Comparison of intranasal naloxone and intranasal nalmefene in a translational model assessing the impact of synthetic opioid overdose on respiratory depression and cardiac arrest.

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 µ-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 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. 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.

Fentanyl, carfentanil and other fentanyl analogues in Canada's illicit opioid supply: A cross-sectional study.

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.

Total-body imaging of mu-opioid receptors with [11C]carfentanil in non-human primates.

PURPOSE: Mu-opioid receptors (MORs) are widely expressed in the central nervous system (CNS), peripheral organs, and immune system. This study measured the whole body distribution of MORs in rhesus macaques using the MOR selective radioligand [11C]carfentanil ([11C]CFN) on the PennPET Explorer. Both baseline and blocking studies were conducted using either naloxone or GSK1521498 to measure the effect of the antagonists on MOR binding in both CNS and peripheral organs. METHODS: The PennPET Explorer was used for MOR total-body PET imaging in four rhesus macaques using [11C]CFN under baseline, naloxone pretreatment, and naloxone or GSK1521498 displacement conditions. Logan distribution volume ratio (DVR) was calculated by using a reference model to quantitate brain regions, and the standard uptake value ratios (SUVRs) were calculated for peripheral organs. The percent receptor occupancy (%RO) was calculated to establish the blocking effect of 0.14 mg/kg naloxone or GSK1521498. RESULTS: The %RO in MOR-abundant brain regions was 75-90% for naloxone and 72-84% for GSK1521498 in blocking studies. A higher than 90% of %RO were observed in cervical spinal cord for both naloxone and GSK1521498. It took approximately 4-6 min for naloxone or GSK1521498 to distribute to CNS and displace [11C]CFN from the MOR. A smaller effect was observed in heart wall in the naloxone and GSK1521498 blocking studies. CONCLUSION: [11C]CFN total-body PET scans could be a useful approach for studying mechanism of action of MOR drugs used in the treatment of acute and chronic opioid use disorder and their effect on the biodistribution of synthetic opioids such as CFN. GSK1521498 could be a potential naloxone alternative to reverse opioid overdose.

The fentanyl-specific antibody FenAb024 can shield against carfentanil effects.

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.

Drug supply measures and drug overdose mortality in the era of fentanyl and stimulants.

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.

Incapacitating agents review: 20 years after Nord Ost Siege.

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.

The Synthesis of Biphasic Metabolites of Carfentanil.

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.

Skin decontamination of Carfentanil in vitro.

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.

Classifying migraine using PET compressive big data analytics of brain's µ-opioid and D2/D3 dopamine neurotransmission.

Introduction: Migraine is a common and debilitating pain disorder associated with dysfunction of the central nervous system. Advanced magnetic resonance imaging (MRI) studies have reported relevant pathophysiologic states in migraine. However, its molecular mechanistic processes are still poorly understood in vivo. This study examined migraine patients with a novel machine learning (ML) method based on their central µ-opioid and dopamine D2/D3 profiles, the most critical neurotransmitters in the brain for pain perception and its cognitive-motivational interface. Methods: We employed compressive Big Data Analytics (CBDA) to identify migraineurs and healthy controls (HC) in a large positron emission tomography (PET) dataset. 198 PET volumes were obtained from 38 migraineurs and 23 HC during rest and thermal pain challenge. 61 subjects were scanned with the selective µ-opioid receptor (µOR) radiotracer [11C]Carfentanil, and 22 with the selective dopamine D2/D3 receptor (DOR) radiotracer [11C]Raclopride. PET scans were recast into a 1D array of 510,340 voxels with spatial and intensity filtering of non-displaceable binding potential (BPND), representing the receptor availability level. We then performed data reduction and CBDA to power rank the predictive brain voxels. Results: CBDA classified migraineurs from HC with accuracy, sensitivity, and specificity above 90% for whole-brain and region-of-interest (ROI) analyses. The most predictive ROIs for µOR were the insula (anterior), thalamus (pulvinar, medial-dorsal, and ventral lateral/posterior nuclei), and the putamen. The latter, putamen (anterior), was also the most predictive for migraine regarding DOR D2/D3 BPND levels. Discussion: CBDA of endogenous µ-opioid and D2/D3 dopamine dysfunctions in the brain can accurately identify a migraine patient based on their receptor availability across key sensory, motor, and motivational processing regions. Our ML-based findings in the migraineur's brain neurotransmission partly explain the severe impact of migraine suffering and associated neuropsychiatric comorbidities.

Carfentanilo: una doble amenaza para la salud pública / Carfentanil: a double threat to public health

El carfentanilo es un opioide sintético con una potencia 10.000 veces superior a la de la morfina. Esta y otras características posicionan al carfentanilo como una sustancia de interés dual, pues ha sido empleada como agente incapacitante y como droga de abuso. Entre las características toxicocinéticas del carfentanilo destacan su elevada liposolubilidad y la posibilidad de que siga una cinética de eliminación no lineal. En 2002 este compuesto fue empleado por las Fuerzas de Seguridad Rusas para intentar resolver la crisis de rehenes del teatro Dubrovka de Moscú, causando la muerte de al menos 123 rehenes. Por otro lado, el carfentanilo, se ha empleado como droga de abuso y como adulterante en otras drogas. En caso de intoxicación por carfentanilo puede ser necesaria la administración de dosis repetidas de antídoto. Los antecedentes expuestos en este trabajo justifican la necesidad de desarrollar y validar un método analítico para la detección del carfentanilo y su metabolito norcarfentanilo en muestras biológicas. (AU)

Carfentanil is a synthetic opioid with a potency 10,000 times greater than that of morphine. For this and other reasons carfentanil is a substance with dual interest, since it has been used as an incapacitating agent and as an abuse drug. Among the toxicokinetic characteristics of carfentanil, its high lipid solubility stands out. In addition, there is the possibility that carfentanil follows a non-linear elimination kinetics. In 2002 this compound 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, carfentanil has been used as a drug of abuse and as an adulterant in other drugs. In case of carfentanil 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. (AU)

Carfentanilo: una doble amenaza para la salud pública / Carfentanil: a double threat to public health

El carfentanilo es un opioide sintético con una potencia 10.000 veces superior a la de la morfina. Esta y otras características posicionan al carfentanilo como una sustancia de interés dual, pues ha sido empleada como agente incapacitante y como droga de abuso. Entre las características toxicocinéticas del carfentanilo destacan su elevada liposolubilidad y la posibilidad de que siga una cinética de eliminación no lineal. En 2002 este compuesto fue empleado por las Fuerzas de Seguridad Rusas para intentar resolver la crisis de rehenes del teatro Dubrovka de Moscú, causando la muerte de al menos 123 rehenes. Por otro lado, el carfentanilo, se ha empleado como droga de abuso y como adulterante en otras drogas. En caso de intoxicación por carfentanilo puede ser necesaria la administración de dosis repetidas de antídoto. Los antecedentes expuestos en este trabajo justifican la necesidad de desarrollar y validar un método analítico para la detección del carfentanilo y su metabolito norcarfentanilo en muestras biológicas. (AU)

Carfentanil is a synthetic opioid with a potency 10,000 times greater than that of morphine. For this and other reasons carfentanil is a substance with dual interest, since it has been used as an incapacitating agent and as an abuse drug. Among the toxicokinetic characteristics of carfentanil, its high lipid solubility stands out. In addition, there is the possibility that carfentanil follows a non-linear elimination kinetics. In 2002 this compound 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, carfentanil has been used as a drug of abuse and as an adulterant in other drugs. In case of carfentanil 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. (AU)

Carfentanil is a ß-arrestin-biased agonist at the µ opioid receptor.

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 ß-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 ß-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 ß-arrestin-biased opioid drug at the µ receptor. It is uncertain how such bias influences in vivo effects of carfentanil relative to other fentanyls.

DO HIGHER DOSES OF NALOXONE INCREASE THE RISK OF PULMONARY COMPLICATIONS?

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.

New Synthetic Opioids: Clinical Considerations and Dangers.

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.

Assessment of abuse potential of carfentanil.

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.

Carfentanil structural analogs found in street drugs by paper spray mass spectrometry and their characterization by high-resolution mass spectrometry.

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 C23 H29 N3 O2 (m/z 380.2333) and C23 H29 N2 O3 (m/z 381.2137). Literature and tandem mass spectrometry results were used to determine the identity of these potential new psychoactive substances, C23 H29 N3 O2 as desmethylcarfentanil amide and C23 H29 N2 O3 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.

Examining fentanyl and its analogues in the unregulated drug supply of British Columbia, Canada using drug checking technologies.

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.

[11C]carfentanil PET imaging for studying the peripheral opioid system in vivo: effect of photoperiod on mu-opioid receptor availability in brown adipose tissue.

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 (ß = - 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.

Metabolism of the active carfentanil metabolite, 4-Piperidinecarboxylic acid, 1-(2-hydroxy-2-phenylethyl)-4-[(1-oxopropyl)phenylamino]-, methyl ester in vitro.

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.

Rejection sensitivity and mu opioid receptor dynamics associated with mood alterations in response to social feedback.

Rejection sensitivity (RS) is the heightened expectation or perception of social rejection and is a feature of many psychiatric disorders. As endogenous opioid pathways have been implicated in response to social rejection and reward, we hypothesize that RS will be negatively associated with mu opioid receptor (MOR) baseline binding and activity during rejection and acceptance stimuli. In exploratory analyses, we assessed the relationships between MOR activity and changes in mood and self-esteem before and after stimuli. Healthy participants, N = 75 (52% female), completed rejection and acceptance tasks during [11C]carfentanil positron emission tomography (PET) scans. MOR activity in the amygdala, midline thalamus, anterior insula, and nucleus accumbens (NAc) was evaluated. RS was not related to MOR baseline binding potential or activity during acceptance or rejection tasks in any region. Increased MOR activity in the NAc was associated with increase in ratings of self-esteem and positive mood during the period between acceptance task administration and approximately 5 min after the task completion. Our results suggest that endogenous opioid response to social rejection is independent of RS in healthy individuals. MOR activity in the NAc was associated with increase self-esteem and positive mood after experiencing social feedback, warranting further investigation.