Search Results (680)

Background and Objectives: Ketamine and magnesium sulfate (MgSO₄) are NMDA receptor antagonists that act through distinct mechanisms. Preclinical data indicate that their analgesic interaction is sequence-dependent: ketamine administered before MgSO₄ produces synergistic antinociception, whereas the reversed sequence is antagonistic. The primary outcomes were postoperative pain intensity (Numerical Rating Scale, NRS 0–10, at rest and on movement) and cumulative intravenous morphine consumption over 48 h, evaluated in patients undergoing open radical nephrectomy to test the hypothesis of sequence-dependent analgesic interaction. Materials and Methods: In this randomized, double-blind, placebo-controlled trial, 208 patients scheduled for elective open radical nephrectomy received two sequential intravenous boluses intraoperatively: Drug A immediately after induction, Drug B 10 min later. Agents were ketamine 0.2 mg/kg, MgSO₄ 15 mg/kg, or placebo (0.9% NaCl) in all nine possible combinations. Primary outcomes were postoperative pain intensity (NRS 0–10, at rest and on movement) and cumulative intravenous morphine consumption, assessed at 14 time points over 48 h. Secondary outcomes included sedation, nausea, vomiting, and the presence of hallucinations. Results: The ketamine → MgSO₄ (K → Mg) sequence significantly reduced NRS pain scores compared to placebo at multiple time points, including 30 min, 1 h, 3 h, 6 h, and 32 h postoperatively, with differences exceeding the minimum clinically important difference of 2 NRS points at the earliest assessments. The MgSO₄ → ketamine (Mg → K) sequence did not differ from placebo at any time point. Cumulative morphine consumption was comparable across groups. No hallucinations or psychomimetic events were observed. Conclusions: Intraoperative ketamine followed by MgSO₄ (K → Mg) provides clinically meaningful postoperative analgesia after open radical nephrectomy; the reversed sequence (Mg → K) offers no benefit over placebo. These findings provide the first clinical confirmation of sequence-dependent NMDA receptor antagonism and support the K → Mg protocol as a safe, simple addition to multimodal perioperative analgesia. Trial registration: ISRCTN registry, ISRCTN83633282. Full article

Background/Objectives: Paracetamol is a widely analgesic and antipyretic drug; however, its limited anti-inflammatory efficacy and safety concerns motivate the search for novel non-opioid alternatives. In this study, a series of 4-hydroxyphenylamino-naphthoquinones were designed as paracetamol-inspired analogs and synthesized via a solvent-free, silica-assisted Michael addition, providing a sustainable and efficient synthetic route. Methods: The compounds were evaluated using an integrated strategy combining in silico prediction, density functional theory calculations, molecular docking, ADMET profiling, and in vivo phenotypic pharmacological assays. Results: In vivo evaluation revealed pronounced peripheral antinociceptive activity in the acetic acid-induced writhing model and robust anti-inflammatory effects in carrageenan-induced paw edema, comparable to those of naproxen. These findings suggest a predominantly peripheral mechanism consistent with anti-inflammatory and antinociceptive profiles linked to cyclooxygenase inhibition. A normalization-based multi-criteria analysis integrating peripheral, anti-inflammatory, central, and antipyretic endpoints enabled transparent phenotypic prioritization within the series. Under this framework, compound 7 emerged as the most balanced peripheral–anti-inflammatory candidate, whereas compound 8, evaluated experimentally as a regioisomeric mixture, showed comparatively stronger central antinociceptive activity in the hot plate test. Antipyretic activity in an LPS-induced fever model was limited and not sustained. Conclusions: Overall, these findings indicated that the 4-hydroxyphenylamino-naphthoquinone scaffold emerges as a promising non-opioid platform for peripheral inflammatory pain, supporting further investigation of its pharmacological and mechanistic properties. Full article

Fentanyl is a potent analgesic widely used in clinical practice. Fentanyl and its analogues are seriously abused and are emerging in the illegal drug market, leading to numerous intoxication cases. However, assessment of the potency of the pharmacological effect of these novel fentanyl analogues remains limited and inconsistent across studies. The development of novel analgesics has largely relied on the assessment of mu opioid receptor (MOR) binding affinity, with insufficient verification through the assessment of antinociceptive effects. This study evaluated the antinociceptive effects of 25 fentanyl analogues to investigate the relationship between chemical structure and antinociceptive effect. In this study, hot plate tests were conducted in mice to generate time–effect and dose–effect curves for the evaluation of the antinociceptive effect of fentanyl and its analogues. The results demonstrated that the antinociceptive effects of fentanyl analogues were dose- and time-dependent. The potency of the antinociceptive effect observed in this study generally aligned with the corresponding MOR binding affinities reported in the literature, although several analogues exhibited discrepancies. Structural modifications in different regions of the fentanyl scaffold affect the antinociceptive potency to different degrees, and the duration of action also varied across fentanyl analogues. Furthermore, opioid-induced hyperalgesia (OIH) was observed following administration of several fentanyl analogues, raising potential concerns regarding their abuse liability and development for analgesic purposes. Taken together, this study systematically evaluated and compared the antinociceptive effects of fentanyl analogues. The findings clarify the relationship between chemical structure and the antinociceptive effect, providing valuable insights for drug regulation and the development of novel analgesics. Full article

Background: Bacopa procumbens is a plant species with medicinal properties. Although several of these properties have already been validated, its use for treating pain remains untested. Objective: the objective was therefore to test the antinociceptive effect of two extracts (n-hexane and hydroalcoholic) and two fractions (aqueous and organic) from the most active extract, as well as to determine the chemical profile of Bacopa procumbens. Methods: analgesic activity was determined by antinociceptive activity using the formalin model in mice. Compounds were identified by high-performance liquid chromatography and gas chromatography coupled with mass spectrometry. Compared to the vehicle treatment (3% Tween 20), licking time was 22.8 s and 141.6 s lower when treated with the hexane extract (200 mg/kg); 43.4 s and 152.5 s with the hydroalcoholic extract (200 mg/kg); 27.2 s and 169 s with the organic fraction; and 5.4 s and 32 s difference with the positive control, in phases 1 and 2, respectively. Phytochemical analysis of the hexane extract allowed us to identify 2-pentadecanone, 6,10,14-trimetil- (11.70%), 6,10,14-trimethyl-, dibutyl phthalate (34.71%), and hexane-dioic acid bis(2-ethylhexyl) ester (45.15%). Conclusions: We identified arbutin (1), 5-(p-hydroxybenzoyl) shikimic acid (2), and procumgastrodin A (3) in the BpFo fraction. In conclusion, we demonstrated that the BpH extract and the BpFo fraction have anti-nociceptive properties that may be associated with compounds 2 and 3. Full article

Introduction: Balancing hypnosis and antinociception during general anesthesia remains challenging, as traditional clinical and hemodynamic signs incompletely reflect cortical and nociceptive processing. Electroencephalogram (EEG)-derived indices such as qCON (hypnosis) and qNOX (nociception probability) (Quantium Medical, Barcelona, Spain), as well as their predecessors IoC1 (Index of consciousness) and IoC2 (Angel-6000 A multi-parameter Anesthesia Monitor, Shenzen Weihao Kang Medical Technology Co., Ltd., Shenzen, Guangdong, China), have been developed to provide a dual assessment of anesthetic state. Their clinical role, technical limitations, and impact on drug titration, however, remain incompletely defined. Methods: A structured narrative review was conducted based on studies investigating IoC/qCON and qNOX in the context of anesthetic depth or nociception monitoring. Studies were grouped into three thematic domains: (1) validation against clinical or EEG standards, (2) use in guiding anesthetic or opioid administration, and (3) technical characteristics, including signal delay and pharmacodynamic modeling implications. Results: Sixteen studies met inclusion criteria. Eight validation studies demonstrated that IoC/qCON correlates strongly with clinical sedation scales and established EEG-derived indices such as BIS and entropy. Five interventional studies evaluating drug titration found limited impact of qCON-guided hypnosis control on anesthetic consumption but more consistent effects of qNOX/IoC2 guidance on opioid dosing and intraoperative stability. Three technical investigations showed that qCON exhibits processing delays on the order of tens of seconds that can be accounted for by incorporating monitor lag into pharmacodynamic analyses. Conclusions: qCON and qNOX provide complementary EEG-based indices of hypnosis and cortical nociceptive responsiveness. Evidence supports their validity as indicators of anesthetic brain state but highlights technical limitations, such as processing delay and susceptibility to physiologic factors. Their optimal clinical use lies in multimodal monitoring strategies that integrate EEG besides classic clinical and monitoring parameters. Full article

Background/Objectives: Pupillometry offers a non-invasive method for assessing nociceptive responses during anesthesia. This study aimed to evaluate the effects of intravenous lidocaine on pupillary reflex dilation (PDR) and the Pupillary Pain Index (PPI) during general anesthesia with orotracheal intubation. Methods: In this prospective, randomized, single-blind trial, 90 ASA I–II patients aged 18–65 years, scheduled for elective surgery under general anesthesia, were enrolled. Participants were randomized into three groups: control, study (lidocaine 1.5 mg/kg), and placebo. Standardized anesthesia induction was performed using propofol, fentanyl, and rocuronium. Pupil diameter was measured using the Algiscan pupillometer. PDR was assessed during intubation, while PPI was measured five minutes post-intubation through controlled electrical stimulation. Hemodynamic parameters and BIS values were recorded throughout. Eighty-six patients completed the study. No significant differences in demographics, anesthetic drug doses, or hemodynamic parameters were noted between groups. Results: PDR during intubation showed no significant difference between the control and study groups (median dilation: 0.34 mm vs. 0.33 mm; p = 0.76), but was significantly lower in the lidocaine group compared to placebo (median dilation: 0.33 mm vs. 0.50 mm; p = 0.02). PPI scores did not differ significantly between groups (p > 0.05). A positive correlation was observed between PDR and BIS values, indicating that lighter anesthesia depth increased PDR response. No such correlation was found with PPI. Conclusions: Intravenous lidocaine attenuates the pupillary response to nociceptive stimuli during orotracheal intubation but does not influence PPI scores. Pupillometry remains a valuable adjunct for intraoperative nociceptive monitoring. Full article

Central to the linkage of pain circuitry with the limbic system is its initial NAα2-mediated antinociceptive effect in acute pain models, followed by contradictory pronociceptive activation by the locus coeruleus seen in chronic pain models. Rats with a stable, long-term (>10 weeks) inflammatory compression of the trigeminal infraorbital nerve (FRICT-ION) preclinical model were given daily doxazosin, a slow-release NAα1 receptor antagonist, in weeks 8–10. Facial hypersensitivity was reversed back to baseline in male and female rats, but anxiety was only reduced in male animals. Doxazosin-decreased astrocytic activation was indicated by a decrease in both intracranial cathepsin B imaging in vivo and GFAP immunostaining in the somatosensory cortex and hippocampus. Doxazosin reduction in NAα1 receptor activation diminished glial-neuronal interactions, resulting in downstream reduction in pain-related behaviors. Other significant differences by sex included improved elevated zero maze anxiety measures only in males, and improved novel recognition scores only in females. Elevated thymus chemokine CXCL7 levels were reduced by doxazosin but only in male rats. These sexually dimorphic contradictions further complicate the understanding of the noradrenergic system’s involvement in nociception. The findings indicate that by reducing NAα1 receptor drive with doxazosin, the role of the locus coeruleus can be shifted back to NAα2-receptor-mediated pain inhibition. Full article

Purpose of Review—sleep disturbance is the main complaint associated with patients who suffer acute postoperative pain. Sleep disturbance may also increase the pain sensitivity and contribute to the development and maintenance of chronic pain. The pathophysiology of pain is complex; management of perioperative pain and preventing chronic pain are challenges in clinical. Use of opioids for pain management are still a therapeutic mainstay and generally safe when taken, in a short time, for severe postoperative pain relief. For long-term use tolerance may be developed, and for their euphoric property, addiction, overdose incidents, and even death may be the social problems. Therefore, the opioid-sparing multimodal analgesia (MMA) for pain management is recommended in current postoperative pain management. The successful MMA for pain management will enhance patient recovery after surgery with less chronic CPSP and long-term opioid use disorder (OUD). The present review discusses all currently used analgesics actions and interactions, and opioid-sparing or opioid-free analgesia in perioperative pain management. Acute pain following major trauma or surgery may originate from both nociceptive and neuropathic mechanisms. Approximately 10–50% of surgical patients develop chronic postoperative pain, which not only causes persistent discomfort but also leads to functional limitations and psychological distress. Growing evidence highlights a close and bidirectional relationship between sleep and pain: pain disrupts sleep architecture, while sleep deprivation intensifies pain sensitivity and impairs recovery. This reciprocal interaction forms a vicious cycle that poses challenges for effective pain management. Melatonin—a neurohormone secreted by the pineal gland—plays a crucial role in regulating circadian rhythm and sleep–wake cycles. Beyond its chronobiotic action, melatonin exhibits anti-nociceptive, anti-inflammatory, and opioid-sparing properties. Recent preclinical studies have demonstrated that exogenous melatonin can attenuate nociceptive responses to noxious stimuli and enhance morphine analgesia while attenuating morphine tolerance. Moreover, environmental light manipulation preserving the circadian rhythm has been shown to synergistically maintain melatonin secretion, improve sleep quality, and modulate neuroimmune responses involved in pain regulation. Together, these findings suggest that circadian alignment and melatonin supplementation may represent a promising integrative approach for improving both pain control and sleep health in perioperative and chronic pain conditions. Chronic pain patients frequently experience opioid tolerance during long-term therapy, resulting in diminished analgesic efficacy and a need for escalating doses. Our recent work revealed that constant light exposure suppresses endogenous melatonin, heightens pro-inflammatory cytokines (TNF-α, IL-1β), reduces IL-10, and accelerates morphine tolerance in a neuropathic pain model. In contrast, maintaining circadian light–dark cycles or supplementing melatonin preserves melatonin rhythm, reduces glial activation, and sustains morphine antinociception. Melatonin’s co-administration not only attenuates morphine tolerance but also enhances morphine efficacy through the modulation of inflammatory and glial pathways. These findings underscore melatonin’s multifaceted role as both a chronotherapeutic and neuroprotective agent, integrating circadian regulation with pain modulation. Clinically, the application of melatonin or circadian-aligned strategies could guide personalized pain and sleep management, offering safer and more effective multimodal analgesic protocols with reduced opioid dependence and improved quality of life. Full article

Natural products have long been integral to traditional medicine, offering diverse therapeutic benefits. Increasing concerns about the side effects of synthetic drugs have heightened interest in plant-derived compounds. The camphor tree (Cinnamomum camphora (L.) J. Presl) and its derivatives, such as camphor oil, have been valued for centuries. Historically, C. camphora was used as a fumigant during the Black Death, a prized ingredient in perfumes, and a key component in embalming fluids. Today, camphor extracted from C. camphora is widely used as a fragrance in cosmetics, a flavoring agent in food, an ingredient in household cleaners, and a topical remedy for minor muscle pain. Camphor is primarily obtained through steam distillation of the wood but can also be synthetically produced from turpentine. Camphor exhibits a broad spectrum of biological activities, including insecticidal, antimicrobial, antiviral, anticoccidial, antinociceptive, anticancer, and antitussive effects, and has historically been employed to alleviate inflammation, congestion, pain, and irritation. This review integrates recently published research (up to 2025) on the biological activities and therapeutic applications of camphor that were not comprehensively addressed in earlier reviews. Furthermore, a mechanistic perspective is provided on camphor’s pharmacological effects, including its antibacterial, antimicrobial, antiviral, and anticancer actions, highlighting the chemical basis underlying these activities. This review provides a comprehensive overview of the history, applications, and biological properties of camphor, emphasizing its potential in preventing and treating serious diseases such as cancer and diabetes. In addition, sustainability and translational relevance are emphasized, demonstrating how camphor exemplifies the integration of traditional knowledge with contemporary medicinal research. Overall, this review offers new insights into the therapeutic potential of camphor, underscoring its promising role in addressing major medical challenges while supporting the growing importance of plant-based compounds in modern healthcare due to their effectiveness, safety, and sustainability. Full article

The chemical composition and antinociceptive potential of a lyophilized decoction of the oregano flowers (Origanum vulgare L.) and the aerial parts of chicory (Cichorium intybus L.) in the flowering phase (LCOD—lyophilized decoction of the oregano and chicory) was investigated by HPLC-DAD and the acetic-acid-induced writhing method. HPLC-DAD analysis of the LCOD revealed the presence of 20 phenolic compounds, where the dominant phenolic components were ferulic acid (205.19 mg/g LCOD), rosmarinic acid (81.55 mg/g) and hyperoside (79.42 mg/g). The results of the antinociceptive activity showed a strong analgesic effect of the LCOD (15 and 30 mg/kg), which significantly (p < 0.001) reduced the number of writhings (98.40 and 99.23%, respectively) induced by acetic acid. These encouraging results indicate the analgesic potential of LCOD and suggest validation through clinical trials. Full article

Background/Objectives:Aster (A.) koraiensis (Nakai) Kitamura (synonym Gymnaster koraiensis), commonly referred to as Korean starwort, belongs to the composite (Asteraceae) family. This endemic perennial species is cultivated for its long-lasting ornamental flowers and for its young leaves and stems, which serve as a nutritious food source. It grows abundantly across the southern and central regions of the Korean Peninsula, including Jeju Island. The presence of diverse secondary metabolites such as phenolic compounds, polyacetylenes, benzofurans, flavonoids, triperpenoidal saponins, and sesquiterpenoids contributes to its importance in both traditional medicine and modern pharmacology. To date, no comprehensive review has been conducted to summarize its phytoconstituents and pharmacological potential. Methods: A non-systematic electronic search of English-language articles using A. koraiensis and its synonyms as keywords was conducted to assess its bioactive constituents and health-promoting potential. Results: This review seeks to compile and discuss the health-promoting activities of A. koraiensis, including its antioxidant, anti-inflammatory, anti-diabetic, anti-tumor, antithrombotic, anticoagulant, anti-angiogenic, antinociceptive, anti-metabolic syndrome, antiviral, hepatoprotective, and cognitive function-enhancing properties, based on evidence from cell and animal studies. To date, more than 75 phytoconstituents have been purified and characterized from this plant. Conclusions: The extensive pharmacological activities of A. koraiensis highlight its medicinal importance. Future studies should concentrate on the separation, identification, and quantification of its bioactive metabolites, alongside an in-depth investigation of its potential health-enhancing properties. Full article

Background: The plant-derived compound n-butylidenephthalide (BP) is an isobenzofuranone that has shown neuropharmacological effects on preclinical models of Parkinson’s, Alzheimer’s, and amyotrophic lateral sclerosis. Methods: This study evaluated the anti-inflammatory, antinociceptive, anxiolytic-like, hypnotic, anticonvulsant, and antidepressant-like effects of BP (50–200 mg/kg p.o.) using Balb/c mice in acute assays. This study also evaluated the antidepressant-like effects of BP in a mouse model of reserpine-induced depression-like behavior for 20 days. Inhibitors involved in the molecular process of depression and in silico studies were used to evaluate a possible mechanism of action for the antidepressant-like effects of BP. Results: BP induced low anti-inflammatory effects, showed low anticonvulsant effects, and lacked hypnotic effects or motor impairment in acute assays. The antidepressant-like effects of BP (100–200 mg/kg p.o.) were comparable to amitriptyline (25 mg/kg p.o.) in acute assays. The participation of serotonergic and adrenergic systems is involved in the acute antidepressant-like effects of BP. In the reserpine-induced depression model, BP (100 mg/kg p.o.) showed antidepressant-like effects in one of the two antidepressant tests, but with a lower effect than amitriptyline (20 mg/kg p.o.). Conclusions: BP (100 and 200 mg/kg) showed antidepressant-like effects in acute assays and, to a lesser extent, in a reserpine-induced chronic model of depression-like behavior. Full article

Currently, commercially available pain medications can cause adverse effects. Within this framework, researchers have been exploring new drug candidates derived from animal venoms and toxins. The objective of this study was to investigate the number of molecules with potential for pain relief derived from animal venoms and toxins, which could potentially contribute to the development of new biopharmaceuticals. We conducted a literature search in January 2025, covering the period from 1960 to 2025, in two Latin American and nine international scientific databases. The results consisted of 212 articles selected for review. From these articles, 152 toxins and venoms with analgesic potential were identified and classified into 14 different types of pharmacological targets. The peptides investigated, with masses between 500 Da and 5000 Da, are strong candidates for alternative biopharmaceuticals. Most of the toxins found interact with ion channels, representing an alternative to commercially available drugs. Full article

Background/Objectives: The present study investigated the local analgesic effect of a novel synthetic cyclohexanone derivative, 2,6-bis-4-(hydroxyl-3-methoxybenzilidine)-cyclohexanone, or BHMC, in a mouse model of peripheral nociception. Methods: Local administration of BHMC (0.5–60 µg/paw) intra-plantarly in the hindpaws of mice exhibited significant inhibition in carrageenan-induced paw hyperalgesia. Intra-plantar pretreatment of naloxone (non-selective opioid receptor blocker), D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-ThrNH2 (CTOP, selective µ-opioid receptor blocker), and nor-binaltorphimine (nor-BNI, selective κ-opioid receptor blocker), but not naltrindole hydrochloride (selective δ-opioid receptor blocker), reversed the anti-nociceptive effect of BHMC. The peripheral analgesic effect of BHMC was also reversed by intra-plantar pretreatment of methylene blue (soluble guanosyl cyclase blocker), but not N^G-nitro-L-arginine (L-NAME, nitric oxide synthase blocker). Involvement of the potassium channel in the local analgesic effect of BHMC was shown through the reversed analgesic effect by intra-plantar pretreatment of glibenclamide (ATP-sensitive potassium channel blocker), but not by charybdotoxin (large-conductance calcium-sensitive potassium channel blocker), apamin (small-conductance calcium-sensitive potassium ion channel blocker), or tetraethylammonium (voltage-sensitive potassium channel blocker). Results: Taken together, the present study demonstrated that the local administration of BHMC attenuated nociception, with possible mechanisms that may involve the desensitization of inflammatory mediators’ receptors, opioid receptor activation, and nitric oxide-independent cyclic guanosine monophosphate activation of ATP-sensitive potassium ion channel opening. Conclusions: The current findings may further support the exploration of BHMC as a new therapeutic agent for pain and inflammation, for the betterment of human health. Full article