UNASSIGNED: Using a validated translational model that quantitatively predicts opioid-induced respiratory depression and cardiac arrest, we compared cardiac arrest events caused by synthetic opioids (fentanyl, carfentanil) following rescue by intranasal (IN) administration of the μ-opioid receptor antagonists naloxone and nalmefene.
UNASSIGNED: This translational model was originally developed by Mann et al. (Clin Pharmacol Ther 2022) to evaluate the effectiveness of intramuscular (IM) naloxone. We initially implemented this model using published codes, reproducing the effects reported by Mann et al. on the incidence of cardiac arrest events following intravenous doses of fentanyl and carfentanil as well as the reduction in cardiac arrest events following a standard 2 mg IM dose of naloxone. We then expanded the model in terms of pharmacokinetic and µ-opioid receptor binding parameters to simulate effects of 4 mg naloxone hydrochloride IN and 3 mg nalmefene hydrochloride IN, both FDA-approved for the treatment of opioid overdose. Model simulations were conducted to quantify the percentage of cardiac arrest in 2000 virtual patients in both the presence and absence of IN antagonist treatment.
UNASSIGNED: Following simulated overdoses with both fentanyl and carfentanil in chronic opioid users, IN nalmefene produced a substantially greater reduction in the incidence of cardiac arrest compared to IN naloxone. For example, following a dose of fentanyl (1.63 mg) producing cardiac arrest in 52.1% (95% confidence interval, 47.3-56.8) of simulated patients, IN nalmefene reduced this rate to 2.2% (1.0-3.8) compared to 19.2% (15.5-23.3) for IN naloxone. Nalmefene also produced large and clinically meaningful reductions in the incidence of cardiac arrests in opioid naïve subjects. Across dosing scenarios, simultaneous administration of four doses of IN naloxone were needed to reduce the percentage of cardiac arrest events to levels that approached those produced by a single dose of IN nalmefene.
UNASSIGNED: Simulations using this validated translational model of opioid overdose demonstrate that a single dose of IN nalmefene produces clinically meaningful reductions in the incidence of cardiac arrest compared to IN naloxone following a synthetic opioid overdose. These findings are especially impactful in an era when >90% of all opioid overdose deaths are linked to synthetic opioids such as fentanyl.

Opioid use disorders (OUD) and overdoses are ever-evolving public health threats that continue to grow in incidence and prevalence in the United States and abroad. Current treatments consist of opioid receptor agonists and antagonists, which are safe and effective but still suffer from some limitations. Murine and humanized monoclonal antibodies (mAb) have emerged as an alternative and complementary strategy to reverse and prevent opioid-induced respiratory depression. To explore antibody applications beyond traditional heavy-light chain mAbs, we identified and biophysically characterized a novel single-domain antibody specific for fentanyl from a camelid variable-heavy-heavy (VHH) domain phage display library. Structural data suggested that VHH binding to fentanyl was facilitated by a unique domain-swapped dimerization mechanism, which accompanied a rearrangement of complementarity-determining region (CDR) loops leading to the formation of a fentanyl-binding pocket. Structure-guided mutagenesis further identified an amino acid substitution that improved the affinity and relaxed the requirement for dimerization of the VHH in fentanyl binding. Our studies demonstrate VHH engagement of an opioid and inform on how to further engineer a VHH for enhanced stability and efficacy, laying the groundwork for exploring the in vivo applications of VHH-based biologics against OUD and overdose.

Novel synthetic opioids (NSOs) represent an emerging group of novel psychoactive substances, acting as agonists at the opioid receptors. NSOs include fentanyl-related compounds, e.g. methoxyacetylfentanyl (MeACF), and non-fentanyl analogs, e.g. \"U compounds\" including U-47700. Here we present three cases of death involving MeACF and U-47700, with particular reference to preliminary data on pharmacokinetics and tissue distribution.After a complete post-mortem examination, general unknown screenings and analysis of drugs of abuse were performed on postmortem samples by immunoassays, gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry. To quantify the analytes of interest in post-mortem blood and tissues, the standard addition method was used. A toxicological significance score (TSS), weighing the role of the NSO in each death case, was assigned.Case 1 died at the hospital after consumption of U-47700, methadone (serum levels: 2,600 ng/ml and 37 ng/ml), tilidine and benzodiazepines. In case 2, U-47700 (204 ng/ml) together with methadone (290 ng/ml), flubromazepam (480 ng/ml) and diazepam (300 ng/ml) were detected in peripheral blood. In case 3, methoxyacetylfentanyl (266 ng/ml), furanylfentanyl (4.3 ng/ml) 4-ANPP (15 ng/ml) and alprazolam (69 ng/ml) were quantified in femoral blood. In all cases, the NSO likely contributed to the death (TSS = 3).NSOs appear to be often consumed in the setting of polydrug intoxications, especially in combination with other opioids and benzodiazepines, which often exert synergistic effects. The standard addition method remains the most reliable in post-mortem analysis and toxicological results should always be evaluated together with circumstantial and autopsy data.

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UNASSIGNED: Opioid and substance misuse has become a widespread problem in the United States, leading to the \"opioid crisis.\" The relationship between substance misuse and mental health has been extensively studied, with one possible relationship being that substance misuse causes poor mental health. However, the lack of evidence on the relationship has resulted in opioids being largely inaccessible through legal means.
UNASSIGNED: This study aims to analyze social media posts related to substance use and opioids being sold through cryptomarket listings. The study aims to use state-of-the-art deep learning models to generate sentiment and emotion from social media posts to understand users\' perceptions of social media. The study also aims to investigate questions such as which synthetic opioids people are optimistic, neutral, or negative about; what kind of drugs induced fear and sorrow; what kind of drugs people love or are thankful about; which drugs people think negatively about; and which opioids cause little to no sentimental reaction.
UNASSIGNED: The study used the drug abuse ontology and state-of-the-art deep learning models, including knowledge-aware Bidirectional Encoder Representations From Transformers-based models, to generate sentiment and emotion from social media posts related to substance use and opioids being sold through cryptomarket listings. The study crawled cryptomarket data and extracted posts for fentanyl, fentanyl analogs, and other novel synthetic opioids. The study performed topic analysis associated with the generated sentiments and emotions to understand which topics correlate with people\'s responses to various drugs. Additionally, the study analyzed time-aware neural models built on these features while considering historical sentiment and emotional activity of posts related to a drug.
UNASSIGNED: The study found that the most effective model performed well (statistically significant, with a macro-F1-score of 82.12 and recall of 83.58) in identifying substance use disorder. The study also found that there were varying levels of sentiment and emotion associated with different synthetic opioids, with some drugs eliciting more positive or negative responses than others. The study identified topics that correlated with people\'s responses to various drugs, such as pain relief, addiction, and withdrawal symptoms.
UNASSIGNED: The study provides insight into users\' perceptions of synthetic opioids based on sentiment and emotion expressed in social media posts. The study\'s findings can be used to inform interventions and policies aimed at reducing substance misuse and addressing the opioid crisis. The study demonstrates the potential of deep learning models for analyzing social media data to gain insights into public health issues.

Illicitly manufactured fentanyl (IMF) is a significant contributor to the increasing rates of overdose-related deaths. Its high potency and lipophilicity can complicate opioid withdrawal syndromes (OWS) and the subsequent management of opioid use disorder (OUD). This scoping review aimed to collate the current OWS management of study populations seeking treatment for OWS and/or OUD directly from an unregulated opioid supply, such as IMF. Therefore, the focus was on therapeutic interventions published between January 2010 and November 2023, overlapping with the period of increasing IMF exposure. A health science librarian conducted a systematic search on November 13, 2023. A total of 426 studies were screened, and 173 studies were reviewed at the full-text level. Forty-nine studies met the inclusion criteria. Buprenorphine and naltrexone were included in most studies with the goal of transitioning to a long-acting injectable version. Various augmenting agents were tested (buspirone, memantine, suvorexant, gabapentin, and pregabalin); however, the liberal use of adjunctive medication and shortened timelines to initiation had the most consistently positive results. Outside of FDA-approved medications for OUD, lofexidine, gabapentin, and suvorexant have limited evidence for augmenting opioid agonist initiation. Trials often have low retention rates, particularly when opioid agonist washout is required. Neurostimulation strategies were promising; however, they were developed and studied early. Precipitated withdrawal is a concern; however, the rates were low and adequately mitigated or managed with low- or high-dose buprenorphine induction. Maintenance treatment continues to be superior to detoxification without continued management. Shorter induction protocols allow patients to initiate evidence-based treatment more quickly, reducing the use of illicit or non-prescribed substances.

UNASSIGNED: Fentanyl and fentanyl analogs (F/FA) have become increasingly common adulterants in counterfeit prescription pills and illicit street drug mixtures due to their ease of synthesis and exceedingly high potency. The ongoing epidemic of fatal overdoses fueled by F/FA continues to highlight the need for longer-acting therapies than naloxone (NLX), the current gold-standard for reversing opioid overdoses, which shows limited efficacy to prevent renarcotization associated with F/FA toxicity. A novel opioid reversal agent based on covalent naloxone nanoparticles (cNLX-NP) has been shown to blunt fentanyl-induced respiratory depression out to 48 hr, demonstrating its potential therapeutic utility. The purpose of this study was to characterize how rapidly cNLX-NP reverses fentanyl-induced respiratory effects as well as the duration of its protective effects.
UNASSIGNED: Sprague Dawley male rats (n=6/group) were tested on an oximeter for baseline percent arterial oxygen saturation (%SaO2) challenged with 0.1 mg/kg SC fentanyl and 15 min later given 10 mg/kg IM doses of NLX, nalmefene (NLMF), or cNLX-NP and continuously monitored via oximetry for 10 minutes. One week later the experiment was repeated using a 1:1 mixture of NLX:cNLX-NP as the reversal agent in the rats that previously received NLX alone.
UNASSIGNED: While both NLX and NLMF rapidly reversed %SaO2 to baseline within 1 min, rats that received cNLX-NP did not return to >90% SaO2 levels until 9 min after administration. Similarly, heart and breath rates returned to baseline within 1 min of treatment with NLX and NLMF but did not return to baseline until 10 minutes after cNLX-NP administration. In contrast, NLX:cNLX-NP reversed all fentanyl-induced respiratory depressive effects within one minute.
UNASSIGNED: While cNLX-NP alone may not sufficiently reverse F/FA overdose in a timely manner, mixing free NLX with cNLX-NP can provide a mechanism to both rapidly reverse fentanyl-related effects and maintain extended protection against synthetic opioid toxicity. These data support further development of cNLX-NP as a fast-acting and long-lasting antidote to treat F/FA-induced respiratory depression and overdose, and potentially prevent renarcotization in humans.

Wastewater-based epidemiology (WBE) can provide objective and timely information on the use of new psychoactive substances (NPS), originally designed as legal alternatives of internationally controlled drugs. NPS have rapidly emerged on the global drug market, posing a challenge to drug policy and constituting a risk to public health. In this study, a WBE approach was applied to monitor the use of more than 300 NPS, together with fentanyl and its main metabolite norfentanyl, in influent wastewater collected from 12 European cities during March-June 2021. Quantitative and qualitative analysis of NPS in composite 24 h influent wastewater samples were based on solid phase extraction and liquid chromatography-mass spectrometry. In-sample stability tests demonstrated the suitability of most investigated biomarkers, except for a few synthetic opioids, synthetic cannabinoids and phenetylamines. Fentanyl, norfentanyl and eight NPS were quantified in influent wastewater and at least three substances were found in each city, demonstrating their use in Europe. N,N-dimethyltryptamine and 3-methylmethcathinone (3-MMC) were the most common NPS found, with the latter having the highest mass loads (up to 24.8 mg/day/1000 inhabitants). Seven additional substances, belonging to five categories of NPS, were identified in different cities. Spatial trends of NPS use were observed between cities and countries, and a changing weekly profile of use was observed for 3-MMC. WBE is a useful tool to rapidly evaluate emerging trends of NPS use, complementing common indicators (i.e. population surveys, seizures) and helping to establish measures for public health protection.

In April 2023, the Taliban banned poppy cultivation and the trade of all narcotics. This caused a 95% reduction in opium production. Usually, that would be good news. But there is a substantial worry: synthetic opioids might fill the void left by heroin. This is concerning because these drugs have led to health emergencies in areas where they are prevalent. This paper highlights the limitations of the current drug surveillance system in Europe and proposes improvements. It argues that reliance on secondary data is insufficient. Instead, we need to interview a sentinel group of people who inject drugs and adjust city-level sentinel systems, such as wastewater analysis, to specifically track the spread of synthetic opioids. Without these proactive steps, we risk only noticing a transition from heroin to synthetic opioids after it has occurred, with its harmful impacts already in place.

BACKGROUND: Dramatic increases in U.S. drug overdose deaths involving synthetic opioids, especially fentanyl, beginning around 2014 have driven a marked progression in overall drug overdose deaths in the U.S., which sharply rose to unprecedented levels amid the COVID-19 pandemic. Disparities in drug overdose deaths by educational attainment (EA) during the fentanyl era of the drug overdose epidemic and its intersection with the COVID-19 pandemic have not been widely scrutinized.
METHODS: Utilizing restricted-use mortality data from the National Vital Statistics System and population estimates from the American Community Survey, we estimated annual national age-adjusted mortality rates (AAMRs) from drug overdoses jointly stratified by EA and sex for adults aged 25-64 from 2015 to 2021. State-level AAMRs in 2015 and 2021 were also estimated to examine the geographic variation in the cumulative evolution of EA-related disparities over the course of the analysis period.
RESULTS: Nationally, AAMRs rose fastest among persons with at most a high school-level education, whereas little to no change was observed for bachelor\'s degree holders, widening pre-existing disparities. During the analysis period, the difference in national AAMRs between persons with at most a high school-level education and bachelor\'s degree holders increased from less than 8-fold (2015) to approximately 13-fold (2021). The national widening of EA-related disparities accelerated amid the COVID-19 pandemic, and they widened in nearly every state. Among non-bachelor\'s degree holders, national AAMRs increased markedly faster for males.
CONCLUSIONS: The widening disparities in drug overdose deaths by EA are a likely indicator of a rapidly increasing socioeconomic divide in drug overdose mortality more broadly. Policy strategies should address upstream socioeconomic drivers of drug use and overdose, particularly among males.