Neuropathic Mechanisms Research Articles

Novel Treatments for Chronic Ocular Surface Pain.

Several etiologies can contribute to ocular surface pain including nociceptive, peripheral neuropathic, and central neuropathic mechanisms. Clinical clues can help identify contributors to ocular surface pain in a patient. In individuals whose pain persists despite targeting nociceptive contributors, neuropathic mechanisms should be considered and addressed using oral, topical, and/or adjuvant agents.

A mechanistic understanding of the relationship between skin innervation and chemotherapy-induced neuropathic pain.

Neuropathic pain is a frequent complication of chemotherapy-induced peripheral neurotoxicity (CIPN). Chemotherapy-induced peripheral neuropathies may serve as a model to study mechanisms of neuropathic pain, since several other common causes of peripheral neuropathy like painful diabetic neuropathy may be due to both neuropathic and non-neuropathic pain mechanisms like ischemia and inflammation. Experimental studies are ideally suited to study changes in morphology, phenotype and electrophysiologic characteristics of primary afferent neurons that are affected by chemotherapy and to correlate these changes to behaviors reflective of evoked pain, mainly hyperalgesia and allodynia. However, hyperalgesia and allodynia may only represent one aspect of human pain, i.e., the sensory-discriminative component, while patients with CIPN often describe their pain using words like annoying, tiring and dreadful, which are affective-emotional descriptors that cannot be tested in experimental animals. To understand why some patients with CIPN develop neuropathic pain and others not, and which are the components of neuropathic pain that they are experiencing, experimental and clinical pain research should be combined. Emerging evidence suggests that changes in subsets of primary afferent nerve fibers may contribute to specific aspects of neuropathic pain in both preclinical models and in patients with CIPN. In addition, the role of cutaneous neuroimmune interactions is considered. Since obtaining dorsal root ganglia and peripheral nerves in patients is problematic, analyses performed on skin biopsies from preclinical models as well as patients provide an opportunity to study changes in primary afferent nerve fibers and to associate these changes to human pain. In addition, other biomarkers of small fiber damage in CIPN, like corneal confocal microscope and quantitative sensory testing, may be considered.

The major pain source of rotator cuff-related shoulder pain: A narrative review on current evidence.

Rotator cuff-related shoulder pain (RCRSP) was proposed to have a complex pain mechanism, but the exact aetiology is still unclear. A recent review summarised the updated research to analyse the traditional concept of shoulder impingement which may not be accurate. Current studies have demonstrated that mechanical factors including a reduction in subacromial space, scapular dyskinesia and different acromial shapes are unlikely directly contributing to RCRSP. Since the precise RCRSP pain mechanism remains unclear, the aim of this narrative review is to discuss possible sources of pain contributing to RCRSP according to the mechanisms-based pain classifications. Research findings on potential mechanical nociceptive factors of RCRSP are conflicting; investigations of neuropathic and central pain mechanisms of RCRSP are limited and inconclusive. Overall, available evidence has indicated moderate to strong correlations between RCRSP and chemical nociceptive sources of pain. Results from current research may provide new directions for future studies on the aetiology of RCRSP and its clinical management towards a biochemical view instead of the traditional mechanical hypothesis.

EVOLUTIONARY METHOD FOR SYNTHESIS SPIKING NEURAL NETWORKS USING THE NEUROPATTHERN MECHANISM

Context. The problem of synthesizing pulsed neural networks based on an evolutionary approach to the synthesis of artificial neural networks using a neuropathic mechanism for constructing diagnostic models with a high level of accuracy is considered. The object of research is the process of synthesis of pulsed neural networks using an evolutionary approach and a neuropathic mechanism.
 Objective of the work is to develop a method for synthesizing pulsed neural networks based on an evolutionary approach using a neuropathic mechanism to build diagnostic models with a high level of accuracy of work.
 Method. A method for synthesizing pulsed neural networks based on an evolutionary approach is proposed. At the beginning, a population of pulsed neural networks is generated, and a neuropathic mechanism is used for their encoding and further development, which consists in separate encoding of neurons with different activation functions that are determined beforehand. So each pattern with multiple entry points can define the relationship between a pair of points. In the future, this simplifies the evolutionary development of networks. To decipher a pulsed neural network from a pattern, the coordinates for a pair of neurons are passed to the network that creates the pattern. The network output determines the weight and delay of the connection between two neurons in a pulsed neural network. After that, you can evaluate each neuromodel after evolutionary changes and check the criteria for stopping synthesis. This method allows you to reduce the resource intensity during network synthesis by abstracting the evolutionary changes of the network pattern from itself.
 Results. The developed method is implemented and investigated on the example of the synthesis of a pulsed neural network for use as a model for technical diagnostics. Using the developed method to increase the accuracy of the neuromodel with a test sample by 20%, depending on the computing resources used.
 Conclusions. The conducted experiments confirmed the operability of the proposed mathematical software and allow us to recommend it for use in practice in the synthesis of pulsed neural networks as the basis of diagnostic models for further automation of tasks of diagnostics, forecasting, evaluation and pattern recognition using big data. Prospects for further research may lie in the use of a neuropathic mechanism for indirect encoding of pulsed neural networks, which will provide even more compact data storage and speed up the synthesis process.

Role of burn severity and posttraumatic stress symptoms in the co-occurrence of itch and neuropathic pain after burns: A longitudinal study.

Itch and pain are common after burns. Neuropathic mechanisms may underlie both modalities but remain not well-understood. This study aims to prospectively document neuropathic pain symptoms and to identify potential itch symptom profiles that differ regarding duration and co-occurrence with neuropathic pain which may inform underlying pathophysiological mechanisms and respond to different treatments. Adult burn survivors (n = 192) self-reported itch and neuropathic pain at 2 weeks post-discharge, 3, 6, 12, and 18 months post-burn. Based on the presence of itch and pain symptoms over time, participants were allocated to one itch profile: transient itch/pain, chronic itch, or chronic itch & pain. Profiles were compared on itch intensity over time using General Linear Modeling. Age, gender, burn severity, posttraumatic stress (PTS) symptoms and baseline itch intensity were examined as potential predictors of the profiles in a Multi-nominal regression analysis. Neuropathic pain occurred in 54% after discharge which decreased to 24% 18 months later. Itch intensity was highest in the chronic itch & pain profile. Compared to the transient itch profile, the chronic itch & pain profile was associated with higher burn severity and more PTS symptoms. Compared to the chronic itch profile, the chronic itch & pain profile was associated with more PTS symptoms. Findings suggest that biological and psycho-dermatological processes underlie both chronic neuropathic pain and itch processes in burn scars. Further research should elucidate the mechanisms underlying the different itch profiles, with specific focus on skin innervation and psychological factors.

Can We Utilize PROMIS Neuropathic Pain Quality for Assessment of Neuropathic Heel Pain?

Category: Hindfoot; Other Introduction/Purpose: Heel pain is one of the most common presentations encountered by foot and ankle specialists. While most etiologies of heel pain such as plantar fasciitis are mechanical stress driven nociceptive pain, a combined neuropathic mechanism may contribute to worse outcomes and challenges in pain management for a subset of these patients. Diagnosis and management of neuropathic pain in foot and ankle patients remain challenging. Since neuropathic pain may play an important part in indicating surgery or counseling heel pain patients, we investigated the plausibility of utilizing the Patient-Reported Outcomes Measurement Information System (PROMIS) Neuropathic Pain Quality (PQN) as an initial screening tool to diagnose and monitor the clinical effects of treatment. Secondary outcomes were prevalence of neuropathic pain and associated risk factors. Methods: New patients presenting to a tertiary care academic institution with heel pain were prospectively recruited. PROMIS PQN t-scores were obtained from all patients to detect and determine the severity of NP. Patients were grouped into no neuropathic pain (NP), mild neuropathic pain (NP), and severe NP based on the initial PROMIS PQN t-scores. Pain Interference (PI), Physical Function (PF), and Self-Efficacy (SE) scores were assessed at baseline, 30, and 90-day follow-up timepoints. Other factors such as age, smoking, body mass index (BMI), low back/neck pain, anxiety, depression, and medications were analyzed for association with outcomes. Linear mixed modeling was utilized to assess the main effects of time and NP on PROMIS t-scores, and meaningful clinically important difference (MCID) was compared. Results: A total of 48 patients with mean age of 52.4+-12.5 years old were recruited at the initial visit. The cohort consisted of 35 (73%) female patients, 7 (15%) diabetics, 6 (13%) current smokers, 18 (38%) with low back/neck pain, 6 (13%) with anxiety, 15 (31%) with depression, and 9 (19%) had taken neuromodulator, such as gabapentin. When using the PROMIS PQN as the assessment tool, 33 patients (69%) had NP at baseline; 23 (48%) with mild, and 10 (21%) with severe NP. BMI was the only significant independent factor associated with NP (p = 0.011). Higher baseline NP was significantly associated with higher PQN (p<0.001) and PI (p=0.005), and lower SE (p=0.04) across timepoints. Patients who were detected to have NP based on the PQN t-score had lower PF at baseline with significantly less improvement in PF (3 vs 9.9, p=0.035), and did not meet MCID (Figure 1). Conclusion: Prevalence of neuropathic pain in patients presenting with heel pain was high. Neuropathic pain at baseline was significantly associated with worse pain and self-efficacy over time, and less clinically meaningful improvements in function. The PROMIS PQN may serve as a valuable tool to identify and guide clinical treatment decision pathways for patients with neuropathic heel pain.

Development of a PET radioligand for α2δ-1 subunit of calcium channels for imaging neuropathic pain

Neuropathic pain affects 7–10% of the adult population. Being able to accurately monitor biological changes underlying neuropathic pain will improve our understanding of neuropathic pain mechanisms and facilitate the development of novel therapeutics. Positron emission tomography (PET) is a noninvasive molecular imaging technique that can provide quantitative information of biochemical changes at the whole-body level by using radiolabeled ligands. One important biological change underlying the development of neuropathic pain is the overexpression of α2δ-1 subunit of voltage-dependent calcium channels (the target of gabapentin). Thus, we hypothesized that a radiolabeled form of gabapentin may allow imaging changes in α2δ-1 for monitoring the underlying pathophysiology of neuropathic pain. Here, we report the development of two 18F-labeled derivatives of gabapentin (trans-4-[18F]fluorogabapentin and cis-4-[18F]fluorogabapentin) and their evaluation in healthy rats and a rat model of neuropathic pain (spinal nerve ligation model). Both isomers were found to selectively bind to the α2δ-1 receptor with trans-4-[18F]fluorogabapentin having higher affinity. Both tracers displayed around 1.5- to 2-fold increased uptake in injured nerves over the contralateral uninjured nerves when measured by gamma counting ex vivo. Although the small size of the nerves and the signal from surrounding muscle prevented visualizing these changes using PET, this work demonstrates that fluorinated derivatives of gabapentin retain binding to α2δ-1 and that their radiolabeled forms can be used to detect pathological changes in vitro and ex vivo. Furthermore, this work confirms that α2δ-1 is a promising target for imaging specific features of neuropathic pain.

The COVID-19 pandemic and its consequences for chronic pain: a narrative review.

SummaryThe COVID‐19 pandemic transformed everyday life, but the implications were most impactful for vulnerable populations, including patients with chronic pain. Moreover, persistent pain is increasingly recognised as a key manifestation of long COVID. This narrative review explores the consequences of the COVID‐19 pandemic for chronic pain. Publications were identified related to the COVID‐19 pandemic influence on the burden of chronic pain, development of new‐onset pain because of long COVID with proposed mechanisms and COVID‐19 vaccines and pain interventions. Broadly, mechanisms underlying pain due to SARS‐CoV‐2 infection could be caused by ‘systemic inflammatory‐immune mechanisms’, ‘direct neuropathic mechanisms’ or ‘secondary mechanisms due to the viral infection or treatment’. Existing chronic pain populations were variably impacted and social determinants of health appeared to influence the degree of effect. SARS‐CoV‐2 infection increased the absolute numbers of patients with pain and headache. In the acute phase, headache as a presenting symptom predicted a milder course. New‐onset chronic pain was reportedly common and likely involves multiple mechanisms; however, its prevalence decreases over time and symptoms appear to fluctuate. Patients requiring intensive support were particularly susceptible to long COVID symptoms. Some evidence suggests steroid exposure (often used for pain interventions) may affect vaccine efficacy, but there is no evidence of clinical repercussions to date. Although existing chronic pain management could help with symptomatic relief, there is a need to advance research focusing on mechanism‐based treatments within the domain of multidisciplinary care.

Understanding Sensitization, Cognitive and Neuropathic Associated Mechanisms behind Post-COVID Pain: A Network Analysis.

This study aimed to describe a network including demographic, sensory-related, psychological/cognitive and other variables in individuals with post-COVID pain after hospitalization. Demographic (i.e., age, height, weight, months with symptoms), sensory-related (Central Sensitization Inventory -CSI-, Self-Report Leeds Assessment of Neuropathic Symptoms -S-LANSS-, PainDETECT), psychological/cognitive (Hospital Anxiety and Depression Scale -HADS-A/HADS-D-, Pain Catastrophizing Scale -PCS-, Tampa Scale for Kinesiophobia -TSK-11-) and other (sleep quality and health-related quality of life -EQ/5D/5L) variables were collected in 146 COVID-19 survivors with post-COVID pain. A network analysis was conducted to quantify the adjusted correlations between the modelled variables, and to assess their centrality indices (i.e., the connectivity with other symptoms in the network and the importance in the system modelled as network). The network revealed associations between sensory-related and psychological/cognitive variables. PainDETECT was associated with S-LANSS (: 0.388) and CSI (: 0.207). Further, CSI was associated with HADS-A (: 0.269), TSK-11 (: 0.165) and female gender (: 0.413). As expected, HADS-A was associated with HADS-D (: 0.598) and TSK-11 with PCS (: 0.405). The only negative association was between sleep quality and EQ-5D-5L (: −0.162). Gender was the node showing the highest strength, closeness, and betweenness centralities. In addition, CSI was the node with the second highest closeness and betweenness centralities, whereas HADS-D was the node with the second highest strength centrality. This is the first study applying a network analysis for phenotyping post-COVID pain. Our findings support a model where sensitization-associated symptoms, neuropathic phenotype, and psychological aspects are connected, reflecting post-COVID pain as a nociplastic pain condition. In addition, post-COVID pain is gender dependent since female sex plays a relevant role. Clinical implications of current findings, e.g., developing treatments targeting these mechanisms, are discussed.

Long‐term observational studies with cannabis‐based medicines for chronic non‐cancer pain: A systematic review and meta‐analysis of effectiveness and safety

This systematic review evaluated the effectiveness, tolerability and safety of cannabis-based medicines (CbMs) for chronic non-cancer pain (CNCP) in long-term observational studies. CENTRAL, EMBASE and MEDLINE were searched until December 2021. We included prospective observational studies with a study duration ≥26 weeks. Pooled estimates of event rates of categorical data and standardized mean differences (SMD) of continuous variables were calculated using a random effects model. Six studies were included with 2686 participants, with study duration ranging between 26 and 52 weeks. Pain conditions included nociceptive, nociplastic, neuropathic and mixed pain mechanisms. The certainty of evidence for every outcome was very low. The weighted mean difference of mean pain reduction was 1.75 (95% confidence interval [CI] 0.72 to 2.78) on a 0-10 scale. 20.8% (95% CI 10.2% to 34.0%) of patients reported pain relief of 50% or greater. The effect size for sleep problems was moderate and for depression and anxiety was low. Study completions was reported for 53.3% (95% CI 26.8% to 79.9%) of patients, with dropouts of 6.8% (95% CI 4.3% to 9.7%) due to adverse events. Serious adverse events occurred in 3.0% (95 CI 0.02% to 12.8%) and 0.3% (95% CI 0.1% to 0.6%) of patients died. Information included in observational studies should be regarded with caution. Within the context of observational studies. CbMs had positive effects on multiple symptoms for some CNCP patients and were generally well tolerated and safe. There is very low quality evidence for the long-term effectiveness (pain, sleep, mood, health-related quality of life), tolerability and safety of medical cannabis for chronic non-cancer pain (CNCP) according to reports of prospective observational studies. Predefined criteria of a large magnitude of effect size in these types of studies were not met. Nevertheless, long-term medical cannabis therapy can be considered in some carefully selected and monitored patients with CNCP.

Toward Composite Pain Biomarkers of Neuropathic Pain-Focus on Peripheral Neuropathic Pain.

Chronic pain affects ~10–20% of the U.S. population with an estimated annual cost of $600 billion, the most significant economic cost of any disease to-date. Neuropathic pain is a type of chronic pain that is particularly difficult to manage and leads to significant disability and poor quality of life. Pain biomarkers offer the possibility to develop objective pain-related indicators that may help diagnose, treat, and improve the understanding of neuropathic pain pathophysiology. We review neuropathic pain mechanisms related to opiates, inflammation, and endocannabinoids with the objective of identifying composite biomarkers of neuropathic pain. In the literature, pain biomarkers typically are divided into physiological non-imaging pain biomarkers and brain imaging pain biomarkers. We review both types of biomarker types with the goal of identifying composite pain biomarkers that may improve recognition and treatment of neuropathic pain.

Patient-reported outcome measures (PROMs) and palliative-care clinician reported outcomes (ClinROs) mutually improve pain and other symptoms assessment of hospitalized cancer-patients.

Patients with malignant diseases are known to have a high symptom burden including pain, and insufficient treatment of pain in this population has been frequently documented. To promote the integration of specialized palliative care and hematology and oncology, this study investigated disease, treatment, and comorbidity related symptoms as well as functional capacity and health-related quality of life (HQoL) by patient-reported outcome measures (PROMs) and clinician-reported outcome measures (ClinROs) among inpatients in a comprehensive cancer center. This cross-sectional study was carried out in a large comprehensive cancer centre of both oncological and hematological inpatients. It combined the use of PROMs and ClinROs. A high symptom burden was reported with fatigue and appetite loss as the most frequent symptoms, and role function being the most impaired function. Further, a low HQoL score was associated with a high number of symptoms/impairments. More than half of all patients reported pain in the last 24h. Out of 95 patients with average pain >0 in the last 24h, 71% were treated with opioids and 24% were treated with adjuvant analgesic (AA) defined as antiepileptics, antidepressants and prednisolone. Out of 57 patients with average pain >0 in the last24h and possible neuropathic pain, 33% were treated with AAs. A high odds ratio for moderate/severe pain in patients with possible neuropathic pain mechanisms was observed. This study did not only emphasize the need for systematic use of PROMs to identify symptoms and needs for inpatients, but also displayed why PROMs supported by ClinROs are a prerequisite to deliver truly individualized and high-quality patient-centered care. This study calls for continuous training of health care professionals to deliver high-quality treatment of pain. Further, it contributes to the growing recognition, that palliative care and standard care must be integrated to strengthen patient-centered care.

Features and methods to discriminate between mechanism-based categories of pain experienced in the musculoskeletal system: a Delphi expert consensus study.

Classification of musculoskeletal pain based on underlying pain mechanisms (nociceptive, neuropathic, and nociplastic pain) is challenging. In the absence of a gold standard, verification of features that could aid in discrimination between these mechanisms in clinical practice and research depends on expert consensus. This Delphi expert consensus study aimed to: (1) identify features and assessment findings that are unique to a pain mechanism category or shared between no more than 2 categories and (2) develop a ranked list of candidate features that could potentially discriminate between pain mechanisms. A group of international experts were recruited based on their expertise in the field of pain. The Delphi process involved 2 rounds: round 1 assessed expert opinion on features that are unique to a pain mechanism category or shared between 2 (based on a 40% agreement threshold); and round 2 reviewed features that failed to reach consensus, evaluated additional features, and considered wording changes. Forty-nine international experts representing a wide range of disciplines participated. Consensus was reached for 196 of 292 features presented to the panel (clinical examination-134 features, quantitative sensory testing-34, imaging and diagnostic testing-14, and pain-type questionnaires-14). From the 196 features, consensus was reached for 76 features as unique to nociceptive (17), neuropathic (37), or nociplastic (22) pain mechanisms and 120 features as shared between pairs of pain mechanism categories (78 for neuropathic and nociplastic pain). This consensus study generated a list of potential candidate features that are likely to aid in discrimination between types of musculoskeletal pain.

Andrographolide regulates phosphorylated p38 mitogen-activated protein kinases and phosphorylated ERK expression in spinal cord and reduces postoperative pain in rats

Andrographolide (Andro) is one of the medically important phytocompounds that has multiple biological properties such as anti-biotic, analgesic, anti-diabetic, anti-viral activities. Recently, andro has gained interest of various clinicians in management of physiological and neuropathic pain mechanisms. In the current study, we analyzed the effect of andro in downregulation of phosphorylated MAPK (p38) and ERK that help in relieving the post-operative pain in rats. Open incisional wound was made in the hind paw of Sprague-Dawley rats and were segregated as control animals (saline) and andro injected animals (0.5 mg/kg of bodyweight). Spinal cord sample was collected 4 days after surgery to study the p38 & pERK expressions by immunofluorescence. Reduction of p38 (∼50%) & pERK (∼30%) expressions was observed in the dorsal funiculus and dorsal horn region of spinal cord, respectively, obtained from animals injected with andro compared to control rats. This suggested that, post-operative pain was relieved in the andro injected animals compared to control rats injected with saline, possibly through down regulated expression of these kinases at the respective regions in spinal cord. In conclusion, andro has shown the potential to relieve the surgical pain by reduction of p38 & pERK expression which could be supportive for patients in pre- and post-operative care.

Differential Effects of Treatment Strategies in Individuals With Chronic Ocular Surface Pain With a Neuropathic Component.

Background: Dysfunction at the ocular system via nociceptive or neuropathic mechanisms can lead to chronic ocular pain. While many studies have reported on responses to treatment for nociceptive pain, fewer have focused on neuropathic ocular pain. This retrospective study assessed clinical responses to pain treatment modalities in individuals with neuropathic component ocular surface pain. Methods: 101 individuals seen at the University of Miami Oculofacial Pain Clinic from January 2015 to August 2021 with ≥3 months of clinically diagnosed neuropathic pain were included. Patients were subcategorized (postsurgical, post-traumatic, migraine-like, and laterality) and self-reported treatment outcomes were assessed (no change, mild, moderate, or marked improvement). One-way ANOVA (analysis of variance) was used to examine relationships between follow up time and number of treatments attempted with pain improvement, and multivariable logistic regression was used to assess which modalities led to pain improvement. Results: The mean age was 55 years, and most patients were female (64.4%) and non-Hispanic (68.3%). Migraine-like pain (40.6%) was most common, followed by postsurgical (26.7%), post-traumatic (16.8%) and unilateral pain (15.8%). The most common oral therapies were α2δ ligands (48.5%), the m common topical therapies were autologous serum tears (20.8%) and topical corticosteroids (19.8%), and the most common adjuvant was periocular nerve block (24.8%). Oral therapies reduced pain in post-traumatic (81.2%), migraine-like (73%), and unilateral (72.7%) patients, but only in a minority of postsurgical (38.5%) patients. Similarly, topicals improved pain in post-traumatic (66.7%), migraine-like (78.6%), and unilateral (70%) compared to postsurgical (43.7%) patients. Non-oral/topical adjuvants reduced pain in postsurgical (54.5%), post-traumatic (71.4%), and migraine-like patients (73.3%) only. Multivariable analyses indicated migraine-like pain improved with concomitant oral α2δ ligands and adjuvant therapies, while postsurgical pain improved with topical anti-inflammatories. Those with no improvement in pain had a shorter mean follow-up (266.25 ± 262.56 days) than those with mild (396.65 ± 283.44), moderate (652 ± 413.92), or marked improvement (837.93 ± 709.35) (p < 0.005). Identical patterns were noted for number of attempted medications. Conclusion: Patients with migraine-like pain frequently experienced pain improvement, while postsurgical patients had the lowest response rates. Patients with a longer follow-up and who tried more therapies experienced more significant relief, suggesting multiple trials were necessary for pain reduction.

Transcranial Direct Current Stimulation (tDCS) Combined with Therapeutic Exercise and Cognitive Rehabilitation to Treat a Case of Burning Mouth Syndrome (BMS) Related Pain

Burning Mouth Syndrome (BMS) is a multifactorial, chronic pain condition with neuropathic and psychogenic mechanisms. Cortical activation as well as sustained attention and executive functions have proven to be affected by chronic pain. The main objectives of this work were to test the efficacy of a multidimensional personalized pain treatment protocol and to investigate if the effects are based on psychophysical pain processing changes or cognitive effects. A 74-year-old female with 2 years of BMS received 10 sessions of a combined protocol of anodal left dorsolateral prefrontal cortex tDCS, cognitive therapy, and therapeutic exercise. The subjective perception of pain decreased by 47% after treatment but returned to the baseline at 45 days. No changes were found in objective pain measurements apart from a transient worsening of conditioned pain modulation. A large effect size was found in all functional scales, processing speed and executive control as well as sustained attention that persisted during follow-up. No changes in anxiety and depression were found. A multimodal therapeutic approach combining TDCS, cognitive rehabilitation and therapeutic exercise produces improved quality of life, disability and pain perception correlated with improvements in processing speed, executive control and sustained attention but independent of changes in psychophysical pain processing.

Complexity Assessment of Chronic Pain in Elderly Knee Osteoarthritis Based on Neuroimaging Recognition Techniques.

The chronic pain of knee osteoarthritis in the elderly is investigated in detail in this paper, as well as the complexity of chronic pain utilising neuroimaging recognition techniques. Chronic pain in knee osteoarthritis (KOA) has a major effect on patients' quality of life and functional activities; therefore, understanding the causes of KOA pain and the analgesic advantages of different therapies is important. In recent years, neuroimaging techniques have become increasingly important in basic and clinical pain research. Thanks to the application and development of neuroimaging techniques in the study of chronic pain in KOA, researchers have found that chronic pain in KOA contains both injury-receptive and neuropathic pain components. The neuropathic pain mechanism that causes KOA pain is complicated, and it may be produced by peripheral or central sensitization, but it has not gotten enough attention in clinical practice, and there is no agreement on how to treat combination neuropathic pain KOA. As a result, using neuroimaging techniques such as magnetic resonance imaging (MRI), electroencephalography (EEG), magnetoencephalography (MEG), and near-infrared spectroscopy (NIRS), this review examines the changes in brain pathophysiology-related regions caused by KOA pain, compares the latest results in pain assessment and prediction, and clarifies the central brain analgesic mechanistic. The capsule network model is introduced in this paper from the perspective of deep learning network structure to construct an information-complete and reversible image low-level feature bridge using isotropic representation, predict the corresponding capsule features from MRI voxel responses, and then, complete the accurate reconstruction of simple images using inverse transformation. The proposed model improves the structural similarity index by about 10%, improves the reconstruction performance of low-level feature content in simple images by about 10%, and achieves feature interpretation and analysis of low-level visual cortical fMRI voxels by visualising capsule features, according to the experimental results.

Oral and parenteral anti-neuropathic agents for the management of pain and discomfort in irritable bowel syndrome: A systematic review and meta-analysis.

Irritable bowel syndrome (IBS) is a highly prevalent and economically burdensome condition; and pain is often the most unpleasant, disruptive, and difficult-to-treat symptom. Visceral hypersensitivity is a common feature driving pain in IBS, suggesting that neuropathic mechanisms may be implicated. We conducted a systematic review of available evidence to examine the role of anti-neuropathic medicines in the management of pain in IBS. We systematically searched scientific repositories for trials investigating conventional oral, and/or parenteral, pharmaceutical antineuropathic treatments in patients with IBS. We summarized key participant characteristics, outcomes related to pain (primary outcome), and selected secondary outcomes. We included 13 studies (n=629 participants): six investigated amitriptyline, three duloxetine, three pregabalin, and one gabapentin. There was considerable methodological and statistical heterogeneity, so we performed a narrative synthesis and limited meta-analysis. Amitriptyline was most extensively studied, though only in diarrhea-predominant patients. In individual trials, amitriptyline, pregabalin and gabapentin generally appeared beneficial for pain outcomes. While duloxetine studies tended to report improvements in pain, all were un-controlled trials with high risk of bias. Meta-analysis of three studies (n=278) yielded a pooled relative-risk of 0.50 (95%CI 0.38-0.66) for not improving with anti-neuropathic agent vs control. We did not identify any eligible studies investigating the role of parenteral anti-neuropathics. Anti-neuropathic analgesics may improve pain in IBS, and deserve further, high-quality investigation, potentially considering parenteral administration and agents with minimal gastrointestinal motility effects. Investigation of amitriptyline's efficacy in non-diarrhea-predominant subtypes is currently lacking, and we recommend particular caution for its use in IBS-C.

Evaluation of serum neuron specific enolase levels among patients with primary and secondary burning mouth syndrome.

Burning mouth syndrome is a painful condition of the oral cavity with ambiguous pathogenesis and diagnosis. Neuron-specific enolase is increased in several conditions including peripheral neuropathy of diabetes, ophthalmopathies, spinal cord injuries and tumors. Evidence on association of burning mouth syndrome and neuron-specific enolase is limited. This study aims to evaluate neuron-specific enolase levels in primary and secondary burning mouth syndrome patients and compare the levels of neuron-specific enolase with associated conditions in secondary burning mouth syndrome. One hundred and twenty-eight patients of more than 18 years of age with no gender predilection and having clinical symptoms of burning mouth syndrome and 135 healthy subjects were included. All the patients fulfilled Scala's criteria for the diagnosis of burning mouth syndrome, including "primary" (idiopathic) and "secondary" (resulting from identified precipitating factors) burning mouth syndrome patients. Blood samples were obtained from burning mouth syndrome patients. Serum neuron-specific enolase was evaluated using enzyme-linked immunosorbent assay. To compare means and standard deviations, among primary and secondary burning mouth syndrome, data was analysed with analysis of variance and multiple comparisons test. The mean age of the study participants for burning mouth syndrome and healthy subjects was 53.30 and 51.6 years, respectively. Amongst the secondary burning mouth syndrome group, 32 (25%) of the patients had menopause, 15 (11.7%) had diabetes, eight (6.2%) of the patients had nutritional deficiency, seven (5.4%) had combined diabetes, menopause, and depression, six (4.6%) had combined diabetes and depression, four (3.1%) were diagnosed with Sjögren's syndrome. A minor percentage of 2.3% (three) had gastroesophageal reflux disease, while the remaining three (2.3%) patients in the secondary burning mouth syndrome group were on anti-depressants. There was a statistically significant increase in the levels of neuron-specific enolase in primary burning mouth syndrome as compared to the secondary burning mouth syndrome and healthy groups. Among the subgroups of secondary burning mouth syndrome, diabetic individuals showed a significant increase in neuron-specific enolase level when compared with other conditions in the secondary burning mouth syndrome patients.Discussion and conclusion: The raised serum neuron-specific enolase levels in patients suffering from primary burning mouth syndrome highlight a possible neuropathic mechanism. It was also increased in the sub-group of secondary burning mouth syndrome patients having diabetes. Although it cannot be ascertained whether the deranged values in the diabetic group were due to burning mouth syndrome or due to diabetes, the raised quantity of neuron-specific enolase in the primary burning mouth syndrome group is a reliable diagnostic indicator. Future studies on the assessment of neuron-specific enolase levels as a diagnostic tool for onset and management of primary and secondary burning mouth syndrome are recommended.

Gambogic Acid Relieves Neuropathic Pain in Rats by Regulating CXCR4-TXNIP/NLRP3 Pathway

Neuropathic pain is caused by abnormal sensory processing in the central nervous system (CNS). The immune response of the CNS is related to the function of glial cells and is critical in neuropathic pain. Agents based on cytokines and glial cells in the CNS have potential for the treatment of neuropathic pain. Gambogic acid (GA) is one of the main components of Garcinia cambogia, which has anti-inflammatory, antitumor, and analgesic effects. However, the effect of GA on neuropathic pain and related mechanisms are still unclear. Previous studies indicated that GA could reduce CXCR4 expression in neuropathic pain. In this study, we found that GA could alleviate nerve pain behavior in rats by measuring the incubation period of heat shrinkage and mechanical pain threshold. Also, GA reduced inflammation in chronic constriction injury rats. We further found GA reduced the apoptosis of spinal cord nerve cells in chronic constriction injury rats. Mechanically, we noticed GA relieved neuropathic pain in rats via regulating CXCR4-TXNIP/NLRP3 pathway. Our data confirmed that GA could serve as a promising drug for the treatment of neuropathic pain.