Search Results (455)

Background: Migraine in older adults represents an increasingly relevant yet underrecognized clinical challenge in aging societies, where multimorbidity, frailty, and polypharmacy complicate both diagnosis and management. Although traditionally considered a disorder of younger individuals, migraine frequently persists or presents after the age of 60 with atypical features, contributing to diagnostic uncertainty. Methods: This narrative review, conducted in accordance with the SANRA principles, aims to provide a comprehensive overview of the epidemiology, clinical presentation, pathophysiology, and management of migraine in older adults, with particular emphasis on age-related complexities, therapeutic challenges, and unmet clinical needs. Results: Migraine in this population often presents with atypical or misleading features, such as aura without headache, vestibular symptoms, or overlap with cerebrovascular conditions, leading to delayed or incorrect diagnoses. The burden of disease is substantial, affecting physical function, mobility, cognition, emotional well-being, and social participation, and is further amplified by comorbid conditions including cardiovascular and metabolic disorders, mood disturbances, and chronic pain syndromes. Aging-related neurobiological changes, such as impaired pain modulation, endothelial dysfunction, and neuroinflammation, may influence disease expression and treatment response. Therapeutic management is challenged by contraindications, increased susceptibility to adverse drug effects, and the complexity of polypharmacy, highlighting the importance of individualized and non-pharmacological approaches. Conclusions: Migraine in older adults is a significant but often overlooked contributor to disability and reduced quality of life. Improved recognition of its unique clinical features and age-specific vulnerabilities is essential to optimize patient-centered care. Future research should prioritize the inclusion of older populations and the development of tailored, safe, and effective management strategies. Full article

Laser acupuncture (LA) integrates principles of traditional acupuncture with photobiomodulation (PBM) and has gained increasing attention as a non-invasive modality for pain management. PBM-based integrative LA in medicine refers to the application of low-level laser irradiation to acupuncture points, combining contemporary biomedical mechanisms with holistic, system-oriented therapeutic principles. This narrative review aimed to critically assess the scientific evidence on the efficacy of LA for pain management within the framework of the Principles of Clinical Integration of Photobiomodulation (PCIPBM) in LA, summarizing frequently used laser parameters and clinical indications. LA involves special protocols in standardized acupoints, using defined parameters of wavelength, irradiation, and energy density, consistent with PBM dosing principles. Therapeutic effects are mediated through point-specific neuromodulation and photobiological mechanisms, including modulation of peripheral and central nociceptive processing, reduction in pro-inflammatory mediators, improvement of microcirculation, and mitochondrial activation via cytochrome c oxidase-dependent adenosine triphosphate (ATP) synthesis. Clinical studies report statistically and clinically significant analgesic effects, particularly in chronic musculoskeletal pain, osteoarthritis, low back and neck pain, temporomandibular disorders, neuropathic pain, and selected postoperative pain conditions, when appropriate laser parameters are applied. Reported adverse effects are minimal, and tolerability is high. LA represents a safe, non-invasive therapeutic option and patient-friendly approach with clinically relevant efficacy in pain management. When applied according to PCIPBM, including evidence-based PBM parameters, it may serve as an effective adjunct or alternative to conventional pharmacologic and interventional approaches. Further standardization and high-quality randomized controlled trials are still required. Full article

Background/Objectives: The uprighting of mesially tipped mandibular second molars following first molar loss is a complex surgical and orthodontic challenge. Conventional methods often result in reciprocal anchorage loss. Mini-implants (MIs) have emerged as essential temporary anchorage devices (TADs) that provide absolute anchorage and enable more predictable tooth movements. Methods: Numerical simulations were performed to evaluate the forces required for mandibular second molar uprighting under two conditions: first, only with the second molar present, and second, with both the second and the third molars present. Although the periodontal ligament exhibits nonlinear and viscoelastic behavior in vivo, a linear elastic approximation was adopted to allow for a reliable evaluation of comparative stress distribution and initial displacement patterns within the scope of this exploratory biomechanical study. Stress distribution in the roots, periodontal ligament, and alveolar bone was assessed for each scenario. Two three-dimensional (3D) models of the left mandibular segment were created from scans of a human mandible and its teeth. The first model included the canine, the first and second premolars, and the second molar. A second model additionally incorporated the third molar. A retromolar MI was placed in both models. Molar uprighting was simulated using a spring connecting the implant to a button bonded on the mesial surface of the second molar. A force of 200 g was applied because in clinical orthodontic practice, forces that exceed approximately 2 N may cause pain or undesirable tooth mobility. Displacements along the X, Y, and Z axes, as well as regions of peak stress, were analyzed. Results: Model 1 showed maximum displacements at the furcation/mid-root, distal root apex, and distal crown, with von Mises stresses of 0.470 to 0.371 MPa. In Model 2, peak displacements occurred at the mesial root and crown, with stresses of 0.185 and 0.149 MPa, respectively. The magnitude of displacements was in the order of 10⁻⁵ mm. Such values represent initial mechanical responses rather than clinically observable tooth movements. However, the differences between models (e.g., the stress reduction) are expected to be clinically meaningful. Conclusions: Since clinical measurements regarding the stress distribution on teeth and surrounding tissues during orthodontic molar uprighting movements are impossible to perform, the finite element method (FEM) can offer insight into these aspects. The presence of the third molar significantly modulates the biomechanics of second molar uprighting via retromolar MIs. When the third molar is present, the second molar exhibits a reduced tendency for deformation during distalization, although this leads to a slower displacement. This FEM provides biomechanical insights but does not support direct clinical decision-making. The present findings should be viewed as theoretical biomechanical tendencies that require confirmation through clinical, experimental, and longitudinal studies before translation into clinical practice. Full article

Tension-type headache (TTH) is the most prevalent primary headache disorder worldwide, contributing substantially to individual disability and global socioeconomic burden. Despite its high prevalence, TTH remains clinically heterogeneous, with episodic and chronic forms influenced by the dynamic interplay of peripheral, central, psychosocial, and lifestyle-related mechanisms. Peripheral musculoskeletal factors, including craniocervical muscle alterations and myofascial trigger points, interact with central sensitization processes, while psychosocial stressors, coping strategies, and lifestyle habits such as sleep and physical activity modulate pain perception and chronification risk. Current approaches often address these domains in isolation, limiting therapeutic effectiveness and the understanding of interindividual variability. This narrative review critically synthesizes evidence on the multifactorial determinants of TTH, providing an integrative conceptual framework. We systematically searched PubMed, Scopus, and Web of Science for articles published between 2010 and 2025, including conceptually or methodologically foundational studies outside this range. Relevant studies were selected based on predefined inclusion criteria and synthesized narratively to highlight key mechanisms and contributing factors. The proposed model emphasizes multidimensional assessment, incorporating peripheral musculoskeletal evaluation, central pain modulation, psychosocial profiling, and lifestyle factors, thereby providing a conceptual basis for future personalized management approaches. Recognizing TTH as a dynamic, multidimensional condition may inform clinical assessment and patient-centered interventions, while also highlighting key gaps for future longitudinal and multimodal research aimed at validating the framework and improving individualized therapeutic strategies. The evidence presented is primarily narrative and observational, and clinical applicability should be confirmed in future studies. Full article

This study provides a comprehensive evaluation of the effects of environmental stressors and physical exertion on human nociceptive processing across multiple ecologically relevant conditions. Using a repeated-measures design, participants (N = 45) completed up to five controlled laboratory (thermoclimatic chamber) sessions (baseline, simulated altitude at 4200 m asl, heat at +42 °C, cold at −10 °C, and exertion). Participants were tested by using electrical stimuli. Linear mixed-effects models with participant-level random intercepts, alongside estimated marginal means and bootstrap derived effect sizes, enabled robust characterization of within-subject differences. Thermal stress emerged as the strongest modulator of nociception. Heat exposure significantly elevated sensory and pain thresholds compared with all other conditions, whereas tolerance thresholds peaked during cold exposure, yielding the largest observed effects. Altitude consistently produced the lowest thresholds across all modalities. These contrasts were confirmed statistically in the mixed-effects models, and effect-size analyses indicated substantial within-subject differences between the thermal extremes. By integrating three distinct nociceptive modalities and extreme environment simulations, this work offers novel and informative insights into how environmental stressors shape pain processing. The discovery of opposing thermal effects on sensory/pain versus tolerance thresholds—within the same cohort and design—reveals modality-specific patterns not previously documented and suggests that hypoxia may further modulate these responses. Full article

Background/Objectives: Photobiomodulation therapy (PBMT) is a non-invasive therapeutic modality that enhances tissue healing, modulates inflammation, and reduces pain. Despite increasing clinical use, evidence regarding PBMT in geriatric oral conditions has not been comprehensively synthesized. This systematic review aimed to evaluate the clinical efficacy and safety of PBMT in managing orofacial conditions in older adults. Methods: A systematic search of PubMed, Embase, Scopus, and Google Scholar was conducted to identify randomized controlled trials (RCTs) published between January 2000 and March 2025. Eligible studies included patients aged ≥60 years receiving PBMT for orofacial conditions. Study selection followed predefined criteria. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool, and findings were narratively synthesized. Results: Twenty-three RCTs were included. Evidence for PBMT was most frequently reported in cancer therapy-induced oral mucositis (n = 8), with consistent reductions in lesion severity and pain. Studies on burning mouth syndrome (n = 7) and hyposalivation (n = 2) generally reported improvements in symptoms, although placebo effects were noted. Fewer studies evaluated postoperative pain (n = 2), oral lichen planus (n = 1), peri-implant conditions (n = 1), and implant osseointegration (n = 2). No clinically significant adverse events were reported. However, heterogeneity in PBMT parameters and outcome measures limited comparability. Conclusions: PBMT is a safe and clinically effective adjunctive therapy for managing orofacial conditions in older adults, particularly oral mucositis. These findings support its integration into geriatric oral care. Standardized protocols and well-designed RCTs are needed to determine optimal treatment parameters and long-term effectiveness. Full article

Background/Objectives: Blunt abdominal trauma is a frequent challenge in emergency medicine, but its diagnosis and treatment become significantly more complex when rare anatomical anomalies are present. Atypical anatomy may mask symptoms or mimic other acute abdominal conditions, causing delays in treatment. The aim of this paper is to review the literature on six rare anatomical anomalies and their impact on the consequences of blunt abdominal trauma. Methods: A Narrative literature review was undertaken, covering PubMed, Scopus, Web of Science and Google Scholar databases, analysing publications from 1960 to 2025. Case reports and case series (91 patients in total) with confirmed organ damage following blunt trauma in the course of: duodenal diverticulum, Meckel’s diverticulum, splenic torsion, rupture or torsion of the accessory spleen, visceral inversion (situs inversus) and horseshoe kidney. Results: Demographic analysis revealed a predominance of perforations of the duodenal diverticulum in older women (mean age 62 years), while younger men predominated in all other groups. The clinical picture was often non-specific or misleading, especially in situs inversus, where the location of pain did not correlate with the typical topography of organs. Contrast-enhanced computed tomography (CECT) has proved to be a key diagnostic tool, surpassing ultrasound/FAST scans due to its ability to provide precise anatomical imaging. Surgical treatment was predominant (100% in Meckel’s diverticulum, 95% in duodenal diverticulum), while conservative treatment was effective in horseshoe kidney injuries (94.8%). Mortality was highest in situs inversus (29%) and duodenal diverticulum perforation (20%). The vast majority of these fatal cases occurred in the era of modern computed tomography, suggesting that the therapeutic challenges stem directly from the specific nature of these anomalies, rather than from past diagnostic limitations. Conclusions: Anatomical anomalies significantly modulate the clinical manifestations of blunt abdominal trauma, increasing the risk of diagnostic errors. Early contrast-enhanced computed tomography and awareness of these rare pathologies are crucial for appropriate management and improved prognosis. Full article

Introduction: Chronic non-cancer pain represents a major global health challenge because of its high prevalence, functional impact, and limited response to conventional therapies, highlighting the need for alternative approaches. In this context, subanesthetic-dose ketamine has emerged as a promising therapeutic option because of its ability to modulate central sensitization and enhance analgesia through NMDA receptor antagonism. However, current evidence regarding its long-term efficacy and safety remains limited and heterogeneous. Objective: To evaluate the efficacy and safety of subanesthetic ketamine for the management of chronic non-cancer pain in adults, based on randomized controlled trials published between 2005 and 2025. Methods: A systematic review was conducted in accordance with the PRISMA 2020 guidelines. Randomized controlled trials involving adults with chronic non-cancer pain were included, comparing ketamine with placebo or other active agents. The databases searched were PubMed, ScienceDirect, and the Cochrane Library. Risk of bias was assessed using the Cochrane RoB-2 tool, and the certainty of evidence was evaluated using GRADE. Results: Five trials met the inclusion criteria. All included studies evaluated intravenous ketamine at doses ranging from 0.3 to 0.5 mg/kg. Overall, ketamine demonstrated significant short-term pain relief (p < 0.05), particularly in neuropathic conditions; however, the magnitude of this effect decreased progressively after the infusion ended. Reported adverse effects were mild and transient, with no evidence of severe toxicity. Heterogeneity in dosing protocols, pain phenotypes, comparator strategies, and follow-up duration limited cross-study comparability. Conclusions: Current evidence supports the short-term efficacy and safety of subanesthetic-dose ketamine as an analgesic option for chronic non-cancer pain, especially in neuropathic syndromes. However, the transient nature of its effects and the heterogeneity among studies underscore the need for standardized protocols and longer follow-up periods. Despite its generally favorable short-term safety profile, subanesthetic ketamine should be used with caution under strict clinical supervision, as the potential for long-term neurocognitive, urological, and hepatic adverse effects remains insufficiently defined. Full article

The regulation of chloride levels is a crucial part of controlling inhibitory signals, but does not occur uniformly throughout the body. Recent data suggest that chloride is regulated within localized “microdomains” which are defined by the interaction of KCC2 and NKCC1, structural restraints on cells due to their internal structure, the metabolic condition of the cell, and the external environment modified by astrocytes. The gradients of chloride concentrations within these compartment-specific microdomains define the local chloride reversal potential, and thereby determine the directionality (i.e., whether excitatory or inhibitory), magnitude, and timing of GABAergic inhibition. The disruption of this organized chloride gradient within microdomains impairs the stability of inhibitory activity at multiple levels of integration, including dendritic input, spike timing, interneuron synchronization, and network oscillation. Disturbances in inhibitory stability have been found in a variety of diseases, including epilepsy, neonatal seizure, neuropathic pain, and schizophrenia-spectrum disorders. This supports the hypothesis that disturbances in chloride homeostasis lead to a loss of stability in cortical circuits. This review will provide a synthesis of the molecular, spatial, and circuit level principles involved in the regulation of chloride and discuss how failures of these mechanisms produce clinically relevant disturbances in inhibitory signal processing. In addition, we will be discussing new therapeutic strategies for the restoration of chloride homeostasis, including KCC2 repair, selective modulation of NKCC1, targeting astrocytes, and microenvironmental engineering. Overall, the studies reviewed here provide a unified model for understanding the pathophysiology of inhibitory dysfunction, and demonstrate that the regulation of chloride microdomains provides a novel and promising area of research for translational intervention. Full article

Different types of skeletal muscle fibers display marked heterogeneity in metabolic, mechanical, and regenerative properties. However, their role in chronic musculoskeletal pain remains insufficiently integrated into clinical models. Chronic pain is associated with altered neuromuscular control, prolonged low-level activation, and reduced recruitment of high-threshold motor units. These factors may promote fiber type-specific remodeling. This narrative review critically synthesizes current evidence on the relationship between musculoskeletal pain and muscle fiber types. The focus was on metabolic vulnerability, mechanical susceptibility, and regenerative capacity. A structured literature search was conducted in PubMed, Scopus, and Web of Science, focused on human studies and key translational models. Chronic musculoskeletal pain is characterized by acquired fiber type-specific adaptations rather than a fixed unfavorable profile. In chronic pain scenarios, Type I fibers present features of chronic overload, including hypertrophy with insufficient capillarization and increased satellite cell activity. Type II fibers exhibit relative disuse, atrophy, and reduced satellite cell content, resembling accelerated muscle aging. Symptom duration, neuromuscular control strategies, and task-specific loading patterns modulate these adaptations, with interindividual variation. Muscle dysfunction in chronic pain reflects maladaptive but potentially reversible neuromuscular and histological plasticity. These findings indicate that rehabilitation strategies should be individualized, involving context-specific exercise strategies to restore muscle structure, function, and regenerative potential in chronic musculoskeletal conditions. Full article

Background/Objective: Health is a multidimensional construct shaped not only by clinical conditions but also by psychological, social, environmental and cultural factors. In low- and middle-income countries undergoing rapid epidemiological transition, understanding health requires integrated and culturally informed approaches. However, quality of life, perceived health status and lifestyle behaviors are often investigated separately, limiting the interpretation of well-being in specific local contexts. This study aimed to provide an integrated assessment of quality of life, perceived health status and lifestyle behaviours among adults attending a peri-urban public hospital in Kenya, using internationally validated instruments applied within a specific local cultural context. Methods: A cross-sectional observational study was conducted at Tigoni Level 4 Hospital, Kiambu County, Kenya. Adult outpatients (N = 40) were consecutively recruited. Quality of life was assessed using the WHOQOL-BREF, perceived health status using the EQ-5D-5L and EQ-VAS, and lifestyle behaviours using selected modules of the WHO STEPS instrument. Descriptive statistics were performed, and exploratory associations were examined using Spearman’s rank correlation coefficient. Results: Participants had a mean age of 35.9 ± 11.4 years, with a balanced gender distribution. Lifestyle risk factors were prevalent, including insufficient physical activity (40%) and overweight or obesity (>50%). WHOQOL-BREF scores revealed a heterogeneous profile, with relatively preserved social relationships and lower scores in the psychological and environmental domains. Pain/discomfort and anxiety/depression were the most frequently reported EQ-5D-5L problems. The mean EQ-VAS score was 68.2 ± 15.7. Perceived health was positively associated with physical and psychological quality of life, while higher body mass index was associated with lower physical quality of life. Mental health emerged as a cross-cutting factor across instruments. Conclusions: The findings highlight the multidimensional nature of health in a peri-urban Kenyan context and suggest the importance of considering local social and cultural influences when interpreting standardized health measures. Mental health and environmental conditions play a central role in shaping quality of life and perceived health, while lifestyle risk factors are already prevalent in a relatively young outpatient population. Integrating standardized health measures within a cross-cultural framework may support more holistic and person-centred approaches in primary care and public health in similar settings. Full article

Background: Neuropathic pain remains a major unmet clinical challenge. Growing evidence identifies sigma receptors (σRs) as pivotal intracellular modulators of maladaptive stress signaling, positioning them as promising non-opioid targets for chronic pain management. Notably, despite the pleiotropic nature of σRs in regulating diverse cellular pathways—which might theoretically suggest a high risk of off-target effects—current selective antagonists have demonstrated remarkable safety and tolerability profiles. Sigma-1 and sigma-2 receptors (σ1R and σ2R) are molecularly and functionally distinct proteins that regulate neuronal excitability, proteostasis, and neuroimmune communication, all mechanisms that characterize neuronal excitability and cellular stress adaptation. σ1R acts as a ligand-operated molecular chaperone at the mitochondria-associated endoplasmic reticulum membrane. Extensive preclinical data demonstrate that σ1R antagonism attenuates peripheral and central sensitization, suppresses neuroinflammation, and restores opioid analgesic efficacy. These findings are supported by the advanced clinical candidate E-52862, which has shown efficacy and a favorable safety profile in neuropathic pain conditions. σ2R, identified as transmembrane protein 97 (σ2R/TMEM97), functions as a regulator of cholesterol trafficking, lysosomal integrity, and integrated stress response (ISR). σ2R modulation alleviates neuropathic pain by restoring proteostatic balance and reducing ISR-driven neuronal vulnerability rather than directly suppressing excitability. Emerging σ2R ligands such as FEM-1689, UKH-1114, and CM-398 provide compelling proof-of-concept for durable, disease-modifying analgesia. Methods: A structured literature search was conducted using PubMed, Scopus, and Web of Science to identify studies published within the last decade describing σ1R and σ2R/TMEM97 biology, ligand development, and their preclinical or clinical evaluation in neuropathic pain. Reference lists were manually screened to ensure comprehensive coverage. Conclusions: This review synthesizes pharmacology, ligand development, and translational evidence supporting σRs as next-generation targets for neuropathic pain therapy, highlighting convergent roles of σ1R and σ2R in pain chronification and outlining future directions for structure-guided therapeutic strategies. Full article

Background: Post-episiotomy wound healing remains largely managed through supportive care, despite growing evidence that local biochemical conditions critically influence tissue regeneration. Lactic acid is of particular interest in this context because it is both an endogenous metabolic intermediate and a physiologic component of the vaginal microenvironment, where it contributes to acidic pH maintenance, microbial homeostasis, and mucosal protection. Beyond these local effects, lactate has emerged as a signaling metabolite involved in angiogenesis, immune regulation, and extracellular matrix remodeling, making it a relevant candidate for regenerative wound care. Methods: This narrative translational review integrates evidence from molecular biology, biomaterials science, and clinical obstetrics to examine the therapeutic potential of lactic acid-loaded hydrogels for post-episiotomy tissue repair. Literature from PubMed, Scopus, and Web of Science was analyzed to evaluate physicochemical design parameters, lactate-mediated signaling pathways, and available clinical outcomes. Results: Lactic acid may function both as a microenvironmental regulator and as a metabolic signal capable of stabilizing hypoxia-inducible factor-1α signaling, enhancing vascular endothelial growth factor expression, modulating macrophage polarization, and influencing fibroblast-mediated extracellular matrix synthesis. Hydrogel matrices provide tunable platforms for controlled lactate release, pH buffering, and mucosal compatibility. Clinical studies suggest improved epithelialization, reduced infection risk, and lower pain scores following topical lactic acid formulations in episiotomy repair. In parallel, platelet-rich plasma provides autologous growth factor enrichment that may complement regenerative signaling pathways. Conclusions: Integrating microenvironment stabilization through lactic acid-based hydrogels with biologically active regenerative strategies represents a promising direction for post-episiotomy wound healing. Further controlled trials and standardized biomaterial characterization are required to define optimal therapeutic protocols and confirm long-term clinical benefit. Full article

Hypnosis has traditionally been conceptualized as a clinical technique for reducing physiological symptoms (e.g., pain, nausea) and psychological symptoms (e.g., anxiety, intrusive thoughts), yet emerging neuroscientific evidence suggests it operates through the fundamental mechanisms of emotional regulation and self-integration. This integrative review synthesizes research on clinical hypnosis from cognitive neuroscience, affective science, and clinical practice to examine how hypnotic phenomena modulate large-scale brain networks—particularly the default mode network (DMN), executive control network (ECN), and salience network (SaN)—to reorganize emotional experience and self-referential processing. We propose a formal mechanistic model in which hypnotic induction produces heightened experiential plasticity through coordinated network reconfiguration, enabling adaptive emotion regulation and reduced dissociative fragmentation. Central to this framework is the construct of Fundamental Peace (FP), operationalized as a dynamic neuro-experiential state characterized by: (1) flexible attentional control without effortful suppression; (2) emotional coherence across self-states; (3) reduced self-referential rigidity; (4) compassionate self-awareness. Unlike equanimity (affective neutrality) or well-being (positive evaluation), Fundamental Peace represents integrated regulatory capacity under changing conditions. Key findings from neuroimaging studies demonstrate that hypnotic states consistently reduce DMN activity, enhance ECN-SaN coupling, and modulate connectivity patterns associated with self-referential processing. Meta-analytic evidence from 85 controlled experimental trials shows robust pain reduction effects, while clinical studies document improvements in trauma-related dissociation and emotional dysregulation. We critically evaluate this framework against alternative theories (dissociated control, cold control, predictive processing, social-cognitive models), specify testable predictions, and assess evidence quality across neuroimaging and clinical domains. Implications for trauma treatment, clinical implementation, and future research integrating causal inference methods are discussed, alongside ethical and cultural considerations. Full article

Chronic pain imposes a substantial burden on global health and remains challenging to manage, despite ongoing advances in pharmacologic and interventional therapies. Recognition of chronic pain as a condition driven by central sensitization and neuroimmune dysregulation has prompted interest in therapies that target these mechanisms rather than peripheral nociception alone. Low-dose naltrexone (LDN), administered at doses substantially lower than those used for opioid or alcohol use disorders, has emerged as a repurposed treatment with potential analgesic and anti-inflammatory properties. This review summarizes the pharmacologic characteristics of LDN, with emphasis on its proposed mechanisms involving transient opioid receptor blockade, modulation of microglial activation, Toll-like receptor signaling, and central neuroimmune pathways. Available clinical evidence evaluating LDN across a range of chronic pain conditions, such as fibromyalgia, neuropathic pain syndromes, inflammatory and autoimmune disorders, headache disorders, and other centralized pain states, is critically reviewed. Although early trials, observational studies, and case series suggest potential benefit in selected populations, the overall evidence base remains limited, heterogeneous, and characterized by variability in dosing strategies and outcome measures. Safety, tolerability, and practical considerations relevant to contemporary pain practice are discussed, including interactions with opioid therapy and challenges related to off-label use. Finally, key gaps in the current evidence and priorities for future research are highlighted, underscoring the need for larger, well-designed randomized trials and mechanism-informed studies to better define LDN’s role in multimodal chronic pain management. Full article