Opioid Drugs Research Articles

An OPRM1-SNAP-tag/CMC method to directly identify drug components in sewage.

The scourge of drug addiction and abuse poses a significant challenge to society. Opioid drugs acting on μ-opioid receptor (OPRM1) make it one of the pivotal targets for drug addiction. In the past decade, sewage analysis has become a prevalent method of drug monitoring. However, traditional methods of detecting drugs in sewage are cumbersome, and rapid detection methods are relatively lacking. To address this, an innovative OPRM1-SNAP-tag/CMC method to directly identify drug components in sewage was established. Cell membrane chromatography (CMC) is an affinity chromatography technique which effectively detects receptor affinity substances. Cells constructed with high expression of specific receptor could be used to screen for compounds acting on the receptor. CMC based on OPRM1 provides a potentially convenient and effective tool for the detection of targeted drug components in sewage. In this study, the selectivity, reproducibility, column lifetime, and carryover of the CMC column had been assessed. Initially, we eluted the collected domestic sewage with methanol and acetonitrile, and the retention peaks were observed on the CMC system. Subsequently, without any preliminary sample preparation, we directly injected filtered samples of suspicious sewage into the OPRM1-SNAP-tag/CMC system, where we observed retention peaks as well. The retained components were further identified as morphine by using UPLC-MS/MS. In conclusion, the OPRM1-SNAP-tag/CMC method stands out as a reliable and robust model for the detection of drug components in sewage. It provides a valuable analytical tool for frontline drug control efforts, enhancing our capacity to monitor and mitigate the impact of drug abuse on society.

Emerging Psychotropic Drug for the Treatment of Trigeminal Pain: Salvinorin A

Trigeminal neuralgia (TN) is chronic pain caused by damage to the somatosensorial system on the trigeminal nerve or its branches, which involves peripheral and central dysfunction pain pathways. Trigeminal pain triggers disruptive pain in regions of the face, including within and around the mouth. Besides clinical experiences, translating the language of suffering into scientific terminology presents substantial challenges. Due to the complex and multifactorial pathophysiology underlying trigeminal pain, elucidating its social impact presents significant difficulties. Carbamazepine and oxcarbazepine are first-line treatments for TN, achieving approximately 50% pain reduction in 60–70% of treated patients. However, their efficacy is often limited by common side effects, such as dizziness, vertigo, nausea, seizures, and cognitive symptoms. In some cases, patients experience severe side effects, including myelosuppression, hyponatremia, hormonal imbalances, liver toxicity, suicidal ideation, teratogenicity, and other adverse reactions. Given these clinical limitations, the search for new painkiller candidates continues. Hence, we focused this review on salvinorin A (SalA), a natural agonist of κ-opioid receptors (KORs), which demonstrated anti-nociceptive, anti-inflammatory, and anti-neuropathic properties in various experimental models of the spinal sensory system. Furthermore, preclinical evidence indicates that SalA does not induce dependence and demonstrates a favorable toxicological and safety profile in comparison with currently marketed opioid drugs. We propose Salvinorin A as a promising candidate for treating trigeminal neuralgia, offering the potential for reduced adverse effects.

Signal profiles and spatial regulation of β-arrestin recruitment through Gβ5 and GRK3 at the μ-opioid receptor

The μ-opioid receptor (MOR) is a G-protein-coupled receptor (GPCR) that mediates both analgesic effects and adverse effects of opioid drugs. Despite extensive efforts to develop a signal-biased drug, drugs with sufficiently reduced side effects have not been established, in part owing to lack of comprehensive signal transducer profiles of MOR. In this study, by profiling the activity of signal transducers including G proteins and GPCR kinases (GRKs), we revealed an unprecedented mechanism of selective GRK3 activation by Gβ5, leading to β-arrestin recruitment. By utilizing multiple genome-edited cell lines and functional assays, we found that oliceridine, an FDA-approved G-protein-biased agonist, selectively activates Gαz- and GRK3-mediated signaling. Notably, among the five Gβ subtypes, only Gβ5 distinguishes GRK3 from GRK2. Using single-molecule imaging, we found that GRK3 is recruited to the plasma membrane upon MOR agonist stimulation by Gβ1 and Gβ5, yet their interaction dynamics with GRK3 and mechanisms of action are different. Furthermore, particle diffusion analysis suggests that Gβ5 is enriched in confined membrane domains, through which GRK3 is recruited to the plasma membrane in a freely diffusible state, thereby allowing GRK3 to efficiently interact with MOR. These findings provide a mechanism by which MOR agonists rely on a specific Gα–Gβ–GRK axis to induce β-arrestin recruitment.

Experiences of the changing illicit drug supply among racial and ethnic minoritized people in three US states: a qualitative study

BackgroundAmidst a national surge in overdose deaths among racial and ethnic minoritized people and people who use stimulants (cocaine or methamphetamines), our objective was to understand how these groups are adapting to a rapidly changing illicit drug supply.MethodsWe conducted semi-structured interviews with 64 people who use drugs and who self-identified as Black, Hispanic, Multiracial, or other Non-White race in three states (Michigan, New Jersey, and Wisconsin). Transcribed interviews were coded thematically.ResultsMost respondents used stimulants alone or in combination with opioids. Respondents perceived that the drug supply had become more unpredictable and dangerous but differed in their personal perception of risk and their adaptations. For example, respondents had very mixed perceptions of their own risk of being harmed by fentanyl, and differing opinions about whether fentanyl test strips would be useful. Xylazine, a novel adulterant in the opioid drug supply that has received public health and media attention, was not well known within the sample.ConclusionOur study highlights the challenges experienced by minoritized people who use drugs in responding to a changing drug supply, underscoring the limits of public health approaches focused solely on individual behavioral change.

Discovering opioid slang on social media: A Word2Vec approach with reddit data

The CDC reported that the overdose of prescription or illicit opioids was responsible for the deaths of over 80,000 Americans in 2021. Social media is a valuable source of insight into problematic patterns of substance misuse. The way people converse with illicit drugs in online forums is highly variable, and slang terms are frequently used. Manually identifying names of specific drugs can be difficult in both time and labor. Subjects and methodsThe study utilized the Gensim Python library and its Word2Vec neural network model to develop an auto-encoding neural network, enabling the innovative analysis of drug-related discourse downloaded from the Reddit website. The slang terms were then used to qualitatively analyze the topics and categories of drugs discussed on the forum. ResultsThe inclusion of slang terms facilitated the introduction of 200,000 specific mentions of opioid drugs and that stimulant drugs share a substantial semantic similarity with opioids, a 200 % increase in the number of drug-related terms as compared to using existing datasets. ConclusionsThis study advances the academic field with an extended collection of drug-related terms, offering a useful methodology and resource for tackling the opioid crisis with innovative, reduced-time detection and surveillance methods.

Exploration of a Novel Terpolymer Nanoparticle System for the Prevention of Alcohol-Induced Dose Dumping.

Alcohol-induced dose dumping (AIDD) remains a serious challenge in the controlled delivery of high potency drugs, such as opioids, which requires extensive investigation and innovative solutions. Current technologies rely on ethanol-insoluble excipients, such as guar gum and sodium alginate, to counteract the increased solubility of hydrophobic polymeric excipients in ethanol. However, these excipients pose several shortcomings, such as high viscosity of coating dispersion, high solution temperature, rapid gelation, and heterogeneity of resulted film. In this work, we explored the application of a cross-linked terpolymer nanoparticle (TPN) as an alcohol-resistant excipient in a water-insoluble controlled release film of ethylcellulose (EC) for the prevention of AIDD. Herein, we optimized the composition of TPN using a central composite design (CCD) to minimize swelling and weight loss of TPN-EC film in the presence of 20% ethanol. The optimized TPN showed a negligible effect on the viscosity of the coating dispersion, while guar gum increased the viscosity by 76-fold. Permeability studies in a pH 1.2 media containing 0% or 40% v/v ethanol revealed that cationic drugs (propranolol HCl, diltiazem HCl, and naloxone HCl (an opioid receptor-binding model drug)) exhibited significantly lower permeability ratios (P40%/P0%) than un-ionized drugs (theophylline and salicylic acid). FTIR analysis indicated an increase in ionic hydrogen bonding between TPN and the cationic drug in the presence of ethanol. These results suggest that drug-polymer-solvent interactions play an important role in alcohol-independent drug permeability through the TPN-EC film. By leveraging the drug permeability altering capability of the TPN-EC system, the release of cationic drugs in hydroethanolic media appeared to be suppressed, suggesting a promising new mechanism of alcohol resistance.

Mu-opioid receptors in tachykinin-1-positive cells mediate the respiratory and antinociceptive effects of the opioid fentanyl.

Opioid drugs are potent analgesics that carry the risk of respiratory side effects due to actions on μ-opioid receptors (MORs) in brainstem regions that control respiration. Substance P is encoded by the Tac1 gene and is expressed in neurons regulating breathing, nociception, and locomotion. Tac1-positive cells also express MORs in brainstem regions mediating opioid-induced respiratory depression. We determined the role of Tac1-positive cells in mediating the respiratory effects of opioid drugs. In situ hybridization was used to determine Oprm1 mRNA expression (gene encoding MORs) in Tac1-positive cells in regions regulating respiratory depression by opioid drugs. Conditional knockout mice lacking functional MORs in Tac1-positive cells were produced and the respiratory and locomotor responses to the opioid analgesic fentanyl were assessed using whole-body plethysmography. A tail immersion assay was used to assess the antinociceptive response to fentanyl. Oprm1 mRNA was highly expressed (>80%) in subpopulations of Tac1-positive cells in the preBötzinger Complex, nucleus tractus solitarius, and Kölliker-Fuse/lateral parabrachial region. Conditionally knocking out MORs in Tac1-positive cells abolished the effects of fentanyl on respiratory rate, relative tidal volume, and relative minute ventilation compared with control mice. Importantly, the antinociceptive response of fentanyl was eliminated in mice lacking functional MORs in Tac1-positive cells, whereas locomotor effects induced by fentanyl were preserved. Our findings suggest that Tac1-positive cells mediate the respiratory depressive and antinociceptive effects of the opioid fentanyl, providing important insights for the development of pain therapies with reduced risk of respiratory side effects.

Role of the GRK2/3 N-terminus in discriminating the endocytic effects of opioid agonist drugs.

Endocytosis of the μ-type opioid receptor (MOR) is a fundamentally important cellular regulatory process that is characteristically driven less effectively by partial relative to full agonist ligands. Such agonist-selective endocytic discrimination depends on how strongly drugs promote MOR binding to β-arrestins and this, in turn, depends on how strongly they stimulate phosphorylation of the MOR cytoplasmic tail by GPCR kinases (GRKs) from the GRK2/3 subfamily. While these relatively 'downstream' steps in the agonist-selective endocytic pathway are now well defined, it remains unclear how agonist-bound receptors are distinguished 'upstream' by GRKs. Focusing on GRK2 as a prototype, we show that this single GRK subtype can distinguish the endocytic activities of different MOR agonists in cells lacking other GRKs, and that agonist-selectivity is introduced at the most upstream step of GRK2 binding to MOR. This interaction requires prior membrane recruitment of GRK2 by its conserved PH domain and is enhanced by phosphorylation of the MOR tail, but neither reaction can explain the high degree of agonist-selectivity in the observed interaction of GRK2 with MOR. We identify the N-terminal domain (NTD) of GRK2, which is identical in GRK3, as a discrete element required for the full agonist-selectivity of MOR-GRK2 interaction and show that the NTD is also required for GRK2 to promote MOR endocytosis after it is bound. We propose a simple cellular mechanism of upstream agonist discrimination that is organized as a series of biochemical checkpoints and utilizes the NTD as an agonist-selective sensor. Significance Statement This study investigates how GPCR kinases (GRKs) distinguish the effects of opioid agonist drugs on regulated endocytosis of the μ-opioid receptor (MOR). It shows that a single GRK subtype is sufficient to determine the agonist-selectivity of MOR internalization, agonists are distinguished by how strongly they promote GRK2 recruitment by MOR, and the GRK2/3 N-terminus is a key determinant of agonist discrimination.

Understanding and Predicting Ligand Efficacy in the μ-Opioid Receptor through Quantitative Dynamical Analysis of Complex Structures.

The μ-opioid receptor (MOR) is a G-protein coupled receptor involved in nociception and the primary target of opioid drugs. Understanding the relationships among the ligand structure, receptor dynamics, and efficacy in activating MOR is crucial for drug discovery and development. Here, we use coarse-grained normal-mode analysis to predict ligand-induced changes in receptor dynamics with the Quantitative Dynamics Activity Relationship (QDAR) DynaSig-ML methodology, training a LASSO regression model on the entropic signatures (ESs) computed from ligand-receptor complexes. We train and validate the methodology using a data set of 179 MOR ligands with experimentally measured efficacies split into strictly chemically different cross-validation sets. By analyzing the coefficients of the ES LASSO model, we identified key residues involved in MOR activation, several of which have mutational data supporting their role in MOR activation. Additionally, we explored a contact-only LASSO model based on ligand-protein interactions. While the model showed predictive power, it failed at predicting efficacy for ligands with low structural similarity to the training set, emphasizing the importance of receptor dynamics for predicting ligand-induced receptor activation. Moreover, the low computational cost of our approach, at 3 CPU s per ligand-receptor complex, opens the door to its application in large-scale virtual screening contexts. Our work contributes to a better understanding of dynamics-function relationships in the μ-opioid receptor and provides a framework for predicting ligand efficacy based on ligand-induced changes in receptor dynamics.

Price Sensitivity and Information Barriers to the Take-Up of Naloxone

We conducted a field experiment that randomized advertisements, advertisement content, and prices across 2,204 counties in the United States to study the impacts on online purchases of naloxone, an opioid overdose reversal drug. Advertising increased web-site users but only impacted purchases when combined with a price reduction. Messages emphasizing the discreet nature of online sales had no additional impact on purchases. Comparing counties with advertisements featuring a highly discounted price to those featuring the full price, we estimate a price elasticity of demand for online naloxone of −1.3. Price is a significant barrier to online purchases of this lifesaving medication. (JEL C93, H75, I12, I18, L65, M37)

The Effect of the Application of Adductor and Infiltration of Local Anesthetic Between the Popliteal Artery and Capsule of the Knee (IPACK) Block to Patients on Postoperative Recovery and Sleep Quality Following Total Knee Arthroplasty: a Randomized, Controlled Study

Aim: The adductor canal block (ACB) and IPACK (Infiltration of local anesthetic between the popliteal artery and capsule of the knee) block are motor protective blocks that provide effective analgesia and allow early ambulation. The aim of this study was to investigate the effect on postoperative recovery and sleep quality of patients applied with ACB and IPACK for total knee arthroplasty (TKA). Material and Method: This prospective, double-blinded, randomized, controlled study included 80 patients who underwent unilateral TKA under spinal anesthesia. The patients were separated as those applied with ACB+IPACK (Group ACB+IPACK, n=40) and a control group (Group C, n=40). The primary outcome was the postoperative first-day quality of recovery scale (QoR-15). Secondary outcomes were postoperative first and second-day Timed-Up-and-Go (TUG) test and range of motion (ROM), the total amount of rescue opioid drugs required, pain scales at different time points in the first 48 hours postoperatively, sleep evaluation on the postoperative and 6 following nights, and evaluation of sleep quality for 1 month using the Pittsburgh Sleep Quality Index (PSQI). Results: The QoR on postoperative days 1 and 7 were better in the ACB+ IPACK group than in the control group (p= 0.001, p= 0.002, respectively). On postoperative days 1 and 2, the TUG (p= 0.035, p= 0.019, respectively) and ROM (p=0.003, p=0.000) values were higher in the ACB+ IPCAK group. Postoperative opioid consumption was lower in the ACB+IPACK group (p= 0.012). The PSQI values at 1 month postoperatively were similar in both groups (p =0.095). Conclusion: The study results demonstrated that ACB+IPACK applied with ultrasound for TKA postoperative analgesia provided effective analgesia, higher QoR and physical performance, and reduced postoperative opioid consumption. However, there was no effect on postoperative sleep quality.

Effects of oxycodone on placental lineages: Evidence from the transcriptome profile of mouse trophoblast giant cells

Pregnant women are often prescribed or abuse opioid drugs. The placenta is likely the key to understanding how opioids cause adverse pregnancy outcomes. Maternal oxycodone (OXY) exposure of pregnant mice leads to disturbances in the layer of invasive parietal trophoblast giant cells (pTGC) that forms the interface between the placenta and uterus. These cells are analogous to extravillous trophoblasts of the human placenta. They are crucial to coordinating the metabolic needs of the conceptus with those of the mother and are primary participants in the placenta-brain axis. Their large nuclear size, however, has precluded both single-cell (sc) and single-nucleus (sn) RNA-seq analyses beyond embryonic day (E) 8.5. Here, we compared the transcriptomes of placentas from pregnant mice exposed to OXY with unexposed controls at E12.5, with particular emphasis on the pTGC. The nonfluidic Parse snRNA-seq approach permitted characterization of the nuclear transcriptomes of all the major placental cell lineages and their presumed progenitors at E12.5. OXY exposure had a negligible effect on components of the placental labyrinth, including the two syncytial cell layers, but caused transcriptomic changes consistent with metabolic stress throughout the spongiotrophoblast. Most notably, there was loss of the majority of pTGC, whose normal gene expression is consistent with elevated energy demand relating to biosynthesis of multiple secretory products, especially hormones, and endoduplication of DNA. This unusual sensitivity of pTGC presumably puts the pregnancy and future health of the offspring at particular risk to OXY exposure.

Total Arthroscopic Resection of the Talocalcaneal Coalition in Adults: Key Points of Surgical Technique.

Potential disadvantages of open technique for talocalcaneal coalition (TCC) include a risk of wound infection, opioid drug dependence, and prolonged hospitalization. The purpose of this study was to retrospectively evaluate the effectiveness and safety of endoscopic resection of the TCC. A retrospective study from June 2019 to February 2023was conducted on 16 consecutively admitted patients who were diagnosed by imaging to have TCC for whom conservative treatment had failed and who undergone arthroscopic resection. The mean age of this cohort was 31.56 ± 10.39 years (range, 16-57 years). The mean follow-up period was 38.93 ± 15.69 months (range, 11-59 months). The site of the coalition, comorbidities, satisfaction with treatment, visual analog scale (VAS), and American Orthopedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot scale scores were evaluated pre- and postoperatively. Preoperative magnetic resonance imaging (MRI) scans were used to categorize the coalition according to the Lim classification. Postoperative computed tomography (CT) scans were used to assess recurrence. The distribution of TCC cases according to the Lim classification was type I in one case, type II in four cases, and type III in 11 cases. The site of coalition involved the middle facets in seven patients, the posterior facets in three patients, and both the above sites in six patients. All patients underwent total arthroscopic resection of TCC. An auxiliary mini-incision was made for three patients due to serious tibial nerve compression. Radiographics showed that the coalition disappeared and pain was relieved postoperatively. The mean VAS score decreased from 4.31 ± 1.54 to 1.81 ± 0.98 points (p < 0.001). The mean AOFAS ankle-hindfoot score improved from 65.56 ± 5.82 to 87.31 ± 6.30 points (p < 0.001). Fifteen patients were satisfied with the procedure, and one patient experienced numbness after surgery. No recurrence was reported based on CT scan and clinical results up to the end of the study. Surgical reconstruction employing total arthroscopic resection of TCC can achieve significant functional and radiographic improvements and symptom relief in selected patients with TCC. Auxiliary mini-incisions were necessitated in complex situations.

Hypoxic Effects of Heroin and Fentanyl and Their Basic Physiological Mechanisms.

Respiratory depression that diminishes oxygen delivery to the brain is the most dangerous effect of opioid drugs. While plethysmography is a valuable tool to examine drug-induced changes in respiration, the primary cause of brain abnormalities induced by opioids is the global decrease in brain oxygen levels. The primary goal of this review is to provide an overview and discussion on fluctuations in brain oxygen levels induced by opioids, with a focus on heroin and fentanyl. To evaluate fluctuations in brain oxygen levels we used oxygen sensors coupled with high-speed amperometry in awake, freely moving rats. First, we provide an overview of brain oxygen responses induced by natural physiological stimuli and discuss the mechanisms regulating oxygen entry into brain tissue. Then, we present data on brain oxygen responses induced by heroin and fentanyl and review their underlying mechanisms. These data allowed us to compare the effects of these drugs on brain oxygen regarding their latency, potency, time-dependency, and potential lethality at high doses as well as their relationships with peripheral oxygen responses. We also discuss data on the effects of naloxone on brain oxygen responses induced by heroin and fentanyl in the paradigms of both the pre-treatment and treatment, when naloxone is administered at different times after the primary opioid drug. Although most data discussed were obtained in rats, they may have clinical relevance for understanding the mechanisms underlying the physiological effects of opioids and developing rational treatment strategies to decrease acute lethality and long-term health complications of opioid misuse.

Classics in Chemical Neuroscience: Medetomidine.

Medetomidine is an FDA-approved α2-adrenoreceptor (α2-AR) agonist used as a veterinary sedative due to its analgesic, sedative, and anxiolytic properties. While it is marketed for veterinary use as a racemic mixture under the brand name Domitor, the pharmacologically active enantiomer, dexmedetomidine, is approved for sedation and analgesia in the hospital setting. Medetomidine has recently been detected in the illicit drug supply alongside fentanyl, xylazine, cocaine, and heroin, producing pronounced sedative effects that are not reversed by naloxone. The pharmacological effects along with the low cost of supply and lack of regulation for medetomidine has made it a target for misuse. Since 2022, medetomidine has been found as an adulterant in samples of seized drugs, as well as in toxicological analyses of patients admitted to the emergency department after suspected overdoses across several U.S. states and Canada. This Review will discuss the history, chemistry, structure-activity relationships, drug metabolism and pharmacokinetics (DMPK), pharmacology, and emergence of medetomidine as an adulterant in drug mixtures in the context of the current opioid drug crisis.

Identifying and quantifying exposures involving counterfeit opioid analgesic products

Introduction The increasing presence of counterfeit opioid drugs in the United States can contaminate data collection systems and confound estimates derived from surveillance of the opioid epidemic. Data sources and analyses that can quantify the contribution of counterfeit opioid products are needed to provide accurate and timely data to inform public health responses. We describe a novel approach to identify and quantify intentional abuse and misuse exposures involving suspected counterfeit opioid products in United States poison center data. Methods An ecological study was performed using data, including narrative case notes, reported to participating United States Poison Centers of the Researched Abuse, Diversion and Addiction Related Surveillance System between 2009-Quarter 1 and 2021-Quarter 4. A machine learning natural language processing approach was used to develop a predictive model. Results Sensitivity for detecting suspected non-counterfeit-involved exposures by the predictive model was 92%, specificity was 73%, and the area under the receiver operating characteristic curve was 92%. Overall, only 2.1% of intentional abuse and misuse exposure calls were predicted to be suspected counterfeit-involved during 2009–2021; however, we observed an exponential increase in suspected counterfeit exposures over this time period. There was a 7-fold increase in the estimated number of suspected counterfeit exposures from 2009 to 2021, and 23.7% of all opioid analgesic intentional abuse and misuse exposures were suspected counterfeit-involved in 2021. Discussion We demonstrate the feasibility and reliability of using machine learning natural language processing to identify exposures involving suspected counterfeit opioid products in United States poison center data. Results suggest that suspected counterfeits have had a meaningful influence on rates of intentional abuse exposures to opioid analgesics in more recent years. Conclusions The increasing presence of counterfeit opioid drugs can contaminate data collection systems and compromise the reliability of the data.

Structural basis of μ-opioid receptor targeting by a nanobody antagonist

The μ-opioid receptor (μOR), a prototypical G protein-coupled receptor (GPCR), is the target of opioid analgesics such as morphine and fentanyl. Due to the severe side effects of current opioid drugs, there is considerable interest in developing novel modulators of μOR function. Most GPCR ligands today are small molecules, however biologics, including antibodies and nanobodies, represent alternative therapeutics with clear advantages such as affinity and target selectivity. Here, we describe the nanobody NbE, which selectively binds to the μOR and acts as an antagonist. We functionally characterize NbE as an extracellular and genetically encoded μOR ligand and uncover the molecular basis for μOR antagonism by determining the cryo-EM structure of the NbE-μOR complex. NbE displays a unique ligand binding mode and achieves μOR selectivity by interactions with the orthosteric pocket and extracellular receptor loops. Based on a β-hairpin loop formed by NbE that deeply protrudes into the μOR, we design linear and cyclic peptide analogs that recapitulate NbE’s antagonism. The work illustrates the potential of nanobodies to uniquely engage with GPCRs and describes lower molecular weight μOR ligands that can serve as a basis for therapeutic developments.

Effect of Methocarbamol on acute low back pain: A systematic review

Introduction Pharamcological treatment for acute low back pain (ALBP) typically involves opioid drugs, and non-steroidal anti-inflammatory drugs (NSAIDs). Methocarbamol is utilized primarily for managing muscle spasms and pain. This systematic review aims to provide an updated synthesis of published literature on the effects of Methocarbamol on pain outcomes in ALBP. Methods This systematic review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Original articles published until December 2023 were sourced from PubMed, Embase, and the Cochrane Library. Articles focusing on the impact of Methocarbamol on pain outcomes in ALBP patients were included. Results Three studies met the inclusion criteria, published between 2018 and 2023. The total study population comprised 405 ALBP patients, with 163 receiving Methocarbamol. Compared to patients not receiving Methocarbamol, those in the Methocarbamol group showed pain improvement at one week. However, at 30 and 60 minutes after intravenous administration, Methocarbamol was less effective than Diazepam. The primary reported adverse event was nausea. Conclusion When administered in combination with Indomethacin or Naproxen, Methocarbamol shows potential for improving pain outcomes at one week in ALBP patients. However, its efficacy appears inferior to Diazepam in the short-term management of pain

Chronic inflammatory pain reduces fentanyl intake during early acquisition of fentanyl self-administration, but does not change motivation to take fentanyl in male and female rats

The co-occurrence of chronic pain and opioid misuse has led to numerous preclinical investigations of pain-opioid interactions to examine how pain manipulations alter the reinforcing properties of opioids. However, preclinical investigations of chronic pain effects on opioid drug self-administration have produced inconsistent results. Our previous work demonstrated that established fentanyl self-administration is resistant to change by induction of chronic inflammatory pain (Complete Freund's Adjuvant; CFA) in male and female rats, while other laboratories have shown that CFA increased fentanyl self-administration in male but not female rats when pain induction precedes self-administration, which may be a critical factor in determining the effects of chronic pain on self-administration. The present study was designed similarly to Higginbotham et al. (2022) to test the effects of CFA on fentanyl self-administration in rats that underwent pain prior to acquisition of fentanyl self-administration. Male and female rats treated with hindpaw CFA or saline were trained to intravenously self-administer (IVSA) fentanyl for 3 weeks under limited access to fentanyl (2 h per day) conditions. After 3 weeks of fentanyl IVSA acquisition, we tested motivation to take fentanyl using progressive ratio testing and dose-response testing. CFA male and female rats self-administered less fentanyl than saline-treated controls during week 1 of acquisition, but not during weeks 2–3 of acquisition. Intra-session analysis of week 1 data demonstrated that chronic inflammatory pain suppressed fentanyl intake towards the end of week 1 and at the end of each operant session. We also report no effects of chronic inflammatory pain on motivation to take fentanyl. We discuss potential methodological explanations for differences between these results and prior reports. Our findings demonstrate that CFA temporarily suppresses fentanyl IVSA in animals without changing motivation to take fentanyl or promoting escalation of opioid use, suggesting that chronic inflammatory pain is unlikely to promote long-term risk of opioid misuse.

Global Trends in Oliceridine (TRV130) Research from 2013 to 2024: A Bibliometrics and Knowledge Graph Analysis.

The adverse effects and drug abuse issues associated with opioid drugs have made finding a safe and effective alternative a focus of research. Oliceridine has attracted attention for its lower adverse reactions, such as respiratory depression and gastrointestinal issues, compared to traditional opioids, and is considered a promising candidate for addressing the current limitations in opioid therapy. This article explored the knowledge structure of oliceridine through bibliometric analysis, highlighting its clinical applications in managing acute pain and its mechanisms that may reduce addiction risk. Our bibliometric analysis highlighted hotspots and trends in oliceridine research, guiding future studies on its safety and efficacy in pain management. This study utilized the Web of Science Core Collection database to search for articles related to oliceridine from 2013 to 2024. Systematic analysis was conducted on publication, country, institution, author, journal, references, and keywords. The software Citespace, Vosviewer, and Bibliometrix were employed to visualize bibliometric analysis. From 2013 to 2024, 159 articles on oliceridine were published in 98 journals by 158 institutions from 28 countries. The United States has rapidly developed in this field, providing significant momentum. Keyword clustering analysis revealed that research on oliceridine primarily focused on exploring its molecular and pharmacological mechanisms and conducting clinical studies to evaluate its efficacy and safety in pain management. Analyses of the strongest citation bursts with references and keywords indicated that protein-biased ligands and oliceridine were hotspots. The emergence of divergent views regarding oliceridine's biased agonism will lead to future hotspots focusing on the underlying mechanisms of biased signaling by G protein-coupled receptors and drug design. Bibliometric analysis provides insights into the current hotspots and emerging areas of oliceridine, which can guide future research. The widespread attention and clinical application of oliceridine lay a solid foundation for further drug development and clinical trials.