Profiling of antioxidant properties and identification of potential analgesic inhibitory activities of Allophylus villosus and Mycetia sinensis employing in vivo, in vitro, and computational techniques.

ETHNOPHARMACOLOGICAL RELEVANCE: The traditional use of plants for medicinal purposes, called phytomedicine, has been known to provide relief from pain. In Bangladesh, the Chakma indigenous community has been using Allophylus villosus and Mycetia sinensis to treat various types of pain and inflammation. AIM OF THE STUDY: The object of this research is to evaluate the effectiveness of these plants in relieving pain and their antioxidant properties using various approaches such as in vitro, in vivo, and computational techniques. Additionally, the investigation will also analyse the phytochemicals present in these plants. MATERIALS AND METHODS: We conducted in vivo analgesic experiment on Swiss albino mice and in-silico inhibitory activities on COX-2 & 15-LOX-2 enzymes. Assessment of DPPH, Anti Radical Activities (ARA), FRAP, H2O2 Free Radical Scavenging, Reducing the power of both plants performed significant % inhibition with tolerable IC50. Qualitative screening of functional groups of phytochemicals was précised by FTIR and GC-MS analysis demonstrated phytochemical investigations. RESULTS: The ethyl acetate (EtOAc) fractioned Mycetia sinensis extract as well as the ethanoic extract and all fractioned extracts of Allophylus villosus have reported a significant percentage (%) of writhing inhibition (p < 0.05) with the concentrated doses 250 mg as well as 500 mg among the Swiss albino mice for writhing observation of analgesic effect. In the silico observation, a molecular-docking investigation has performed according to GC-MS generated 43 phyto-compounds of both plants to screen their binding affinity by targeting COX-2 and 15-LOX-2 enzymes. Consequently, in order to assess and ascertain the effectiveness of the sorted phytocompounds, ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) investigation, DFT (Density-functional theory) by QM (Quantum mechanics), and MDS (Molecular dynamics simulation) were carried out. As the outcome, compounds like 5-(2,4-ditert-butylphenoxy)-5-oxopentanoic acid; 2,4-ditert-butylphenyl 5-hydroxypentanoate; 3,3-diphenyl-5-methyl-3H-pyrazole; 2-O-(6-methylheptan-2-yl) 1-O-octyl benzene-1,2-dicarboxylate and dioctan-3-yl benzene-1,2-dicarboxylate derived from the ethnic plant A. villosus and another ethnic plant M. sinensis extracts enchants magnificent analgesic inhibitions and performed more significant drug like activities with the targeted enzymes. CONCLUSIONS: Phytocompounds from A. villosus & M. sinensis exhibited potential antagonist activity against human 15-lipoxygenase-2 and cyclooxygenase-2 proteins. The effective ester compounds from these plants performed more potential anti-nociceptive activity which could be used as a drug in future.

Steroidal Anti-Inflammatory Drugs for Oral Surgery: A Systematic Review and Meta-Analysis.

Objectives: The aim of the present study was to investigate if there are differences in mitigation acute pain following oral surgery procedures within a hospital setting and regarding various medication regimens. Materials and methods: A systematic literature search was performed between the years 2013 and 2023, including the databases PUBMED, Cochrane and Scopus, to identify the clinical trials investigating the prescription of non-steroidal (NSAID's) anti-inflammatory drugs before or after an oral surgery. A meta-analysis with meta-regression model was employed on the primary and secondary outcomes, such as pain, swelling and trismus. Results: Thirty-six articles were included, 6 of them being retrospective and 30 prospective, with a higher proportion of women than men, at a ratio of 1.34:1 and an average age of 31.9 years. Drugs with medium duration of action demonstrated lower values for pain and swelling. Regarding these parameters, pain and swelling, propionic acid derivatives and acetic acid derivatives exhibited lower values respectively. Conclusions: The quality of evidence was low to very low- certainty. The meta-analysis suggests that postoperative pain, swelling and trismus following oral surgery management may be effectively treated with the following drugs: NSAID medium-duration action drugs; propionic acid derivatives for lower pain levels and acetic acid derivatives for lower swelling measures; and Ibuprofen 400mg every 8h for 3 days or less. Clinical Relevance: Anti-inflammatory and analgesic drugs are prescribed to prevent or treat dental pain. Ibuprofen 400mg was the most prescribed drug after or before an oral surgery procedure. However, the evidence is indirect and needs to be interpreted with caution.

A Novel Cortex Phellodendri Chinensis-Based Carbon Dots Platform for Remarkable Analgesia for Clinical Pain Management.

In this study, we explored the eco-friendly synthesis of photoluminescent CCDs employing a direct one-step pyrolysis process, utilizing natural Cortex Phellodendri Chinensis as the precursor material and studied their analgesic effect in mice. The synthesized carbon dots underwent comprehensive characterization through a range of spectroscopic and microscopic techniques. These included UV-Vis, FTIR, fluorescence spectroscopy and HR-TEM, DLS instruments. HR-TEM results exhibited the presence of homogenous spherical-shaped C-dots of about 3.3 nm without aggregates. Furthermore, the prepared CCDs were studied for their in vivo analgesic effect in mice by performing tail-immersion, hot plate and acetic acid writhing tests. Also, an MTT assay was performed to assess the in vitro cytotoxicity of CCDs against L929 cells. In vitro cytotoxicity studies revealed that L929 cells exhibited higher cell viability when treated with prepared CCDs. The cellular uptake studies revealed the phase contrast images of MG-63 cells at wavelength 488 nm clearly depicted the aggregation of green, fluorescent CCDs within the cells while leaving nuclei unobscured. In addition, to the best of our understanding, the results presented in this paper showed that CCDs exhibited an important analgesic effect and enhanced anti-nociceptive activity, which may be due to stimulation of the opioidergic system. Consequently, CCDs appear to be a viable analgesic alternative for traditional analgesic candidates in pain management.

In vivo and in silico antihypertensive, anti-inflammatory, and analgesic activities of Vernonia amygdalina Del. leaf extracts.

Vernonia amygdalina (VA) leaves contain many potential active ingredients and exhibit diverse pharmacological activities. The antihypertensive, anti-inflammatory, and analgesic effects of VA crude and fraction extracts were carried out using Swiss albino mice models. VAE is considered safe to be administered due to LD50 being greater than 10,000 mg/kg body weight. A dose-dependent increase in antihypertensive, anti-inflammatory, and analgesic activities was observed in both VAE and fractions, similar to the reference drugs. The antihypertensive effect of the VAE 2.0 (2000 mg/kg, SBP: ↓26.05 %, DBP: ↓34.51 %) was nearly equivalent to Captopril (100 mg/kg, SBP: ↓30.28 %, DBP: ↓40.71 %) with no statistically significant difference (p > 0.05). The VAE 1.0 (1000 mg/kg), and EA 30 (30 mg/kg) showed potent anti-inflammatory activity when reducing the total edematous paw volume significantly (p < 0.01) by ↓65.58 %, and ↓69.34 %, respectively, similar to Ibuprofen (7.5 mg/kg, ↓67.03 %). Besides, VAE (>500 mg/kg), and W 400 (water, 400 mg/kg) fraction extracts showed a potent analgesic effect equivalent to Para 50 (paracetamol 50 mg/kg) for the highest protection (>65 %) against the acetic acid-induced writhing after 35 min. Moreover, cepharanthine, cynaroside, and vernoniosides of VA leaf extract exhibited the highest affinity (>10 kcal/mol) in anti-inflammatory and analgesic targets (iNOS and COX-2) and antihypertensive targets (ACE and ß1 adrenoreceptor). Therefore, the crude and fraction extracts of VA leaves from the percolation method and bioactive metabolites are a potential source that can be developed into antihypertensive, anti-inflammatory, and analgesic agents in herbal medicine.

Discovery of glycosidated glycyrrhetinic acid derivatives: Natural product-based soluble epoxide hydrolase inhibitors.

There are few reports on soluble epoxide hydrolase (sEH) structure-activity relationship studies using natural product-based scaffolds. In this study, we discovered that C-30 urea derivatives of glycyrrhetinic acid such as 33, rather than C-20/C-3 urea derivatives, possess in vitro sEH inhibitory capabilities. Furthermore, we explored the impact of stereoconfigurations at C-3 and C-18 positions, and glycosidic bonds at the 3-OH on the compound's activity. Consequently, a glycoside of 33, specifically 49Cα containing alpha-oriented mannose, exhibited promising in vivo efficacy in alleviating carrageenan-induced paw edema and acetic acid-induced writhing. Meanwhile, 49Cα demonstrated potential in mitigating acute pancreatitis by modulating the ratios of anti-inflammatory epoxyeicosatrienoic acids (EETs) to pro-inflammatory dihydroxyeicosatrienoic acids (DHETs). The co-crystal structure of sEH in complex with 49Cα revealed that the N-tetrahydropyranylmethylene urea hydrogen bonded with the residues within the sEH tunnel, contrasting with the mannose component that extended beyond the tunnel's confines. Our findings highlight 49Cα (coded LQ-38) as a promising candidate for anti-inflammatory and analgesic effects, and pave the way for the future rational design of triterpenoid-based sEH inhibitors.

Trends and hospital practice variation for analgesia for children with sickle cell disease with vaso-occlusive pain episodes: An 11-year analysis.

This cross-sectional analysis of 86,111 visits for sickle cell disease and vaso-occlusive episodes (VOE) in U.S. pediatric emergency departments between 2013 and 2023 shows increased use of NSAIDs, ketamine, and acetaminophen, with unchanged opioid use. Hospitals with a higher volume of VOE visits more frequently administered opioids. BACKGROUND: Vaso-occlusive episodes (VOEs) are a hallmark of sickle cell disease (SCD), leading to frequent emergency department (ED) visits. Effective pain management is crucial, with guidelines recommending routine use of non-steroidal anti-inflammatory drugs (NSAIDs) with opioids, and emerging evidence supporting ketamine use. However, these recommendations are based on low-certainty evidence, and the impact of these guidelines on analgesia use over time remains unclear. OBJECTIVE: This study aimed to analyze trends in analgesia use over an 11-year period in pediatric SCD patients presenting to U.S. EDs with VOE and assess variations in treatment across hospitals. METHODS: A cross-sectional study was conducted using data from the Pediatric Health Information System covering 34 U.S. children's hospitals from January 1, 2013, to December 31, 2023. The primary outcomes were the proportions of visits where opioids, NSAIDs, acetaminophen, and/or ketamine were administered on the first calendar day of the initial visit. Secondary outcomes included the co-administration of NSAIDs with opioids. Logistic and linear regression models were used to assess trends and hospital-level variations. RESULTS: A total of 86,111 ED visits for VOE were analyzed. Opioids were administered in 82 % of encounters, NSAIDs in 72 %, acetaminophen in 17 %, and ketamine in 1 %. Co-administration of NSAIDs with opioids occurred in 59 % of the visits. Among discharged patients, there was a positive trend for NSAID use (slope: 1.68 %/year, 95 % CI: 0.91 %, 2.45 %) and NSAID-opioid co-administration (slope: 1.03 %/year, 95 % CI: 0.37 %, 1.69 %) over time. Acetaminophen use also increased over the study period (slope: 0.99 %/year, 95 % CI: 0.80 %, 1.17 %). In hospitalized patients, there was a significant upward trend for acetaminophen (slope: 1.29 %/year, 95 % CI: 0.69 %, 1.89 %) and ketamine (slope: 0.36 %/year, 95 % CI: 0.27 %, 0.45 %), while opioid use remained unchanged. Significant hospital-level variations were observed, with larger hospitals more likely to administer opioids but less likely to co-administer NSAIDs with opioids compared to medium-volume hospitals. CONCLUSION: Over the past decade, the use of NSAIDs, acetaminophen, and ketamine has increased in the management of VOE in pediatric SCD patients, while opioid use remains consistent. The co-administration of NSAIDs and opioids has also increased, reflecting guideline adherence. Variations in analgesia practices across hospitals underscore the need for standardizing pain management strategies in this population.

Ultrasound-Guided Erector Spinae Plane Block in Elderly Patients Undergoing Total Hip Arthroplasty (THA): A Triple-blind, Randomized, Controlled Trial.

BACKGROUND: Total hip arthroplasty (THA) induces postoperative pain in elderly individuals. The erector spinae plane block (ESPB) is a novel analgesic approach for postoperative pain control. This randomized controlled trial evaluated the effectiveness of ultrasound-guided ESPB with ropivacaine in reducing pain in elderly patients undergoing THA METHODS: Patients aged 60 to 80 years who had an American society of Aneshesiologists (ASA) physical status I to III were eligible for this study. There were 50 patients who were randomized into two groups: the ESPB group receiving ultrasound-guided ESPB with ropivacaine, and the control group receiving ESPB with normal saline. All patients underwent general anesthesia, and the mean arterial pressure (MAP), heart rate (HR), intraoperative opioid consumption, numerical rating scale (NRS) scores, and postoperative adverse reactions were recorded throughout the perioperative period. RESULTS: A significant reduction in NRS scores was observed in the ESPB group compared to the control group at various time points, including in the recovery room and at 12 and 24 hours postoperatively (P < 0.05). When the observation period was extended to 48 hours, no significant difference in NRS scores was noted between the two groups (P > 0.05). No significant differences in MAP and HR were found between the two groups, but the ESPB group showed lower coefficients of variation (CV) for both MAP and HR. Moreover, the ESPB group demonstrated a significantly lower total remifentanil consumption than the control group. There was no significant difference in complications between these two groups (P < 0.05). CONCLUSIONS: Ultrasound-guided ESPB enhances the perioperative stability of mean arterial pressure and heart rate, providing effective analgesia within the initial 24 hours post-surgery, thereby reducing opioid requirements and improving overall postoperative recovery quality for elderly THA patients.

Inhibitory Effects of Reynoutria japonica Houtt. on Pain and Cartilage Breakdown in Osteoarthritis Based on Its Multifaceted Anti-Inflammatory Activity: An In Vivo and In Vitro Approach.

In the past 30 years, the number of years lived with disability due to osteoarthritis (OA) has doubled, making it an increasing global health burden. To address this issue, interventions that inhibit the progressive pathology driven by age-related low-grade inflammation, the primary mechanism of OA, are being actively pursued. Recent investigations have focused on modulating the age-related low-grade inflammatory pathology of this disease as a therapeutic target. However, no agent has successfully halted the disease's progression or reversed its irreversible course. Reynoutria japonica Houtt. (RJ), a promising East Asian herbal medicine, has been utilized for several diseases due to its potent anti-inflammatory activity. This study aims to determine RJ's capacity to inhibit OA symptoms and associated inflammation, exploring its potential for further development. In vivo and in vitro experiments demonstrated RJ's anti-OA activity and modulation of multifaceted inflammatory targets. RJ significantly inhibited pain, gait deterioration, and cartilage destruction in a monosodium iodoacetate-induced OA rat model, with its analgesic effect further confirmed in an acetic acid-induced writhing model. RJ exhibited consistent anti-inflammatory activity against multiple targets in serum and cartilage of the OA rat model and lipopolysaccharide-induced RAW 264.7 cells. The inhibition of inflammatory cytokines, including interleukin-1ß, interleukin-6, matrix metalloproteinase-13, tumor necrosis factor-α, and nitric oxide synthase 2, suggests that RJ's alleviation of OA manifestations relates to its multifaceted anti-inflammatory activity. These results indicate that RJ merits further investigation as a disease-modifying drug candidate targeting OA's inflammatory pathology. To further characterize the pharmacological properties of RJ, future studies with expanded designs are warranted.

Exploring the therapeutic potential of Saudi Kleinia anteuphorbium (L.) DC. Essential oil: Insights into antioxidant, analgesic, and hepatorenal protective effects.

Lately, the herb's essential oils have received the intense attention of researchers and pharmaceutical agencies. The chemical composition, antioxidant, analgesic activity, anti-hyperpyrexia, and hepatorenal protective effects of the Kleinia anteuphorbium (L.) DC. Essential oil (KAEO) were evaluated. The KAEO was yanked by steam distillation and subjected to a GC/MS system. The antioxidant powers of KAEO were evaluated by DPPH, NO, and FRAP tests. Besides the anti-hyperpyrexia, the analgesic effects were assessed. Moreover, the hepatorenal curative effects were evaluated in a carbon tetrachloride-rat model. Sixty-eight active components were identified by GC/MS. α-pinene was the most dominant monoterpene in KAEO. KAEO showed anti-hyperpyrexia, anti-captive, and great antioxidant powers through DPPH, NO, and FRAP. The oral LD50 of KAEO was 187.5 mg/kg in rats. Furthermore, KAEO treatment succeeded in reliving the adverse effects of CCL4 in rats as a standard toxic model through reliving the hepatic pathological and oxidative stress and restoring the hepatic and renal functions. Overall, the obtained results demonstrated that KAEO might be used as a potential natural medicine to relieve a variety of modern symptoms and hepatorenal disorders associated with oxidative stress.

Comparison of ultrasound-guided erector spinae plane block versus transmuscular quadratus lumborum block for postoperative analgesia after caesarean delivery: A prospective randomized non-inferiority clinical trial.

Background and Aims: Regional techniques are a part of multimodal analgesia following cesarean delivery. Cesarean delivery warrants a regional technique, which can provide somatic and visceral analgesia-like quadratus lumborum block (QLB) and erector spinae plane block (ESPB). In this study, we investigated the non-inferiority of ESPB at T12 and transmuscular-QLB (TQLB) at L2-L3 for postoperative analgesia in cesarean delivery. Material and Methods: In this prospective, randomized, non-inferiority trial, 124 patients undergoing cesarean delivery were enrolled to receive bilateral TQLB or ESPB with 20 mL of 0.25% ropivacaine on each side. All patients received prophylactic acetaminophen and ketorolac for 2 days. Our primary objective was to compare the total tramadol consumption in the first 48 h between the two groups. Secondary objectives were to compare cumulative tramadol consumption, postoperative Numeric Rating Scale (NRS) score at rest, and with movement at various time points, the time for first rescue analgesic requirement, development of complications related to the block, and patient satisfaction with analgesia between the two groups. Results: The total tramadol consumption in 48 h (47.3 ± 34.9 mg in ESPB and 50.9 ± 38.7 mg in TQLB), duration of first rescue analgesic (22.8 ± 15.8 h in ESPB and 22.7 ± 15.6 h in TQLB), and patient satisfaction were similar between the two groups. Both groups had similar pain scores except at rest at 6 h and on movement at 4 h, 6 h, and 36 h, whereas the ESPB group had lower NRS scores (P < 0.05). Conclusion: The analgesic effect of bilateral ESPB at T12 was non-inferior to that of bilateral TQLB post-caesarean delivery.

Effects of the WHO analgesic ladder on pain severity, pain interference, and blood pressure control in hypertensive patients with chronic musculoskeletal pain: a cross-sectional study.

AIM: This study aimed to investigate the effects of pain management according to the World Health Organization (WHO) analgesic ladder on pain severity, pain interference, and blood pressure (BP) in treated hypertensive patients with chronic musculoskeletal pain. BACKGROUND: Pain management can affect BP control owing to the proposed mechanism by which persistent pain contributes to increased BP. However, there are inadequate studies investigating the benefit of pain management in controlling both pain and BP in hypertensive patients who have chronic pain. METHODS: In this cross-sectional study, demographic data and pain characteristics (resting pain score on the numerical pain rating scale, pain severity, and pain interference subscale of the Brief Pain Inventory) were collected via face-to-face interviews. BP was measured thrice on the same day. Data on pain medications taken in the previous 1 month were retrieved from the medical records. Participants were categorized into three groups following pain management patterns according to the WHO analgesic ladder: no, partial, and complete treatment. Multivariate logistic regression analysis (MLRA) was used to analyse the association between the variables and uncontrolled BP. FINDINGS: Among 210 participants, the mean (standard deviation) age was 68 (15.5) years, and 60.47% had uncontrolled BP. The resting pain score, pain severity, and pain interference subscale scores of the complete treatment group were significantly lower than that of the partial treatment group (P = 0.036, 0.026, and 0.044, respectively). The MLRA revealed that pain management patterns were associated with uncontrolled BP (adjusted odds ratio [AOR]: 6.75; 95% confidence interval [CI]: 2.71-16.78; P < 0.001) and resting pain scores (AOR: 1.17; 95% CI: 1.04-1.38; P = 0.048). Our findings suggest that pain management patterns adhering to the WHO analgesic ladder can reduce pain severity and pain interference and also control BP in hypertensive patients with chronic musculoskeletal pain.

Making Sense of Topical Pain Relief Options: Comparing Topical Analgesics in Efficacy and Safety.

CONTEXT: In patients with musculoskeletal (MSK) conditions, pain is the leading contributor to disability and significantly limits mobility and dexterity. This narrative review describes the efficacy and safety of topical analgesics in common use today. EVIDENCE ACQUISITION: Secondary literature gained via a literature search using PubMed.gov and the Cochrane library were used. STUDY DESIGN: Recent literature (2000-2023) on several major classes of topical analgesics and topical delivery systems were reviewed to provide strength of recommendation taxonomy (SORT) levels. A total of 86 articles were reviewed. LEVEL OF EVIDENCE: Level 2. RESULTS: Topical nonsteroidal anti-inflammatory drugs (NSAIDs) and cabbage leaf wraps (CLW) appear to be best suited for multiple types of acute MSK pain, and topical nitroglycerin is helpful when used specifically for rotator cuff pain in patients seeking relief while performing activities of daily living and willing to treat for long periods of time. For compounded topical formulations, it may be better to offer single agent creams based on patient preferences. Little data support the use of cryotherapy. Traumeel could be a promising natural analgesic that compares with diclofenac. Topical lidocaine appears best suited for postherpetic neuropathic pain. O24 is a reasonable alternative with a low risk profile to treat pain in patients with fibromyalgia syndrome. CONCLUSION: Choice of topical agents should be guided by current evidence accounting for type of pain, medication side effects, patient comorbidities, as well as patient preference, convenience, and cost. STRENGTH-OF-RECOMMENDATION TAXONOMY (SORT): Of the topical analgesics and modalities reviewed, SORT level A evidence was found for topical NSAID use in decreasing MSK pain, topical lidocaine for postherpetic neuralgia, and nitroglycerin patches for treating rotator cuff pain if used for prolonged periods of time. Alternative treatments such as CLW and Traumeel show promising results (SORT level B).

Assessing a "Least-Concern" Red List Tree Species from Madagascar Used in Traditional Medicine: Morella spathulata (Myricaceae) Phyto-Compounds and Anti-Inflammatory Properties.

Morella spathulata (Myricaceae family) is a common plant from Madagascar and is present on the IUCN Red List of threatened species classified at the 'least concern' level, used by the local population to treat numerous illnesses and pain. Despite its frequent use, comprehensive phytochemical and pharmacological research on the species is limited. This study evaluated the antioxidant, analgesic, and anti-inflammatory properties, as well as the toxicity of methanol extracts from the leaves (MS_L) and bark (MS_B) of M. spathulata. The research involved the analysis of nutritional traits such as sugars, organic acids, vitamin C, polyphenolic content (TPC) and the main phytochemicals by HPLC analysis. Antioxidant capacity was assessed through DPPH and FRAP assays. Analgesic and anti-inflammatory activities were evaluated using acetic acid-induced writhing and carrageenan-induced paw oedema tests in mice. The results showed a high content of phenolic and bioactive components in the leaf and bark extracts, associated with antioxidant, analgesic and anti-inflammatory properties. The interaction of key compounds such as ferulic acid and ellagic acid with proteins involved in pH regulation and immune modulation provides clues to the mechanisms underlying the therapeutic effects. However, conservation efforts are crucial due to habitat loss and illegal logging, and further studies are needed to fully explore the plant's therapeutic potential.

Design, synthesis, and biological evaluation of novel imidazole derivatives as analgesic and anti-inflammatory agents: experimental and molecular docking insights.

Imidazole moieties exhibit a broad range of biological activities, including analgesic, anti-depressant, anticancer, anti-fungal, anti-tubercular, anti-inflammatory, antimicrobial, antiviral, and antifungal properties. In this study, we explored the use of Schiff base for the synthesis of new imidazole derivatives as anti-inflammatory and pain-relieving agents. A series of eight novel imidazole analogues (2a-h) were prepared in three steps with excellent yields. All compounds were characterized using IR, NMR, and mass spectral data. Their analgesic and anti-inflammatory activities were evaluated using hot plate and paw oedema methods. Compound 2 g (1-(2,3-dichlorophenyl)-2-(3-nitrophenyl)-4,5-diphenyl-1H-imidazole) showed significant analgesic activity (89% at 100 mg/kg b.w.), while compounds 2a (2-(2,6-dichlorophenyl)-1-(4-ethoxyphenyl)-4,5-diphenyl-1H-imidazole) and 2b (2-(2,3-dichlorophenyl)-1-(2-chlorophenyl)-4,5-diphenyl-1H-imidazole) exhibited good anti-inflammatory activity (100% at 100 mg/kg b.w.), comparable to diclofenac salt (100% at 50 mg/kg b.w.). Molecular docking studies were conducted using Schrödinger software version 2021-2, employing the OPLS4 force field for both receptor and ligand preparation. The results were visualized using molecular visualization software such as PyMOL. These studies revealed that compound 2g exhibited the highest binding affinity with the COX-2 receptor (-5.516 kcal/mol). Compound 2g formed three conventional hydrogen bonds with residues GLN-242 (bond length: 2.3 Å) and ARG-343 (bond lengths: 2.2 Å & 2.4 Å). This binding affinity was comparable to that of Diclofenac salt, which showed the highest binding affinity of -5.627 kcal/mol with the COX-2 receptor. Diclofenac salt formed two conventional hydrogen bonds with the residues ARG-344 (bond length: 2.0 Å) and TRP-140 (bond length: 1.7 Å). Later, molecular dynamic simulations confirmed the stable binding affinity of compound 2g with the protein. Furthermore, other compounds also demonstrated potential binding to the receptor-binding pocket region. The anti-inflammatory potential of the synthesized compounds was evaluated using the carrageenan-induced rat hind paw oedema model, while the analgesic potential was assessed using the hot plate method. These evaluations were conducted in comparison with Diclofenac sodium, serving as the standard compound. However, compound 2g stood out for its superior analgesic activity, as confirmed by in-vivo examination. These findings suggest that these novel imidazole derivatives have potential as anti-inflammatory and analgesic agents.

Electroacupuncture Relieves Neuropathic Pain via Adenosine 3 Receptor Activation in the Spinal Cord Dorsal Horn of Mice.

Neuropathic pain (NPP) is a devastating and unbearable painful condition. As prevailing treatment strategies have failed to mitigate its complications, there remains a demand for effective therapies. Electroacupuncture (EA) has proved a potent remedial strategy in NPP management in humans and mammals. However, past studies have investigated the underlying mechanism of the analgesic effects of EA on NPP, focusing primarily on adenosine receptors in peripheral tissues. Herein, we elucidate the role of the adenosine (Adora-3) signaling pathway in mediating pain relief through EA in the central nervous system, which is obscure in the literature and needs exploration. Specific pathogen-free (SPF) male adult mice (C57BL/6 J) were utilized to investigate the effect of EA on adenosine metabolism (CD73, ADA) and its receptor activation (Adora-3), as potential mechanisms to mitigate NPP in the central nervous system. NPP was induced via spared nerve injury (SNI). EA treatment was administered seven times post-SNI surgery, and lumber (L4-L6) spinal cord was collected to determine the molecular expression of mRNA and protein levels. In the spinal cord of mice, following EA application, the expression results revealed that EA upregulated (p < 0.05) Adora-3 and CD73 by inhibiting ADA expression. In addition, EA triggered the release of adenosine (ADO), which modulated the nociceptive responses and enhanced neuronal activation. Meanwhile, the interplay between ADO levels and EA-induced antinociception, using an Adora-3 agonist and antagonist, showed that the Adora-3 agonist IB-MECA significantly increased (p < 0.05) nociceptive thresholds and expression levels. In contrast, the antagonist MRS1523 exacerbated neuropathic pain. Furthermore, an upregulated effect of EA on Adora-3 expression was inferred when the Adora-3 antagonist was administered, and the EA treatment increased the fluorescent intensity of Adora-3 in the spinal cord. Taken together, EA effectively modulates NPP by regulating the Adora-3 signaling pathway under induced pain conditions. These findings enhance our understanding of NPP management and offer potential avenues for innovative therapeutic interventions.

Fentanyl: New Wave, New Age, New Addiction?

This paper aims to take over the rampant phenomenon of the illicit use/abuse for volutary purposes of fentanyl. This synthetic drug is normally used as a potent anaesthetic and analgesic molecule. Unfortunately, in recent decades, this substance has conquered and seduced millions of people in the 'westernised' world, claiming numerous victims, especially young people. To this end, the most recent scientific literature will be examined and the pharmacological effects of both therapeutic and intentional abuse will be considered. Finally, the consequences and psychosocial damage produced will be described.

Analgesic effects of intraarticular anaesthetic lidocaine and methylprednisolone versus methylprednisolone alone following knee arthroscopy.

Background: Knee arthroscopy is a widely practiced orthopaedic procedure known for its minimally invasive approach, allowing quicker recovery times and less postoperative discomfort than traditional open surgeries. However, managing postoperative pain remains a critical aspect of patient care and satisfaction. The main objective of this research is to examine the relationships between patient demographics (age, gender, BMI) and early postoperative outcomes, including pain, physiotherapy, and walking. Method: Randomized data collection, clinical trial study of 2 groups of patients. The patients were split into lidocaine 1 % 16 ml + methylprednisolone 160 mg 4 ml) and (methylprednisolone only 160 mg 4 ml) groups. All patients in both groups were queried about age, gender, BMI, and pain on the first, third, and 15th days following surgery. All patients were tested for physiotherapy on the second, third, and fourth postop days. After surgery, walking was tested on the third, fourth, and fifth days. Results: Significant differences in postoperative pain relief and physiotherapy initiation times were observed. There are notable associations between treatment groups and recovery metrics, such as pain levels and mobility on various days' post-surgery. Significant demographic influences (age, gender, BMI) on recovery outcomes are observed, particularly in walking and pain at day 15 post-operation. Conclusion: lidocaine and methylprednisolone improve postoperative pain relief and functional recovery in knee arthroscopy patients, with most experiencing reduced pain early post-surgery (early physiotherapy) and an expedited return to walking (decreased morbidity). Patients taking just methylprednisolone recovered slower. Age, gender, and BMI affected pain and walking abilities post-operation but not physiotherapy time, underscoring the personalised approach needed in postoperative treatment.

Updated Meta-analysis Reveals Limited Efficacy of Vitamin D Supplementation in Chronic Low Back Pain.

BACKGROUND/AIM: Chronic low back pain (CLBP) significantly reduces quality of life and increases reliance on healthcare resources. Despite many individuals opting for vitamin D supplementation to alleviate CLBP, its efficacy remains debatable. This meta-analysis aimed to evaluate the potential benefits of vitamin D supplementation in treating this condition. PATIENTS AND METHODS: Adhering to PRISMA guidelines, we systematically reviewed the effectiveness of vitamin D supplementation in adults with CLBP, focusing exclusively on randomized controlled trials (RCTs). A comprehensive literature search was conducted up to May 2024 across multiple databases, including PubMed, Scopus, Cochrane Library, and Web of Science. RESULTS: Ten RCTs meeting our inclusion criteria were analyzed. The results indicated that vitamin D supplementation did not significantly reduce pain scores compared to control groups (SMD: -0.130, 95%CI=-0.260 to 0.000; I2=0%), regardless of participants' baseline vitamin D levels. Moreover, long-term supplementation showed no notable improvement in CLBP outcomes (SMD: -0.097, 95%CI=-0.290 to -0.097; I2=19.878%). Additionally, supplementation with active forms of vitamin D (SMD: -0.321, 95%CI=-0.670 to 0.028; I2=0.000%) did not result in significant pain relief for chronic lower back pain. CONCLUSION: Vitamin D supplementation does not substantially alleviate CLBP. Nevertheless, it may still be considered as part of a comprehensive treatment plan. Further research is necessary to explore its long-term effects and the underlying mechanisms that may explain the observed lack of benefit.

Glycine Transporter 1 Inhibitors Minimize the Analgesic Tolerance to Morphine.

Opioid analgesic tolerance (OAT), among other central side effects, limits opioids' indispensable clinical use for managing chronic pain. Therefore, there is an existing unmet medical need to prevent OAT. Extrasynaptic N-methyl D-aspartate receptors (NMDARs) containing GluN2B subunit blockers delay OAT, indicating the involvement of glutamate in OAT. Glycine acts as a co-agonist on NMDARs, and glycine transporters (GlyTs), particularly GlyT-1 inhibitors, could affect the NMDAR pathways related to OAT. Chronic subcutaneous treatments with morphine and NFPS, a GlyT-1 inhibitor, reduced morphine antinociceptive tolerance (MAT) in the rat tail-flick assay, a thermal pain model. In spinal tissues of rats treated with a morphine-NFPS combination, NFPS alone, or vehicle-comparable changes in µ-opioid receptor activation, protein and mRNA expressions were seen. Yet, no changes were observed in GluN2B mRNA levels. An increase was observed in glycine and glutamate contents of cerebrospinal fluids from animals treated with a morphine-NFPS combination and morphine, respectively. Finally, GlyT-1 inhibitors are likely to delay MAT by mechanisms relying on NMDARs functioning rather than an increase in opioid efficacy. This study, to the best of our knowledge, shows for the first time the impact of GlyT-1 inhibitors on MAT. Nevertheless, future studies are required to decipher the exact mechanisms.

Discovery of cyanoguanidine derivatives as biased µ-opioid receptor agonists.

Opioid agonists, including morphine and its derivatives, have historically been utilized in conventional pain relief therapies. However, the morphine-like side effects associated with these compounds have constrained their broader application in clinical environments. Fortunately, novel compounds that selectively activate µ-opioid receptors (MOR) without activating the ß-arrestin2 pathway, such as PZM21 and TRV130, demonstrate the potential to mitigate side effects while maintaining analgesic efficacy. In this study, we structurally modified PZM21 to get a series of compounds with a 2-cyanoguanidine scaffold, the majority of which display significant analgesic effects. Notably, Compound I-11 exhibited an analgesic effect comparable to that of morphine and selectively activates µ-opioid receptors while avoiding the activation of the ß-arrestin2 pathway. Our work not only introduces a novel biased µ-opioid receptor agonist but also serves as a valuable reference for the further optimization of PZM21.