Advancements in Health Research (#AHRjournal) has the aim to become a world-leading medical journal, initially published on a quarterly basis. It accepts, with an open-access policy, studies by highly ranked scientists worldwide, providing scientific material to a large global audience, and aiming to have an impact on health. The publication of this journal was decided by the Fondazione Paolo Procacci based on a large consensus experienced by the previous editorial initiatives of the Fondazione. Our goal is to make science easily available to all those interested. The ambition of #AHRjournal is to serve and aid in a transformation of society, providing an improved and ethical approach to research on health, with a preferential focus on Pain Medicine and Quality of Life. We would be proud to publish papers that provide a crucial contribution to science and human health. #AHRjournal invites the submission of original content, as well as narrative reviews, systematic reviews, and meta-analyses, which may contribute to advances in medical science and practice. Advancements in Health Research promotes open science and supports the early dissemination of research through recognized preprint platforms, facilitating rapid knowledge sharing within the global health research community.
Anorectal examination can be crucial in classifying spinal cord injuries, but there is much more to explore - it is one piece of the puzzle, but not the entire puzzle
The International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) remain the reference framework for classifying spinal cord injury, with the absence of deep anal pressure and voluntary anal contraction defining complete injury (AIS A). Accumulating evidence, however, suggests that anorectal examination alone may not fully capture residual physiological connectivity in some individuals clinically classified as complete. Neurophysiological studies have reported preserved sensory, motor, or autonomic conduction despite the absence of sacral sparing on standard examination, challenging the conceptual boundaries between complete and incomplete injury. This commentary argues for a refined and integrative interpretation of neurological assessment that preserves the central role of ISNCSCI while incorporating complementary neurophysiological information and systematically collected patient‑reported manifestations. Rather than proposing reclassification or operational thresholds, the perspective presented is conceptual and hypothesis‑generating. Emphasizing preserved connectivity and neuroplastic potential may enhance prognostic understanding and support more individualized rehabilitation approaches. Future progress will depend on prospective validation studies, methodological standardization, and expert consensus to determine how multimodal information may responsibly inform classification without compromising clinical reliability.
Copyright (c) 2026 the Author(s) https://creativecommons.org/licenses/by-nc/4.0
Therapeutic target for reversal of overdose-induced respiratory depression: BK channels in the carotid body
Opioid-overdose has morphed from a mainly single-entity problem (e.g., heroin, or fentanyl, or some other opioid) to a predominantly polysubstance combination of opioid + non-opioid problem. Reversal of opioid-alone respiratory depression is straightforward (albeit not always easy) using an opioid receptor antagonist such as naloxone. Unfortunately, combinations containing non-opioid contributors to respiratory depression are not so pharmacologically straightforward. Given that the non-opioid component is often not known, a reversal agent that would work independently of the combination components (‘agnostic’) is highly desired. A promising target for such a drug is the peripherally-located carotid body, the primary peripheral arterial chemoreceptor that detects arterial hypoxia and responds with compensatory signals. Large-conductance Ca²⁺- and voltage-activated potassium channels (BK, Maxi-K, KCa1.1) within the glomus cells regulate the response of the carotid body to hypoxia, and the gain and stability of the respiratory feedback loop. Hypoxia inhibits BK channels via direct and indirect mechanisms, enhancing the gain of signaling from the carotid body to brainstem respiratory nuclei. Although initially proposed to be intrinsic oxygen sensors, current evidence supports a more integrative role in modulatory control of carotid body activity. This minireview gives a succinct overview of the molecular biology and structural diversity of BK channels and their accessory β/g subunits, the physiological mechanisms linking BK channel activity to hypoxia chemotransduction, and systems-level roles in negative-feedback drive of ventilatory responsiveness. Also included are future directions and a proposed control system model of carotid body BK feedback.
Reframing chronic pain through the microbiota-gut-brain axis: from mechanisms to clinical meaning
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.
Virtual reality as a treatment for acute antiemetic-induced akathisia
Many patients receiving common antiemetic medications for a variety of complaints ranging from gastroenteritis to headache to surgery experience the distressing extra-pyramidal neuropsychiatric side effect of akathisia due to the dopamine-antagonist mechanism of these drugs. Akathisia involves a persistent restlessness and urge to move, common in those taking antiemetics. Currently, a literature gap exists surrounding how virtual reality (VR) often used for general mental health treatment can be leveraged in a biosensor capacity toward neurotransmitter analysis and balancing among patients experiencing antiemetic-induced akathisia. This review examined the potential benefits of wearable VR technology as a non-pharmacological treatment solution for patients displaying signs of akathisia in an acute setting such as the emergency department. The review concluded with a Python code foundation for two machine learning algorithms for a wearable biosensor to correlate neurochemical fluctuations of dopamine and stress-induced cortisol with VR audiovisual inputs among patients with akathisia stemming from these drugs. Potential obstacles included the risk of invasiveness implicated by administration of neurotransmitter saliva tests among wearers experiencing these stressful symptoms as well as the technical challenge of integrating biosensing capabilities into a virtual reality wearable device.
From symptom control to biological restoration: the expanding role of microfragmented adipose tissue in pain and regenerative medicine
Hold my paw: the unseen exchange in our homes and its impact on health
The human-animal bond represents a topic of growing scientific and public health relevance, as companion animals share close living environments with humans in a substantial proportion of households across many countries. This intimate cohabitation creates a shared microbial environment, facilitating constant, bidirectional exchange of microorganisms between pets and their owners. Here, we explore the dynamics of this microbial transfer and its influence on human health, specifically focusing on immune-mediated, metabolic, and gastrointestinal disorders. Drawing from the “One Health” concept, which recognizes the interconnectedness of human, animal, and environmental health, we examine how companion animals shape the composition of the human gut microbiota. Evidence suggests that while this exchange carries potential risk for transmitting pathogens and antimicrobial resistance, the overall effect appears beneficial. Pet exposure, particularly in early life, is associated with increased microbial diversity and enrichment of beneficial taxa such as Ruminococcus and Oscillospira. These alterations are linked to reduced risk of immune-mediated conditions like allergies and asthma, consistent with the ”microbiota hypothesis”. Furthermore, pet ownership correlates with lower prevalence of metabolic syndrome, potentially mediated by favorable shifts in gut microbiota, such as a reduced Firmicutes-to-Bacteroidetes ratio. However, household transmission of extended-spectrum β-lactamase-producing Enterobacterales represents a tangible public health concern requiring antimicrobial stewardship. We synthesize current findings, highlighting the household as a key epidemiological unit and positioning the shared microbiome as a critical factor in health outcomes of pet-owning families.
A translational mathematical model linking systemic biomarkers to disease recurrence in diabetic macular edema: a proof-of-concept analysis
This study aimed to develop a translational mathematical model that links systemic biomarkers to diabetic macular edema (DME) dynamics and to provide a proof‑of‑concept assessment of its plausibility for informing anti‑vascular endothelial growth factor (anti‑VEGF) treatment strategies. A hybrid modeling approach was employed, combining mechanistic reasoning with a retrospective analysis of DRCR.net Protocol H data. A mechanistic model formalized the biological interaction between systemic drivers -glycated hemoglobin (HbA1c), systolic blood pressure (BP), and glycemic variability- and retinal VEGF dynamics, while an empirical penalty model translated these drivers into a framework for estimating personalized injection intervals (Imodel). Using data from 97 eyes treated with bevacizumab, we assessed the association between Imodel and a theoretical time to disease recurrence (Trec), defined as a >10% increase in central subfield thickness or a >5‑letter loss in visual acuity. The model’s hierarchical structure, which prioritized HbA1c, produced a shorter or equivalent interval compared to Trec in 63.6% of the overall cohort, and in a targeted subgroup where the model’s logic was fully applicable, the concordance rate was 77.6%. In Group E, simulating a post‑loading phase with two injections plus laser, the mean deviation between Imodel and Trec was minimal (-0.1 weeks) with reduced variability (SD=5.6 weeks). Sensitivity analysis confirmed the designed hierarchy, showing HbA1c exerted a 36‑fold greater influence on the model’s output than BP. These findings present a novel mathematical framework linking systemic metabolic and hemodynamic control to DME progression. The proof‑of‑concept analysis supports the biological plausibility of using HbA1c and BP to stratify recurrence risk and provides a transparent, interpretable foundation for future research. This model bridges systemic and ocular care and proposes a structured hypothesis for personalized treatment scheduling that warrants prospective validation in appropriately designed clinical cohorts.
Postoperative respiratory depression and pulmonary complications: serious but underappreciated
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.
Physiotherapeutic management of primary dysmenorrhea for adolescent students: a systematic review and meta-analysis
Primary dysmenorrhea (PD) affects up to 80% of adolescent girls, significantly impacting their school attendance and quality of life. This systematic review and meta-analysis evaluated the efficacy of physiotherapeutic interventions, including acupressure, massage, exercise, and transcutaneous electrical nerve stimulation (TENS), in managing PD among adolescents. Following PRISMA guidelines and utilizing the PICO framework, a comprehensive search was conducted across four electronic databases (Scopus, PubMed, Medline, and Cochrane Library) and grey literature for English-language randomized controlled trials (RCTs) published between May 2000 and May 2025. Ten RCTs involving 1,496 participants met the inclusion criteria, focusing on adolescents aged 10–19 years with PD. Pain reduction, measured using visual analogue scale (VAS) and numerical rating scale (NRS), was the primary outcome, with significant improvements observed across most interventions. A meta-analysis supported the effectiveness of these therapies, though heterogeneity in study designs and interventions was noted. The findings suggest that physiotherapy is a promising non-pharmacological approach for PD management, with potential benefits for both physical and psychological health. However, the findings should be interpreted with caution due to study heterogeneity and moderate methodological quality. Further high-quality trials are recommended to strengthen the evidence base and guide clinical practice. Trial Registration Number: PROSPERO 2025 CRD420251074405.
Exercise pain and alexithymia: exploring the relationship
Alexithymia, a psychological trait characterized by impaired emotional awareness and regulation, has been linked to altered pain perception and emotional processing. Despite its established role in chronic pain and psychological disorders, little is known about its influence on exercise-induced pain. To investigate the relationship between alexithymia and exercise-induced pain perception, differences in pain intensity, perceived exertion, heart rate, and task endurance were measured during isometric exercise in alexithymic and control participants. Sixty participants were categorized into alexithymic and control groups based on the Alexithymia Scale. Participants performed an isometric contraction task, holding a mass of 20% of their one-repetition maximum (1RM) at a 90° elbow flexion for as long as they could, during which pain intensity, perceived exertion, and heart rate were recorded. Statistical analyses, including MANOVAs and correlation analyses, evaluated the effects of alexithymia on these outcomes. Alexithymic participants reported significantly higher pain intensity compared to controls across all time points. However, no significant differences were found between groups for perceived exertion, heart rate, or task endurance. These findings suggest that exercise-induced pain is increased in alexithymia, but without limiting muscular endurance. Targeted pain management interventions focusing on emotional processing deficits may benefit individuals with alexithymia. Future research should explore adaptive mechanisms over prolonged exposure and the development of tailored therapeutic interventions to improve emotional resilience and quality of life. This study is the first to demonstrate that alexithymia is associated with heightened pain perception during exercise, independent of exercise intensity and physiological response. These findings offer novel insights into the interplay between emotional processing and pain sensitivity, highlighting the need for targeted pain management interventions in alexithymic individuals. The results have potential implications for both psychological and physical rehabilitation strategies, improving therapeutic approaches for populations with emotional processing deficits.
Hyperspectral retinal imaging for micro- and nanoplastics detection: a conceptual and methodological framework
This manuscript presents a conceptual and methodological framework rather than empirical results, outlining a pathway for applying hyperspectral retinal imaging (HSRI) to detect micro- and nanoplastics (MNPs). The retina, with its transparent optical media, layered architecture, and vascularization, offers an ideal biomedical model for adapting spectroscopic techniques that have been widely used in environmental and materials sciences. The framework consists of four staged phases: i) construction of a spectral library of common synthetic polymers; ii) phantom experiments that replicate retinal optical properties and are spiked with defined MNPs; iii) ex vivo validation in ocular tissues with Raman and Fourier-transform infrared spectroscopy as chemical ground truth; and iv) pilot in vivo studies in small-animal models to assess HSRI sensitivity, specificity, and safety. Machine-learning classifiers and spectral unmixing algorithms are incorporated to separate polymer-specific signals from endogenous chromophores such as hemoglobin, melanin, and lipofuscin. While no experimental data are presented, the framework anticipates the establishment of polymer spectral libraries, demonstration of separable spectral signatures, and translational feasibility for detecting polymer deposits under safe irradiance conditions. If validated, HSRI could enable the retina to serve as a sentinel organ for systemic pollutant exposure, bridging ophthalmology, toxicology, and environmental health with spectroscopy. ______________________________________________________________________________________________________________________________________________________ Graphical Abstract
Copyright (c) 2025 the Author(s) https://creativecommons.org/licenses/by-nc/4.0
Advancements in cardiovascular pharmacology
Cardiovascular pharmacology is entering a period of profound transformation, driven by novel therapies that extend far beyond traditional approaches. Recent advances include RNA-based drugs targeting lipoprotein(a) and angiotensinogen, new stabilizers for transthyretin amyloidosis, and selective aldosterone synthase inhibitors for resistant hypertension. These developments illustrate a decisive shift from symptomatic management toward disease modification and precision targeting. Yet, significant challenges remain. Translating biomarker reductions into hard outcomes such as reduced mortality, myocardial infarction, or stroke requires large, long-term clinical trials now underway. Equally critical is the need for rigorous monitoring of long-term safety, particularly for new platforms such as siRNA and gene therapies, where off-target effects and tolerability over decades remain uncertain. High cost and limited accessibility further threaten to widen global health inequities, while gaps in diagnostic infrastructure hinder appropriate patient selection. Regulatory frameworks, especially outside high-income regions, must also evolve to keep pace with these scientific advances. Despite these obstacles, the future is rich with promise. Gene editing and novel gene therapies hold the potential to correct underlying disease mechanisms, while long-acting drugs offer solutions to adherence challenges. Personalized, multimodal strategies, combining metabolic, anti-inflammatory, and genetic risk-modifying agents, may soon become standard, tailored to each patient’s biomarker and genetic profile. Importantly, early detection of subclinical disease could shift cardiovascular pharmacology from treating advanced illness toward prevention and preservation of health. The coming decade will determine whether these breakthroughs translate into equitable, lasting improvements in outcomes, heralding a new era in cardiovascular care.
PAIN AS A NEUROCARDIAC STRESSOR: REFRAMING PAIN BEYOND NOCICEPTION
Background and Aims. Pain is usually considered a sensory and emotional experience. However, growing evidence shows that pain also triggers integrated neuroendocrine and autonomic responses with broad effects. Through the brain–heart axis, both acute and chronic pain can act as biological stressors that impact cardiovascular health, regardless of how pain is perceived. The aim is to develop a clinically focused conceptual framework that describes pain as a neurocardiac stressor and highlights its possible role as a systemic disease modifier. Methods. We conducted a narrative, mechanism-focused synthesis of current evidence on pain-related activation of the hypothalamic–pituitary–adrenal (HPA) axis, autonomic imbalance, and downstream cardiovascular effects, with an emphasis on clinically relevant pathways. Results. Pain triggers a coordinated stress response involving activation of the limbic system, hypothalamic signaling, and engagement of the HPA axis, resulting in cortisol release and dominance of sympathetic activity. This autonomic imbalance is linked to decreased vagal tone, reduced heart rate variability, and elevated catecholamine levels. The downstream effects include endothelial dysfunction, microvascular impairment, pro-inflammatory signaling, and increased myocardial oxygen demand. These mechanisms may contribute to arrhythmogenic vulnerability, hemodynamic instability, and stress-related cardiomyopathy. Importantly, persistent pain can sustain these pathways over time, indicating a role as a chronic systemic stressor. Conclusions. Pain should be viewed as more than just a symptom; it acts as a neurocardiac stressor with possible systemic effects. Incorporating pain assessment into cardiovascular risk evaluation and adopting a brain–heart approach could lead to new opportunities in both clinical management and translational research.
Copyright (c) 2026 The Author(s) https://creativecommons.org/licenses/by-nc/4.0
REGENERATIVE ULTRASOUND-GUIDED PRP PLUS HYALURONIC ACID PROVIDES DURABLE PAIN CONTROL IN KNEE OSTEOARTHRITIS
Background and Aims. Knee osteoarthritis (OA) is a major cause of chronic nociceptive and inflammatory pain. Intra-articular hyaluronic acid (HA) is widely used, but its analgesic effect is often temporary. Platelet-rich plasma (PRP), through growth factor release and modulation of synovial inflammation, may enhance and prolong pain relief. This study aimed to evaluate whether ultrasound-guided PRP combined with high-molecular-weight HA provides superior and sustained analgesia compared with HA alone in patients with knee OA. Methods. In this prospective observational study, 100 patients with MRI-confirmed knee OA (Kellgren–Lawrence II–III) received three ultrasound-guided intra-articular injections at 30-day intervals. Group A received leukocyte-poor PRP plus 60 mg high-molecular-weight HA; Group B received identical HA alone. Pain intensity was assessed using the Numeric Rating Scale (NRS, 0–10) and functional status using WOMAC at baseline, 30 days, 2, 3, 6, and 12 months. Statistical significance was set at p < 0.05. Results. The PRP + HA group demonstrated progressive and sustained analgesia, with mean NRS decreasing from 7.0 at baseline to 2.1 at 12 months (−70%). WOMAC improved from 62 to 24 (−61%). In contrast, the HA-only group showed early transient improvement, with NRS changing from 6.9 to 6.8 at 12 months and WOMAC from 60 to 58. Between-group differences at 6 and 12 months were statistically significant (p < 0.05). Conclusions. Ultrasound-guided PRP combined with high-molecular-weight HA provides clinically meaningful and durable pain reduction compared with HA alone in knee OA, supporting its role in regenerative pain management (see Table below).
WOUND PAIN ASSESSMENT IN ITALIAN DOMICILIARY PALLIATIVE CARE: AN AUDIT OF LAW 38/2010 COMPLIANCE IN HOMENURSING
Background and Aims. Law 38/2010 guarantees access to palliative care and pain therapy in all settings, including home care. Chronic wound pain — prevalent in pressure injuries, diabetic foot ulcers, and vascular ulcers — is a cardinal palliative symptom in end-of-life patients. Italian nurses in palliative home care report feeling "alone during emergencies and sensitive communications" and identify inadequate training as a primary challenge (Iotti et al., PMC 2025; N=39 nurses, Reggio Emilia). No Italian study has assessed wound pain assessment competency specifically in home-based palliative nursing. This study aims to quantify the wound pain assessment gap in palliative care nursing for Italian patients at home. Methods. Sequential mixed-methods. Phase 1: retrospective audit of palliative home care records in ASL Bari U.O. Cure Palliative Domiciliari (N=60 patients, January–March 2026): wound pain documentation frequency, validated scale use (NRS, PAINAD, and Edmonton Symptom Assessment Scale), and analgesic adequacy (Pain Management Index). Phase 2: focus groups with palliative home care nurses (N=12, ASL Bari) on wound pain barriers. Ethical approval: ASL Bari IRB. Results. Preliminary audit (N=22 records): wound pain formally assessed in 31.8%; PAINAD or ESAS used in 9.1%; Pain Management Index negative (undertreated) in 63.6%. Focus group preliminary findings: wound pain perceived as "minor" compared to disease pain by 83.3% of nurses interviewed. Conclusions. Wound pain in Italian domiciliary palliative care is systematically underassessed and undertreated. Integrating structured wound pain protocols into Law 38/2010 palliative home care pathways is an urgent, measurable imperative for patient dignity.
FROM PHENOTYPE TO GENOTYPE: DO COMT, MTHFR, BDNF, OPRM1, AND HTR2A POLYMORPHISMS CONTRIBUTE TO CHRONIC MUSCULOSKELETAL PAIN?
Background and Aims. This study sought to determine whether functional polymorphisms in COMT, MTHFR, BDNF, OPRM1, and HTR2A are differentially distributed across major chronic musculoskeletal pain phenotypes and whether they are associated with pain severity, fatigue, stress, and disease duration. Methods. In this single-center retrospective observational study, the researchers included 19 adults with chronic musculoskeletal pain lasting more than 3 months. Primary diagnoses were fibromyalgia, myofascial pain syndrome, lumbar disc herniation, and arthritis-related pain. Clinical data (demographics, diagnosis, disease duration, VAS pain/fatigue/stress) were extracted from the records. Genomic DNA was isolated from buccal swabs and genotyped for COMT (rs4680, rs4633, rs4818, rs6269), MTHFR (rs1801133, rs1801131), BDNF rs6265, OPRM1 rs1799971, and HTR2A (rs6311). Nonparametric tests (Kruskal–Wallis, chi-square/Fisher's exact) were applied (p<0.05). Results. Fibromyalgia (n=11) showed the greatest genetic heterogeneity, with COMT and MTHFR intermediate/low-activity genotypes and predominantly AA OPRM1 rs1799971. Myofascial pain syndrome (n=3) displayed a similar “nociplastic” profile with heterozygous COMT and MTHFR and OPRM1 AA. Arthritis and lumbar disc herniation were characterized by preserved MTHFR/BDFN patterns and higher frequencies of OPRM1 rs1799971 AG, suggesting a more nociceptive, opioid-modulated profile. OPRM1 rs1799971 distribution differed significantly across diagnoses (p=0.017), while no SNP showed significant associations with VAS pain, fatigue, or stress. Conclusions. Diagnosis-specific genotype patterns, particularly for OPRM1 rs1799971, support biologically distinct nociplastic versus nociceptive profiles in chronic musculoskeletal pain. Although underpowered for definitive associations, this pilot study illustrates the potential of multimarker genetic panels for mechanism-oriented phenotyping and calls for larger, prospective, multi-omic studies to refine genotype-informed, personalized pain management.
FUNCTION, SATISFACTION, AND RESPONDER RATES AFTER PULSED RADIO FREQUENCY, CRYOABLATION, AND INTRA-ARTICULAR BOTULINUM TOXIN FOR KNEE OSTEOARTHRITIS: A THREE-ARM TRIAL
Background and Aims. Beyond mean pain scores, functional recovery and clinically meaningful responders are crucial for guiding interventional choices in knee osteoarthritis (KOA). We compared function, satisfaction, analgesic pattern, and ≥30% pain-responder rates after pulsed RF, cryoablation, and intra-articular Botox. Methods. In a three-arm comparative study (Assiut University; March 2023–December 2025), 79 KOA patients received pulsed RF (n=27), cryoablation (n=27), or Botox (n=25) with a 12-month follow-up. Function was assessed by WOMAC (baseline, 1, 3, 6, and 12 months) and the Lequesne index (baseline, 3, 6, and 12 months). Satisfaction (4-point Likert) was recorded at 3, 6, and 12 months. Responders were defined as ≥30% VAS improvement from baseline. Results. Functional outcomes improved most with Botox (WOMAC ≈ 26.7–30.0 at 1–12 months), with lower Lequesne scores at 3–12 months (4.10–5.00). Cryoablation showed intermediate early WOMAC improvement versus pulsed RF, with partial loss by 12 months. Satisfaction favored Botox at 3 and 6 months (Likert category 4: 76.0% and 68.0%). Responder rates were highest with Botox across timepoints (72–88%). Cryoablation exceeded pulsed RF early (55.6–74.1% vs. 25.9%) but declined to 0% at 12 months. Conclusions. Botox provided the most durable functional improvement, patient satisfaction, and clinically meaningful responder rates. Cryoablation delivered strong short-term benefit but limited durability, while pulsed RF showed lower responder proportions.
CHRONIC PAIN TREATMENT DURING PREGNANCY: NAVIGATING THE EVIDENCE GREY ZONE
Background and Aims. Chronic pain during pregnancy is a significant yet underexplored condition. Low back pain, pelvic girdle pain, neuropathic syndromes, headache, fibromyalgia, and pre-existing chronic pain disorders can considerably impair mobility, sleep, daily functioning, and psychological well-being. Despite this burden, therapeutic decisions remain challenging because maternal needs for symptom control must be balanced against fetal and neonatal safety within a limited and often inconsistent evidence base. This review aims to provide a clinically oriented overview of the main evidence gaps affecting the pharmacological management of chronic pain during pregnancy and to highlight key priorities for future research. Methods. We performed a narrative review of the existing literature on pharmacological treatment of chronic pain during pregnancy, focusing on five key areas: the availability of pregnancy-specific data, pharmacokinetic evidence, maternal-fetal safety, long-term outcomes for offspring, and the methodological consistency of published studies and recommendations. Results. Current evidence remains fragmented, heterogeneous, and often indirect. Pharmacokinetic data in pregnant women are limited, long-term neurodevelopmental outcomes are inadequately defined for many common analgesic or adjuvant drugs, and reported endpoints differ significantly across studies. As a result, many treatment decisions are based on extrapolation from non-pregnant populations, trimester-specific precautions, and individualized clinical judgment rather than solid pregnancy-specific guidance. This uncertainty may lead to both the undertreatment of disabling pain and excessive caution in therapy. Conclusions. Treatment of chronic pain during pregnancy remains an area with limited evidence. There is an urgent need for prospective studies, standardized maternal and fetal outcome measures, and pregnancy-specific, clinician-focused guidelines to promote safer and more personalized pain management.
MICROBIAL DRIVERS OF PAIN IN ANKYLOSING SPONDYLITIS: THE ROLE OF INFECTIONS AND GUT MICROBIOME DYSBIOSIS
Background and Aims. Pain is the predominant disabling symptom in ankylosing spondylitis (AS). Emerging evidence suggests that occult infections and intestinal dysbiosis may enhance nociceptive pathways through systemic inflammation and gut-joint immune interactions. This study investigated the association between infectious triggers, gut microbiota alterations, and pain intensity in AS patients. Methods. A cross-sectional case-control study included 316 AS patients and 124 healthy controls. Pain intensity was assessed using VAS alongside BASDAI, BASFI, and ASDAS-CRP. Infectious pathogens were detected by PCR, and gut microbiota composition was analyzed using 16S rRNA sequencing with diversity and machine-learning analyses. Results. AS patients exhibited a high pain burden (mean VAS 5.98±1.45) accompanied by elevated disease activity (mean BASDAI 5.8±1.4). At least one infectious trigger was detected in 50.9% of patients, most commonly Chlamydia trachomatis (21.2%), which was associated with a higher prevalence of peripheral inflammatory pain. Microbiome analysis demonstrated significant dysbiosis compared with controls (PERMANOVA p 90% specificity). Conclusions. Ankylosing spondylitis pain is influenced not only by structural inflammation but also by microbial-immune interactions involving infections and intestinal dysbiosis. These findings support a gut-joint-pain axis in AS and highlight microbial profiling as a potential tool for understanding pain mechanisms and identifying novel therapeutic targets.
Background and Aims. Overlapping chronic pain conditions (OCPCs) are increasingly recognized in patients with rheumatic diseases, potentially influencing disease assessment and treatment decisions. To evaluate the prevalence and impact of OCPC in rheumatic patients. Methods. We conducted an observational study including 150 patients, divided equally into rheumatoid arthritis (RA) (n=50), systemic lupus erythematosus (SLE) (n=50), and systemic sclerosis (SSc) (n=50) groups. OCPCs were identified based on clinical evaluation and patient-reported pain characteristics. Disease activity scores and treatment requirements were compared between patients with and without OCPC. Results. OCPCs were identified in 36 patients (24%): RA 12/50 (24%), SLE 16/50 (32%), and SSc 8/50 (16%). In RA, fibromyalgia (58.3%) and chronic low back pain (33.3%) predominated. In SLE, fibromyalgia (50%), chronic headache (37.5%), irritable bowel syndrome–related pain (31.3%), and chronic pelvic pain (18.8%) were common, with multiple overlapping conditions frequent. In SSc, musculoskeletal pain (50%), fibromyalgia-like pain (37.5%), and headache (25%) were observed. Patients with OCPC exhibited higher disease activity scores: RA DAS28 5.1 ± 0.8 vs 3.8 ± 0.7, SLE SLEDAI 12.4 ± 3.1 vs 8.6 ± 2.9, and SSc mRSS 18.2 ± 4.5 vs 13.1 ± 3.8. Intensified immunosuppressive therapy was required in 69.4% of patients with OCPC versus 36.0% without. Conclusions. OCPC are common in rheumatic diseases, linked to higher disease activity and greater therapy needs, highlighting the risk of misattributing pain to inflammation and the need for precise pain phenotyping and multimodal management.
DEEP BRAIN STIMULATION FOR REFRACTORY CHRONIC PAIN: CLINICAL TARGETS, INDICATIONS, AND EMERGING STRATEGIES
Background and Aims. Chronic pain remains a major unmet clinical challenge, particularly in patients who are refractory to pharmacological, interventional, and neuromodulatory therapies. Deep brain stimulation (DBS) has re-emerged as a potential option for select chronic pain syndromes, targeting both sensory-discriminative and affective-emotional pain circuits. This paper aims to synthesize current clinical evidence on DBS for chronic pain, focusing on therapeutic targets, pain indications, treatment outcomes, and emerging strategies relevant to pain medicine practice. Methods. A narrative review of clinical and translational studies evaluating DBS for chronic pain was performed. Evidence was analyzed according to pain etiology, neuroanatomical target, stimulation strategy, and reported clinical outcomes. Results. DBS demonstrates the most consistent benefit in neuropathic and mixed pain syndromes, including cluster headache, phantom limb pain, and failed back surgery syndrome. Stimulation of the periaqueductal/periventricular gray (PAG/PVG) and sensory thalamus is associated with meaningful pain reduction in a substantial proportion of patients, while limbic targets such as the anterior cingulate cortex and ventral striatum primarily modulate the affective dimensions of pain. The clinical response varies greatly and is affected by the choice of patients, the type of pain, the accuracy of lead placement, and the stimulation parameters. New methods, such as dual-target stimulation, advanced imaging-guided targeting, and combination neuromodulation therapies, look like they could help improve results. Conclusions. DBS represents a viable therapeutic option for carefully selected patients with refractory chronic pain, particularly those with neuropathic components. While its use remains off-label in many regions, advances in targeting strategies and patient phenotyping may enhance efficacy and expand its role within multidisciplinary pain management.
GENDER DIFFERENCES IN THE PRESENTATION AND MANAGEMENT OF CHRONIC PAIN: EVIDENCE FROM AN OBSERVATIONAL STUDY
Background and Aims. Gender-specific medicine in pain management requires considering biological sex and psychosocial factors, as they influence the prevalence, perception, and outcomes of pain treatment. The objective is to analyze the interaction between pain intensity, biopsychosocial impact, and disability. Methods. The observational study was conducted at the Pain Medicine Outpatient Clinic of the Foggia Polyclinic on adult patients suffering from chronic persistent pain. The analysis involved 85 patients (32 males and 53 females). Internationally validated scales were used: NRS, Oswestry Disability Index, and Hamilton. Statistical correlations between these indices, clinical covariates, and administered therapies were assessed, monitoring recurrence rates at 1-, 3-, and 6-month follow-ups. Results. Male patients presented at admission with higher pain intensity (NRS 7.1 vs. 6.5) and functional disability (ODI 63 vs. 40). Females show a higher Hamilton score (11 vs. 8). The temporal analysis clearly shows the different behaviors of the two genders. In males (NRS-ODI: r = 0.730), treatment approaches are delayed ("male stoicism") until the onset of actual disability. In females, functional resilience is greater but influenced by emotional state (Hamilton-ODI: r = 0.461). Males receive more interventional therapies (fix-it approach) than females (conservative medicalization). Conclusions. In males, the interventional approach must be integrated with counseling and functional rehabilitation to prevent relapses. In females, early management of the anxiety-depressive component that underpins disability and reconsidering the use of interventional therapy are priorities.
TRANSARTERIAL EMBOLIZATION FOR CHRONIC SHOULDER TENDINOPATHY AND BURSITIS: EARLY CLINICAL OUTCOMES USING DEGRADABLE STARCH MICROSPHERES
Background and Aims. The aim of this study is to evaluate the clinical effectiveness and safety of transarterial embolization (TAE) with degradable starch microspheres (EmboCept®) in patients with chronic shoulder tendinopathy/bursitis refractory to conservative therapy. Methods. This prospective single-center study (July - December 2025) included 10 consecutive patients (6 women, 4 men; mean age 66.3 ± 15.6 years) with unilateral shoulder tendinopathy/bursitis treated with TAE. Laterality was left in 7 and right in 4 cases. All procedures used EmboCept® degradable starch microspheres. Clinical outcome was assessed with the Shoulder Pain and Disability Index (SPADI) at baseline, 48 hours, 3 months, and 6 months when available. Descriptive statistics were calculated for available follow-ups. Results. The mean baseline SPADI was 96.3 ± 30.1 (n = 11). At 48 hours (n = 10), mean SPADI decreased to 37.1 ± 35.0, corresponding to a 61% relative improvement. At 3 months (n = 8), mean SPADI was 42.4 ± 34.5 (56% relative improvement vs. baseline). One patient had 6-month follow-up (SPADI 31). Most patients demonstrated rapid early pain and disability reduction; however, variability at 3 months was observed, including one case with clinical worsening (SPADI 100). No major complications were recorded in the dataset. Conclusions. TAE with degradable starch microspheres for chronic shoulder tendinopathy/bursitis appears technically feasible and is associated with substantial early SPADI improvement, with maintained benefit at 3 months in most patients. Outcomes show inter-individual variability, emphasizing the necessity of larger prospective studies with standardized imaging selection and complete follow-up to define durability and predictors of response.
ULTRASOUND-GUIDED CRYONEUROLYSIS: A NOVEL APPROACH TO PAIN MANAGEMENT IN RHEUMATOID ANKLE AND FOOT ARTHRITIS
Background and Aims. Rheumatoid arthritis (RA) is a systemic autoimmune disease that frequently affects the foot and ankle. More than 90% of patients develop symptoms in these regions during the course of the disease, leading to pain, deformity, and disability. Chronic ankle and foot pain in RA may persist despite pharmacological and surgical interventions, severely impairing daily activities and professional duties. This case report aims to demonstrate the efficacy of ultrasound‑guided cryoneurolysis in refractory RA‑related ankle and foot pain, emphasizing its impact on pain relief, functional recovery, and preservation of gait and proprioception. Methods. A 45-year-old female pediatric physician with a 15-year history of rheumatoid arthritis and prior subtalar and talo-navicular arthrodesis presented with severe chronic left ankle and foot pain (VAS 10/10). Over five years, she received multiple systemic and local therapies, including NSAIDs, gabapentin, pregabalin, duloxetine, intra-articular steroids, hyaluronic acid, ozone, botulinum toxin, and rehabilitation modalities, without improvement. Prior to definitive cryoneurolysis, an ultrasound-guided (USG) diagnostic block was performed targeting the superficial fibular, sural, saphenous, and deep peroneal nerves, resulting in >90% pain relief that was sustained for 24 hours. On August 17, 2025, USG cryoneurolysis was subsequently carried out on the same nerves. Results. The procedure resulted in immediate and complete pain relief (VAS 0/10). The patient resumed activities of daily living and professional work without limitations. Importantly, gait and proprioception were not affected. Pain relief persisted for six months, with no reported complications. Conclusions. Ultrasound-guided cryoneurolysis of ankle nerves is a safe and effective minimally invasive option for refractory RA-related ankle and foot pain. This case demonstrates sustained analgesia, functional recovery, and preservation of gait and proprioception, underscoring its potential role in patients unresponsive to conventional therapies
BEYOND ANALGESIA: FASCIAL PLANE BLOCKS AS MODULATORS OF THE SURGICAL STRESS RESPONSE
Background and Aims. Fascial plane blocks are increasingly used as part of multimodal analgesia in perioperative care. While traditionally seen only as pain-relief techniques, their ability to influence the systemic stress response to surgery is still not well understood. Surgical trauma triggers a complex neuroendocrine and inflammatory response, involving sympathetic activation, hypothalamic–pituitary–adrenal (HPA) axis activation, and cytokine release, all of which can affect postoperative recovery and organ function. To create a clinically relevant framework that views fascial plane blocks as modulators of the surgical stress response, beyond their role in pain relief. Methods. We conducted a narrative, mechanism-based review that integrates current evidence on regional anesthesia, autonomic modulation, and perioperative stress physiology, with a focus on fascial plane techniques. Results. By reducing nociceptive input at its source, fascial plane blocks may decrease central sensitization and limit activation of stress-related pathways. This could result in lower sympathetic output, better autonomic balance, and decreased neuroendocrine activation. Emerging evidence suggests potential downstream effects, including reduced catecholamine release, modulation of inflammatory responses, improved hemodynamic stability, and decreased opioid requirements. These mechanisms may help enhance recovery, reduce complication rates, and improve patient-centered outcomes. However, current data are heterogeneous and largely indirect, with few studies specifically evaluating systemic effects. Conclusions. Fascial plane blocks should be viewed not only as pain management tools but also as potential modulators of the surgical stress response. Adopting a broader physiological perspective can facilitate their incorporation into strategies to improve perioperative resilience and recovery.
CHRONIC PAIN PREVALENCE AND ASSESSMENT GAP IN ITALIAN PUA/UVM PATIENTS: A CROSS-SECTIONAL STUDY
Background and Aims. Chronic pain (CP) affects 24.1% of Italian adults (Violini et al., Pain Res Manag 2025; DOI:10.1155/prm/3401242), yet 86.2% remain unaware of pain management centers. The IFoC (Infermiere di Famiglia o Comunità), mandated by DM 77/2022 with approximately 3,000 patients per nurse, conducts routine multidimensional assessments in U.O. PUA/UVM yet lacks standardized pain assessment protocols. This study quantifies chronic pain prevalence, severity, and functional impact in the PUA/UVM population and maps current IFoC pain assessment practices. Methods. Cross-sectional observational study. Phase 1: consecutive patients referred to U.O. PUA/UVM ASL Bari (N=32 completed, target N=120) administered the NRS and the interview-administered Brief Pain Inventory Short Form (BPI-SF; Cleeland & Ryan, Ann Acad Med Singap 1994; PMID 8080219; validated for chronic nonmalignant pain: Cronbach α=0.85–0.88) during routine multidimensional assessment visits. DN4-interview administered to patients with NRS ≥ 4 to screen for the neuropathic component. Phase 2: semi-structured interviews with IFoC (N=8). IRB waiver for anonymized data; Phase 2 ethics pending. Results. In Phase 1 preliminary results (N=32), 56.3% of patients experienced moderate-to-severe pain (NRS ≥ 4), no patients had a documented pain management plan, and BPI-SF severity and interference data are currently under analysis. Phase 2 (N=8 IFoC): Pain assessment was absent from the standard multidimensional evaluation protocol in all cases; zero had received pain assessment training in the past 3 years. Conclusions. Chronic pain is highly prevalent but unassessed in the PUA/UVM population. Standardizing interview-administered BPI-SF and NRS within the IFoC multidimensional evaluation is a low-cost, evidence-based intervention to close Italy's chronic pain assessment gap.
RADIOFREQUENCY DENERVATION IN THE MANAGEMENT OF SACROILIAC JOINT PAIN: A COMPARATIVE STUDY OF TWO TECHNIQUES
Background and Aims. Sacroiliac joint (SIJ) dysfunction is a significant source of chronic low back pain, affecting 10% to 25% of patients. When conservative treatments fail, radiofrequency (RF) denervation is a common second-line intervention. This study aims to evaluate the efficacy of RF denervation in SIJ dysfunction and to compare the clinical efficacy and operational efficiency of two different RF techniques: the monopolar clock technique and the bipolar palisade technique. Methods. A retrospective observational study was conducted on 81 patients who underwent RF for SIJ dysfunction: 35 underwent monopolar clock RF and 46 underwent bipolar palisade RF. We collected NRS, BPI (BPI_DOL and BPI_QUAL), and opioid consumption at baseline and in the follow-up at 1, 3, and 6 months after the procedure. Operational parameters, including fluoroscopy time and the number of shots, were also recorded. Results. Both techniques significantly reduced pain and opioid use by over 30% at the 6-month follow-up, with no statistically significant difference between groups. However, the bipolar palisade technique demonstrated superior operational efficiency, requiring significantly shorter fluoroscopy times and fewer shots. Conclusions. Radiofrequency denervation is highly effective for the mid-to-long-term management of SIJ pain. While both techniques provide comparable clinical relief at 6 months, the bipolar palisade technique is more efficient by reducing radiation exposure for both patients and operators.
GUT MICROBIOTA AND PAIN EXPRESSION IN ANKYLOSING SPONDYLITIS: CLINICAL-MICROBIAL CORRELATES (GRASP-STUDY)
Background and Aims. Pain is the dominant clinical manifestation in ankylosing spondylitis (AS), reflecting both structural inflammation and neuroimmune mechanisms. Emerging evidence suggests that gut microbiota dysbiosis may contribute to systemic inflammation and pain amplification. This study aimed to evaluate the relationship between intestinal microbiota composition and pain expression in AS. Methods. A cohort of 60 subjects (41 AS patients, 19 controls) was analyzed. Patients were stratified into axial (axAS) and peripheral (pAS) phenotypes. Clinical data included inflammatory markers and disease activity indices. Pain intensity was assessed indirectly through disease activity parameters. Gut microbiota composition was evaluated using PCR-based analysis, followed by multivariate and classification modeling. Results. AS patients demonstrated a distinct microbial profile compared to controls (p < 0.001), with 12 predominant bacterial species identified versus 8 in controls. A significant reduction in Bacteroides (0.332 vs. 0.430) and marked increase in Prevotella (0.168 vs. 0.031) were observed, indicating dysbiosis associated with inflammatory activation. Patients with peripheral AS exhibited earlier disease onset (18.0 vs 25.5 years; p < 0.01) and higher inflammatory burden, corresponding to increased pain-related clinical expression. Multivariate analysis identified 8 microbial genera (including Dialister, Collinsella, and Streptococcus) as key discriminators of AS, with a classification accuracy of 95%, suggesting strong biological relevance. These taxa are known to induce pro-inflammatory pathways, supporting a mechanistic link between gut dysbiosis and nociceptive sensitization. Conclusions. Gut microbiota alterations are associated with inflammatory activity and pain expression in AS. Microbial profiling may represent a novel biomarker for early identification of high-pain phenotypes and a potential therapeutic target.
LAW 38/2010 AND COMMUNITY NURSING: THE IFOC/IFEC AS MISSING GATEWAY TO ITALY'S PAIN THERAPY NETWORK
Background and Aims. Italy's Law 38/2010 established citizens' right to access palliative care and pain therapy as essential levels of care. Fourteen years later, Violini et al. (Pain Res Manag 2025; DOI:10.1155/prm/3401242) confirm this landmark law has produced very few achievements for the real benefit of relieving chronic pain in the population compared with expectations. The IFoC (Infermiere di Famiglia o Comunità), mandated by DM 77/2022 with approximately 3,000 patients per nurse, is strategically positioned to function as the missing gateway between citizens and the pain therapy network. This study aims to assess whether IFoC systematically identify and refer chronic pain patients to Law 38/2010 network centers in Bari province. Methods. Mixed-methods implementation study. Phase 1: retrospective audit of U.O. PUA/UVM referral records (January–December 2025; target N=200 multidimensional assessments): extraction of pain-related documentation, NRS recording, and pain center referrals generated. Phase 2: semi-structured interviews with IFoC (N=15, ASL Bari) and MMG (N=10) on awareness of the local Law 38 network and referral practice barriers. Ethical approval: ASL Bari IRB Results. Preliminary audit (N=58 records): pain documentation present in 29.3%; NRS recorded in 15.5%; referral to the pain network under Law 38/2010 generated in 3.4%. IFoC interviews (N=8): 62.5% were unaware of local pain therapy center contacts; zero had received Law 38 training in the past 3 years. Conclusions. The IFoC is the closest professional to the chronic pain patient yet remains structurally disconnected from Italy's pain therapy network. A structured Law 38/2010 integration protocol within DM 77/2022 territorial care frameworks is urgently needed.
WOUND PAIN ASSESSMENT AND NEGATIVE PRESSURE WOUND THERAPY COMPETENCY GAP IN ITALIAN COMMUNITY NURSES: A CROSS-SECTIONAL MIXED-METHODS STUDY
Background and Aims. Negative pressure wound therapy (NPWT) requires pain monitoring as a critical management dimension, yet Italian nurses show low NPWT-specific self-knowledge (Krówczynska et al., IJERPH 2023; PMID 36834085; N = 401) and significant geographic training disparities—33.3% of Southern Italian nurses received zero wound care training (Ielapi et al., Nurs Rep 2022; PMID 35893640). No Italian study has specifically measured wound pain assessment practices alongside NPWT competency. This study characterizes wound pain assessment practices and NPWT-related pain monitoring competency in Italian community nurses. Methods. Cross-sectional mixed-methods study. Phase 1: Online survey of community nurses (N=41 completed, target N=120; ASL Bari coordination and FNOPI network) using the adapted NPWT Perception Questionnaire (Krówczynska 2023) supplemented with pain-specific items (NRS applicability, procedural pain protocols, and analgesic documentation). Phase 2: three focus groups of N=6 nurse managers each (N=18 total; first group completed; thematic analysis in progress). IRB approval: ASL Bari. Results. Preliminary survey (N=41): 73.2% report no standardized wound pain protocol; 61.0% never used a validated pain scale in wound care; 87.8% received no pain management content in NPWT CPD. First focus group (N=6): wound dressing pain underdocumented as a recurring pattern due to time constraints and absent institutional protocols. Conclusions. Wound pain assessment is a critical competency gap in Italian community NPWT nursing. A structured pain monitoring protocol integrated within NPWT governance frameworks is the evidence-based response to this gap and to Law 38/2010 obligations.