane Gyllenberg Foundation, the Emil Aaltonen Foundation, and the Finnish Medical Foundation. Funding Information: Eija Kalso has received personal fees for participation in advisory board meetings of Pfizer and Orion Pharma, unrelated to this work. Dr. Juhani Ojala reports grants from Suomen Lääketieteen säätiö, outside the submitted work. Dr. Jukka Vanhanen reports grants from The Emil Aaltonen Foundation, grants from State funding for university‐level health research, during the conduct of the study. Part of Dr. Mari A. Kaunisto's salary is covered by a large Finnish biobank study FinnGen, funded by 12 international pharmaceutical companies (Abbvie, AstraZeneca, Biogen, Celgene, Genentech, a member of the Roche Group, GSK, Janssen, Maze Therapeutics, Merck/MSD, Novartis, Pfizer, and Sanofi) and Business Finland. Pantelis Lioumis has been consulting Nexstim Ltd. for issues not related to this study, such as motor and speech functional mapping until 2016. Dr. Jukka Putaala reports personal fees from Boehringer‐Ingelheim, personal fees and other from Bayer, grants and personal fees from BMS‐Pfizer, grants and personal fees from Abbott/St. Jude Medical, other from Vital Signum, other from Nokia Technologies, other from Bittium, other from BcB Medical, personal fees from Portola, personal fees from Terve Media, grants from Business Finland, grants from Amgen, personal fees from Herantis Pharma, other from Medixine, outside the submitted work; and he has participated in the European Stroke Organisation's guideline working groups on 1) poststroke hyperglycemia and 2) secondary prevention in patients with AF. He also has participated in the Finnish Duodecim Society's guideline working group on Ischemic stroke and TIA. The remaining authors have no potential conflicts to disclose. Conflict of Interest: Publisher Copyright: ©2021 The Authors. Neuromodulation: Technology at the Neural Interface published by Wiley Periodicals LLC on behalf of International Neuromodulation Society. Objectives: Central poststroke pain (CPSP), a neuropathic pain condition, is difficult to treat. Repetitive transcranial magnetic stimulation (rTMS) targeted to the primary motor cortex (M1) can alleviate the condition, but not all patients respond. We aimed to assess a promising alternative rTMS target, the secondary somatosensory cortex (S2), for CPSP treatment. Materials and Methods: This prospective, randomized, double-blind, Sham-controlled three-arm crossover trial assessed navigated rTMS (nrTMS) targeted to M1 and S2 (10 sessions, 5050 pulses per session at 10 Hz). Participants were evaluated for pain, depression, anxiety, health-related quality of life, upper limb function, and three plasticity-related gene polymorphisms including Dopamine D2 Receptor (DRD2). We monitored pain intensity and interference before and during stimulations, and at one month. A conditioned pain modulation test was performed using the cold pressor test. This assessed the efficacy of the descending inhibitory system, which maytransmit TMS effects in pain control. Results: We prescreened 73 patients, screened 29, and included 21, of whom 17 completed the trial. NrTMS targeted to S2 resulted in long-term (from baseline to one-month follow-up) pain intensity reduction of ≥30% in 18% (3/17) of participants. All stimulations showed a short-term effect on pain (17–20% pain relief), with no difference between M1, S2, or Sham stimulations, indicating a strong placebo effect. Only nrTMS targeted to S2 resulted in a significant long-term pain intensity reduction (15% pain relief). The cold pressor test reduced CPSP pain intensity significantly (p = 0.001), indicating functioning descending inhibitory controls. The homozygous DRD2 T/T genotype is associated with the M1 stimulation response. Conclusions: S2 is a promising nrTMS target in the treatment of CPSP. The DRD2 T/T genotype might be a biomarker for M1 nrTMS response, but this needs confirmation from a larger study.

Objectives The aim of the present study was to investigate the analgesic effects of repetitive transcranial magnetic stimulation over the primary motor cortex (M1-rTMS) using different stimulation parameters to explore the optimal stimulus condition for treating neuropathic pain. Materials and methods We conducted a randomized, blinded, crossover exploratory study. Four single sessions of M1-rTMS at different parameters were administered in random order. The tested stimulation conditions were as follows: 5-Hz with 500 pulses per session, 10-Hz with 500 pulses per session, 10-Hz with 2000 pulses per session, and sham stimulation. Analgesic effects were assessed by determining the visual analog scale (VAS) pain intensity score and Short-Form McGill Pain Questionnaire 2 (SF-MPQ2) score immediately before and immediately after intervention. Results We enrolled 22 adults (age: 59.8 ± 12.1 years) with intractable neuropathic pain. Linear-effects models showed significant effects of the stimulation condition on changes in VAS pain intensity (p = 0.03) and SF-MPQ2 (p = 0.01). Tukey multiple comparison tests revealed that 10-Hz rTMS with 2000 pulses provided better pain relief than sham stimulation, with greater decreases in VAS pain intensity (p = 0.03) and SF-MPQ2 (p = 0.02). Conclusions The results of this study suggest that high-dose stimulation (specifically, 10-Hz rTMS at 2000 pulses) is more effective than lower-dose stimulation for treating neuropathic pain.

Traumatic peripheral nerve injuries are common and socioeconomically highly relevant. Despite significant microsurgical advances, the results of surgical reconstruction are still far from optimal and the rate of life-long complications, such as impaired motor and sensory function or neuropathic pain, is high. Moreover, the regeneration of peripheral nerves is a complex and fragile process that is not yet completely understood. Hence, there is an urgent need to further elucidate the underlying biological mechanisms. Herein, we propose that the neural lymphatic vasculature and lymphangiogenesis play an essential role in both peripheral nerve injury and regeneration and discuss hypothetical mechanisms implementing the current literature. Finally, specific research approaches to test our hypothesis are introduced.

Trigeminal neuralgia is a chronic pain condition affecting one or more distributions of the trigeminal nerve. Patients with this condition experience short, sharp, shooting pain attacks, which can progress to longer, more frequent durations. The pain is often difficult to control. We report of a man who was admitted with severe neuralgia of the third division of the trigeminal nerve. Talking and any oral intake triggered a severe agonising pain. The latter made the regular oral intake of analgesia challenging. The pain was temporarily controlled with frequent local anaesthesia (LA). Dental core trainees were performing regular inferior alveolar nerve blocks which significantly improved patients’ condition allowing him to communicate and have oral intake. Subsequently, a catheter was placed allowing for a continuous anaesthesia. The connecting tube of the cannula was then used by nursing staff to administer LA providing pain relief without the need of repeated intraoral injections.

OBJECTIVE The objective of this study was to evaluate the feasibility and complications of the over-the-arch (OTA) technique for screw insertion into the C1 lateral mass in patients in whom conventional techniques (i.e., posterior arch [PA] and inferior lateral mass [ILM]) are not feasible due to 1) PA with a very small height (< 3.5 mm), 2) a caudally tilted PA blocking the inferior part of the C1 lateral mass, or 3) loss of height at the ILM (< 3.5 mm). METHODS The authors reviewed the medical records of 60 patients who underwent C1 screw fixation with the OTA technique (13 screws) and the PA/ILM technique (107 screws) between 2011 and 2019. Vertebral artery (VA) injuries, screw malposition, and bony union were radiologically assessed. Clinical outcome measures, including Neck Disability Index (NDI), Japanese Orthopaedic Association (JOA) scale score, and occipital neuralgia, were recorded. RESULTS Thirteen OTA screws were successfully inserted without any major complications. NDI and JOA scale scores did not show significant differences between the two groups at final follow-up. No VA injuries were recognized during screw insertion. There was no evidence of ischemic damage to the VA or bony erosion in the occiput or atlas. Medial wall violation was observed in 1 screw (7.7%); however, no C0–1, C1–2, or lateral wall violations were observed. No patients developed new-onset neuralgia postoperatively after C1 fixation with the OTA technique. CONCLUSIONS The OTA technique was safe and useful for C1 screw fixation in patients in whom conventional techniques could not be employed.

Background Pain in knee osteoarthritis is considered to be nociceptive. Recently, involvement of neuropathic pain and psychosocial factors in knee osteoarthritis has been reported. However, the following details are unclear: 1) How often are neuropathic pain and psychosocial factors involved? And 2) Which patients are associated with neuropathic pain and psychosocial factors? Methods In 104 patients with knee osteoarthritis, we evaluated neuropathic pain factor with a painDETECT questionnaire and catastrophic thinking using the pain catastrophizing scale. Pain intensity was assessed using the visual analog scale; patients with scores below the median were defined as low-pain group and others as high-pain group. Radiographic severity was categorized according to the Kellgren–Lawrence classification, with grades I–II and III–IV defined as low- and high-grades, respectively. We compared the painDETECT and pain catastrophizing scale scores between the low- and high-pain groups and low- and high-grade groups. Furthermore, the painDETECT and pain catastrophizing scale scores were compared among the following four groups: low-grade/low-pain, low-grade/high-pain, high-grade/low-pain, and high-grade/high-pain. Results Neuropathic pain factor and catastrophic thinking were found in 16% and 34% of patients, respectively. There were no significant differences in both painDETECT and pain catastrophizing scale scores between the two pain intensity groups. Between the two groups of radiographic severity, there was no significant difference in the painDETECT scores; however, the pain catastrophizing scale score was significantly high in the low-grade group. In addition, there was no significant difference in the painDETECT scores among the four groups; however, the pain catastrophizing scale scores were significantly higher in low-grade/high-pain than in high-grade/low-pain patients. Conclusions Therefore, 64% had only nociceptive pain factor. Catastrophic thinking was strong in patients with low radiographic severity, especially in those with high pain intensity. Patients with neuropathic pain factor could not be identified from radiographic severity and pain intensity.

Objectives To assess the immediate and three days postintervention effect of one dry needling session compared to one sham needling session on pain, central pain processing, muscle co-contraction and spatiotemporal parameters during gait in knee osteoarthritis patients. Methods A double-blind randomized controlled trial was conducted. Sixty-one knee osteoarthritis patients were randomly assigned to the dry needling or sham needling group. Primary outcomes were pain and central pain processing. Secondary outcomes included muscle co-contraction and spatiotemporal parameters during gait. Patients were assessed at baseline and 15 min after the intervention, and pain also three days after the intervention. Linear mixed models were used to examine between- and within-group differences. Results No significant between-group differences for pain were found, but within-group scores showed a significant decrease 15 min after sham needling and three days after dry needling. The mean conditioned pain modulation effect measured at the m. Trapezius worsened significantly 15 min after sham needling compared to after dry needling (between-group difference). However, individual conditioned pain modulation percentage scores remained stable over time. Various significant within-group differences were found 15 min after sham needling: a decrease of conditioned pain modulation measured at m. Quadriceps and m. Trapezius and stride- and step-time scores, and an increase in step length and widespread pain pressure threshold. A significant decrease in muscle co-contraction index of the m. Vastus Medialis and Semitendinosus was found as within-group difference 15 min after dry needling. Conclusions Dry needling has no larger effect on pain, central pain processing, muscle co-contraction and gait pattern 15 min and three days postintervention compared to sham needling. Mean conditioned pain modulation scores worsened after sham needling compared to after dry needling. Further research remains necessary.

STUDY DESIGN A cross-sectional study. OBJECTIVE The present study aimed to investigate the prevalence of neuropathic pain (NeP) in subjects suffering from neck and shoulder pain (NSP) to reveal the impact of NeP on the health-related quality of life (HRQOL) in middle-aged and elderly people with NSP in a health checkup. SUMMARY OF BACKGROUND DATA No previous studies have established the relationship between NSP and NeP as potential risk factors contributing to a decreased quality of life (QOL) in the general population. METHODS The present study involved 203 participants (men: 84, women: 119; mean age: 63.3 years). For each subject, anthropometric measurements, physical function examinations, and blood testing were performed. A cut-off score of ≥0 on the short-form Spine painDETECT questionnaire (SF-SPDQ) defined the presence of NeP. Subsequently, the NSP (+) subjects were divided into two sub-groups: the NeP (+) and NeP (-) groups. For the assessment of QOL, the Medical Outcomes Study 36-item short-form health survey (SF-36) and the EuroQol 5 dimension 5 level version (EQ-5D-5L) tool were used. RESULTS The study included 100 NSP (+) and 103 NSP (-) subjects. Among the NSP (+) subjects, 46 and 54 subjects were found to be NeP (+) and NeP (-), respectively. For SF-36, the multivariate regression analysis revealed that the prevalence of NeP was associated with a lower physical QOL (odds ratio [OR] 3.56) and lower mental QOL (OR 4.04). Similarly, the NeP prevalence was found to be the predictor for low QOL scores in EQ-5D-5L (EQ-5D-5L index value

To compare prevalence, intensity ratings, and interference ratings of neuropathic pain (NeuP) and nociceptive pain in people with chronic spinal cord injury (SCI) DESIGN: Cross-sectional survey.Six SCI Model System centers in the United States.Convenience sample of 391 individuals (N=391) with traumatic SCI, 18 years or older, 81% male, 57% White.Not applicable.Survey based on the International Spinal Cord Injury Pain Basic Data Set and the Spinal Cord Injury Pain Instrument, including 0-10 numeric ratings of pain intensity and pain interference with daily activities, mood, and sleep RESULTS: A total of 80% of those surveyed reported having at least 1 pain problem; 58% reported 2 or more pain problems; 56% had probable NeuP; and 49% had non-NeuP. When comparing ratings for all pains (n=354 for NeuP, n=290 for non-NeuP) across participants, probable NeuPs were significantly more intense (6.9 vs 5.7) and interfered more with activities (5.2 vs 3.7), mood (4.9 vs 3.2), and sleep (5.4 vs 3.6) than non-NeuPs (all P.001). However, when comparing ratings for probable NeuPs and non-NeuPs within participants, for the subgroup of 94 participants with both pain types, only ratings for sleep interference were found to be significantly different between the pain types. Additionally, we found significantly greater prevalence of NeuP and non-NeuP for women compared with men and of NeuP for those with paraplegia compared with those with tetraplegia.Independent assessment of the pain conditions experienced by an individual with SCI is useful in understanding the differential effect that pain type has on quality of life. This is particularly important regarding sleep interference and should be kept in mind when determining treatment strategies for meeting patient-centered outcome goals.

Background Complex Regional Pain Syndrome (CRPS) is a neuropathic pain condition with no universally recognised treatment. The study evaluates the efficacy of a therapeutic protocol consisting of oral citalopram and lidocaine injections in patients affected by CRPS. Methods Between January 2010 and December 2014, 150 consecutive patients with CRPS were enrolled in the study and randomly assigned into three groups: group one - lidocaine injection and oral citalopram, group two - lidocaine injection and oral placebo, group three - injective and oral placebo. The Impairment Sum Score (ISS) was used to assess the severity of CRPS before, as well as at regular intervals after treatment commenced. Statistical significance (p Results The combined treatment proved to be more effective (ISS 47.6 to 12.6) than local anesthetic alone (ISS 47.5 to 21.5) and to placebo (ISS 47.2 to 29.9). Conclusion This study indicates that CRPS may be managed with well-tolerated association of oral citalopram and lidocaine injections.

Introduction: Cannabis use for pain relief is commonly reported, yet laboratory studies and clinical trials suggest that cannabinoids are weak analgesics, and it is unclear whether perceived reductions in pain from before to after cannabis use relate to factors such as dose, method of administration, phytocannabinoid content, or the age or gender of the user. We determined whether inhalation of cannabis decreased self-reported pain ratings as well as whether user gender, age, time, method of administration, tetrahydrocannabinol (THC)/cannabidiol (CBD) content, or dose of cannabis contribute to changes in these ratings. We also examined whether tolerance may develop to the analgesic effects of cannabis over time. Materials and Methods: Archival data were obtained from Strainprint(®), a medical cannabis app that allows patients to track symptoms before and after using different strains and doses of cannabis. Latent change score models and multilevel models were used to analyze data from 131,582 sessions in which inhaled cannabis was used to treat “muscle pain,” “joint pain,” or “nerve pain.” Results: For all three pain symptoms, severity ratings decreased significantly after cannabis use. Women reported higher baseline and postcannabis pain severity than did men, and men reported larger decreases in pain than did women. Neither THC nor CBD content nor their interaction predicted reductions in pain ratings. However, vaping was associated with larger reductions in joint pain ratings than was smoking, and lower doses were associated with larger reductions in nerve pain ratings. Additionally, for all three pain symptoms, the dose of cannabis used to manage pain increased significantly over time. Conclusions: Inhaled cannabis reduces self-reported pain severity by ∼42–49%. However, these reductions appear to diminish across time, and patients use larger doses across time, suggesting that analgesic tolerance develops with continued use.

Objectives The spinal cord injury (SCI) patient population is overwhelmingly affected by neuropathic pain (NP), a secondary condition for which therapeutic options are limited and have a low degree of efficacy. The objective of this study was to identify novel deep brain stimulation (DBS) targets that may theoretically benefit those with NP in the SCI patient population. We hypothesize that localized changes in white matter identified in SCI subjects with NP compared to those without NP could be used to develop an evidence-based approach to DBS target identification. Materials and methods To classify localized neurostructural changes associated with NP in the SCI population, we compared white matter fiber density (FD) and cross-section (FC) between SCI subjects with NP (N = 17) and SCI subjects without NP (N = 15) using diffusion-weighted magnetic resonance imaging (MRI). We then identified theoretical target locations for DBS using fiber bundles connected to significantly altered regions of white matter. Finally, we used computational models of DBS to determine if our theoretical target locations could be used to feasibly activate our fiber bundles of interest. Results We identified significant increases in FC in the splenium of the corpus callosum in pain subjects when compared to controls. We then isolated five fiber bundles that were directly connected to the affected region of white matter. Our models were able to predict that our fiber bundles of interest can be feasibly activated with DBS at reasonable stimulation amplitudes and with clinically relevant implantation approaches. Conclusions Altogether, we identified neuroarchitectural changes associated with NP in the SCI cohort and implemented a novel, evidence-driven target selection approach for DBS to guide future research in neuromodulation treatment of NP after SCI.

Gut dysbiosis, defined as pathogenic alterations in the distribution and abundance of different microbial species, is associated with neuropathic pain in a variety of clinical conditions, but this has not been explored in the context of neuropathy in people with HIV (PWH). We assessed gut microbial diversity and dysbiosis in PWH and people without HIV (PWoH), some of whom reported distal neuropathic pain (DNP). DNP was graded on a standardized, validated severity scale. The gut microbiome was characterized using 16S rRNA sequencing and diversity was assessed using phylogenetic tree construction. Songbird analysis (https://github.com/mortonjt/songbird) was used to produce a multinomial regression model predicting counts of specific microbial taxa through metadata covariate columns. Participants were 226 PWH and 101 PWoH, mean (SD) age 52.0 (13.5), 21.1% female, 54.7% men who have sex with men, 44.7% non-white. Among PWH, median (interquartile range, IQR) nadir and current CD4 were 174 (21, 302) and 618 (448, 822), respectively; 90% were virally suppressed on antiretroviral therapy. PWH and PWoH did not differ with respect to microbiome diversity as indexed by Faith's phylogenetic diversity (PD). More severe DNP was associated with lower alpha diversity as indexed by Faith's phylogenetic diversity in PWH (Spearman's ρ=.224, P=0.0007), but not in PWoH (Spearman's ρ=.032, P=.748). These relationships were not confounded by demographics or disease factors. In addition, the log-ratio of features identified at the genus level as Blautia to Lachnospira was statistically significantly higher in PWH with DNP than in PWH without DNP (t-test, P=1.01e-3). Furthermore, the log-ratio of Clostridium features to Lachnospira features also was higher in PWH with DNP than in those without (t-test, P=6.24e-5). Our results, in combination with previous findings in other neuropathic pain conditions, suggest that gut dysbiosis, particularly reductions in diversity and relative increases in the ratios of Blautia and Clostridium to Lachnospira, may contribute to prevalent DNP in PWH. Two candidate pathways for these associations, involving microbial pro-inflammatory components and microbially-produced anti-inflammatory short chain fatty acids, are discussed. Future studies might test interventions to re-establish a healthy gut microbiota and determine if this prevents or improves DNP. PERSPECTIVE: The association of neuropathic pain in people with HIV with reduced gut microbial diversity and dysbiosis raises the possibility that re-establishing a healthy gut microbiota might ameliorate neuropathic pain in HIV by reducing proinflammatory and increasing anti-inflammatory microbial products.

OBJECTIVE Spinal cord stimulation (SCS) has been considered an ineffective procedure for patients with central poststroke pain (CPSP). However, recent case series that included small numbers of patients reported the possible efficacy of SCS as a treatment of CPSP. This multicenter retrospective study aimed to examine the outcomes of using SCS to treat patients with CPSP and to explore factors related to outcomes. METHODS The authors reviewed the medical records of patients with CPSP who underwent SCS to collect data regarding their background, surgical information, and outcomes of SCS at trial stimulation and last follow-up after long-term implantation in six study centers. Outcomes were evaluated with a pain score for intensity (range 0–10) and the Patient Global Impression of Changes (PGIC) scale. Factors associated with outcomes were explored with univariable and multivariable analyses. RESULTS The authors collected data from a total of 166 patients (mean age 63.4 years; mean pain score at baseline 8.2). Of these patients, 163 underwent trial stimulation. The mean pain score decreased by 42.0%, 104 (64%) patients had ≥ 30% decrease in pain score, and 96 (59%) reported much or very much improved condition on the PGIC scale at trial stimulation. Moreover, 106 (64%) patients underwent long-term implantation of SCS devices. The mean decrease in pain score was 41.4%, 63 (59%) patients continued to show ≥ 30% decrease in pain score at last follow-up, and 60 (56%) reported much or very much improved condition on the PGIC scale at last follow-up (median [range] follow-up period 24 [24–63] months). Eleven device-related complications and 10 permanent explantations were observed. Univariable and multivariable analyses suggested that young age, less sensory disturbance, implantation of cervical leads, treatment of upper-limb pain, and extensive treated regions were associated with satisfactory outcomes at last follow-up after long-term implantation. CONCLUSIONS These findings indicate that SCS may modestly benefit patients with CPSP. SCS has therapeutic potential for patients with intractable CPSP owing to the lower invasiveness of the SCS procedure and refractory nature of CPSP. Nevertheless, trial stimulation is necessary because of the high initial failure rate.

Nociceptive pain involves the activation of nociceptors without damage to the nervous system, whereas neuropathic pain is related to an alteration in the central or peripheral nervous system. Chronic pain itself and the transition from acute to chronic pain may be epigenetically controlled. In this cross-sectional study, a genome-wide DNA methylation analysis was performed using the blood DNA reduced representation bisulfite sequencing (RRBS) technique. Three prospective cohorts including 20 healthy controls (CTL), 18 patients with chronic nociceptive pain (NOCI), and 19 patients with chronic neuropathic pain (NEURO) were compared at both the single CpG and differentially methylated region (DMR) levels. Genes with DMRs were seen in the NOCI and NEURO groups belonged to the neuro-musculoskeletal system and differed between NOCI and NEURO patients. Our results demonstrate that the epigenetic disturbances accompanying nociceptive pain are very different from those accompanying neuropathic pain. In the former, among others, the epigenetic disturbance observed would affect the function of the opioid analgesic system, whereas in the latter it would affect that of the GABAergic reward system. This study presents biological findings that help to characterize NOCI- and NEURO-affected pathways and opens the possibility of developing epigenetic diagnostic assays. Perspectives Our results help to explain the various biological pathways modifications underlying the different clinical manifestations of nociceptive and neuropathic pains. Furthermore, the new targets identified in our study might help to discover more specific treatments for nociceptive or neuropathic pains.

Pregabalin is a first-line treatment option for neuropathic pain. Recently, some cases of pregabalin-induced hypoglycemia have been reported, which can complicate the treatment of neuropathic pain and worsen patient outcomes. Therefore, a better understanding of the clinical condition of patients with pregabalin-induced hypoglycemia is desirable. In this study, we evaluated the risk of hypoglycemia in patients administered pregabalin, using the Japanese Adverse Drug Event Report database. All patients on pregabalin not taking any antidiabetic agents were screened from April 2004 to July 2020, and data on adverse events related to hypoglycemia, sex, age, weight, and the presence of chronic kidney disease were collected. Gabapentin and duloxetine, which are usually indicated for neuropathic pain, were used for comparison. Among 242,275 patients, 4,287 were administered pregabalin, which included 37 patients who reported hypoglycemic incidents. Disproportionality of hypoglycemia was observed in patients administered pregabalin (reporting odds ratio, 2.25; 95% confidence intervals [CI], 1.16-3.13; P < 0.01), whereas this was not the case in patients taking gabapentin and duloxetine. Multivariate logistic regression showed that hypoglycemia in patients on pregabalin was associated with age ≥ 70 years (odds ratio, 2.76; 95% CI, 1.29-5.91; P < 0.01) and weight < 40 kg (odds ratio, 2.97; 95% CI, 1.32-6.71; P < 0.01). These findings suggest that pregabalin may be associated with a higher risk of hypoglycemia, especially in elderly individuals with low body weight. Healthcare providers may need to be aware of pregabalin-induced hypoglycemia in patients with these risk factors during therapy. This article is protected by copyright. All rights reserved.

For centuries, cannabis has been used with many different purposes, including medicinal use, usually bypassing any formal approval process. However, during the last decade, interest in cannabis in medicine has been increasing, and several countries, including the United States and Canada, have produced their own legislation about marihuana and cannabis-based medicines. Because of this, interest in research has been increasing and evidence about its medical effects is becoming necessary. We conducted a review examining the evidence of cannabis in pain. Cannabis had been shown to be useful in acute and chronic pain, however recently, these results have been controverted. Within the different types of chronic pain, it has a weak evidence for neuropathic, rheumatic pain, and headache, modest evidence for multiple sclerosis related pain, and as adjuvant therapy in cancer pain. There is no strong evidence to recommend cannabis in order to decrease opioids in patients with chronic use. Even though cannabis-based medications appear to be mostly safe, mild adverse effects are common; somnolence, sedation, amnesia, euphoric mood, hyperhidrosis, paranoia, and confusion may limit the use of cannabis in clinical practice. Risks have not been systematically analyzed. Special concern arises on how adverse effect might affect vulnerable population such as elderly patients. More research is needed in order to evaluate benefits and risks, as well as the ideal administration route and dosages. As cannabis use increases in several countries, answers to these questions might be coming soon.

Background/Aim. Chronic low back pain syndrome (CLBPS) is the most common cause of functional disability and loss of working ability in developed countries. Some research shows that neuropathic pain (NP) is present in almost 50% of patients with CLPBS. The aim of this study was to determine the characteristics of NP and its impact on quality of life (QoL) in patients with CLBPS. Methods. Patients were tested using three questionnaires for NP: Pain Detect Questionnaire, Leeds Assessment of Neuropathic Symptoms and Signs, and Douleur Neuropathique 4 questions. Thirty-two patients diagnosed with NP based on current clinical criteria and with positive results for NP on all three NP questionnaires formed an experimental group. A control group consisted of 32 patients with CLBPS who did not fulfill clinical criteria for NP and were negative for NP on all three questionnaires. Hamilton depression and anxiety rating scales (Ham-D and Ham-A, respectively) and Short Form (SF)-36 questionnaire were also applied. Results. According to magnetic resonance imaging (MRI), disc herniation was typically detected in the experimental group, while degenerative changes were commonly found in the control group. Patients from the experimental group had significantly greater intensity of pain, pain radiation in the legs, and the pain was usually presented as episodes of sudden attacks with mild pain between them. The most distinctive features of NP were allodynia, electric shock sensation, and hypoesthesia to prick. Patients from the experimental group also had significantly higher depression and anxiety scores, as well as worse QoL compared to the control group, especially in mental domains. Predictors of worse QoL in the patients with CLBPS were a higher level of anxiety and depression. Conclusion. The presence of allodynia, electric shock-like sensations, and hypoesthesia to prick in patients with CLBPS suggest NP. CLBPS patients with NP had worse scores in mental domains of QoL compared to CLPBS patients without NP.

Aim: Chronic postsurgical pain (CPSP) is a common complication of surgery. This study was conducted to evaluate the efficacy and safety of paresthesia-free, 10-kHz spinal cord stimulation (SCS) as a treatment for CPSP. Patients & methods: Subjects in this prospective, single-arm study had an average pain intensity of ≥5 cm on a 10-cm visual analog scale. The subjects who had pain relief of ≥50% (response) with temporary trial stimulation were permanently implanted with 10-kHz SCS and assessed for 1 year. Results: At 12 months, 94% of subjects were responders to 10-kHz SCS, and 88% had pain remission (visual analog scale ≤2.5 cm). Conclusion: The pain relief was durable in CPSP subjects and the safety profile of 10-kHz SCS was as expected. Clinical Trial registration number: VT005076953 (Privacy Commission of Belgium)

Recent studies have revealed that glial sigma-1 receptor (Sig-1R) in the spinal cord may be a critical factor to mediate sensory function. However, the functional role of Sig-1R in astrocyte has not been clearly elucidated. Here, we determined whether Sig-1Rs modulate calcium responses in primary cultured astrocytes and pathological changes in spinal astrocytes, and whether they contribute to pain hypersensitivity in naive mice and neuropathic pain following chronic constriction injury (CCI) of the sciatic nerve in mice. Sig-1R was expressed in glial fibrillary acidic protein (GFAP)-positive cultured astrocytes. Treatment with the Sig-1R agonist, PRE-084 or neurosteroid dehydroepiandrosterone (DHEA) increased intracellular calcium responses in cultured astrocytes, and this increase was blocked by the pretreatment with the Sig-1R antagonist, BD-1047 or neurosteroid progesterone. Intrathecal administration of PRE-084 or DHEA for 10 days induced mechanical and thermal hypersensitivity and increased the number of Sig-1R-immunostained GFAP-positive cells in the superficial dorsal horn (SDH) region of the spinal cord in naive mice, and these changes were inhibited by administration with BD-1047 or progesterone. In CCI mice, intrathecal administration of BD-1047 or progesterone at post-operative day 14 suppressed the developed mechanical allodynia and the number of Sig-1R-immunostained GFAP-positive cells that were increased in the SDH region of the spinal cord following CCI of the sciatic nerve. These results demonstrate that Sig-1Rs play an important role in the modulation of intracellular calcium responses in cultured astrocytes and pathological changes in spinal astrocytes and that administration of BD-1047 or progesterone alleviates the Sig-1R-induced pain hypersensitivity and the peripheral nerve injury-induced mechanical allodynia.

Neuropathic pain (NP) is a chronic pain condition caused by lesion or disease of the somatosensory nervous system. Repetitive transcranial magnetic stimulation (rTMS) is a neuroregulatory tool that uses pulsed magnetic fields to modulate the cerebral cortex. This review aimed to ascertain the therapeutic effect of rTMS on NP and potential factors regulating the therapeutic effect of rTMS. Database search included Web of Science, Embase, Pubmed, and Cochrane Library from inception to July 2021. Eligible studies included randomized controlled studies of the analgesic effects of rTMS in patients with NP. Thirty-eight studies were included. Random effect analysis showed effect sizes of -0.66 (95 % CI, -0.87 to -0.46), indicating that real rTMS was better than sham condition in reducing pain (P < 0.001). This comprehensive review indicated that stimulation frequency, intervention site, and location of lesion were important factors affecting the therapeutic effect. The findings of this study may guide clinical decisions and future research.

Chronic neuropathic pain affects 7%-10% of the population. Deep brain stimulation (DBS) has shown variable but promising results in its treatment. This study prospectively assessed the long-term effectiveness of DBS in a series of patients with chronic neuropathic pain, correlating clinical results with neuroimaging. Sixteen patients received 5 years' post-surgical follow-up in a single center. Six had phantom limb pain after amputation and 10 had deafferentation pain after traumatic brachial plexus injury. Patient-reported outcome measures were completed before and after surgery, using VAS, UWNPS, BPI and SF-36 scores. Neuroimaging evaluated electrode location and effective volumes of activated tissue (VAT). Two subgroups were created based on the percentage of VAT superimposed upon the ventroposterolateral thalamic nucleus (eVAT), and clinical outcomes were compared. Analgesic effect was assessed at 5 years and compared to preoperative pain, with an improvement on VAS of 76.4% (p=0.0001), on UW-NPS of 35.2% (p=0.3582), on BPI of 65.1% (p=0.0505) and on SF-36 of 5% (p=0.7406). Eight patients with higher eVAT showed improvement on VAS of 67.5% (p=0.0017) while the remaining patients, with lower eVAT, improved by 50.6% (p=0.03607). DBS remained effective in improving chronic neuropathic pain after 5 years. While VPL-targeting contributes to success, analgesia is also obtained by stimulating surrounding posterior ventrobasal thalamic structures and related spinothalamocortical tracts.

Neuropathic pain (NP) results from a lesion or disease of the nervous system and accompanied by chronic pain, leading a serious public health issue and economic burden. In terms of the NP mechanisms remaining poorly understood, circular RNAs (circRNAs), owing to their high stability and evolutionary conservation, are expected to be used as potential therapeutic targets or diagnostic biomarkers. In this review, we concisely discuss the characteristics and biological functions of circRNAs. As emerging evidence we reviewed, deregulation of circRNAs (e.g., circ-Filip1l, circHIPK3, ciRS-7, circRNA.2837, circ-Ankib1 and circAnks1a) were involved in NP development. It suggested that specific circRNAs modulated through sponging their target miRNAs and thus regulated the homologous downstream mRNAs and proteins in neuropathic pain. These findings provide a theoretical basis for circRNAs use as biomarkers and therapeutic targets in neuropathic pain.

Objective Patients with instability because of congenital craniovertebral anomalies often have complex C1-C2 osseovascular anomalies. C2 nerve root sacrifice has been described to address such difficult anatomy during posterior C1-C2 fixation and has its own downsides. Its preservation as a recent alternative poses greater surgical challenge, and the considerations differ from other causes of craniovertebral junctional instability; the pertaining outcomes have been scarcely studied. The objective of this study was to prospectively determine the feasibility and outcomes related to C2 nerve root preservation in patients with congenital atlantoaxial dislocation (CAAD) after posterior C1-C2 fixation. Methods In this observational study, 63 patients (126 nerve roots) with CAAD after posterior fixation were prospectively assessed. Underlying osseovascular anomalies affecting the feasibility of C2 nerve root preservation, and C2 nerve–related dysfunction at 12 months follow-up were analyzed. Results The overall C2 nerve root preservation rate was 89.7%. Even in the presence of extreme joint obliquity/spondyloptosis and anomalous vertebral artery, it was feasible in about three fourths. After preservation, 28.3% patients developed new-onset C2 nerve root dysfunction: neuralgia in 2, dysesthesia in 6, and hypoesthesia/paresthesia in 9. The symptoms were not disabling in most patients. Conclusions In most patients with CAAD, C2 nerve root preservation is feasible despite an aberrant bony and vascular anatomy. A few patients after nerve root preservation develop related symptoms that are conservatively manageable, with no significant adverse consequences. Given the controversy in the literature on C2 nerve sacrifice–related outcomes, we favor an attempt at C2 nerve root preservation.

BACKGROUND: Nerve injury can lead to ectopic activation of injured nociceptorsand central sensitization characterized by allodynia and hyperalgesia. Reduction in the activity of primary afferent neurons has been shown to be sufficient in alleviating peripherally generated pain. The cell bodies of such trigeminal nociceptors are located in the trigeminal ganglia (TG) with central processes that terminate in the brainstem trigeminal nucleus caudalis (TNC). The TG is therefore a strategic locus where afferent input can be manipulated. We hypothesized that chemogenetic inhibition of TG would suppress TNC neuronal activity and attenuate pain behaviour in a rat model of painful traumatic trigeminal neuropathy (PTTN). METHODS: Trigeminal neuropathic pain was induced in adult male Sprague–Dawley rats (n = 24) via chronic constriction injury to the infraorbital nerve (ION-CCI). Naïve and sham rats were used as controls (n = 20/group). Rats within each group received TG-directed microinjections of AAV virus containing either the inhibitory hM4Di-DREADD construct or EGFP. RESULTS: In the ION-CCI group, systemic administration of the DREADD agonist clozapine N-oxide (CNO) reversed the hypersensitivity phenotype in animals expressing hM4Di but not EGFP. CNO-mediated activation of hM4Di DREADD in ION-CCI animals was also associated with reduced Fos expression in the TNC elicited by repeated mechanical stimulation of the dermatome ipsilateral to the injury. There was no effect of CNO on pain behaviour or TNC Fos expression in eGFP animals. CONCLUSION: Our results indicate that DREADDs may offer an effective therapeutic approach for treatment of trigeminal neuropathic pain. SIGNIFICANCE: Trigeminal neuropathic pain is highly resistant to therapy and we are in dire need of novel approaches. This study provides further evidence for the successful application of DREADDs as an effective tool for modulating central nervous system function. CNO mediated activation of hM4Di-DREADDs in the trigeminal ganglion (TG) attenuates nerve injury induced neuropathic pain by acting on hyperactive TG cells. It also establishes the TG as an effective target to manage pain in the face and head. Accessing the TG in clinical populations is a relatively simple and safe procedure, making this approach highly significant. Moreover, the methodology described here has applications in trigeminal neuropathic pain from traumatic other etiologies and in spinal neuropathic pain. Chronic pain syndromes are characterized by a progressive failure of brain centers to adequately inhibit pain and as these are identified, we may be able to target them for therapy. Therefore, our findings might have wide application in chronic pain syndromes.

Benefits of phototherapy were characterized in multiple diseases including depression, circadian rhythm disruptions, and neurodegeneration. Studies on migraine and fibromyalgia patients revealed that green light-emitting diodes (GLED) exposure provides a pragmatic and safe therapy to manage chronic pain. In rodents, GLED reversed hypersensitivity related to neuropathic pain. However, little is known about the underlying mechanisms of GLED efficacy. Here, we sought to understand how green light modulates the endogenous opioid system. We first characterized how exposure to GLED stimulates release of β-endorphin and proenkephalin in the central nervous system of male rats. Moreover, by individually editing each of the receptors, we found that µ- and δ-opioid receptors are required for green light's antinociceptive effect in naïve rats and a model of HIV-induced peripheral neuropathy. We investigated how GLED could increase pain thresholds, and explored its potential in reversing hypersensitivity in a model of HIV-related neuropathy. Through behavioral and gene editing approaches, we identified that green light provides antinociception via modulation of the endogenous opioid system in the spinal cord. This work identifies a previously unknown mechanism by which GLED can improve pain management. Clinical translation of these results will advance the development of an innovative therapy devoid of adverse effects. PERSPECTIVE: Development of new pain management therapies, especially for HIV patients, is crucial as long-term opioid prescription is not recommended due to adverse side effects. Green light addresses this necessity. Characterizing the underlying mechanisms of this potentially groundbreaking and safe antinociceptive therapy will advance its clinical translation.

The aim of this study was to evaluate the effects of transcranial direct current stimulation (tDCS) on anxiety-like behavior and neural parameters in rats with chronic pain exposed to alcohol. Thirty-six adult male Wistar rats were randomly assigned to control (CT), neuropathic pain (NP), NPtDCS, NP + alcohol (NPAL), or NPALtDCS groups, subjected to sciatic nerve chronic constriction injury (CCI) and exposed to alcohol (20% v/v solution, 4 g/kg) or vehicle by gavage for 15 days. Afterward, rats were treated using bimodal tDCS (0.5 mA/20 min/8 days) and tested in the open field. Rats were killed 24 h after the last behavioral assessment, and brain and spinal cord tissue samples were collected and processed for NPY immunohistochemistry, expression of Il1a and Il1b in the spinal cord, cerebellum, and hippocampus, and levels of IL-1α and IL-1β in the same brain structures and the striatum. tDCS reverted the anxiety-like behavior induced by CCI and alcohol, and the increased expression of Il1a in the spinal cord induced by alcohol, which increased the expression of Il1b in the cerebellum. In addition, tDCS modulated the hypothalamic NPY-immunoreactivity, increased the levels of IL-1α in the hippocampus (like NP and AL), and increased the expression of Il1b in the spinal cord (like AL). Thus, this study shows that tDCS changes NP and alcohol-induced anxiety-like behavior, possibly through its central modulatory effect of NPY and spinal cord expression of Il1a and Il1b, being considered a treatment option for alcohol and NP-induced anxiety symptoms.

Objectives Pulsed radiofrequency (PRF) stimulation is widely used for intractable pain; however, there is no consensus on treatment protocols and appropriate types of pain. We compared effectiveness of bipolar and unipolar PRF on neuropathic or inflammatory pains, and of targets at the dorsal root ganglion (DRG) and sciatic nerve (SN). We also examined efficacy of repetitive PRF stimulations. This preclinical study could serve as an extensive survey before human trials. Materials Spare nerve injury (SNI)-induced neuropathic pain and complete Freund's adjuvant (CFA) injection-induced inflammatory pain were used. Behavioral responses were measured using von Frey test, acetone test, and Hargreave's test at preinjury and postinjury time points. In both models, we evaluated results of DRG stimulation with unipolar PRF (45 V) versus bipolar PRF (5 V), stimulation at DRG vs. SN, and repetitive stimulations. Results Both unipolar and bipolar PRFs reduced SNI- or CFA-induced pain for a similar duration. In the SNI model, PRF-DRG had a stronger effect on tactile pain than PRF-SN but lower effect on cold allodynia, whereas in the CFA model PRF-DRG and PRF-SN showed similar effects. Repetitive PRF stimulation, by open technique or implantation method, produced analogous effect by each stimulus, and no evident analgesic tolerance or neurological deficit was shown. Conclusions PRF temporarily attenuates neuropathic and inflammatory pain. Bipolar PRF generates significant analgesia with a much lower electrical power than unipolar PRF. Meanwhile, the minor variant effects between PRF-DRG and PRF-SN may indicate distinct mechanisms. The sustained-analgesia by repetitive treatments suggests implantation technique could be a promising choice.

Background Recent studies have suggested that neuropathic pain exhibits a daily diurnal pattern, with peak levels usually occurring in the late afternoon to evening and the trough in the morning hours, although literature on this topic has been sparse. This scoping review examines current evidence on the chronobiology of neuropathic pain both in animal models and in humans with neuropathic pain. Methods A literature search was conducted in major medical databases for relevant articles on the chronobiology of neuropathic pain both in animal models and in humans with neuropathic pain. Data extracted included details of specific animal models or specific neuropathic pain conditions in humans, methods and timing of assessing pain severity, and specific findings of diurnal variation in pain intensity or its surrogate markers. Results Thirteen animal and eight human studies published between 1976 and 2020 were included in the analysis. Seven of the 13 animal studies reported specific diurnal variation in pain intensity, with five of the seven studies reporting a trend toward increased sensitivity to mechanical allodynia or thermal hyperalgesia in the late light to dark phase. All eight studies in human subjects reported a diurnal variation in the intensity of neuropathic pain, where there was an increase in pain intensity through the day with peaks in the late evening and early night hours. Conclusions Studies included in this review demonstrated a diurnal variation in the pattern of neuropathic pain that is distinct from the pattern for nociceptive pain. These findings have implications for potential therapeutic strategies for neuropathic pain.

Chronic pain is caused by cellular damage with an obligatory inflammatory component. In response to noxious stimuli, high levels of ATP leave according to their concentration gradient, the intracellular space through discontinuities generated in the plasma membrane or diffusion through pannexin-1 hemichannels, and activate P2X7Rs localized at peripheral and central immune cells. Because of the involvement of P2X7Rs in immune functions and especially the initiation of macrophage/microglial and astrocytic secretion of cytokines, chemokines, prostaglandins, proteases, reactive oxygen, and nitrogen species as well as the excitotoxic glutamate/ATP, this receptor type has a key role in chronic pain processes. Microglia are equipped with a battery of pattern recognition receptors that detect pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS) from bacterial infections or danger associated molecular patterns (DAMPs) such as ATP. The co-stimulation of these receptors leads to the activation of the NLRP3 inflammasome and interleukin-1β (IL-1β) release. In the present review, we invite you to a journey through inflammatory and neuropathic pain, primary headache, and regulation of morphine analgesic tolerance, in the pathophysiology of which P2X7Rs are centrally involved. P2X7R bearing microglia and astrocyte-like cells playing eminent roles in chronic pain will be also discussed.

Background: Neuropathic pain (NP) is a complex disease that remains challenging to treat. Low-frequency dense-and-disperse (DD) electroacupuncture (EA) has been used as adjuvant therapy for neuropathic pain; however, its analgesic effect decreases as stimulation time increases, or when it is repeatedly used. We hypothesized that a new frequency parameter could improve the effectiveness of EA, and aimed to compare the efficacy and duration of the analgesic effect between classic DD-EA and non-repetitive and non-sequential frequency (random frequency (RF)-EA) in neuropathic rats. Furthermore, the effect of RF-EA at local traditional acupuncture point locations versus auricular vagus nerve stimulation (aVNS) was evaluated. Methods: Male Wistar rats with peripheral neuropathy were subjected to a single session of DD-EA or RF-EA for 20 or 40 min at ST36 + GB34. An additional group of rats was treated with RF-EA for 20 min using aVNS at the appropriate ear point locations. Paw pressure test, von Frey filaments and spontaneous pain scores were evaluated. Sham-operated rats were used as controls. Results: In all, 20 min of RF-EA reversed hyperalgesia (for 24 h) and allodynia (for 8 h), showing a longer analgesic effect than DD-EA. Both RF-EA and DD-EA induced partial inhibition of spontaneous pain for 8 h. Forty minutes of DD-EA did not interfere with the NP phenomena; however, RF-EA induced significant long-term analgesia. aVNS induced an analgesic effect similar to local stimulation. Conclusion: This pilot study shows that RF-EA at both local traditional acupuncture point and auriculotherapy point locations induces long-lasting analgesia in neuropathic rats, and more effectively so than classical DD-EA.

Neuroinflammation is a major contributor to neuropathic pain. Receptor interacting serine/threonine kinase 3 (RIP3) senses cellular stress, promotes inflammatory responses and activates c-Jun N-terminal kinase (JNK) signaling. Here, we assessed the involvement of RIP3-induced JNK signaling in chronic constriction injury (CCI)-induced neuropathic pain. We found that RIP3 inhibitors (GSK’872) and JNK inhibitors (SP600125) not only alleviated the radiant heat response and mechanical allodynia in CCI rats, but also reduced inflammatory factor levels in the lumbar spinal cord. CCI surgery induced RIP3 mRNA and protein expression in the spinal cord. GSK’872 treatment after CCI surgery reduced RIP3 and phosphorylated (p)-JNK expression in the spinal cord, whereas SP600125 treatment after CCI surgery had almost no effect on RIP3. Sinomenine treatment reduced RIP3, p-JNK and c-Fos levels in the spinal cords of CCI rats. These data demonstrated that RIP3 inhibition (particularly via sinomenine treatment) alleviates neuropathic pain by suppressing JNK signaling. RIP3 could thus be a new treatment target in patients with neuropathic pain.

Shingles are triggered by the reactivation of an infection with the varicella zoster virus (VZV) and are characterized by specific vesicular skin lesions. Mostly, elderly patients are affected. Depending on the affected dermatome, some serious complications can be observed. The introduction of a vaccine against shingles in Germany offers a great potential for reducing the frequency and severity of this disease. There are both a live vaccine, which is no longer recommended, and an inactivated vaccine, which, however, is still not sufficiently recommended to the authorized patient groups and is also only available to a limited extent due to delivery bottlenecks. HZ neuralgia is a serious complication of the disease that requires rapid and effective therapy and should be handed over to experienced pain therapists rather too early than too late. Unfortunately, in everyday clinical practice only a few people are familiar with VZV vasculopathy, which is associated with a significantly increased risk of cerebral insults.

Background Dorsal root ganglion (DRG) stimulation, an invasive method of neuromodulation, and transcranial direct current stimulation (tDCS), a non-invasive method of altering cortical excitability, have both proven effective in relieving chronic pain. Objective We employed a randomized, sham-controlled crossover study design to investigate whether single-session tDCS would have an additive therapeutic effect alongside DRG stimulation (DRGS) in the treatment of chronic pain. Methods Sixteen neuropathic pain patients who were previously implanted with DRG stimulators were recruited. Baseline pain scores were established with DRGS-OFF. Pain scores were then recorded with DRGS-ON, after paired sham tDCS stimulation, and after paired active anodal tDCS (a-tDCS) stimulation. For active tDCS, patients were randomized to ‘MEG (magnetoencephalography) localized’ tDCS or contralateral motor cortex (M1) tDCS for 30 min. EEG recordings and evaluations of tDCS adverse effects were also collected. Results All participants reported the interventions to be tolerable with no significant adverse effects during the session. Paired DRGS/active tDCS resulted in a significant reduction in pain scores compared to paired DRGS-ON/sham tDCS or DRGS alone. There was no difference in the additive effect of M1 vs. MEG-localized tDCS. Significant augmentation of beta activity was observed between DRGS-OFF and DRGS-ON conditions, as well as between paired DRGS-ON/sham tDCS and paired DRGS-ON/active tDCS. Conclusion Our results indicate that a single session of tDCS alongside DRGS is safe and can significantly reduce pain acutely in neuropathic pain patients. Paired invasive/non-invasive neuromodulation is a promising new treatment strategy for pain management and should be evaluated further to assess long-term benefits.

OBJECTIVES: Intravenous lidocaine can alleviate painful diabetic peripheral neuropathy (DPN) in some patients. Whether quantitative sensory testing (QST) can identify treatment responders have not been prospectively tested. METHODS: This was a prospective, randomized, double-blind, crossover, placebo-controlled trial comparing intravenous lidocaine to normal saline (placebo) for painful DPN. Thirty-four participants with painful DPN were enrolled and given intravenous lidocaine (5 mg/kg ideal body weight) or placebo as a 40-minute infusion, after a battery of QST parameters were tested on the dorsal foot, with a three-week washout period between infusions. RESULTS: Thirty-one participants completed both study sessions and were included in the final analysis. Lidocaine resulted in a 51% pain reduction 60-120 minutes after infusion initiation, as assessed on a 0-10 numerical rating scale, while placebo resulted in a 33.5% pain reduction (difference = 17.6%, 95% CI 1.9-33.3%, p = 0.03). Neither mechanical pain threshold, heat pain threshold, nor any of the other measured QST parameters predicted the response to treatment. Lidocaine administration reduced mean Neuropathic Pain Symptom Inventory paresthesia/dysesthesia scores when compared to placebo by 1.29 points (95% CI −2.03 to −0.55, p = 0.001), and paroxysmal pain scores by 0.84 points (95% CI −1.62 to −0.56, p = 0.04), without significant changes in burning, pressing or evoked pain sub-scores. DISCUSSION: While some participants reported therapeutic benefit from lidocaine administration, QST measures alone were not predictive of response to treatment. Further studies, powered to test more complex phenotypic interactions, may be required to identify reliable predictors of response to pharmacotherapy in patients with DPN.