Fentanyl Concentrations Research Articles

The effect of high concentrations of fentanyl on an isolated heart of rat

The effect of high concentrations of fentanyl on an isolated heart of rat

Performance of a Norfentanyl Immunoassay in Specimens with Low Concentrations of Fentanyl and/or Norfentanyl.

Many fentanyl immunoassays are limited in their ability to detect norfentanyl. Urine specimens collected from individuals who have been exposed to fentanyl frequently have detectable concentrations of norfentanyl (≥2 ng/mL) but low concentrations of fentanyl (<2 ng/mL) by LC-MS/MS. The Lin-Zhi Fentanyl II Immunoassay (Lin-Zhi) claims 100% cross-reactivity with norfentanyl and therefore may detect exposure missed by other assays. In addition to verifying the manufacturer's analytical sensitivity claims, we selected 92 urine specimens with low-positive Lin-Zhi results (1-99 absorbance units, lowest 10%) for analysis by the Immunalysis Health Equity Impact Assessment and ARK II fentanyl methods. The accuracy of the 3 immunoassays was compared to LC-MS/MS as the reference method. Spiking studies using purified fentanyl and norfentanyl and a set of 100 consecutive specimens confirmed the manufacturer's claims of limit of detection for fentanyl (3.8 ng/mL) and norfentanyl (5.0 ng/mL). However, the 92 low-positive patient specimens demonstrated concentrations of norfentanyl and fentanyl below 2.0 ng/mL by LC-MS/MS, with 47 (51%) having only norfentanyl detected. When comparing Lin-Zhi to the Immunalysis and ARK II immunoassays, only 27 (29%) of the 92 specimens were concordant. Fifty-two (57%) of the specimens were positive by LC-MS/MS and Lin-Zhi but false negative by one or both other immunoassays. Seven specimens (8%) were positive by Lin-Zhi but negative by the other immunoassays and had undetectable concentrations (<2 ng/mL) of fentanyl and norfentanyl by LC-MS/MS. The clinical sensitivity of the Lin-Zhi exceeds the manufacturer's claims, providing results comparable to LC-MS/MS methods.

Physiologically based modeling reveals different risk of respiratory depression after fentanyl overdose between adults and children.

Despite a rapid increase in pediatric mortality rate from prescription and illicit opioids, there is limited research on the dose-dependent impact of opioids on respiratory depression in children, the leading cause of opioid-associated death. In this article, we extend a previously developed translational model to cover pediatric populations by incorporating age-dependent pharmacokinetic, pharmacodynamic, and physiological changes compared to adults. Our model reproduced previous perioperative clinical findings that adults and children have similar risk of respiratory depression at the same plasma fentanyl concentration when specific endpoints (minute ventilation, CO2 tension in the blood) were used. However, our model points to a potential caveat that, in a perioperative setting, routine use of mechanical ventilation and supplemental oxygen maintained the blood and tissue oxygen partial pressures in patients and prevented the use of oxygen-related endpoints to evaluate the consequences of respiratory depression. In a community setting when such oxygenation procedures are not immediately available, our model suggests that the higher oxygen demand and reduced cerebrovascular reactivity could make children more susceptible to severe hypoxemia and brain hypoxia, even with the same plasma fentanyl concentration as adults. Our work indicates that when developing intervention strategies to protect children from opioid overdose in a community setting, these pediatric-specific factors may need to be considered.

Beyond a spec: assessing heterogeneity in the unregulated opioid supply

BackgroundDrug checking services aim to provide compositional information for the illicit drug supply and are being employed in public health responses to extreme rates of overdose associated with fentanyl within street opioids. The technologies used within these services range from basic qualitative tests, such as immunoassay test strips, to comprehensive quantitative analyses, such as mass spectrometry. In general, there is concern that heterogeneity of a drug mixture adds significant uncertainty when using drug checking results based on a small subsamples. The presence of hot spots of active drug components in this context is often termed the ‘chocolate chip cookie effect’. Establishing the limitations of the service are essential for interpretation of the results.MethodsThis study assesses the consequence of drug heterogeneity and sampling of consumer level opioid purchased in Victoria, British Columbia (n=21\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$n=21$$\\end{document}, 50–100 mg each) on quantitative fentanyl results determined from testing with paper spray mass spectrometry.Results:Using descriptive statistics, such as relative standard deviation and interquartile range, the results demonstrate varied distributions of fentanyl concentrations within a single drug batch. However, the presence of hot spots, defined as outliers, were relatively rare.ConclusionsThis study found that the variability in fentanyl concentration from drug heterogeneity and sampling is greater than that attributed to the analytical technique. On a practical level, this provides data to help guide communication of limitations of drug checking services, supporting the aim of trust and transparency between services and people who use drugs. However, if drug checking services continue to be restricted from fully engaging with the reality of manufacturing, buying, selling, mixing and dosing practices, the accuracy, usefulness, and impact will always be limited.

Implementing physics-based digital patient twins to tailor the switch of oral morphine to transdermal fentanyl patches based on patient physiology

Fentanyl transdermal patches are widely implemented for cancer-induced pain treatment due to the high potency of fentanyl and gradual drug release. However, transdermal fentanyl up-titration for opioid-naïve patients is difficult, which is why opioid treatment is often started with oral/iv morphine. Based on the daily dose of morphine, the initial dose of the fentanyl patch is decided upon. After reaching a stable level of pain, the switch is made from oral/iv morphine to transdermal fentanyl. There are standard calculation tools for transferring from oral/iv morphine to transdermal fentanyl, which is the same for all patients. By considering the variations in the physiology of the patients, a unique switching strategy cannot meet the needs of different patients. This study explores the outcome in terms of pain relief and minute ventilation during opioid therapy. For this, we used physics-based simulations on a virtually-generated population of patients, and we applied the same therapy to all patients. We could show that patients' physiology, such as gender, age, and weight, greatly impact the outcome of the therapy; as such, the correlation coefficient between pain intensity and age is 0.89, and the correlation coefficient between patient's weight and maximum plasma concentration of morphine and fentanyl is -0.98 and -0.97. Additionally, a different combination of the duration of overlap between morphine and fentanyl therapy with different doses of fentanyl was considered for the virtual patients to find the best opioid-switching strategy for each patient. We explored the impact of combining physiological features to determine the best-suited strategy for virtual patients. Our findings suggest that tailoring morphine and fentanyl therapy only based on a limited number of features is insufficient, and increasing the number of impactful physiological features positively influences the outcome of the therapy.

Fentanyl as a marker of illicit drug use in morphine-positive urine specimens from workplace drug testing.

Total morphine is an important urinary marker of heroin use but can also be present from prescriptions or poppy seed ingestion. In specimens with morphine concentrations consistent with poppy seed ingestion (<4,000 ng/mL), 6-acetylmorphine has served as an important marker of illicit drug use. However, as illicit fentanyl has become increasingly prevalent as a contaminant in the drug supply, fentanyl might be an alternative marker of illicit opioid use instead of or in combination with 6-acetylmorphine. The aim of this study was to quantify opiates, 6-acetylmorphine, fentanyl and fentanyl analogs in 504 morphine-positive (immunoassay 2,000 ng/mL cutoff) urine specimens from workplace drug testing. Almost half (43%) of morphine-positive specimens had morphine concentrations below 4,000 ng/mL, illustrating the need for markers to differentiate illicit drug use. In these specimens, fentanyl (22% co-positivity) was more prevalent than 6-acetylmorphine (12%). Co-positivity of 6-acetylmorphine and semi-synthetic opioids increased with morphine concentration, while fentanyl prevalence did not. In 110 fentanyl-positive specimens, the median norfentanyl concentration (1,520 ng/mL) was 9.6× higher than the median fentanyl concentration (159 ng/mL), illustrating the possibility of using norfentanyl as a urinary marker of fentanyl use. The only fentanyl analog identified was para-fluorofentanyl (n = 50), with results from most specimens consistent with para-fluorofentanyl contamination in illicit fentanyl. The results confirm the use of fentanyl by employees subject to workplace drug testing and highlight the potential of fentanyl and/or norfentanyl as important markers of illicit drug use.

SERUM FENTANYL CONCENTRATIONS AND BEHAVIOR ASSOCIATED WITH TRANSDERMAL FENTANYL APPLICATION ON HEALTHY CORN SNAKES (PANTHEROPHIS GUTTATUS).

Snakes are common household pets and frequently managed in zoos. Geriatric snakes commonly develop osteoarthritis, leading to a declining quality of life that often results in euthanasia. Anecdotally, the application of transdermal fentanyl patches (TFP) appears to contribute to clinical improvement, including increased activity level, in osteoarthritic snakes presumed to be in pain. This study evaluated serum fentanyl concentrations over time and the effects of TFP on the normal behavior of healthy, captive, adult corn snakes (Pantherophis guttatus) using constant video monitoring. Serum fentanyl concentrations were evaluated over 4 wk during 12.5 µg/h TFP application, and the results demonstrated long-lasting (>4 wk) serum concentrations that were consistent with analgesic efficacy in mammalian species during TFP application. At 4 wk of TFP application, mean serum fentanyl concentrations were 11.5 ± 5.5 ng/ml. Snakes were videotaped for 1 wk prior to and 2 wk after 12.5 µg/h TFP application, and behavior was evaluated by an ethogram. Behavioral changes associated with TFP application included decreased mean time spent active, decreased mean number of climbs, and decreased mean number of water visits; feeding behavior was unchanged. Overall, these results suggest that TFP application may provide safe, clinically effective analgesia in healthy corn snakes for at least 4 wk without inducing deleterious side effects, and may therefore be appropriate analgesia for management of osteoarthritic snakes.

Evaluation of the relationship of xylazine and fentanyl blood concentrations among fentanyl-associated fatalities

Introduction Illicit fentanyl and fentanyl-analogs have produced a devastating increase in opioid fatalities in the United States. Increasingly, xylazine has been found in the illicit fentanyl supply. The role of xylazine in fentanyl intoxication remains unclear. We reviewed coroner records to evaluate trends and effects associated with xylazine in fentanyl-related fatalities. Methods This is a retrospective cohort study of all deaths reported to the Franklin County Coroner’s Office in Ohio from 1 January 2019 to 16 March 2023, in which fentanyl was determined causative or contributory to death. Cases identified as fentanyl-associated fatalities were separated into two groups based on whether or not xylazine was also detected. Results There were 3,052 fentanyl-related fatalities during the study period. 4.8 percent of these decedents also tested positive for xylazine. There was no meaningful demographic difference between fentanyl-related fatalities in which xylazine was detected versus those without xylazine detected. There was a mean of 726 fentanyl-associated fatalities per year, with a peak of 846 deaths in 2020 and a decline thereafter. The percentage of fentanyl-related fatalities with xylazine detected increased in linear fashion from 2.7 percent in 2019 to 6.6 percent in 2022. The median fentanyl concentration was 17.0 µg/L (inter-quartile range: 7.9, 27.0) in cases with xylazine detected and 10.0 µg/L (inter-quartile range: 5.6, 18.0) without xylazine. The odds of a fentanyl concentration greater than 40 µg/L in cases with xylazine detected was more than twice as great (odds ratio: 2.41; 95 percent confidence interval: 1.58–3.64) than that in cases without xylazine detected. Conclusions Postmortem fentanyl concentrations were greater in cases with xylazine detected than those without xylazine detected. Though it is unclear why patients who were exposed to xylazine tolerated higher opioid doses prior to succumbing to death, we postulate that xylazine may act to competitively antagonize some degree of mu-opioid receptor binding by opioids.

Developing mathematical models to compare and analyse the pharmacokinetics of morphine and fentanyl.

The two-compartment model is generally used in pharmacokinetics to illustrate the distribution and excretion of drugs. In this study, we evaluated the distribution patterns of morphine and fentanyl by using a two-compartment model. Using numeric analysis techniques, non-linear ordinary differential equations were used to mathematically analyse drug distribution, transition, and concentration in the body compartments. Math Works, Inc., MATLAB, version 2023a, a programming tool, was used to characterise the impact of initial concentration and rate constants on the kinetics of the drug. For a definite therapeutic concentration of morphine and fentanyl in blood, pharmacokinetic characteristics were plotted. The study results showed the time taken by morphine and fentanyl to reach a target concentration in the blood that is sufficient to generate the preferred therapeutic effects. The mathematical models comparing morphine and fentanyl pharmacokinetics showed that fentanyl reached the target therapeutic concentration 125 minutes earlier than morphine and was metabolised and removed from the body more rapidly (44 minutes earlier than morphine). These comparative mathematical models on morphine and fentanyl enable the determination of drug dosages and understanding of drug efficacy that facilitates optimising dosing regimens. The right choice between them can be made based on the time to reach the target therapeutic concentration in the blood, elimination time, severity of pain, and patient characteristics.

The evolution of fentanyl-related substances: Prevalence and drug concentrations in postmortem biological specimens at the Miami-Dade Medical Examiner Department.

Since 2014, the Miami-Dade Medical Examiner Department (MDME) has observed a drastic increase in the number of fentanyl and fentanyl analog (fentanyl-related substances (FRSs)) fatalities since its introduction into the heroin and cocaine supply. Due to the prevalence of FRS in Miami-Dade County, the MDME toxicology laboratory began documenting each case in which fentanyl and/or a fentanyl analog was identified. Additional information monitored included demographics (age, race and sex), other drugs identified, cause of death (COD) and manner of death (MOD). From 2014 to 2022, the MDME toxicology laboratory analyzed a total of 1,989 cases that tested positive for FRS, of which 1,707 had detectable and/or quantifiable fentanyl concentrations in postmortem cases. The majority of decedents were white males (62%), and the predominant age range was 25-34 years. The most prevalent MOD was accident (93%) with the most common COD listed as acute combined drug toxicity of fentanyl in combination with other drugs (79%). Other drugs found in combination with fentanyl included heroin, cocaine (most prevalent), synthetic cathinones and ethanol. Of all FRS cases, 9% (170 cases) involved fentanyl alone as a COD, while 2% (38 cases) included only fentanyl analogs. Fentanyl concentrations ranged from 1.0 to 1,646 ng/mL in peripheral blood, 1.2 to 449 ng/mL in central blood, 3.2 to 28 ng/mL in donor blood (obtained during tissue harvesting), 1.1 to 108 ng/mL in antemortem blood, 8.5 to 1,130 ng/g in liver and 2.0 to 471 ng/g in brain. Drug concentrations were also reported for an additional eight fentanyl analogs. Considering the prevalence, high potency and constant evolution of FRS, it is important to continuously monitor trends and report drug concentrations in complex medical examiner casework in an effort to educate pathologists, law enforcement and local governments.

Population Pharmacokinetics of Single Bolus Dose Fentanyl in Obese Children.

Childhood obesity is a significant problem. Obesity may alter the pharmacokinetics (PKs) of medications. Fentanyl is commonly used for procedural sedation, but there is a paucity of bolus dose fentanyl PK data in obese children. Better understanding of fentanyl PK in obese children would facilitate dosing recommendations. We conducted a study involving children with and without obesity to assess the potential differences in bolus dose fentanyl PK between the 2 groups. We enrolled children 2 to 12 years of age with and without obesity, defined as >95th percentile body mass index (BMI) for age and sex, undergoing elective tonsillectomy ± adenoidectomy. After induction, subjects had 2 intravenous (IV) lines placed in 2 different extremities: 1 for medications and IV fluids and 1 for obtaining blood aliquots for fentanyl concentration analysis. After administration of 1 mcg/kg of fentanyl based on total body weight (TBW), blood sample collections for fentanyl concentration analysis were attempted at 5, 15, 30, 60, 90, and 120 minutes. Five-minute fentanyl concentrations were compared between obese and nonobese cohorts. Population PK analysis to examine the differences between obese and nonobese children was performed and included various body size descriptors, such as TBW, BMI, and fat-free mass (FFM), to examine their influence on model parameters. Half of the 30 subjects were obese. Mean fentanyl concentrations at 5 minutes were 0.53 ng/mL for the nonobese group and 0.88 ng/mL for the obese group, difference 0.35 ng/mL (95% CI, 0.08-0.61 ng/mL; P = .01). Population PK analysis showed that FFM was a significant covariate for the central volume of distribution. The potential clinical effect of an IV bolus dose of fentanyl based on TBW versus FFM in an obese child was assessed in a simulation using our model. 1 mcg/kg fentanyl dose based on TBW resulted in an approximately 60% higher peak fentanyl effect site concentration than dosing based on FFM. Our data demonstrated higher peak plasma fentanyl concentrations in obese compared to nonobese subjects. Population PK analysis found that FFM was a significant covariate for the central volume of distribution. Model simulation showed dosing of fentanyl in obese children based on TBW resulted in significantly higher peak concentrations than dosing based on FFM. Based on this modeling and the known concentration-effect relationship between fentanyl and adverse effects, our results suggest that bolus dosing of fentanyl in obese children should be based on FFM rather than TBW, particularly for procedures of short duration.

Quantifying a potential protective effect of buprenorphine on fatality risk during acute fentanyl exposures

IntroductionBuprenorphine is an important therapy for opioid use disorder and may also reduce the risk of fatal overdoses in fentanyl exposures. However, the role of buprenorphine in reducing this risk has not been quantified. This cross-sectional study examined the association between buprenorphine presence, decedent characteristics, and other factors with the predicted fentanyl concentrations in overdose deaths. MethodsThe study identified unintentional fentanyl overdose decedents (n = 3036) from the West Virginia Forensic Drug Database, 2011 through mid-2020. The main outcome was fentanyl concentrations in overdose deaths in the presence and absence of buprenorphine. A multiple linear regression model examined the association of fentanyl concentrations with buprenorphine presence based on the concentrations of the parent drug buprenorphine (B) and its metabolite norbuprenorphine (N), adjusting for demographics, toxicological characteristics (presence of multiple opioids, benzodiazepines, stimulants, marijuana, and alcohol), and comorbidities. We used a B/N concentration ratio < 1 as an indirect indicator of longer-term buprenorphine exposure prior to drug overdose death. ResultsThe median fentanyl concentration was 65 % higher when buprenorphine was present (N = 168) vs. absent (N = 2868) (0.028 vs. 0.017 μg/mL, p < 0.001). In the multivariable model, statistically significant associations occurred between buprenorphine presence and increased fentanyl concentrations (+28.7 %) with a B/N ratio < 1. Obesity, male sex, alcohol presence, and comorbid cardiovascular diseases were statistically significantly associated with lower (−11.3 % to −20.7 %) fentanyl concentrations, whereas marijuana presence and a history of substance use disorder were associated with statistically significant higher fentanyl concentrations (+8.8 % to +31.3 %). ConclusionsThese findings suggest that sustained or longer-term buprenorphine intake might exert some protective effect on fatalities resulting from fentanyl exposure as documented by the association of higher fentanyl blood concentrations with buprenorphine presence among fatal drug overdoses. As fentanyl availability and overdose rates increase nationally, buprenorphine is a vital tool for effective opioid use disorder treatment that might also reduce the risk of fatality in an acute fentanyl exposure.

Rapid appearance of negative emotion during oral fentanyl self-administration in male and female rats.

Opioid use disorder has become an epidemic in the United States, fuelled by the widespread availability of fentanyl, which produces rapid and intense euphoria followed by severe withdrawal and emotional distress. We developed a new preclinical model of fentanyl seeking in outbred male and female rats using volitional oral self-administration (SA) that can be readily applied in labs without intravascular access. Using a traditional two-lever operant procedure, rats learned to take oral fentanyl vigorously, escalated intake across sessions, and readily reinstated responding to conditioned cues after extinction. Oral SA also revealed individual and sex differences that are essential to studying substance use risk propensity. During a behavioural economics task, rats displayed inelastic demand curves and maintained stable intake across a wide range of fentanyl concentrations. Oral SA was also neatly patterned, with distinct 'loading' and 'maintenance' phases of responding within each session. Using our software DeepSqueak, we analysed ultrasonic vocalizations (USVs), which are innate expressions of current emotional state in rats. Rats produced 50 kHz USVs during loading then shifted quickly to 22 kHz calls despite ongoing maintenance of oral fentanyl taking, reflecting a transition to negative reinforcement. Using fibre photometry, we found that the lateral habenula differentially processed drug cues and drug consumption depending on affective state, with potentiated modulation by drug cues and consumption during the negative affective maintenance phase. Together, these results indicate a rapid progression from positive to negative reinforcement occurs even within an active drug taking session, revealing a within-session opponent process.

B-342 Fentanyl Urine Drug Screen Comparison of the ARK II and Lin Zhi Immunoassays

Abstract Background Given the opioid epidemic, screening for fentanyl in urine has become increasingly important. Routine opiate immunoassays cannot identify fentanyl, given its structural variance from the more common opiates such as morphine and codeine. Therefore, the detection of fentanyl by immunoassay urine drug screen depends on antibody specificity for fentanyl. The ARK II is a widely used immunoassay that will detect fentanyl and norfentanyl. Recently, a novel fentanyl assay by Lin-Zhi has become available on the Roche platform; here, we evaluate its performance. Methods One hundred twenty nine urine samples were analyzed for fentanyl across the Lin-Zhi and ARK II assay on the Cobas c502 platform. Samples were either analyzed immediately upon request for drug of abuse screening or frozen for subsequent analysis. Liquid chromatography coupled tandem mass spectrometry (LC-MS/MS) and/or prescription was used as confirmation for the presence of fentanyl. Our of the total 129 tested samples, so far 59 have been confirmed and additional studies are ongoing. The mass spectrometry assay has a limit of detection of 1 ng/mL for fentanyl/norfentanyl. The ARK II immunoassay has a 1 ng/mL cut-off for fentanyl and 7% cross-reactivity for norfentanyl; the Lin Zhi has a 5 ng/mL cut-off for norfentanyl and 131.58% cross reactivity for fentanyl. Results There were 9/129 discrepant samples between ARK II and Lin Zhi immunoassays as shown in Fig. 1. From the 59 confirmed samples Ark II resulted in one false positive sample and seven false negative samples (Fig. 1B) while the Lin Zhi assay resulted in 9 false negatives. Conclusion Given the current data set, there appear to be some discrepant results between the ARK II and Lin Zhi immunoassays. Most of the discrepant results observed have concentrations of fentanyl and norfentanyl that are close to the lower limit of immunoassay detection.

B-324 Comparison of Two Urine Fentanyl Assays on the Abbott Alinity c Analyzer

Abstract Background Mass spectrometry (MS) remains the gold standard, however immunoassays can provide a preliminary test result while the patient is still in the emergency room or clinic. Methods The ARK Fentanyl II assay (ARK Diagnostics Inc, Fremont, CA) was compared to the Immunalysis SEFRIA Fentanyl (Immunalysis Corporation, Pomona, CA) assay on the Abbott Alinity c analyzer (Abbott Park, IL) using leftover deidentified urine samples. MS analysis was performed at ARUP Laboratories (Salt Lake City, UT) to quantitate the amount of fentanyl or norfentanyl metabolite in each sample. Medications prescribed at the time of sampling were reviewed to assess for possible cross reactivity with the assays. Results A total of 142 urine samples were analyzed with 70 MS positive and 72 MS negative samples. Positive and negative assay specific quality control precision (N = 10) was 3.0% and 9.6% CV for the ARK Fentanyl II assay and 10.2% and 15.9% CV for the Immunalysis SEFRIA assays respectively. ARK Fentanyl II Sensitivity = 95.7%, Specificity = 94.4%, PPV = 94.4%, NPV = 95.8% and Efficiency = 95.1% compared to the Immunalysis SEFRIA Fentanyl Sensitivity = 95.7%, Specificity = 81.9%, PPV = 83.8%, NPV = 95.2% and Efficiency = 88.7%. Upon repeat analysis, 4 of 4 ARK and 6 of 13 Immunalysis false positives reported as negative, indicating some variability around the cutoff concentration. Possible carryover from high samples has also been reported (ARK Technical Note 20-001-August 2020) and high samples were analyzed prior to some of the false positive samples. Six MS positive samples were reported as negative (false negatives), 3 samples by each of the assays. However, 4/6 of those samples had combined fentanyl and norfentanyl concentrations &amp;lt;3 ng/mL by MS. Conclusion The ARK Fentanyl II and Immunalysis SEFRIA assays demonstrated acceptable performance in the detection of fentanyl in our patient population.

Self-Adjuvanting TLR7/8 Agonist and Fentanyl Hapten Co-Conjugate Achieves Enhanced Protection against Fentanyl Challenge.

Currently approved pharmacotherapies for opioid use disorders (OUDs) and overdose reversal agents are insufficient to slow the spread of OUDs due to the proliferation of fentanyl. This is evident in the 31% rise in drug overdose deaths from 2019 to 2022, with rates increasing from 21.6 to 28.3 overdoses per 100,000 deaths. Vaccines are a potential alternative or adjunct therapy for the treatment of several substance use disorders (nicotine, cocaine) but have shown limited clinical success due to suboptimal antibody titers. In this study, we demonstrate that coconjugation of a Toll-like receptor 7/8 (TLR7/8) agonist (UM-3006) alongside a fentanyl-based hapten (F1) on the surface of the carrier protein cross-reactive material 197 (CRM) significantly increased generation of high-affinity fentanyl-specific antibodies. This demonstrated enhanced protection against fentanyl challenges relative to an unconjugated (admix) adjuvant control in mice. Inclusion of aluminum hydroxide (alum) adjuvant further increased titers and enhanced protection, as determined by analysis of fentanyl concentration in serum and brain tissue. Collectively, our findings present a promising approach to enhance the efficacy of antiopioid vaccines, underscoring the need for extensive exploration of TLR7/8 agonist conjugates as a compelling strategy to combat opioid use disorders.

Fentanyl Concentration in Drug Checking Samples and Risk of Overdose Death in Vancouver, Canada

The proliferation of fentanyl and its analogs in illegal, unregulated drug markets remains a major driver of the overdose crisis in North America. Drug checking services have been implemented as a harm reduction strategy to address the crisis. However, little is known about their potential utility as a mechanism for monitoring population-level risk of overdose stemming from changing fentanyl concentration in unregulated drugs over time. Therefore, this study assessed the relationship between median fentanyl concentration in expected opioid drug checking samples and the death rate due to illicit drug toxicity over time in Vancouver, Canada. Monthly population-based rates of death due to illicit drug toxicity were drawn from provincial coroner records. Monthly median percent fentanyl concentration was calculated using a validated quantification model from point-of-care Fourier-transform infrared spectra among expected opioid samples that tested positive for fentanyl at community drug checking services. A time-series analysis using generalized additive modeling was conducted to examine the association between monthly median fentanyl concentration and monthly death rate due to illicit drug toxicity, controlling for calendar month. Analyses were conducted in 2021-2022. Between January 2019 and October 2020, 577 deaths due to illicit drug toxicity occurred in Vancouver, and the observed monthly rate ranged from 1.75 to 7.65 deaths per 100,000 population. A significant, positive association was observed between monthly median fentanyl concentration and monthly death rate due to illicit drug toxicity, adjusting for calendar month (chi-square=52.21, p<0.001). Findings suggest a role for point-of-care drug checking as a tool for monitoring evolving overdose risk at the population level.

Evaluating the Pharmacokinetics of Fentanyl in the Brain Extracellular Fluid, Saliva, Urine, and Plasma of Newborns from Transplacental Exposure from Parturient Mothers Dosed with Epidural Fentanyl Utilizing PBPK Modeling.

Fentanyl can mitigate the mother and newborn complications resulting from labor pain. However, fentanyl shows a narrow therapeutic index between its respiratory depressive and analgesic effects. Thus, prenatally acquired high fentanyl levels in the newborn brain extracellular fluid (bECF) may induce respiratory depression which requires therapeutic drug monitoring (TDM). TDM using saliva and urine in newborns can reduce the possibility of infections and distress associated with TDM using blood. The objective of this study was to develop aphysiologically based pharmacokinetic (PBPK) modelto predict fentanyl concentrations in different newborn tissues due to intrauterine exposure. A fentanyl PBPK model in adults after intravenous and epidural administration was built, validated, and scaled to pregnancy and newborn populations. The dose that the newborn received transplacentally at birth was calculated using the pregnancy model. Then, the newborn bECF, saliva, plasma, and urine concentrations after such a dose were predicted using the newborn PBPK model. After a maternal epidural dose of fentanyl245 µg, the predicted newborn plasma and bECF levels were below the toxicity thresholds. Furthermore, the salivary threshold levels in newborns for fentanyl analgesic and respiratory depression effects were estimated to be 0.39 and 14.7-18.2 ng/ml, respectively. The salivary TDM of fentanyl in newborns can be useful in newborns exposed to intrauterine exposure from parturient females dosed with epidural fentanyl. However, newborn-specific values of µ-opioid receptors IC50 for respiratory depression are needed.

Longitudinal evaluation of fentanyl concentrations in equine plasma and synovial fluid following application of transdermal fentanyl patches over one carpal joint.

To determine if transdermally delivered fentanyl can achieve greater concentrations of fentanyl in synovial fluid when applied over a synovial structure. Randomized, experimental study. Six healthy adult horses. Each horse had two 100 μg/h fentanyl matrix patches applied on the dorsal aspect of one, randomly assigned, carpometacarpal joint (CMCJ) for 48 h. Whole blood and bilateral synovial samples from the intercarpal joint were obtained at 0, 2, 6, 12, 24, 36 and 48 h. Fentanyl concentrations were measured with liquid chromatography-mass spectrometry. All subjects achieved detectable concentrations of fentanyl in both plasma and synovial fluid. Time to peak synovial and plasma concentration was 12 h. At 6 h, the synovial concentration in the untreated carpus (0.104 ng/mL ± 0.106) was lower than plasma fentanyl concentrations 0.31 ± 0.27 (p = .036). At 12 h, both treated (0.55 ng/mL ± 0.3) and untreated (0.53 ng/mL ± 0.28) synovial fluid fentanyl concentrations were lower than plasma (0.87 ng/mL ± 0.48) concentrations (p < .001 and p = .001, respectively). Synovial concentrations of fentanyl did not differbetween treated and untreated joints (p > 0.608 for all time points). Application of fentanyl matrix patches directly over the CMCJ did not result in increased fentanyl concentrations in the synovial fluid of the treated intercarpal joint in normal horses. There is likely no analgesic advantage to placing fentanyl patches directly over the affected joint, as it did not result in increased synovial concentrations at the tested site.

The rise and rise of fentanyl in postmortem casework.

Forensic toxicology laboratories are navigating a period of time with increasing drug overdose deaths, an opioid epidemic, the impact of the COVID-19 pandemic, and the illicit drug market flooded with novel psychoactive substances. In New York City, the Department of Forensic Toxicology has experienced a 56% increase in postmortem casework in the past decade with fentanyl detected in 80% of all overdose deaths. Over a period of 2.5 years, 15,638 postmortem cases were tested for the presence of fentanyl and fentanyl analogs using liquid-chromatography tandem mass spectrometry (LCMSMS). Fentanyl was detected in approximately one third of cases and of these 4447 cases with femoral blood. A twofold increase in cases with high concentrations of fentanyl (>100 ng/mL) was observed between 2021 and 2022. The minor metabolite and precursor chemical, 4-ANPP (4-anilino-N-phenethylpiperidine) may help differentiate between illicit and licit fentanyl. 4-ANPP blood concentrations were <10 ng/mL in 98% of the cases and the 4-ANPP:fentanyl ratio was <0.67 for 99.1% of blood specimens. Only six cases had 4-ANPP concentrations higher than the corresponding fentanyl blood concentration. This study also highlights, the changing fentanyl analogs found in postmortem cases since 2016 in NYC with the emergence of fluorofentanyl initially identified in 2020 and continuing to dominate in comparison with the prevalence of other analogs, many of which are no longer detected in casework. The detection of one of the latest drugs to be mixed with fentanyl, namely xylazine, has also increased in prevalence by 36.7% in 2022 compared with 2021.