Search Results (2,300)

Schoenoplectus californicus, a macrophyte from Peruvian marine–coastal wetlands, is traditionally used for medicinal purposes, yet its pharmacological potential remains insufficiently explored. This study evaluated the chemical profile, antioxidant capacity, psychopharmacological effects, and analgesic activity of a hydroethanolic extract from its rhizomes. Phytochemical screening and LC–MS/MS analyses were performed to characterize secondary metabolites. Antioxidant activity was assessed using DPPH and ABTS assays, while in vivo anxiolytic, sedative, and analgesic effects were evaluated in Balb/c mice through open field, elevated plus maze, rotarod, analgesimeter, tail-flick, and hot plate tests, with diazepam and tramadol as reference drugs. In silico PASS and BOILED-Egg analyses were used to predict pharmacological mechanisms and central nervous system permeability. The extract contained flavonoids, phenolic compounds, and stilbenes and exhibited notable antioxidant activity (IC₅₀: 0.7319 mg/mL for DPPH and 0.6207 mg/mL for ABTS). Anxiolytic effects were observed at 50 mg/kg, sedative effects at 200 mg/kg, and significant analgesic activity at 50 mg/kg. Several compounds were predicted to cross the blood–brain barrier, with inhibition of GABA aminotransferase suggested as a potential mechanism. Acute toxicity was detected (LD₅₀ > 2000 mg/kg). These findings support S. californicus as a promising source of neuroactive and analgesic compounds, although further mechanistic and dose-optimization studies are required. Full article

Nigella sativa cold-pressed oil (NSO) is rich in nutrients and biologically active compounds. This study aimed to evaluate its effects on symptoms and serum levels of inflammatory and disease activity markers in rats with Freund’s adjuvant-induced arthritis (AIA). Animals were treated orally with NSO at doses of 1 and 3 mL/kg for two weeks before arthritis induction and throughout the experiment. Hind paw edema and nociceptive thresholds were measured by plethysmometer, Hargreaves apparatus, and Randall–Selitto test, respectively. At the end of the experiment, TNF-α, IL-1β, IL-10, brain-derived neurotrophic factor (BDNF), and neuropeptide Y (NPY) serum levels were measured. NSO preventive administration significantly reduced paw edema of the affected hind paw, along with an increase in the nociceptive threshold to both thermal and mechanical stimuli. Administration of NSO resulted in a significant reduction in serum levels of IL-1β and NPY (p < 0.01 and p < 0.05, respectively), while TNF-α and IL-10 levels remained comparable to those in the untreated AIA control group. These findings indicate that NSO exerts anti-inflammatory and analgesic effects and modulates circulating IL-1β and NPY (an independent marker associated with disease activity) in experimental arthritis. Full article

Background/Objectives: Interscalene brachial plexus block (ISB) is a common regional anesthesia technique for analgesia in patients undergoing shoulder surgery. Liposomal bupivacaine (LB) was developed to prolong analgesia duration; however, the existing literature demonstrates mixed results regarding its efficacy. This study aimed to compare the analgesic effectiveness of near-equipotent doses of LB and plain bupivacaine (PB) for patients undergoing total shoulder arthroplasty (TSA). Methods: This prospective double-blinded randomized controlled trial enrolled 78 elective TSA patients. Participants were randomized to receive an ISB with either 36 mL of 0.5% PB (180 mg) or a mixture of 10 mL of LB, 20 mL of 0.25% PB, and 6 mL of saline (183 mg). The primary outcome was the proportion of patients with clinically tolerable pain scores (visual analog scale (VAS) ≤ 4) on postoperative day (POD) 1 in each group. Secondary outcomes included the proportion of patients with clinically tolerable pain scores on POD 2–5, overall pain scores in the post-anesthesia care unit (PACU) and on POD 1–5, Quality of Recovery Survey-15 (QoR-15) scores on POD 1–5, analgesic consumption on the day of surgery and on POD 1–5, and adverse events. Results: A total of 67 patients completed the study. There was a statistically significant increase in median body mass index (BMI) in the PB vs. LB group (30.0 (27.4–33.1) vs. 27.0 (24.3–29.4), p = 0.0197). All other demographic characteristics were comparable between groups. There was no difference in the primary outcome or any of the secondary outcomes. Conclusions: LB did not reduce postoperative pain compared to PB. Larger, multicenter studies are warranted to further evaluate the clinical benefit of LB in this population. Full article

The genus Serjania (family Sapindaceae) comprises more than 240 species, primarily distributed in Brazil and Mexico, and it exhibits considerable ethnobotanical and therapeutic potential. Ethnobotanical evidence documents the widespread use of decoctions prepared from the leaves, stems, and roots of Serjania species for the treatment of gastrointestinal disorders, renal pain, inflammatory conditions, and infections. Among the most extensively studied species are S. marginata, S. erecta, S. lethalis, S. caracasana, S. goniocarpa, S. schiedeana, S. yucatenensis, S. triquetra, and S. racemose. Phytochemical research has identified a diverse array of bioactive secondary metabolites, including saponins, flavonoids, phenolic acids, tannins, and terpenoids. Significant experimental evidence supports the broad spectrum of biological activities of these Serjania species, including antimicrobial, anti-inflammatory, antioxidant, gastroprotective, antihypertensive, analgesic, antivenom, cytotoxic, antimutagenic, anti-ulcer, photoprotective, antiparasitic, and vasorelaxant effects, as demonstrated in both in vitro and in vivo models. Although preliminary toxicity assessments of extracts from some Serjania species in murine models, Oreochromis niloticus (Nile tilapia), and Artemia salina suggest a favorable safety profile, significant research gaps remain. Additionally, several Serjania species have shown potential as natural pesticides and bioherbicides, highlighting their relevance in agricultural applications. Future studies should prioritize the isolation and structural characterization of individual bioactive compounds, as well as the elucidation of their molecular mechanisms of action, moving beyond crude extract-based screening approaches. Overall, this review summarizes current knowledge on traditional uses, phytochemical composition, biological activities, and biotechnological applications of Serjania species. Full article

Venlafaxine, a serotonin–norepinephrine reuptake inhibitor, shows analgesic effects in rodents, but its efficacy and pharmacological profile in acute stimulus-evoked nociception may depend on the nociceptive test used and the pharmacological context. The aim of this review was to identify the receptors implicated in venlafaxine antinociceptive effects and to examine which molecular processes most consistently explain its acute antinociceptive profile. We reviewed in vivo rodent studies testing venlafaxine in acute nociceptive assays (writhing, tail-flick, hot-plate, and other eligible acute tests) as monotherapy or associated with other pharmacologically active substances. PubMed/MEDLINE and Web of Science were searched from 1993 to 5 January 2026, and reference lists were also screened. Outcomes were synthesized and stratified by type of nociceptive test and interaction class. Fourteen studies were identified as relevant to the scope of this review. Venlafaxine produced dose-dependent antinociception across tests, reducing writhing and increasing thermal withdrawal latency. Central administration generally yielded effects at lower absolute doses than systemic routes. Interaction studies most consistently supported modulation of opioid receptors (e.g., leftward opioid dose–response shifts and attenuation of morphine tolerance in repeated-exposure designs), with convergent evidence implicating opioid and α₂-adrenergic mechanisms and context-dependent serotonergic contributions. Additional pathways were variably implicated, including nitric oxide – cyclic guanosine monophosphate (NO–cGMP) signaling and oxidative/mitochondrial processes in opioid tolerance paradigms. Preclinical evidence supports venlafaxine as a modulator of acute nociceptive control with notable opioid-interaction potential. Standardized pharmacodynamic reporting and translationally oriented studies are needed. Full article

Background/Objectives: Opioids paradoxically induce hypersensitivity that typically resolves after discontinuation. Despite normalization of sensitivity, the nociceptive system may remain primed. Descending pathways contribute to opioid-induced hyperalgesia (OIH), and the following latently maintained sensitization. The mechanisms underlying the latter vulnerability remain unknown. We previously showed that the dorsal reticular nucleus (DRt), a key brainstem area involved in pain facilitation, drives OIH through a maladaptation in μ-opioid receptor (MOR) signaling. Whether cellular alterations in the DRt persist after opioids are discontinued and hyperalgesia resolves is unknown. Here, we investigated the long-term effects of morphine on DRt MOR expression, signaling, and function after hyperalgesia has been resolved. Methods: Male Wistar rats received morphine for 7 days either subcutaneously or continuously. Nociceptive sensitivity was evaluated by von Frey and hot-plate tests. MOR and phosphorylated CREB (pCREB) expression in the DRt were quantified during OIH and after hyperalgesia resolution. In the post-OIH phase, we evaluated the effects of MOR activation by DAMGO at DRt, postoperative pain behavior, and systemic morphine dose–response curves. Results: Both morphine regimens induced hypersensitivity that subsided within two weeks. MOR expression in the DRt increased during OIH and normalized in the post-OIH phase, whereas pCREB levels remained elevated in both phases. In the post-OIH phase, DAMGO microinjection at the DRt reinstated robust hypersensitivity and systemic morphine showed reduced antiallodynic potency in postoperative pain. Conclusions: Chronic morphine leaves a lasting molecular imprint in the DRt, sustaining excitatory MOR signaling that can reinstate hyperalgesia and likely diminishes later opioid analgesic efficacy. Full article

Postoperative pain management (POPM) remains a major clinical challenge despite its vital importance in reducing surgical stress, enabling early mobilization, and limiting postoperative complications. Conventional analgesic strategies are often constrained by short drug half-lives, repeated dosing requirements, systemic adverse effects, and the risk of opioid-related toxicity or dependence. These limitations suggest that the mode of drug delivery, in addition to drug selection itself, is a critical determinant of therapeutic performance. In this context, electrospun fibrous meshes represent a promising platform for localized and sustained analgesic delivery. Their high surface-area-to-volume ratio, tuneable porosity, broad polymer compatibility, and capacity to incorporate single or multiple bioactive agents make them attractive candidates for postoperative applications. This review summarizes recent advances in electrospun meshes for POPM, with particular emphasis on fabrication strategies, polymer selection, drug incorporation approaches, drug-release behaviour, biological performance, and translational challenges. Full article

Opioid-induced constipation (OIC) represents a prevalent adverse effect of opioid analgesics, affecting 60–90% of patients and ssignificantly compromising quality of life. This review delineates the multifactorial pathogenesis of OIC. Peripheral μ-opioid receptor (MOR) activation suppresses enteric neuronal excitability, inhibits intestinal motility and secretion, and impairs rectoanal function. Notably, the colon appears to exhibit a distinctive lack of tolerance to opioids. Enteric glial cell activation has been implicated in neuroinflammation, while interstitial cells of Cajal show impaired pacemaker function. Central mechanisms are increasingly recognized to involve the brain–gut axis. Furthermore, opioid-induced barrier disruption, microbiota dysbiosis, and LPS/TLR4-mediated inflammation are proposed to interact and may contribute to a self-reinforcing cycle. Animal models have been instrumental in dissecting these mechanisms. However, they present limitations in reproducibility, clinical phenotype fidelity, and translational validity, particularly regarding microbiome composition and neuroimmune responses. Future research should prioritize the development of standardized, physiologically relevant animal models incorporating multi-omics approaches, and validate mechanism-based therapeutic strategies, including peripherally acting MOR antagonists and microbiota-targeted interventions, for precision management of OIC. Full article

Background/Objectives: Ambroxol is a mucolytic agent widely used in the treatment of respiratory diseases; however, evidence in the literature indicates anti-inflammatory, analgesic, and immunomodulatory properties, suggesting potential for therapeutic repositioning. This study aimed to evaluate the analgesic and anti-inflammatory effects of ambroxol in an experimental model of osteoarthritis (OA). Methods: Adult male Wistar rats underwent OA induction on day zero (D0) by sodium monoiodoacetate (MIA) injection and were allocated into the following groups: Healthy, negative control (CTRL−), and groups treated with meloxicam (2 mg/kg) or ambroxol (10, 50, and 100 mg/kg). Treatments were administered orally (gavage) once daily for 28 days. Behavioral tests were performed, including rotarod, walkway gait analysis, weight-bearing, Von Frey, and Rat Grimace Scale assessments, along with radiographic and histopathological analyses and quantification of pro- and anti-inflammatory cytokines (IL-1β, IL-6, and IL-10). Results: Ambroxol treatment improved nociceptive parameters and motor function, reduced radiographic and histopathological scores, and showed performance comparable to meloxicam in several tests. There was a marked reduction in IL-1β and IL-6 levels, while IL-10 levels were lower in ambroxol-treated groups, suggesting early control of the inflammatory response. Conclusions: The results indicate that ambroxol exhibits antinociceptive and anti-inflammatory actions and suggest a potential chondroprotective effect, reinforcing its viability as a candidate for therapeutic repositioning in osteoarthritis. Further studies are required to more precisely elucidate its mechanisms of action, define optimal dosing and treatment duration, and support translation to clinical models. Full article

Kratom (Mitragyna speciosa) is a botanical candidate for pain management with potentially reduced opioid-related risks, partly through modulation of neuroimmune pathways involving Toll-Like Receptor 4 (TLR4). This study aimed to characterize the phytochemical profile of kratom ethanol extract and evaluate its effects on TLR4 signalling, neuroinflammatory cytokines, analgesic activity, withdrawal behaviours, and organ safety in morphine-dependent mice. Metabolite profiling was conducted using UHPLC–Q-Exactive Orbitrap HRMS, followed by molecular docking of major constituents to the TLR4 complex. In vivo assessments included flow cytometry and gene expression analyses of TLR4-mediated cytokines (NF-κB, IL-1β, IL-6), behavioural assays for antinociception, endurance, and withdrawal symptoms, and histopathological and biochemical evaluation of liver, kidney, and spleen tissues. More than 100 metabolites were identified, including mitragynine and flavonoids such as rutin and isoquercetin, which showed interactions with key TLR4 residues. Selected fractions suppressed pro-inflammatory cytokine expression, increased tail-pinch latency comparable to morphine, reduced withdrawal manifestations, and demonstrated nephroprotective and immunomodulatory effects, although mild reversible hepatic alterations were observed in specific fractions. Overall, kratom ethanol extract exhibited fraction-dependent analgesic and anti-neuroinflammatory activities associated with TLR4 modulation, supporting its potential as a botanical analgesic candidate while emphasizing the importance of safety optimization and standardized fraction development. Full article

Background/Objectives: Goupi plaster (GP) is a traditional black plaster composed of a biphasic fibrous–oil matrix containing multiple bioactive compounds, and it has been widely used for the treatment of musculoskeletal disorders. Representative active compounds include sinomenine, osthole, cinnamaldehyde, and imperatorin, which exhibit anti-inflammatory and analgesic effects. However, due to its heterogeneous matrix structure and multi-component nature, the pharmaceutical delivery behavior of GP remains difficult to evaluate using conventional methods. Therefore, this study aimed to establish an integrated structure–release–permeation–pharmacokinetic evaluation framework to systematically characterize the transdermal delivery behavior of GP. Methods: GP was evaluated using multi-level analysis, including microstructural imaging (FESEM), in vitro release, ex vivo skin permeation, and in vivo dual-site microdialysis. Four representative bioactive compounds (sinomenine, osthole, cinnamaldehyde, and imperatorin) were selected as marker compounds. Release data were fitted to kinetic models, and structure–release relationships were examined using the Higuchi release constant (k_h). Skin-barrier alterations were assessed by attenuated total reflectance–Fourier transform infrared spectroscopy (ATR–FTIR) and differential scanning calorimetry (DSC). Local concentrations in subcutaneous (SC) and intra-articular (IA) compartments were measured by ultra-performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) to explore potential in vitro–in vivo correlation (IVIVC). Results: FESEM revealed a fibrous–oil network structure. GP exhibited sustained, diffusion-dominated release, with k_h = 0.9908–0.9977 and Korsmeyer–Peppas (K–P) release exponents (n) = 0.61–0.66, differing from active pharmaceutical ingredient (API) controls. Fiber area fraction and fiber length density showed negative correlations with k_h (r = −0.91 to −0.99); ex vivo permeation profiles varied among compounds, and ATR–FTIR and DSC analyses showed moderate changes in skin-barrier properties. Dual-site microdialysis demonstrated sustained local exposure, and a positive relationship was observed between in vitro release and in vivo concentrations. Conclusions: This study establishes an integrated structure–release–permeation–pharmacokinetic evaluation framework for traditional black plaster systems. The observed IVIVC is descriptive rather than predictive, reflecting a trend-level association under the current experimental conditions. These findings highlight the importance of integrating in vitro release, skin permeation, and local pharmacokinetics for understanding drug delivery behavior in complex transdermal matrix systems, and provide a methodological basis for quality consistency evaluation of traditional black plaster formulations. Full article

Breathing-controlled electrical stimulation (BreEStim) is an innovative neuromodulation intervention that synchronizes deep voluntary breathing with peripheral electrical stimulation. Prior studies have shown its analgesic effects in healthy adults and spinal cord injury patients with neuropathic pain. The present study used EEG to examine BreEStim’s neural effects on sensory, affective, and cognitive components of pain. Fourteen healthy participants (7 M, 7 F) completed 30 min of BreEStim and conventional electrical stimulation (EStim) interventions in a randomized, crossover within-subject design. Electrical pain thresholds (EPT) and EEG were recorded pre- and post-intervention. Event-related potentials (ERPs) at pre-EPT-level stimuli before and immediately after each intervention were analyzed for early sensory (P30) and affective (P250) processing, while resting-state EEG assessed spectral power across delta, theta, alpha, and beta bands for cognitive processing. Both BreEStim and EStim increased EPT, indicating short-term habituation. There was no change in early ERP responses (P30) after each intervention, suggesting preserved sensory perception. BreEStim selectively reduced P250, reflective of the affective component of pain. BreEStim significantly increased delta and theta band power and reduced alpha band power on resting-state EEG analyses, whereas no significant changes after EStim were observed. Collectively, BreEStim preserves sensory encoding while selectively modulating affective and cognitive dimensions of pain, supporting its potential as a targeted, non-pharmacological neuromodulation strategy. Full article

Background: Magnesium sulfate (MgSO₄) added to local anesthetics has been investigated as an adjuvant in regional anesthesia, but its role in ultrasound-guided erector spinae plane block (ESPB) remains uncertain. Methods: We conducted a PRISMA 2020-compliant systematic review of randomized controlled trials evaluating MgSO₄ added to the local anesthetic solution in ESPB. In the predefined core comparison (MgSO₄ added to local anesthetic vs. local anesthetic alone in adult postoperative surgery), four trials (225 participants enrolled; 160 contributing to the comparison) informed the qualitative synthesis. Results: Eight randomized controlled trials were included. In the predefined core comparison, 24 h pain intensity was reported heterogeneously and was frequently not extractable as continuous data, precluding pooling. Opioid consumption or rescue analgesia more often favored MgSO₄; however, outcome metrics, analgesic drugs, and assessment windows were not harmonized, and these effects were not consistently accompanied by reductions in pain intensity at 24 h, limiting their interpretation as true analgesic benefit. Safety reporting was frequently incomplete and often lacked structured adverse event tabulation. Risk of bias varied across domains, and GRADE certainty for all core outcomes was very low. Conclusions: Current randomized evidence does not support routine use of MgSO₄ as an adjuvant in ESPB. Future trials using standardized ESPB techniques, harmonized magnesium dosing strategies, and core outcome sets are required to determine whether magnesium provides clinically meaningful incremental analgesic benefit. Full article

Background and Objectives: Functional neurosurgery encompasses surgical interventions aimed at modulating the function of the central and peripheral nervous systems. Spinal cord stimulation (SCS), as a form of neuromodulation, is an established treatment for chronic pain and is increasingly utilized by both anesthesiologists and neurosurgeons. The aim of this study was to evaluate the effectiveness of SCS in patients with chronic neuropathic spinal pain. Materials and Methods: This prospective study included 42 patients who demonstrated a positive response to trial stimulation. Only patients achieving a clinically meaningful response (≥50% pain reduction) during the trial phase were included in the final analysis. Pain intensity and functional disability were assessed using the Visual Analog Scale (VAS) and the Oswestry Disability Index (ODI). All patients underwent a two-stage percutaneous implantation procedure using burst stimulation. A follow-up assessment was performed 3–6 months after implantation. Results: A statistically significant reduction in pain intensity was observed (p < 0.0001), with median VAS scores decreasing from 8 to 3, corresponding to a 62.5% reduction in pain intensity and exceeding the minimal clinically important difference (MCID) for VAS. Functional status improved significantly, with ODI scores decreasing from 74% to 38%, markedly surpassing the established MCID threshold. A clinically meaningful reduction in pain (≥50%) was achieved in the majority of patients. All patients requiring opioid analgesics at baseline discontinued their use following SCS implantation, and a reduction in overall analgesic consumption was observed across the cohort. Conclusions: These findings suggest that burst SCS may be an effective treatment option for carefully selected patients with chronic neuropathic spinal pain who are not candidates for conventional spine surgery. However, the results should be interpreted with caution due to the enriched study design and limited follow-up period. Full article

Background: Mild and moderate pain represent a large proportion of emergency department (ED) presentations but are frequently underestimated and inconsistently managed, particularly in vulnerable populations such as children and older adults. Standardised and evidence-based approaches are needed to ensure timely, safe, and effective pain control across the entire emergency care pathway. Methods: A national multidisciplinary Delphi consensus was conducted under the auspices of the Italian Society of Emergency Medicine (SIMEU). A Scientific Steering Committee performed a systematic literature review and developed 26 statements comprising 92 items across four thematic areas: analgesia at triage, risk factors and analgesia at discharge, analgesia in children, and analgesia in elderly patients. Thirty-three experts from across Italy participated in three Delphi rounds, rating each item using a five-point Likert scale. Consensus was defined as ≥66% agreement (scores 4–5). Results: Consensus was achieved for 78 out of 92 items. Key recommendations include early pain assessment at triage using validated scales, paracetamol as first-line therapy for mild and moderate pain across all age groups, and the use of multimodal analgesia for moderate pain. Fixed-dose combinations of paracetamol and ibuprofen were strongly endorsed for their efficacy, safety, and opioid-sparing effect in adults, children, and elderly patients. Clear guidance was also provided for analgesic selection at discharge, duration of therapy, patient education, and management of special populations. Conclusions: This multidisciplinary Delphi consensus provides practical, evidence-based recommendations to harmonize the management of mild and moderate pain in ED. Implementation of these recommendations may improve pain control, patient safety, and quality of care in non-urgent emergency settings. Full article