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In neuropathic pain clinical trials, the patient's perspective is often insufficiently reflected focusing mainly on pain intensity. Comparability of outcome assessment is limited due to heterogenous patient reported outcome measures (PROMs). The MEDLINE, CENTRAL, and Embase databases and reference lists of published meta-analyses were searched. Randomized controlled studies assessing treatment efficacy of drugs for chronic neuropathic pain were included. PROMs were assigned to recommended IMMPACT/NeuPSIG domains: pain intensity, pain other aspects, physical functioning, emotional functioning, global improvement and satisfaction, adverse events, participant disposition. Domains and PROMs were compared regarding the publication year and methodological quality of the studies. Within the 251 included studies 200 PROMs were used with 27 being recommended by IMMPACT/NeuPSIG. The number of domains was higher in high/moderate quality studies. The (sub-) domains 'physical functioning', 'global improvement and satisfaction', and 'neuropathic pain quality' were assessed more frequently in high/moderate quality studies and those published after 2011. Recent studies and those of better quality more often used the recommended PROMs. Although neuropathic assessment via PROMs has improved, there is still a high heterogeneity. A standardized core set of outcome domains and should be defined to improve neuropathic pain treatment and to achieve better comparability of clinical trials. Perspective: This systematic literature review assesses the use of patient reported outcome measures (PROMs) in chronic neuropathic pain. The results show that there is still a high heterogeneity, highlighting the need for a standardized core set of outcome domains and PROMs to improve comparability of clinical trials and neuropathic pain treatment.

Aim. To study the Bcl-2 level in mitochondria of various organs in female mice with standard and stimulated growth of an experimental B16/F10 melanoma.Materials and methods. The study included С57ВL/6 female mice (n = 168). The experimental animals were divided into the following groups: an intact group (n = 21), a group with modelled chronic neuropathic pain (CNP) (n = 21), an M group with B16/F10 melanoma (n = 63), and a CNP + M group (n = 63). The Bcl-2 concentration (ng / mg protein) in mitochondrial samples was determined by ELISA (Thermo Fisher Scientific, Austria). Statistical analysis of the results was carried out using Statistica 10.0.Results. Compared to the Bcl-2 levels in the intact animals, CNP decreased this parameter in the cardiac mitochondria by 1.3 times, while increasing it by 5.9 times in the skin mitochondria. In the dynamics of standard melanoma growth, the Bcl-2 content changed compared with the corresponding intact values in the mitochondria of the brain, heart, and skin, but did not change in the liver and kidneys. In the mitochondria in melanoma, the Bcl-2 levels were high throughout the entire period of standard tumor growth in comparison with the intact skin. The stimulated melanoma growth in CNP was involving more organs into the pathological process as the tumor was growing. Thus, in comparison with the values in the CNP group, the mitochondrial Bcl-2 levels changed in the heart at week 1; in the heart and skin – at week 2; in the heart, skin, and brain – at week 3. The Bcl-2 levels did not change in the liver and kidney mitochondria. In the mitochondria in the CNP-stimulated melanoma, the Bcl-2 levels were lower than in the skin mitochondria in CNP throughout the entire tumor growth period.Conclusion. The liver and kidney mitochondria are somewhat Bcl-2 stable in both standard and stimulated tumor growth. It is assumed that different Bcl-2 dynamics in the mitochondria in melanoma depending on the variant of tumor development reflects the modulating effect of CNP and the ability to change the Bcl-2 levels according to the growth phase.

The prelimbic division (PrL) of the medial prefrontal cortex (mPFC) is a cerebral division that is putatively implicated in the chronic pain and depression. We investigated the activity of PrL cortex neurons in Wistar rats that underwent chronic constriction injury (CCI) of sciatic nerve and were further subjected to the forced swimming (FS) test and mechanical allodynia (by von Frey test). The effect of blockade of synapses with cobalt chloride (CoCl2), and the treatment of the PrL cortex with cannabidiol (CBD), the CB1 receptor antagonist AM251 and the 5-HT1A receptor antagonist WAY-100635 were also investigated. Our results showed that CoCl2 decreased the time spent immobile during the FS test but did not alter mechanical allodynia. CBD (at 15, 30 and 60 nmol) in the PrL cortex also decreased the frequency and duration of immobility; however, only the dose of 30 nmol of CBD attenuated mechanical allodynia in rats with chronic NP. AM251 and WAY-100635 in the PrL cortex attenuated the antidepressive and analgesic effect caused by CBD but did not alter the immobility and the mechanical allodynia when administered alone. These data show that the PrL cortex is part of the neural substrate underlying the comorbidity between NP and depression. Also, the previous blockade of CB1 cannabinoid receptors and 5-HT1A serotonergic receptors in the PrL cortex attenuated the antidepressive and analgesics effect of the CBD. They also suggest that CBD could be a potential medicine for the treatment of depressive and pain symptoms in patients with chronic NP/depression comorbidity.

Objectives: The aim of this study is to study the modulation of extracellular signal-regulated protein kinase (ERK) and tissue inhibitors of matrix metalloproteases 1 (TIMP 1) gene in patients with neuropathic pain (NP). Materials and Methods: In the present, cross-sectional, observational study, 2 ml of venous baseline sample was withdrawn from all the patients with neuropathic (NP) or non NP (NNP) soon after their diagnosis or on their first visit to the pain clinic. A real-time quantitative polymerase chain reaction experiment was conducted to measure the mRNA expression of TIMP1 and ERK genes in blood samples. The Delta Ct, Delta Ct, and fold change analysis of both the genes were conducted between patients with NP and NNP. Results: A total of 285 patients with chronic pain were assessed, out of which, 153 patients had NP and 132 had NNP. The average duration of chronic pain was 11 months for 285 patients. The mRNA expression of TIMP1 gene is significantly down regulated (2.65-fold) (P (-f. 01), and the mRNA expression level of ERK is significantly up regulated (2.03-fold) (P (-f. 01) in NP patients when compared with NNP. Conclusion: The mRNA expression of TIMP1 gene is significantly down regulated, and ERK is significantly up regulated in patients with NP. Further, multicentric trials with larger sample size are recommended to confirm this finding.

Several different reporting biases cited in scientific literature have raised concerns about the overestimation of effects and the subsequent potential impact on the practice of evidence-based medicine and human health. Up to 7-8% of the population experiences neuropathic pain, and established treatment guidelines are based predominately on published, clinical trial results. Therefore, we examined published randomized controlled trials (RCTs) of first-line drugs for neuropathic pain and assessed the relative proportions with statistically significant (i.e., positive) and non-significant (i.e., negative) results and their rates of citation. We determined the relationships between reported study outcome and the frequency of their citations with journal impact factor, sample size, time to publication after study completion, and study quality metrics. We also examined the association of study outcome with maximum study drug dosage and conflict of interest. We found that of 107 published RCTs, 68.2% reported a statistically significant outcome regarding drug efficacy for chronic peripheral and central neuropathic pain. Positive studies were cited nearly twice as often as negative studies in the literature (P=0.01), despite similar study sample size, quality metrics, and publication in journals with similar impact factors. The time to publication, journal impact factor, and conflict of interest did not differ statistically between positive and negative studies. Our observations that negative and positive RCTs were published in journals with similar impact at comparable time-lags after study completion are encouraging. However, the citation bias for positive studies could affect the validity and generalization of conclusions in literature and potentially influence clinical practice.

Chronic pain is common after burn injuries, and post-burn neuropathic pain is the most important complication that is difficult to treat. Scrambler therapy (ST) is a non-invasive modality that uses patient-specific electrocutaneous nerve stimulation and is an effective treatment for many chronic pain disorders. This study used magnetic resonance imaging (MRI) to evaluate the pain network-related mechanisms that underlie the clinical effect of ST in patients with chronic burn-related pain. This prospective, double-blinded, randomized controlled trial (ClinicalTrials.gov: NCT03865693) enrolled 43 patients who were experiencing chronic neuropathic pain after unilateral burn injuries. The patients had moderate or greater chronic pain (a visual analogue scale (VAS) score of ≥5), despite treatment using gabapentin and other physical modalities, and were randomized 1:1 to receive real or sham ST sessions. The ST was performed using the MC5-A Calmare device for ten 45 min sessions (Monday to Friday for 2 weeks). Baseline and post-treatment parameters were evaluated subjectively using the VAS score for pain and the Hamilton Depression Rating Scale; MRI was performed to identify objective central nervous system changes by measuring the cerebral blood volume (CBV). After 10 ST sessions (two weeks), the treatment group exhibited a significant reduction in pain relative to the sham group. Furthermore, relative to the pre-ST findings, the post-ST MRI evaluations revealed significantly decreased CBV in the orbito-frontal gyrus, middle frontal gyrus, superior frontal gyrus, and gyrus rectus. In addition, the CBV was increased in the precentral gyrus and postcentral gyrus of the hemisphere associated with the burned limb in the ST group, as compared with the CBV of the sham group. Thus, a clinical effect from ST on burn pain was observed after 2 weeks, and a potential mechanism for the treatment effect was identified. These findings suggest that ST may be an alternative strategy for managing chronic pain in burn patients.

Emerging evidence has shown that protocatechuic acid (PCA) has antioxidant and anti-inflammatory effects. Evidence suggests that PCA can alleviate the injury of sciatic nerve, while the mechanism of its therapeutic effect on neuralgia remains unknown. Chromium bowel ligation was used in vivo to establish a chronic constriction injury (CCI) rat model to induce sciatic nerve pain. Subsequently, two doses of PCA were used to treat CCI rats. In vitro, 10 ng/mL TNF-α was used to stimulate glial satellite cells derived from the dorsal root ganglia (DRG) L4-L6 of the sciatic nerve to simulate sciatic nerve pain. PCA relieved mechanical allodynia and thermal hyperalgesia in CCI rats. CCK-8 assay revealed that PCA inhibited the proliferation of glial satellite cells induced by TNF-α. Moreover, ELISA demonstrated that PCA could improve the inflammatory response of rats caused by CCI and cells induced by TNF-α. Next, RT-qPCR and Western blot assays showed that PCA blocked the c-Jun N-terminal kinase/the chemokine ligand 1/CXC chemokine receptor 2 (JNK/CXCL1/CXCR2) pathway by inhibiting CXCL1 levels in cells induced by TNF-α and DRG in CCI rats. In conclusion, PCA can alleviate neuropathic pain in CCI rats and improve oxidative stress by inhibiting the JNK/CXCL1/CXCR2 signaling pathway. Thus, these findings provide a new perspective for the treatment of neuropathic pain caused by CCI.

Acute pain serves as a protective mechanism that alerts us to potential tissue damage and drives a behavioural response that removes us from danger. The neural circuitry critical for mounting this behavioural response is situated within the brainstem and is also crucial for producing analgesic and hyperalgesic responses. In particular, the periaqueductal grey, rostral ventromedial medulla, locus coeruleus and subnucleus reticularis dorsalis are important structures that directly or indirectly modulate nociceptive transmission at the primary nociceptive synapse. Substantial evidence from experimental animal studies suggests that plasticity within this system contributes to the initiation and/or maintenance of chronic neuropathic pain, and may even predispose individuals to developing chronic pain. Indeed, overwhelming evidence indicates that plasticity within this circuitry favours pro-nociception at the primary synapse in neuropathic pain conditions, a process that ultimately contributes to a hyperalgesic state. Although experimental animal investigations have been crucial in our understanding of the anatomy and function of the brainstem pain-modulation circuitry, it is vital to understand this system in acute and chronic pain states in humans so that more effective treatments can be developed. Recent functional MRI studies have identified a key role of this system during various analgesic and hyperalgesic responses including placebo analgesia, offset analgesia, attentional analgesia, conditioned pain modulation, central sensitisation and temporal summation. Moreover, recent MRI investigations have begun to explore brainstem pain-modulation circuitry plasticity in chronic neuropathic pain conditions and have identified altered grey matter volumes and functioning throughout the circuitry. Considering the findings from animal investigations, it is likely that these changes reflect a shift towards pro-nociception that ultimately contributes to the maintenance of neuropathic pain. The purpose of this review is to provide an overview of the human brain imaging investigations that have improved our understanding of the pain-modulation system in acute pain states and in neuropathic conditions. Our interpretation of the findings from these studies is often guided by the existing body of experimental animal literature, in addition to evidence from psychophysical investigations. Overall, understanding the plasticity of this system in human neuropathic pain conditions alongside the existing experimental animal literature will ultimately improve treatment options.

While numerous studies and patient experiences have demonstrated the efficacy of spinal cord stimulation as a treatment for chronic neuropathic pain, the exact mechanism underlying this therapy is still uncertain. Recent studies highlighting the importance of microglial cells in chronic pain and characterizing microglial activation transcriptomes have created a focus on microglia in pain research. Our group has investigated the modulation of gene expression in neurons and glial cells after spinal cord stimulation (SCS), specifically focusing on transcriptomic changes induced by varying SCS stimulation parameters. Previous work showed that, in rodents subjected to the spared nerve injury (SNI) model of neuropathic pain, a differential target multiplexed programming (DTMP) approach provided significantly better relief of pain-like behavior compared to high rate (HRP) and low rate programming (LRP). While these studies demonstrated the importance of transcriptomic changes in SCS mechanism of action, they did not specifically address the role of SCS in microglial activation. The data presented herein utilizes microglia-specific activation transcriptomes to further understand how an SNI model of chronic pain and subsequent continuous SCS treatment with either DTMP, HRP, or LRP affects microglial activation. Genes for each activation transcriptome were identified within our dataset and gene expression levels were compared with that of healthy animals, naïve to injury and interventional procedures. Pearson correlations indicated that DTMP yields the highest significant correlations to expression levels found in the healthy animals across all microglial activation transcriptomes. In contrast, HRP or LRP yielded weak or very weak correlations for these transcriptomes. This work demonstrates that chronic pain and subsequent SCS treatments can modulate microglial activation transcriptomes, supporting previous research on microglia in chronic pain. Furthermore, this study provides evidence that DTMP is more effective than HRP and LRP at modulating microglial transcriptomes, offering potential insight into the therapeutic efficacy of DTMP.

Chronic neuropathic pain (CNP) is a disabling medical condition that impairs the health-related quality-of-life of affected patients. A high prevalence of anxiety, depression, sleep disturbance and cognitive impairment has frequently been reported in association with CNP, making the management of this disease complex and often multidisciplinary. Dual-acting agents such as selective serotonin and noradrenalin reuptake inhibitors (SNRIs) are considered particularly useful in the modulation of pain and in treatment of the mood disorders frequently associated with CNP. Recent evidence suggests that the top-down inhibitory control of pain involves the engagement and enhancement of descending endogenous opioidergic, cannabinoid and serotonergic systems, with the effect of serotonin being particularly related to the receptor subtypes that are preferentially activated; indeed serotonin induces analgesia via activation of 5-HT7 receptors and hyperalgesia via activation of 5-HT3 receptors. Vortioxetine (VO) is a novel multimodal serotonergic antidepressant with a unique mechanism of action. It has been demonstrated recently in experimental and clinical studies to have efficacy on pain hypersensitivity and on mood disorders. This drug inhibits the serotonin transporter with a high affinity, antagonises the 5-HT3, 5-HT1D and 5HT7 serotonin receptors, and activates the 5-HT1A and 5-HT1B receptors. In clinical studies, VO has proved effective at a dose of 10–20 mg/daily in short- and long-term treatment of patients with chronic orofacial pain, demonstrating a higher rate of clinical response and remission, a better acceptability, safety rate and tolerability, and a lower latency of action compared with other antidepressants. In the light of these recent findings, VO may be considered as a new pharmacological treatment also in relation to various types of CNP, particularly in elderly patients with concomitant mood disorders and cognitive impairment. The purpose of this review is to provide an up-to-date overview of the pharmacology and clinical applications of VO and to highlight its potential therapeutic properties and advantages in the management of CNP.

The management of chronic neuropathic pain remains a challenge, because pain is subjective, and measuring it objectively is usually out of question. However, neuropathic pain is also a signal provided by maladaptive neuronal activity. Thus, the integral management of chronic neuropathic pain should not only rely on the subjective perception of the patient, but also on objective data that measures the evolution of neuronal activity. We will discuss different objective and subjective methods for the characterization of neuropathic pain. Additionally, the gaps and proposals for an integral management of chronic neuropathic pain will also be discussed. The current management that relies mostly on subjective measures has not been sufficient, therefore, this has hindered advances in pain management and clinical trials. If an integral characterization is achieved, clinical management and stratification for clinical trials could be based on both questionnaires and neuronal activity. Appropriate characterization may lead to an increased effectiveness for new therapies, and a better quality of life for neuropathic pain sufferers.

Spinal cord stimulation is a proven effective therapy for treating chronic neuropathic pain. Previous work in our laboratory demonstrated that spinal cord stimulation based on a differential target multiplexed programming approach provided significant relief of pain-like behavior in rodents subjected to the spared nerve injury model of neuropathic pain. The relief was significantly better than obtained using high rate and low rate programming. Furthermore, transcriptomics-based results implied that differential target multiplexed programming modulates neuronal–glial interactions that have been perturbed by the pain process. Although differential target multiplexed programming was developed to differentially target neurons and glial cells, our previous work did not address this. This work presents transcriptomes, specific to each of the main neural cell populations (neurons, microglia, astrocytes, and oligodendrocytes), obtained from spinal cord subjected to continuous spinal cord stimulation treatment with differential target multiplexed programming, high rate programming, or low rate programming compared with no spinal cord stimulation treatment, using the spared nerve injury model. To assess the effect of each spinal cord stimulation treatment on these cell-specific transcriptomes, gene expression levels were compared with that of healthy animals, naïve to injury and interventional procedures. Pearson correlations and cell population analysis indicate that differential target multiplexed programming yielded strong and significant correlations to expression levels found in the healthy animals across every evaluated cell-specific transcriptome. In contrast, high rate programming only yielded a strong correlation for the microglia-specific transcriptome, while low rate programming did not yield strong correlations with any cell types. This work provides evidence that differential target multiplexed programming distinctively targeted and modulated the expression of cell-specific genes in the direction of the healthy state thus supporting its previously established action on regulating neuronal–glial interaction processes in a pain model.

Mesocorticolimbic dopaminergic (DA) neurons have been implicated in regulating nociception in chronic pain, yet the mechanisms are barely understood. Here, we found that chronic constructive injury (CCI) in mice increased the firing activity and decreased the KCNQ channel-mediated M-currents in ventral tegmental area (VTA) DA neurons projecting to the nucleus accumbens (NAc). Chemogenetic inhibition of the VTA-to-NAc DA neurons alleviated CCI-induced thermal nociception. Opposite changes in the firing activity and M-currents were recorded in VTA DA neurons projecting to the medial prefrontal cortex (mPFC) but did not affect nociception. In addition, intra-VTA injection of retigabine, a KCNQ opener, while reversing the changes of the VTA-to-NAc DA neurons, alleviated CCI-induced nociception, and this was abolished by injecting exogenous BDNF into the NAc. Taken together, these findings highlight a vital role of KCNQ channel-mediated modulation of mesolimbic DA activity in regulating thermal nociception in the chronic pain state.

Bo Fu,1 Shao-Nan Wen,1 Bin Wang,1 Kun Wang,2 Ji-Yan Zhang,3 Xie-Chuan Weng,1 Shao-Jun Liu1 1State Key Laboratory of Proteomics, Department of Neurobiology, Institute of Military Cognitive and Brain Sciences, Academy of Military Medical Sciences, Beijing 100850, China; 2Department of Occupational Medicine, Tianjin Institute of Environmental and Occupational Medicine, Tianjin 300050, China; 3Department of Molecular Immunology, Institute of Military Cognitive and Brain Sciences, Academy of Military Medical Sciences, Beijing 100850, China Purpose: Ventral tegmental area (VTA) dopamine system plays an important role in depression and is also involved in pain experience. In this study, we investigated the VTA dopaminergic (DA) neuron firing and local field potential (LFP) in pain-related depression, and we try to explore the underlying relationship between pain and depression.Materials and methods: We used neuropathic pain model [spare nerve injury (SNI)] to induce pain-related depression. The Dixon up–down method was used to test mechanical hypersensitivity. Behavioral changes like open field test, sucrose preference test, and forced swim test were used to test depression-like behaviors. Gabapentin (GBP) was used to explore the chronic analgesic treatment that could reverse pain-related depression. To investigate the in vivo variations of VTA DA neuron firing and LFP, multichannel acquisition processor system was used.Results: We used SNI to induce depression-like behaviors. Repeated GBP treatment reversed these behaviors after 14 days of injection. An in vivo electrophysiological analysis of the firing characteristics of VTA DA neurons and LFP revealed that SNI increased the firing rate of DA neurons, but not the burst firing activity. Surprisingly, chronic GBP reversed the firing rate of DA neurons and reduced the burst firing activity. Moreover, SNI increased the LFP power in delta and theta oscillation and decreased it in beta oscillation. Repeated administration of GBP significantly suppressed theta oscillation. Above all, chronic GBP altered these characteristics to reverse depression-like behaviors.Conclusion: The present study confirmed that the tonic firing activity of VTA DA neurons, but not the burst firing activity, was the key factor in peripheral neuropathy–induced depression. Chronic GBP regulated the firing pattern of DA neurons and decreased theta oscillation in VTA to treat pain-related depression. This variation tendency of electrophysiological characteristics of VTA DA neurons and theta oscillation in VTA might represent an attempt to cope with pain-related negative mood disorder. Keywords: chronic neuropathic pain, depression, dopaminergic neuron, LFP, VTA

BackgroundA sex-difference in susceptibility to chronic pain is well-known. Although recent studies have begun to reveal the sex-dependent mechanisms of nerve injury-induced pain sensitization, sex differences in the affective and cognitive brain dysfunctions associated with chronic pain have not been investigated. Therefore, we tested whether chronic pain leads to affective and cognitive disorders in a mouse neuropathic pain model and whether those disorders are sexually dimorphic.MethodsChronic neuropathic pain was induced in male and female mice by L5 spinal nerve transection (SNT) injury. Pain sensitivity was measured with the von Frey test. Affective behaviors such as depression and anxiety were assessed by the forced swim, tail suspension, and open field tests. Cognitive brain function was assessed with the Morris water maze and the novel object location and novel object recognition tests.ResultsMechanical allodynia was induced and maintained for up to 8 weeks after SNT in both male and female mice. Depressive- and anxiety-like behaviors were observed 8 weeks post-SNT injury regardless of sex. Chronic pain-induced cognitive deficits measured with the Morris water maze and novel object location test were seen only in male mice, not in female mice.ConclusionsChronic neuropathic pain is accompanied by anxiety- and depressive-like behaviors in a mouse model regardless of sex, and male mice are more vulnerable than female mice to chronic pain-associated cognitive deficits.

Contains fulltext : 219586.pdf (Publisher’s version ) (Open Access) Objective: Invasive motor cortex stimulation (iMCS) has been proposed as a treatment for intractable neuropathic pain syndromes. Although the mechanisms underlying the analgesic effect of iMCS remain largely elusive, several studies found iMCS-related changes in regional cerebral blood flow (rCBF) in neuropathic pain patients. The aim of this study was to meta-analyze the findings of neuroimaging studies on rCBF changes to iMCS. Methods: PubMed, Embase, MEDLINE, Google Scholar, and the Cochrane Library were systematically searched for retrieval of relevant scientific papers. After initial assessment of relevancy by screening title and abstract by two investigators, independently, predefined inclusion and exclusion criteria were used for final inclusion of papers. Descriptive results were statistically assessed, whereas coordinates were pooled and meta-analyzed in accordance with the activation likelihood estimation (ALE) methodology. Results: Six studies were included in the systematic narrative analysis, suggesting rCBF increases in the cingulate gyrus, thalamus, insula, and putamen after switching the MCS device "ON" as compared to the "OFF" situation. Decreases in rCBF were found in for example the precentral gyrus and different occipital regions. Two studies did not report stereotactic coordinates and were excluded from further analysis. ALE meta-analysis showed that, after switching the iMCS electrode "ON," increased rCBF occurred in the (1) anterior cingulate gyrus; (2) putamen; (3) cerebral peduncle; (4) precentral gyrus; (5) superior frontal gyrus; (6) red nucleus; (7) internal part of the globus pallidus; (8) ventral lateral nucleus of the thalamus; (9) medial frontal gyrus; (10) inferior frontal gyrus; and (11) claustrum, as compared to the "OFF" situation. Reductions in rCBF were found in the posterior cingulate gyrus when the iMCS electrode was turned "OFF." Conclusions: These findings suggested that iMCS induces changes in principal components of the default mode-, the salience-, and sensorimotor network. 8 p.

Background High frequency stimulation (HFS) may provide pain relief without the paresthesias typical of traditional low-frequency Spinal cord stimulation (SCS). Methods A consecutive single-center series of patients was retrospectively reviewed to evaluate safety and efficacy of HF10 therapy. In this 24-month study, 62 patients with variables pathologies (44 patients with back failure surgery syndrome (FBSS), 18 patients with chronic peripheral neuropathic pain in the lower limbs (NeppL) were included to be treated with HF10. Pain outcomes were compared from preoperative baseline and at the conclusion of each study period. Clinical features, outcomes and complications were reviewed. Results 62 patients completed this study. All patients had a successful trial before the definitive implantation of a spinal cord stimulator at the low dorsal level. The mean follow-up period was 11 months, ranging from 6 to 24 months. 6 patients showed no change from baseline visual analogue scale (VAS) after permanent implant and 2 had improved during the trial but was aggravated after the permanent implant placement. At 1 month, 63% of implanted HF10 therapy subjects were responders and 77% at 6 months. The average baseline, trial and postoperative Visual Analogue Scale (VAS) was 8.1, 3.6 and 4.2 respectively. When compared to the baseline, the average reduction achieved during the VAS trial was 4.5 points, accounting for a 56% pain reduction. The long-term failure rate was 22%. Conclusions This study generated preliminary evidence showing improved VAS current pain scores in absence of paresthesias and increase patient satisfaction with HF10 spinal cord stimulation.

Patients suffering from chronic pain may benefit from learning adaptive coping strategies. Consensus on efficient strategies for this group of patients is, however, lacking, and previous studies have shown inconsistent results. The present study has examined coping strategies in two distinctly different groups of chronic pain patients and a group of healthy controls. Thirty neuropathic pain (NP) patients, 28 fibromyalgia (FM) patients, and 26 pain-free healthy controls completed the Coping Strategy Questionnaire (CSQ-48/27) and rated their daily pain. The results showed that FM and NP patients did not cope differently with pain. The only difference between the groups was that FM patients felt more in control of their pain than NP patients. Both patient groups used more maladaptive/passive coping strategies, but surprisingly also more adaptive/active coping strategies than healthy controls. However, FM patients with high levels of passive strategies felt less in control than FM patients with low levels of passive strategies. This was not seen in NP patients. An important implication for clinical practice is therefore that passive coping strategies should be restructured into active ones, especially for FM patients. Otherwise, the same psychological treatment model can be applied to both groups since they use similar coping styles.

Highlights • Regional brain gray matter morphology robustly predict TN radiosurgery response. • Surface area ML model was 96.7% accurate, 100.0% sensitive, and 89.1% specific. • Top predictor for surface area model was contralateral superior frontal gyrus. • Cortical thickness ML model was 90.5% accurate, 93.5% sensitive, and 83.7% specific. • Top predictor for cortical thickness model was contralateral isthmus cingulate gyrus., Background Trigeminal neuralgia, a severe chronic neuropathic pain disorder, is widely believed to be amenable to surgical treatments. Nearly 20% of patients, however, do not have adequate pain relief after surgery. Objective tools for personalized pre-treatment prognostication of pain relief following surgical interventions can minimize unnecessary surgeries and thus are of substantial benefit for patients and clinicians. Purpose To determine if pre-treatment regional brain morphology-based machine learning models can prognosticate 1 year response to Gamma Knife radiosurgery for trigeminal neuralgia. Methods We used a data-driven approach that combined retrospective structural neuroimaging data and support vector machine-based machine learning to produce robust multivariate prediction models of pain relief following Gamma Knife radiosurgery for trigeminal neuralgia. Surgical response was defined as ≥ 75% pain relief 1 year post-treatment. We created two prediction models using pre-treatment regional brain gray matter morphology (cortical thickness or surface area) to distinguish responders from non-responders to radiosurgery. Feature selection was performed through sequential backwards selection algorithm. Model out-of-sample generalizability was estimated via stratified 10-fold cross-validation procedure and permutation testing. Results In 51 trigeminal neuralgia patients (35 responders, 16 non-responders), machine learning models based on pre-treatment regional brain gray matter morphology (14 regional surface areas or 13 regional cortical thicknesses) provided robust a priori prediction of surgical response. Cross-validation revealed the regional surface area model was 96.7% accurate, 100.0% sensitive, and 89.1% specific while the regional cortical thickness model was 90.5% accurate, 93.5% sensitive, and 83.7% specific. Permutation testing revealed that both models performed beyond pure chance (p

JUSTIFICATIVA E OBJETIVOS: O uso da estimulação elétrica de nervos periféricos para o tratamento da dor crônica constitui um armamentário neurocirúrgico utilizado há bastante tempo, sendo uma modalidade indicada no tratamento das síndromes dolorosas de caráter neuropático, juntamente com outras formas de neuroestimulação: estimulação elétrica da coluna dorsal e a estimulação cerebral profunda. O objetivo deste estudo foi analisar a relevância da estimulação nervosa periférica no tratamento das síndromes dolorosas crônicas. CONTEÚDO: A principal indicação é a dor neuropática crônica, intensa, refratária ao tratamento conservador. Apresenta, contudo, necessidade de a área acometida ter uma distribuição anatômica definida e relacionada ao nervo periférico no qual se deseja realizar a estimulação. Deve-se perceber também sinais de comprometimentoobjetivo do nervo. É necessária a realização de teste de neuroestimulação entre 7 e 10 dias previamente ao implante definitivo e deve-se obter melhora de pelo menos 50% da dor em escalas de avaliação específicas. Existem duas formas de implante de eletrodo em nervos periféricos: abordagem cirúrgica direta e técnica percutânea. Após o teste ser completado, é realizado o implante do sistema de gerador permanente. CONCLUSÃO: O uso da estimulação de nervos periféricos no tratamento das síndromes dolorosas crônicas tem mostrado resultados promissores. O desenvolvimento de novos materiais é extremamente necessário para a evolução da técnica e o tratamento dessas síndromes dolorosas crônicas. Nesse sentido, novas próteses estão sendo desenvolvidas e uma das características de implante mais viável para uso no sistema nervoso periférico seria uma prótese de baixo perfil, com bateria já implantada com os eletrodos e recarregável.

Neuropathic pain is clinically described as pain caused by a lesion or disease of the somatosensory nervous system. The aim of this study was to assess the validity of the Dutch version of the DN4, in a cross-sectional multicentre design, as a screening tool for detecting a neuropathic pain component in a large consecutive, not pre-stratified on basis of the target outcome, population of patients with chronic pain. Patients' pain was classified by two independent (pain-) physicians as the gold standard. The analysis was initially performed on the outcomes of those patients (n = 228 out of 291) in whom both physicians agreed in their pain classification. Compared to the gold standard the DN4 had a sensitivity of 75% and specificity of 76%. The DN4-symptoms (seven interview items) solely resulted in a sensitivity of 70% and a specificity of 67%. For the DN4-signs (three examination items) it was respectively 75% and 75%. In conclusion, because it seems that the DN4 helps to identify a neuropathic pain component in a consecutive population of patients with chronic pain in a moderate way, a comprehensive (physical-) examination by the physician is still obligate.

The interaction of nurses with chronic pain patients is often difficult. One of the reasons is that chronic pain is difficult to explain, because no obvious anatomic defect or tissue damage is present. There is now enough evidence available indicating that chronic pain syndromes such as low back pain, whiplash, and fibromyalgia share the same pathogenesis, namely, sensitization of pain modulating systems in the central nervous system. Sensitization is a neuropathic pain mechanism in which neurophysiologic changes may be as important as behavioral, psychologic, and environmental mechanisms. The sensitization model provides nurses with an opportunity to explain pain as a physical cause related to changes in the nervous system. This explanation may improve the patient's motivation to discuss the importance of psychosocial factors that contribute to the maintenance of chronic pain. In this article, sensitization is described as a model that can be used for the explanation of the existence of chronic pain. The sensitization model is described using a metaphor. The sensitization model is a useful tool for nurses in their communication and education toward patients. (C) 2012 by the American Society for Pain Management Nursing

Elevated spinal extracellular gamma-aminobutyric acid (GABA) levels have been described during spinal cord stimulation (SCS)-induced analgesia in experimental chronic peripheral neuropathy. Interestingly, these increased GABA levels strongly exceeded the time frame of SCS-induced analgesia. In line with the former, pharmacologically-enhanced extracellular GABA levels by GABA(B) receptor agonists in combination with SCS in non-responders to SCS solely could convert these non-responders into responders. However, similar treatment with GABA(A) receptor agonists and SCS is known to be less efficient. Since K+ Cl- cotransporter 2 (KCC2) functionality strongly determines proper GABA(A) receptor-mediated inhibition, both decreased numbers of GABA(A) receptors as well as reduced KCC2 protein expression might play a pivotal role in this loss of GABA(A) receptor-mediated inhibition in non-responders. Here, we explored the mechanisms underlying both changes in extracellular GABA levels and impaired GABA(A) receptor-mediated inhibition after 30 min of SCS in rats suffering from partial sciatic nerve ligation (PSNL). Immediately after cessation of SCS, a decreased spinal intracellular dorsal horn GABA-immunoreactivity was observed in responders when compared to non-responders or sham SCS rats. One hour later however, GABA-immunoreactivity was already increased to similar levels as those observed in non-responder or sham SCS rats. These changes did not coincide with alterations in the number of GABA-immunoreactive cells. C-Fos/GABA double-fluorescence clearly confirmed a SCS-induced activation of GABA-immunoreactive cells in responders immediately after SCS. Differences in spinal dorsal horn GABA(A) receptor-immunoreactivity and KCC2 protein levels were absent between all SCS groups. However, KCC2 protein levels were significantly decreased compared to sham PSNL animals. In conclusion, reduced intracellular GABA levels are only present during the time frame of SCS in responders and strongly point to a SCS-mediated on/off GABAergic release mechanism. Furthermore, a KCC2-dependent impaired GABA(A) receptor-mediated inhibition seems to be present both in responders and non-responders to SCS due to similar KCC2 and GABA(A) receptor levels.

Objective Analyze the epidemiological data on neuropathic pain in spinal cord injury patients and determine the risk factors for its occurrence and chronicity. Method Review and analysis of the literature. Results Epidemiological data report that 40% of spinal cord injury (SCI) patients suffer from neuropathic pain and 40% of these patients report an intense neuropathic pain. Some factors do not seem to be predictive for the onset of neuropathic pain: the level of injury, complete or incomplete injury, the existence of an initial surgery, sex. However, old age at the time of injury, bullet injury as the cause of trauma, early onset of pain in the weeks following the injury, their initial nature, intensity and continuous pain, as well as associated symptoms all appear to be negative prognostic factors. Conclusion Neuropathic pain in SCI patients is a major issue, its determining factors still need to be evaluated properly by refining the epidemiological data.

BackgroundChronic pain is frequent in persons living with spinal cord injury (SCI). Conventionally, the pain is treated pharmacologically, yet longterm pain medication is often refractory and associated with side effects. Non-pharmacological interventions are frequently advocated, although the benefit and harm profiles of these treatments are not well established, in part because of methodological weaknesses of available studies.ObjectivesTo critically appraise and synthesise available research evidence on the effects of non-pharmacological interventions for the treatment of chronic neuropathic and nociceptive pain in people living with SCI.Search methodsThe search was run on the 1st March 2011. We searched the Cochrane Injuries Group's Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (OvidSP), Embase (OvidSP), PsycINFO (OvidSP), four other databases and clinical trials registers. In addition, we manually searched the proceedings of three major scientific conferences on SCI. We updated this search in November 2014 but these results have not yet been incorporated.Selection criteriaRandomised controlled trials of any intervention not involving intake of medication or other active substances to treat chronic pain in people with SCI.Data collection and analysisTwo review authors independently extracted data and assessed risk of bias in the included studies. The primary outcome was any measure of pain intensity or pain relief. Secondary outcomes included adverse events, anxiety, depression and quality of life. When possible, meta-analyses were performed to calculate standardised mean differences for each type of intervention.Main resultsWe identified 16 trials involving a total of 616 participants. Eight different types of interventions were studied. Eight trials investigated the effects of electrical brain stimulation (transcranial direct current stimulation (tDCS) and cranial electrotherapy stimulation (CES); five trials) or repetitive transcranial magnetic stimulation (rTMS; three trials). Interventions in the remaining studies included exercise programmes (three trials); acupuncture (two trials); self-hypnosis (one trial); transcutaneous electrical nerve stimulation (TENS) (one trial); and a cognitive behavioural programme (one trial). None of the included trials were considered to have low overall risk of bias. Twelve studies had high overall risk of bias, and in four studies risk of bias was unclear. The overall quality of the included studies was weak. Their validity was impaired by methodological weaknesses such as inappropriate choice of control groups. An additional search in November 2014 identified more recent studies that will be included in an update of this review.For tDCS the pooled mean difference between intervention and control groups in pain scores on an 11-point visual analogue scale (VAS) (0-10) was a reduction of -1.90 units (95% confidence interval (CI) -3.48 to -0.33; P value 0.02) in the short term and of -1.87 (95% CI -3.30 to -0.45; P value 0.01) in the mid term. Exercise programmes led to mean reductions in chronic shoulder pain of -1.9 score points for the Short Form (SF)-36 item for pain experience (95% CI -3.4 to -0.4; P value 0.01) and -2.8 pain VAS units (95% CI -3.77 to -1.83; P value Authors' conclusionsEvidence is insufficient to suggest that non-pharmacological treatments are effective in reducing chronic pain in people living with SCI. The benefits and harms of commonly used non-pharmacological pain treatments should be investigated in randomised controlled trials with adequate sample size and study methodology.

Electroacupuncture has traditionally been used to treat pain, but its effect on pain following brachial plexus injury is still unknown. In this study, rat models of an avulsion injury to the left brachial plexus root (associated with upper-limb chronic neuropathic pain) were given electroacupuncture stimulation at bilateral Quchi (LI11), Hegu (LI04), Zusanli (ST36) and Yanglingquan (GB34). After electroacupuncture therapy, chronic neuropathic pain in the rats' upper limbs was significantly attenuated. Immunofluorescence staining showed that the expression of β-endorphins in the arcuate nucleus was significantly increased after therapy. Thus, experimental findings indicate that electroacupuncture can attenuate neuropathic pain after brachial plexus injury through upregulating β-endorphin expression.

In the present study, a rat model of chronic neuropathic pain was established by ligation of the sciatic nerve and a model of learning and memory impairment was established by ovariectomy to investigate the analgesic effect of repeated electroacupuncture stimulation at bilateral Zusanli (ST36) and Yanglingquan (GB34). In addition, associated synaptic changes in neurons in the paraventricular nucleus of the hypothalamus were examined. Results indicate that the thermal pain threshold (paw withdrawal latency) was significantly increased in rats subjected to 2-week electroacupuncture intervention compared with 2-day electroacupuncture, but the analgesic effect was weakened remarkably in ovariectomized rats with chronic constrictive injury. 2-week electroacupuncture intervention substantially reversed the chronic constrictive injury-induced increase in the synaptic cleft width and thinning of the postsynaptic density. These findings indicate that repeated electroacupuncture at bilateral Zusanli and Yanglingquan has a cumulative analgesic effect and can effectively relieve chronic neuropathic pain by remodeling the synaptic structure of the hypothalamic paraventricular nucleus.

Postherpetic neuralgia (PHN) is a debilitating complication of herpes zoster, especially in elderly and comorbid patients. Unfortunately, the currently available treatments have shown limited efficacy and some adverse events that are poorly tolerated in elderly patients. Scrambler Therapy, proposed as an alternative treatment for chronic neuropathic pain recently, is a noninvasive approach to relieve pain by changing pain perception at the brain level. Here, we report our clinical experiences on the effect of Scrambler Therapy for three patients with PHN refractory to conventional treatment.

Objective: To explore the economic viability of N-of-1 trials for improving access to selected high cost medications in Australia. Methods: Cost and effectiveness estimates were derived from two N-of-1 trials conducted by The University of Queensland from 2003 to 2005—celecoxib versus sustained-release paracetamol for osteoarthritis in a general practice setting and gabapentin versus placebo for chronic neuropathic pain in a hospital setting. Effectiveness was determined by the proportion of responders to each medication. The costs of trials were offset against the savings generated by subsequent changes in prescribing. Decision analysis models with semi-Markov processes were used to compare different scenarios of N-of-1 trials versus usual care. Results: The fixed cost of performing N-of-1 trials was approximately AUS$23,000 for each trial and the variable cost was approximately AUS$1300 per participant. Clinical outcomes favored celecoxib over paracetamol in 17% of participants and gabapentin over placebo in 24% of participants. Modeling these results showed that the cost-offsets from efficient use of medications were less than the cost of running a trial; however, the incremental costs per quality-adjusted life-year gained were AUS$6,896 and AUS$29,550 for the gabapentin/placebo and celecoxib/paracetamol trials, respectively, over a 5-year horizon. Key factors affecting the viability were the time horizon modeled, the variable cost per participant, the probability of response to the intervention medication, and rates of use in nonresponders and the usual care alternative. Conclusions: The N-of-1 strategy offers a realistic and viable option for increasing access to selected high cost medications where the medications are used for the symptomatic treatment of chronic disease, have rapid onset of action, and clinical response is unpredictable without a trial.

Background In animal models, the impact of social and environmental manipulations on chronic pain have been investigated in short term studies where enrichment was implemented prior to or concurrently with the injury. The focus of this study was to evaluate the impact of environmental enrichment or impoverishment in mice three months after induction of chronic neuropathic pain. Methods Thirty-four CD-1 seven to eight week-old male mice were used. Mice underwent surgery on the left leg under isoflurane anesthesia to induce the spared nerve injury model of neuropathic pain or sham condition. Mice were then randomly assigned to one of four groups: nerve injury with enriched environment (n = 9), nerve injury with impoverished environment (n = 8), sham surgery with enriched environment (n = 9), or sham surgery with impoverished environment (n = 8). The effects of environmental manipulations on mechanical (von Frey filaments) heat (hot plate) and cold (acetone test) cutaneous hypersensitivities, motor impairment (Rotarod), spontaneous exploratory behavior (open field test), anxiety-like behavior (elevated plus maze) and depression-like phenotype (tail suspension test) were assessed in neuropathic and control mice 1 and 2 months post-environmental change. Finally, the effect of the environment on spinal expression of the pro-nociceptive neuropeptides substance P and CGRP form the lumbar spinal cord collected at the end of the study was evaluated by tandem liquid chromatography mass spectrometry. Results Environmental enrichment attenuated nerve injury-induced hypersensitivity to mechanical and cold stimuli. In contrast, an impoverished environment exacerbated mechanical hypersensitivity. No antidepressant effects of enrichment were observed in animals with chronic neuropathic pain. Finally, environmental enrichment resulted lower SP and CGRP concentrations in neuropathic animals compared to impoverishment. These effects were all observed in animals that had been neuropathic for several months prior to intervention. Conclusions These results suggest that environmental factors could play an important role in the rehabilitation of chronic pain patients well after the establishment of chronic pain. Enrichment is a potentially inexpensive, safe and easily implemented non-pharmacological intervention for the treatment of chronic pain.

Objetivos. Determinar la prevalencia del dolor neuropático (DN) en una muestra de pacientes con lesión medular (LM), examinar la relación entre las características clínicas, demográficas y psicológicas con la prevalencia del DN después de una LM y a su vez con los diferentes tipos de DN, y estudiar el valor predictivo de los factores más significativos. Pacientes y métodos. Estudio transversal observacional de un total de 260 pacientes que acudieron a una revisión anual. Las principales medidas de resultados incluyeron presencia/ausencia de DN, índice de bienestar psicológico, historia detallada del dolor y escala de puntuación numérica de 0-10 para la media de intensidad del dolor. Resultados. 93 pacientes (36%) con LM tenían DN. De los pacientes que presentaron DN, un 35% mostró dolor a nivel de la lesión, mientras que un 65% presentó DN por debajo. La única variable con capacidad predictiva sobre la prevalencia del DN fue la edad en el momento de la LM. Se observaron diferencias estadísticamente significativas entre la prevalencia del DN y la percepción de bienestar psicológico; el grupo de pacientes con DN fue el que tuvo proporcionalmente un malestar psicológico mayor. En cuanto a los diferentes tipos de DN, las variables con capacidad predictiva sobre la clasificación del DN eran el inicio temprano del dolor en el DN a nivel y el hecho de que la lesión sea incompleta en el DN por debajo. Conclusión. El DN aparece con frecuencia después de la LM y se da de forma más común en aquellos pacientes que han sufrido la lesión a edades más avanzadas. El DN tiene un impacto negativo en la percepción de bienestar psicológico AIMS. To determine the prevalence of neuropathic pain (NP) in a sample of patients with spinal cord injury (SCI), to examine the relation between clinical, demographic and psychological characteristics with the prevalence of NP after SCI and the different types of NP, and to study predictive factors. PATIENTS AND METHODS. Transversal observational study of 260 patients who attended their annual revision. Main outcome measures included presence/absence of NP, psychological well-being index, detailed pain history and 0-10 numerical rating scale of average pain intensity. RESULTS. 93 patients (36%) with SCI had NP. Of the patients with NP, 35% showed pain at level, while 65% showed NP below the level of injury. The only variable with a predictive value on the prevalence of NP was older age at the time of SCI. Statistically significant differences were observed between the prevalence of NP and the perception of psychological well-being; patients with NP were the ones with more psychological distress. As for the different types of NP, the variables with predictive value on the classification of NP were early onset of pain at level, and incompleteness of the lesion in the below level NP. CONCLUSION. The results of this study show that NP appears frequently after SCI being more prevalent in patients who suffered the injury at more advanced ages. NP has a negative impact on the perception of psychological well-being