Search Results (157)

Neural oscillations are fundamental to the integration of sensory, affective, and cognitive processes that contribute to pain perception. Transcranial alternating current stimulation (tACS) provides a valuable tool for investigating and modulating these oscillatory dynamics. In this review, we examine the effects of tACS on pain perception and pain-related oscillations in both healthy participants and individuals with chronic pain, highlighting methodological variability and mechanistic uncertainties that may contribute to mixed findings. We identified 14 studies, including 9 studies of experimental pain in healthy individuals and 5 of clinical pain disorders, comparing tACS to sham. Somatosensory alpha was the most frequently targeted oscillatory feature. Results varied considerably. Several studies reported reductions in pain, increases in alpha power, or changes in sensorimotor and prefrontal connectivity, but others showed no meaningful neural or behavioral effects. Out of the 14 studies, 6 demonstrated analgesic benefits and 2 showed improvements only under specific conditions or within subgroups, for a total of 8/14 studies with positive findings. Possible sources of heterogeneity include variation in stimulation duration, electrode montage, frequency alignment with individual rhythms, contextual state, and anatomical and neurophysiological differences across individuals. Pre-registered studies with sufficient power are needed to replicate effects within the most promising intervention protocols to establish a foundation in the field. We also recommend inclusion of brain imaging or electrophysiological recordings to verify whether stimulation effectively modulates the targeted neural oscillations. Finally, recent methodological advances, including phase-specific tACS, amplitude-modulated tACS, and individualized electric-field modeling, offer new opportunities to enhance mechanistic precision and clinical applicability. We argue that by integrating these approaches, future research can move beyond fixed, one-size-fits-all protocols toward personalized, state-dependent, closed-loop tACS approaches. Exploring these frontiers will transform tACS from an exploratory tool into a reliable intervention for pain. Full article

Background: Persistent pain following orthopaedic trauma is common, often disproportionate to structural healing, and increasingly interpreted as reflecting centrally mediated pain mechanisms. However, the mechanisms, clinical features, diagnostic approaches, prognostic indicators, and management strategies relevant to trauma-related central sensitisation (CS) remain poorly understood. Objective: To map and synthesise existing evidence on CS following orthopaedic trauma, addressing mechanistic pathways, clinical manifestations, epidemiology, assessment methods, management approaches, and health system implications. Methods: A scoping review was conducted in accordance with PRISMA-ScR. Twenty-one studies met the eligibility criteria, comprising nine primary trauma cohorts and 12 contextual mechanistic or review studies relevant to trauma-associated CS. Data were charted across six prespecified domains of mechanistic processes, clinical presentation and diagnostic features, epidemiology and prognosis, assessment tools and outcome measures, interventions, and health system and care delivery considerations. Results: Mechanistic studies demonstrated trauma-induced neuroimmune activation, altered cortical and spinal excitability, and molecular pathways consistent with sensitisation. Clinical studies have identified neuropathic features, widespread pain, and heightened sensory responsiveness following fractures and other injuries. Neurophysiological evidence has indicated early cortical disinhibition following upper limb trauma, whereas epidemiological cohorts have reported persistent pain and disability years after major trauma. Measurement studies have highlighted the limited reliability and specificity of current tools in trauma populations, including quantitative sensory testing and self-report instruments. Early predictors of adverse trajectories include severe acute pain, neuropathic descriptors, psychological distress, and opioid-dominant analgesia. Evidence regarding early intervention, rehabilitation strategies, and system-level screening pathways remains limited. Conclusions: Central sensitisation (CS)–consistent mechanisms after orthopaedic trauma are suggested by convergent mechanistic, neurophysiological, and clinical findings. However, trauma-specific diagnostic criteria, prognostic models, and management frameworks remain underdeveloped. High-quality longitudinal research is needed to clarify early trajectories, refine assessment methods, and establish targeted interventions to reduce long-term pain and disability. Full article

Background: The mirror neuron system (MNS) has been proposed as a key neural mechanism linking action perception, motor representation, and social cognition. This framework has increasingly been applied to pain research, encompassing pain empathy, observational learning of pain, and rehabilitative interventions such as mirror therapy. However, the literature is conceptually heterogeneous, methodologically diverse, and spans experimental, social, and clinical domains. Objective: This scoping review aims to map the extent, nature, and characteristics of the available evidence on the relationship between the MNS and pain, clarifying how MNS-related mechanisms are defined, investigated, and applied across different contexts. Methods: A scoping review was conducted using the methodological framework proposed by the Joanna Briggs Institute and reported in accordance with PRISMA-ScR guidelines. We searched PubMed/MEDLINE, Scopus, Web of Science, and PsycINFO. Studies were included if they addressed MNS-related mechanisms in pain processing, pain empathy, pain modulation, or pain rehabilitation. Eligible studies were charted and synthesized descriptively and thematically. Results: Twenty-one studies met the inclusion criteria. The evidence was predominantly derived from clinical and rehabilitative settings, with most studies focusing on mirror therapy or mirror visual feedback interventions. The majority of included populations consisting of adults with chronic pain conditions, particularly phantom limb pain and complex regional pain syndrome. Pain intensity, assessed mainly through self-reported clinical scales, was the most frequently reported outcome. A smaller number of studies investigated action observation or motor imagery paradigms, primarily in chronic musculoskeletal pain, showing short-term hypoalgesic effects. Across studies, substantial heterogeneity was observed in the conceptualization of MNS-related constructs, intervention protocols, outcome measures, and follow-up duration. Conclusions: Despite extensive theoretical discussion of the MNS, empirical applications are largely confined to clinical mirror-based interventions, with limited use of direct neurophysiological or neuroimaging markers. Since crucial conceptual and methodological gaps constrain comparability and translation into clinical practice, there is a need for clearer operational definitions and more integrated experimental and clinical research approaches. Full article

Background: Feigned restriction of shoulder joint movement for secondary gain is clinically relevant and may misdirect care, distort disability determinations, and inflate system costs. Distinguishing feigning from structural pathology and from functional or psychosocial presentations is difficult because pain is subjective, performance varies, and no single sign or test is definitive. This comprehensive review hypothesizes that the systematic integration of clinical examination, objective biomechanical and neurophysiological testing, and emerging technologies can substantially improve detection accuracy and provide defensible medicolegal documentation. Methods: PubMed and reference lists were searched within a prespecified time frame (primarily 2015–2025, with foundational earlier works included when conceptually essential) using terms related to shoulder movement restriction, malingering/feigning, symptom validity, effort testing, functional assessment, and secondary gain. Evidence was synthesized narratively, emphasizing objective or semi-objective quantification of motion and effort (goniometry, dynamometry, electrodiagnostics, kinematic sensing, and imaging). Results: Detection is best approached as a stepwise, multidimensional evaluation. First-line clinical assessment focuses on reproducible incongruence: non-anatomic patterns, internal inconsistencies, distraction-related improvement, and mismatch between claimed disability and observed function. Repeated examinations and documentation strengthen inference. Instrumented strength testing improves quantification beyond manual testing but remains effort-dependent; repeat-trial variability and atypical agonist–antagonist co-activation can indicate submaximal performance without proving intent. Imaging primarily tests plausibility by confirming lesions or highlighting discordance between claimed limitation and minimal pathology, while recognizing that normal imaging does not exclude pain. Diagnostic anesthetic injections and electrodiagnostics can clarify pain-mediated restriction or exclude neuropathic weakness but require cautious interpretation. Motion capture and inertial sensors can document compensatory strategies and context-dependent normalization, yet validated standalone thresholds are limited. Conclusions: Feigned shoulder impairment cannot be confirmed by any single test. The desirable strategy combines structured assessment of inconsistencies with objective biomechanical and neurophysiologic measurements, interpreted within the whole clinical context and rigorously documented; however, prospective validation is still needed before routine implementation. Full article

Background and Objectives: Chronic low back pain (CLBP) is a prevalent condition that impairs quality of life, functionality, and work productivity. While most acute episodes of back pain resolve, 4–25% become chronic due to factors such as high pain intensity, psychological distress, and maladaptive behaviors. Nonspecific CLBP is best understood through the biopsychosocial model, encompassing biological, psychological, and social influences, including kinesiophobia. Management relies on physical activity, pain education, and psychological interventions, with therapist knowledge and attitudes affecting outcomes. This study aimed to assess the prevalence of CLBP among healthcare workers, examine their knowledge of pain neurophysiology, evaluate kinesiophobia, and explore how personal experience with CLBP influences their beliefs, attitudes, and interactions with patients. Materials and Methods: A cross-sectional observational study was conducted from January to May 2025 among healthcare professionals. A total of 50 participants completed an online questionnaire, of which 42 were valid and included in the analysis. The questionnaire collected demographic and professional data, determined the presence of CLBP, and included three standardized instruments: the Revised Neurophysiology of Pain Questionnaire (rNPQ) to assess knowledge of pain mechanisms, the Health Care Providers’ Pain and Impairment Relationship Scale (HC-PAIRS) to evaluate beliefs about pain and disability, and the Tampa Scale of Kinesiophobia (TSK-11) to measure fear of movement. Data were analyzed using SPSS and Microsoft Excel. Results: Among the 42 participants, 11 demonstrated low, 28 moderate, and 3 high knowledge of pain neurophysiology (rNPQ), with a mean score of 5.66. On the HC-PAIRS, the majority (30 participants) scored above 60, indicating beliefs that pain leads to disability, while 12 scored below 60, reflecting a biopsychosocial perspective; gender did not significantly affect HC-PAIRS scores (p = 0.213). As for kinesiophobia (TSK-11), 24 participants had low, 17 moderate, and 1 clinically significant fear of movement. Correlation analysis revealed that younger participants had higher rNPQ scores (r = −0.358, p = 0.020) and lower TSK-11 scores (r = −0.389, p = 0.011). TSK-11 scores increased with age (r = 0.432, p = 0.004), while HC-PAIRS scores showed no significant correlations. Conclusions: Healthcare professionals, particularly physiotherapists, show gaps in knowledge of pain neurophysiology and a tendency toward biomedical beliefs regarding chronic low back pain. This cross-sectional study indicates that a greater understanding of pain mechanisms is associated with lower kinesiophobia, emphasizing the importance of education. Integrating the biopsychosocial model into undergraduate and continuing professional training, through interdisciplinary and practical modules, may improve knowledge, reduce maladaptive fear-avoidance behaviors, and enhance patient care. Future studies should include larger, more diverse samples and assess the long-term impact of educational interventions on clinical practice. Full article

Background: This study investigates the influence of emotional processing on flexor reflex responses in the upper limbs, focusing on cutaneomuscular reflexes (CMRs) and the cutaneous silent period (CSP) in patients with chronic neuropathic pain. The modulation of motor reflexes by emotions remains unclear. Methods: Fifty-one patients with chronic upper limb neuropathic pain (carpal tunnel syndrome, other neuropathies, post-burn hypertrophic scars) and twenty healthy controls underwent standardized electrodiagnostic signal acquisition. Neurophysiological assessments (CMRs, CSP, standard nerve conduction tests) and psychological evaluations (anxiety, depression, emotion processing) were conducted. Neurophysiological signal acquisition included median and ulnar nerve conduction studies recorded with an electrodiagnostic system (48 kHz sampling rate; 30–3000 Hz bandpass). CSP and CMRs were recorded from the abductor pollicis brevis using surface electrodes (bipolar belly–tendon montage) and were evoked by electrical stimulation delivered through ring electrodes, with individualized perceptual-threshold calibration. Statistical analyses examined correlations between neurophysiological and psychological measures. Results: Patients showed significantly longer duration and higher intensity of CMRs and CSP than controls (p < 0.01). CMR and CSP durations correlated positively with anxiety, depression, and alexithymia scores, and negatively with facial emotion recognition. General Linear Model analyses indicated these relations were mediated by tactile and pain perception thresholds. Conclusions: The findings support that spinal reflex responses in the upper limbs are modulated by emotional and cognitive-affective processes, especially in chronic pain contexts. This highlights the complex interaction between emotion regulation and motor control in neuropathic pain conditions. Full article

Background/Objectives: Pain and pain-related conditions are considered a global health and financial burden. In order to improve pain management, pain intensity assessment, and pain diagnosis, various biomarkers have been proposed. Since their clinical utility is not proven yet, the aim of this umbrella review is to synthesize existing evidence of all types of pain biomarkers available. Methods: Systematic searches were conducted in PubMed, Scopus, and the Cochrane Library from inception to 2 June 2025. Eligible studies were systematic reviews and meta-analyses examining any clinical, biochemical, genetic, neurophysiological, or imaging biomarker related to pain. The screening of studies, data extraction, and assessment of methodological quality using the AMSTAR-2 tool were conducted by two independent reviewers. Findings were summarized narratively. Results: A total of 49 systematic reviews and meta-analyses were included. Most reviews were rated as low or critically low quality. Inflammatory biomarkers (CRP, IL-6, TNF-α) reported the most consistent associations with chronic musculoskeletal pain, while neuroimaging and EEG measures reflected central nervous system alterations. Proteomic multi-protein panels demonstrated exploratory diagnostic potential, particularly for fibromyalgia, but lacked clinical validation. Evidence for genetic, hormonal, metabolic, neurochemical, and tissue-specific biomarkers was inconsistent and methodologically limited, supporting mechanistic rather than clinical inference. Conclusions: No single biomarker has achieved clinical validation for chronic pain, but several biomarker classes show promise. Future implications include high-quality longitudinal studies, standardized protocols, and multidimensional biomarker panels. Full article

Chronic pain and sleep disturbances are frequently associated and profoundly affect the quality of life, creating intertwined physical, emotional, and social challenges. This narrative review synthesizes current evidence on the molecular mechanisms and pharmacological influences underlying this bidirectional relationship. Elevated pro-inflammatory cytokines (IL-1β, IL-6, IL-10, TNF-α), neurodegenerative markers (tau, β-amyloid 42), metabolic hormones, and fasting glucose have been consistently associated with both objective and subjective sleep impairments in chronic pain conditions. Pharmacological agents such as melatonin and opioids exhibit heterogeneous effects on neurophysiological pathways, reflecting differences in mechanisms of action and their modulation of biological processes. Rather than offering therapeutic recommendations, this review aims to clarify how these mediators and drugs shape the complex interplay between pain and sleep. Overall, the evidence suggests that persistent dysregulation of inflammatory, neurodegenerative, and metabolic pathways may drive the reciprocal and detrimental interaction between chronic pain and sleep disturbances, highlighting opportunities for targeted research and integrated clinical strategies. Full article

Introduction: Persistent Spinal Pain Syndrome Type 2 (PSPS-T2) is associated with changes in the brain’s pain processing. This is often due to problems with the body’s natural way of handling the pain management system. Exercise therapy, such as motor control and spinal stabilization, can help reduce pain and disability. However, exercise alone may not be sufficient. Approaches that consider both body mechanics and brain function are gaining popularity. Since brain changes play a role in muscle and bone problems, noninvasive brain stimulation (NIBS) is considered a helpful adjunctive treatment. Studies have shown that NIBS may help people with spinal pain and mood disorders. The aim of this study is to assess the impact of combining tDCS targeting the dorsolateral prefrontal cortex with spinal motor control exercises in patients diagnosed with PSPS-T2. This investigation is based on the hypothesis that such a combined intervention could result in a more significant reduction in disability. Methods/Materials: This randomized controlled trial (RCT) is structured as a double-blind, comparative, longitudinal design in accordance with the CONSORT guidelines. This RCT has been registered at ClinicalTrials.gov (NCT06969456). Forty-two participants diagnosed with PSPS-T2 will be randomized in a 1:1 ratio into two groups: tDCS + rehabilitation (E_tDCS) or sham tDCS + rehabilitation (E_SHAM). The intervention will use tDCS to deliver low-intensity direct current to modulate cortical excitability. The intervention will consist of 24 supervised sessions (2 per week, 60 min each) over 12 weeks. Neuromodulation and exercise protocols will be adapted to the intervention phases based on previous research. The sample size has been calculated using GPower^®, assuming an effect size of 0.81, α = 0.05, power = 0.95, and a 40% dropout rate. Data will be collected from October 2025 to January 2027. Impact Statement: This study integrates neurophysiological modulation via tDCS with targeted exercise therapy, presenting an innovative approach to enhance pain modulation, functional recovery, and cortical reorganization in patients with PSPT-2. This approach has the potential to inform future evidence-based strategies for neurorehabilitation and pain management. Full article

Background: Delayed Onset Muscle Soreness (DOMS) is a transient, exercise-induced condition characterized by muscle pain, stiffness, and functional impairment, particularly following eccentric or high-intensity physical activity. Recent advances in diagnostic imaging, neurophysiology, and therapeutic techniques have led to a reassessment of DOMS pathophysiology and management. Objective: This scoping review aims to critically evaluate non-pharmacological strategies for DOMS management, focusing on clinical studies published between 2020 and 2025. Emphasis is placed on physical, thermal, neurophysiological, and nutritional interventions in athletic populations. Methods: A comprehensive literature search was conducted using PubMed, Scopus, and Web of Science. Included studies were randomized controlled trials, systematic reviews, meta-analyses, and high-quality scoping reviews. Methodological quality was assessed using PEDro, AMSTAR 2, and ROBIS tools. Key outcome measures included pain (VAS), functional recovery (ROM, performance), biochemical markers (CK, IL-6), and neuromuscular activation (iEMG). Results: Twenty-five studies met the inclusion criteria. Emerging strategies such as cryosauna, vibration therapy, percussive massage, and polyphenol supplementation demonstrated significant benefits in reducing DOMS-related symptoms and enhancing recovery. Evidence supports the integration of multimodal, personalized interventions over monotherapies. Imaging techniques (7T MRI, ultrasound) confirmed microstructural muscle changes consistent with DOMS, strengthening diagnostic precision. Conclusions: Non-pharmacological approaches to DOMS have evolved considerably, highlighting the importance of combining mechanical, thermal, and nutritional modalities. Personalized, multimodal recovery strategies appear most effective for symptom relief and performance restoration. Future studies should aim to standardize treatment protocols and outcome measures to improve clinical applicability. Full article

Environmental sensitivity illnesses—including fibromyalgia syndrome (FMS), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and multiple chemical sensitivity (MCS)—are chronic, disabling disorders characterized by hypersensitivity to environmental stimuli, persistent fatigue, widespread pain, and neurocognitive and autonomic dysfunction. Although their diagnostic criteria differ, increasing evidence suggests overlapping clinical features and shared biological mechanisms. A unifying hypothesis highlights the gut–brain–immune axis, where alterations in the intestinal microbiome, epithelial barrier dysfunction, and aberrant immune signaling interact with central sensitization and systemic metabolic dysregulation. Recent studies demonstrate reduced microbial diversity, depletion of anti-inflammatory taxa (e.g., Faecalibacterium prausnitzii, Bifidobacterium), and enrichment of pro-inflammatory Clostridium species across these conditions. These shifts likely alter production of short-chain fatty acids, amino acid metabolites, and complex lipids, with downstream effects on mitochondrial function, neuroinflammation, and host energy metabolism. Moreover, emerging clinical interventions—including probiotics, prebiotics, synbiotics, and fecal microbiota transplantation—suggest a potential role for microbiome-targeted therapies, though controlled evidence remains limited. This review synthesizes current knowledge on microbiome alterations in FMS, ME/CFS, and MCS, emphasizing their convergence on metabolic and immune pathways. By integrating microbial, immunological, and neurophysiological perspectives, we propose a microbiome-centered framework for understanding environmental sensitivity illnesses and highlight avenues for translational research and therapeutic innovation. Full article

Chronic pain (CP) represents a multidimensional condition in which cognitive and emotional factors shape the individual experience from perception to action. The purpose of this study was to characterize the functional significance of alterations in neural oscillatory dynamics underlying the transition from resting-state to cognitive load across distinct CP phenotypes. Continuous electroencephalographic data were acquired from patients with headache, migraine, and spine-related pain, as well as healthy controls, during rest and three visual–cognitive–motor (VCM) tasks: reaction time, working memory, and associative learning. First, within CP subgroups, we examined cognitive-load-related changes in oscillatory activity. In migraine patients, alpha/beta power attenuation induced during cognitive processing correlated with higher reported pain intensity. Relative to the spine-related pain group, migraine patients exhibited increased occipital alpha and gamma band activity during working memory and associative learning conditions, as a possible neurophysiological signature of cortical hyperexcitability. By comparing a subset of headache patients to healthy controls, we found elevated resting-state delta and gamma activity in the patient group. Under cognitive load conditions, headache patients showed higher power across delta, theta, beta, and gamma frequency bands. Delta and theta activity elicited during the working memory task correlated negatively with pain intensity. Our results demonstrate that the experience of chronic pain is accompanied by frequency-specific alterations in both resting and cognitive-associated oscillatory dynamics, reflecting impaired visual working-memory processing and top–down modulation of behaviorally relevant stimuli. Full article

Fibromyalgia is a chronic syndrome characterized by widespread musculoskeletal pain, fatigue, non-restorative sleep, and cognitive impairment. Its pathogenesis reflects a complex interplay between central and peripheral mechanisms, including altered pain modulation, neuroinflammation, mitochondrial dysfunction, autonomic imbalance, and genetic and epigenetic factors. Evidence from neuroimaging, omics studies, and neurophysiology supports this multifactorial model. Epidemiological updates confirm a global prevalence of 2–8%, with a strong female predominance and a significant impact on quality of life and healthcare costs. Diagnostic criteria have evolved from the 1990 American College of Rheumatology tender points to the 2010/2011 revisions and the 2016 update, improving case ascertainment but still lacking objective biomarkers. Recent omics and systems biology approaches have revealed transcriptional, proteomic, and metabolic signatures that may enable molecularly informed stratification. Therapeutic management remains multidisciplinary, combining pharmacological interventions (e.g., duloxetine, pregabalin, milnacipran) with non-pharmacological strategies such as graded aerobic exercise and cognitive behavioral therapy. Emerging approaches include drug repurposing to target neuroinflammation, mitochondrial dysfunction, and nociceptive pathways. Despite promising advances, progress is limited by small sample sizes, heterogeneous cohorts, and lack of standardization across studies. Future priorities include large-scale validation of biomarkers, integration of multi-omics with clinical phenotyping, and the design of precision-guided trials. By synthesizing mechanistic insights with clinical evidence, this review provides an updated framework for the diagnosis and management of fibromyalgia, highlighting pathways toward biomarker-guided, personalized medicine. Full article

Background and Objectives: Music therapy has a long tradition in palliative care, and recent studies have investigated its Neuro-Psycho-Endocrine-Immunological (NPEI) effects in terminally ill patients. Despite numerous published articles, there is a lack of a compendium connecting the physiological basis of music therapy with the specific musical elements most effective in end-of-life settings. This narrative review aims to synthesize current evidence on the physiological mechanisms underlying responses to music, with a focus on terminal patients and implications for nursing practice. Materials and Methods: For quality and possible reproducibility, a narrative review was conducted in accordance with Scale for the Assessment of Narrative Review Articles (SANRA) guidelines. The review targeted articles from the past five years indexed in PubMed, CINAHL, Cochrane Library, Embase, Scopus, Web of Science, and PsycInfo, supplemented by additional relevant references identified through manual searching. The PICOS framework was performed to structure the search strategy and study selection, focusing on studies relevant to the biological effects of music therapy in end-of-life care and their practical implications for nursing care. Results: The neurophysiology of music perception in terminal patients is complex, involving a wide array of clinical and cultural factors. Key musical elements—such as rhythm, melody, harmony, tempo, and mode—can influence physiological and psycho-emotional responses. Music therapy interventions, when tailored to the individual’s preferences and cultural background, may modulate parameters like heart rate, blood pressure, stress hormone levels, and pain perception. Evidence supports the need for individualized approaches and highlights the NPEI rationale for integrating music therapy into end-of-life care. Conclusions: A deeper understanding of the scientific mechanisms discussed in this narrative review can enhance the effectiveness of music therapy interventions in end-of-life settings. Nursing practice can benefit by integrating evidence-based selection of musical pieces and personalizing interventions to the clinical and cultural profile of each patient. Further interdisciplinary research is needed to establish standardized criteria for music therapy in palliative care and to optimize outcomes for terminally ill patients. Full article

Refractory neuropathic pain of the head and neck remains a major clinical challenge, particularly when mediated through the cervicotrigeminal complex (CTC), a unique anatomical hub integrating trigeminal and upper cervical nociceptive inputs. This narrative review synthesizes neuroanatomical, pathophysiological, and clinical evidence to provide a unifying framework for diagnosis and management. A structured search of PubMed, Scopus, and Web of Science identified English-language clinical and mechanistic studies addressing CTC-mediated pain, with case reports excluded unless mechanistically informative. We propose multidimensional refractoriness criteria that integrate pharmacological non-response, failed interventional strategies, and objective functional impairment. Current treatments span pharmacotherapy, peripheral interventions (nerve blocks, radiofrequency ablation), and neuromodulation at multiple network levels (occipital nerve stimulation, spinal cord stimulation, motor cortex stimulation, deep brain stimulation). Non-invasive approaches such as rTMS, tDCS, and vagus nerve stimulation are emerging but remain investigational. Advances in imaging and neurophysiological biomarkers now permit greater precision in detecting CTC dysfunction and tailoring therapy. By combining anatomical precision, mechanistic insight, and multidisciplinary strategies, this review proposes a clinically actionable definition of refractoriness and supports a stepwise, mechanism-based approach to therapy. CTC emerges as a targetable hub for diagnostic and therapeutic strategies in refractory head and neck pain. Full article