Potent Synthetic Opioids Research Articles

Oral fentanyl consumption and withdrawal impairs fear extinction learning and enhances basolateral amygdala principal neuron excitatory-inhibitory balance in male and female mice

The number of opioid overdose deaths has increased over the past several years, mainly driven by an increase in the availability of highly potent synthetic opioids, like fentanyl, in the un-regulated drug supply. Over the last few years, changes in the drug supply, and in particular the availability of counterfeit pills containing fentanyl, have made oral use of opioids a more common route of administration. Here, we used a drinking in the dark (DiD) paradigm to model oral fentanyl self-administration using increasing fentanyl concentrations in male and female mice over 5 weeks. Fentanyl consumption peaked in both female and male mice at the 30 µg/mL dose, with female mice consuming significantly more fentanyl than male mice. Mice consumed sufficient fentanyl such that withdrawal was precipitated with naloxone, with males having increased withdrawal symptoms as compared to females, despite lower pharmacological exposure. We also performed behavioral assays to measure avoidance behavior and reward-seeking during fentanyl abstinence. Female mice displayed reduced avoidance behaviors in the open field assay, whereas male mice showed increased avoidance in the light/dark box assay. Female mice also exhibited increased reward-seeking in the sucrose preference test. Fentanyl-consuming mice of both sexes showed impaired cued fear extinction learning following fear conditioning and increased excitatory synaptic drive and increased excitability of BLA principal neurons. Our experiments demonstrate that long-term oral fentanyl consumption results in wide-ranging physiological and behavioral disruptions. This model could be useful to further study fentanyl withdrawal syndrome and behaviors and neuroplasticity associated with protracted fentanyl withdrawal.

Timely, Granular, and Actionable: Designing a Social Listening Platform for Public Health 3.0

Every day, patients access and generate online health content through a variety of channels, creating an ever-expanding sea of digital data. At the same time, proponents of public health have recently called for timely, granular, and actionable data to address a range of public health issues, stressing the need for social listening platforms that can identify and compile this valuable data. Yet previous attempts at social listening in healthcare have yielded mixed results, largely because they have failed to incorporate sufficient context to understand the communications they seek to analyze. Guided by activity theory to design HealthSense, we propose a platform for efficiently sensing and gathering data across the web for real-time analysis to support public health outcomes. HealthSense couples theory-guided content analysis and graph propagation with graph neural networks (GNNs) to assess the relevance and credibility of information, as well as intelligently navigate the complex online channel landscape, leading to significant improvements over existing social listening tools. We demonstrate the value of our artifact in gathering information to support two exemplar public health tasks: (1) performing postmarket drug surveillance for adverse reactions and (2) addressing the opioid crisis by monitoring for potent synthetic opioids released into communities. Our results across data, user, and event experiments show that effective design artifacts can enable better outcomes across both automated and human decision-making contexts, making social listening for public health possible, practical, and valuable. Through our design process, we extend activity theory to address the complexities of modern online communication platforms, where information resides not only in the collection of individual communication activities but also in the complex network of interactions among them.

Fentanyl-positive urine drug screens in the emergency department: Association with intentional opioid misuse and racial disparities

BackgroundAn increase in opioid-related overdoses, notably from potent synthetic opioids like fentanyl, prompted this consideration of characteristics of emergency department (ED) patients with evidence for illicit fentanyl use or exposure, the correlation with intentional opioid misuse, and subsequent ED management. MethodsA retrospective review was performed of patients presenting to an urban academic medical center ED with evidence for illicit fentanyl use, determined by positive urine drug screens (UDS), from 6/2021 through 11/2021. Participant demographics, comorbidities, ED chief complaint and disposition, and evidence of intentional opioid misuse were considered. Secondary outcomes included provision of buprenorphine/naloxone and/or naloxone kits at discharge, ED recidivism, and six-month mortality. Bivariate comparisons and logistic regression models were performed. ResultsAmong 409 unique patients, most were white and male with a mean age of 39.4. Approximately half presented with opioid-related complaints. Evidence of intentional opioid misuse was identified in 72.6 % of patients. Black patients had 79 % lower odds of intentional opioid misuse compared to white patients. Regarding ED management, 28.8 % were discharged with buprenorphine/naloxone and 14.0 % with a naloxone kit. Black patients had 63 % lower odds of receiving buprenorphine/naloxone compared to white patients after controlling for covariates. Nearly 6 % of the study population died within six months of the initial ED visit. ConclusionThis fentanyl-focused review describes patient characteristics which largely mirror the epidemiology of the current opioid epidemic; however, despite evidence of objective exposure, it also suggests that Black patients may be less likely to use fentanyl intentionally. It also highlights potential disparities related to ED-based opioid misuse patient management.

Evolution of an epidemic: Understanding the opioid epidemic in the United States and the impact of the COVID-19 pandemic on opioid-related mortality.

We conduct this research with a two-fold aim: providing a quantitative analysis of the opioid epidemic in the United States (U.S.), and exploring the impact of the COVID-19 pandemic on opioid-related mortality. The duration and persistence of the opioid epidemic lends itself to the need for an overarching analysis with extensive scope. Additionally, studying the ramifications of these concurrent severe public health crises is vital for informing policies to avoid preventable mortality. Using data from CDC WONDER, we consider opioid-related deaths grouped by Census Region spanning January 1999 to October 2022 inclusive, and later add on a demographic component with gender-stratification. Through the lens of key events in the opioid epidemic, we build an interrupted time series model to reveal statistically significant drivers of opioid-related mortality. We then employ a counterfactual to approximate trends in the absence of COVID-19, and estimate excess opioid-related deaths (defined as observed opioid-related deaths minus projected opioid-related deaths) associated with the pandemic. According to our model, the proliferation of fentanyl contributed to sustained increases in opioid-related death rates across three of the four U.S. census regions, corroborating existing knowledge in the field. Critically, each region has an immediate increase to its opioid-related monthly death rate of at least 0.31 deaths per 100,000 persons at the start of the pandemic, highlighting the nationwide knock-on effects of COVID-19. There are consistent positive deviations from the expected monthly opioid-related death rate and a sizable burden from cumulative excess opioid-related deaths, surpassing 60,000 additional deaths nationally from March 2020 to October 2022, ∼70% of which were male. These results suggest that robust, multi-faceted measures are even more important in light of the COVID-19 pandemic to prevent overdoses and educate users on the risks associated with potent synthetic opioids such as fentanyl.

Oral Fentanyl Consumption and Withdrawal Impairs Fear Extinction Learning and Enhances Basolateral Amygdala Principal Neuron Excitatory-Inhibitory Balance in Male and Female Mice.

The number of opioid overdose deaths has increased over the past several years, mainly driven by an increase in the availability of highly potent synthetic opioids, like fentanyl, in the un-regulated drug supply. Over the last few years, changes in the drug supply, and in particular the availability of counterfeit pills containing fentanyl, have made oral use of opioids a more common route of administration. Here, we used a drinking in the dark (DiD) paradigm to model oral fentanyl self-administration using increasing fentanyl concentrations in male and female mice over 5 weeks. Fentanyl consumption peaked in both female and male mice at the 30 µg/mL dose, with female mice consuming significantly more fentanyl than male mice. Mice consumed sufficient fentanyl such that withdrawal was precipitated with naloxone, with males having more withdrawal symptoms, despite lower pharmacological exposure. We also performed behavioral assays to measure avoidance behavior and reward-seeking during fentanyl abstinence. Female mice displayed reduced avoidance behaviors in the open field assay, whereas male mice showed increased avoidance in the light/dark box assay. Female mice also exhibited increased reward-seeking in the sucrose preference test. Fentanyl-consuming mice of both sexes showed impaired cued fear extinction learning following fear conditioning and increased excitatory synaptic drive and increased excitability of BLA principal neurons. Our experiments demonstrate that long-term oral fentanyl consumption results in wide-ranging physiological and behavioral disruptions. This model could be useful to further study fentanyl withdrawal syndrome and behaviors and neuroplasticity associated with protracted fentanyl withdrawal.

Trends in recurrent overdose and treatment initiation following emergency department visits for opioid overdose between 2016 and 2021

BackgroundOverdose remains a pressing public health concern in the United States, particularly with the emergence of fentanyl and other potent synthetic opioids in the drug supply. We evaluated trends in recurrent overdose and opioid use disorder (OUD) treatment initiation following emergency department (ED) visits for opioid overdose to inform response efforts. MethodsThis retrospective cohort study used electronic health record and statewide administrative data from Rhode Island residents who visited EDs for opioid overdose between July 1, 2016, and June 30, 2021, a period with fentanyl predominance in the local drug supply. The primary outcome was recurrent overdose in the 365 days following the initial ED visit. OUD treatment initiation within 180 days following the initial ED visit was considered as a secondary outcome. Trends in study outcomes were summarized by year of the initial ED visit. ResultsAmong 1745 patients attending EDs for opioid overdose, 20 % (n=352) experienced a recurrent overdose within 365 days, and this percentage was similar by year (p=0.12). Among patients who experienced any recurrent overdose, the median time to first recurrent overdose was 88 days (interquartile range=23–208), with 85 % (n=299/352) being non-fatal. Among patients not engaged in OUD treatment at their initial ED visit, 33 % (n=448/1370) initiated treatment within 180 days; this was similar by year (p=0.98). ConclusionsFollowing ED visits for opioid overdose in Rhode Island from 2016–2021, the one-year risk of recurrent overdose and six-month treatment initiation rate remained stable over time. Innovative prevention strategies and improved treatment access are needed.

Low-dose overlap initiation with split tablets of buprenorphine in intubated intensive care unit patients with opioid use disorder

BackgroundAs the opioid public health crisis evolves to include fentanyl and other potent synthetic opioids, more patients are admitted to the hospital with serious complications of drug use and frequently require higher levels of care, including intensive care unit (ICU) admission, for acute and chronic conditions related to opioid use disorder (OUD). This patient population poses a unique challenge when managing sedation and ensuring adequate ventilation while intubated given their high opioid requirements. Starting a patient on medications such as buprenorphine may be difficult for inpatient providers unfamiliar with its use, which may lead to undertreatment of patients with OUD, prolonged mechanical ventilation and length of stay.MethodsWe developed a 7-day buprenorphine low dose overlap initiation (LDOI) schedule for patients with OUD admitted to the ICU (Table 1). Buprenorphine tablets were split by pharmacists and placed into pre-made blister packs as a kit to be loaded into the automated medication dispensing machine for nursing to administer daily. An internal quality review validated the appropriate dosing of split-dose tablets. To simplify order entry and increase prescriber comfort with this new protocol, we generated an order set within our electronic health record software with prebuilt buprenorphine titration orders. This protocol was implemented alongside patient and healthcare team education and counseling on the LDOI process, with follow-up offered to all patients upon discharge.ResultsHere we report a series of 6 ICU patients started on buprenorphine using the LDOI schedule with split buprenorphine tablets. None of the 6 patients experienced precipitated withdrawal upon buprenorphine initiation using the LDOI schedule, and 5/6 patients were successfully extubated during the buprenorphine initiation. Four of six patients had a decrease in daily morphine milligram equivalents, with 3 patients transitioning to buprenorphine alone.ConclusionInitiating buprenorphine via LDOI was found to be successful in the development of a protocol for critically ill patients with OUD. We examined LDOI of buprenorphine in intubated ICU patients and found no events of acute precipitated withdrawal. This protocol can be used as a guide for other institutions seeking to start critically ill patients on medication treatment for OUD during ICU admission.

Methadone's Resurgence in Bridging the Treatment Gap in the Overdose Crisis: Position Statement of AMERSA, Inc (Association for Multidisciplinary Education, Research, Substance Use, and Addiction).

The United States is grappling with an unprecedented overdose crisis, exacerbated by the proliferation of potent synthetic opioids like illicitly manufactured fentanyl. Despite the efficacy of methadone treatment in managing opioid use disorder, regulatory barriers hinder its widespread utilization. This article examines the complex landscape of methadone regulation across federal, state, and local levels, highlighting disparities and opportunities for reform. The COVID-19 public health emergency prompted temporary flexibility in methadone regulations, including expanded take-home doses and telehealth counseling, leading to improved treatment experiences and retention. Permanent revisions to federal guidelines have since been introduced by the Substance Abuse and Mental Health Services Administration, reflecting a progressive shift toward patient-centered care and streamlined access. State regulations, managed by Single State Agencies and State Opioid Treatment Authorities, vary widely, often imposing additional restrictions that impede access to methadone treatment. Local OTP clinics further exacerbate barriers through stringent policies, despite federal and state guidelines advocating for flexibility. Coordinated efforts among policymakers, healthcare providers, and communities are needed to promote the development of accountability measures, incentives, and community involvement to ensure equitable access and quality of care. To truly meet the demand needed to end the existing overdose crisis and enhance accessibility and comprehensive healthcare services, methadone treatment expansion beyond traditional OTP settings into primary care offices and community pharmacies should take place.

Metabolism of highly potent synthetic opioid nitazene analogs: N-ethyl-N-(1-glucuronyloxyethyl) metabolite formation and degradation to N-desethyl metabolites during enzymatic hydrolysis.

The metabolism of the highly potent synthetic opioids metonitazene, etonitazene, and protonitazene was investigated in fresh human hepatocytes. In the hydrolyzed culture medium, N-desethyl-, N,N-di-desethyl-, O-desalkyl-, N-desethyl-O-desalkyl-, N,N-di-desethyl-O-desalkyl-, and N-oxidated metabolites were detected as phase I metabolites, whereas in the unhydrolyzed culture medium, O-glucuronides of phase I metabolites with O-dealkylation were detected as phase II metabolites. The detected phase I metabolites were identified by comparing their analytical data with those of synthesized authentic standards. In contrast, phase II metabolites were identified by comparing their analytical data with those of the glucuronidated products formed by the incubation of the corresponding substrates with human liver microsomes in the presence of uridine diphosphate glucuronic acid. In addition to the aforementioned metabolites, some putative N-ethyl-N-(1-glucuronyloxyethyl) metabolites were detected in the unhydrolyzed culture medium. Purification and hydrolysis experiments revealed that N-ethyl-N-(1-glucuronyloxyethyl) metabolites formed the corresponding N-desethyl metabolites via unstable N-ethyl-N-(1-hydroxyethyl) metabolites during enzymatic hydrolysis.

Development and validation of a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method including 25 novel synthetic opioids in hair and subsequent analysis of a Swiss opioid consumer cohort.

Major public health concern is raised by the evidence that common drugs like heroin are now frequently laced or replaced with highly potent novel synthetic opioids (NSOs). The objective of this study was to explore the prevalence and patterns of NSOs in a cohort of Swiss opioid users by hair analysis. Hair analysis is considered an ideal tool for retrospective consumption monitoring. Hair samples from 439 opioid users in Zurich were analyzed. Study inclusion required a previous positive hair test result for heroin metabolites, oxycodone, fentanyl, methadone, or tramadol. The samples were extracted with a two-step extraction procedure, followed by a targeted LC-MS/MS (QTRAP® 6500+) analysis in multiple reaction monitoring mode for a total of 25 NSOs. The method underwent full validation and demonstrated good selectivity and sensitivity with limits of detection (LOD) as low as 0.1pg/mg. The analyzed sample cohort demonstrated a positivity rate for NSOs of 2.5%, including the following NSOs: butyrylfentanyl, acrylfentanyl, furanylfentanyl, methoxyacetylfentanyl, ocfentanil, U-47700, isobutyrylfentanyl and benzylfentanyl. Furthermore, we were able to identify specific consumption patterns among drug users. The results indicate that hair analysis is a valuable tool for investigating the prevalence of NSOs in drug-using populations, which seems to be low in the case of Swiss opioid users. Nevertheless, the results highlight the need for sensitive analytical detection methods in forensic toxicology to identify and monitor substance distribution in different populations.

N-desethyl isotonitazene detected in polydrug users admitted to hospital in Birmingham, United Kingdom

Introduction Nitazenes are potent synthetic opioids and N-desethyl isotonitazene, a metabolite of isotonitazene, has emerged as a drug in its own right. Methods This is an observational case series of patients with suspected or declared substance use who were admitted to hospitals in the Sandwell and West Birmingham National Health Service Trust between July and October 2023. All patients were found on toxicological screening to have been exposed to N-desethyl isotonitazene. Results Twenty presentations involving 19 patients who tested positive for N-desethyl isotonitazene were included in the study. In 19 presentations, multiple substances were detected on toxicological screening. The number of patients testing positive for other substances were: 19 for cocaine and its main metabolite benzoylecgonine, 13 for morphine, 11 for the heroin-specific metabolite 6-monoacetylmorphine, ten for xylazine, eight for gabapentinoids (pregabalin and/or gabapentin), seven for methadone and/or the metabolite, 2-ethylidene-1, 5-dimethyl-3, 3-diphenylpyrrolidine, six for benzodiazepines and five for the synthetic cannabinoid MDMB-4en-PINACA. Only one patient had no other substances detected apart from N-desethyl isotonitazene. This patient presented with coma, miosis, bradypnoea and hypercapnia and responded to naloxone. In this cohort, the median concentration of N-desethyl isotonitazene was 1.53 µg/L (n = 14; range 0.59–5.48) in whole blood and 27.75 µg/L (n = 16; range 0.51–91.53) in urine. Discussion The majority of the patients in this cohort presented with features typical of an opioid overdose, which is unsurprising as they were all experienced users of diamorphine. Although these features are also consistent with the known effects of N-desethyl isotonitazene, in only one case is it possible to attribute the patient’s features to N-desethyl isotonitazene toxicity alone. Conclusions This case series highlights the need for toxicovigilance in the illicit drug market as patterns of substance misuse evolve and novel psychoactive substances continue to emerge.

Software-assisted automated detection and identification of "unknown" fentanyl analogues.

Fentanyl and its non-pharmaceutical analogues (NPFs) are potent synthetic opioids, traditionally used for pain management, with ever-increasing illicit uses. Tightening the regulation for known fentanyls leads to new synthetic analogues in the opioid market. Furthermore, the Organization for the Prohibition of Chemical Weapons (OPCW) has recently issued a decision regarding aerosolized use of central nervous system (CNS)-acting agents, such as fentanyl and its analogues, under the concern that these materials could be misused for terror or war purposes. The ever-increasing development of new fentanyl analogues makes the task of detection and identification of these new, unknown analogues crucial. In this work, we introduce an automated tool for the detection and putative identification of "unknown" fentanyl analogues, using liquid chromatography-mass spectrometry (LC-MS) (high-resolution mass spectrometry [HRMS]) analysis, subsequently followed by data processing using the "Compound Discoverer" software. This software, in our modified use, enabled the automatic detection of various fentanyl analogues, by "digging" out components and comparing them to pre-calculated theoretical molecular ions of possible modifications or transformations on the fentanyl backbone structure (no library or database used). Subsequently, structural elucidation for the proposed component of interest is carried out by automated MS/MS data interpretation, as performed by the software. This method was explored on 12 fentanyl-based "unknown" analogues used as model examples, including chemical modifications such as fluorination and methylation. In all tested compounds, automatic detection and identification were achieved, even at concentrations as low as 1 ng/mL in an environmental soil matrix extract.

IUPHAR review: Recent progress in the development of Mu opioid receptor modulators to treat opioid use disorders

Opioid Use Disorder (OUD) can be described as intense preoccupation with using or obtaining opioids despite the negative consequences associated with their use. As the number of OUD cases in the U.S. increase, so do the number of opioid-related overdose deaths. In 2022, opioid-related overdose became the No. 1 cause of death for individuals in the U.S. between the ages of 25 and 64 years of age. Because of the introduction of highly potent synthetic opioids (e.g. fentanyl) to the illicit drug market, there is an urgent need for therapeutics that successfully reduce the number of overdoses and can help OUD patients maintain sobriety. Most abused opioids stimulate the mu-opioid receptor (MOR) and activation of this receptor can lead to positive (e.g., euphoria) consequences. However, the negative side effects of MOR stimulation can be fatal (e.g., sedation, respiratory depression). Therefore, the MOR is an attractive target for developing medications to treat OUD. Current FDA drugs include MOR agonists that aid in detoxification and relapse prevention, and MOR antagonists that also serve as maintenance therapies or reverse overdose. These medications are limited by their abuse potential, adverse effects, or pharmacological profiles which leaves ample room for research into designing new chemical entities with optimal physiological effects. These includes, orthosteric ligands that target the primary binding site of the MOR, allosteric ligands that positively, negatively, or “silently” modulate receptor function, and lastly, bitopic ligands target both the orthosteric and allosteric sites simultaneously.

Postmortem toxicology findings from the Camden Opioid Research Initiative.

The United States continues to be impacted by decades of an opioid misuse epidemic, worsened by the COVID-19 pandemic and by the growing prevalence of highly potent synthetic opioids (HPSO) such as fentanyl. In instances of a toxicity event, first-response administration of reversal medications such as naloxone can be insufficient to fully counteract the effects of HPSO, particularly when there is co-occurring substance use. In an effort to characterize and study this multi-faceted problem, the Camden Opioid Research Initiative (CORI) has been formed. The CORI study has collected and analyzed post-mortem toxicology data from 42 cases of decedents who expired from opioid-related toxicity in the South New Jersey region to characterize substance use profiles. Co-occurring substance use, whether by intent or through possible contamination of the illicit opioid supply, is pervasive among deaths due to opioid toxicity, and evidence of medication-assisted treatment is scarce. Nearly all (98%) of the toxicology cases show the presence of the HPSO, fentanyl, and very few (7%) results detected evidence of medication-assisted treatment for opioid use disorder, such as buprenorphine or methadone, at the time of death. The opioid toxicity reversal drug, naloxone, was detected in 19% of cases, but 100% of cases expressed one or more stimulants, and sedatives including xylazine were detected in 48% of cases. These results showing complex substance use profiles indicate that efforts at mitigating the opioid misuse epidemic must address the complications presented by co-occurring stimulant and other substance use, and reduce barriers to and stigmas of seeking effective medication-assisted treatments.

A qualitative assessment of key considerations for drug checking service implementation

BackgroundWith many drug-related deaths driven by potent synthetic opioids tainting the illicit drug supply, drug checking services are becoming a key harm reduction strategy. Many drug checking technologies are available, ranging from fentanyl test strips to mass spectrometry. This study aimed to identify key considerations when implementing drug checking technologies and services to support harm reduction initiatives.MethodsKey informant interviews were conducted with harm reduction stakeholders throughout Illinois. Participants included members of existing drug checking services and recovery centers. Interviews were recorded, transcribed, and coded by two researchers using the framework method. Findings were contextualized according to micro (client)-, meso (organization)-, and macro (policy)-level themes.ResultsSeven interviews were conducted with ten participants. Fourier transform infrared spectroscopy was consistently identified as a technology of choice given its accuracy, range of substance detection, portability, and usability. Recommendations included the use of confirmatory testing, which can help address the limitations of technologies and provide a mechanism to train technicians. Locations of drug checking services should maximize public health outreach and leverage existing harm reduction agencies and staff with lived experience, who are critical to developing trust and rapport with clients. Criminalization and loss of privacy were major concerns for clients using drug checking services. Additional issues included the need to raise awareness of the legitimacy of services through public support from governing bodies, and funding to ensure the sustainability of drug checking services.ConclusionsThis research facilitated the identification of issues and recommendations from stakeholders around key considerations for the adoption of drug checking technologies, which not only included the cost and technical specifications of instrumentation, but also broader issues such as accessibility, privacy, and well-trained personnel trusted by clients of the service. Successful implementation of drug checking services requires knowledge of local needs and capacity and an in-depth understanding of the target population.

Fentanyl-induced reward seeking is sex and dose dependent and is prevented by D-cysteine ethylester.

Introduction: Despite their inclination to induce tolerance, addictive states, and respiratory depression, synthetic opioids are among the most effective clinically administered drugs to treat severe acute/chronic pain and induce surgical anesthesia. Current medical interventions for opioid-induced respiratory depression (OIRD), wooden chest syndrome, and opioid use disorder (OUD) show limited efficacy and are marked by low success in the face of highly potent synthetic opioids such as fentanyl. D-Cysteine ethylester (D-CYSee) prevents OIRD and post-treatment withdrawal in male/female rats and mice with minimal effect on analgesic status. However, the potential aversive or rewarding effects of D-CYSee have yet to be fully characterized and its efficacy could be compromised by interactions with opioid-reward pathology. Methods: Using a model of fentanyl-induced conditioned place preference (CPP), this study evaluated 1) the dose and sex dependent effects of fentanyl to induce rewarding states, and 2) the extent to which D-CYSee alters affective state and the acquisition of fentanyl-induced seeking behaviors. Results: Fentanyl reward-related effects were found to be dose and sex dependent. Male rats exhibited a range-bound dose response centered at 5µg/kg. Female rats exhibited a CPP only at 50µg/kg. This dose was effective in 25% of females with the remaining 75% showing no significant CPP at any dose. Pretreatment with 100mg/kg, but not 10mg/kg, D-CYSee prevented acquisition of fentanyl seeking in males while both doses were effective at preventing acquisition in females. Discussion: These findings suggest that D-CYSee is an effective co-treatment with prescribed opioids to reduce the development of OUD.

An Engineered Human-Antibody Fragment with Fentanyl Pan-Specificity That Reverses Carfentanil-Induced Respiratory Depression.

The opioid overdose crisis primarily driven by potent synthetic opioids resulted in more than 500,000 deaths in the US over the last 20 years. Though naloxone, a short-acting medication, remains the primary treatment option for temporarily reversing opioid overdose effects, alternative countermeasures are needed. Monoclonal antibodies present a versatile therapeutic opportunity that can be tailored to synthetic opioids and help prevent post-treatment renarcotization. The ultrapotent analog carfentanil is especially concerning due to its unique pharmacological properties. With this in mind, we generated a fully human antibody through a drug-specific B cell sorting strategy with a combination of carfentanil and fentanyl probes. The resulting pan-specific antibody was further optimized through scFv phage display, producing C10-S66K. This monoclonal antibody displays high affinity to carfentanil, fentanyl, and other analogs and reversed carfentanil-induced respiratory depression. Additionally, X-ray crystal structures with carfentanil and fentanyl bound provided structural insight into key drug:antibody interactions.

A TLR7/8 agonist increases efficacy of anti-fentanyl vaccines in rodent and porcine models.

Opioid use disorders (OUD) and overdose are public health threats worldwide. Widespread access to highly potent illicit synthetic opioids such as fentanyl is driving the recent rise in fatal overdoses. Vaccines containing fentanyl-based haptens conjugated to immunogenic carrier proteins offer a long-lasting, safe, and cost-effective strategy to protect individuals from overdose upon accidental or deliberate exposure to fentanyl and its analogs. Prophylactic or therapeutic active immunization with an anti-fentanyl vaccine induces the production of fentanyl-specific antibodies that bind the drug in the blood and prevent its distribution to the brain, which reduces its reinforcing effects and attenuates respiratory depression and bradycardia. To increase the efficacy of a lead anti-fentanyl vaccine, this study tested whether the incorporation of synthetic toll-like receptor (TLR) 4 and TLR7/8 agonists as vaccine adjuvants would increase vaccine efficacy against fentanyl challenge, overdose, and self-administration in either rats or Hanford miniature pigs. Formulation of the vaccine with a nucleolipid TLR7/8 agonist enhanced its immunogenicity and efficacy in preventing fentanyl-induced respiratory depression, analgesia, bradycardia, and self-administration in either rats or mini-pigs. These studies support the use of TLR7/8 adjuvants in vaccine formulations to improve their clinical efficacy against OUD and potentially other substance use disorders (SUD).

Evaluation of portable gas chromatography-mass spectrometry (GC-MS) for the analysis of fentanyl, fentanyl analogs, and other synthetic opioids.

Potent synthetic opioids including fentanyl and its analogs are frequently encountered in the field and require detection and identification by first responders to maintain the safety of drug abusers, first responders, health-care providers, and the public at large. Due to the low concentration at which these substances may be encountered and the complicating matrices within which they may be dispersed, the use of portable gas chromatography-mass spectrometry (GC-MS) for their identification in the field offers great potential value. This research established that portable GC-MS is a useful method for the detection and identification of a large number of synthetic opioids, especially fentanyl and its analogs. In this study, 250 synthetic opioids and related substances including 210 fentanyl analogs were analyzed using portable GC-MS. It was concluded that 225 of the 250 (90.0%) opioids analyzed were successfully detected onboard at the time of analysis and identified as either the substance (55.2%) or an analog (34.8%). These outcomes have equivalent benefit for the field analysis of illicit drugs due to both initiating the same subsequent actions by first responders.

Current attitudes toward drug checking services and a comparison of expected with actual drugs present in street drug samples collected from opioid users

BackgroundThe opioid epidemic continues to be associated with high numbers of fatalities in the USA and other countries, driven mainly by the inclusion of potent synthetic opioids in street drugs. Drug checking by means of various technologies is being increasingly implemented as a harm reduction strategy to inform users about constituent drugs in their street samples. We assessed how valued drug checking services (DCS) would be for opioid street drug users given the ubiquity of fentanyl and related analogs in the drug supply, the information they would most value from drug checking, and compared expected versus actual constituent drugs in collected samples.MethodsA convenience sample of opioid street drug users (N = 118) was recruited from two syringe service exchange programs in Chicago between 2021 and 2022. We administered brief surveys asking about overdose history, whether fentanyl was their preferred opioid, and interest in DCS. We also collected drug samples and asked participants what drug(s) they expected were in the sample. Provided samples were analyzed using LC–MS technology and the results compared to their expected drugs.ResultsParticipants reported an average of 4.4 lifetime overdoses (SD = 4.8, range = 0–20) and 1.1 (SD = 1.8, range = 0–10) past-year overdoses. A majority (92.1%) believed they had recently used drugs containing fentanyl whether intentionally or unintentionally. Opinions about the desirability of fentanyl were mixed with 56.1% indicating they did not and 38.0% indicating they did prefer fentanyl over other opioids, mainly heroin. Attitudes toward DCS indicated a general but not uniform receptiveness with a majority indicating interest in DCS though sizeable minorities believed DCS was “too much trouble” (25.2%) or there was “no point” in testing (35.4%). Participants were especially inaccurate identifying common cutting agents and potentiating drugs such as diphenhydramine in their samples (sensitivity = .17).ConclusionsResults affirmed street drug users remain interested in using DCS to monitor their drugs and such services should be more widely available. Advanced checking technologies that provide information on the relative quantities and the different drugs present in a given sample available at point-of-care, would be most valuable but remain challenging to implement.