Peripheral neuropathic pain (PNP) is a chronic condition that often requires long-term treatment. In 2025, the Neuropathic Pain Special Interest Group (NeuPSIG) updated its recommendations for treatment of neuropathic pain based on data from double-blind, randomized controlled trials (RCTs) with a duration of ≥ 3 weeks. To complement the existing body of evidence, we reviewed the long-term efficacy/safety of NeuPSIG-recommended treatments for PNP. We conducted a systematic literature review including clinical trials and observational studies of any design. Two literature searches were performed using PubMed and Embase (December 2024, May 2025). We included studies that enrolled ≥ 50 adult patients with PNP receiving ≥ 1 treatment recommended in the 2025 NeuPSIG guidance and with duration of ≥ 13 weeks. A supplemental search for long-term studies on high-concentration capsaicin 8
Knee osteoarthritis (OA) is a major cause of disability worldwide and disproportionately affects women and individuals with obesity. Treatment response might vary by sex and body mass index (BMI). This study assessed whether celecoxib pain reduction differs across sex (male versus female) or BMI (obese ≥ 30 kg/m2 versus nonobese < 30 kg/m2) in knee OA patients, using change from baseline in Visual Analog Scale (VAS) pain at Week 6 as primary endpoint. This post hoc pooled analysis included two randomized, double-blind, placebo-controlled trials (NH49-96-02-060; NH49-98-02-087). Adults with knee OA flare and baseline VAS pain ≥ 40 mm received placebo, 100 mg of celecoxib twice daily (BID), or 200 mg once daily (OD) for 6 weeks. Mild baseline pain was excluded to align with original trial criteria. The full analysis set (FAS) included patients with ≥ 1 dose and ≥ 1 post-baseline assessment. Primary subgroups were assessed using analysis of covariance (ANCOVA) with last observation carried forward (LOCF) for missing data, with longitudinal evaluation at Week 2 and 6 using mixed model for repeated measures (MMRM). Sensitivity analyses using alternative imputation methods were also performed. A total of 1360 participants (427 men, 933 women) were included. Baseline VAS pain score was higher in women and patients with obesity (both p < 0.0001), who also showed greater placebo response. At Week 6, both celecoxib regimens significantly reduced pain versus placebo across sex and BMI subgroups. Women had greater observed pain reductions with similar efficacy between sexes, and obese participants showed comparable benefit with both doses. Similar findings were observed in MMRM analyses. Celecoxib provided rapid, sustained OA pain relief across the two subpopulations. 100 mg of celecoxib BID and 200 mg OD showed consistent analgesic efficacy across sex and BMI subgroups, despite higher baseline pain and stronger placebo response in women and obese participants. These findings support the use of either regimen across diverse OA patient profiles and suggest that baseline pain differences do not necessarily reduce response to cyclooxygenase (COX)-2 inhibition.
Musculoskeletal injuries (MSKI) often progress from acute tissue damage to chronic pain and dysfunction when mechanical overload and microdamage sustain sterile inflammation and neuroimmune sensitization. These processes amplify nociception, impair loading tolerance, and limit the efficacy of rehabilitation, underscoring the need for mechanism-based strategies that interrupt the transition from acute injury to chronic musculoskeletal disease. This etiological review was conducted in accordance with the Scale for the Assessment of Narrative Review Articles (SANRA) guidelines. A comprehensive search of PubMed/MEDLINE and Google Scholar (1990–2026) identified mechanistic, translational, and therapeutic research reports that examined damage-associated molecular pattern (DAMP) signaling, innate immune activation, stromal cell responses, nociceptor sensitization, and interventions targeting these pathways. Eligible studies addressed DAMP-related mechanisms in musculoskeletal tissues or evaluated therapies that modulate the underlying inflammatory and mechanobiological drivers of chronic MSKI. Information was synthesized thematically to construct an integrated model of how DAMPs contribute to chronicity. Across tendon, cartilage, ligament, muscle, and fibrocartilage, mechanical overload and microdamage trigger the release of DAMPs that activate Toll-like receptors (TLRs), receptor for advanced glycation end-products (RAGE), and inflammasome pathways, thereby sustaining cytokine production, stromal cell activation, and nociceptor sensitization. Persistent DAMP signaling is strongly associated with impaired inflammation resolution, failed tissue healing, and progression to chronic tendinopathy, osteoarthritis, and mechanical low back pain. Emerging therapeutic approaches, including targeted loading, regenerative injections, metabolic modulation, and immune-modifying strategies, demonstrate potential to attenuate DAMP activity, promote resolution, and restore tissue homeostasis. Sterile inflammation driven by DAMPs provides a unifying mechanistic framework explaining why many musculoskeletal injuries fail to resolve and instead evolve into chronic, refractory conditions. Therapies that modulate DAMP signaling, enhance inflammatory resolution, and normalize mechanobiological loading represent promising avenues for preventing or reversing chronic MSKI pathology. A mechanistically informed approach may improve clinical outcomes by addressing the etiological drivers rather than the downstream symptoms of chronic musculoskeletal disease.
Suzetrigine, a non-opioid voltage-gated sodium channel 1.8 (NaV1.8) pain signal inhibitor with no addiction potential, is approved in the USA for moderate-to-severe acute pain. In this phase 4, single-arm study, suzetrigine (100 mg preoperatively, then 50 mg every 12 h) was administered as part of multimodal therapy (MMT) for ≤ 14 days. Participants (N = 47) underwent arthroscopic or laparoscopic procedures wherein opioids are commonly used ≥ 72 h postoperatively for pain management. Pre- and postoperative MMT was prespecified as suzetrigine, acetaminophen, and ibuprofen. Oxycodone or hydromorphone were permitted as opioid rescue. The primary endpoint was the proportion of participants reporting good/very good/excellent on a patient global assessment (PGA) for pain control after treatment. Opioid rescue and safety were also assessed. Participants had various surgeries, the most common being arthroscopic knee procedures (38.3
Targeted neuromodulation therapies are increasingly used for the management of peripheral neuropathy; however, data on symptom and functional outcomes following standardized treatment courses remain limited. This report evaluates the efficacy of NeuroGen Neuromodulation treatments administered at the National Neuropathy Center, focusing on changes in sensory symptoms and functional task performance from the first treatment (T1) to the twelfth treatment (T12) over a mean treatment duration of 36 sessions. Patients completing a standardized 12-treatment course using the NeuroGen Neuromodulation device were analyzed. Outcomes included patient-reported sensory symptoms (tingling, numbness, and pain) and measures of functional task performance. Changes from baseline (T1) to posttreatment (T12) were assessed to determine treatment effectiveness, response patterns, and areas for clinical optimization. Patients demonstrated clear and measurable benefits following completion of 12 treatments. The greatest improvements were observed in sensory symptoms, with tingling, numbness, and pain each improving by approximately one point on the severity scale. More than half of patients achieved clinically meaningful relief in these sensory domains. Functional improvement was more modest, with meaningful gains observed in approximately one-quarter to one-third of patients. Nonresponse rates were low, although residual symptoms and functional limitations remained common. The standard NeuroGen Neuromodulation treatment protocol provides substantial relief of sensory neuropathic symptoms, with consistent benefits across patients. While functional gains were less pronounced, the low nonresponse rate supports overall treatment effectiveness. Persistent symptoms in some patients suggest a potential role for maintenance therapy and adjunctive interventions to optimize long-term outcomes.
Regenerative medicine has emerged as a transformative paradigm in contemporary healthcare, shifting the therapeutic focus from symptomatic management toward the restoration of tissue structure and function through biologically active interventions. Within this framework, adipose-derived products have attracted substantial interest owing to their relative abundance, ease of harvesting, and rich cellular and paracrine composition, including mesenchymal stromal cells, pericytes, and bioactive mediators with immunomodulatory potential. Among these technologies, microfragmented adipose tissue (MFAT) constitutes an innovative, minimally manipulated approach because it preserves the native stromal vascular niche and extracellular matrix architecture while avoiding enzymatic processing. This characteristic not only maintains biological integrity but also facilitates regulatory compliance in multiple jurisdictions. This narrative review provides a comprehensive synthesis of the current evidence on microfragmented adipose tissue in pain management, integrating biological rationale, mechanistic insights, and clinical applications across musculoskeletal disorders and chronic pain conditions. Particular attention is devoted to its capacity to modulate inflammatory pathways, promote angiogenesis, and support tissue regeneration within complex pathological environments. In addition, the review critically appraises the methodological limitations of existing clinical studies, including heterogeneity of design and limited high-quality randomized evidence. Finally, future perspectives are explored, emphasizing the integration of precision medicine approaches, biomarker-driven patient stratification, and combinatorial regenerative strategies to optimize therapeutic outcomes.
Moderate-to-severe postoperative pain is common after cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC). Evidence that liposomal bupivacaine provides clinically important advantages over conventional local anesthetics is inconsistent, and evidence in CRS + HIPEC remains limited. This trial evaluated the incremental efficacy and safety of liposomal bupivacaine incisional infiltration added to patient-controlled intravenous analgesia (PCIA) compared with saline infiltration plus PCIA. In this single-center, randomized, participant- and assessor-blinded, placebo-controlled trial, adults aged 18–65 years scheduled for elective CRS + HIPEC were assigned 1:1 to standardized PCIA plus liposomal bupivacaine incisional infiltration (PCIA-LB) or PCIA plus normal saline infiltration (PCIA-NS). The primary endpoint was the incidence of moderate-to-severe movement-evoked incisional pain (numeric rating scale > = 4) within 72 h. The prespecified primary efficacy analysis used the per-protocol set (PPS), with a conservative intention-to-treat (ITT) sensitivity analysis. PCIA followed an institutional standard operating procedure. Monitoring was continuous in the intensive care unit (ICU); after transfer to the ward, pulse oximetry was continued through postoperative day 3, with intermittent electrocardiography and noninvasive blood pressure monitoring. The PPS included 94 patients (PCIA-NS, n = 48; PCIA-LB, n = 46). Moderate-to-severe movement-evoked pain within 72 h was less frequent with PCIA-LB than with PCIA-NS (19.6
Persistent postoperative low back pain remains a concern after unilateral biportal endoscopic (UBE) surgery, but the impact of surgery-related interspinous ligament edema is unclear. This study investigated whether magnetic resonance imaging (MRI)-detected interspinous ligament region edema (ISLRE) was associated with delayed pain recovery and persistent postoperative low back pain after UBE surgery. This retrospective cohort study included patients who underwent single-level UBE surgery between October 2021 and October 2024. On the basis of MRI within 3 days postoperatively, ISLRE was graded as grade 0 (no/minimal edema), grade 1 (localized edema), or grade 2 (diffuse or confluent edema involving most of the operated interspinous region). Clinical outcomes included visual analogue scale scores for low back pain (VAS-LBP), Oswestry disability index (ODI), and persistent postoperative low back pain, defined as 12-month VAS-LBP > 3. Multivariable linear and logistic regression analyses were performed to assess independent associations, and linear mixed-effects modeling was used to evaluate longitudinal pain recovery trajectories. A total of 245 patients were included (grade 0: n = 117; grade 1: n = 74; grade 2: n = 54). Interobserver agreement for MRI grading was substantial (κ = 0.802). At 12 months, VAS-LBP scores increased progressively across edema grades (1.66 ± 1.20, 2.34 ± 1.45, and 3.54 ± 1.65 for grades 0–2, respectively; P < 0.001), while persistent postoperative low back pain occurred in 21.4
Spinal cord stimulation (SCS) has emerged as a promising modality for managing zoster-associated pain (ZAP). This study aimed to evaluate the efficacy and safety of short-term spinal cord stimulation (SCS) for treating ZAP during the subacute phase. Records of patients undergoing transforaminal epidural injection (TFEI), pulsed radiofrequency (PRF), and short-term SCS were retrospectively reviewed. A 1:2:2 propensity-score matching was performed. The primary endpoint was Numeric Rating Scale (NRS) pain scores at 3 months after rash onset. Secondary endpoints included postherpetic neuralgia (PHN) incidence, Hospital Anxiety and Depression (HADS) scores, Pittsburgh Sleep Quality Index (PSQI) scores, quality-adjusted life years (QALY) scores, and adverse events. At 3 months post-rash onset, mean NRS pain score was 1.59 ± 1.18 in SCS cohort, which was lower than that of 4.80 ± 1.41 in TFEI cohort and 4.54 ± 1.40 in PRF cohort, with the difference exceeding the prespecified minimal clinically important difference of three points (p < 0.001). PHN occurred in 8.9
This study aimed to assess knowledge gaps, perceptions, and prescribing approaches of healthcare professionals (HCPs) in Saudi Arabia regarding pain management, particularly neuropathic pain, in the context of recent reclassification of gabapentinoids. A three-lecture webinar was attended by 4922 HCPs across Saudi Arabia. Two structured surveys were embedded within the lectures: a 9-item knowledge questionnaire on pain management and a 10-item questionnaire on HCPs’ opinions and attitudes on gabapentinoid use and prescribing challenges. Responses were recorded on the platform’s interactive dashboard as percentage. The knowledge scores were normalized to percentage. Overall knowledge levels varied across specialties with internal medicine (68.7
The MiroTAS study demonstrated the pain-relieving effect and safety of mirogabalin in patients with lumbar spinal stenosis (LSS); however, whether mirogabalin-related adverse drug reactions (mrADRs) affect clinical courses, treatment continuation, or adherence remained unknown. We examined recovery outcomes and treatment status following mrADR onset and whether the analgesic effects of mirogabalin correlated with LSS and leg pain durations. This post hoc analysis of the 12-week, randomized controlled MiroTAS study summarized mrADRs (dizziness, somnolence, peripheral edema, and edema) by severity and outcome. Spearman’s rank correlations between leg pain changes and duration of LSS and leg pain were examined. Data from 214 patients in the modified intention-to-treat set (mirogabalin add-on: 110; nonsteroidal anti-inflammatory drugs alone: 104) and 216 in the safety analysis set (110 and 106 patients, respectively) were analyzed. Regarding mrADRs, 27/33 dizziness, 25/35 somnolence, 3/6 peripheral edema, and 2/2 edema events recovered or improved. Median times to recovery for dizziness and somnolence were 8.0 and 33.5 days, respectively. Recovery or improvement of dizziness and somnolence occurred in most patients even without dose modification, with a higher proportion of recovery following dose reduction. Most events with moderate dizziness or somnolence (80.0
INTRODUCTION:Migraine and tension-type headache (TTH) are leading causes of neurological disability globally. While their macro-trends are documented, the nonlinear drivers and the regulatory role of socio-economic development across G20 countries remain under-explored. METHODS:Based on Global Burden of Disease (GBD) 2023 data, the headache burden across G20 members was quantified. Developmental trajectories were identified by integrating the Socio-demographic Index (SDI). Crucially, a comparative analysis was conducted between a decomposition analysis model and an explainable machine learning framework, Shapley Additive Explanations-Extreme Gradient Boosting (SHAP-XGBoost), to quantify nonlinear marginal contributions and complex feature interactions. Finally, future trends from 2024 to 2035 were projected utilizing Autoregressive Integrated Moving Average (ARIMA) models. RESULTS:In 2023, the number of prevalent cases for migraine and TTH across G20 countries was estimated at 705 million and 1.27 billion, respectively. A significant nonlinear correlation between headache burden and the SDI was identified, with the burden for both disorders peaking at an SDI of approximately 0.8 before plateauing or declining. While population growth was identified as the primary macro-driver in both decomposition and SHAP analyses, a "saturation effect" within the headache models was revealed by SHAP analysis. Specifically, the marginal contribution of population size was found to diminish once specific thresholds were exceeded. Furthermore, according to ARIMA model projections, the age-standardized incidence rate (ASIR) of migraine is expected to stabilize in the coming years, whereas the ASIR of TTH is forecast to maintain a continuous upward trajectory through 2035. CONCLUSIONS:This study provides a comprehensive re-evaluation of migraine and TTH burden across G20 countries, shifting the focus from descriptive status quo to mechanistic explanation. Our findings confirm that while population growth remains a key contributor, variations in burden appear to be associated with differences in development level, age structure, and population scale.
INTRODUCTION:The burden of migraine on an individual's life is associated with an individual's background. However, limited evidence in Japan exists on the association of age, sex, employment, income, and family caregiving with patient-reported outcomes (PROs) and migraine treatment patterns. This analysis of the ObserVational survey of the Epidemiology, tReatment, and Care Of MigrainE (OVERCOME [Japan]) 2nd study describes the migraine burden and treatment usage of individuals with migraine across these demographic subgroups. METHODS:Participants self-reported demographic and clinical characteristics, and PRO instrument responses, such as Headache Impact Test-6, Migraine Disability Assessment Scale (MIDAS), Migraine-Specific Quality of Life Questionnaire version 2.1, Migraine Interictal Burden Scale-4 (MIBS-4), and Impact of Migraine on Partners and Adolescent Children Scale. They also reported use of over-the-counter and prescription drugs for migraine, and headache-related expenses. Descriptive statistics were reported according to sex, employment status, menstrual-related migraine status and frequency, annual personal and family income, age, and family caregiving status for the elderly. RESULTS:Female sex, unemployment, presence of menstrual-related migraine, low personal or family income, and family caregiving for elders appeared to increase migraine burden and impact prescription drug use. Specifically, men tended to have higher triptan (11.7% vs. 8.7%) and preventive medication use (18.3% vs. 11.2%) than women; unemployed women had the highest proportion of MIDAS grade IV (14.1%); women with menstrual-related migraine appeared to have greater MIBS-4 severe burden (36.3% vs. 27.8%) than those without; and family caregivers tended to have higher MIBS-4 severe burden (39.2% vs. 26.0%) and prescription drug use than non-caregivers. Respondent sex further appeared to influence migraine burden and treatment patterns within the employment and income subgroups. CONCLUSION:These data suggest certain sociodemographic groups may suffer from greater migraine burden and have reduced access to effective treatment and care. We hope this study's results will help healthcare providers and societies identify such populations with migraine and address potential clinical care gaps.
INTRODUCTION:Intrathecal drug delivery systems (IDDS) are used for selected patients with refractory cancer pain. Fully implanted and semi-implanted systems differ in implantation pathway, maintenance requirements, external component exposure, and tissue-device interaction. This study aimed to describe real-world complication profiles of these two IDDS models in a large single-center Chinese cohort. METHODS:This retrospective registry-based cohort study included 409 patients with advanced cancer who underwent initial IDDS implantation at Sichuan Cancer Hospital between 1 January 2023, and 31 December 2025. Complications were classified into level I categories and level II subtypes. Each level II complication subtype was counted once per affected patient. Frequencies were reported as counts, patient-level proportions using the device group as denominator, and event-level proportions using recorded complication events as denominator. Because detailed baseline characteristics, standardized follow-up durations, mortality timing, event timing, and paired efficacy outcomes were not systematically available, analyses were descriptive and hypothesis-generating. RESULTS:Among 409 patients, 38 received fully implanted systems and 371 received semi-implanted systems. A total of 101 complications were recorded: 10 in the fully implanted group and 91 in the semi-implanted group. In the semi-implanted group, postdural puncture headache occurred in 38 patients (10.2% of 371; 41.8% of 91 events), cerebrospinal fluid leak in 22 patients (5.9%; 24.2%), and catheter blockage in 17 patients (4.6%; 18.7%). In the fully implanted group, skin erosion occurred in four patients (10.5% of 38; 40.0% of 10 events), and inadequate analgesia occurred in two patients (5.3%; 20.0%). Findings in the fully implanted group were based on single-digit subtype counts and should not be interpreted as stable comparative risk estimates. CONCLUSIONS:Fully implanted and semi-implanted IDDS showed different recorded complication profiles in this real-world Chinese cohort. Semi-implanted systems were characterized mainly by puncture-related and catheter-pathway events, whereas fully implanted systems showed tissue-integrity and treatment-adaptation events among the small number of recorded complications. These findings support individualized device selection but cannot establish device superiority or time-dependent risk because baseline, follow-up, mortality, event-timing, and efficacy data were incomplete.
Low back pain (LBP) is a leading cause of disability worldwide, and treatment often necessitates invasive interventions that carry significant risks and economic burdens. While prior studies demonstrated durable benefit following percutaneous 60-day peripheral nerve stimulation (PNS), real-world data are needed to characterize long-term outcomes across routine clinical practice. This survey evaluated the durability of patient-reported improvements among a real-world cohort of patients with LBP who responded to 60-day PNS. A cross-sectional follow-up survey was administered to patients who previously responded to 60-day PNS targeting the lumbar medial branch nerves. Outcomes assessed included patient-reported percent pain relief and impression of change in quality of life (QoL), physical function, mood, and sleep. Participants also reported use or avoidance of other LBP treatments or interventions since completing 60-day PNS. The survey was completed by 602 participants, with follow-up durations ranging from 6 to 68 months. Overall, 79
Opioid medications play a central role in pain management but are associated with significant risks, including dependence, opioid use disorder (OUD), and overdose. In response to rising concerns, the French National Authority for Health convened a multidisciplinary working group to develop updated guidelines on the appropriate use of opioids. These recommendations, grounded in the high-level international evidence and developed through a rigorous formal consensus method, represent the most comprehensive and recent guidelines addressing the entire opioid pharmacological class, regardless of indication. The first part focuses on the clinical use of opioid analgesics in acute and chronic pain, both cancer-related and non-cancer-related. The guidelines emphasize prudent prescribing, prioritization of non-opioid therapies, and the integration of multimodal analgesia. Specific clinical situations are addressed, including management in primary care, emergency settings, postoperative care, inpatient treatment, and the perioperative management of patients already receiving opioids or opioid agonist treatment. Practical tools such as equianalgesic conversion principles, criteria for opioid rotation, and strategies to minimize adverse effects are provided to support prescribers. By considering opioids as a single pharmacological class, these guidelines enable consistent principles to be applied across diverse clinical contexts, from the initiation of short-term opioid therapy to the safe management of patients with complex dependence profiles. Although developed in France, the recommendations are intended to have international relevance, given their reliance on global evidence and their focus on balancing effective pain relief with risk reduction. A second part, addressing the prevention and management of OUD and overdoses, complements the present manuscript.
Opioid use disorder (OUD) and overdoses represent critical challenges linked to the widespread availability of opioid medications. To address these risks, the French National Authority for Health convened a multidisciplinary working group to develop comprehensive guidelines on the prevention and management of OUD and overdoses. These recommendations expand on the second part of the guidelines, which specifically addressed the prevention and management of OUD and overdoses. Grounded in the highest level of international evidence and developed through a rigorous formal consensus process, the guidelines emphasize appropriate opioid prescribing as the cornerstone of prevention. They provide practical recommendations for identifying patients at risk, detecting problematic use early, and initiating opioid agonist treatment when indicated. The role of naloxone as an essential tool to prevent fatal overdoses is highlighted, along with strategies for coordinated and multidisciplinary care across diverse healthcare settings. By integrating prevention, treatment, and harm reduction measures, these guidelines seek to balance legitimate access to opioid analgesics with robust safeguards against opioid use disorder and overdose. Although developed within the French healthcare system, their strong evidence base and underlying clinical principles make them applicable to international practice. Together with the first part on pain management, they constitute one of the most comprehensive and up-to-date sets of recommendations on the safe and effective use of opioid medications.
Transcutaneous pulsed radiofrequency (TcPRF) is a non-invasive neuromodulation technique increasingly investigated for the management of chronic pain. However, its clinical efficacy and safety across different chronic pain conditions remains uncertain. A systematic search of PubMed, Scopus, and Google Scholar was performed from database inception to March 2026. Randomized controlled trials (RCTs) evaluating TcPRF in chronic pain conditions were included. Pain intensity, functional outcomes, and safety data were extracted. Risk of bias was assessed using the Cochrane RoB 2 tool. Eight RCTs were included, encompassing both musculoskeletal and neuropathic pain conditions. TcPRF was associated with reductions in pain intensity in most studies, with more consistent effects observed in sham-controlled trials and at later follow-up time points. Functional outcomes generally improved in parallel with pain, although results varied depending on the outcome measures used. TcPRF was well tolerated, with no serious adverse events reported. However, substantial heterogeneity was noted in patient populations, comparator interventions, treatment protocols, and outcome measures. TcPRF appears to be a promising non-invasive treatment option for selected chronic pain conditions, particularly when a minimally invasive approach is preferred. Nevertheless, current evidence remains limited by heterogeneity and methodological variability. Further large-scale, well-designed RCTs with standardized treatment protocols and longer follow-up are required to clarify its clinical role.
IntroductionPulsed radiofrequency (PRF) is a pivotal neuromodulation strategy for zoster-associated pain (ZAP); however, clinical outcomes exhibit significant interindividual heterogeneity. This study aimed to identify robust predictors and develop a transparent machine learning (ML) framework to forecast treatment response, thereby facilitating individualized pain management.MethodsWe conducted a retrospective analysis of a large-scale cohort comprising 1773 patients with ZAP treated with PRF. Patients were stratified into "responders" and "nonresponders" on the basis of clinical outcomes at a 3-month follow-up. To handle an initial pool of 47 multidimensional clinical and laboratory variables, a tripartite feature selection pipeline-incorporating least absolute shrinkage and selection operator (LASSO), Boruta, and multivariable logistic regression-was implemented. We benchmarked eight ML architectures. The optimal model was interpreted using Shapley additive explanations (SHAP) to ensure biological transparency and subsequently deployed as an interactive point-of-care tool.ResultsThe favorable clinical response rate for PRF was 68.0%. A parsimonious set of five core predictors was identified: age, baseline Numerical Rating Scale (NRS) score, preoperative opioid use, apolipoprotein B (ApoB), and neutrophil-to-monocyte ratio (NMR). Among the candidate algorithms, the CatBoost architecture was selected for its robust performance, achieving the highest F1 score (0.853) and an area under the receiver operating characteristic curve (AUROC) of 0.834. SHAP analysis revealed that preoperative opioid use was the most potent determinant of suboptimal response, followed by advanced age and high baseline pain intensity. Notably, elevated ApoB levels emerged as a novel metabolic indicator of favorable prognosis, whereas an increased NMR suggested a systemic pro-inflammatory state associated with diminished PRF efficacy.ConclusionsWe developed and internally validated a high-performance CatBoost-based model for predicting PRF outcomes in ZAP. By integrating novel metabolic (ApoB) and immunoinflammatory (NMR) biomarkers with established clinical metrics, this model provides a granular approach to risk stratification. The deployment of a Streamlit-based calculator translates complex algorithmic insights into an accessible clinical decision-support system.
Neuropathic pain (NP) has attracted growing attention in recent years; however, its pathogenesis remains incompletely understood, and therapeutic options remain limited. Neuromodulation techniques have demonstrated considerable promise in managing NP, offering advantages including noninvasiveness, minimal discomfort, and precise anatomical targeting. Nevertheless, therapeutic parameters have yet to be standardized as a result of variability across multiple factors such as modality type, stimulation site, and treatment duration. Microglia, as the resident immune cells of the central nervous system, play a pivotal role in the development and maintenance of NP. Following nerve injury, microglia become activated and release various inflammatory mediators and signaling molecules that modulate pain transmission pathways. Importantly, emerging evidence indicates that neuromodulation can regulate microglial activation states and associated inflammatory cascades through either indirect or direct pathways. Indirect mechanisms involve modulating neuronal activity and downstream signaling, thereby influencing microglial functional phenotypes. Direct mechanisms act via microglia-specific properties such as electrophysiological sensitivity, receptor expression, or local field potential interactions. This review synthesizes current evidence on the mechanisms and recent advances in microglia-targeted neuromodulation strategies for NP relief, distinguishing between preclinical and clinically validated findings, and aiming to provide a theoretical foundation for future research.
