Letter to the editor: synergistic effect of dry needling and instrument-assisted soft tissue mobilization in patellofemoral pain syndrome: a randomized controlled trial

Osteoarthritis (OA), a leading cause of disability worldwide, impacts over 300 million people through progressive joint degeneration marked by chronic pain and functional impairment. A key driver of osteoarthritis progression is synovitis, characterized by inflamed synovial tissue harboring senescent fibroblasts and pro-inflammatory macrophages. These senescent cells secrete senescence-associated secretory phenotype (SASP) components, includining cytokines and proteases, which drive macrophage polarization toward a pro-inflammatory M1 state. Simultaneously, M1 macrophages release reactive oxygen species (ROS) and inflammatory mediators, amplifying cellular senescence and establishing a pathological feedback loop. Unfortunately, conventional single-target therapies, such as senolytics or macrophage modulators, fail to address this interdependence vicious cycle. Herein, guided by bioinformatics analysis integrated with clinical and murine specimen data, we developed an easy-to-produce combinatorial nanomedicine platform comprising: (i) synovium-targeting liposomes delivering senolytics to clear senescent fibroblasts and suppress SASP, and (ii) M2 macrophage-derived exosomes to convert M1 macrophages into regenerative M2 phenotypes. In rat OA models, this dual approach combined disrupted the senescence-inflammation cascade, achieving 73.53% synovitis index reduction and 75.00% OARSI score reduction. In summary, by concurrently clearing SASP-producing senescent cells and pro-inflammatory M1 macrophages, our strategy restores joint homeostasis and presents a translatable framework for treating age-related inflammatory disorders.

We present a rare, previously unreported case of total hip arthroplasty (THA) implantation in a patient with an ankylosed hip and pelvic-femoral synostosis who sustained a subtrochanteric fracture. A 70-year-old woman had previously undergone right-sided infectious coxitis treatment, leading to hip ankylosis and pelvic-femoral synostosis. The patient had experienced no hip joint movement from her 20s for over 50 years due to bone fusion at 2 levels. Walking was feasible with compensation, given the ankylosis at an "ideal position" of 15° of flexion, 10° of abduction, and neutral rotation. The patient sustained a subtrochanteric fracture at the age of 70. Given the ankylosis and pelvic-femoral synostosis in the proximal femur fragment, an ideal solution was sought for the surgical management of this case. Synostosis was resected, total hip replacement was performed using revision arthroplasty components, solving both the problem of the ankylosed hip and that of the subtrochanteric fracture. The subtrochanteric fracture united, and sufficient motion was achieved after THA. THA led to adequate fracture healing, relief of chronic lumbosacral pain and significant improvements in function, proving to be a promising solution for challenging complex hip cases, offering significant improvements in quality of life when combined with careful surgical technique, thorough planning, and attentive postoperative care.

Peripheral nerve injuries (PNIs) remain a major clinical and socioeconomic challenge, frequently resulting in motor weakness, sensory loss, and chronic neuropathic pain that cause long-term disability and restrict daily function. Functional recovery is limited by slow axonal regrowth, Wallerian degeneration, interstitial fibrosis, and progressive denervation-induced muscle atrophy. Although microsurgical epineurial repair and autologous nerve grafting are standard treatments, clinical outcomes remain inconsistent, especially in long-gap or delayed repairs. These limitations underscore the need for more effective regenerative strategies that address both the structural and biological barriers to nerve recovery. Contemporary research on PNIs focuses on four interconnected domains: structural reconstruction, biological acceleration, functional remodelling, and anatomical restoration. Advanced nerve-guidance conduits offer biomimetic, aligned pathways that reduce axonal misdirection and complement microsuture or autograft repair. Biological approaches, including localized delivery of neurotrophic factors, mesenchymal stem cells, induced-pluripotent stem cell derivatives, and their exosomes, enhance Schwann cell reprogramming, angiogenesis, and pro-regenerative immune polarization while reducing risks associated with live cell transplantation. Non-invasive biophysical stimulation modalities, such as electrical stimulation, magnetic fields, photobiomodulation, low-intensity pulsed ultrasound, and piezoelectric scaffolds, further promote axonal growth and neurotrophic signaling. Emerging integrated strategies that combine stem cell-derived exosomes with physical cues demonstrate synergistic regeneration in preclinical models, representing promising avenues for treating critical-sized nerve gaps. Multi-omics technologies, including transcriptomics, proteomics, metabolomics, and spatial profiling, have deepened mechanistic understanding of Schwann cell plasticity, axon-glia communication, and injury-induced inflammatory dynamics. However, clinical translation remains constrained by heterogeneity in study design, biomaterial manufacturing, regulatory requirements, and the lack of validated biomarkers for monitoring nerve regeneration. Overcoming these obstacles will require coordinated efforts across surgery, biomaterials engineering, stem cell biology, pharmacology, neuromodulation, and rehabilitation medicine. Recent progress in biomaterial conduits, cell-free biologics, and biophysical stimulation is transforming PNI treatment and providing options that surpass conventional microsurgical repair. Continued advancement will require reliable biomarkers, standardized production and evaluation methods, and well-designed randomized controlled trials. Coordinated collaboration across research, clinical practice, industry, and regulatory agencies is essential to develop safe, effective, and widely applicable neuroregenerative therapies that restore meaningful function after peripheral nerve injury.

Chronic pain affects approximately one-third of active-duty service members (ADSMs), yet effective treatment remains challenging. Salivary cortisol and urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) are established non-invasive biomarkers of stress and oxidative DNA damage and may provide reliable unbiased indicators of treatment efficacy in chronic pain. However, their associations with pain outcomes and potential sex differences remain unclear. It was hypothesized that interdisciplinary pain treatment would result in decreased levels of stress and oxidative DNA damage biomarkers, as well as decreased pain intensity, and that the magnitude of challenge might vary by sex. Our objective was to compare longitudinal changes in salivary cortisol and urinary 8-OHdG in relation to pain outcomes and sex. A total of 190 ADSMs who referred for chronic pain treatment completed data collection on the Patient-Reported Outcomes Measurement Information System (PROMIS) measures and urine and saliva samples at baseline and post-treatment. Multivariable regression models were used to predict changes in PROMIS scores relative to changes in cortisol and 8-OHdG, while adjusting for baseline levels. Interaction terms between participants' sex and changes in biomarkers were added to each model. Given the study's exploratory nature, a significance threshold of p < .10 was used for all analyses. Five statistically significant sex-by-cortisol interactions were identified for pain measures (pain impact, pain interference, physical functioning, sleep impairment, and social functioning), but none for 8-OHdG. Future work is needed to replicate these findings in larger samples. The research protocol was registered in ClinicalTrials.gov (NCT03297905; https://clinicaltrials.gov/study/NCT03297905).

Introduction Photobiomodulation (PBM) stands out as a promising therapeutic alternative for the management of chronic pain, but there is still controversy regarding its efficacy and safety, given the diversity of protocols and populations evaluated. Objectives To critically review the available literature on the use of PBM in adults with chronic pain conditions, synthesizing the evidence on analgesic and functional effects, impact on quality of life, and safety profile. Methods: A systematic search was conducted in PubMed, Embase, Scopus, LILACS, and MEDLINE, including articles published between September 2015 and September 2025. Randomized clinical trials that compared PBM protocols to placebo, sham, or conventional care were selected. The outcomes investigated included pain intensity (primary), function, quality of life, and occurrence of adverse events (secondary). Results Fourteen studies were included, covering populations with fibromyalgia, peripheral neuropathies, orofacial pain, and musculoskeletal pain. Most trials demonstrated significant pain reduction with PBM, particularly in fibromyalgia and neuropathy. In some studies, functional gains and improved quality of life were observed. The incidence of adverse events was low, reinforcing the method’s safety, although the heterogeneity of technical parameters compromises the standardization of results. Conclusion PBM has analgesic potential and a safe profile for managing chronic pain, especially in cases difficult to control with conventional therapies. However, the variability of clinical parameters and limited follow-up still hinder more comprehensive recommendations. Additional multicenter studies with standardized protocols are needed to consolidate clinical guidelines. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/view/CRD420251140711 , Identifier: CRD420251140711.

Endometriosis is a prevalent chronic condition that causes persistent pelvic pain, significantly impairing quality of life and contributing to psychological distress. This study aimed to assess the prevalence of clinically significant symptoms of depression and anxiety among women with endometriosis and to identify factors associated with these mental health outcomes. This cross-sectional study was conducted between 2023 and 2024 at Shahid Kamali Hospital, Karaj, Iran. Women with a confirmed diagnosis of endometriosis by a gynecologist were recruited using convenience sampling. Participants completed the Hospital Anxiety and Depression Scale (HADS), a validated self-report screening tool, and clinical data were extracted from medical records. Univariate and multivariate logistic regression analyses were performed to identify demographic and clinical factors associated with clinically significant symptoms of depression and anxiety. A total of 112 women participated (mean age: 31.6 ± 4.9 years; mean BMI: 26.3 ± 3.7kg/m²). The prevalence of clinically significant symptoms of depression and anxiety was 59.8% (95% CI: 50.4-68.6) and 54.5% (95% CI: 45.1-63.6), respectively. Univariate analyses showed that longer disease duration and higher pain intensity were significantly associated with depression, while education level was associated with anxiety. No significant association was found between endometriosis severity and either outcome. In the multivariate model, age, disease duration, and pain intensity remained significant correlates of depression, while education level and age were associated with anxiety. Clinically significant symptoms of depression and anxiety were highly prevalent among women with endometriosis. Disease duration and pain intensity were the main factors associated with depressive symptoms, while education level was linked to anxiety. These findings emphasize the need for integrated physical and psychological care for women with endometriosis, particularly those experiencing prolonged disease and chronic pain.

Chronic pain is among the most devastating and poorly understood symptoms after traumatic brain injury (TBI). Disruption of endogenous descending pain control pathways may contribute to chronic pain after TBI. In prior work, we found that TBI induces a two-stage pain dysregulation involving acute mechanical hindpaw hypersensitivity that resolves by 28 days post-injury (DPI), followed by chronic failure of descending control of nociception (DCN) lasting up to 180 DPI. However, the impact of sex on the dysfunction of endogenous pain control systems after TBI has not been explored. Using a lateral fluid percussion model of TBI in male and female rats, we assessed mechanical nociceptive responses using von Frey fibers and tested pharmacological interventions targeting established descending pain modulatory systems. We employed the selective noradrenergic (NA) reuptake inhibitor, reboxetine, the selective serotonin reuptake inhibitor, escitalopram, adrenoceptor antagonists' prazosin (α1-adrenoceptors) and atipamezole (α2-adrenoceptors), and the serotonin 5-HT3 receptor antagonist, ondansetron. Findings revealed that acute hindlimb hypersensitivity involved enhanced descending serotonergic pain facilitation via the 5-HT3 receptor in both sexes. In uninjured rats, pain control relies on descending NA inhibitory signaling via spinal α2-adrenoceptors. Boosting noradrenaline in the acute phase after TBI with reboxetine reduced acute mechanical pain, but studies with selective adrenoceptor antagonists revealed a persistent switch from an α2- to an α1-adrenoceptor-driven antinociceptive pathway after TBI in both males and females. Acute phase mechanical pain resolved by 28 DPI, exposing a chronic phase of DCN failure up to 180 DPI. Reboxetine treatment restored the DCN response in female TBI rat via α1-adrenoceptor but failed in male TBI rats. Restoration of the DCN response in male TBI rats was restored by enhancing serotonin signaling with escitalopram. These results demonstrate key differences in the susceptibility of endogenous pain modulatory pathways and the adaptations of those pathways between male and female rats after TBI. These findings suggest that sex needs to be considered when designing mechanism-based therapies for pain after TBI.

Introduction Osteoarthritis (OA) is characterized by articular degeneration and chronic joint pain, partly resulting from synovial inflammation. Accumulating evidence suggests that alterations in the synovial ketone body metabolism (KBM) are closely associated with OA pathogenesis. This study aimed to investigate the metabolic changes in synovial tissues to optimize the treatment of clinical OA. Methods Analysis of OA and normal control synovial transcriptomic datasets extracted from the Gene Expression Omnibus (GEO) identified 808 differentially expressed genes (DEGs). These DEGs were integrated with KBM-related genes from the metabolic databases, yielding 50 candidates related to OA progression. Following enrichment analysis, protein-protein interaction network construction via STRING, and machine learning with expression analysis, two genes were identified as OA biomarkers: ACADL, encoding long-chain acyl-CoA dehydrogenase and ADH1B , alcohol dehydrogenase 1 B. Results The nomogram based on these data revealed high accuracy in the training and validation sets. Functional analysis revealed that these genes function in lipid oxidation, a process critical for synovial cell energy metabolism, as well as in the redox balance that prevents oxidative stress from worsening OA inflammation. Immune infiltration analysis revealed that their expression significantly correlated with 21 immune subtypes, including pro-inflammatory M1 macrophages and Th17 cells, which drive synovial inflammation. Molecular docking analysis identified progesterone and fomepizole as potential agents with satisfactory affinities for ACADL and ADH1B , respectively. Assessment of mouse models of OA confirmed a significant reduction in the synovium at the protein level. Discussion ACADL and ADH1B link KBM abnormalities to immune dysregulation in the OA synovium. The nomogram enables the precise early diagnosis of OA, and progesterone and fomepizole are promising targeted therapies. These findings deepen the current understanding of OA pathogenesis and support the advancement of personalized treatments for clinical translation.

Early life nutrition is associated with child behaviour; however, the interplay with genetic vulnerability is understudied. We hypothesised that psychiatric genetic risk interacted with early nutrition to predict behavioural problems in childhood and adolescence. The Raine Study participants with genetic information aged 2-17 were repeatedly evaluated with the child behaviour checklist total problems score (CBCLTOT). Breastfeeding duration was recalled at age 1, 2 and 3 follow-up, and toddler diet derived by an age-1 24-h maternal recall (EAT1, scale 0-70, SD 10, higher scores proxying healthy diet). We derived polygenic scores (PGS) impacting general psychopathology: attention-deficit hyperactivity disorder (ADHD), depression, chronic multisite pain (CMSP), total behaviour problems and birthweight. In confounder-adjusted mixed-effects models of CBCLTOT throughout follow-up we examined nutrition-by-PGS interactions. In 1393 participants, a borderline signal suggests that 1 month longer breastfeeding reduces CBCLTOT by -0.108 (95% CI [-0.184, -0.0289]) exclusively in individuals with a higher CMSP PGS (Interaction p = 0.03). In 1310 participants, a strong signal suggests that 1 EAT1 point increase results in a reduced CBCLTOT by 0.121 points (95% CI [-0.171, -0.0704]) exclusively in individuals with a lower ADHD PGS (Interaction p = 0.0005). Post hoc analysis suggests that plant-based food consumption drives the favourable EAT1-CBCLTOT association. Nutrition in early life and psychiatric genetic risk may interact to determine lasting child behaviour. Contrary to our hypothesis, we find dietary benefits in individuals with lower ADHD PGS, necessitating replication. We also highlight the possibility of including genetics in early nutrition intervention trials for causal inference.

The relationship between cannabinoids and mental health has become a major focus of scientific inquiry and public discourse. Cannabinoids are diverse chemical compounds from the Cannabis species that have been explored for their therapeutic applications in treating chronic pain, psychiatric and neurological conditions, such as depression, schizophrenia, epilepsy and anxiety. Additionally, cannabinoids are frequently used for recreational purposes. The evolving legislation surrounding cannabis has added a layer of complexity to the understanding of its pharmacological effects. Societal attitudes shifting towards a more permissive acceptance of cannabis use make it essential to balance individual freedom with public health concerns. While the use of cannabinoids remains a subject of ongoing research, clinical data have shown promise in the treatment of mental health disorders. However, debates and concerns have been raised regarding the potential pharmacokinetic (PK) drug-drug interactions that may occur, involving changes in the absorption, distribution, metabolism and excretion (ADME) of the prescribed drugs. The future prospect of patients having unrestricted access to cannabis requires special attention in case of concurrent use with the common medical treatments they may be receiving for a cardiovascular or metabolic disease or with medications related to the treatment of psychiatric disorders. This comprehensive review aims to critically discuss the main PK interactions of major cannabinoids (tetrahydrocannabinol, cannabidiol, cannabinol, cannabichromene and cannabigerol) in relation to the drugs prescribed in neuropathic pain, depression, anxiety, schizophrenia, epilepsy and cancer, as well as with the most common cardiometabolic disease treatments such as statins, beta-blockers, warfarin, insulin analogues and metformin.

Chronic pain (CP) and hazardous/harmful drinking (HD) commonly co-occur. HD contributes to the onset and severity of CP, while CP severity predicts alcohol use disorder relapse. Integrated treatments for CP and HD are needed in rural areas, where CP and alcohol-related consequences occur at higher rates and treatment accessibility is lower. This study assessed the acceptability and feasibility of an app-based cognitive-behavioral intervention for CP and HD. Participants (n = 32) were rural residents reporting CP and HD (mean age = 49.81, SD = 8.79). Participants were randomized to intervention or assessment-only control. Self-report questionnaires at baseline and 12-week follow-up assessed program acceptability, pain, alcohol involvement, and functioning. Timely recruitment and low attrition (3.2%) supported procedure feasibility, while app engagement suggested intervention feasibility and acceptability. Descriptive statistics suggest reductions in pain (37% reduction in median pain in intervention group vs. 10% in control group). Changes in alcohol-related behavior were not consistent across outcomes and warrant further study (e.g., no change in median heavy drinking episodes in intervention, with 77% reduction in control; 60% reduction in alcohol consequences in intervention vs. 27% in control). This mobile intervention is feasible and acceptable for rural residents and may help address CP and functioning among those who engage in HD.

Comparison of dynamic neuromuscular stabilization exercises with and without the feldenkrais method on pain, balance, and hip muscle strength in elderly women with chronic non-specific low back pain.

There are few effective treatments for acute whiplash-associated disorder (WAD) following a road traffic crash. Early clinical features of central sensitisation, for example widespread hyperalgesia, predict poor recovery. Pregabalin's effects on central sensitisation suggest the potential to prevent or modulate these processes after whiplash injury and prevent later chronic pain. Preliminary evidence indicates that pregabalin provided in the Emergency Department and within 96hours of injury shows promise to prevent chronic pain. This trial aims to definitively evaluate, in patients at risk for poor recovery following whiplash injury, the effectiveness of early (within 96hours of injury) pregabalin, compared to placebo, to reduce pain severity. The PReventing chronic pain after whiplash Road Traffic Injury (PRioRTI) study is a 12-month randomised, placebo-controlled, triple-blind trial. Individuals with acute WAD (aged 18-70years) and at risk of poor recovery (pain ≥ 5/10) will be recruited from hospital Emergency Departments in Australia. Participants will be randomly assigned 1:1 to receive pregabalin or placebo. All participants will additionally receive an evidence-based advice booklet. Pregabalin will be commenced at 75mg bd and titrated to 300mg bd over 4weeks, then weaned for 2weeks. Participants will complete online questionnaires at 6weeks and 3, 6 and 12months post-randomisation. The primary outcome will be average pain intensity over 24hours (0-10 numerical rating scale) at 3months post-randomisation. Secondary outcomes include disability, patient global impression of recovery, psychological distress, quality of life and the number of adverse events. A cost-effectiveness analysis will be conducted. Potential mediators of treatment effects will be explored. A process evaluation will be conducted to explore barriers and facilitators for future implementation. There are few effective treatments for acute WAD. To address this gap, the PRioRTI trial aims to improve health outcomes by targeting central nociceptive processes very soon after whiplash injury using a readily available medication, pregabalin. If successful, the results of this trial will address an urgent unmet need to reduce pain severity after injury and will have clear implications for the early treatment of patients with whiplash injury. TRIAL REGISTRATION {2A AND 2B}: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12624001359527. Registered 13th November 2024.

Traumatic brain injury (TBI) in the U.S. military can result in lasting health issues, with insomnia being a common symptom that worsens recovery, cognitive function, and performance, especially when combined with common co-occurring conditions like chronic pain, post-traumatic stress disorder (PTSD), and depression. Insomnia may be an important intervention target for managing post-concussive symptoms and overall functioning in service members who have sustained a TBI. However, the standard of care for the treatment of insomnia, Cognitive Behavioral Therapy for Insomnia (CBTI), is not widely available in military health care settings. The aim of this paper is to describe the design and analysis plan of the clinical trial to evaluate and compare two methods for delivering CBTI including in-person CBTI or CBTI delivered remotely via a clinician-supervised digital platform in a sample of active-duty service members presenting for care in a military TBI specialty clinic. This is a phase II, randomized clinical trial designed to evaluate and compare the effects of CBTI (in-person or via a digital health platform) on sleep, behavioral health, and cognitive functions relative to treatment as usual among a sample of service members with a history of TBI. The effectiveness of in-person CBTI and CBTI delivered via a digital health platform, relative to treatment as usual, will be compared at baseline, after the six-week intervention, and again three months later on symptoms of insomnia, sleep quality, post-concussive symptoms, neurocognitive functioning, and psychological health. TBI is common in military personnel, often leading to insomnia that affects health and performance. While CBTI is the first-line recommended treatment for insomnia, CBTI is rarely implemented as the standard of care in military TBI specialty clinics, highlighting the need to assess its role in treating post-concussion symptoms and related issues. Clinical trials evaluating insomnia treatment in U.S. military service members with a history of TBI are essential to inform clinical practice for military TBI patients affected by insomnia and to potentially improve recovery, duty readiness, and cognitive function in this population. ClinicalTrials.gov: NCT06867666. Registered on 2/26/2025.

Chronic nonbacterial prostatitis/chronic pelvic pain syndrome (CP/CPPS), classified as National Institutes of Health (NIH) category III prostatitis, is a common urological disorder, accounting for 90%-95% of prostatitis cases. Its pathogenesis involves inflammatory cascades along the bladder-prostate axis, neurogenic inflammation, and impairment of the mucosal barrier. Sodium hyaluronate (Cystistat), a glycosaminoglycan (GAG) layer replenishment agent, has demonstrated efficacy in treating bladder pain syndrome. However, its therapeutic role in CP/CPPS remains underexplored. This study aimed to evaluate the clinical efficacy of intravesical hyaluronic acid (Cystistat) instillation in patients with CP/CPPS, identify potential predictive factors, and develop a predictive model to support personalized treatment strategies. A retrospective analysis was conducted on 41 patients with CP/CPPS who received intravesical Cystistat between January 2023 and April 2024. NIH Chronic Prostatitis Symptom Index (NIH-CPSI) scores-including total score and subdomains (pain, urinary symptoms, and quality of life)-and visual analog scale (VAS) scores were compared before and after treatment using paired t-tests. Cohen's d was calculated to assess effect size. A treatment response was defined as a Global Response Assessment (GRA) score ≥2. Multivariate logistic regression was used to explore predictors of treatment response. Model performance was evaluated using the area under the receiver operating characteristic curve (AUC), with fivefold cross-validation and sensitivity analyses. NIH-CPSI total scores significantly improved following treatment (25.71 ± 2.91 to 19.56 ± 4.28; mean change: -6.15 [95% CI: -7.27 to -5.02]; p < 0.001; Cohen's d = 1.68). VAS scores also showed significant reduction (7.07 ± 1.07 to 4.16 ± 1.67; mean change: -2.91 [95% CI: -3.36 to -2.46]; p < 0.001; Cohen's d = 2.07). Improvements were observed across all NIH-CPSI subdomains, with the greatest effect noted in the pain domain (Cohen's d = 1.32). Overall, 70.7% of patients achieved a GRA score ≥2. Logistic regression identified that elevated C-reactive protein (CRP) levels (OR = 1.28, 95% CI: 0.90-1.82) were positively associated with response, while longer disease duration (OR = 0.98, 95% CI: 0.94-1.02) and lower maximum urinary flow rate (Qmax) (OR = 0.88, 95% CI: 0.67-1.15) were negatively associated. However, none of these associations reached statistical significance. A model incorporating CRP, disease duration, and Qmax yielded an AUC of 0.76 (cross-validated AUC: 0.73 ± 0.12). Sensitivity analyses confirmed the model's robustness across alternative definitions of treatment success. Intravesical hyaluronic acid (Cystistat) therapy appears to be clinically effective for CP/CPPS, particularly in pain relief and quality-of-life improvement. Patients with elevated CRP levels and shorter disease duration may benefit more from this treatment. The derived predictive model offers a tool for individualized clinical decision-making. These findings lend indirect support to the "bladder-prostate axis" hypothesis, suggesting that Cystistat may alleviate pelvic pain by restoring bladder mucosal integrity and reducing inflammatory mediator activity. Future prospective randomized controlled trials are needed to validate these findings and further elucidate the underlying mechanisms. Further prospective, large-scale studies are needed to confirm efficacy, especially in OAB-associated subtypes, and refine predictive modeling approaches.

Endometriosis is a chronic, estrogen-dependent inflammatory condition affecting approximately 10% of women of reproductive age worldwide. It is characterized by the presence of endometrial-like tissue outside the uterine cavity, which frequently results in dysmenorrhea, chronic pelvic pain, dyspareunia, and infertility. While hormonal medications and surgical procedures are common treatments, they are often constrained by adverse effects and high recurrence rates. The aim was to systematically identify, critically appraise, and synthesize randomized controlled trials evaluating vitamin D, C, and E supplementation in women with endometriosis, focusing on their effects on pelvic pain, dysmenorrhea, dyspareunia, quality of life, oxidative and inflammatory biomarkers, and fertility-related outcomes, and to highlight methodological gaps that can inform future research and integrated therapeutic strategies. Following PRISMA guidelines, seven eligible RCTs were identified from databases including PubMed, Scopus, and ScienceDirect. The quality of these studies was assessed using the Jadad Scoring System and Cochrane RoB 2 tool. High-dose supplementation of vitamin D (50,000 IU) was found to significantly reduce pelvic pain and improve biochemical markers such as hs-CRP and total antioxidant capacity (TAC). Vitamin D appears to modulate endometrial pathways by reducing active β-catenin protein activity, which may disrupt signaling associated with lesion invasion and survival. Additionally, combined Vitamin C and E therapy (typically 1000 mg/day of Vitamin C and 800 IU/day of Vitamin E) acts synergistically to scavenge free radicals. This intervention significantly decreased oxidative stress markers, including malondialdehyde (MDA) and reactive oxygen species (ROS). Patients reported significant improvements in symptoms, including a 43% reduction in daily pelvic pain and a 37% reduction in dysmenorrhea. Despite physiological improvements, there was no statistically significant increase in pregnancy rates observed across the trials. Vitamin supplementation with D, C, and E represents a safe, low-cost adjunct therapy that can effectively mitigate endometriosis-related oxidative stress and pelvic pain. While these vitamins show promise for symptom relief, further research with larger sample sizes is required to determine their long-term impact on fertility outcomes and lesion regression.

Fibromyalgia (FM) is a chronic pain condition associated with substantial quality-of-life impairments and economic burden. Although multiple pharmacologic options are recommended in clinical guidelines, the relative cost-effectiveness of off-label amitriptyline compared with FDA-approved treatments remains poorly defined due to a scarcity of direct economic comparisons and the use of heterogenous outcome measures in the extant literature. To evaluate the cost-effectiveness of pregabalin, duloxetine, and milnacipran compared with amitriptyline in adults with moderate to severe FM. Decision analytical model using a Markov cohort state transition model to estimate lifetime costs and quality-adjusted life-years (QALYs) for each investigated pharmacologic strategy. Model inputs included treatment-specific transition probabilities, utility values, and direct and indirect costs for each health state, which were derived from published sources. The simulated cohort reflected adults (aged ≥18 years) with moderate to severe FM. Data were analyzed between September 2024 and February 2025. Amitriptyline (25-100 mg), pregabalin (150, 300, 450, and 600 mg), duloxetine (60 and 120 mg), and milnacipran (100 and 200 mg), evaluated from US health care payer and societal perspectives. Expected lifetime cost, QALYs, incremental cost-effectiveness ratios (ICERs), and incremental net monetary benefit (iNMB) at willingness-to-pay (WTP) thresholds of $50 000, $100 000, and $150 000 per QALY. The simulated cohort included predominantly women (94.4%), had a mean (SD) age of 48.4 (10.4) years, and was parameterized using demographic distributions derived from published FM populations. From the US health care payer perspective, duloxetine 120 mg was associated with increased QALYs versus amitriptyline at slightly higher cost (ICER, $1536 per QALY), while pregabalin 450 mg was dominated by duloxetine 120 mg. When societal costs were considered, duloxetine 120 mg and pregabalin 450 mg were cost saving relative to amitriptyline. Amitriptyline remained both more effective and less costly than milnacipran, lower doses of pregabalin and duloxetine, and no treatment. At a $100 000 WTP threshold, iNMB for duloxetine 120 mg was $40 375 from the health care payer perspective and $70 063 from the societal perspective; for pregabalin 450 mg, iNMB was $21 211 and $40 190 for the health care payer and societal perspectives, respectively. In this decision analytical model, duloxetine 120 mg was the preferred strategy across perspectives; pregabalin 450 mg was economically favorable relative to amitriptyline only when societal costs were included. Amitriptyline provided greater net benefit than milnacipran and the lower doses of pregabalin and duloxetine. These findings may help inform the selection of value-based treatments for moderate to severe FM.

Adding insult to injury: Examining the influence of peer pain-related stigma on daily functioning in youth with chronic musculoskeletal pain.

Savoring pleasure to relieve pain: An ecological momentary assessment study in patients with chronic low back pain.