Background/Objectives: Because affect is challenging to quantify in fibrom-yalgia, previous network analyses have primarily relied on symptom-severity measures, whereas emotion regulation and affective hypersensitivity have rarely been included. We examined where emotional allodynia, the tendency to respond with disproportion-ate distress to neutral or low-intensity interpersonal cues, sits in this network. Methods: Cross-sectional analysis of 149 consecutive outpatients with fibromyalgia (2016 Ameri-can College of Rheumatology criteria; 91.9% women; mean age 57.5 years). A regularized partial correlation network (EBICglasso: extended Bayesian information criterion graphical lasso; γ = 0.5, Spearman) was estimated over twelve nodes: emotional allo-dynia, pain catastrophizing, central sensitization, depression, state and trait anxiety, and six facets of emotion dysregulation. Accuracy was assessed with 5000 bootstrap replica-tions. Results: The correlation of emotional allodynia with depression (ρ = 0.502) was shrunk to exactly zero in the network and under every sensitivity analysis, and was near zero when the penalty was removed (ρ = -0.033). Its two strongest edges were with pain catastrophizing (0.190) and the Impulse facet of emotion dysregulation (0.184), non-zero in 98.9% and 99.6% of replications. It was among the less connected nodes, but, forming a community of one, all its connectivity crossed a domain boundary. Of that, 59.8% went to emotion regulation and 30.2% to pain, the largest share of any node outside either domain (77.0% and 48.1% of replications). Depression and anxiety received 10.0% (24.6% for catastrophizing). Conclusions: In this exploratory analysis, emotional allodynia oc-cupied a bridging position directed at emotion regulation and pain rather than at de-pression and anxiety, and was not reducible to depressive symptom severity once the other measures were held constant. It overlapped substantially with catastrophizing, and these data do not adjudicate their separability. These preliminary single-centre findings are hypothesis-generating and require replication.

Chronic pain affects 20% of the global population, with current treatments achieving meaningful relief in less than 30% of patients. Growing evidence indicates that immuno-inflammatory mechanisms critically mediate the transition from acute to chronic pain, extending beyond sustained nociceptive input. This narrative review synthesizes current understanding of cellular and molecular immuno-inflammatory processes underlying pain chronification, emphasizing therapeutic implications of immune-neural interactions. Peripheral tissue injury triggers coordinated immune responses involving pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, tumor necrosis factor alpha (TNF-α), and algesic mediators that sensitize nociceptors. Infiltrating macrophages, T lymphocytes, and mast cells perpetuate pro-nociceptive environments. Centrally, microglial and astrocytic activation induces persistent neuroinflammation, synaptic remodeling, and enhanced excitatory neurotransmission while impairing descending inhibition. The balance between pro-inflammatory T helper 1 and T helper 17 (Th1/Th17) and anti-inflammatory T helper 2 and regulatory T cell (Th2/Treg) responses determines pain outcomes. Critically, premature suppression of acute inflammation with nonsteroidal anti-inflammatory drugs (NSAIDs) or corticosteroids may paradoxically promote chronification by disrupting endogenous resolution pathways mediated by specialized pro-resolving mediators and regulatory immune cells. Local inflammation proves more relevant than systemic inflammation for pain persistence. The gut-brain-immune axis emerges as a novel therapeutic target, with microbiota composition influencing pain susceptibility through immunomodulation. Finally, chronic pain represents a failure of natural resolution mechanisms rather than prolonged nociceptive activation. Understanding temporal dynamics of immune responses, individual variability, and sex-specific mechanisms opens avenues for precision medicine approaches. Future strategies should restore homeostatic mechanisms rather than simply suppress symptoms, incorporating biomarker-guided treatment selection and multimodal interventions targeting the complex immuno-inflammatory cascade.

Acute pain and chronic pain represent major global public health challenges; however, no data on their prevalence and determinants have been available in Albania. This study aimed to estimate the prevalence of both acute and chronic pain by gender, and to identify sociodemographic factors associated with chronic pain. A nationwide cross-sectional study was conducted, using a random cluster sampling method to recruit a representative sample of 380 families across all the regions of Albania. A total of 1424 participants completed a structured questionnaire. Descriptive statistics, univariate, and multivariate logistic regression analyses were performed to explore associations between chronic pain and potential predictors. Acute pain was reported by 39.8% of respondents, while chronic pain affected 37.1% of the sample. Multivariate analysis revealed that chronic pain was significantly associated with female sex (adjusted odds ratio (aOR) = 1.99; 95% confidence interval (CI): 1.07-2.26), age over 60 years (aOR = 2.55; 95% CI: 1.15-5.38), in particular range between 31 and 50 years old (aOR = 2.58; 95% CI: 1.71-3.88), low annual income (< €1000; aOR = 2.35; 95% CI: 1.13-5.30), who smoke/alcohol use (aOR = 0.42; 95% CI: 0.18-0.97). Over weight (OR = 2.36; 95% CI: 1.24-4.60) and to be cancer affected (OR = 2.63; 95% CI: 1.59-4.40) only in univariate analysis are associated with chronic pain. In both cases, these results are not confirmed in the multivariate analysis. This is the first study to assess the prevalence and determinants of pain in Albania. The findings highlight a substantial burden of untreated pain and underscore the need for equity-oriented public health strategies, integrated pain services, academic education strategies, and targeted interventions for vulnerable groups.

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, Lipogems® represents an innovative approach based on minimally manipulated microfragmented adipose tissue, 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 Lipogems®, 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 aimed at optimizing therapeutic outcomes.

Greater occipital nerve blocks (GONBs) are used across headache phenotypes, but short-term effectiveness and predictors of response in mixed real-world cohorts remain uncertain. We conducted a prospective observational study of adults with chronic headache phenotypes receiving a single ultrasound-guided proximal (C2) GONB. Primary outcomes were T0 → T1 (1-month) changes in pain (NRS), headache impact (HIT-6), sleep (PSQI), and monthly attacks (crises) using paired Wilcoxon tests. We defined HIT-6 responders as ≥ 10-point reduction. Predictors of response were evaluated with multivariable logistic regression; continuous reductions were modeled with multivariable linear regression. Twenty-nine patients were included (chronic migraine n = 10; cluster n = 5; occipital neuralgia n = 7; cervicogenic n = 7; 69

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.

Background/Objectives: Cancer pain affects 55-95% of patients with advanced malignancy, representing a complex syndrome involving nociceptive, neuropathic and nociplastic mechanisms. Despite therapeutic advances, two-thirds of patients with metastatic cancer experience inadequate pain control. This scoping review synthesizes recent advances in cancer pain pathophysiology and management, focusing on molecular and cellular mechanisms, emerging pharmacological, interventional and technological therapies and key evidence gaps to inform future precision-based pain management strategies. Methods: Following PRISMA-ScR methodology, we searched PubMed, Embase, Scopus, and Web of Science for studies published between January 2022 and September 2025. After screening 3412 records, 278 studies were included and analyzed across different domains: biological mechanisms, pharmacological management, interventional and neuromodulatory approaches, radiotherapy developments, and digital health innovations. Results: Recent mechanistic research reveals cancer pain arises from tumor-neuron-immune crosstalk, with malignant cells secreting neurotrophic factors that promote axonal sprouting and nociceptor sensitization. Genetic polymorphisms and epigenetic modifications contribute to inter-individual pain variability. Management strategies are evolving toward multimodal precision medicine: NSAIDs and opioids remain foundational, complemented by adjuvant agents and interventional procedures including nerve blocks, intrathecal delivery, and neuromodulation (spinal cord and dorsal root ganglion stimulation). Stereotactic body radiotherapy demonstrates superior analgesic durability versus conventional approaches. Digital health innovations, such as mobile applications, remote monitoring, wearables, and AI-enabled predictive models, enable continuous assessment and personalized treatment optimization. Conclusions: Cancer pain management is transitioning toward mechanism-based precision medicine integrating biological insights, advanced interventional techniques, and digital technologies. However, implementation challenges persist, including limited randomized trials for interventional approaches, the incomplete external validation of AI tools, and digital health equity concerns. Future research must prioritize prospective controlled studies and equitable integration into routine care.

BACKGROUND:For decades, clinicians and researchers have struggled to classify pain conditions that do not fit neatly into the nociceptive, neuropathic or nociplastic frameworks. Many common disorders-from chronic low back pain to cancer pain and osteoarthritis-exhibit overlapping mechanisms and have long fallen into the 'grey zone' of mixed pain. This area has intrigued researchers yet frustrated clinicians due to the absence of a clear, unified definition. METHODS:Through an international consensus process led by global leading experts, mixed pain has now been defined as pain that is associated with a lesion, disease or disorder resulting in an overlap of at least two mechanistic pain descriptors (nociceptive, neuropathic or nociplastic). CONCLUSIONS:This new definition may help provide the context needed to align research, refine diagnosis and design mechanism-based therapies for patients with mixed pain. It marks an important step towards conceptual clarification-from confusion to consensus, from overlap to action-transforming mixed pain from an ambiguous concept into a potential framework of modern pain taxonomy. SIGNIFICANCE STATEMENT:This work provides an internationally unified consensus definition of mixed pain, addressing inconsistency in pain terminology and mechanistic classification. By defining mixed pain as the overlap of at least two mechanistic pain descriptors (nociceptive, neuropathic or nociplastic), the framework clarifies conceptual ambiguity while stressing the importance of identifying the underlying pain descriptors, supports a mechanism-based assessment and may facilitate more individualized treatment approaches in complex pain conditions while providing a practical foundation for future research, validation and clinical application.

Fibromyalgia (FM) is a chronic pain disorder marked by widespread pain and significant impairment of daily life. Despite evolving diagnostic criteria and recognition as a primary chronic pain condition, current treatments yield limited success, and underlying mechanisms remain under investigation.This narrative review focuses on oxygen-ozone autohaemotherapy (O2-O3-AHT) as a potential intervention for FM, evaluating its biological rationale and possible mechanisms of action. The therapeutic interest in O2-O3-AHT centres on its capacity to activate the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, reduce oxidative stress, improve mitochondrial function, and address small fibre pathology. The review employed a structured narrative synthesis, adhering to SANRA guidelines to ensure methodological rigor and transparency. Comprehensive literature searches included peer-reviewed articles published in English from 2015 to 2025.Evidence suggests that O2-O3-AHT may provide multi-target benefits for FM patients by modulating redox balance, enhancing mitochondrial resilience, and potentially alleviating neuropathic components related to small fibre dysfunction. Clinical studies, though limited and often heterogeneous, report improvements in pain, sleep quality, fatigue, and overall functional status in FM patients treated with O2-O3-AHT. Biomarker analyses further support reduced oxidative stress and inflammatory mediators post-intervention. However, the variability in treatment protocols, sample sizes, and outcome measures across studies complicates definitive conclusions about efficacy and safety.O2-O3-AHT represents a promising, mechanism-based approach to FM management, particularly for patients unresponsive to conventional therapies. Its ability to target central and peripheral biological processes aligns with the complex pathophysiology of FM. However, the current evidence base is restricted by methodological inconsistencies and a paucity of large, high-quality randomised trials. Future research should prioritise standardised protocols, robust clinical endpoints, and long-term safety assessment to validate the role of O2-O3-AHT in FM treatment. Until then, its use should be considered experimental and guided by careful patient selection and monitoring.

Pain is a frequent and clinically meaningful feature of both neurological and cardiovascular diseases, yet it is rarely examined from an integrated brain–heart perspective. Growing evidence indicates that pain perception, autonomic regulation, and cardiovascular vulnerability are closely interconnected through shared central networks, particularly the insula, cingulate cortex, and brainstem, as well as peripheral neuroimmune and neuroendocrine pathways. Despite this progress, current knowledge remains fragmented across neurology, cardiology, and pain medicine, limiting mechanistic insight and translational application. This narrative review synthesizes literature published from January 2020 to December 2025 on pain within brain–heart interactions. The synthesis highlights mechanistic pathways, clinical pain phenotypes, prognostic relevance, and emerging therapeutic strategies bridging neurological and cardiovascular domains. Key thematic areas include stroke–heart syndrome and central autonomic dysfunction, central post-stroke pain and maladaptive nociceptive processing, the role of chronic pain as a modifier of cardiovascular risk, the burden and impact of pain in heart failure and cardiac surgery survivorship, advances in neuroimaging of central autonomic networks, and the translational potential of neuromodulatory interventions such as vagal nerve and spinal cord stimulation. The reviewed evidence supports the concept of pain as a mechanistic “connector” between brain and heart diseases, influencing symptoms, disease progression, and outcomes. However, heterogeneity in pain definitions, study designs, and outcome measures continues to limit causal interpretation. A unified pain–brain–heart framework, incorporating harmonized phenotyping and mechanism-informed research, is warranted to advance precision assessment and management in this complex clinical domain.

Neurodegenerative diseases represent a major and growing global health burden characterized by progressive neuronal dysfunction, axonal degeneration, and irreversible neural tissue loss. Increasing evidence identifies oxidative stress as one of several interacting pathogenic mechanisms in Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and several optic neuropathies. Interest has increasingly focused on the brain-retina axis, as the retina and optic nerve share structural, metabolic, and molecular features with the central nervous system and may provide accessible insights into neurodegeneration. This scoping review mapped current evidence on oxidative stress in neurodegeneration, emphasizing cranial nerve involvement, optic nerve vulnerability, retinal ganglion cell degeneration, visual dysfunction, oxidative biomarkers, and emerging therapeutic strategies. The review followed established methodological frameworks and PRISMA-ScR recommendations; no formal risk-of-bias appraisal was undertaken, consistent with scoping-review methodology. The literature shows that oxidative stress interacts with mitochondrial dysfunction, neuroinflammation, impaired mitophagy, ferroptosis, and altered bioenergetics, contributing to neuronal injury in cerebral and retinal disorders. Retinal ganglion cells appear particularly vulnerable because of their high metabolic demands and reliance on oxidative phosphorylation. Glaucoma and other optic neuropathies share molecular signatures with central neurodegenerative diseases. Retinal imaging and oxidative biomarkers show promise for diagnosis, monitoring, and stratification. The evidence base is nonetheless dominated by preclinical work; biomarker performance is inconsistent across matrices and assay platforms and most antioxidant clinical trials have been negative. Oxidative stress is therefore best regarded as one interacting node of a broader pathogenic network rather than a universal or predominant driver and the brain-retina continuum as a mechanistically plausible but not yet clinically validated framework for biomarker-guided neuroprotection.

Chronic pain is increasingly recognized as a complex neuroimmune disorder rather than a purely nociceptive phenomenon. Emerging evidence suggests that microbial ecosystems, particularly the gut microbiota, act as upstream modulators of immune and neural signaling pathways that shape pain perception and chronification. This narrative review synthesizes current mechanistic and translational evidence supporting the concept of a microbiome-immune-neural axis in acute and chronic pain conditions. We examine how dysbiosis and epithelial barrier dysfunction promote systemic translocation of microbial-derived molecules, including lipopolysaccharide and other pathogen-associated molecular patterns, leading to activation of innate immune pathways (e.g., Toll-like receptor 4, inflammasomes) and sustained cytokine release. These immune signals sensitize peripheral nociceptors, prime spinal microglia, and alter descending inhibitory circuits, thereby facilitating peripheral and central sensitization. Attention is given to nociplastic pain syndromes, neuropathic pain, musculoskeletal disorders, and cancer-related pain, where low-grade inflammation and immune dysregulation intersect with microbial alterations. We further discuss microbial metabolites, short-chain fatty acids, tryptophan-kynurenine derivatives, secondary bile acids, and endocannabinoid-modulating compounds, as bidirectional regulators of neuroimmune homeostasis. Developmental immune imprinting, stress-related dysbiosis, and epigenetic mechanisms are explored as potential contributors to long-term vulnerability to pain chronification. Finally, we evaluate translational implications, including microbiome-derived biomarkers of pain phenotypes, dietary and probiotic interventions, fecal microbiota transplantation, and integration with artificial intelligence-based profiling strategies. While causality remains incompletely established and methodological heterogeneity limits definitive conclusions, converging data support a model in which microbial-immune signaling functions as a mechanistic amplifier of pain persistence. Positioning chronic pain within a microbial-immunological framework may redefine therapeutic targets and open precision-medicine pathways aimed at restoring neuroimmune and microbial homeostasis.

Postoperative pulmonary complications represent one of the most consequential but underappreciated sources of peri- and post-operative morbidity and mortality. Among these, postoperative respiratory depression, characterized by inadequate ventilatory drive, hypoxemia, and hypercapnia following anesthesia and surgery, has emerged as a subtle, but serious threat to patient safety.

BackgroundEmotional allodynia, a condition in which neutral or low-intensity interpersonal stimuli provoke disproportionate emotional distress, has been proposed as a clinically relevant feature of fibromyalgia. The Emotional Allodynia Questionnaire (AEQ) was recently preliminarily validated and showed a strong association with emotion dysregulation as measured by the Difficulties in Emotion Regulation Scale (DERS). However, which specific DERS facets underlie emotional allodynia, independently of depression, anxiety, pain catastrophizing and central sensitization, remains unknown.MethodsCross-sectional data from 136 adults with fibromyalgia (91.9% female; mean age 57.6 ± 11.3 years) were analyzed. AEQ total score was examined against each DERS subscale (Non-Acceptance, Goals, Impulse, Awareness, Strategies, Clarity) using Spearman correlations, partial correlations controlling for BDI-II, STAI-Y2, PCS and CSI, and hierarchical linear regression with incremental R2.ResultsAt zero order, five subscales correlated with AEQ with the exception of Awareness. After controlling for all covariates, Impulse (ρ_partial = 0.286, p = 0.001), Strategies (ρ_partial = 0.245, p = 0.005), Non-Acceptance (ρ_partial = 0.220, p = 0.011) and Clarity (ρ_partial = 0.201, p = 0.021) remained significantly associated with AEQ, and each contributed incremental variance above the base model (ΔR2 = 0.019–0.038, p < 0.05). Awareness was not significant.ConclusionEmotional allodynia in fibromyalgia is associated with loss of behavioral control (Impulse), limited confidence in emotion regulation (Strategies), non-acceptance and difficulty identifying emotional states (Clarity), but not reduced attention to emotional states (Awareness), suggesting emotions that are noticed but difficult to identify and regulate, with implications for targeted psychological treatments.

Chronic pain is increasingly accepted in the scientific literature as a multidimensional disorder shaped by dynamic interactions between peripheral tissues, the nervous system, and immune pathways, rather than as a direct consequence of structural pathology alone. Within this evolving framework, the microbiota-gut-brain axis has emerged as a compelling systems-level model capable of integrating nociceptive, neuropathic, and nociplastic mechanisms into a unified biological context. This narrative review reframes chronic pain through this axis, synthesizing current evidence on how gut microbial ecosystems influence pain processing via interconnected epithelial, immune, neural, and neuroendocrine pathways. We examine key mechanistic domains, including intestinal barrier integrity, microbial-derived metabolites such as short-chain fatty acids and tryptophan products, vagal and autonomic signaling, hypothalamic-pituitary-adrenal axis modulation, and neuroimmune reprogramming involving glial and peripheral immune cells. These pathways converge to modulate nociceptor sensitivity, central sensitization, and symptom clusters frequently accompanying chronic pain, including fatigue, mood disturbance, and bowel dysfunction. Evidence from human observational studies, translational experiments, Mendelian randomization analyses, and early interventional trials suggest that microbiota-related alterations are not merely epiphenomenal but may contribute to pain vulnerability and persistence across selected phenotypes, with the most consistent and clinically supported evidence observed in visceral pain disorders such as irritable bowel syndrome, while evidence in other conditions, including fibromyalgia, neuropathic pain, and cancer-related pain, remains more heterogeneous or predominantly translational. Despite growing mechanistic plausibility, clinical translation remains constrained by heterogeneity in study design, inconsistent microbial signatures, and limited high-quality interventional data. Accordingly, we propose a pragmatic interpretation for clinicians, emphasizing microbiome-informed adjunctive strategies within multimodal pain management rather than standalone therapeutic approaches. The microbiota-gut-brain axis should therefore be viewed not as a discrete target, but as a regulatory network that refines our understanding of chronic pain complexity and opens avenues for personalized, systems-based care.