Search Results (2,174)

This review summarizes the role of nuclear factor erythroid 2–related factor 2 (Nrf2) as a common link between aging, neurodegeneration, and neuropathic pain. Aging is characterized by oxidative stress and constant inflammation, which coincides with reduced Nrf2 activity and weaker antioxidant responses, increasing vulnerability to diseases. In neurodegenerative disorders—including Alzheimer’s, Parkinson’s, Huntington’s disease, and amyotrophic lateral sclerosis—evidence indicates that impaired Nrf2 signaling contributes to oxidative damage, neuroinflammation, and mitochondrial dysfunction. Furthermore, in neuropathic pain, similar mechanisms are involved, and Nrf2 could play a role as a potential analgesic target because of its role in regulating cellular defense pathways. We also review natural Nrf2 modulators (e.g., flavonoids, other polyphenols, terpenoids, alkaloids), discussing their benefits alongside common translational limitations such as poor solubility, low oral bioavailability, rapid metabolism, and potential safety issues, including possible pro-oxidant effects and chemoresistance. We also outline future directions that should prioritize improving delivery systems, addressing NRF2/KEAP1 gene variations, evaluating combinations with standard therapies, exploring preventive applications, and defining dosing, treatment duration, and long-term safety. Overall, current evidence indicates that Nrf2 modulation is a practical, cross-cutting approach relevant to healthy aging and disease management. Full article

Background/Objectives: The optimal duration of pulsed radiofrequency (PRF) applied to the dorsal root ganglion (DRG) remains unclear, particularly in patients with chronic lumbosacral radicular pain (LRP) who are unresponsive to conservative therapy. Although preclinical data suggest duration-dependent neuromodulatory effects, comparative clinical evidence for specific exposure times is limited. This study aimed to evaluate the outcomes of 4 min and 8 min DRG-targeted PRF applications performed in combination with transforaminal epidural steroid injection (TFESI) in patients with chronic LRP unresponsive to conservative treatment, to determine whether prolonged exposure provides superior analgesic and functional outcomes. Methods: In this prospective, single-center, observational comparative study, 72 patients with chronic lumbar radicular pain (LRP) refractory to conservative management received DRG-targeted PRF using standardized parameters (45 V, 20 ms, 2 Hz, ≤42 °C). Participants underwent either 4 min (n = 36) or 8 min (n = 36) PRF, assigned according to clinical discretion. All procedures were followed by transforaminal epidural injection of dexamethasone and bupivacaine. The primary endpoint was Numeric Rating Scale (NRS) pain intensity at 6 months. Secondary endpoints included Oswestry Disability Index (ODI), patient satisfaction, responder rates, and analgesic use across 1-, 3-, and 6-month follow-up. Results: Both groups achieved significant improvements from baseline at all time points. Linear mixed-effects analysis demonstrated a significant overall association favoring the 8 min protocol for pain (estimate: −0.81, 95% CI: −1.52 to −0.10, p = 0.025) and functional disability (estimate: −12.84, 95% CI: −19.36 to −6.32, p < 0.001). Functional benefits emerged by 3 months (p = 0.006), while pain reduction reached borderline statistical significance at 6 months (p = 0.048). The 8 min group showed numerically higher responder rates and patient satisfaction without increased adverse events. Conclusions: In this study evaluating a combined PRF and corticosteroid injection protocol, 8 min PRF exposure was associated with superior pain and functional outcomes compared to 4 min, without compromising safety. However, the observational design and concurrent medication administration limits causal inference. Randomized controlled trials are needed to confirm these findings and isolate the independent effect of PRF duration. Full article

The impact of genetic variation in sickle cell patients plays a significant role in opioid therapy individual response and pain management. This review aims to provide a comprehensive overview of the importance of exploring genetic variability and its impact on pain management in patients with sickle cell disease. It also explores opioid therapy variability and opioid Safety. With respect to literature, the polymorphisms in the key metabolic enzymes CYP2D6, UGT2B7, and COMT, as well as variations in the OPRM1, are important modifiers of the pharmacokinetics and pharmacodynamics of opioids. Variations in the COMT gene can influence how the body manages certain brain chemicals and how pain is experienced, while changes in the OPRM1 gene can alter how well opioids bind to their receptors. They help determine how opioids are broken down in the body, how well they attach to pain receptors, and how pain is felt by someone with sickle cell disease. Patients with reduced-function and ultra-rapid CYP2D6 alleles have a modified metabolism of codeine and tramadol, which presents either a reduced analgesic response or a risk for increased toxicity. These observations support the case for the need for tailored opioid prescriptions in a population that is genetically diverse, as well as the risk of not having standardized pain measurement, and the absence of clinical implementation. There remains the risk of unrecognized pharmacogenomics, lack of data, and personalized opioid descriptions persist. Future research should focus on integrating genetic testing into clinical practice to optimize opioid selection, personalize medicine, minimize adverse effects, and ensure each patient receives treatment that is both effective and safe to enhance quality of life for individuals with sickle cell disease. Full article

Postoperative pain management in pediatric patients remains a significant challenge despite improvements in perioperative care. Regional anesthesia techniques applied as part of multimodal analgesia strategies offer the potential to reduce opioid use, accelerate recovery, and minimize side effects such as respiratory depression, nausea, and delayed mobilization. This review examines the clinical applications, advantages, and limitations of regional anesthesia blocks in the context of common pediatric surgical procedures—appendectomy, inguinal hernia repair, circumcision, cholecystectomy, and pyloromyotomy. We provide procedural comparisons in terms of analgesic efficacy, opioid-sparing effects and suitability for ambulatory surgery. In conclusion, regional anesthesia techniques have significant potential to improve postoperative outcomes in pediatric patients. However, block selection should be individualized, considering the type of surgical procedure, patient characteristics, and operator experience. Increasing applicability and routinely implementing ultrasound-guided procedures will encourage the safer and more effective use of these techniques in pediatric anesthesia. Full article

Amaryllidaceae alkaloids are of notable pharmacological relevance. For instance, galanthamine is used in the treatment of Alzheimer’s disease, while other alkaloids (lycorine, crinine, etc.) derived from Amaryllidaceae plants are also of great interest because they exhibit antitumour, antiviral, antibacterial, antifungal, antimalarial, analgesic and cytotoxic properties. Phenolic acids comprise a group of natural bioactive substances that have commercial value in the cosmetic, food and medicinal industries due to their antioxidant, anticancer, anti-inflammatory and cardioprotective potential. In the present study, the effect of temperature (15, 20, 25 and 30 °C) on Amaryllidaceae alkaloid and phenolic acid biosynthesis in Leucojum aestivum in vitro plant cultures was investigated. The highest diversity of alkaloids (i.e., galanthamine, crinan-3-ol, demethylmaritidine, crinine, 11-hydroxyvitattine, lycorine, epiisohaemanthamine, chlidanthine) was noted in plants cultured at 30 °C. By contrast, ismine and tazettine were only present in plants cultured at 15 °C. Temperatures of 20 °C and 30 °C were found to stimulate galanthamine accumulation. The highest lycorine content was noted in plants grown at temperatures of 15 and 30 °C, and it was negatively correlated with the expression of the gene that encodes the cytochrome P450 96T (CYP96T) enzyme which catalyses a key step in the biosynthesis of different types of Amaryllidaceae alkaloids. This observation may reflect temperature-induced shifts in metabolic flux among different branches of Amaryllidaceae alkaloid biosynthesis. The observed stimulating effect of a 15 °C temperature on the chlorogenic, caffeic, p-coumaric, sinapic, ferulic and isoferulic acid content was in line with the highest expression of a gene that encodes the tyrosine decarboxylase (TYDC) enzyme, which is involved in plant stress response mechanisms. At 30 °C, however, the highest content of the caffeic, vanillic, p-coumaric and isoferulic acids was noted. Full article

Objectives: This systematic review aims to evaluate the effectiveness of autologous Plasma Rich in Growth Factors (PRGF) in enhancing post-extraction socket healing by synthesizing evidence from randomized controlled trials and assessing outcomes related to bone regeneration, soft-tissue healing, and postoperative discomfort. Methods: A comprehensive search was conducted in MEDLINE, Embase, Cochrane Library, Scopus, Web of Science, and CINAHL, using a fully reproducible Boolean search strategy. Non-English studies were screened but excluded only when a reliable translation was not feasible. Only randomized controlled trials (RCTs) involving PRGF application in human extraction sockets were included. Risk of bias was assessed using the Cochrane RoB2 tool. A meta-analysis could not be performed due to substantial heterogeneity in PRGF preparation protocols, follow-up duration, and outcome measurements. Results: Seven RCTs met the eligibility criteria. Four studies demonstrated significantly improved healing outcomes in the PRGF group compared with controls, whereas two studies reported comparable results. Pain reduction was consistently observed in PRGF-treated sockets in studies that reported standardized postoperative analgesic protocols. Mineralized tissue formation favored PRGF in high-quality trials. Considerable heterogeneity was identified in PRGF centrifugation parameters, outcome tools, and evaluation timelines. Conclusions: Evidence from current RCTs supports PRGF as an effective and well-established adjunct for enhancing early post-extraction healing. The novelty of this review lies in its updated methodological rigor, corrected risk-of-bias analysis, standardized data handling, and clarification of long-standing gaps in reporting PRGF preparation variability. Future trials with standardized PRGF protocols and long-term follow-up are needed to improve comparability and strengthen clinical recommendations. Full article

A wound has been defined as a disruption of tissue integrity. Pain, bleeding, and the risk of infection are inherent features of wounds, while chronic wounds are often accompanied by serous exudate. Pain associated with chronic wounds is usually underestimated and inadequately addressed in routine clinical care, despite being considered by patients as one of the most burdensome factors affecting their quality of life. Traditionally, management of wound-related pain has relied primarily on systemic analgesics, commonly administered orally. However, recently, there has been accumulated interest in the potential of topical analgesics. Unfortunately, both systemic and local administrations of conventional analgesics (e.g., NSAIDs, opioids) might carry risks of adverse effects, including delayed wound healing and systemic absorption. In this review, we summarize current research on the use of local analgesia for painful wounds and explore the potential of topically applied peptides with analgesic activity as a promising alternative to conventional pain management strategies. We also discuss recent innovations in the development of therapeutic peptides, including those with anti-inflammatory and regenerative activities, which might further enhance outcomes in the wound healing process. Finally, we address challenges associated with topical peptide delivery across compromised skin barriers and examine strategies to overcome these limitations, while outlining future directions for formulation and clinical application of peptide-based wound therapies. Full article

Background/Objectives: Balloon eustachian tuboplasty (BET) is an effective surgical option for obstructive eustachian tube dysfunction (OETD). However, the feasibility of performing BET under local anesthesia (LA) using simplified analgesic protocols remains underexplored. We examined the feasibility of a streamlined LA-BET protocol. Methods: Fifty patients (sixty-four ears) diagnosed with primary OETD between March 2024 and December 2025 were enrolled. All patients underwent BET under LA using intramuscular ketorolac and topical lidocaine gel without sedation or nerve blocks. Pain scores, blood pressure changes, and patient acceptance were analyzed for each patient; Eustachian Tube Dysfunction Questionnaire-7 (ETDQ-7) scores, tympanogram types, and Valsalva results were analyzed for each ear. All outcome measures were assessed 3 months postoperatively. Results: The mean ETDQ-7 score significantly improved from 24.9 ± 7.4 to 11.9 ± 5.4 (p < 0.001). The minimal clinically important difference (MCID ≥ 3.7) was achieved in 90.6% of ears, and normalization (ETDQ-7 ≤ 14.5) in 75.0%. The proportion of ears with positive Valsalva maneuvers increased from 39.1 to 76.6% (p < 0.01), and type A tympanograms improved from 64.1 to 84.4% (p = 0.018). Mean pain scores were 3.5 during insertion, 2.1 during balloon inflation, and 0.6 after deflation. All patients completed the procedure, and 96% would undergo LA again. Conclusions: LA-BET performed using intramuscular ketorolac and topical lidocaine gel is safe, tolerable, and effective. This protocol provides symptom relief and functional improvement without sedation or nerve block and offers a practical outpatient alternative for chronic OETD management. Full article

Sheep are routinely used as orthopedic models due to their similarities to human joints. Spinal anesthesia provides adequate analgesia for these procedures, and its duration can be enhanced with adjuvant drugs. Clonidine is commonly used in human spinal anesthesia, while dexmedetomidine is a newer and more selective α-2 agonist. This study compared the duration and analgesic effect of these two drugs as adjuvants in spinal anesthesia. Thirty-nine sheep undergoing experimental pelvic limb cartilage damage surgery were enrolled. Animals were sedated with diazepam (0.4 mg kg⁻¹) and buprenorphine (10 μg kg⁻¹) intravenously. Propofol was given as needed (0.5 mg kg⁻¹) and oxygen support via face mask was continuous. Animals were positioned with the treated limb in a dependent position for the lumbosacral spinal block. Sheep were divided into three groups (n = 13), receiving lidocaine 2% (L group), lidocaine 2% + clonidine 20 μg mL⁻¹ (CL group), or lidocaine 2% + dexmedetomidine 1 μg mL⁻¹ (LD group) for spinal block (1 mL every 10 kg). Recovery times (minute) from the spinal block were recorded: anal sphincter tone (AS), recovery of sensibility (RoS), first limb movements (FMov), time of standing (ToS), and first rescue analgesia; ataxia (ATA) was also measured after standing. Dexmedetomidine increased the duration of spinal anesthesia, affecting both motor and sensory functions. Full article

Background/Objectives: Neuropathic pain remains a significant clinical challenge, with current treatments often providing inadequate relief and adverse effects. Sigma receptors (SRs) modulate nociception and have emerged as potential therapeutic targets for neuropathic pain. Although putative sigma-1 receptor (S1R) ligands have demonstrated analgesic efficacy in preclinical models, their in vivo efficacy and safety profiles require further clarification. Methods: Analogs of well-known selective S1R ligand UVM147 were synthesized using 3-component Ugi reactions and examined in vitro for receptor affinity in radioligand competition binding assays and in vivo with mouse models of neuropathic and inflammatory pain and adverse effects. Results: Three novel heterocyclic compounds (RO-4-3, RO-5-3, and RO-7-3) displayed in vitro nanomolar affinity with varying selectivity for both SR subtypes (S1R and S2R). When screened in vivo at a dose of 30 mg/kg s.c. in mice first subjected to chronic constriction injury (CCI), RO-5-3 and RO-7-3 possessed anti-allodynic potential, while UVM147 was inactive. Upon full characterization, RO-5-3 significantly attenuated mechanical allodynia in a dose-dependent manner, while RO-7-3 was ineffective at higher doses. Both compounds dose-dependently attenuated nociceptive behaviors in the mouse formalin assay. RO-5-3 induced mild respiratory depression without impairing locomotor activity, whereas RO-7-3 caused transient respiratory depression and locomotor impairment. Additionally, RO-5-3, but not RO-7-3, induced conditioned place aversion consistent with potential S2R involvement. Conclusions: RO-5-3 exerts antinociceptive and anti-allodynic effects with minimal adverse behavioral effects, supporting the role of SRs in pain modulation. These results add to growing evidence supporting the development of SR ligands as efficacious therapeutics for neuropathic pain with fewer clinical liabilities. Full article

This investigation explored how seasonal variation affects the phytochemical composition and biological potential of Rosmarinus officinalis L., a widely used aromatic and medicinal plant. Aerial parts collected during spring, summer, autumn, and winter were extracted with ethanol and analyzed using LC-ESI-MS/MS, while total phenolic (TPC) and flavonoid (TFC) contents were determined spectrophotometrically. The extracts were evaluated for antioxidant, anti-inflammatory, enzyme inhibitory, analgesic, antimicrobial, cytotoxic, and photoprotective properties. Major constituents identified in all seasons included luteolin, kaempferol, rutin, and biochanin A. The autumn extract contained the highest phenolic (353.21 ± 4.05 µg GAE/mg) and flavonoid (190.11 ± 5.65 µg QE/mg) levels. Antioxidant assays revealed that the autumn extract had the strongest DPPH radical scavenging activity (IC₅₀ = 24.72 ± 0.16 µg/mL), while the spring extract exhibited the greatest reducing power (A_0.5 = 7.62 ± 0.30 µg/mL). The winter extract demonstrated superior anti-inflammatory activity (IC₅₀ = 28.60 ± 2.84 µg/mL), exceeding the reference drug diclofenac. Only the spring extract inhibited urease (IC₅₀ = 62.26 ± 0.58 µg/mL) and moderately inhibited α-amylase. All seasonal extracts showed notable photoprotective potential, with SPF values between 25.18 and 32.46, well above the recommended minimum. The spring extract also presented strong analgesic activity and no acute toxicity up to 2000 mg/kg. Antimicrobial effects were weak, limited to slight inhibition of Staphylococcus aureus, while moderate cytotoxicity was observed against MCF-7 and MDA-MB-231 breast cancer cells. Overall, seasonal variation significantly influenced the chemical profile and bioactivities of R. officinalis, with autumn and spring identified as the most suitable harvesting periods for pharmaceutical and cosmetic applications. Full article

Background: Opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) for clavicle fracture pain management carry significant adverse effect and allergic reaction risks. This study assessed ultrasound-guided nerve block (USNB) efficacy for acute clavicle fracture pain in emergency department (ED) patients, providing an alternative to NSAIDs and opioids with fewer adverse effects. Methods: This retrospective, single-center observational study was conducted in accordance with Methods of Medical Record Review Studies in Emergency Medicine Research guidelines. Adult patients (≥20 years) who presented to the ED with traumatic clavicle fractures between 1 January 2015 and 30 November 2023 were included. Of the 343 eligible patients, 12 received ultrasound-guided nerve blocks (USNB) and 331 received standard care. To improve exchangeability, 1:10 matching with replacement was performed according to patients’ characteristics, such as age, sex, initial pain score, and comorbidities. The primary outcome was pain relief, assessed via the pain intensity difference (PID) on the Numerical Rating Scale within 360 min post-intervention. Meaningful pain relief was defined as a PID ≥ 4. Secondary outcomes included rescue opioid use, ED length of stay, hospital length of stay, and USNB-associated complications, such as vascular puncture, nerve injury, or local anesthetic systemic toxicity. Data were analyzed using time-course, time-to-event (time to meaningful pain relief), and linear regression analyses. Results: A total of 12 patients in the USNB group and 85 matched patients in the standard care group were analyzed after baseline characteristics matching with replacement. Compared to standard care, USNB was associated with significantly greater pain relief (p < 0.001). In the time-to-event analysis, USNB led to a 3.41-fold faster achievement of meaningful pain relief compared with that achieved with standard care (HR = 3.41; 95% CI, 1.47–7.90; p = 0.004). No significant differences were observed between groups in rescue opioid use, ED length of stay, or hospital length of stay. No USNB-associated complication developed in the USNB group. Conclusions: In patients with traumatic clavicle fractures, USNB provides more rapid and sustained pain relief than standard analgesic care in the ED, without increasing the ED length of stay. Large prospective studies are needed to confirm these findings. Full article

Background: Depression and diabetic neuropathy (DN) commonly complicate diabetes and impair glycemic control and quality of life. Ketamine and its S-enantiomer, esketamine, provide rapid antidepressant and analgesic effects, yet diabetes-related pathophysiology and co-therapies may modify exposure, response, and safety. Methods: We conducted a scoping review following PRISMA-ScR. MEDLINE/PubMed, CINAHL, and APA PsycInfo were searched (January 2020–31 May 2025). Eligible human and animal studies evaluated ketamine, esketamine, or norketamine in the context of diabetes (type 1 [T1DM], type 2 [T2DM], gestational [GDM]), or DN, and reported psychiatric, analgesic, metabolic, or mechanistic outcomes. Two reviewers independently screened and charted data; no formal risk-of-bias assessment was performed. Results: Eleven studies met inclusion criteria: four human case reports/series (three T1DM, one T2DM), one randomized trial in GDM, two narrative reviews of topical ketamine for DN, and four preclinical rodent studies using streptozotocin- or diet-induced diabetes models. Short-term improvements were reported for treatment-resistant depression and neuropathic pain, including opioid-sparing postoperative analgesia in GDM. Glycemic effects varied across settings, with both hyperglycemia and hypoglycemia reported. Mechanistic and clinical drug–drug and drug-disease interactions (particularly involving metformin, GLP-1 receptor agonists, SGLT2 inhibitors, and CYP3A4/CYP2B6 modulators) remain insufficiently studied. We outline a forward-looking population pharmacokinetic (popPK) and pharmacokinetic-pharmacodynamic (PK-PD) research agenda, including priority covariates (eGFR, hepatic function, inflammatory status, HbA1c, genotype, co-medications) and sparse-sampling windows for future model-informed precision dosing. Conclusions: Current evidence supports cautious, selective use of ketamine for refractory depression and DN within multidisciplinary diabetes care. Purpose-built popPK/PK-PD studies in both human and preclinical diabetic models cohorts are needed to quantify variability, define drug–disease–drug interactions and glycemic risk, and inform individualized dosing strategies. Full article

Paracetamol (acetaminophen) is one of the most widely used analgesics and antipyretics. Due to its widespread use, it is also one of the chief contaminants in surface water and wastewater, raising a significant environmental concern. Traditional wastewater treatment systems are ineffective at removing pharmaceutical residues, which makes it necessary to search for alternative methods. One of the promising techniques is adsorption which is valued for its simplicity, cost-effectiveness and high efficiency. This review provides an in-depth analysis of the adsorption efficiency of paracetamol on various adsorbent materials. The physical and chemical mechanisms of adsorption are discussed together with the factors affecting the efficiency, such as pH, temperature and ionic strength. Of the materials tested, activated carbon shows the greatest efficiency, but nanomaterials, biocomposites, clays and zeolites also give promising results. The potential of emerging materials, including modified silica, polymer-grafted nanocomposites and biosorbents derived from waste biomass is also explored. Special attention is paid to regeneration capabilities and environmental sustainability. The study emphasizes the importance of adsorption as a technique for enhancing the treatment of pharmaceutical wastewater and mitigating ecological risks. Full article

Background: Pleurodesis is a treatment method that aims to create permanent adhesion between the pleural layers to prevent recurrent fluid or air accumulation in the pleural cavity. Talc, one of the most commonly preferred agents in this procedure, is widely used in clinical practice. In this study, a new talc formulation with a modified surface to impart antibacterial and analgesic properties was experimentally evaluated for the first time. The main objective of the study was to comparatively assess the inflammatory and fibrotic responses following standard talc and modified talc applications. Methods: Thirty-six 12-week-old female Wistar albino rats were simply randomly divided into three different groups: control (n = 12), standard talc (n = 12), and modified talc (n = 12). Under anesthesia, 1 mL of physiological saline containing 17 mg of talc was injected intrapleurally into the right hemithorax. The presence of pneumothorax after the procedure was assessed by chest radiography. After a 12-day follow-up period, the animals were euthanized. Bronchoalveolar lavage (BAL) fluid samples, blood samples, and lung and pleural tissue samples were collected for biochemical, histopathological, and immunohistochemical analyses. Results: Modified talc application resulted in a significant increase in both visceral and parietal pleural thickness (p < 0.05). Granulation tissue formation and collagen deposition were significantly higher in the modified talc group. In addition, TGF-β expression and CD68-positive macrophage count increased significantly in the modified talc group (p < 0.05). Inflammatory changes in the lung parenchyma were limited and not statistically significant. Conclusions: The modified talc formulation enriched with lidocaine and antibacterial agents produced a stronger inflammatory and fibrotic response compared to standard talc. These findings indicate that modified talc may increase the effectiveness of pleurodesis. Furthermore, the absence of significant lung parenchymal damage suggests that this treatment is locally effective and feasible. However, further long-term and advanced studies are needed to translate these results into clinical use. Full article