Effects Of Analgesic Drugs Research Articles

Intrathecal administration of MCRT produced potent antinociception in chronic inflammatory pain models via μ-δ heterodimer with limited side effects

An important goal in the opioid field is to discover effective analgesic drugs with minimal side effects. MCRT demonstrated potent antinociceptive effects with limited side effects, making it a promising candidate. However, its pharmacological properties and how it minimizes side effects remain unknown. Various mouse pain and opioid side effect models were used to evaluate the antinociceptive properties and safety at the spinal level. The targets of MCRT were identified through cAMP measurement, isolated tissue assays, and pharmacological experiments. Immunofluorescence was employed to visualize protein expression. MCRT displayed distinct antinociceptive effects between acute and chronic inflammatory pain models due to its multifunctional properties at the μ opioid receptor (MOR), µ-δ heterodimer (MDOR), and neuropeptide FF receptor 2 (NPFFR2). Activation of NPFFR2 reduced MOR-mediated antinociception, leading to bell-shaped response curves in acute pain models. However, activation of MDOR produced more effective antinociception in chronic inflammatory pain models. MCRT showed limited tolerance and opioid-induced hyperalgesia in both acute and chronic pain models and did not develop cross-tolerance to morphine. Additionally, MCRT did not exhibit addictive properties, gastrointestinal inhibition, and effects on motor coordination. Mechanistically, peripheral chronic inflammation or repeated administration of morphine and MCRT induced an increase in MDOR in the spinal cord. Chronic administration of MCRT had no apparent effect on microglial activation in the spinal cord. These findings suggest that MCRT is a versatile compound that provides potent antinociception with minimal opioid-related side effects. MDOR could be a promising target for managing chronic inflammatory pain and addressing the opioid crisis.

Nursing Care of Acute Pain in Multiple Fractures with Spiritual Therapy Quantum Touch and Finger Holding: A Case Study

Background: Multiple Fractures or broken bones are a condition where the continuity of the bones is broken in a complex manner, this is caused by trauma caused by frequent traffic accidents. Objective: To analyze the effect of a combination of non-pharmacological therapies Quantum Spiritual Touch Therapy" (QST) and Finger Holding in multiple fraktur patients with acute pain at RSD dr. Soebandi Jember. Method: This research is an observational study with a case study design. Primary data obtained through anamnesis and physical assessment. Assessment of the effect of QST therapy and finger holding was carried out a total period of 35 minutes, 20 minutes for QST therapy and 15 minutes for finger holding therapy, based on initial, process, and final data. Results: The results showed a reduction in pain levels with a Numerical Rating Scale (NRS) was carried out for 6 meetings with the implementation of therapy once a day. Pain levels decreased in the pre-implantation measurements with an average of 5,4 to 4,7 at the time of post-implementation. Discussion: The combination of pharmacological therapy from QST therapy and finger holding aims to help the effectiveness of analgesic drugs by improving the psychological structure with implementations that contain spiritual elements.

Machine learning-based evaluation of spontaneous pain and analgesics from cellular calcium signals in the mouse primary somatosensory cortex using explainable features.

Pain that arises spontaneously is considered more clinically relevant than pain evoked by external stimuli. However, measuring spontaneous pain in animal models in preclinical studies is challenging due to methodological limitations. To address this issue, recently we developed a deep learning (DL) model to assess spontaneous pain using cellular calcium signals of the primary somatosensory cortex (S1) in awake head-fixed mice. However, DL operate like a "black box", where their decision-making process is not transparent and is difficult to understand, which is especially evident when our DL model classifies different states of pain based on cellular calcium signals. In this study, we introduce a novel machine learning (ML) model that utilizes features that were manually extracted from S1 calcium signals, including the dynamic changes in calcium levels and the cell-to-cell activity correlations. We focused on observing neural activity patterns in the primary somatosensory cortex (S1) of mice using two-photon calcium imaging after injecting a calcium indicator (GCaMP6s) into the S1 cortex neurons. We extracted features related to the ratio of up and down-regulated cells in calcium activity and the correlation level of activity between cells as input data for the ML model. The ML model was validated using a Leave-One-Subject-Out Cross-Validation approach to distinguish between non-pain, pain, and drug-induced analgesic states. The ML model was designed to classify data into three distinct categories: non-pain, pain, and drug-induced analgesic states. Its versatility was demonstrated by successfully classifying different states across various pain models, including inflammatory and neuropathic pain, as well as confirming its utility in identifying the analgesic effects of drugs like ketoprofen, morphine, and the efficacy of magnolin, a candidate analgesic compound. In conclusion, our ML model surpasses the limitations of previous DL approaches by leveraging manually extracted features. This not only clarifies the decision-making process of the ML model but also yields insights into neuronal activity patterns associated with pain, facilitating preclinical studies of analgesics with higher potential for clinical translation.

Methadone Requires the Co-Activation of μ-Opioid and Toll-Like-4 Receptors to Produce Extracellular DNA Traps in Bone-Marrow-Derived Mast Cells.

Methadone is an effective and long-lasting analgesic drug that is also used in medication-assisted treatment for people with opioid use disorders. Although there is evidence that methadone activates μ-opioid and Toll-like-4 receptors (TLR-4s), its effects on distinct immune cells, including mast cells (MCs), are not well characterized. MCs express μ-opioid and Toll-like receptors (TLRs) and constitute an important cell lineage involved in allergy and effective innate immunity responses. In the present study, murine bone-marrow-derived mast cells (BMMCs) were treated with methadone to evaluate cell viability by flow cytometry, cell morphology with immunofluorescence and scanning electron microscopy, reactive oxygen species (ROS) production, and intracellular calcium concentration ([Ca2+]i) increase. We found that exposure of BMMCs to 0.5 mM or 1 mM methadone rapidly induced cell death by forming extracellular DNA traps (ETosis). Methadone-induced cell death depended on ROS formation and [Ca2+]i. Using pharmacological approaches and TLR4-defective BMMC cultures, we found that µ-opioid receptors were necessary for both methadone-induced ROS production and intracellular calcium increase. Remarkably, TLR4 receptors were also involved in methadone-induced ROS production as it did not occur in BMMCs obtained from TLR4-deficient mice. Finally, confocal microscopy images showed a significant co-localization of μ-opioid and TLR4 receptors that increased after methadone treatment. Our results suggest that methadone produces MCETosis by a mechanism requiring a novel crosstalk pathway between μ-opioid and TLR4 receptors.

Prostanoids in Cardiac and Vascular Remodeling.

Prostanoids are biologically active lipids generated from arachidonic acid by the action of the COX (cyclooxygenase) isozymes. NSAIDs, which reduce the biosynthesis of prostanoids by inhibiting COX activity, are effective anti-inflammatory, antipyretic, and analgesic drugs. However, their use is limited by cardiovascular adverse effects, including myocardial infarction, stroke, hypertension, and heart failure. While it is well established that NSAIDs increase the risk of atherothrombotic events and hypertension by suppressing vasoprotective prostanoids, less is known about the link between NSAIDs and heart failure risk. Current evidence indicates that NSAIDs may increase the risk for heart failure by promoting adverse myocardial and vascular remodeling. Indeed, prostanoids play an important role in modulating structural and functional changes occurring in the myocardium and in the vasculature in response to physiological and pathological stimuli. This review will summarize current knowledge of the role of the different prostanoids in myocardial and vascular remodeling and explore how maladaptive remodeling can be counteracted by targeting specific prostanoids.

The Role and Mechanism of Spinal NF-κB-CXCL1/CXCR2 in Rats with Nucleus Pulposus-induced Radicular Pain.

Experimental study of the role and mechanism of spinal NFκB-CXCL1/CXCR2 in rats with nucleus pulposus-induced radicular pain. This study investigated the role and mechanism of spinal NFκB-CXCL1/CXCR2 in autologous nucleus pulposus-induced pain behavior in rats and to clarify the involvement and regulation of spinal NFκB as an upstream molecule of CXCL1 in autologous nucleus pulposus-induced radicular pain in rats. The inflammatory response of nerve roots is an important mechanism for the occurrence of chronic pain. NFκB-CXCL1/CXCR2 pathway plays an important role in the development of radicular pain, but its regulatory mechanism in the model of radicular pain induced by autologous nucleus pulposus is still unclear. We established a rat model of autologous medullary nucleus transplantation. We observed and recorded the changes in 50% mechanical withdrawal threshold and thermal withdrawal latency before and after the administration of CXCL1-neutralizing antibodies, CXCR2 inhibitor, and NFκB inhibitor in each group of rats and evaluated the expression of NFκB, CXCL1, and CXCR2 in the spinal dorsal horn using immunofluorescence and Western blot. To compare differences between groups in behavioral testing, analysis of variance was employed. Dunnett's method was used to compare differences at different time points within a group and between different groups at the same time point. A comparison of the relative concentration of protein, relative concentration of mRNA, and semiquantitative data from immunofluorescence staining was conducted utilizing one-way ANOVA and Dunnett's pairwise comparison. Autologous nucleus pulposus transplantation can induce radicular pain in rats and upregulate the expression of CXCL1, CXCR2, and NFκB in the spinal cord. CXCL1 is co-expressed with astrocytes, CXCR2 with neurons, and NFκB with both astrocytes and neurons. The application of CXCL1 neutralizing antibodies, CXCR2 inhibitors, and NFκB inhibitors can alleviate pain hypersensitivity induced by autologous nucleus pulposus transplantation in rats. Inhibitors of NFκB could downregulate the expression of CXCL1 and CXCR2. We found that spinal NFκB is involved in NP-induced radicular pain in rats through the activation of CXCL1/CXCR2, enriching the mechanism of medullary-derived radicular pain and providing a possible new target and theoretical basis for the development of more effective anti-inflammatory and analgesic drugs for patients with chronic pain following LDH.

Optogenetic Activation of Peripheral Somatosensory Neurons in Transgenic Mice as a Neuropathic Pain Model for Assessing the Therapeutic Efficacy of Analgesics.

Optogenetics is a novel biotechnology widely used to precisely manipulate a specific peripheral sensory neuron or neural circuit. However, the use of optogenetics to assess the therapeutic efficacy of analgesics is elusive. In this study, we generated a transgenic mouse stain in which all primary somatosensory neurons can be optogenetically activated to mimic neuronal hyperactivation in the neuropathic pain state for the assessment of analgesic effects of drugs. A transgenic mouse was generated using the advillin-Cre line mated with the Ai32 strain, in which channelrhodopsin-2 fused to enhanced yellow fluorescence protein (ChR2-EYFP) was conditionally expressed in all types of primary somatosensory neurons (advillincre/ChR2+/+). Immunofluorescence and transdermal photostimulation on the hindpaws were used to verify the transgenic mice. Optical stimulation to evoke pain-like paw withdrawal latency was used to assess the analgesic effects of a series of drugs. Injury- and pain-related molecular biomarkers were investigated with immunohistofluorescence. We found that the expression of ChR2-EYFP was observed in many primary afferents of paw skin and sciatic nerves and in primary sensory neurons and laminae I and II of the spinal dorsal horns in advillincre/ChR2+/+ mice. Transdermal blue light stimulation of the transgenic mouse hindpaw evoked nocifensive paw withdrawal behavior. Treatment with gabapentin, some channel blockers, and local anesthetics, but not opioids or COX-1/2 inhibitors, prolonged the paw withdrawal latency in the transgenic mice. The analgesic effect of gabapentin was also verified by the decreased expression of injury- and pain-related molecular biomarkers. These optogenetic mice provide a promising model for assessing the therapeutic efficacy of analgesics in neuropathic pain.

Alleviating morphine-induced itching while sustaining its analgesic efficacy: Esketamine as a potential co-administrating choice

Morphine is one of the most commonly used and effective analgesic drugs in clinical practice. Morphine injected directly into the epidural and subarachnoid space acts directly on the central nervous system compared to oral or intravenous administration. This route of morphine delivery requires only a small dose to achieve satisfactory analgesia and greatly reduces the risk of adverse effects. However, morphine-induced itching significantly limits the clinical use of morphine and the maximization of its analgesic effects. Drugs commonly used worldwide to treat morphine-induced pruritus have different degrees of limitations. N-Methyl-D-aspartate (NMDA) receptors are involved in the mechanisms associated with morphine-induced itching. Theoretically, esketamine, an NMDA antagonist, which is commonly used in clinical practice to exert analgesic and sedative effects and contributes to circulatory stability, has the potential to effectively relieve morphine-induced itching without compromising its analgesic effects. In this paper, we discuss the possibility of co-administration of esketamine in cases of morphine-induced pruritus based on the current clinical situation and relevant mechanisms, with the intention of developing novel therapeutic options for morphine-induced pruritus.

A pill as a quick solution: association between painkiller intake, empathy, and prosocial behavior

Previous research has demonstrated a link between the administration of analgesic drugs and the reduction of empathy levels in humans. This apparent blunting effect of pain medication has been explained through shared neural mechanisms for the first-hand and the empathic experience of pain (simulation theory). Considering that analgesics are among the most consumed drugs in the world and the ability to empathize with others is fundamental to human social interactions, the aim of the present study was to investigate whether the typical day-to-day analgesic consumption rate in Austria and Germany is associated with a reduction in empathy and prosocial behavior. We therefore collected self-reports of analgesic consumption behavior as well as empathy for pain and prosocial behavior measures in an online survey (n = 940). Analyses revealed no significant association between the analgesic intake frequency and measures of empathy or prosocial behavior. However, liberal intake of analgesics (i.e. mind-set of “a pill is a quick solution”) was linked to lower empathic concern and helping behavior, which may hint towards a negative effect in people who take pain medication for non-pain related issues or episodes of low pain. Nevertheless, further research is needed to investigate the effects of analgesic drugs in high frequency users.

Safety and effectiveness of HSK21542 for hemodialysis patients: a multiple ascending dose study.

Background: HSK21542, a novel selective peripherally-restricted κ-opioid receptor agonist has been proven to be a safe and effective analgesic and antipruritic drug in both in vitro and in vivo studies. We aimed to evaluate its safety, pharmacokinetics and efficacy in hemodialysis patients over a 1-week treatment period, and to establish the optimal dosage for a further 12-week stage 2 trial. Methods: In this multiple ascending dose study, hemodialysis patients were randomly assigned to receive HSK21542 (0.05-0.80μg/kg), or a placebo three times within 2.5h at the end of each dialysis session for 1week. Safety evaluations included reports of treatment-emergent adverse events (TEAEs); pharmacokinetics and efficacy outcomes were also assessed. Results: Among the 44 screened patients, 41 were enrolled and completed the trial. The overall incidence of TEAEs was higher in the HSK21542 group compared to the placebo group, with an incidence of 75.0%, 50.0%, 75.0%, and 88.9% in the range of 0.05-0.80μg/kg. All TEAEs were grade 1 or 2 in severity. HSK21542 exhibited linear pharmacokinetics characteristics within the dose range 0.05-0.80μg/kg, without drug accumulation after multiple-doses. Compared to the placebo, a significant decrease of the weekly mean Worst Itching Intensity Numerical Rating Scale was found in the HSK21542-0.30μg/kg group (p = 0.046), but without significant improvement in the Skindex-16 score. Conclusion: HSK21542 was well tolerated in the dose range 0.05-0.80μg/kg in hemodialysis patients. HSK21542-0.3μg/kg exhibited promising efficacy in patients with moderate to severe pruritus and warrants a further Stage 2 trial. Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT04470154.

Propranolol reduces risk of knee or hip replacement due to osteoarthritis: A propensity score matched cohort study-using data from the Clinical Practice Research Datalink

Background: There is paucity of safe and effective analgesic drugs for osteoarthritis (OA). β-adrenoreceptor blockers have demonstrated anti-nociceptive effects in several painful conditions. We investigated whether β-blockers are associated with a reduced risk of total joint replacement (TJR) at the knee or the hip in people with incident knee or hip OA. Methods: This was a cohort study. We used data from the Clinical Practice Research Datalink. Participants aged 40 years or older with incident knee or hip OA, prescribed β-blockers following OA diagnosis (new-user design) and their age, sex, OA location and propensity score (PS) for β-blocker prescription matched controls were included in the study. Cox-proportional hazard ratios (HRs) and 95% confidence intervals (CI) were calculated. The analyses were adjusted for factors that influence health-seeking behaviour, progression of OA, and stratified according to β-blocker classification. Data analysis was conducted using STATA-MP v15. Results: Data for 6,970 PS-matched β-blocker exposed and unexposed participants were included. Any β-blocker prescription was not associated with knee or hip TJR (aHR 1.11; 95 % CI 0.98 – 1.25). However, prescription of lipophilic non-selective β-blockers with membrane stabilising effect associated with reduced risk of knee or hip TJR (aHR 0.69; 95 % CI 0.52 – 0.93). Of these, there was a protective effect for propranolol (aHR 0.71; 95 % CI 0.53 – 0.95), the commonest prescribed drug in this class. The number needed to treat (95%CI) with propranolol for two years, in order to prevent one TJR was 32 (23–52). Conclusions: The non-selective β-blocker propranolol reduces the risk of knee or hip TJR, consistent with its analgesic effects demonstrated in other conditions. A randomised controlled trial is required to further evaluate the analgesic potential of propranolol in OA.

Targeting Members of the Chemokine Family as a Novel Approach to Treating Neuropathic Pain.

Neuropathic pain is a debilitating condition that affects millions of people worldwide. Numerous studies indicate that this type of pain is a chronic condition with a complex mechanism that tends to worsen over time, leading to a significant deterioration in patients' quality of life and issues like depression, disability, and disturbed sleep. Presently used analgesics are not effective enough in neuropathy treatment and may cause many side effects due to the high doses needed. In recent years, many researchers have pointed to the important role of chemokines not only in the development and maintenance of neuropathy but also in the effectiveness of analgesic drugs. Currently, approximately 50 chemokines are known to act through 20 different seven-transmembrane G-protein-coupled receptors located on the surface of neuronal, glial, and immune cells. Data from recent years clearly indicate that more chemokines than initially thought (CCL1/2/3/5/7/8/9/11, CXCL3/9/10/12/13/14/17; XCL1, CX3CL1) have pronociceptive properties; therefore, blocking their action by using neutralizing antibodies, inhibiting their synthesis, or blocking their receptors brings neuropathic pain relief. Several of them (CCL1/2/3/7/9/XCL1) have been shown to be able to reduce opioid drug effectiveness in neuropathy, and neutralizing antibodies against them can restore morphine and/or buprenorphine analgesia. The latest research provides irrefutable evidence that chemokine receptors are promising targets for pharmacotherapy; chemokine receptor antagonists can relieve pain of different etiologies, and most of them are able to enhance opioid analgesia, for example, the blockade of CCR1 (J113863), CCR2 (RS504393), CCR3 (SB328437), CCR4 (C021), CCR5 (maraviroc/AZD5672/TAK-220), CXCR2 (NVPCXCR220/SB225002), CXCR3 (NBI-74330/AMG487), CXCR4 (AMD3100/AMD3465), and XCR1 (vMIP-II). Recent research has shown that multitarget antagonists of chemokine receptors, such as CCR2/5 (cenicriviroc), CXCR1/2 (reparixin), and CCR2/CCR5/CCR8 (RAP-103), are also very effective painkillers. A multidirectional strategy based on the modulation of neuronal-glial-immune interactions by changing the activity of the chemokine family can significantly improve the quality of life of patients suffering from neuropathic pain. However, members of the chemokine family are still underestimated pharmacological targets for pain treatment. In this article, we review the literature and provide new insights into the role of chemokines and their receptors in neuropathic pain.

Quantification of tramadol and serotonin by cobalt nickel tungstate in real biological samples to evaluate the effect of analgesic drugs on neurotransmitters

In this work, CoNiWO4 nanocomposite was used as an electrochemical sensor for the simultaneous electrochemical detection of tramadol and serotonin. The nanocomposite was synthesized using a hydrothermal method and characterized via XRD, SEM, TGA, Zeta, UV, and FTIR. The sensor was developed by depositing CoNiWO4-NPs onto the glassy carbon electrode surface. Tramadol and serotonin were detected by employing cyclic voltammetry (CV), differential pulse voltammetry (DPV), electrochemical impedance spectroscopy (EIS), and chronoamperometry. Analytes were detected at different pH, concentrations, and scan rates. The prepared sensor showed a 0–60 µM linear range, with a LOD of 0.71 µM and 4.29 µM and LOQ of 14.3 µM and 2.3 µM for serotonin and tramadol, respectively. Finally, the modified electrode (CoNiWO4–GCE) was applied to determine tramadol and serotonin in biological samples.

Efficacy of Patient-Controlled Intravenous Analgesia with Esketamine for Herpes Zoster Associated with Breakthrough Pain

BACKGROUND: Some patients with herpes zoster (HZ) experience an intermittent spontaneous, short-lived and severe pain, which is called breakthrough pain (BTP). The effect of analgesic drugs and invasive procedures is not significant. Therefore, treatment of HZ associated with BTP is challenging. Esketamine is a new N-methyl-D-aspartate receptor antagonist, with enhanced analgesic effects. This study aimed to evaluate the efficacy and adverse reactions of patient-controlled intravenous analgesia (PCIA) with low-dose esketamine for HZ associated with BTP. OBJECTIVES: To evaluate the efficacy and adverse reactions of PCIA with low-dose esketamine for HZ associated with BTP. STUDY DESIGN: A retrospective, observational study. SETTING: The study was carried out in the Pain Department of the Affiliated Hospital of Jiaxing University in Jiaxing, China. METHODS: The clinical data of HZ associated with BTP treated by PCIA with low-dose esketamine at the Pain Department of the Affiliated Hospital of Jiaxing University, between October 2015 to October 2021, were collected retrospectively. The Numeric Rating Scale (NRS-11) scores of rest pain (RP) and BTP, frequency of BTP, Pittsburgh Sleep Quality Index (PSQI) score, and fasting blood glucose (FBG) were recorded and analyzed before treatment (T0) and on days one (T1) and 3 (T2), week one (T3), months one (T4), 3 (T5), and 6 (T6) after treatment. Adverse reactions during the treatment were recorded. RESULTS: Twenty-five patients treated by PCIA with low-dose esketamine were included finally. Compared with T0, the NRS-11 scores of RP at T2, T3, T4, T5, and T6 decreased significantly (P < 0.05). The NRS-11 score of RP at T4 was significantly lower than that of T3 (P < 0.001), but there was no statistical difference between T5 and T4 (P > 0.05), the efficacy of esketamine in the treatment of RP was stable at one month after treatment. Likewise, compared with T0, the NRS-11 scores of BTP, frequency of BTP, and PSQI score decreased significantly at each time point after treatment (P < 0.05). These at T5 were significantly lower than T4 (P < 0.05), but there was no statistical difference between T6 and T5 (P > 0.05), the efficacy of esketamine was stable at 3 months after treatment. FBG also decreased significantly at each time point after treatment (P < 0.05), it tended to be normal and stable one month after treatment. All patients had mild symptoms of dizziness during treatment, and though a slight increase in noninvasive blood pressure (BP) was noted in all, the elevated BP did not exceed 30% of the baseline value. Four patients (16%) developed nausea without vomiting. There were no serious adverse reactions, such as respiratory depression. LIMITATIONS: The nonrandomized, single-center, small sample size, retrospective design is a major limitation of this study. CONCLUSIONS: PCIA with low-dose esketamine has a significant and long-term effect in the treatment of HZ associated with BTP. The RP was controlled, and the degree and frequency of BTP were significantly reduced after treatment, leading to improved quality of life. There were no serious adverse reactions worthy of clinical promotion. KEY WORDS: Patient-controlled intravenous analgesia, esketamine, herpes zoster, breakthrough pain

Monitorización de la nocicepción: índice NOL®. Revisión narrativa

IntroductionThe limitations of estimating nociception in routine clinical practice are substantial, so it is desirable to have nociception monitors that allow better estimation and control of the response to surgical stress. Until now, monitors have been developed based mainly on biopotentials and on the response of the autonomic nervous system. The NOL® index is a contribution to this last group. ObjectiveDescription of the performing of the NOL® index and the results of the studies using it. MethodologyNarrative review based on a systematic review of the literature in the main medical databases. ConclusionsNOL® index provides the simultaneous examination of a greater number of parameters than previous devices, a complementary method of artifact removal and an analysis based on a robust artificial learning system with the capacity to manage a large number of parameters and nonlinear relationships between them. It shows a sensitivity/specificity profile superior to the usual clinical parameters and the ability to discriminate stimuli of different intensity, without being influenced by the direct effects of analgesic drugs.

Analgesic and Anti-Inflammatory Effects of 80% Methanol Extract and Solvent Fractions of the Leaves of Vernonia auriculifera Hiern. (Asteraceae).

The leaves of V. auriculiferahas been used traditionally for the treatment of inflammatory disorders, and pain in various parts of Ethiopia. However, to our knowledge, the analgesic and anti-inflammatory activity of the crude extract and solvent fractions has never been experimentally studied. To assess the analgesic and anti-inflammatory activitiesof V. auriculifera leaf extract and solvent fractions in rodent models. Air-dried leaves ofV. auriculiferawere grounded and macerated using 80% methanol. The air-dried, grounded leaves were also successively extracted with ethyl acetate, and methanol. The residue was then macerated in water for 72 hr. The extract's peripheral analgesic activity, as well as the solvent fractions, were determined using an acetic acid-induced writhing test. The hot plate model was used to assess the central analgesic effect. Carrageenan-induced hind paw edema and cotton pellet-induced granuloma models were used to assess the anti-inflammatory effect in rats. The 80% methanol leaf extract and solvent fractions have demonstrated significant (p < 0.05) peripheral and central analgesic activity. Both 80% methanol leaf extract and solvent fractions of V. auriculifera were found to have anti-inflammatory activity in a carrageenan-induced rat paw edema model. In the cotton pellet-induced granuloma model, all concentrations of 80% methanol leaf extract (ME), methanol fraction (MEF), and aqueous fractions (AQF) of V. auriculifera inhibited exudate and granuloma formation. Although all tested doses significantly inhibited granuloma mass formation, only the medium and highest ethyl acetate fraction (EAF) doses significantly inhibited the generation of inflammatory exudate. This study's findings indicate that the solvent fractions and 80% methanol extract of V. auriculifera have analgesic and anti-inflammatory properties. This study's findings not only confirm the plants' traditional claim but also provide clues for further investigation of the active principles of this plant for the development of effective and safe analgesic and anti-inflammatory drugs.

Novel dual-target μ‑opioid and TRPV1 ligands as potential pharmacotherapeutics for pain management

Currently, the development of effective analgesic drugs with few side effects remains a great challenge. Studies have suggested that multi-target drug treatments show high efficacy and reduced side effects compared to single-target drug therapies. In this work, we designed and synthesized two series of novel MOR/TRPV1 dual active ligands in which the phenylpiperidine group or the N-phenyl-N-(piperidin-4-yl) propionamide group as the MOR pharmacophore was fused to the benzylpiperazinyl urea-based TRPV1 pharmacophore. In particular, compound 5a exhibited promising dual pharmacological activity for MOR (EC50 = 53.7 nM) and TRPV1 (IC50 = 32.9 nM) in vitro. In formalin tests, compound 5a showed potent, dose-dependent in vivo analgesic activity in both the 1st and 2nd phases. Gratifyingly, compound 5a did not cause the side effects of hyperthermia and analgesic tolerance. Consistent with its in vitro activity, compound 5a also simultaneously agonized MOR and antagonized TRPV1 in vivo. Further studies on compound 5a showed acceptable pharmacokinetic properties and brain permeability. Furthermore, molecular docking studies showed that compound 5a tightly bound to the active pockets of hMOR and hTRPV1, respectively. Overall, this work shows the promise in discovering new analgesic treatments through the strategy of simultaneously targeting MOR and TRPV1 with a single molecule.

Penggunaan Lidokain Intravena untuk Adjuvan Obat Analgesik pada Operasi Bedah Saraf

Pain is a subjective feeling or experience involving sensory, emotional, and unpleasant behavior caused by tissue damage. Postoperative management is considered essential because it will provide excellent results for patients and improve postoperative quality of life. Opioids are intravenous analgesic drugs that are most often used as perioperative pain therapy but have unpleasant side effects. Developments in using more effective analgesic drugs are needed, one of which is intravenous lidocaine which has fewer side effects than opioids. Several studies have shown that lidocaine as an intraoperative analgesic drug has minimal side effects and faster recovery. Other studies have also shown lidocaine as an analgesic in neurosurgery surgery to have a fairly good effect. Therefore, this literature will discuss lidocaine as an adjuvant therapy, especially in neurosurgery operations.

Development of Effective and Safe Analgesic and Anti-Inflammatory Drugs: Harnessing Natural Substances for Clinical Solutions.

Development of Effective and Safe Analgesic and Anti-Inflammatory Drugs: Harnessing Natural Substances for Clinical Solutions.

Clinical evaluation of the treatment complex of acute odontogenic periostitis in children on the base of diffused non-toxic goiter

Inflammatory diseases in the maxillo-facial region in children occupy a leading place in the work of a polyclinic doctor. At the same time, their diagnosis is imperfect and they often occur on a premorbid background. The clinical features of acute odontogenic periostitis against the background of thyroid pathology in children were studied to improve the effectiveness of treatment. We examined 38 children, formed two groups of observations. Children of both groups were given generally accepted treatment. Children of the main group were additionally prescribed means "Imupret" and "Calcemin advance" to normalize the main protective indicators of oral fluid. Statistically assessed the degree of probability of the obtained results. The results of clinical observation of children showed the absence of pain on the 7th day of observation in both the children of the main group and the comparison group, indicating the pronounced anti-inflammatory and analgesic effects of drugs in complexes treatment. On the 7th day of treatment, clear hyperemia was not diagnosed in children of the follow-up groups, but patients with moderate oral mucosa hyperemia in the main group were in 2.22 times less than in the comparison ones (5.0% vs 11.11%, respectively). Minor swelling and exudation on the 7th day of observation were found only in children of the comparison group. Oral hygiene at the time of completion of treatment in all children was within satisfactory values. Analysis of the periodontal index of PMA showed the presence of catarrhal gingivitis in a third of children of both observation groups. Thus, the obtained results of clinical indicators of the state of the oral cavity of children indicate the effectiveness of our proposed method of treatment of acute purulent periostitis in children, which is confirmed by the stabilization of microvascular circulation, namely a decrease in the phenomena of edema and exudation. Due to local immunocorrective action, wound healing conditions are also improved and postoperative complications are prevented. Keywords: acute odontogenic periostitis, children, thyroid disease, Imupret, Calcemin advance.