Search Results (3,653)

The genus Glaucium (Papaveraceae), comprising approximately 30 species, is widely distributed across the Mediterranean region, Europe, North Africa, and Central and Southwest Asia. In the flora of Türkiye, the genus is represented by 11 taxa and is commonly known as “boynuzlu gelincik” and “çömlek çatlatan”. The aim of this study is to explore the analgesic and anti-inflammatory properties of Glaucium corniculatum (L.) Rud subsp. refractum (NAB) Cullen, and Glaucium leiocarpum Boiss., which are found in Türkiye and are known for their high alkaloid content. Traditionally, G. leiocarpum has been used for wound care, cuts, bruises, acne, hemorrhoids, headache, and diarrhea, while G. corniculatum subsp. refractum has been employed as an antitussive and for external applications against ocular inflammations. Ethanolic extracts and crude alkaloid fractions from the aerial parts were evaluated in vivo in anti-inflammatory and antinociceptive test models. Anti-inflammatory activity was assessed by the carrageenan-induced paw edema model, while antinociceptive activity was determined using tail-flick and hot-plate tests. G. leiocarpum ethanolic extract (200 mg/kg) showed the highest anti-inflammatory activity, effectively suppressing carrageenan-induced edema (1.58 ± 0.30–1.73 ± 0.51 mL), and displayed the strongest antinociceptive activity, with tail-flick latencies reaching 23.91 ± 2.08 s (90 min) and 22.23 ± 1.97 s (150 min) and hot-plate latencies of 22.27 ± 4.76 s (30 min) and 23.00 ± 4.61 s (90 min). Bioactivity-guided fractionation of the most active extract was carried out using various chromatographic techniques. Thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC) analyses were employed throughout the isolation process to monitor fractions and determine their phytochemical profiles. As a result, two compounds were obtained and subsequently evaluated for their biological activities. The chemical structures of the isolated compounds were elucidated by spectroscopic methods, including ¹H-NMR, ¹³C-NMR, 2D-NMR, and LC-MS analyses as kaempferol-3-O-glucorhamnoside and quercetin-3-O-glucorhamnoside. Biological activity evaluation demonstrated that these compounds significantly contributed to the observed antinociceptive activity. These findings confirm that Glaucium species are traditionally used and highlight their potential to provide bioactive compounds with anti-inflammatory and pain-relieving effects. Full article

Total knee arthroplasty (TKA) is increasingly performed in older adults, a population with a growing prevalence of frailty and sarcopenia. Analgesic strategies focused mainly on pain reduction may overlook mobility, functional independence, fall prevention, and delirium risk, making motor preservation a central goal of perioperative care. This narrative review examines the anatomical basis, clinical evidence, and practical application of motor-sparing regional analgesia for older adults undergoing TKA, with emphasis on frailty, sarcopenia, and mobility-centred recovery, synthesising current evidence on established, emerging, and experimental techniques. Evidence was classified as geriatric-specific, older-enriched mixed-age, or mixed-age adult. Most technique-specific evidence derives from cohorts that included younger adults; only two small randomised trials reported cohorts composed exclusively of patients aged ≥65 years, and no regional-analgesia trial stratified outcomes by frailty or sarcopenia. A pragmatic clinical decision framework was developed to support individualised strategy selection in frail and sarcopenic patients. Current evidence supports adductor canal block combined with local infiltration analgesia as the foundation of motor-sparing analgesia after TKA; supplementary techniques such as iPACK, popliteal plexus block, genicular nerve block, and anterior femoral cutaneous nerve block may further optimise sensory coverage while preserving quadricep strength, whereas femoral nerve block produces predictable motor impairment and appears less suitable for this population. The existing literature remains largely focused on pain scores and opioid consumption, while mobility-related outcomes are infrequently reported. Direct evidence for falls, near-falls, delirium, discharge destination, functional independence, and long-term mobility remains sparse or absent. Successful analgesia after TKA should be defined not only by pain relief but by preservation of mobility and functional recovery, and future research should prioritise frailty-specific, mobility-centred outcomes. Full article

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

Gymnaconitum gymnandrum, a Tibetan medicinal herb, is distributed across high-altitude regions of China. Despite its high toxicity, it exhibits analgesic, anti-inflammatory, antitumor, and other pharmacological activities. It is used topically for skin conditions and orally for rheumatism. Its main bioactive components are alkaloids. A new organic amine alkaloid has been isolated from the plant and structurally identified using HRMS, NMR, and X-ray diffraction. Full article

Efforts to liberate patients from invasive mechanical ventilation (MV) begin when the underlying cause of acute hypoxemic respiratory failure (AHRF) or adult respiratory distress syndrome (ARDS) that led to use of invasive ventilation has resolved or improved and patients can initiate spontaneous breaths. In preparation for liberation, clinicians transition patients to spontaneous modes of ventilation as soon as possible while ensuring that patients’ respiratory effort is not insufficient or excessive during weaning attempts. Concurrently, clinicians aim to minimize the effects of sedative and analgesic agents, screen daily to identify patients who are ready to undergo a spontaneous breathing trial (SBT), and conduct SBTs to help assess patients’ readiness for extubation. Extubation failure is rarely the consequence of a single physiological abnormality. Rather, it reflects the interaction of multiple mechanisms that often coexist, including an imbalance between respiratory system load and capacity, ineffective cough, and secretion burden among others. For these reasons, single weaning parameters and SBTs may fail to identify some patients who are at risk for extubation failure. Conversely, indices and scores that combine two or more parameters and newer techniques may provide mechanistic insights into the pathways that lead to extubation failure, help to characterize ‘at-risk’ phenotypes, and identify patients who may benefit from closer monitoring, targeted therapeutic strategies, and/or early application of noninvasive respiratory support strategies such as high-flow nasal cannula (HFNC) and bilevel noninvasive positive pressure ventilation (NIV). Full article

Lavender essential oil (LEO) possesses broad therapeutic potential, yet translating empirical knowledge into evidence-based medicine is hindered by the descriptive literature that conflates isolated monoterpene mechanisms with whole-oil efficacy. Addressing these critical shortcomings, this review presents a target-centric synthesis that explicitly delineates the molecular pathways of pure constituents (e.g., linalool, linalyl acetate) versus intact LEO matrices and standardized oral preparations (Silexan™). We systematically integrate LEO’s multi-target signaling networks across neuroregulatory, analgesic, anti-inflammatory, and skin-regenerative domains, while critically examining how genetic taxonomy, environmental stress, and green extraction technologies dictate chemotype diversity. Furthermore, we candidly address current evidence limitations, including pre-clinical predominance, publication bias, and clinical trial narrowness. Finally, we outline actionable translational strategies centered on chemotype-driven standardization, smart delivery systems, and a dual pharmacological paradigm that valorizes non-volatile processing byproducts. This synthesis establishes a rigorous theoretical foundation for LEO’s clinical translation and pharmaceutical standardization. Full article

Background: Doyerea emetocathartica (Cucurbitaceae) is endemic to the Brazilian Caatinga, commonly known as “cabeça-de-negro”, and is traditionally used to treat various conditions, including pain. Previous studies have demonstrated that the aqueous stem extract exhibits anti-inflammatory activity, which may be associated with the presence of cayaponoside D2, a major component of this extract. Given this, the aim of this study was to characterize the aqueous extract of D. emetocatharthica stems in terms of its Cayaponoside D2 content and to evaluate its antinociceptive activity using in vivo models, as well as to assess the involvement of the opioid pathway in the observed effect. Methods: For this purpose, the extract was analyzed by HPLC to quantify cayaponoside D2, and formalin- and acetic acid-induced nociception models were used to evaluate antinociceptive activity; the rats were divided into six groups (n = 6). The test groups received the aqueous extract of the D. emetocathartica stem (DEAQ) at doses of 25, 50, and 100 mg/kg; the control group received 0.9% saline; and morphine and indomethacin were used as positive controls. To investigate the mechanism of action involved in the antinociceptive effect, an evaluation was conducted of the role of the opioid pathway and the involvement of opioid receptors in the antinociceptive effect in the presence of specific antagonists: naloxone, CTOP, naltrindole, and Nor-BNI. Results: The analgesic activity of DEAQ was demonstrated in acetic acid-induced abdominal writhing and formalin-induced nociception models, with the most pronounced effects observed at doses of 50 and 100 mg kg⁻¹. In the formalin test, DEAQ showed a predominant effect during the inflammatory phase. Mechanistic investigations revealed that the antinociceptive activity involves the opioid system, mainly through μ-opioid receptors, with additional participation of δ-opioid receptors, as evidenced by the partial reversal of the effect by selective antagonists. These findings suggest that DEAQ may exert a multimodal analgesic effect involving both opioid and non-opioid pathways. This activity can be attributed to the presence of cayaponoside D2, which was quantified in the extract at a concentration of 108 mg g⁻¹ of dry extract. Conclusions: These findings demonstrate that the aqueous stem extract from D. emetocathartica exhibits promising analgesic activity mediated by the opioid pathway, reinforcing its pharmacological potential and supporting its traditional use in pain management. Full article

Levetiracetam (LEV) is an antiepileptic drug and is used in the management of various types of seizures and other clinical conditions, including anxiety and neuropathic pain. Its unique mechanism primarily involves selective interaction with synaptic vesicle protein 2A (SV2A), which stabilizes synaptic function and the release of neurotransmitters. The objective of the present study was to evaluate LEV activity in morphine (MPH) dependence. In mice, LEV was used at doses ranging from 31.25 to 125 mg/kg, depending on the experimental paradigm. It was studied in three schedules: (1) MPH tolerance to antinociceptive effects (the hot plate test—HPT); (2) MPH withdrawal signs, manifested as jumps, induced by naloxone (NAL)—2 mg/kg, i.p.; (3) MPH sensitization to locomotor activity. In this study, LEV reduced MPH tolerance to analgesic effects. Moreover, LEV diminished the intensity of NAL-precipitated MPH withdrawal signs. This drug was also effective in attenuating MPH-induced sensitization. These findings suggest that LEV may modulate behavioral adaptations associated with repeated MPH exposure. However, further mechanistic studies are required to identify the molecular and neurochemical pathways involved in these effects. Full article

Cridanimod (acridoneacetic acid), the active ingredient of the immunomodulatory drug Cycloferon^®, has a well-characterized antiviral profile, but an unexplored analgesic potential. Bornane monoterpenes, notably (+)-camphor and (−)-fenchone, are established scaffolds for analgesic drug design. We therefore synthesized thirteen cridanimod–monoterpene conjugates—seven amides, three acylhydrazones, and three esters—by EDCI/DMAP-mediated coupling or CDI/DBU-promoted esterification, and evaluated them in mice at an oral dose of 10.0 mg/kg in the acetic acid writhing and hot plate tests, with diclofenac sodium (10.0 mg/kg) as the reference. Acridoneacetic acid and Cycloferon^® were themselves inactive in both assays. By contrast, six of the thirteen conjugates were significantly active (p < 0.05) in at least one test, with distinct leads in each: amide 19 matched diclofenac in the writhing test (−63.7% vs. −64.4%), whereas acylhydrazone 23 exceeded diclofenac in the hot plate test (+43.9% vs. +25.7%). The divergent profiles suggest that different structural subclasses engage peripheral and central antinociceptive mechanisms. Conjugation thus converts an analgesically inactive immunomodulator into a substance yielding analgesics that match or exceed a standard NSAID at the same oral dose, providing a promising starting point for the development of new pain-relieving agents. Full article

Marrubium vulgare L. aerial parts are a rich source of polyphenols with recognized antioxidant and anti-inflammatory properties; however, their therapeutic potential is limited due to poor stability and bioavailability. To enhance its pharmacological efficacy, a liposomal formulation of M. vulgare polyphenolic extract (MV-Lipos) was developed in this study by employing the thin-film hydration method. Before encapsulating, the free-extract (MV-Ext) was analyzed using LC-MS, and the resultant nanoliposomes were tested for physicochemical qualities, biological activity, and safety. MV-Lipos exhibited particle sizes ranging from 127 to 200 nm, an 84% encapsulation efficiency, and high colloidal stability (zeta potential −29.58 ± 0.40 mV). In vitro evaluations revealed anti-inflammatory and antioxidant activities without cytotoxic effects. In vivo, MV-Lipos significantly improved analgesic and anti-inflammatory responses. Specifically, a dose of 100 mg/kg lowered acetic acid induced writhing by up to 75.9% and carrageenan induced paw edema by 72%, with efficacy comparable to ibuprofen. A 28-day subacute toxicity assessment found no treatment-related adverse effects. Furthermore, molecular docking analyses validated the experimental results by revealing possible interactions with inflammation-related targets. Overall, liposomal encapsulation improved the biological efficacy and safety profile of M. vulgare polyphenols, highlighting their potential as natural agents for the management of pain and inflammatory conditions. Full article

Background/Objectives: Postoperative opioid requirements vary substantially after gastrointestinal surgery. Oxycodone-based patient-controlled intravenous analgesia (PCIA) is used for postoperative pain control, but perioperative factors associated with early postoperative oxycodone requirement remain insufficiently defined. This study investigated factors associated with 48 h oxycodone consumption after gastrointestinal surgery. Methods: This single-center retrospective cohort study included 493 adults who underwent elective gastrointestinal surgery and received oxycodone-based PCIA between January and December 2025. The primary outcome was cumulative oxycodone consumption within 48 h after surgery. Multivariable linear regression was used for the primary continuous-outcome analysis. An exploratory analgesia-adjusted model additionally included regional block, incisional local infiltration, and routine postoperative non-opioid analgesic use. High consumption, defined as a 48 h dose >38 mg, was evaluated using exploratory logistic regression models. Results: The median 48 h oxycodone consumption was 34 mg (interquartile range, 27–38 mg), and 105 patients (21.3%) had high consumption. In the prespecified clinical continuous-outcome model, gastric surgery, rectal surgery, open surgery, converted-to-open surgery, radical resection, and longer operation time were associated with higher 48 h oxycodone consumption, whereas older age was associated with lower consumption. After adjustment for available analgesia-related variables, the main associations remained broadly stable, although the association for converted-to-open surgery was attenuated. Regional block and incisional local infiltration were associated with lower 48 h oxycodone consumption in the analgesia-adjusted model. In the exploratory logistic models, younger age, rectal surgery, open or converted-to-open surgery, radical resection, and longer operation time were associated with high consumption. Body mass index (BMI) was not independently associated with oxycodone requirement. Conclusions: Age and procedure-related characteristics were associated with 48 h oxycodone requirement after gastrointestinal surgery. These routinely available perioperative factors may help identify patients who warrant earlier postoperative pain reassessment, closer acute pain service follow-up, and individualized multimodal analgesic planning. Prospective multicenter validation is required before formal risk-stratified analgesic protocols can be recommended. Full article

Background/objectives: Benzodiazepines are widely prescribed as adjuvants in pain management, particularly for musculoskeletal conditions, with prescription rates for back and chronic pain more than doubling between 2003 and 2015. Yet, the evidence supporting this practice remains poorly defined. This study evaluates the efficacy of benzodiazepines in pain management, analyzing comparative data, pharmacological mechanisms, and global clinical guidelines. Methods: Narrative review informed by a predefined systematic search of PubMed, Scopus, Cochrane Library and Web of Science. We searched for direct comparative studies between diazepam, alprazolam, and lorazepam in pain management identified no eligible studies, revealing a significant evidence gap despite decades of clinical use. This absence of comparative evidence prompted a broader narrative examination of the evidence base for benzodiazepines across pain conditions. Results: The available literature consistently fails to support benzodiazepine analgesia. Across 111 chronic pain conditions, analgesic benefit has been demonstrated for only two rare conditions: burning mouth syndrome (evidence primarily for topical clonazepam) and stiff person syndrome (primarily case series and clinical experience). In low back pain, the condition most associated with benzodiazepine prescribing, recent randomized trials show no benefit or even harm compared to placebo, and the only positive pooled evidence derived from trials of tetrazepam, a drug withdrawn from the European market in 2013. In rheumatoid arthritis, pooled data from six small trials show no benefit over placebo at any time point. The pharmacological basis for this clinical failure is now well characterized: conventional non-selective benzodiazepines produce dose-limiting sedation before achieving sufficient receptor occupancy at the α2/α3 GABA-A subtypes responsible for antihyperalgesic effects. Despite the lack of demonstrated efficacy, prescribing persists, likely driven by clinical inertia and patient expectations reflecting anxiolytic rather than analgesic properties. Guidelines from the WHO, NICE, the VA/DoD, the American College of Physicians, the American Academy of Family Physicians, and the Wilderness Medical Society uniformly recommend against benzodiazepine use for pain. This convergence of absent efficacy, well-documented harm, and unanimous guideline opposition supports the conclusion that benzodiazepines should not be prescribed as analgesic adjuvants. Conclusions: Although the focused search targeted head-to-head trials, a broader narrative synthesis and prior comprehensive reviews likewise demonstrate a paucity of high-quality evidence for benzodiazepine analgesia. Future research should focus on subtype-selective GABA-A modulators and on strategies to align clinical practice with the existing evidence, including structured deprescribing interventions. Full article

Background/Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly encountered in pain practice, but reported pain improvement may reflect direct antinociception, weight loss, metabolic change, or disease-specific effects. This structured narrative review examined these possibilities and relevant safety issues. Methods: PubMed/MEDLINE, Embase, and Web of Science Core Collection were searched through 15 May 2026. Peer-reviewed human studies, key mechanistic preclinical studies, systematic reviews and meta-analyses, and professional guidance relevant to pain outcomes or procedural safety were considered. Metabolic-only and non-peer-reviewed reports were excluded, and human pain-primary evidence was prioritized. Results: Preclinical data support plausible mechanisms involving spinal microglia, interleukin-10, beta-endorphin, neuroinflammation, and sensory-neuron signaling, but direct analgesic efficacy at systemic clinical doses has not been demonstrated. In STEP 9 (n = 407), mean WOMAC pain scores at 68 weeks changed from baseline by −41.7 points with semaglutide 2.4 mg and −27.5 points with a placebo; body weight changed by −13.7% and −3.2%, respectively. Liraglutide produced additional weight loss without superior knee-pain reduction. Diabetic peripheral neuropathy evidence was mainly structural or neurophysiologic; idiopathic intracranial hypertension and ROSE-010-treated irritable bowel syndrome showed disease-specific signals, whereas fibromyalgia- and opioid-related findings remained observational or hypothesis-generating. Gastrointestinal dysmotility, reduced intake, and lean-mass loss may offset functional benefits. Conclusions: GLP-1RAs are not established analgesics. Current human signals are best interpreted as indirect metabolic–functional or disease-specific effects. Future trials should use validated pain-primary outcomes, control for weight loss, and monitor treatment-related harms. Full article

Introduction: Neuromonitoring during general anesthesia (GA) is recommended to reduce the incidence of postoperative delirium and intraoperative awareness, particularly during total intravenous anesthesia. Guidelines emphasize that anesthesiologists should not rely solely on processed depth-of-anesthesia indices such as the Bispectral Index or Patient State Index but should also interpret the raw electroencephalographic (EEG) waveform and the density spectral array (DSA). Although EEG patterns associated with individual anesthetic agents or combinations of hypnotics and opioids have been described, limited evidence exists regarding EEG activity during multimodal anesthetic regimens. This systematic review aimed to evaluate DSA patterns as pharmacodynamic markers of the cortical effects of GABAergic anesthetics, opioids, and ketamine. Methods: PubMed, Embase, and the Cochrane Library were searched without date restrictions up to September 2025. Eligible studies included adult patients undergoing general anesthesia and reporting raw EEG data or specific DSA patterns associated with the investigated drugs. Risk of bias was assessed using RoB 2 and ROBINS-I according to study design. Owing to the limited number of eligible studies, findings were synthesized narratively. Results: Out of 273 papers screened, 3 studies met the inclusion criteria, comprising 72 patients. The studies achieved an appropriate and stable effect-site concentration of propofol–remifentanil GA, demonstrated by a baseline DSA recorded before ketamine administration. Ketamine administration produced a shift from the baseline alpha–delta pattern to a beta–delta DSA pattern. Conclusions: Ketamine administration during stable propofol–remifentanil anesthesia produces a characteristic shift towards a beta–delta DSA pattern, which may increase processed EEG indices, leading to misinterpretation of anesthetic depth. Further studies are needed to characterize DSA signatures associated with multimodal anesthesia and to identify patterns indicative of adequate anesthetic depth when multiple agents are administered. Full article

Full-length ACTH molecule and ACTH-related hexapeptide H-PKKRRP-OH are demonstrated by the patch-clamp method to decrease the Na_V1.8 channel activation gating system effective charge in the nociceptive neuron membrane, while ACTH-related tetrapeptide Ac-KKRR-NH₂ has no effect. ACTH(1–24), a fully functional ACTH mimetic, and H-PKKRRP-OH show analgesic effects in the formalin test in vivo. All peptides contain the cationic KKRR motif, but only H-PKKRRP-OH and ACTH(1–24) relieve acute pain, targeting the Na_V1.8 channel as a receptor. This seemingly controversial result is explained by application of conformational analysis and blind docking. Though conformational analysis indicates that both H-PKKRRP-OH and Ac-KKRR-NH₂ contain the cationic functional groups at the earlier suggested characteristic distance of 9–12 Å, Ac-KKRR-NH₂ does not interact with the S4_I voltage sensor of the Na_V1.8 channel activation gating system. The docking demonstrates that an extensive network of ligand–receptor ionic and hydrogen bonds involving D151, E157, R218, and R221 VSD_I residues, essential for the analgesic tripeptide Ac-KKK-NH₂ binding, is formed upon the H-PKKRRP-OH binding. Particularly important are the ionic bonds between the H-PKKRRP-OH C-terminal carboxylate anion and the S4_I R218 and R221 guanidinium groups. The described mechanism of Na_V1.8 channel modulation is fundamentally different from the effect of channel blockers. Full article