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Introduction: 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 m-opioid receptor antagonists naloxone and nalmefene. Methods: 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 µopioid 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. Results: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

The surge in opioid-related deaths, driven predominantly by fentanyl and its synthetic derivatives, has become a critical public health concern, which is particularly evident in the United States. While the situation is less severe in Europe, the European Monitoring Centre for Drugs and Drug Addiction reports a rise in drug overdose deaths, with emerging concerns about the impact of fentanyl-related molecules. Synthetic opioids, initially designed for medical use, have infiltrated illicit markets due to their low production costs and high potency, with carfentanil posing additional threats, including potential chemical weaponization. Existing overdose mitigation heavily relies on naloxone, requiring timely intervention and caregiver presence, while therapeutic prevention strategies face many access challenges. To provide an additional treatment option, we propose the use of a fentanyl-specific monoclonal antibody (mAb), as a non-opioid method of prophylaxis against fentanyl and carfentanil. This mAb shows protection from opioid effects in a pre-clinical murine model. mAbs could emerge as a versatile countermeasure in civilian and biodefense settings, offering a novel approach to combat opioid-associated mortality. • FenAb024 has picomolar affinity to fentanyl and minimal affinity loss to carfentanil • The antibody is robustly thermostable • FenAb024 is a fentanyl and carfentanil-binding IgG that protects from drug effects • Protection is strongly correlated with antibody and drug dosage [ABSTRACT FROM AUTHOR]

Fentanyls are synthetic opioids up to 10,000 times more potent than morphine. Although initially developed for medical applications, fentanyl and its analogues have recently grown synonymous with the ongoing opioid epidemic. To combat the continued spread of these substances, there is a need for rapid and sensitive techniques for chemical detection. Surface‐enhanced Raman spectroscopy (SERS) has the potential for trace detection of harmful chemical substances. However, vibrational spectra obtained by SERS often differ between SERS substrates, as well as compared with spectra from normal Raman (NR) spectroscopy. Herein, SERS and NR responses from two fentanyl analogues, carfentanil (CF) and thiofentanil (TF), were measured and analysed with support from density functional theory (DFT) modelling. Using commercially available silver nanopillar SERS substrates, the SERS signatures of samples diluted in acetonitrile between 0.01 and 1000 µg/mL were studied. Relative SERS peak intensities measured in the range of 220–1800 cm−1 vary with concentration, while SERS and NR spectra largely agree for CF at higher concentrations (≥100 µg/mL). For TF, three distinct NR peaks at 262, 366 and 667 cm−1 are absent or strongly suppressed in the SERS spectrum, attributed to the lone‐pair electrons of the thiophene's sulphur atom binding to the Ag surface. The concentration dependence of the Raman peak at ∼1000 cm−1, assigned to trigonal bending of the phenyl ring, approximately follows a Langmuir adsorption isotherm. This work elucidates similarities and differences between SERS and NR in fentanyl detection and discusses the chemical rationale behind these differences. [ABSTRACT FROM AUTHOR]

Background: Despite the increase in fentanyl-involved overdose deaths in Canada, there have been no national-level studies evaluating the proportion of illicit opioids containing fentanyl or fentanyl analogues in Canada. Methods: This cross-sectional exploratory study characterized trends in fentanyl, carfentanil and other fentanyl analogues within opioids seized by law enforcement agencies in Canada from 2012 to 2022 and submitted to the Health Canada Drug Analysis Service (DAS). Analyses were stratified by province/region. Mann-Kandell tests were used to test for trends. Results: A total of 157,616 samples containing any opioid (“opioid-containing samples”) were submitted to the DAS from Canadian provinces between 2012 and 2022, of which 81,165 (51.5%) contained fentanyl or a fentanyl analogue. The percentage of opioid-containing samples that were positive for fentanyl or a fentanyl analogue increased from 3.0% (95% CI: 2.6–3.4%) in 2012–68.3% (67.7–68.9%) in 2022 (p < 0.001 for trend). The percentage of opioid-containing samples that were positive for fentanyl or a fentanyl analogue increased between 2012 and 2022 in all regions. In 2022, the percentage of samples containing fentanyl or an analogue followed an east-to-west gradient: 15.8% (13.3–18.6%) of samples in Atlantic Canada and 84.7% (83.6–85.7%) in British Columbia. Carfentanil was present in 4.9% (4.6–5.2%) of opioid-containing samples in Canada in 2022 and 19.7% (18.3–21.2%) of opioid-containing samples in Alberta. Conclusions: The illicit opioid supply in Canada increasingly contains toxic synthetic opioids. As of 2022, important regional differences existed in the illicit opioid supply in Canada.

This article, published in Frontiers in Psychiatry, discusses the discovery, development, and implementation of improved options for treating opioid overdose in the synthetic opioid era. The article highlights the challenges posed by synthetic opioids, such as fentanyl and carfentanil, which have led to an increase in fatal overdoses. The main focus of the article is on four manuscripts that provide new insights into the treatment of opioid overdose, including the effects of opioids on brain oxygen responses, the efficacy of naloxone in reversing opioid agonist activity, the use of a novel long-acting naloxone nanoparticle, and a comparison of intranasal naloxone and nalmefene in reversing respiratory depression and cardiac arrest. The article emphasizes the urgency and importance of finding effective treatments for opioid overdose in the current synthetic opioid era. [Extracted from the article]

IntroductionUsing 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.MethodsThis 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.ResultsFollowing 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.ConclusionSimulations 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.

Carfentanil is an ultra-potent synthetic opioid. The Russian police force used both carfentanil and remifentanil to resolve a hostage incident in Moscow. This reported use sparked an interest in the pharmacology and toxicology of carfentanil in the human body, and data on its metabolites were later published. However, there have been few studies on the synthesis of carfentanil metabolites, and biological extraction has also put forward large uncertainty in subsequent studies. The aim of the present study is to investigate the synthesis of biphasic metabolites that are unique to carfentanil. The purpose was to produce corresponding metabolites conveniently, quickly, and at low cost that can be used for comparison with published structures and to confirm the administration of carfentanil. [ABSTRACT FROM AUTHOR]

Skin decontamination of Chemical Biological Radioactive and Nuclear (CBRN) materials involves the timely and effective removal of the contaminants from the skin surface. The current work evaluated Fuller's Earth & The Reactive Skin Decontaminant Lotion Kit (RSDL®) to investigate whether they were as efficacious against free base Carfentanil skin contamination as they are against chemical warfare agents. The in vitro methodology used allowed for evaluation of decontamination regimens as specified by the decontaminant manufacturer rather than as an application of a bolus dose left in situ for the study duration. A selection of novel decontaminants, including Dermal Decontamination Gel (DDGel), Trivorex®, itaconic acid (IA), N,N′-methylenebisacrylamide (MBA), 2-trifluoromethylacrylic acid (TFMAA) and NanoSan Sorb were also tested for efficacy. All the evaluated decontaminants were successful at removing the majority of the Carfentanil skin surface contamination. The current work has shown that the Fuller's Earth decontamination kit, removes as much (or more) free base carfentanil from the skin surface in comparison to other products tested in this study series. • in vitro methodology for testing of skin decontamination regimens. • Investigation of decontamination efficacy against free base carfentanil skin contamination. • Evaluation of existing and novel skin decontaminants. • The majority of carfentanil skin contamination removed by tested decontaminants. [ABSTRACT FROM AUTHOR]

Background: Illicitly-manufactured fentanyl and stimulants have replaced prescription opioids as the primary contributors to fatal overdoses in the United States (US), yet the street supply of these substances is challenging to quantify. Building on the foundation of prior research on law enforcement drug reports, the present study compares publicly available forensic laboratory drug report measures to identify which measures account for the most variation in drug overdose mortality between states, within states over time, and in various demographic groups. Methods: Drug reports from the National Forensic Laboratory Information System and drug overdose mortality rates from the Centers for Disease Control and Prevention were examined for all US states and the District of Columbia, 2013–2021 (459 state-years). State- and year- fixed effects models regressed drug overdose mortality rates (in the overall population and subpopulations by sex, age, and race/ethnicity) on various drug report measures, including rates per population and proportional shares of drug reports positive for fentanyl/fentanyl-related compounds, heroin, cocaine, methamphetamine, and xylazine. Results: For drug overdose death rates in the overall population and nearly all subpopulations examined by sex, race/ethnicity, and age, the model including all drug report proportional measures represented the best-performing model (as identified via the lowest Akaike Information Criterion and highest within R-squared value), followed by the model including only the fentanyl/fentanyl-related compounds proportion. Conclusions: Findings support the utility of publicly available drug report composition measures, particularly the proportion of fentanyl/fentanyl-related compounds, as predictors of drug overdose mortality in the US and in various subpopulations.

Background and Purpose: The illicit use of fentanyl‐like drugs (fentanyls), which are μ opioid receptor agonists, and the many overdose deaths that result, has become a major problem. Fentanyls are very potent in vivo, leading to respiratory depression and death. However, the efficacy and possible signalling bias of different fentanyls is not clearly known. Here, we compared the relative efficacy and bias of a series of fentanyls. Experimental Approach: For agonist signalling bias and efficacy measurements, Bioluminescence Resonance Energy Transfer experiments were undertaken in HEK293T cells transiently transfected with μ opioid receptors, to assess Gi protein activation and β‐arrestin 2 recruitment. Agonist‐induced cell surface receptor loss was assessed using an enzyme‐linked immunosorbent assay, whilst agonist‐induced G protein‐coupled inwardly rectifying potassium channel current activation was measured electrophysiologically from rat locus coeruleus slices. Ligand poses in the μ opioid receptor were determined in silico using molecular dynamics simulations. Key Results: Relative to the reference ligand DAMGO, carfentanil was β‐arrestin‐biased, whereas fentanyl, sufentanil and alfentanil did not display bias. Carfentanil induced potent and extensive cell surface receptor loss, whilst the marked desensitisation of G protein‐coupled inwardly rectifying potassium channel currents in the continued presence of carfentanil in neurones was prevented by a GRK2/3 inhibitor. Molecular dynamics simulations suggested unique interactions of carfentanil with the orthosteric site of the receptor that could underlie the bias. Conclusions and Implications: Carfentanil is a β‐arrestin‐biased opioid drug at the μ receptor. It is uncertain how such bias influences in vivo effects of carfentanil relative to other fentanyls. [ABSTRACT FROM AUTHOR]

Incapacitating agents are chemical weapons that produce a temporary disabling condition that persists for hours or days after exposure. Their main site of action is the central nervous system and includes substances that are considered depressants or stimulants. While not intended to cause death, can produce significant morbidity in affected patients. The objective of this narrative review is to update the toxicokinetics, toxicodynamics, diagnosis, and treatment of these chemicals, considering that 20 years have passed since the Nord Ost Siege, where a fentanyl derivative was used by Russian forces to neutralize a group of Chechen dissidents. A bibliographic search was carried out in PubMed, SciELO, and Cochrane Library databases as well as nonindexed scientific literature. Abbreviation: AChE: Acetylcholinesterase; BZ: 3-Quinuclidinyl benzilate; CNS: Central nervous system; CSA: Controlled Substances Act; CW: Chemical weapon; CWC: Chemical Weapons Convention; DEA: Drug Enforcement Administration; DOR: Delta opioid receptor; EMCDDA: European Monitoring Center for Drugs and Drug Addiction; HEPA: High Efficiency Particulate Air; IAB: InterAgency Board; ICAs: Incapacitating agents; ID50: Incapacitating dose 50; IM: Intramuscular; IN: Intranasally; IV: Intravenous; KOR: Kappa opioid receptor; LSD: Diethylamide; MDMA: Methylenedioxy-methylamphetamine; MOR: Mu opioid receptor; NIOSH: National Institute for Occupational Safety and Health; NOR: Nociceptin opioid receptor; NSOs: Novel synthetic opioids; PCP: Phencyclidine; PKC: Protein kinase C; PLCb: Phospholipase C b; PNS: Peripheral nervous system; PPE: Personal protective equipment; QNB: 3-Quinuclidinyl benzilate; RCAs: Riot control agents; UDSs: Urine drug screens; UN: United Nations; US: United States; WHO: World Health Organization; ZOR: Zeta opioid receptor [ABSTRACT FROM AUTHOR]

BACKGROUND: The US has seen a rapid increase in synthetic opioid-related overdose deaths. We investigate Ohio, a state with one of the highest overdose death rates in 2017 and substantial numbers of deaths related to fentanyl, carfentanil, and other fentanyl analogs, to provide detailed evidence about the relationship between changes in the illicit drug market and overdose deaths. METHODS: We investigate the illicit drug market using Ohios Bureau of Criminal Investigations (BCI) crime lab data from 2009 to 2018 that shows the content of drugs seized by law enforcement. We use Poisson regression analysis to estimate the relationship between monthly crime lab data and monthly unintentional drug overdose death data at the county level. RESULTS: During this time period there has been a rapid change in the composition of drugs analyzed by the BCI labs, with a rapid fall in heroin observations, simultaneous rise in synthetic opioids, and an increase in the number of different fentanyl analogs. We find that the increased presence of fentanyl, carfentanil, and other fentanyl analogs have a strong correlation with an increase in overdose deaths. The types of opioids most associated with deaths varies by the population size of the county. CONCLUSIONS: Crime lab data has the potential to be used as an early warning system to alert persons who inject drugs, harm reduction services, first responders, and law enforcement about changes in the illicit opioid risk environment.

Abstract Since the early 2010s, synthetic opioids have significantly contributed to overall opioid-related overdose mortalities. For point of reference, of the 68,630 opioid-related deaths recorded in 2020, 56,516 involved synthetic opioids. During much of this period, fentanyl has been the most commonly used synthetic opioid. This time when fentanyl was the most popular opioid has been called the “third wave” of the opioid crisis, partly because it led to a sharp rise in deaths from overdoses. Other synthetic opioids, such as carfentanil, protonitazene, and isotonitazene, have also become more widely diverted for nonmedical used. Carfentanil is an even more potent fentanyl derivative that was initially used in the mid-1980s as a general anesthetic for large animals such as elephants. Related to its strong affinity for mu opioid receptors, carfentanil is still utilized in medicine and science today as a radiotracer for positron emission tomography imaging. Protonitazene and isotonitazene belong to a novel class of synthetic opioids called benzimidazoles that were manufactured in the 1950s as novel analgesics. These agents have come under recent scrutiny as designer synthetic opioids becoming more prevalent. However, to date, there is incomplete data regarding the prevalence of synthetic opioids, as traditional toxicology screenings may not be sensitive to detect these compounds at such low doses post-mortem, particularly when blood is drawn from the periphery instead of central tissues such as the brain, lung, or heart. This narrative review aims to highlight the clinical challenges presented by these new synthetic opioids.

Carfentanil is one of the most potent synthetic opioids ever developed, with an estimated analgesic potency approximately 20–100 times that of fentanyl and 10,000 times that of morphine. Carfentanil has been appearing in the illicit drug supply in many regions and has been linked to fatal overdose events. A subset of 59 street drug samples obtained in Victoria, B.C., that were confirmed to contain carfentanil were analyzed by mass spectrometry for this study. Carfentanil quantitation by paper spray mass spectrometry ranged from 0.05 to 2.95 w/w% (median = 0.32%) in the original drug sample. Paper spray mass spectrometry analysis also detected two unknown peaks at m/z 380.2 and 381.2 in 31 of these 59 samples (53%). Initial tandem mass spectrometry experiments revealed structural similarities between these unknown compounds and carfentanil, suggesting they were potential structural analogs, possibly arising from incomplete purification during synthesis. High‐resolution mass spectrometry determined the chemical formulas of these compounds as C23H29N3O2 (m/z 380.2333) and C23H29N2O3 (m/z 381.2137). Literature and tandem mass spectrometry results were used to determine the identity of these potential new psychoactive substances, C23H29N3O2 as desmethylcarfentanil amide and C23H29N2O3 as desmethylcarfentanil acid. μ‐Opioid receptor binding modeling determined that the binding poses of these analogs were nearly identical to that of carfentanil with relative binding energy calculations of 0.544 kJ/mol (desmethylcarfentanil amide) and −0.171 kJ/mol (desmethylcarfentanil acid); these data suggest they may share the toxic effects of carfentanil and have similar potencies. [ABSTRACT FROM AUTHOR]

Carfentanil is a synthetic opioid 10.000 times stronger than morphine. This is why it is a substance with dual interest, since it has been used both as an analgesic and as a drug of abuse. Among the toxicokinetic characteristics of carfentanil, its high lipid solubility stands out. In addition, there is a possibility that carfentanil follows a non-linear elimination kinetics. In 2002, it was used by the Russian Security Forces to try to resolve the hostage crisis at the Dubrovka theater in Moscow, causing the death of at least 123 hostages. On the other hand, it has been used as a drug of abuse and as an adulterant in other drugs. In case of overdose, the administration of repeated doses of antidote may be necessary. The content of this review justifies the need to develop and validate an analytical method for the detection of carfentanil and its metabolite norcarfentanil in biological samples. [ABSTRACT FROM AUTHOR]

Since the early 2010s, synthetic opioids have significantly contributed to overall opioid-related overdose mortalities. For point of reference, of the 68,630 opioid-related deaths recorded in 2020, 56,516 involved synthetic opioids. During much of this period, fentanyl has been the most commonly used synthetic opioid. This time when fentanyl was the most popular opioid has been called the "third wave" of the opioid crisis, partly because it led to a sharp rise in deaths from overdoses. Other synthetic opioids, such as carfentanil, protonitazene, and isotonitazene, have also become more widely diverted for nonmedical used. Carfentanil is an even more potent fentanyl derivative that was initially used in the mid-1980s as a general anesthetic for large animals such as elephants. Related to its strong affinity for mu opioid receptors, carfentanil is still utilized in medicine and science today as a radiotracer for positron emission tomography imaging. Protonitazene and isotonitazene belong to a novel class of synthetic opioids called benzimidazoles that were manufactured in the 1950s as novel analgesics. These agents have come under recent scrutiny as designer synthetic opioids becoming more prevalent. However, to date, there is incomplete data regarding the prevalence of synthetic opioids, as traditional toxicology screenings may not be sensitive to detect these compounds at such low doses post-mortem, particularly when blood is drawn from the periphery instead of central tissues such as the brain, lung, or heart. This narrative review aims to highlight the clinical challenges presented by these new synthetic opioids. [ABSTRACT FROM AUTHOR]

Background: Although naloxone has proven to be an effective opioid reversal agent, concern that high doses of naloxone can cause pulmonary edema may prevent health care providers from administering it in initial high doses. Objective: Our aim was to determine whether increased doses of naloxone are correlated with an increase in pulmonary complications in patients presenting to the emergency department (ED) after an opioid overdose. Methods: This was a retrospective study of patients treated with naloxone by emergency medical services (EMS) or in the ED at an urban level I trauma center and three associated freestanding EDs. Data were queried from EMS run reports and the medical record and included demographic characteristics, naloxone dosing, administration route, and pulmonary complications. Patients were grouped by naloxone dose received, defined as low (≤ 2 mg), moderate (> 2 mg to ≤ 4 mg), and high (> 4 mg). Results: Of the 639 patients included, 13 (2.0%) were diagnosed with a pulmonary complication. There was no difference in the development of pulmonary complications across groups (p = 0.676). There was no difference in pulmonary complications based on the route of administration (p = 0.342). The administration of higher doses of naloxone was not associated with longer hospital stays (p = 0.0327). Conclusions: Study results suggest that the reluctance of many health care providers to administer larger doses of naloxone on initial treatment may not be warranted. In this investigation, there were no poor outcomes associated with an increase in naloxone administration. Further investigation in a more diverse population is warranted. [ABSTRACT FROM AUTHOR]

Introduction: The emergence of fentanyl and its analogues have contributed to a drastic rise in overdose‐related mortality in recent years. The objective of this study was to determine the number of drug checking samples containing fentanyl and fentanyl analogues using both point of care and confirmatory drug checking technologies. Methods: Point‐of‐care drug checking data, using a combination of fentanyl immunoassay strips and Fourier‐transform infrared spectroscopy (FTIR), were collected at harm reduction sites in Vancouver and Surrey, British Columbia. Based on current recommendations from the British Columbia Centre on Substance Use Drug Checking Project, a subset of these samples was sent for confirmatory analysis using quantitative nuclear resonance spectroscopy, gas chromatography–mass spectrometry and/or liquid chromatography‐mass spectrometry. Results: A total of 22,916 samples were tested using FTIR and fentanyl immunoassay strips, of which 6125 (29%) were positive for fentanyl and/or fentanyl analogues. FTIR identified a fentanyl analogue in five samples (all carfentanil). Of the 1467 samples sent for confirmatory analysis, fentanyl was identified in 855 (58%) and fentanyl analogues in 85 (6%), including: carfentanil (n = 56), acetyl fentanyl (n = 15), furanyl fentanyl (n = 9) and cyclopropyl fentanyl (n = 5). Discussion and Conclusion: Our research found that FTIR does not consistently distinguish between fentanyl and its analogues at point of care and that highly sensitive confirmatory drug checking technologies are needed to identify fentanyl analogues. These findings underscore the limitations of current drug checking technologies and the importance of using both point of care and confirmatory drug checking initiatives for monitoring changes in the drug supply. [ABSTRACT FROM AUTHOR]

Carfentanil, as a fentanyl analogue, is a potent synthetic opioid. It has been controlled in many countries, and its emergence has been highlighted by many recent reports. However, although discriminative stimulus effects of carfentanil in rats had been reported, its abuse potential has not been fully evaluated. In this study, we evaluated the abuse potential of carfentanil via the tests of conditioned place preference (CPP), drug self‐administration and naloxone‐precipitated opioid withdrawal assay, compared with fentanyl and heroin. Carfentanil exhibited significant place preference at a minimum dose of 1 μg/kg in mice, whereas fentanyl and heroin induced significant place preference at the minimum doses of 100 μg/kg and 1000 μg/kg, respectively. In the drug‐substitution test in heroin self‐administered rats (50 μg/kg/infusion), carfentanil and fentanyl acquired significant self‐administrations above saline levels from 0.05–0.1 and 0.1–10.0 μg/kg/infusion, respectively. Carfentanil induced the maximum number of infusions at 0.1 μg/kg, whereas fentanyl and heroin at 1 and 25 μg/kg, respectively. In short, carfentanil showed the highest potency to induce CPP and self‐administration. Furthermore, repeated treatment with escalating doses of carfentanil, fentanyl or heroin induced typical withdrawal symptoms in mice, including a greater number of jumping and weight loss than saline group. This indicated that carfentanil could produce physical dependence similar to fentanyl and heroin. Taken together, the present study demonstrated the higher abuse potential of carfentanil compared with fentanyl and heroin. The rank order of abuse potential for these compounds is carfentanil > fentanyl > heroin. [ABSTRACT FROM AUTHOR]

Purpose: Photoperiod determines the metabolic activity of brown adipose tissue (BAT) and affects the food intake and body mass of mammals. Sympathetic innervation of the BAT controls thermogenesis and facilitates physiological adaption to seasonal changes, but the exact mechanism remains elusive. Previous studies have shown that central opioid signaling regulates BAT thermogenesis, and that the expression of the brain mu-opioid receptor (MOR) varies seasonally. Therefore, it is important to know whether MOR expression in BAT shows seasonal variation. Methods: We determined the effect of photoperiod on BAT MOR availability using [11C]carfentanil positron emission tomography (PET). Adult rats (n = 9) were repeatedly imaged under various photoperiods in order to simulate seasonal changes. Results: Long photoperiod was associated with low MOR expression in BAT (β = − 0.04, 95% confidence interval: − 0.07, − 0.01), but not in muscles. We confirmed the expression of MOR in BAT and muscle using immunofluorescence staining. Conclusion: Photoperiod affects MOR availability in BAT. Sympathetic innervation of BAT may influence thermogenesis via the peripheral MOR system. The present study supports the utility of [11C]carfentanil PET to study the peripheral MOR system. [ABSTRACT FROM AUTHOR]

Introduction: the detection of Carfentanil, a dangerous opioid, is critical due to its appearance in other drugs and its high potency. Its consumption carries a series of negative effects such as respiratory depression, hypotension, bradycardia and decreased intestinal motility. Objectives: the purpose of this systematic review is to examine or evaluate or summarize the main toxicological detection methods related to deaths caused by carfentanil, focusing on the study of the adverse chemical effects it produces in humans. Methodology: this research collected relevant information in the field of forensic toxicology. Which focused on carfentanil detection methods and how it affects people. PRISMA review guidelines were followed and the PICO strategy was used to define the focus of the study. Results: different detection methods have been found such as blood, urine, saliva, liver, pericardial fluid and vitreous humor tests. These methods involve the extraction of biological samples and their subsequent analysis using advanced techniques such as chromatography and mass spectrometry. Even advanced techniques, such as portable mass spectrometry, have been developed to rapidly identify the presence of carfentanil in drug samples. However, the availability of these methods in healthcare settings remains limited. Conclusions: it is crucial to understand the deterioration and damage caused to the body and address the crisis regarding the marketing of this highly dangerous substance. This highlights the urgent need to address this issue and protect society from the risks associated with carfentanil. [ABSTRACT FROM AUTHOR]

Carfentanil is an ultra-potent synthetic opioid. The Russian police force used both carfentanil and remifentanil to resolve a hostage incident in Moscow. This reported use sparked an interest in the pharmacology and toxicology of carfentanil in the human body, and data on its metabolites were later published. However, there have been few studies on the synthesis of carfentanil metabolites, and biological extraction has also put forward large uncertainty in subsequent studies. The aim of the present study is to investigate the synthesis of biphasic metabolites that are unique to carfentanil. The purpose was to produce corresponding metabolites conveniently, quickly, and at low cost that can be used for comparison with published structures and to confirm the administration of carfentanil.

Chemical weapons are a diverse range of substances that can be used to cause intentional death or harm through their toxic properties. They include nerve agents, vesicants, lung-damaging agents, cyanide, biological toxins, and riot control agents, as well as emerging threats such as the highly potent opioid carfentanil. Although infrequent, chemical weapons casualties can and have presented to civilian hospitals as the result of terrorist attacks, assassination attempts, and accidental exposure. Recognition of the potential chemical casualty is required to initiate specific treatment and appropriate personal protective measures. However, this is made challenging by a low index of suspicion, unclear history of exposure, limitations of field-testing equipment, and variable presentations that may be confounded by psychological symptoms, physical injuries, hyperthermia from personal protective equipment (PPE), and the side effects of antidotes. This article gives a brief overview of how to identify and manage chemical incidents, the toxicology, symptomatology, and treatment of a selected number of chemical agents. Further detail can be found in the listed references. [ABSTRACT FROM AUTHOR]

Carfentanil, a µ-opioid receptor (MOR) agonist with an analgesic potency 10,000 times that of morphine, is extensively metabolized to norcarfentanil (M1), 4-Piperidinecarboxylic acid, 1-(2-hydroxy-2-phenylethyl)-4-[(1-oxopropyl)phenylamino]-, methyl ester (M0 in this article), and other low abundant metabolites in human hepatocytes and liver/lung microsomes. M0 possessed comparable MOR activity to carfentanil, and accounted for approximately 12 % of the total carfentanil metabolite formation in human liver microsomes (HLMs). Little is known about the subsequent elimination of M0. This study investigated its metabolic pathway in HLMs, separation and preliminary identification of metabolites by liquid chromatography-tandem mass spectrometry, and possible involvement of cytochrome P450 enzymes in M0 metabolism with kinetic analysis. M0 produced 9 metabolites via N-dealkylation (M1), oxidation (M3, M6–9), N-dealkylation followed by oxidation (M2 and M4), and glucuronidation (M5). Formation of the major metabolite M1 fitted typical Michaelis-Menten kinetics. Recombinant human CYP3A5 showed the highest activity toward M1 formation followed by CYP3A4 and CYP2C8, while M8 was primarily formed by CYP3A4 followed by CYP2C19 and CYP2C8. These findings reveal the main involvement of CYP3A5 and 3A4 in human hepatic elimination of M0 with a kinetic profile similar to carfentanil which may inform development of treatment protocols for carfentanil exposure. • The dominant metabolite norcarfentanil (M1) of carfentanil active metabolite M0 was predominantly formed by isozyme CYP3A5. • Phase II glucuronidation is a minor pathway for M0 biotransformation in human liver microsomes (HLM). • CYP3A5 exhibited about 2.7-fold of Cl int value compared with that of CYP3A4 for metabolite M1. [ABSTRACT FROM AUTHOR]

Background: Ohio's age-adjusted opioid overdose fatality rate is double the national average. In an ever-evolving epidemic, it is crucial to monitor trends to inform public health interventions. Methods: A retrospective study was conducted using the Medical Examiner's decedent case files for all accidental opioid-related adult overdose deaths in Cuyahoga County (Cleveland), Ohio in 2017. Characterization of trends was based on autopsy/toxicology and first responder reports, medical records and death scene investigations. Results: Of 543 accidental opioid-related adult overdose fatalities, 64.1% died from 3+ drugs. The most common cause of death (COD) drugs included fentanyl (63.4%), heroin (44.4%), cocaine (37.0%) and carfentanil (35.0%). There were four times as many African American decedents as two years prior. Three or more COD drugs was >50% more common in those with fentanyl (Prevalence Ratio (PR) = 1.56[1.34–1.70]; p

The geometrical molecular structures, atomic charges, frontier molecular orbitals, and UV–visible electronic data of analgesic drugs carfentanil and acetylfentanyl were computed using quantum chemical code. In addition, NMR (1H and 13C) chemical shifts, harmonic vibrational wavenumbers, and the corresponding vibrational assignments were proposed on the basis of potential energy distribution. The calculations were carried out at Becke-3-Lee–Yang–Parr (B3LYP) functional with density functional theory (DFT) and time-dependent density functional theory (TD-DFT) using the 6–311 + + G(d,p) basis set. The piperidine rings of the two molecules adopt a more stable chair conformation of a six-membered ring structure with slight distortion at the point of substitution. This shows that the piperidine moiety of the carfentanil and acetylfentanyl have similar geometric parameters and thus support the hypothesis that the piperidine ring in these molecules is the primary structural feature that is responsible for their analgesic activities. In addition, the introduction of the carbomethoxy (-COCH3) group into the piperidine ring of fentanyl has little or no effect on the electronic properties of this class of molecules. The theoretical results were successfully compared with similar piperidine-based analgesic drugs fentanyl and available experimental data. This research gives precise and invaluable information that will help in the structural elucidation of analogs of fentanyl that could be used in the development of analytical methods for the accurate and reliable detection and monitoring of these important molecules. [ABSTRACT FROM AUTHOR]

Carfentanil is a powerful synthetic opioid that is approximately 100 times more potent than fentanyl and 10,000 times more potent than morphine. Carfentanil was originally intended to be used as a sedative for big game animals in a veterinary setting, but it is becoming increasingly recognized as a public health concern. We set out to investigate the effectiveness of naloxone against a potentially lethal dose of inhaled carfentanil in male ferrets. Ferrets were implanted with telemetry devices to study cardiac parameters and exposed to aerosolized carfentanil in a whole-body plethysmography chamber to record respiratory parameters. We observed profound respiratory depression in exposed animals, which led to apneic periods constituting 24–31 % of the exposure period. Concomitant with these apneic periods, we also observed cardiac abnormalities in the form of premature junctional contractions (PJCs). At our acute exposure dose, lethal in 3 % of our animals, naïve ferrets were unresponsive and incapacitated for a total of 126.1 ± 24.6 min. When administered intramuscularly at human equivalent doses (HEDs) of either 5 mg or 10 mg, naloxone significantly reduced the time that ferrets were incapacitated following exposure, although we observed no significant difference in the reduction of time that the animals were incapacitated between the treatment groups. Naloxone was able to quickly resolve the respiratory depression, significantly reducing the frequency of apneic periods in carfentanil-exposed ferrets. Our results suggest that naloxone, when administered via intramuscular injection following incapacitation, is a viable treatment against the effects of a potentially lethal dose of inhaled carfentanil.

Carfentanil is a highly potent fentanyl analogue as well as a new psychoactive substance (NPS) which aroused concerns and research efforts in recent years. In this paper, 2 cases involving carfentanil and the quantitative assay using LC-MS/MS is described. Deceased 1 was a 52-year-old male with carfentanil detected in the peripheral blood at a level of 0.5 ng/mL. Carfentanil was also detected in the gastric content. Deceased 2 was a 25-year-old male with carfentanil detected in iliac blood at a level of 0.9 ng/mL. Without information revealing the potential involvement of carfentanil, screening of gastric content provided crucial information in these cases. Since the carfentanil concentration was very low in the blood, a sensitive LC-MS/MS method for determination of carfentanil in blood is also described.

Carfentanil, an ultrapotent analog of fentanyl, has invaded the street drug market, unbeknownst to many heroin users. About 10,000 times more potent than morphine, it was initially suspected that 20 μg of the substance was lethal. In this case series, we present 17 confirmed carfentanil overdoses in Michigan, with a primary focus on the concentration levels. Through a retrospective review, each public death reported in Oakland County, Michigan, with a subsequent toxicology report was investigated for suspected carfentanil use. To characterize each fatality, the autopsy results were collected, including the postmortem findings at scene and the decedent's medical and social history. Carfentanil levels were measured through liquid chromatography and tandem mass spectrometry (LC-MS-MS) by National Medical Services (NMS) Laboratories. Our case series found postmortem carfentanil concentrations as low as 10 ng/mL, with a mean concentration of 0.387 ng/mL. Ultimately, there are implications on law enforcement, first responders, and health care providers when dealing with this emerging illicit substance, and there is an alarmingly high mortality rate associated with the abuse of carfentanil.

Background and Aims: It is widely believed that the 2018 decline in overdose deaths in the United States was attributable to a range of public health interventions, however, this decline also coincided with the regulation and decline in use of potent fentanyl analogs, especially carfentanil. The aim of this study was to investigate the association between overdose deaths and carfentanil availability in the United States. Design Secondary analysis of drug overdose deaths from the Center for Disease Control and Prevention (CDC) and carfentanil exhibit data from drug seizures submitted to drug crime labs and published by the Drug Enforcement Administration (DEA). Trends in overdose deaths were compared in states with high carfentanil exhibits with states with low or no carfentanil exhibits. Setting: United States. Participants: A total of 1 035 923 drug overdose death records in the United States from 1979 through 2019 were studied. Measurements The outcomes studied were number of overdose deaths and mortality rates by state. Findings Drug overdose deaths have been closely tracked along an exponential curve. The years 2016 and 2017 witnessed a hyper‐exponential surge with increases in overdose deaths of 11 228 (+21.4%) and 6605 (+10.4%), respectively. Subsequently in 2018, drug overdose deaths declined by −2870 (−4.1%). This rise and then fall coincided with a surge and then decline in carfentanil drug seizure exhibits during these same years: 0 (2015), 1292 (2016), 5857 (2017) and 804 (2018). The majority of carfentanil exhibits were localized to a few states. The 2018 decline in overdose deaths in the top five states with the greatest spike in carfentanil exhibits in 2017 (Ohio, Florida, Pennsylvania, Kentucky and Michigan) was 2848, which accounted for nearly all of the total US decline. Conclusions: The 2016–2017 acceleration and then 2018 decline in drug overdose deaths in the United States was associated with the sudden rise and then fall of carfentanil availability. Given the regional variation, carfentanil's decreased availability may have contributed to the reduction in overdose deaths in 2018. [ABSTRACT FROM AUTHOR]

• Carfentanil metabolites M1, M11, and M15 were predominantly formed by isozyme CYP3A5. • CYP3A5 exhibited about 3-, 3-, and 8-fold of Cl int value compared with that of CYP3A4 for metabolites M1, M11 and M15, respectively. • Highly potent carfentanil metabolite M13 was predominantly formed by isozyme CYP2C9. Carfentanil is an ultra-potent opioid with an analgesic potency 10,000 times that of morphine but has received little scientific investigation. In the present study, the human cytochrome P450 (CYP) isozymes catalyzing the oxidative metabolism of carfentanil were investigated. Using UHPLC-HRMS, Michaelis-Menten kinetics of formation for three major metabolites norcarfentanil (M1), pharmaceutical active metabolite 4-[(1-oxopropyl)phenylamino]-1-(2-hydroxyl-2-phenylethyl)-4-piperidinecarboxylic acid methyl ester (M11), and 4-[(1-oxopropyl)phenylamino]-1-(2-oxo-2-phenylethyl)-4-piperidinecarboxylic acid methyl ester (M15) were determined. Isozymes catalyzing the formation of the low abundant, highly active metabolite 1-[2-(2-hydroxylphenyl)ethyl]-4-[(1-oxopropyl)phenylamino]-4-piperidinecarboxylic acid methyl ester (M13) were also identified. Selective P450 inhibition studies with pooled human liver microsomes (HLMs) and recombinant CYP isozymes suggested that metabolites M1, M11, and M15 were predominantly formed by isozyme CYP3A5, followed by CYP3A4. Isozymes CYP2C8 and CYP2C9 also made contributions but to a much lesser extent. Highly potent metabolite M13 was predominantly formed by isozyme CYP2C9, followed by CYP2C8. These findings indicate that CYP3A5, CYP3A4, CYP2C8 and CYP2C9 play a major role in the transformation of carfentanil to M1 (norcarfentanil), M11, M13 and M15 through N-dealkylation of piperidine ring, hydroxylation of phenethyl group and ketone formation on phenethyl linker by human liver micrsomes. [ABSTRACT FROM AUTHOR]

The opioid epidemic in Ontario has seen opioid-related deaths double in recent years, from 676 deaths in 2014 to 1,474 in 2018, with an overwhelming prevalence of fentanyl and fentanyl-analogues, such as carfentanil. The presence of drug paraphernalia and a history of drug-use is often a strong indicator of a drug-related death, indicating a need for toxicological analysis. Demographic and drug-related patterns associated with opioid deaths in Ontario from June 2017 to December 2018 (n = 2403) were investigated using data collected from the Coroner's Opioid Investigative Aid (OIA). This work aims to provide insight on how the opioid epidemic affects certain demographics to aid investigators conduct targeted analyses and help public health officials identify vulnerable communities. Chi-square and logistic regressions were conducted to evaluate if age and sex were predictors for the presence of drug paraphernalia, and if drug paraphernalia, sex, age, or history of drug use were associated with causes of deaths (COD). Chi-square analysis revealed that sex (p < 0.001), the presence of drug-use history (p < 0.001), and the presence of drug paraphernalia at the scene of death (p < 0.001) were significantly associated with CODs. Sex was also significantly associated with the presence of drug paraphernalia (p < 0.001). Logistic regression analysis indicated that age (p < 0.001) influenced the probability of opioid-related deaths. Probability models relating age to various opioid-related CODs were also generated. These results demonstrated that fentanyl-related deaths are more associated with males, younger individuals, individuals with a history or drug-use, and the presence of drug paraphernalia. [ABSTRACT FROM AUTHOR]

Background: Despite the increase in fentanyl-involved overdose deaths in Canada, there have been no national-level studies evaluating the proportion of illicit opioids containing fentanyl or fentanyl analogues in Canada., Methods: This cross-sectional exploratory study characterized trends in fentanyl, carfentanil and other fentanyl analogues within opioids seized by law enforcement agencies in Canada from 2012 to 2022 and submitted to the Health Canada Drug Analysis Service (DAS). Analyses were stratified by province/region. Mann-Kandell tests were used to test for trends., Results: A total of 157,616 samples containing any opioid ("opioid-containing samples") were submitted to the DAS from Canadian provinces between 2012 and 2022, of which 81,165 (51.5%) contained fentanyl or a fentanyl analogue. The percentage of opioid-containing samples that were positive for fentanyl or a fentanyl analogue increased from 3.0% (95% CI: 2.6-3.4%) in 2012-68.3% (67.7-68.9%) in 2022 (p < 0.001 for trend). The percentage of opioid-containing samples that were positive for fentanyl or a fentanyl analogue increased between 2012 and 2022 in all regions. In 2022, the percentage of samples containing fentanyl or an analogue followed an east-to-west gradient: 15.8% (13.3-18.6%) of samples in Atlantic Canada and 84.7% (83.6-85.7%) in British Columbia. Carfentanil was present in 4.9% (4.6-5.2%) of opioid-containing samples in Canada in 2022 and 19.7% (18.3-21.2%) of opioid-containing samples in Alberta., Conclusions: The illicit opioid supply in Canada increasingly contains toxic synthetic opioids. As of 2022, important regional differences existed in the illicit opioid supply in Canada., (© 2024 The Author(s).)

Processing of positron emission tomography (PET) data typically involves manual work, causing inter-operator variance. Here we introduce the Magia toolbox that enables processing of brain PET data with minimal user intervention. We investigated the accuracy of Magia with four tracers: [11C]carfentanil, [11C]raclopride, [11C]MADAM, and [11C]PiB. We used data from 30 control subjects for each tracer. Five operators manually delineated reference regions for each subject. The data were processed using Magia using the manually and automatically generated reference regions. We first assessed inter-operator variance resulting from the manual delineation of reference regions. We then compared the differences between the manually and automatically produced reference regions and the subsequently obtained binding potentials and standardized-uptake-value-ratios. The results show that manually produced reference regions can be remarkably different from each other, leading to substantial differences also in outcome measures. While the Magia-derived reference regions were anatomically different from the manual ones, Magia produced outcome measures highly consistent with the average of the manually obtained estimates. For [11C]carfentanil and [11C]PiB there was no bias, while for [11C]raclopride and [11C]MADAM Magia produced 3–5% higher binding potentials. Based on these results and considering the high inter-operator variance of the manual method, we conclude that Magia can be reliably used to process brain PET data.

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This study was to validate a LC–MS/MS method for the determination of 17 new synthetic opioids (NSOs) in hair including 3‐fluorofentanyl, 3‐methylfentanyl, acetylfentanyl, acetylnorfentanyl, alfentanyl, butyrylfentanyl, butyrylnorfentanyl, carfentanil, fentanyl, furanylfentanyl, furanylnorfentanyl, methoxyacetylfentanyl, norcarfentanil, norfentanyl, ocfentanil, sufentanil, and U‐47700, and to apply it to 137 authentic samples. Twenty milligrams of hair was decontaminated in dichloromethane and underwent liquid extraction. 10 μL of the reconstituted residue were injected onto the system. The separation was performed in 12 minutes in a gradient mode at a flow rate of 300 μL/min using a Hypersyl Gold PFP column (100 × 2.1 mm i.d., 1.9 μm) maintained at 30°C. Compounds were detected in positive ionization and MRM modes using a TSQ Endura mass spectrometer (ThermoFisher). The method was validated according to EMA guidelines. The LLOQ was in the range 1–50 pg/mg, and the calibration ranged from the LLOQ‐1000 pg/mg. Intra‐ and inter‐day accuracy (bias) and precision were < 15%. Extraction recoveries of parent drugs and metabolites were 74–120% and 7–62%, respectively. The matrix effect was in the range 59–126% (CVs ≤ 12.9%). Fentanyl was found in six cases at concentrations of < 1–1650 pg/mg (n = 14 segments). Five fentanyl analogs were quantified in two cases: 3‐fluorofentanyl (25–150 pg/mg, n = 5), furanylfentanyl (15–500 pg/mg, n = 5), methoxyacetylfentanyl (500–600 pg/mg, n = 2), acetylfentanyl (1 pg/mg, n = 2), carfentanyl (2.5–3 pg/mg, n = 2). This fully validated method allowed us to test for the first time 3‐fluorofentanyl and norcarfentanil in hair among 15 other NSOs, and brings new data regarding 3‐fluorofentanyl and methoxyacetylfentanyl hair concentrations. [ABSTRACT FROM AUTHOR]

Purpose: The metabolism of carfentanil was assessed using human, dog, and rat pulmonary microsomes. Mass spectrometry based analysis allowed for metabolite identification and species differentiation. Participation of different metabolic enzymes in carfentanil biotransformation was also assessed. Methods: Metabolite profiling was accomplished by incubating 10 µM carfentanil in human, dog, and rat lung microsomes. The metabolites were separated and analyzed by ultra-high performance liquid chromatography/high-resolution mass spectrometry. Results: In total, 18 metabolites were detected. Nine metabolites were authentically identified through comparison to synthesized reference standards. In human lung microsomes, nine metabolites were identified. In dog lung microsomes, 15 metabolites were identified with three being dog specific. In rat lung microsomes, 15 metabolites were identified and two were rat specific. Proposed metabolic pathways included N-dealkylation, monohydroxylation, dihydroxylation, N-oxidation of piperidine ring nitrogen, and ketone formation. Participation of enzymes CYP2B6, CYP2E1, CYP2J2, and CYP3A4/5 to carfentanil metabolism was suggested by selective enzymatic inhibition. Conclusions: The pulmonary clearance in human lung microsomes was lower than the previously reported hepatic metabolism suggesting organ specific metabolic rates. The contribution of multiple cytochrome P450 enzymes to human, dog, and rat pulmonary microsomal carfentanil biotransformation varied between species. The identified metabolites may provide useful markers for possible forensic and clinical determination of the mode of ingestion but the use of dog and rat animal models was not indicated. To our knowledge, this is the first reported use of chemically synthesized reference standards for the unequivocal identification of lung carfentanil metabolites. [ABSTRACT FROM AUTHOR]

Processing of positron emission tomography (PET) data typically involves manual work, causing inter-operator variance. Here we introduce the Magia toolbox that enables processing of brain PET data with minimal user intervention. We investigated the accuracy of Magia with four tracers: [11C]carfentanil, [11C]raclopride, [11C]MADAM, and [11C]PiB. We used data from 30 control subjects for each tracer. Five operators manually delineated reference regions for each subject. The data were processed using Magia using the manually and automatically generated reference regions. We first assessed inter-operator variance resulting from the manual delineation of reference regions. We then compared the differences between the manually and automatically produced reference regions and the subsequently obtained binding potentials and standardized-uptake-value-ratios. The results show that manually produced reference regions can be remarkably different from each other, leading to substantial differences also in outcome measures. While the Magia-derived reference regions were anatomically different from the manual ones, Magia produced outcome measures highly consistent with the average of the manually obtained estimates. For [11C]carfentanil and [11C]PiB there was no bias, while for [11C]raclopride and [11C]MADAM Magia produced 3–5% higher binding potentials. Based on these results and considering the high inter-operator variance of the manual method, we conclude that Magia can be reliably used to process brain PET data. [ABSTRACT FROM AUTHOR]

Purpose: To demonstrate the usefulness of hair testing to determine exposure pattern to fentanyls. Methods: A 43-year-old male was found unconscious with respiratory depression 15 min after snorting 3 mg of a powder labeled as butyrylfentanyl. He was discharged from hospital within 2 days without blood or urine testing. Two locks of hair were sampled 1 month (M1 A: 0–2 cm (overdose time frame); B: 2–4 cm; C: 4–6 cm) and 1 year (Y1: A: 0–2 cm; B: 2–4 cm) later to monitor his exposure to drugs of abuse by liquid chromatography–tandem mass spectrometry after liquid-liquid extraction. Results: Hair analysis at M1 showed a repetitive exposure to 3-fluorofentanyl (A/B/C: 150/80/60 pg/mg) with higher concentration in segment A reflecting the overdose period. The non-detection of butyrylfentanyl was consistent with the analysis of the recovered powder identified as 3-fluorofentanyl. Furanylfentanyl (40/20/15 pg/mg) and fentanyl (37/25/3 pg/mg) were also detected in hair. The second hair analysis at Y1 showed the use of three new fentanyls, with probably repetitive exposures to methoxyacetylfentanyl (A/B: 500/600 pg/mg), and single or few exposures to carfentanil (2.5/3 pg/mg) and acetyl fentanyl (1/1 pg/mg). A decreasing exposure to 3-fluorofentanyl (25/80 pg/mg), and increasing consumption of furanylfentanyl (310/500 pg/mg) and fentanyl (620/760 pg/mg) were also observed despite methadone treatment initiation. The patient claimed not consuming three out of the six detected fentanyls. Conclusions: We report single or repetitive exposure to several fentanyls using hair testing. To our knowledge, this is the first demonstration of 3-fluorofentanyl and methoxyacetylfentanyl in hair samples collected from an authentic abuser. [ABSTRACT FROM AUTHOR]

• Exposure to carfentanil reduced respiratory minute volume for up to 24 h post-exposure. • Naloxone and naltrexone treatment mitigated carfentanil-induced decreases in minute volume. • Carfentanil-induced changes in respiratory duty cycle were not alleviated by treatment. • Prophylactic treatment may be a viable option to protect first responders. Carfentanil (CRF) is an extremely potent opioid capable of inducing fatal respiratory depression. Naloxone (NX) and naltrexone (NTX) are opioid antagonists for which the efficacy against CRF remains largely unexplored. In this study, the effects of aerosolized CRF on respiratory function were investigated using adult male CD-1 mice. Mice were exposed to 0.4 mg/m3 of CRF for 15 min using custom whole-body plethysmograph units. Minute volume (MV), respiratory frequency (f), duty cycle (DC), and tidal volume (TV) were monitored and compared to control animals exposed to aerosolized H 2 O. CRF exposure induced respiratory depression, characterized by a marked decrease in MV, which was sustained throughout 24 h post-exposure. Prophylactic and therapeutic treatment with intramuscular (i.m.) NX marginally improved MV, with slight dose-dependent effects. Analogous treatment with i.m. NTX returned MV to baseline levels, with all doses and intervention times performing similarly. Despite improvements in MV, treatment administration did not reverse changes in DC, a measure of respiratory timing. Overall, NX and NTX administration alleviated volumetric aspects of opioid-induced respiratory toxicity, while changes in respiratory timing remained unresolved throughout post-exposure observation. These sustained changes and differences in recovery between two aspects of respiratory dynamics may provide insights for further exploration into the underlying mechanism of action of opioids and opioid antagonists. [ABSTRACT FROM AUTHOR]