Search Results (131)

Background and Objectives: Orthobiologic injectables—principally platelet-rich plasma (PRP), bone marrow aspirate concentrate (BMAC), cell-based therapies and, increasingly, extracellular vesicles—are widely used for chronic musculoskeletal (MSK) pain, yet their evidence base is inconsistent and guideline endorsement is heterogeneous. One frequently proposed contributor to this inconsistency is the use of biologically dissimilar products as interchangeable, one-size-fits-all injections in poorly stratified populations. This narrative review examines current evidence through a conceptual “precision” framework organized around three axes—the biology of the product, the pathology of the target tissue, and the phenotype of the patient—and around image-guided delivery as the procedural context in which these axes are operationalized. It spans osteoarthritis, tendinopathy, plantar fasciopathy, discogenic and spinal pain, and impaired bone healing, with emphasis on PRP, BMAC, and platelet- and cell-derived extracellular vesicles. Materials and Methods: PubMed/MEDLINE, Embase, Cochrane CENTRAL and Web of Science were searched from inception to 15 January 2026 and updated on 31 August 2026; 4812 de-duplicated records were screened by two authors independently, and 435 full texts were assessed, from which 76 sources are cited (36 clinical studies and evidence syntheses, 11 guidelines, consensus statements or reporting standards, and 29 narrative, mechanistic, regulatory or methodological references). Evidence was prioritized as guidelines and formal consensus, then syntheses with a certainty assessment, then individual trials, with neutral and negative trials given equal weight. This is a narrative, not a systematic, review; SANRA was used as a critical-appraisal checklist, not as a reporting guideline. Results: Across indications, pooled efficacy signals are frequently positive but of low-to-moderate certainty, with substantial risk of bias, small-study effects, and inconsistent product reporting; adequately controlled trials in knee osteoarthritis, Achilles and lateral-elbow tendinopathy, and discogenic pain have returned neutral results. Candidate response modifiers—structural phenotype, inflammatory and metabolic status, pain-processing phenotype, intraprocedural signals, and machine-learning models—are at present largely prognostic associations rather than validated treatment-effect modifiers. Guideline positions diverge, reflecting differences in methodology and evidence thresholds as well as in the underlying evidence. Conclusions: We present the three-axis framework as a testable hypothesis and a structure for stratified prospective trials, not as a validated clinical algorithm. We classify its components by clinical readiness, distinguish prognostic from predictive biomarkers, temper regenerative language where only symptomatic benefit is demonstrated, and identify platelet- and cell-derived extracellular vesicles as an early-stage, predominantly preclinical direction whose translational promise remains to be established. Full article

The emotional benefits of pet ownership depend critically on the pet’s physical, behavioural, and cognitive health—all of which can be improved by targeted nutritional interventions that may reduce pain, anxiety, problem behaviours, and cognitive decline. However, almost no studies have tested whether nutrition-induced behavioural improvements translate into measurable gains in owner emotional well-being or relationship satisfaction. It is important to note that the evidence base for cats remains considerably more limited than that for dogs, and many conclusions drawn from canine studies should be extrapolated to cats with caution. Furthermore, the human–animal relationship is bidirectional: owner psychology and feeding practices feed back to affect pet health. This review synthesises evidence across veterinary medicine, nutritional science, and human- animal interaction research to support a central thesis: that the relational value of pet ownership may be a function of pet health, may be modifiable by targeted nutrition, and is hypothesized to be embedded in bidirectional feedback loops that require dyadic interventions. The review explicitly distinguishes between evidence-supported findings and the proposed conceptual framework. The field now requires dyadic randomised controlled trials with co-primary outcomes for both pet and owner, plus precision stratification, pragmatic effectiveness studies, mechanistic biomarkers, and one health approaches. Closing this translational gap requires a coordinated research effort focused on designing dyadic interventions that measurably improve the welfare of both pets and their owners. Full article

Osteoarthritis (OA) and other rheumatic diseases are among the leading causes of chronic pain, disability, and reduced quality of life worldwide. Increasing evidence indicates that disturbances in metal homeostasis contribute to the pathogenesis of these disorders through their effects on oxidative stress, immune regulation, cartilage metabolism, bone remodeling, and extracellular matrix degradation. This review summarizes current knowledge regarding the role of essential metals and trace elements, including zinc, iron, copper, magnesium, selenium, and manganese, as well as toxic metals such as cadmium, lead, mercury, and arsenic, with primary emphasis on their involvement in the development and progression of osteoarthritis. Other rheumatic diseases are discussed briefly to provide a comparative perspective. Particular attention is given to the molecular mechanisms underlying metal-mediated pathology, including oxidative stress, ferroptosis, mitochondrial dysfunction, activation of intracellular signaling pathways, and inflammasome activation. The diagnostic and therapeutic potential of metal-related biomarkers, metalomics, and targeted interventions aimed at restoring metal homeostasis are also discussed. Furthermore, current limitations of available studies and emerging research directions, including single-cell technologies, spatial transcriptomics, multi-omics approaches, and personalized medicine, are highlighted. A better understanding of metal homeostasis may improve the identification of novel biomarkers and therapeutic targets, ultimately contributing to more precise diagnosis and individualized treatment strategies for osteoarthritis and other rheumatic diseases. Full article

Background/Objectives: Chronic orofacial pain disorders are highly heterogeneous and therapeutically challenging. Although current classifications such as the International Classification of Orofacial Pain (ICOP) and the concept of nociplastic pain have improved diagnostic consistency, patients with the same diagnosis may show substantial differences in symptom severity, underlying biology, and treatment response. This suggests that disease classifications may describe clinical phenotypes more effectively than the biological mechanisms sustaining persistent pain. This article proposes the Adaptive Hierarchical Domain Network (AHDN) as a conceptual framework for understanding chronic orofacial pain from a precision medicine perspective. Conceptual Framework: AHDN integrates concepts from systems biology, network neuroscience, predictive processing, biomarker research, and precision medicine. It organizes chronic pain across five hierarchically related but dynamically interacting layers: biological susceptibility, peripheral nociceptive drivers, central adaptive plasticity, behavioral adaptation, and social embedding. The framework is intended to complement, rather than replace, established diagnostic classifications. Implications: The proposed framework suggests that burning mouth syndrome, persistent dentoalveolar pain disorder, persistent idiopathic facial pain, occlusal dysesthesia, and subsets of temporomandibular disorders may represent different mechanistic configurations within a shared adaptive network. AHDN provides a hypothesis-generating structure for mechanistic phenotyping, biomarker development, and individualized management. However, the framework remains conceptual and requires prospective clinical validation, standardized assessment methods, and evaluation of its clinical utility before routine implementation. Full article

Chemotherapy-induced neurotoxicity is a major dose-limiting complication of systemic anticancer therapy that adversely affects neurological function, treatment continuity, and long-term quality of life among cancer survivors. Chemotherapy-induced peripheral neuropathy (CIPN) is the most common manifestation, whereas chemotherapy-related cognitive impairment (CRCI) and selected immune-mediated neurological toxicities increasingly contribute to survivorship-related morbidity. Although these immune-mediated syndromes are distinct from conventional chemotherapy-induced neurotoxicity, they are included because they share several downstream pathogenic mechanisms relevant to biomarker discovery and neuroprotective strategies. This structured narrative review critically synthesizes current evidence on the molecular mechanisms, clinical manifestations, biomarkers, and emerging neuroprotective strategies underlying chemotherapy-induced neurotoxicity. A comprehensive PubMed/MEDLINE search was performed, with emphasis on studies published between 2014 and 2026. Evidence from systematic reviews, meta-analyses, clinical guidelines, randomized controlled trials, prospective clinical studies, and high-quality translational research was critically evaluated. Current evidence indicates that chemotherapy-induced neurotoxicity arises through interconnected mechanisms involving oxidative stress, mitochondrial dysfunction, neuroinflammation, calcium dysregulation, blood–brain barrier disruption, and SARM1-mediated programmed axonal degeneration. Among emerging biomarkers, neurofilament light chain (NfL) demonstrates the greatest translational potential for early detection and monitoring, while inflammatory cytokines, circulating microRNAs, pharmacogenomic markers, cerebrospinal fluid biomarkers, and advanced neuroimaging may improve individualized risk stratification. Although duloxetine remains the only guideline-recommended pharmacological treatment for established painful CIPN, mechanism-based therapies targeting mitochondrial dysfunction, neuroinflammation, oxidative stress, and SARM1 signaling, together with structured exercise and biomarker-guided precision medicine, represent promising translational approaches. However, clinical implementation remains limited by incomplete biomarker validation, heterogeneous study methodologies, and the absence of effective disease-modifying neuroprotective therapies, underscoring the need for large biomarker-guided multicenter clinical trials. Full article

Background: Temporomandibular disorders (TMD) comprise a heterogeneous group of musculoskeletal conditions that may manifest during childhood and adolescence. However, standardized information regarding TMD-related clinical findings in pediatric populations remains limited because of methodological heterogeneity and the inconsistent application of validated diagnostic protocols. Objective: The aim of this study was to characterize clinical findings related to temporomandibular disorders in schoolchildren and to explore their potential contribution to individualized assessment strategies within the framework of personalized pediatric oral healthcare. Methods: A multicenter cross-sectional study was conducted in 1052 schoolchildren recruited from participating educational institutions. All participants underwent a standardized clinical examination that included assessment of masticatory muscle tenderness, temporomandibular joint tenderness, joint sounds, pain intensity, and perceived stress using an adapted pediatric DC/TMD protocol. Categorical variables were summarized as frequencies, percentages, and 95% confidence intervals (95% CIs). Associations between categorical variables were evaluated using Pearson’s chi-square test, and multivariable logistic regression was performed to identify factors independently associated with pain. Results: Pain during clinical examination was identified in 111 participants (10.6%; 95% CI: 8.8–12.6%), whereas temporomandibular joint sounds and myofascial pain were detected in 1.4% and 0.3% of participants, respectively. Most pain was classified as mild, and the masseter muscle was the most frequently affected anatomical site. Increasing age and female sex were independently associated with pain. Compared with children aged 4–6 years, participants aged 10–12 years (adjusted OR = 9.61; 95% CI: 2.22–41.51) and 13–16 years (adjusted OR = 35.49; 95% CI: 8.59–146.61) showed significantly greater odds of pain. Female participants also demonstrated higher odds of pain than males (adjusted OR = 7.49; 95% CI: 3.68–15.21; all p < 0.05). Conclusions: Clinically detectable TMD-related findings were generally uncommon among schoolchildren aged 4–16 years and were predominantly mild and muscular. Increasing age and female sex were independently associated with pain, emphasizing the importance of demographic factors in the early clinical expression of TMD. Standardized pediatric clinical examination protocols may facilitate early identification of TMD-related findings and support preventive strategies during childhood and adolescence. These findings support the implementation of individualized clinical assessment strategies for early identification of children at risk of temporomandibular disorders, contributing to personalized preventive and therapeutic approaches in pediatric oral healthcare. Full article

Pain is a leading cause of morbidity and healthcare utilization in sickle cell disease (SCD), and opioids remain central to treating vaso-occlusive and chronic pain. Yet opioid response varies widely, raising the question of whether pharmacogenetic testing should inform opioid prescribing. Our review examined the PubMed literature on pharmacogenomics and opioid efficacy in SCD. We focus on CYP2D6 as the clearest current pharmacogenetic signal for codeine and tramadol, and assess SCD-specific implementation studies, preemptive testing, and African pharmacoequity. The current evidence supports targeted CYP2D6-informed prescribing in selected contexts rather than universal testing for all opioids, while highlighting the need to integrate genotype with pain phenotype, drug–drug interactions, liver function, and clinically grounded implementation studies, and better characterize African and African-ancestry pharmacogene variation. Full article

Circadian rhythms determine biological clocks that manage daily biological functions, including the sleep–wake rhythm, hormone release, and immune function. This can affect immune-mediated chronic inflammation in rheumatoid arthritis (RA), which leads to joint damage, pain, swelling, and morning stiffness. These clinical manifestations follow a distinct circadian rhythm because of the cyclic pattern of leukocyte movement, secretion of pro-inflammatory cytokines such as IL-6, IL-1β, and TNF-α at night, and fluctuations in cortisol and melatonin levels. Despite the increasing amount of evidence showing that insufficient sleep and disruption of the biological clock may play a role in RA development through suppression of the immune response in macrophages and resorption processes in osteoclasts, the cause of this phenomenon is still under investigation. The present-day guidelines continue to endorse DMARDs as the basis of treatment, while studies are exploring the role of chronotherapy as an adjunctive method for alleviating symptoms and enhancing disease outcomes. In this review, we explore current knowledge regarding the links between the molecular basis of circadian biology and the pathogenesis of RA, highlight recent trends in immune and bone remodeling mechanisms, and discuss modern possibilities for using chronotherapy, precision medicine, and advanced drug-delivery methods based on circadian rhythms to create optimal treatment strategies for RA. Full article

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) remain the cornerstone of pharmacological treatment for osteoarthritis (OA) and are recommended by international guidelines for the management of symptomatic pain. Despite their well-established efficacy, substantial interindividual variability exists in treatment response, with some patients experiencing meaningful pain relief while others derive little clinical benefit despite appropriate drug selection and dosing. This variability reflects, at least in part, the biological heterogeneity of OA pain. Objective: To review the mechanisms underlying variability in NSAID responsiveness in OA and to propose a practical framework for personalized NSAID prescribing based on pain phenotype, individual safety profile, and treatment timing. Methods: A narrative review of the contemporary scientific literature was conducted using major biomedical databases to summarize the current evidence on phenotype-guided NSAID therapy in OA. Particular attention was given to the emerging concepts of nociceptive, nociplastic, and neuropathic-like pain phenotypes and their implications for personalized anti-inflammatory therapy. Results: Current evidence indicates that OA pain is a heterogeneous and dynamic condition in which inflammatory nociceptive, nociplastic, and neuropathic-like mechanisms coexist to varying degrees. NSAIDs primarily target inflammatory nociceptive pain by inhibiting cyclooxygenase (COX)-mediated prostaglandin synthesis and reducing peripheral sensitization. Consequently, patients with predominantly inflammatory nociceptive pain are the most likely to benefit from NSAID therapy, whereas those with predominant nociplastic or neuropathic-like pain mechanisms may require alternative or multimodal treatment strategies. Beyond pain phenotype, optimal NSAID selection should integrate cardiovascular, gastrointestinal, and renal risk assessment, recognizing the important pharmacological and safety differences among individual agents. Treatment timing is also clinically relevant, as anti-inflammatory therapy appears most effective when initiated during periods of active inflammatory nociceptive pain. Based on the available evidence, we propose a conceptual clinical decision framework integrating patient selection, NSAID choice, and treatment timing. Conclusions: Personalized NSAID prescribing should move beyond a diagnosis-based approach toward a mechanism-based strategy that integrates pain phenotyping, individualized safety assessment, and appropriate treatment timing. The proposed framework is built upon three complementary principles, identifying the right patient, selecting the right treatment, and initiating therapy at the right time. It provides a practical foundation for implementing precision medicine in the pharmacological management of OA. Full article

Cancer pain affects more than half of all oncology patients and represents one of the most challenging therapeutic problems in modern medicine. Despite the central role of opioids in cancer pain management—codified by the WHO analgesic ladder—the clinical response to these agents is highly variable between individuals. Pharmacogenomics promises to explain this heterogeneity by identifying functionally relevant genetic polymorphisms in genes encoding opioid receptors, metabolizing enzymes, and membrane transport proteins. However, after two decades of intensive research, clinical translation of genetic data into actionable prescribing strategies remains elusive. A narrative-critical review of the literature was conducted by searching PubMed, Scopus, and Web of Science databases from inception to March 2026, using the search terms “opioid,” “pharmacogenomics,” “pharmacogenetics,” “cancer pain,” “polymorphism,” and individual gene names (OPRM1, CYP2D6, COMT, ABCB1, SLC22A1, UGT2B7, and others). Reference lists of included articles were hand-searched for additional relevant studies. Inclusion was restricted to English-language articles reporting original data or systematic reviews on genetic polymorphisms and opioid response, with priority given to studies conducted in cancer pain populations. Clinical practice guidelines from CPIC, NCCN, ESMO, EAPC, and ASCO were consulted for current recommendations. This narrative-critical review examines the evidence on genetic polymorphisms relevant to opioid response in cancer pain, covering three functional categories: (1) pharmacodynamic genes, including opioid receptors (OPRM1, OPRD1, OPRK1) and neuromodulatory targets (COMT, KCNJ6, MC1R); (2) pharmacokinetic enzymes (CYP2D6, CYP3A4/5, UGT2B7); and (3) membrane transporters, including ABC efflux pumps (ABCB1, ABCG2, ABCC2) and SLC uptake carriers (SLC22A1, SLCO1B1, SLC6A4, SLC6A2). A dedicated section addresses the direct and indirect interference of the tumour itself—through the tumour microenvironment, neuroimmune signalling, epigenetic reprogramming, and cancer-induced organ dysfunction—on opioid pharmacogenomics. The overall evidence is poor and fragmented, a finding intrinsic to the extraordinary diversity, large number, and context-dependent biological activity of the polymorphisms identified. The tumour itself acts as a pervasive confounder that systematically distorts genotype–phenotype relationships. The path forward requires a paradigm shift from candidate-gene association studies to system pharmacogenomics and multi-omic integration. Full article

Perioperative stress induces profound molecular and cellular responses that contribute to postoperative complications, including perioperative neurocognitive disorders (PND), chronic postsurgical pain, organ dysfunction, immunothrombosis, fibrosis, and cancer progression. Increasing evidence demonstrates that epigenetic mechanisms act as central regulators linking surgical trauma, inflammation, metabolic stress, ischemia–reperfusion injury, and immune activation to long-term alterations in gene expression and tissue remodeling. DNA methylation, histone modifications, chromatin remodeling, non-coding RNAs, and RNA epitranscriptomic mechanisms such as N6-methyladenosine (m6A) collectively orchestrate perioperative responses across multiple organ systems. Recent translational studies have identified histone deacetylases (HDACs), histone methyltransferases, NETosis-associated chromatin signaling, HMGB1/NF-κB activation, and epigenetic regulation of neuroimmune pathways as major contributors to postoperative cognitive dysfunction, chronic pain, cardiac dysfunction, pulmonary injury, and fibrosis. In parallel, advances in liquid biopsy, circulating tumor DNA (ctDNA), and single-cell epigenomics have opened new opportunities for biomarker-guided perioperative precision medicine. This review summarizes current evidence regarding epigenetic regulation in perioperative medicine with special emphasis on neuroepigenetics, NETosis, fibrosis, cardiac epigenetics, immune remodeling, and perioperative oncological outcomes. Furthermore, we discuss emerging therapeutic strategies targeting HDACs, DNA methylation, m6A pathways, and chromatin-associated inflammatory signaling as potential future interventions for perioperative complications. Full article

Exosomes, nanoscale extracellular vesicles released by virtually all cell types, have emerged as pivotal mediators of intercellular communication and play a crucial role in the pathophysiology of numerous acute and chronic diseases, including a wide spectrum of urological disorders. By acting as sophisticated biological shuttles, exosomes transport a rich and highly specific molecular cargo—comprising proteins, lipids, messenger RNAs, microRNAs, and other nucleic acids—that reflects the physiological or pathological state of their cell of origin. Owing to these unique properties, exosomes are increasingly recognized as promising biomarkers for the diagnosis, prognosis, and monitoring of a broad range of inflammatory, degenerative, and neoplastic diseases. Beyond their diagnostic value, exosomes have attracted considerable attention as therapeutic tools, given their ability to promote tissue regeneration, modulate immune responses, and serve as potential targeted drug-delivery systems for small molecules, biologics, vaccines, and gene-based therapies. Notably, exosomes recapitulate many of the beneficial biological effects traditionally attributed to stem cells, while potentially offering a more practical alternative. As cell-free entities, they may reduce—though not entirely eliminate—several risks associated with cell transplantation, such as uncontrolled proliferation and immune rejection, and they raise fewer ethical concerns, making them attractive candidates for regenerative and precision medicine. In urology, the diagnostic, prognostic, and therapeutic applications of exosomes are rapidly expanding, with particularly promising advances observed in bladder, prostate, and kidney diseases. Growing evidence also supports their relevance in a variety of benign urological conditions, including erectile dysfunction, male infertility, neurogenic bladder, urethral stricture disease, stress urinary incontinence, and bladder pain syndrome. This review synthesizes contemporary knowledge on the biological significance and clinical potential of exosomes in urology, highlighting their emerging role as biomarkers and therapeutics, with a special focus on benign urological disorders. We emphasize that the current evidence base in benign urology is largely preclinical, and that clinical translation, although promising, remains at an early stage. Full article

Background/Objectives: Chemotherapy-induced peripheral neuropathy (CIPN) is a common, dose-limiting complication of cancer therapy and a major contributor to chronic neuropathic pain among cancer survivors. Although traditionally managed as a treatment-related toxicity, persistent CIPN frequently persists long after chemotherapy completion and is increasingly recognized as a major survivorship and palliative care challenge. This review synthesizes current mechanistic, clinical, and translational evidence and reframes persistent CIPN as a chronic neuropathic cancer pain syndrome. Methods: A narrative review of peer-reviewed literature was conducted using PubMed/MEDLINE, Embase, and the Cochrane Library, supplemented by manual review of key references and clinical guidelines. Emphasis was placed on mechanistic investigations, clinical management, survivorship, palliative care, and emerging therapeutic strategies relevant to CIPN. Results: Current evidence suggests that persistent CIPN reflects a multifactorial chronic neuropathic pain state involving neuronal injury, mitochondrial dysfunction, oxidative stress, neuroimmune activation, and maladaptive nociceptive signaling. Existing pharmacologic therapies provide limited symptomatic benefit and largely fail to address the underlying biologic mechanisms that contribute to symptom persistence. Emerging approaches involving mitochondrial-targeted therapies, neuroimmune modulation, biomarker-guided risk stratification, and multimodal supportive care suggest the potential for earlier intervention and disease modification rather than symptom palliation alone. Conclusions: Persistent CIPN should be conceptualized as a chronic neuropathic cancer pain syndrome rather than solely as a treatment-related toxicity. Future progress will likely require mechanism-informed therapeutic development, biologic stratification, earlier intervention, and survivorship-focused multidisciplinary care to improve long-term outcomes and quality of life in patients living with persistent CIPN. Full article

Pain and stress are frequent and clinically relevant challenges in neonatal intensive care, particularly among preterm and critically ill newborns exposed to repeated invasive procedures, mechanical ventilation, surgery, and advanced life-support interventions. Effective analgosedation is essential to reduce discomfort, attenuate physiological instability, improve tolerance of intensive care procedures, and potentially limit adverse neurodevelopmental consequences. However, neonatal pain and analgosedation management remain complex because of developmental immaturity, pharmacokinetic and pharmacodynamic variability, and the need to balance adequate analgosedation against treatment-related complications. This narrative review summarizes current evidence on analgosedation in the Neonatal Intensive Care Unit, focusing on clinical indications, pharmacological agents, non-pharmacological strategies, monitoring tools, adverse effects, and future perspectives. Opioids, benzodiazepines, dexmedetomidine, and ketamine each have specific potential benefits and limitations, requiring individualized selection, careful titration, and continuous reassessment. Non-pharmacological interventions, including oral sucrose, non-nutritive sucking, facilitated tucking, breastfeeding, skin-to-skin care, and environmental modulation, should be integrated into multimodal pain-management protocols. Validated instruments such as COMFORTneo, N-PASS, and PIPP-R support standardized assessment and guide therapeutic decisions. Future advances may derive from objective monitoring technologies, artificial intelligence, developmental pharmacology, and precision-medicine approaches. A multidisciplinary, protocol-driven, and family-centered strategy is essential to optimize neonatal comfort while minimizing avoidable drug exposure. Full article

Pain biomarkers have been proposed as potential tools to improve patient stratification, treatment selection, and individualized therapeutic strategies in chronic pain. However, despite an increasing volume of research across neuroimaging, electrophysiological, and molecular domains, their translation into clinical practice remains limited. A central challenge lies in the conceptual and methodological misalignment between biomarker discovery and clinical applicability. Many studies labelled as “predictive” rely on measurements obtained during or after intervention, small sample sizes, or lack of external validation, limiting their ability to inform real-world decision-making. In addition, the distinction between predictive, monitoring, and mechanistic biomarkers is often blurred, further complicating interpretation and implementation. This Perspective examines why many candidate pain biomarkers, although biologically informative, have not yet become clinically actionable tools for treatment selection. We distinguish between associative, mechanistic, monitoring, preventive, and truly predictive biomarkers using clinically relevant examples from pain research, and we outline the methodological requirements needed to translate biomarker discovery into precision pain medicine. We argue that the field requires a more rigorous framework for defining and validating predictive biomarkers, encompassing appropriate timing of measurement, robust study design, external validation, and patient-relevant endpoints. Without this framework, pain biomarker research risks continuing to generate biologically informative but clinically non-actionable findings that do not advance individualized therapeutic decision-making. Full article