Exploring the thermally-controlled fentanyl transdermal therapy to provide constant drug delivery by physics-based digital twins.

Transdermal drug delivery is suitable for low-molecular-weight drugs with specific lipophilicity, like fentanyl, which is widely used for cancer-induced pain management. However, fentanyl's transdermal therapy displays high intra-individual variability. Factors like skin characteristics at application sites and ambient temperature contribute to this variation. In this study, we developed a physics-based digital twin of the human body to cope with this variability and propose better adapted setups. This twin includes an in-silico skin model for drug penetration, a pharmacokinetic model, and a pharmacodynamic model. Based on the results of our simulations, applying the patch on the flank (side abdominal area) showed a 15.3 % higher maximum fentanyl concentration in the plasma than on the chest. Additionally, the time to reach this maximum concentration when delivered through the flank was 19.8 h, which was 10.3 h earlier than via the upper arm. Finally, this variation led to an 18 % lower minimum pain intensity for delivery via the flank than the chest. Moreover, the impact of seasonal changes on ambient temperature and skin temperature by considering the activity level was investigated. Based on our result, the fentanyl uptake flux by capillaries increased by up to 11.8 % from an inactive state in winter to an active state in summer. We also evaluated the effect of controlling fentanyl delivery by adjusting the temperature of the patch to alleviate the pain to reach a mild pain intensity (rated three on the VAS scale). By implementing this strategy, the average pain intensity decreased by 1.1 points, and the standard deviation for fentanyl concentration in plasma and average pain intensity reduced by 37.5 % and 33.3 %, respectively. Therefore, our digital twin demonstrated the efficacy of controlled drug release through temperature regulation, ensuring the therapy toward the intended target outcome and reducing therapy outcome variability. This holds promise as a potentially useful tool for physicians.

Protonitazene detection in two cases of opioid toxicity following the use of tetrahydrocannabinol vape products in Australia.

INTRODUCTION: Protonitazene is an opioid belonging to the 2-benzylbenzimidazole structural class. We describe two cases of opioid toxicity involving the reported inhalation of a delta-9-tetrahydrocannabinol vape product in which protonitazene was detected. CASE REPORTS: Case 1 was a young male found unconscious after the reported use of a delta-9-tetrahydrocannabinol vape. He suffered two subsequent apnoeic episodes requiring bag-valve-mask ventilation before eventual recovery. Only protonitazene was detected in blood at a concentration of 0.74 µg/L. Case 2 was a young male who died shortly after being found unresponsive. The postmortem femoral blood concentrations of protonitazene and delta-9-tetrahydrocannabinol were 0.33 µg/L and 2 µg/L, respectively. Analysis of a pod vaping device found in the decedent's hand and a separate e-liquid bottle labelled as delta-9-tetrahydrocannabinol showed a mixture of protonitazene and delta-9-tetrahydrocannabinol. DISCUSSION: The opioid effects of protonitazene are mediated through ß-arrestin2 and mu opioid receptor signalling pathways. Benzimidazole opioids are lipophilic and, when mixed with a suitable solvent, can be used in a vape device. It is anticipated that naloxone would have provided effective reversal of toxicity in our cases. CONCLUSIONS: Novel routes of opioid administration, like vaping, may appear relatively innocuous in comparison to intravenous administration, but opioids may still be absorbed at high concentrations, resulting in severe opioid toxicity or death.

The role of drug efflux and uptake transporters in the plasma pharmacokinetics and tissue disposition of morphine and its main metabolites.

Morphine is a widely used opioid for the treatment of pain. Differences in drug transporter expression and activity may contribute to variability in morphine pharmacokinetics and response. Using appropriate mouse models, we investigated the impact of the efflux transporters ABCB1 and ABCG2 and the OATP uptake transporters on the pharmacokinetics of morphine, morphine-3-glucuronide (M3G), and M6G. Upon subcutaneous administration of morphine, its plasma exposure in Abcb1a/1b-/-;Abcg2-/--, Abcb1a/1b-/-;Abcg2-/-;Oatp1a/1b-/-;Oatp2b1-/- (Bab12), and Oatp1a/1b-/-;Oatp2b1-/- mice was similar to that found in wild-type mice. Forty minutes after dosing, morphine brain accumulation increased by 2-fold when mouse (m)Abcb1 and mAbcg2 were ablated. Relative recovery of morphine in small intestinal content was significantly reduced in all the knockout strains. In the absence of mOatp1a/1b and mOatp2b1, plasma levels of M3G were markedly increased, suggesting a lower elimination rate. Moreover, Oatp-deficient mice displayed reduced hepatic and intestinal M3G accumulation. Mouse Oatps similarly affected plasma and tissue disposition of subcutaneously administered M6G. Human OATP1B1/1B3 transporters modestly contribute to the liver accumulation of M6G. In summary, mAbcb1, in combination with mAbcg2, limits morphine brain penetration and its net intestinal absorption. Variation in ABCB1 activity due to genetic polymorphisms/mutations and/or environmental factors might, therefore, partially affect morphine tissue exposure in patients. The ablation of mOatp1a/1b increases plasma exposure and decreases the liver and small intestinal disposition of M3G and M6G. Since the contribution of human OATP1B1/1B3 to M6G liver uptake was quite modest, the risks of undesirable drug interactions or interindividual variation related to OATP activity are likely negligible.

Electrochemical sensor based on mesoporous g-C3N4/N-CNO/gold nanoparticles for measuring oxycodone.

Oxycodone, often used as an analgesic, is a potent opioid. While its effectiveness has been proven in the control of moderate to acute pain, excessive use of oxycodone imposes heart failure, heart palpitations, reduction of red blood cells, bone pain, and even death. Therefore, monitoring the oxycodone concentration in blood is vital for emergency care. For this purpose, a novel electrochemical sensor was designed based on a glassy carbon electrode modified with mesoporous g-C3N4 (M-C3N4), carbon nano-onions doped with nitrogen (N-CNO), and gold nanoparticles. At first, the SEM and XRD techniques were employed to characterize prepared M-C3N4 and N-CNO samples. The electro-oxidation behavior of the oxycodone was evaluated by cyclic and differential pulse voltammetric methods. Based on the influence of the potential scanning rate and solution pH on the voltammetric response of oxycodone oxidation, a redox mechanism was proposed. A 16 nM detection limit was acquired for the oxycodone analysis with a linear response in the 0.05-150 µM range. This sensor showed a remarkable ability for oxycodone detection in plasma samples. The long-term stability, superior selectivity, and reproducibility of this sensor prove its ability to measure oxycodone accurately and precisely in authentic spices.

High-performance fentanyl molecularly imprinted electrochemical sensing platform designed through molecular simulations.

BACKGROUND: Fentanyl and its derivatives are a type of potent opioid analgesics, with the characteristics of diverse structure, high toxicity, extremely low content, and high fatality rate. Currently, they have become one of the most serious problems in international drug abuse control due to their extensive use in drug production and use. Therefore, the development of a rapid, sensitive, and accurate method for detecting trace fentanyl is of great significance. In this study, in view of its complex structure and trace concentration, a new molecular imprinting electrochemical sensor was developed through molecular simulations followed by experimental validation to detect trace fentanyl. RESULTS: The process consisted of first obtaining the optimal functional monomer and its molar ratio through molecular simulations. The recognition sites of fentanyl-imprinted polymers were predicted to guide the synthesis of imprinted membranes with precision approach to ensure an efficient and accurate reaction process. Reduced graphene oxide (ErGO) was then deposited on glassy carbon electrode surface by electrochemical reduction to yield large numbers of active sites suitable for catalyzing reactions of fentanyl piperidine for promoted efficient electron transfer and amplified sensitivity of the sensor. Accordingly, fentanyl molecularly imprinted film was formed through one-step electropolymerization to yield greatly improved sensing selectivity due to the specific recognition of molecularly imprinted polymer. Under optimal experimental conditions, the fentanyl sensor showed an extended detection range of 3.84 × 10-9 mol L-1-1.72 × 10-6 mol L-1 and a detection limit of 1.28 × 10-9 mol L-1. SIGNIFICANCE: A distinctive feature of this sensor is its molecularly imprinted polymerized membrane, which offers excellent specific recognition, thereby boosting the sensor's selectivity. Throughout the sensor's development process, molecular simulations were employed to steer the synthesis of molecularly imprinted polymers and predict the recognition sites of fentanyl-imprinted polymers. The experimental outcomes proved to align with the simulation data. The final sensor exhibited outstanding selectivity, repeatability, stability, and high sensitivity. The sensor was effectively used to reliably track fentanyl in human serum samples, with acceptable analytical reliability, suggesting its potential for practical applications.

Intoxications involving methoxyacetylfentanyl and U-47700: a study of 3 polydrug fatalities.

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

Fentanyl Deaths in Infants and Children: A Case Series and Literature Review.

ABSTRACT: Death due to fentanyl and its various analogs has resulted in an exponential rise in deaths throughout the United States, overwhelming many medical examiner offices for over a decade. Its potency and prevalence have caused fentanyl to become the most reported substance in overdose fatalities, with an accompanying increase in exposure of the most vulnerable, infants and children. This report provides information about fentanyl in the pediatric population, including case examples, proposed investigative practices, published therapeutic and lethal blood concentrations, and available resources for future cases. Nine cases of pediatric death between 2013 and 2023 due to fentanyl were reviewed. Five case summaries are presented that highlight classic features of fentanyl deaths in infants, children, and teenagers. Deaths due to fentanyl have continued to rise year after year. Infants and children, most of whom are opioid naive, are at ever increased risk for exposure to high levels of fentanyl. The legal ramifications of a positive fentanyl level in a child increase the need for caution on the part of the forensic pathologist. Understanding what can and cannot be proven by autopsy as well as what resources are available to strengthen one's justification for fentanyl being the primary cause of death is critical.

OPRM1 rs2075572 has potential to affect plasma buprenorphine level in opioid users, but not OPRM1 rs562859.

OPRM1 gene encoding mu-opioid receptor (MOR) is the primary candidate gene for buprenorphine (BUP) pharmacogenetics. OPRM1 undergoes alternative splicing leading to multiple MOR subtypes. Thus, in the current study 2 SNPs (rs1799972 and rs562859) were selected due to evidence for their contribution to alternative splicing of OPRM1. The effects of 2 SNPs of OPRM1 gene on plasma buprenorphine and norbuprenorphine levels in a sample of 233 OUD patients receiving BUP/naloxone were examined. Polymorphisms were analyzed by PCR and RFLP. BUP and norbuprenorphine concentrations in plasma were measured by LC-MS/MS. OPRM1 rs2075572 GC + CC (0.12 ng/ml) had significantly higher plasma BUP level compared to GG (0.084 ng/ml) (p = 0.043). Although there was not a statistically significant difference between OPRM1 rs562859 genotypes (p = 0.46), patients with OPRM1 rs562859 CT + TT had higher plasma BUP and BUP-related values as compared to those with CC. In conclusion, the effect of OPRM1 rs2075572 on BUP levels in opioid users' plasma was shown in a Caucasian population for the first time. On the other hand, OPRM1 rs562859 seems not to influence the BUP pharmacology.

Endocannabinoids and related lipids linked to social exclusion in individuals with chronic non-medical prescription opioid use.

Opioid-related overdose deaths are still on the rise in North America, emphasizing the need to better understand the underlying neurobiological mechanisms regarding the development of opioid use disorder (OUD). Recent evidence from preclinical and clinical studies indicate that the endocannabinoid system (ECS) may play a crucial role in stress and reward, both involved in the development and maintenance of substance use disorders. Animal models demonstrate a specific crosstalk between the ECS and the endogenous opioid system. However, translational studies in humans are scarce. Here, we investigated basal plasma levels of the endocannabinoids anandamide (AEA) and 2-arachidonoyglycerol (2-AG), and eight endocannabinoid-related lipids, including oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), as well as whole blood fatty acid amide hydrolase (FAAH) activity in chronic non-medical prescription opioid users (NMPOU; n = 21) compared to opioid-naïve healthy controls (n = 29) considering age, sex, and cannabis use as potential confounders. Additionally, the association of endocannabinoids and related lipids with the participants' response to experimentally induced social exclusion was examined. We found significantly elevated basal AEA, OEA, and PEA levels in NMPOU compared to controls, but no differences in FAAH activity, 2-AG, or other endocannabinoid-related lipids. Within NMPOU, higher AEA levels were associated with lower perception of social exclusion. Robust positive correlations within N-acylethanolamines (i.e., AEA, OEA, and PEA) indicate strong metabolic associations. Together with our recent findings of elevated basal 2-AG levels in dependent cocaine users, present results indicate substance-specific alterations of the ECS that may have implications in the search for novel therapeutic interventions for these populations.

Determination of remifentanil in neonatal dried blood spots by liquid chromatography-tandem mass spectrometry.

Remifentanil is an ultra-short-acting synthetic opioid-class analgesic which might be increasingly used "off-label" as pain management during labour. Side effects in parturients during labour, and in the infant at birth are of particular concern, especially respiratory depression which is concentration-dependent, and can occur at levels as low as 3-5 ng mL-1. The safety of such use, particularly in newborns due to remifentanil placental transfer, has not been fully demonstrated yet, partly due to the lack of a suitable non-invasive analytical method. The aim of our work was to develop a sensitive method to monitor the levels of remifentanil in neonates by a non-invasive sampling of umbi lical cord blood to support efficacy and safety trials. The presented LC-MS method is sensitive enough to reliably quantify remifentanil in just 20 µL of blood at only 0.3 ng mL-1. The dried blood spot sample preparation included solvent extraction with subsequent solid-phase extraction. The method was validated in terms of accuracy, precision, recovery, matrix effect, and stability, and was successfully applied to a small pilot study. The estimated arterial blood concentrations at the time of delivery ranged from 0.2 to 0.3, and up to 0.9 ng mL-1 in neonatal, and maternal samples, respectively.

Quantitative determination of R/S-methadone in human serum using ultra-high performance supercritical fluid chromatography-tandem mass spectrometry: A method for routine use.

Methadone has two enantiomers, which exhibit differences in pharmacological effects, with R-methadone being the active and S-methadone the inactive enantiomer. A robust, simple and rapid method for chiral separation of the two enantiomers in serum samples using ultra-high performance supercritical fluid chromatography-tandem mass spectrometry (UHPSFC-MSMS) has been developed and validated. Enantiomeric separation was achieved using a Chiralpak IH-3 column with a mobile phase consisting of CO2 and 30mM ammonium acetate in methanol/water (98/2, v/v). Runtime was 4 minutes. Sample preparation was semi-automated using a Hamilton ML Star robot with protein precipitation, and phospholipid removal was carried out using a Waters OSTRO™ 96-well plate. The calibration range was 50.0-1,500 nM for each enantiomer. The between-assay relative standard deviations were in the range of 1.2-3.6%. Matrix effects ranged from 99% to 115% corrected with internal standard. The method has been implemented in our laboratory and has proven to be a robust and reliable method for determining the ratio of R/S-methadone in authentic patient samples.

In vitro, in vivo metabolism and quantification of the novel synthetic opioid N-piperidinyl etonitazene (etonitazepipne).

OBJECTIVES: N-piperidinyl etonitazene (etonitazepipne) is a newly synthesized opioid related to the 2-benzylbenzimidazole analog class. Etonitazepipne has been formally notified and placed under intensive monitoring in Europe in January 2022. Nitazenes have high affinity at µ-opioid receptor (MOR). Etonitazepipne, specifically shows a EC50 of 2.49 nM, suggesting about 50 times higher potency combined with higher efficacy compared to morphine. Antinociceptive potency l ('hot plate test' with rats) was 192-fold greater than that of morphine. METHODS: Here we report on a post-mortem case involving etonitazepipne and its quantification using a standard addition method (SAM) through liquid chromatography tandem mass spectrometry (LC-MS/MS). In addition, characterization and identification of phase I human metabolites using in vitro assay based on pooled human liver microsomes (pHLM) was performed along with the analysis of authentic urine samples by means of high-performance liquid chromatography high-resolution tandem mass spectrometry (LC-HRMS/MS). RESULTS: The concentration of etonitazepipne in post-mortem blood and urine was 8.3 and 11 ng/mL, respectively. SAM was validated by assessing the following parameters: intraday and interday repeatability, matrix effect and recovery rate in post-mortem blood. A total of 20 and 14 metabolites were identified after pHLM incubation and urine analysis, respectively. Most pronounced in vitro and in vivo transformations were O-deethylation, hydroxylation, ketone reduction, and combinations thereof. CONCLUSIONS: Considering small traces of the parent drug often found in real cases, the identification of metabolic biomarkers is crucial to identify exposure to this drug. O-deethylated, oxidated metabolites, and combination thereof are proposed as urinary biomarkers along with the parent compound.

A Series of 8 Illicit Fentanyl Intoxication Deaths in Infants and Toddlers.

ABSTRACT: We report 8 children younger than 2 years who died from acute illicit fentanyl intoxications in Connecticut between 2020 and 2022.The Connecticut Office of the Chief Medical Examiner (CT OCME) investigates all unexpected, violent, and suspicious deaths in Connecticut. The CT OCME's electronic database was searched for fentanyl deaths by age. All underwent autopsies and toxicology testing.The ages ranged from 28 days to 2 years (mean age, 12 months). The causes of death involved acute fentanyl intoxications with 1 having xylazine, 1 having para-fluorofentanyl, and 1 having cocaine and morphine. All the manners of death were certified as homicide. The postmortem fentanyl blood concentrations ranged from 0.40 to 46 ng/mL. Most of the children were found unresponsive after being put to sleep. Three were co-sleeping with adults (2 in bed; 1 on a recliner). There was a known history of parental/caregiver drug abuse in 7 of 8 of the fatalities.We summarize the key investigative, autopsy, and toxicological findings. As illicit fentanyl use increases, there is a potential for infant exposure and death. The investigation and certification of these deaths and the role of intentional administration versus inadvertent exposure due to caregiver neglect in the context of the certification of the manner of death are described.

Intrathecal morphine plus general anesthesia in cardiac surgery: effects on pulmonary function, postoperative analgesia, and plasma morphine concentration

OBJECTIVES: To evaluate the effects of intrathecal morphine on pulmonary function, analgesia, and morphine plasma concentrations after cardiac surgery. INTRODUCTION: Lung dysfunction increases morbidity and mortality after cardiac surgery. Regional analgesia may improve pulmonary outcomes by reducing pain, but the occurrence of this benefit remains controversial. METHODS: Forty-two patients were randomized for general anesthesia (control group n=22) or 400 µg of intrathecal morphine followed by general anesthesia (morphine group n=20). Postoperative analgesia was accomplished with an intravenous, patient-controlled morphine pump. Blood gas measurements, forced vital capacity (FVC), forced expiratory volume (FEV), and FVC/FEV ratio were obtained preoperatively, as well as on the first and second postoperative days. Pain at rest, profound inspiration, amount of coughing, morphine solicitation, consumption, and plasma morphine concentration were evaluated for 36 hours postoperatively. Statistical analyses were performed using the repeated measures ANOVA or Mann-Whiney tests (*p<0.05). RESULTS: Both groups experienced reduced FVC postoperatively (3.24 L to 1.38 L in control group; 2.72 L to 1.18 L in morphine group), with no significant decreases observed between groups. The two groups also exhibited similar results for FEV1 (p=0.085), FEV1/FVC (p=0.68) and PaO2/FiO2 ratio (p=0.08). The morphine group reported less pain intensity (evaluated using a visual numeric scale), especially when coughing (18 hours postoperatively: control group= 4.73 and morphine group= 1.80, p=0.001). Cumulative morphine consumption was reduced after 18 hours in the morphine group (control group= 20.14 and morphine group= 14.20 mg, p=0.037). The plasma morphine concentration was also reduced in the morphine group 24 hours after surgery (control group= 15.87 ng.mL-1 and morphine group= 4.08 ng.mL-1, p=0.029). CONCLUSIONS: Intrathecal morphine administration did not ...

Determining plasma morphine levels using GC-MS after solid phase extraction to monitor drug levels in the postoperative period

OBJECTIVE: To implement a selective and sensitive analytical method to quantify morphine in small volumes of plasma by gas-liquid chromatography-mass spectrometry (GC-MS), aimed at post-operatively monitoring the drug. METHOD: A gas-liquid chromatographic method with mass detection has been developed to determine morphine concentration in plasma after solid phase extraction. Morphine-d3 was used as an internal standard. Only 0.5 mL of plasma is required for the drug solid-phase extraction in the Bond Elut-Certify®, followed by the quantification of morphine derivative by GC-MS using a linear temperature program, a capillary fused silica column, and helium as the carrier and make-up gas. The method was applied to determine morphine content in plasma samples of four patients during the postoperative period of cardiac surgery. Patient-controlled analgesia with morphine was performed by a venous catheter, and a series of venous blood samples were collected. After the oro-After the orotracheal extubation, morphine plasma levels were monitored for up to 36 hours. RESULTS: The run time was 16 minutes because morphine and the internal standard were eluted after 8.8 minutes. The GC-MS method had 0.5 -1000 ng/mL linearity range (r²=0.9995), 0.1 ng/mL limit of detection, intraday and interday precision equivalent to 1.9 percent and 6.8 percent, and 0.1 percent and 0.8 percent systematic error (intraday and interday, respectively). The analytical method showed optimal absolute (98 percent) and relative (100.7 percent) recoveries. Morphine dose requirements and plasma levels are discussed. CONCLUSION: The analytical gas-liquid chromatography-mass spectrometry method is selective and adequate for morphine measurements in plasma for applications in clinical studies.

Modulación opioide en la cefalea en racimos / Opioid systems in cluster headache

La corta duración y la frecuencia de los ataques, hacen de la cefalea en racimos un buen modelo para estudiar los niveles plasmáticos y licuorales de sustancias endógenas. Hemos encontrado un claro aumento de la ME plasmática relacionado con el episodio doloroso, sin modificación en los niveles de catecolaminas, pero sí con una disminución significativa en los niveles de los péptidos que contienen ME en neutrófilos concomitante, como si estas células liberaran ME durante el dolor.En los pacientes tratados con sales de litio o con prednisona encontramos un incremento plasmático de ME y de ME total en neutrófilos pudiendo especular que estas drogas estimulan su síntesisy liberación