An important sensation that warns of potential harm to a specific area of the body is pain. The prevalence of pain-related conditions globally is a significant and growing public health issue. Chronic pain affects an estimated 1.5 billion people worldwide, with prevalence rates varying by region and demographic factors. Along with diabetes, cardiovascular disease, and cancer, pain is among the most frequent medical diseases. Opioid analgesics are the mainstay of current pain therapies, which are ineffective. Opioid addiction and its potentially fatal side effects necessitate novel treatment strategies. Nanotechnology offers potential advantages in pain management by enabling targeted drug delivery, which can enhance the efficacy and reduce the side effects of analgesic medications. Additionally, nanoparticles can be designed to release drugs in a controlled manner, improving pain relief duration and consistency. This approach also allows for the delivery of therapeutics across biological barriers, potentially enhancing treatment outcomes for chronic pain conditions. Nanomedicine enables sensitive and focused treatments with fewer side effects than existing clinical pain medicines; it is worth exploring as a potential solution to these problems. Furthermore, medication delivery systems that use nanomaterials are being used to treat pain. Whether it\'s the distribution of a single medication or a combination of therapies, this review seeks to summarise the ways in which drug delivery systems based on nanomaterials can be utilised to successfully treat and alleviate pain. For the purpose of writing this paper, we consulted several online libraries, including Pubmed, Science Direct, Pubmed Prime, and the Cochrane Library, to gather fresh and up-to-date material. This overview delves into the ins and outs of pain\'s pathophysiology, the present state of pain treatment, potential new pain treatment targets, and the various initiatives that have been launched and are still in the works to address pain with nanotechnology. Recent developments in nanomaterials-based scavenging, gene therapy for pain aetiology, and nanoparticle-based medicine delivery for side effect reduction are highlighted. Analgesics have been further covered in our discussion on FDA-approved pharmaceuticals and clinical advancements.

BACKGROUND: Neuropathic pain is a complex chronic condition resulting from the damage or dysfunction of the nervous system. Conventional therapies offer limited success and often come with various adverse effects. Therefore, the exploration of alternative therapies, such as phytoconstituents, may be of substantial interest for their potential to alleviate neuropathic pain.
OBJECTIVE: This review systematically examines the diverse roles and mechanisms of various phytoconstituents in modulating neuropathic pain. In this study, a comprehensive analysis of phytoconstituents in neuropathic pain is carried out to understand their mechanism in preventing the disease.
METHODS: The current search is done in the databases of Google Scholar, PubMed Central, ScienceDirect, and Scopus using the keywords: neuropathic pain, phytoconstituents as analgesics, physiological effects of medicinal plants, and natural products, to find the most relevant articles of the last 10 years.
RESULTS: Out of 125 articles, 112 were included in this study, which revealed that several phytoconstituents inhibit several biomarkers responsible for neuropathic pain. Moreover, this review highlights the underlying molecular pathways and targets through which these bioactive compounds exert their therapeutic effects, emphasizing their potential as novel pharmacological agents.
CONCLUSIONS: This study concludes that phytoconstituents may possess potential applications in managing neuropathic pain and could be effectively used as an alternative approach to mitigate the condition with enhanced risk of safety and tolerability.

OBJECTIVE: Pain is a common symptom following proximal femoral fractures (PFF), however, information on its treatment in terms of agents and type of use (scheduled vs. pro re nata [PRN]) is scarce. The main objective of this study was to examine pain medication regimens according to pain intensity following PFF. Furthermore, we explored the utilization of medication plans.
METHODS: The \"ProFem\"-study on healthcare provision, functional ability, and quality of life after PFF is a German population-based prospective cohort study based on statutory health insurance data and individually linked survey data from different time points including information on the currently used medication. This present analysis refers to the participants\' baseline interviews (about 3 months following PFF) conducted from 2018 to 2019 in the participants\' private surroundings.
RESULTS: The study population comprised 444 participants (mean age: 81.2 years, 71.0% female). Half of them reported high intensity pain, and the mean value for the EuroQol visual analogue scale was 50.8. Most commonly used analgesics were metamizole and tilidine/naloxone. Among participants with high intensity pain, 21.9% received only PRN pain medication and 17.2% no pain medication at all. Overall, 61.5% of participants presented any (printed) medication plan and only 25.2% a \"federal standardized medication plan\" (BMP).
CONCLUSIONS: As a substantial number of patients reports high intensity pain about 3 months following a PFF, the large proportion of those receiving no or only PRN pain medication raises questions regarding the appropriateness of the therapy. The overall low utilization of the BMP indicates potential for improvement.

UNASSIGNED: Buprenorphine (BPN) is a widely used analgesic in the pediatric population, although there are few studies on the pharmacokinetics and pharmacodynamics of this drug.
UNASSIGNED: The objective was to characterize the pharmacokinetics of BPN after intravenous administration and analyze the effect of age, gender, weight, height, body mass index (BMI), and drug-drug interactions as covariates.
UNASSIGNED: Ninety-nine children (2-10 years), who underwent orthopedic surgery under regional, general, or combined anesthesia were included. Patients evaluated according to the American Society of Anesthesiologists Physical Status Classification, who received intravenous BPN 2 μg/kg were enrolled. Blood was collected from 1-240 min. Drug plasma concentrations were determined by LC-MS/MS. Population pharmacokinetic parameters were obtained with Monolix 2021R1 software. Pearson\'s correlation and/or ANOVA were used for statistical analysis.
UNASSIGNED: Age was associated with changes in clearance and central compartment volume and the female gender was associated with lower intercompartmental clearance, while BMI modified clearance, central and peripheral compartment volume. Concomitant administration of BPN with fentanyl and dexamethasone produced decreases in clearance.
UNASSIGNED: The covariates of sex, age, and BMI are directly related to the increase or decrease in BPN pharmacokinetic parameters.

Osteoarthritis (OA), characterized by chronic pain and joint degradation, is a progressive joint disease primarily induced by age-related systemic inflammation. Angelica gigas Nakai (AG), a medicinal plant widely used in East Asia, exhibits promising results for such conditions. This study aimed to evaluate the potential of AG as a drug candidate for modulating the multifaceted pathology of OA based on its anti-inflammatory properties. We evaluated the efficacy of AG in pain relief, functional improvement, and cartilage erosion delay using monosodium iodoacetate-induced OA rats and acetic acid-induced writhing mice, along with its anti-inflammatory effects on multiple targets in the serum and cartilage of in vivo models and lipopolysaccharide-stimulated RAW 264.7 cells. In vivo experiments demonstrated significant analgesic and chondroprotective effects of AG, along with functional recovery, in model animals compared with the active controls. AG dose-dependently modulated inflammatory OA pathology-related targets, including interleukin-1β, tumor necrosis factor-α, matrix metalloproteinase-13, and cyclooxygenase-2, both in vitro and in vivo. In conclusion, AG could be a potential drug candidate for modulating the multifaceted pathology of OA. Nevertheless, further comprehensive investigations, involving a broader range of compounds, pathologies, and mechanisms, are warranted to validate these findings.

This study investigates the anti-inflammatory, analgesic, and antioxidant properties of polyphenols extracted from Brassica oleracea var. capitata (cabbage) ethanolic extract (BOE). Given the historical use of cabbage in traditional medicine for treating various ailments, this research aims to validate these effects scientifically. The study involved the characterization of BOE\'s bioactive compounds using Fourier Transform Infrared Spectroscopy (FTIR) and Liquid Chromatography-Diode Array Detection-Electro-Spray Ionization Mass Spectrometry (HPLC-DAD-ESI MS) analysis. We assessed the anti-inflammatory and analgesic effects of topical and oral BOE administration on rodent models with acute and subacute inflammation. Additionally, the antioxidant capacity of orally administered BOE was evaluated. The results showed that BOE possesses significant levels of phenolic compounds with a potent antioxidant activity. The topical administration of BOE demonstrated notable anti-inflammatory effects in the tested rodent models, which were comparable with nonsteroidal anti-inflammatory drugs. These findings suggest that BOE could be a valuable natural remedy for inflammation-related conditions, supporting its traditional uses and highlighting its potential for further pharmacological development.

In the pursuit of safer and more effective treatments, there is a growing interest in plant-derived compounds, particularly lectins, because of their diverse pharmacological properties. This study focused on isolating, purifying, and characterizing lectin from Combretum glutinosum seeds (CGSLs) to assess its potential as an analgesic and antiulcer agent. CGSL extraction involved defatting and buffer extraction, followed by purification using ammonium sulfate fractionation and fetuin-agarose affinity column chromatography. The isolectins (iso-CGSLs), each consisting of 60 kDa and 57 kDa heterodimeric subunits, displayed glycoprotein properties with a 40 % neutral sugar content. They exhibited peak activity at 55 °C and remained stable for up to the fifth day at room temperature. The activity exhibited a pH dependence, peaking between 7.5 and 10.5, and all seemingly operated independently of metal ions. CGSL, at optimal doses ranging from 6 to 12 mg/kg, had significant analgesic effects on acetic acid-induced writhing and hot plate tests in mice. Evaluation using 0.7 % acetic acid resulted in notable pain reduction across all doses (P < 0.05). The analgesic effect of lectin was partially reversed by naloxone (a morphine antagonist), indicating partial involvement of the opioid receptor system. Furthermore, CGSL exhibited antiulcer effects in ethanol-induced gastric ulcer models in rats, highlighting its therapeutic potential as a natural alternative for analgesic and antiulcer treatments.

Botulinum neurotoxins (BoNTs), produced by Clostridium botulinum, have been used for the treatment of various central and peripheral neurological conditions. Recent studies have suggested that BoNTs may also have a beneficial effect on pain conditions. It has been hypothesized that one of the mechanisms underlying BoNTs\' analgesic effects is the inhibition of pain-related receptors\' transmission to the neuronal cell membrane. BoNT application disrupts the integration of synaptic vesicles with the cellular membrane, which is responsible for transporting various receptors, including pain receptors such as TRP channels, calcium channels, sodium channels, purinergic receptors, neurokinin-1 receptors, and glutamate receptors. BoNT also modulates the opioidergic system and the GABAergic system, both of which are involved in the pain process. Understanding the cellular and molecular mechanisms underlying these effects can provide valuable insights for the development of novel therapeutic approaches for pain management. This review aims to summarize the experimental evidence of the analgesic functions of BoNTs and discuss the cellular and molecular mechanisms by which they can act on pain conditions by inhibiting the transmission of pain-related receptors.

Although opioid analgesics are indispensable in treating pain, these drugs are accompanied by life-threatening side effects. While clinically relevant opioid drugs target the µ opioid receptor (MOR), a heterodimer between the MOR and the δ opioid receptor (DOR) has emerged as another target to develop safer analgesics. Although some heterodimer-preferring agonists have been reported so far, it is still difficult to activate the MOR/DOR heterodimer selectively in the presence of MOR or DOR monomers/homodimers. To gain insights to develop selective agonists for MOR/DOR, herein we prepared analogs of CYM51010, one of the reported heterodimer-preferring agonists, and collected structure-activity relationship information. We found that the ethoxycarbonyl group was needed for the activity for the heterodimer, although this group could be substituted with functional groups with similar sizes, such as an ethoxycarbonyl group. As for the acetylaminophenyl group, not a type of substituent, but rather a substituent located at a specific position (para-position) was essential for the activity. Changing the linker length between the acetylaminophenyl group and the piperidine moiety also had deleterious effects on the activity. On the other hand, the substitution of the acetylamino group with a trifluoroacetylamino group and the substitution of the phenethyl group with a benzyl group diminished the activities for the monomers/homodimers while keeping the activity for MOR/DOR, which enhanced the selectivity. Our findings herein will play an important role in developing selective agonists for MOR/DOR and for elucidating the physiological roles of this heterodimer in analgesic processes and in the establishment of side effects.

Uncontrolled inflammation is a crucial factor in the development of many diseases. Anti-inflammatory molecules based on natural sources are being actively studied, among which Aristida depressa Retz (Ar.dp) has been traditionally used as a paste to heal inflammation. The present study aimed to evaluate the anti-inflammatory, analgesic, and antipyretic potential of an ethanolic extract of A. depressa through a battery of in vivo and in vitro models. The ethanolic extract of A. depressa was prepared by maceration and chemically characterized using high-performance liquid chromatography, which revealed the presence of quercetin, vanillic acid, chlorogenic acid, p-coumaric acid, m-coumaric acid, ferulic acid, cinnamic acid, and sinapic acid; its antioxidant capacity was then screened with the DPPH in vitro assay, which indicated moderate scavenging capacity. A protein denaturation assay was next performed to evaluate the in vitro anti-inflammatory potential of Ar.dp, which showed significant inhibition (44.44%) compared to the standard drug (diclofenac sodium), with 89.19% inhibition at a concentration of 1 mg/mL. The in vivo safety profile of Ar.dp was evaluated in accordance with the OECD-425 acute toxicity guidelines and found to be safe up to 5 g/kg. The in vivo anti-inflammatory potentials of Ar.dp were evaluated at three different doses (125, 250, and 500 mg/kg) in acute (carrageenan-induced edema: 84.60%, histamine-induced paw edema: 84%), sub-chronic (cotton-pellet-induced granuloma: 57.54%), and chronic (complete-Freund\'s-adjuvant-induced arthritis: 82.2%) models. Our results showed that Ar.dp had significant (p < 0.05) anti-inflammatory effects over diclofenac sodium in the acute and chronic models. Histopathology studies indicated reduced infiltration of paw tissues with inflammatory cells in Ar.dp-treated animals. Similarly, Ar.dp showed significant (p < 0.05) analgesic (yeast-induced-pyrexia model: 23.53%) and antipyretic (acetic-acid-induced writhing model: 51%) effects in a time-dependent manner. In silico studies on the interactions of COX-1 and COX-2 with the eight ligands mentioned earlier confirmed the inhibition of enzymes responsible for inflammation and fever. Based on the findings of the present study, it is concluded that Ar.dp has anti-inflammatory, analgesic, and antipyretic properties that are likely linked to its pharmacologically active phenolic bioactive molecules.