Neuropathic Pain In Patients Research Articles

Repetitive transcranial magnetic stimulation regulates neuroinflammation, relieves hyperalgesia and reverses despair-like behaviour in chronic constriction injury rats.

Repetitive transcranial magnetic stimulation (rTMS) could effectively relieve the pain and depression in neuropathic pain (NP) patients. However, the specific treatment parameters and exact mechanism are still unclear. Our purpose is to observe the effects of rTMS on pain and despair-like behaviour in chronic constriction injury (CCI) rats and explore its possible mechanism. Thirty-two 8-week-old male Sprague-Dawley rats were randomly divided into four groups: sham operation group (S, n = 8), CCI group (n = 8), 1 Hz-rTMS group (n = 8) and 10 Hz-rTMS group (n = 8). The rTMS was applied to the left dorsal anterior agranular insular (AId) 1 week after the operation, once a day, 5 days/week for 4 consecutive weeks. Mechanical hyperalgesia, despair-like behaviours and sciatic nerve function were used to evaluate the effects of rTMS. Besides, glucose metabolism, the metabotropic glutamate receptors 5 (mGluR5), N-Methyl-D-Aspartic acid receptor type 2B (NMDAR2B), tumour necrosis factor-α (TNF-α), interleukin-6 (Ll-6) and interleukin-1β (Ll-1β) in AId were tested to explore the possible mechanism. Compared with 1 Hz-rTMS, the rats of 10 Hz-rTMS had higher the mechanical hyperalgesia, higher sugar preference and shorter swimming immobility time. Besides, the expressions of mGluR5, NMDAR2B, TNF-α, Ll-1β and Ll-6 both in 1 Hz-rTMS and 10 Hz-rTMS groups were reduced compared with the CCI group; the 10 Hz-rTMS group had a more decrease than that of 1 Hz-rTMS. Furthermore, the [18]F-FDG uptake was lower than that in the 1 Hz-rTMS group. Compared with 1 Hz-rTMS, 10 Hz-rTMS could more effectively relieve mechanical hyperalgesia and reverse despair-like behaviour in rats. The mechanism could be related to regulating mGluR5/NMDAR2B-related inflammatory signalling pathways in the AId.

Alterations in local activity and functional connectivity in patients with postherpetic neuralgia after short-term spinal cord stimulation.

IntroductionThe efficacy of short-term spinal cord stimulation (stSCS) as a treatment for neuropathic pain in patients with postherpetic neuralgia (PHN) has already been validated. However, the potential alterations in brain functionality that are induced by such treatment have yet to be completely elucidated.MethodsThis study use resting-state functional magnetic resonance imaging (rs-fMRI) to detect the changes in regional homogeneity (ReHo) and degree centrality (DC) related to stimulator-induced pain relief in patients with PHN. A total of 10 patients with PHN underwent an MRI protocol at baseline and after stSCS. Alterations in ReHo and DC were then compared between baseline and after stSCS. We investigated the relationship between clinical parameters and functional changes in the brain.ResultsClinical parameters on pain, emotion, and sleep quality were correlated with ReHo and DC. ReHo and DC were significantly altered in the middle temporal gyrus, precuneus, superior frontal gyrus, supramarginal gyrus, inferior parietal lobule, rolandic operculum, middle occipital gyrus, superior parietal gyrus, and the precentral gyrus after stSCS. A significant correlation was detected between ReHo changes in the middle occipital gyrus, precuneus, inferior parietal gyrus, and changes in pain, emotion, and sleep quality. A significant negative correlation was detected between DC changes in the middle temporal gyrus, rolandic operculum, supramarginal gyrus, precuneus, inferior parietal gyrus, and changes in pain, emotion, and sleep quality.ConclusionThis study found that stSCS is able to induce ReHo and DC changes in patients with PHN, thus suggesting that stSCS can change brain function to alleviate pain, sleep, and emotional disorder.

Pro-inflammatory cytokines and leukocyte integrins associated with chronic neuropathic pain in traumatic and inflammatory neuropathies: Initial observations and hypotheses.

Leukocyte infiltration and persistence within peripheral nerves have been implicated in chronic nociception pathogenesis in murine peripheral neuropathy models. Endoneurial cytokine and chemokine expression contribute to leukocyte infiltration and maintenance of a pro-inflammatory state that delays peripheral nerve recovery and promotes chronic pain behaviors in these mice. However, there has been a failure to translate murine model data into safe and effective treatments for chronic neuropathic pain in peripheral neuropathy patients, or develop reliable biomarkers that may help diagnose or determine treatment responses in affected patients. Initial work showed that persistent sciatic nerve CD11b+ CD45+ leukocyte infiltration was associated with disease severity in three mouse models of inflammatory and traumatic peripheral neuropathies, implying a direct contributing role in disease pathogenesis. In support of this, CD11b+ leukocytes were also seen in the sural nerve biopsies of chronic neuropathic pain patients with three different peripheral neuropathies. Systemic CD11b antagonism using a validated function-neutralizing monoclonal antibody effectively treated chronic nociception following unilateral sciatic nerve crush injury (a representative traumatic neuropathy model associated with axonal degeneration and increased blood-nerve barrier permeability) and does not cause drug addiction behaviors in adult mice. These data suggest that CD11b could be an effective molecular target for chronic neuropathic pain treatment in inflammatory and traumatic peripheral neuropathies. Despite known murine peripheral neuropathy model limitations, our initial work suggests that early expression of pro-inflammatory cytokines, such as tissue inhibitor of metalloproteinases-1 may predict subsequent chronic nociception development following unilateral sciatic nerve crush injury. Studies aligning animal model investigation with observational data from well-characterized human peripheral neuropathies, including transcriptomics and proteomics, as well as animal model studies using a human clinical trial design should foster the identification of clinically relevant biomarkers and effective targeted treatments with limited addiction potential for chronic neuropathic pain in peripheral neuropathy patients.

Frequency of neuropathic pain in patients with shoulder pain.

Shoulder pain is one of the most common musculoskeletal disorders in general population. Although shoulder pain is completely resolved within one year after treatment in more patients, persistent pain is observed in remaining patients. Neuropathic pain may play a role in persistent shoulder pain in some patients. The aim of the study was to investigate the neuropathic pain component in patients with shoulder pain. 49 patients with shoulder pain were enrolled in this study. The Pain-Detect questionnaire was used to determine the presence of neuropathic pain. Visual analogue scale (VAS) was used to evaluate shoulder pain. Quick Disabilities of the Arm, Shoulder and Hand (Quick-Dash) was used to determine to measure physical function and symptoms. The neuropathic pain component in patients with shoulder pain was 20% and possible neuropathic pain was 19% according to Pain-Detect questionnaire. The mean VAS score, Quick-Dash score and symptom duration were significantly higher in the neuropathic pain group. The patients with shoulder pain have a neuropathic pain component. We suggest that neuropathic pain should be assessed when prescribing treatment programs in patients with shoulder pain.

Hidden Neuropathic Pain in Chronic Low Back Pain: Prevalence, Pattern, and Impact on Quality of Life

Objective: A patient with Neuropathic Pain (NP) may suffer from pure NP or may have mixed nociceptive and neuropathic pain. No previous study has investigated NP among Thai patients with Chronic Low Back Pain (CLBP). This study aimed to investigate the prevalence and clinical presentation of NP, and the impact of NP on Quality of Life (QoL) in Thai Chronic Low Back Pain (CLBP) patients.Materials and Methods: Adult patients with CLBP longer than 3 months were included. NP was detected by painDETECT questionnaire, and NP was defined as a score 19. Demographic data, pain characteristics, treatment, Oswestry Disability Index (ODI), and quality of life score (Short Form 36, SF-36) were recorded.Results: 371 CLBP patients were enrolled. The overall prevalence of neuropathic pain was 50.1% (95% CI: 44.9-55.3%). The prevalence of NP in patients with axial low back pain, back pain with pain radiating above the knee, and back pain with pain radiating below the knee was 28.3%, 58.21%, and 59.5%, respectively. Only 48.9% of patients with NP received neuropathic pain medication. Multivariate analysis showed only older age to be associated with NP (OR: 1.017, 95% CI: 1.002-1.033). NP patients had a significantly higher ODI score. There is no difference in most dimension of SF-36 scores, except marginally higher general health and vitality dimension scores.Conclusion: Prevalence of NP in Thai CLBP patients is high. Additionally, it is undertreated and associated with higher disability especially among patients with radiating pain above the knee. Older age is an independent predictor of NP.

RNA profiling of human dorsal root ganglia reveals sex differences in mechanisms promoting neuropathic pain.

Neuropathic pain is a leading cause of high-impact pain, is often disabling and is poorly managed by current therapeutics. Here we focused on a unique group of neuropathic pain patients undergoing thoracic vertebrectomy where the dorsal root ganglia is removed as part of the surgery allowing for molecular characterization and identification of mechanistic drivers of neuropathic pain independently of preclinical models. Our goal was to quantify whole transcriptome RNA abundances using RNA-seq in pain-associated human dorsal root ganglia from these patients, allowing comprehensive identification of molecular changes in these samples by contrasting them with non-pain-associated dorsal root ganglia. We sequenced 70 human dorsal root ganglia, and among these 50 met inclusion criteria for sufficient neuronal mRNA signal for downstream analysis. Our expression analysis revealed profound sex differences in differentially expressed genes including increase of IL1B, TNF, CXCL14 and OSM in male and CCL1, CCL21, PENK and TLR3 in female dorsal root ganglia associated with neuropathic pain. Coexpression modules revealed enrichment in members of JUN-FOS signalling in males and centromere protein coding genes in females. Neuro-immune signalling pathways revealed distinct cytokine signalling pathways associated with neuropathic pain in males (OSM, LIF, SOCS1) and females (CCL1, CCL19, CCL21). We validated cellular expression profiles of a subset of these findings using RNAscope in situ hybridization. Our findings give direct support for sex differences in underlying mechanisms of neuropathic pain in patient populations.

Local hyperexcitability of C-nociceptors may predict responsiveness to topical lidocaine in neuropathic pain.

We explored whether increased C-nociceptor excitability predicts analgesic effects of topical lidocaine in 33 patients with mono- (n = 15) or poly-neuropathy (n = 18). Excitability of C-nociceptors was tested by transcutaneous electrical sinusoidal (4 Hz) and half sine wave (single 500 ms pulse) stimulation delivered to affected and non-affected sites. Analgesic effects of 24 hrs topical lidocaine were recorded. About 50% of patients reported increased pain from symptomatic skin upon continuous 4 Hz sinusoidal and about 25% upon 500 ms half sine wave stimulation. Electrically-evoked half sine wave pain correlated to their clinical pain level (r = 0.37, p < 0.05). Lidocaine-patches reduced spontaneous pain by >1-point NRS in 8 of 28 patients (p < 0.0001, ANOVA). Patients with increased pain to 2.5 sec sinusoidal stimulation at 0.2 and 0.4 mA intensity had significantly stronger analgesic effects of lidocaine and in reverse, patients with a pain reduction of >1 NRS had significantly higher pain ratings to continuous 1 min supra-threshold sinusoidal stimulation. In the assessed control skin areas of the patients, enhanced pain upon 1 min 4 Hz stimulation correlated to increased depression scores (HADS). Electrically assessed C-nociceptor excitability identified by slowly depolarizing electrical stimuli might reflect the source of neuropathic pain in some patients and can be useful for patient stratification to predict potential success of topical analgesics. Central neuronal circuitry assessment reflected by increased pain in control skin associated with higher HADS scores suggest central sensitization phenomena in a sub-population of neuropathic pain patients.

The etiological roles of miRNAs, lncRNAs, and circRNAs in neuropathic pain: A narrative review.

BackgroundNon‐coding RNAs (ncRNAs) are involved in neuropathic pain development. Herein, we systematically searched for neuropathic pain‐related ncRNAs expression changes, including microRNAs (miRNAs), long non‐coding RNAs (lncRNAs), and circular non‐coding RNAs (circRNAs).MethodsWe searched two databases, PubMed and GeenMedical, for relevant studies.ResultsPeripheral nerve injury or noxious stimuli can induce extensive changes in the expression of ncRNAs. For example, higher serum miR‐132‐3p, ‐146b‐5p, and ‐384 was observed in neuropathic pain patients. Either sciatic nerve ligation, dorsal root ganglion (DRG) transaction, or ventral root transection (VRT) could upregulate miR‐21 and miR‐31 while downregulating miR‐668 and miR‐672 in the injured DRG. lncRNAs, such as early growth response 2‐antisense‐RNA (Egr2‐AS‐RNA) and Kcna2‐AS‐RNA, were upregulated in Schwann cells and inflicted DRG after nerve injury, respectively. Dysregulated circRNA homeodomain‐interacting protein kinase 3 (circHIPK3) in serum and the DRG, abnormally expressed lncRNAs X‐inactive specific transcript (XIST), nuclear enriched abundant transcript 1 (NEAT1), small nucleolar RNA host gene 1 (SNHG1), as well as ciRS‐7, zinc finger protein 609 (cirZNF609), circ_0005075, and circAnks1a in the spinal cord were suggested to participate in neuropathic pain development. Dysregulated miRNAs contribute to neuropathic pain via neuroinflammation, autophagy, abnormal ion channel expression, regulating pain‐related mediators, protein kinases, structural proteins, neurotransmission excitatory–inhibitory imbalances, or exosome miRNA‐mediated neuron–glia communication. In addition, lncRNAs and circRNAs are essential in neuropathic pain by acting as antisense RNA and miRNA sponges, epigenetically regulating pain‐related molecules expression, or modulating miRNA processing.ConclusionsNumerous dysregulated ncRNAs have been suggested to participate in neuropathic pain development. However, there is much work to be done before ncRNA‐based analgesics can be clinically used for various reasons such as conservation among species, proper delivery, stability, and off‐target effects.

Prevalence of post-traumatic neuropathic pain after digital nerve repair and finger amputation

Post-traumatic neuropathic pain is a major factor affecting the quality of life after finger trauma and is reported with considerable variance in the literature. This can partially be attributed to the different methods of determining neuropathic pain. The Douleur Neuropathique 4 (DN4) has been validated to be a reliable and non-invasive tool to assess the presence of neuropathic pain. This study investigated the prevalence of neuropathic pain after finger amputation or digital nerve repair using the DN4 questionnaire. Patients with finger amputation or digital nerve repair were identified between 2011 and 2018 at our institution. After a minimal follow-up of 12 months, the short form DN4 (S-DN4) was used to assess neuropathic pain. A total of 120 patients were included: 50 patients with 91 digital amputations and 70 patients with 87 fingers with digital nerve repair. In the amputation group, 32% of the patients had pain, and 18% had neuropathic pain. In the digital nerve repair group, 38% of the patients had pain, and 14% had neuropathic pain. Secondly, of patient-, trauma-, and treatment-specific factors, only the time between trauma and surgery had a significant negative influence on the prevalence of neuropathic pain in patients with digital nerve repair. This study shows that persistent pain and neuropathic pain are common after finger trauma with nerve damage. One of the significant prognostic factors in developing neuropathic pain is treatment delay between trauma and time of digital nerve repair, which is of major clinical relevance for surgical planning of these injuries.

ID:15848 Health-Related Quality of Life Associated With Pain Health States in SCS for Chronic Neuropathic Pain

A substantial proportion of chronic neuropathic pain patients have recently reported pain reduction levels of ≥80% following treatment with Evoked Compound Action Potential (ECAP) spinal cord stimulation (SCS) (1,2). The additional health-related quality of life (HRQoL) utility gain that can be achieved in this ≥80% pain relief (‘remission’) patient group is unclear.

Neurodynamic Treatment Promotes Mechanical Pain Modulation in Sensory Neurons and Nerve Regeneration in Rats

Background: Somatic nerve injuries are a rising problem leading to disability associated with neuropathic pain commonly reported as mechanical allodynia (MA) and hyperalgesia. These symptoms are strongly dependent on specific processes in the dorsal root ganglia (DRG). Neurodynamic treatment (NDT), consisting of selective uniaxial nerve repeated tension protocols, effectively reduces pain and disability in neuropathic pain patients even though the biological mechanisms remain poorly characterized. We aimed to define, both in vivo and ex vivo, how NDT could promote nerve regeneration and modulate some processes in the DRG linked to MA and hyperalgesia. Methods: We examined in Wistar rats, after unilateral median and ulnar nerve crush, the therapeutic effects of NDT and the possible protective effects of NDT administered for 10 days before the injury. We adopted an ex vivo model of DRG organotypic explant subjected to NDT to explore the selective effects on DRG cells. Results: Behavioural tests, morphological and morphometrical analyses, and gene and protein expression analyses were performed, and these tests revealed that NDT promotes nerve regeneration processes, speeds up sensory motor recovery, and modulates mechanical pain by affecting, in the DRG, the expression of TACAN, a mechanosensitive receptor shared between humans and rats responsible for MA and hyperalgesia. The ex vivo experiments have shown that NDT increases neurite regrowth and confirmed the modulation of TACAN. Conclusions: The results obtained in this study on the biological and molecular mechanisms induced by NDT will allow the exploration, in future clinical trials, of its efficacy in different conditions of neuropathic pain.

Lack of impact of OCTN1 gene polymorphisms on clinical outcomes of gabapentinoids in Pakistani patients with neuropathic pain.

Gabapentinoids are the first-line drugs for neuropathic pain. These drugs are the substrate of organic cation transporter (OCTN1) for renal excretion and absorption across the intestinal epithelium. Gabapentinoids exhibit wide interindividual variability in daily dosage and therapeutic efficacy which makes titration regimens prolonged for optimal efficacy. The present study aimed to investigate the possible influence of the single nucleotide polymorphism (SNP) of OCTN1 on therapeutic efficacy and safety of gabapentinoids in neuropathic pain patients of the Pakistani population. Four hundred and twenty-six patients were enrolled in the study. All participants were genotyped for OCTN1 rs1050152 and rs3792876 by PCR-RFLP method and followed up for eight weeks. The therapeutic outcomes of gabapentinoids, reduction in pain score, inadequate or complete lack of response, adverse events (AEs) in responders and discontinuation of treatment on account of AEs were recorded for all patients. There was no significant association of genotypes and alleles of both SNPs on the clinical response of gabapentinoids (P ˃ 0.05). Similarly, significant differences were not found in the reduction of pain scores and AEs among different genotypes in the responders. The present study has reported the association of OCTN1 rs1050152 and rs3792876 polymorphisms with clinical outcomes of gabapentinoids for the first time in the real-world clinical setting. Our results suggest a lack of influence of OCTN1 genetic variants in the determination of clinical response to gabapentinoids in patients with neuropathic pain in the Pakistani population. These findings signify the role of renal functions in predicting the interindividual variability to therapeutic responsiveness of gabapentinoids.

Peripheral Neuropathies Derived from COVID-19: New Perspectives for Treatment.

Peripheral neuropathies constitute a group of disorders affecting the peripheral nervous system. Neuropathies have multiple causes such as infections (i.e., COVID-19), diabetes, and nutritional (low vitamin levels), among others. Many micronutrients, such as vitamins (A, C, D, E, B6, B12, and folate), certain minerals (Fe, Mg, Zn, Se, and Cu), and ω-3 fatty acids have immunomodulatory effects. Therefore, they may play an instrumental role in the treatment of COVID-19 infection. However, many COVID-19 patients can undergo neuropathy. In this context, there is a wealth of information on a variety of first-, second-, and third-line treatment options. This review focuses on the application of nutraceutical strategies in order to improve the symptomatology of neuropathy and neuropathic pain in patients that suffered from COVID-19. Our aim is to provide an alternative vision to traditional medical-pharmacological treatment through nutraceuticals.

Prevalence and determinants of pain in chronic inflammatory demyelinating polyneuropathy: Results from the German INHIBIT registry.

Pain, fatigue and depression in chronic inflammatory demyelinating polyneuropathy (CIDP) are often underestimated, as the focus lies on sensorimotor dysfunction and gait instability. The aim of this study was to investigate their prevalence, characteristics and contribution to disability in a prospective cohort of 84 patients with CIDP. Pain, fatigue, depression and quality of life were measured using the Pain Detect Questionnaire, Krupp's Fatigue Severity Scale, Beck Depression Inventory II and the German Short-Form 36 Health Survey. Sensorimotor deficits and disability were assessed using the Inflammatory Neuropathy Cause and Treatment overall disability score, the Rasch-built Overall Disability Scale, the Medical Research Council sum score and the Inflammatory Neuropathy Cause and Treatment sensory sum score. The interrelation between the five factors was assessed using analysis of variance and linear regression analysis. Pain was reported in 62%, mostly of moderate and severe intensity, whereas pain characteristics indicated neuropathic pain (NP) in 29%. Sensory dysfunction was stronger in NP patients compared to pain-free patients (p=0.001). Pain of any type, especially NP, was associated with more pronounced fatigue symptoms (p=0.010). Depressive symptoms were more frequent in patients with pain compared to the pain-free patients (61% vs. 33%, p=0.02) and were more severe and frequent in NP than in non-NP patients (p=0.005). Patients with pain had a worse physical quality of life than pain-free patients (p=0.001). Pain, depression and fatigue are relevant disability factors in CIDP affecting quality of life. Sensory dysfunction is associated with NP. Therefore, evaluation of CIDP-related disability should include pain and sensory function for adequate monitoring of therapeutic interventions.

GPR177 in A-fiber sensory neurons drives diabetic neuropathic pain via WNT-mediated TRPV1 activation.

Diabetic neuropathic pain (DNP) is a common and devastating complication in patients with diabetes. The mechanisms mediating DNP are not completely elucidated, and effective treatments are lacking. A-fiber sensory neurons have been shown to mediate the development of mechanical allodynia in neuropathic pain, yet the molecular basis underlying the contribution of A-fiber neurons is still unclear. Here, we report that the orphan G protein-coupled receptor 177 (GPR177) in A-fiber neurons drives DNP via WNT5a-mediated activation of transient receptor potential vanilloid receptor-1 (TRPV1) ion channel. GPR177 is mainly expressed in large-diameter A-fiber dorsal root ganglion (DRG) neurons and required for the development of DNP in mice. Mechanistically, we found that GPR177 mediated the secretion of WNT5a from A-fiber DRG neurons into cerebrospinal fluid (CSF), which was necessary for the maintenance of DNP. Extracellular perfusion of WNT5a induced rapid currents in both TRPV1-expressing heterologous cells and nociceptive DRG neurons. Computer simulations revealed that WNT5a has the potential to bind the residues at the extracellular S5-S6 loop of TRPV1. Using a peptide able to disrupt the predicted WNT5a/TRPV1 interaction suppressed DNP- and WNT5a-induced neuropathic pain symptoms in rodents. We confirmed GPR177/WNT5A coexpression in human DRG neurons and WNT5A secretion in CSF from patients with DNP. Thus, our results reveal a role for WNT5a as an endogenous and potent TRPV1 agonist, and the GPR177-WNT5a-TRPV1 axis as a driver of DNP pathogenesis in rodents. Our findings identified a potential analgesic target that might relieve neuropathic pain in patients with diabetes.

Electrophysiological Alterations Driving Pain-Associated Spontaneous Activity in Human Sensory Neuron Somata Parallel Alterations Described in Spontaneously Active Rodent Nociceptors

Neuropathic pain in rodents can be driven by ectopic spontaneous activity (SA) generated by sensory neurons in dorsal root ganglia (DRG). The recent demonstration that SA in dissociated human DRG neurons is associated with reported neuropathic pain in patients enables a detailed comparison of pain-linked electrophysiological alterations driving SA in human DRG neurons to alterations that distinguish SA in nociceptors from SA in low-threshold mechanoreceptors (LTMRs) in rodent neuropathy models. Analysis of recordings from dissociated somata of patient-derived DRG neurons showed that SA and corresponding pain in both sexes were significantly associated with the three functional electrophysiological alterations sufficient to generate SA in the absence of extrinsic depolarizing inputs. These include enhancement of depolarizing spontaneous fluctuations of membrane potential (DSFs), which were analyzed quantitatively for the first time in human DRG neurons. The functional alterations were indistinguishable from SA-driving alterations reported for nociceptors in rodent chronic pain models. Irregular, low-frequency DSFs in human DRG neurons closely resemble DSFs described in rodent nociceptors while differing substantially from the high-frequency sinusoidal oscillations described in rodent LTMRs. These findings suggest that conserved physiological mechanisms of SA in human nociceptor somata can drive neuropathic pain despite documented cellular differences between human and rodent DRG neurons. PerspectiveElectrophysiological alterations in human sensory neurons associated with patient-reported neuropathic pain include all three of the functional alterations that logically can promote spontaneous activity. The similarity of distinctively altered spontaneous depolarizations in human DRG neurons and rodent nociceptors suggests that spontaneously active human nociceptors can persistently promote neuropathic pain in patients.

Targeting Chemokines and Chemokine GPCRs to Enhance Strong Opioid Efficacy in Neuropathic Pain.

Neuropathic pain (NP) originates from an injury or disease of the somatosensory nervous system. This heterogeneous origin and the possible association with other pathologies make the management of NP a real challenge. To date, there are no satisfactory treatments for this type of chronic pain. Even strong opioids, the gold-standard analgesics for nociceptive and cancer pain, display low efficacy and the paradoxical ability to exacerbate pain sensitivity in NP patients. Mounting evidence suggests that chemokine upregulation may be a common mechanism driving NP pathophysiology and chronic opioid use-related consequences (analgesic tolerance and hyperalgesia). Here, we first review preclinical studies on the role of chemokines and chemokine receptors in the development and maintenance of NP. Second, we examine the change in chemokine expression following chronic opioid use and the crosstalk between chemokine and opioid receptors. Then, we examine the effects of inhibiting specific chemokines or chemokine receptors as a strategy to increase opioid efficacy in NP. We conclude that strong opioids, along with drugs that block specific chemokine/chemokine receptor axis, might be the right compromise for a favorable risk/benefit ratio in NP management.

Is transcranial magnetic stimulation as treatment for neuropathic pain in patients with spinal cord injury efficient? A systematic review.

Neuropathic pain is a clinically relevant complication in individuals with spinal cord injury (SCI). Pharmacological pain treatment is often insufficient and leads to undesirable side effects. Thus, alternative therapeutic approaches such as repetitive transcranial magnetic stimulation (rTMS) are of critical importance. We aimed to evaluate the effectiveness of rTMS in neuropathic pain secondary to SCI. We conducted a systematic review using the PubMed/MEDLINE, EMBASE, and PsycInfo (via OVID) database up April 2021. Only randomized controlled trials were included. Results regarding the pain intensity scores were pooled using a random-effects model. The search identified a total of 203 potential articles. Of these, eight randomized controlled trials (RCTs) met the eligibility criteria for qualitative synthesis providing the total data of 141 patients. All studies applied high-frequency rTMS. In seven studies, rTMS was applied over the motor cortex, and in one study over the left dorsolateral prefrontal cortex. Five studies reported a significant improvement in baseline pain scores after treatment, and three studies found a significant difference between sham vs. non-sham stimulation at any time. Six RCTs were included in the quantitative synthesis and showed a significant overall reduction of pain intensity in the rTMS groups compared with the sham groups (mean difference - 0.81, 95%CI - 1.45 to - 0.17). Our findings indicate that high-frequency rTMS of the primary motor cortex and left dorsolateral prefrontal cortex might be promising stimulation targets for neuropathic pain in SCI.

Factors associated with neuropathic pain in Colombian patients with spinal cord injury of traumatic origin: case-control study.

Case-control study. To identify factors associated with neuropathic pain (NP) in patients with spinal cord injury of traumatic origin (TSCI). University Hospital of Valle, Cali, Colombia. Study participants were individuals with diagnosis of TSCI who visited a trauma referral center from January 1st, 2016, to December 31st, 2016. Information was retrospectively extracted from the Hospital's Spinal Cord Injury registry and patients' medical records. Cases were defined as patients with NP and controls were those without NP. The exposure of interest was intentional injuries. Individuals were matched by age and stratified into 11 groups of ±3 years each. We found 164 participants with an average age of 34 ± 13 years, of whom 95.1% were male, and 53.6% had NP. Neurogenic bladder and bowel occurred in 94.3% of NP patients. Cause of injury was not associated with NP. Older injuries were protective for NP (>10 years since injury OR = 0.10, 95% CI = 0.03-0.37, p < 0.0001) and neurogenic bladder and bowel were found as risk factors (OR = 5.89, 95% CI = 1.84-18.88; p = 0.003). Our study uniquely shows time since injury as a protective factor for NP and neurogenic bladder and bowel as a risk factor, while violence was not found associated. This could help guide the scope of future research about NP secondary to SCI.

Progress in the efficacy and mechanism of spinal cord stimulation in neuropathological pain.

Neuropathic pain (NP) is a long-term recurrent disease caused by somatosensory nervous system injury, with spontaneous pain, hyperalgesia, ectopic pain, and paresthesia as the main clinical manifestations. It adversely affects patients' quality of life. NP treatments often include medication, physical therapy, and invasive therapy; the first two therapies are generally ineffective for some NP patients. These patients sometimes rely on invasive therapy to alleviate pain. Spinal cord stimulation (SCS) is a very effective therapeutic method. SCS is a neuroregulatory method that involves placing the electrodes on the corresponding painful spinal cords. Pain is greatly alleviated after SCS. SCS has been proven to be an effective therapeutic method for the treatment of neurological pain. Furthermore, SCS provides a feasible approach for patients with unsuccessful drug treatment. This paper reviews the relevant literature of spinal cord electrical stimulation, focusing on the mechanism of action, clinical application, clinical efficacy and technical progress of spinal cord electrical stimulation. SCS is widely used in the treatment of NP diseases such as postherpetic neuralgia, back surgery failure syndrome, and phantom limb pain. With advancements in science and technology, tremendous progress has also been made in the spinal cord electrical stimulation method and good momentum has been maintained.