Longitudinal Opioid Surveillance Project Involving Toxicologic Analysis of Postmortem Specimens from 9 Counties in Michigan Suggests the Discovery of New High-Intensity Drug Trafficking Areas.

ABSTRACT: Acetyl fentanyl (AF) is a Schedule I fentanyl analog that has been increasingly seen in heroin and fentanyl polydrug toxicity overdoses in Michigan (MI). Drug users are often unaware of the presence of AF in their drugs because it is often sold mixed into or disguised as heroin. High levels of AF in heroin drug products can cause increased incidence of overdose. This article describes data from a longitudinal opioid surveillance program and details 102 decedents in MI who were found to have evidence of heroin in their postmortem blood. A large portion of these decedents were also found to have evidence of fentanyl and AF. Our data further show significant overlap in incidence rates of AF and heroin-related overdose deaths in several MI counties, suggesting that AF is becoming enmeshed in heroin trafficking. Furthermore, we report unprecedented high incidence rates of AF and heroin-related overdose deaths in Calhoun county, and we propose that it is a high-intensity drug trafficking area. Highways US-131 and US-31 are likely used to transport these drugs. More study is needed into the drug trafficking trends in MI to ascertain drug sources and monitor the ever developing and dangerous polydrug heroin combinations.

Remifentanil and perioperative glycaemic response in cardiac surgery: an open-label randomised trial.

BACKGROUND: This study investigated whether remifentanil infusion decreased intraoperative hyperglycaemia and insulin resistance compared with intermittent fentanyl administration in patients undergoing elective cardiac surgery. METHODS: This was a randomised, prospective, open-label trial. Patients undergoing elective cardiac surgery (n=116) were randomised to receive either continuous intravenous remifentanil infusion or intermittent fentanyl boluses. Hourly blood glucose values were obtained for 24 h starting from induction of anaesthesia. The difference in percentage of patients with ≥2 intraoperative blood glucose concentrations >10 mM (180 mg dl-1) between the groups was the primary outcome measure. Secondary outcome measures included insulin requirements, select stress hormone and inflammatory cytokine concentrations, and safety events and adverse outcomes. RESULTS: The trial included 106 subjects in the final intention-to-treat analysis. There were fewer patients with ≥2 intraoperative blood glucose values >10 mM (180 mg dl-1) in the remifentanil group (17 [31.5%]) compared with the fentanyl group (33 [63.5%]) (relative risk: 0.50; 95% confidence interval [CI]: 0.32-0.77; P=0.001). The administered intraoperative insulin was a median of 8.1 units (range: 0-46.7) in the fentanyl group and 2.9 units (range: 0-35.1) in the remifentanil group (median difference=5 units; 95% CI: 1-7; P=0.004). Cortisol and adrenocorticotropic hormone were increased less in the remifentanil group (P<0.001), but there was no relative decrease in this group in select inflammatory cytokines. Postoperative measures of glycaemic control and adverse clinical outcomes were not significantly different between groups. CONCLUSIONS: Compared with patients treated with intermittent fentanyl, patients receiving continuous remifentanil infusion had fewer episodes of hyperglycaemia and less need for insulin administration during the intraoperative period of cardiac surgery. CLINICAL TRIAL REGISTRATION: NCT02349152.

Screening procedure for 38 fentanyl analogues and five other new opioids in whole blood by liquid chromatography-tandem mass spectrometry.

In recent years, many new opioids, particularly fentanyl analogues, have appeared on the drug market. The extreme potency of even low doses of these compounds leads to numerous fatal poisonings. This also results in the fact that only sophisticated techniques are capable of detecting fentanyl analogues at concentrations that can be expected in blood. In this context, the purpose of this study was to develop a fast liquid chromatography-tandem mass spectrometry screening method for the detection of fentanyl analogues, and other new synthetic opioid receptor agonists in whole blood. Blood samples were extracted with ethyl acetate under basic conditions. The separation was achieved with the gradient of the mobile phase composition and the gradient of the flow rate in 13 minutes. The detection of all compounds was based on dynamic multiple reaction monitoring. Most of the compounds were well differentiated by their retention times and/or transitions; however, separation of some isomers has not been achieved. The validation was performed for 21 compounds. The limits of detection were in the range 0.01-0.20 ng/mL. The developed procedure enables simultaneous qualitative screening, detection and identification of 38 fentanyl analogues and five other new opioids. The method was implemented to analyze authentic samples (positive; n = 3) demonstrating its suitability for this application. The procedure can be easily expanded to include new emerging opioids, which is an indispensable advantage in the dynamically developing drug market. The developed protocol can be adopted for routine work in both forensic and clinical analytical laboratories worldwide.

A Fatal Case of Poisoning with Fentanyl Transdermal Patches in Japan.

Fentanyl transdermal patches have been used to treat cancer- and noncancer-related chronic pain. However, its inappropriate or illegal application may cause fatal poisoning. We herein present the case of a Japanese woman in her 40s who was found dead with seven 25-µg/h fentanyl transdermal patches on her body. We established a detailed toxicological analysis procedure to quantify fentanyl, and its metabolite norfentanyl, and other drugs (acetaminophen, allylisopropylacetylurea, celecoxib, estazolam, promethazine, and sertraline) in human whole blood by ultra-high-performance liquid chromatography-tandem mass spectrometry. The measured fentanyl and norfentanyl concentrations in the femoral and cardiac blood were 0.051 and 0.072 µg/mL and 0.033 and 0.076 µg/mL, respectively. The decedent's fentanyl concentrations were consistent with previously reported postmortem blood levels for fatal cases of poisoning by fentanyl transdermal patches. Based on the decedent's case history, autopsy findings, and toxicological analyses, the cause of death was identified as intoxication with transdermal fentanyl.

Analysis of Acetyl Fentanyl in Postmortem Specimens by Gas Chromatography-Mass Spectrometry (GC-MS): Method Validation and Case Report.

In 2013, the Centers for Disease Control and Prevention released a warning regarding a new recreational drug, acetyl fentanyl. Acetyl fentanyl is a µ-opioid receptor agonist, and its pharmacological effects include euphoria, altered mood, miosis and central nervous system depression. The objective of this report was to develop a sensitive and specific method for the quantitation of acetyl fentanyl by gas chromatography-mass spectrometry in postmortem casework. Acetyl fentanyl was isolated from biological matrices using solid-phase extraction and acetyl fentanyl-13C6 was employed as an internal standard. The method was validated utilizing the Scientific Working Group for Forensic Toxicology's published method validation parameters, and the biological matrices used for analysis were postmortem blood and urine. In addition to the quantitation of acetyl fentanyl, a demographic study of cases obtained from the Rhode Island Office of State Medical Examiners and the University of Florida Health Pathology Laboratories-Forensic Toxicology Laboratory was performed to examine potential risk factors for acetyl fentanyl use. The results from this study found that the blood concentrations in these individuals ranged from 17 to 945 ng/mL. This suggests acetyl fentanyl is less potent than its prototype drug, fentanyl and requires an increased dose to achieve its desired effects. The demographic analysis indicated white males aged 21-40 years and individuals with a previous history of drug use have the highest risk for acetyl fentanyl abuse.

Five Postmortem Case Reports with Qualitative Analysis of Cyclopropylfentanyl by LC-MS-MS.

In January 2018, the Drug Enforcement Agency temporarily designated cyclopropylfentanyl as a Schedule I drug. Over the course of 5 months (December 2017-May 2018), the Nassau County Medical Examiner Toxicology Laboratory qualitatively identified and confirmed cyclopropylfentanyl in specimens obtained from five postmortem cases. We describe the five cases and include pertinent autopsy findings and decedent histories, along with results for cyclopropylfentanyl determined in postmortem cardiac blood. Samples were prepared by an alkaline liquid-liquid extraction, with sample pH adjusted to >9 and utilizing an extraction solvent consisting of 90:10 hexane:ethyl acetate. Instrumental analysis was achieved via liquid chromatography tandem mass spectrometry with a dual jetstream electrospray source operating in positive ion mode. Two ion transitions were monitored for each analyte of interest and the internal standard. The estimated concentration range of cyclopropylfentanyl in the reported cases was 5.6 to 82 ng/mL for five postmortem cardiac blood specimens. All five cases included cyclopropylfentanyl in the established cause of death.

A Fatality Involving Furanylfentanyl and MMMP, with Presumptive Identification of Three MMMP Metabolites in Urine.

The prevalence of new psychoactive substances (NPS) on the illicit drug market continues to grow, with new analogs being routinely synthesized. Routes of administration for these compounds are also diversifying, and recent research has shown an increase in the incorporation of NPS into vaping liquids. Among the most commonly encountered NPS are the cathinone and fentanyl analogs. Fentanyl analogs in particular have been implicated in a significant number of deaths, usually in combination with other prescription and illicit drugs. We report the case of a 44-year-old male with a history of polysubstance abuse found deceased at his home address. Items located within the vicinity of the deceased were found to contain furanylfentanyl and 2-methyl-4'-(methylthio)-2-morpholinopropiophenone (MMMP also known as MTMP, MMTMP, Irgacure 907 and Caccure 907). Both of these compounds were detected in the post-mortem peripheral blood of the deceased: furanylfentanyl at 1.6 ng/mL and MMMP at 6.7 ng/mL. MMMP is an unrestricted, commercially available photo-initiator used in the printing and polymer industry, which structurally can be classed as a highly modified cathinone. Although MMMP has been found previously in drug seizures, this is the first fatality in which MMMP has been detected. A number of other prescription and illicit drugs were also detected in the blood. MMMP was not detected in the post-mortem urine; however three metabolites, beta-hydroxy-MMMP, beta-hydroxy-MMMP-sulfoxide and beta-hydroxy-MMMP-sulfone, were presumptively identified. The significance of MMMP to the cause of death is uncertain as its pharmacological and toxicological profile is unclear.

Is the transdermal fentanyl patch an efficient way to achieve acute postoperative pain control?: A randomized controlled trial.

BACKGROUPD: This study investigated the plasma fentanyl concentration and efficacy of transdermal fentanyl patch (TFP) (25 µg/h) in the management of acute postoperative pain. METHODS: Patients undergoing laparoscopic cholecystectomy were randomly allocated to 2 groups. The TFP group (n = 30) received a single TFP 25 µg/ h to the anterior chest wall 14 h before operation. The IV group (n = 30) received a placebo patch. After the operation, intravenous fentanyl infusion (25 µg/h) was begun with loading dose 25 µg in the IV group and only normal saline in the TFP group. Plasma fentanyl levels were measured at admission, 1, 6, 12, 24, and 48 h postoperatively. Pain severity and adverse effects were evaluated too. RESULTS: The fentanyl level peaked 1 h after operation in the TFP group (3.27 ±â€Š0.34 ng/mL) and 24 h postoperatively in the IV group (2.9 ±â€Š0.42 ng/mL). Pain scores and the use of rescue analgesics were not significantly different between 2 groups. Respiratory depression was not happened in both groups. CONCLUSIONS: The TFP (25 µg/h) affixed 14 h before surgery reached a higher constant concentration than the same dose setting of a constant IV infusion of fentanyl after surgery. Although the concentration of fentanyl was higher than those of previous researches, there was no respiratory depression. But, there was no advantage of reducing pain score and the use of rescue analgesics. CLINICAL TRIAL REGISTRATION: (available at: http://cris.nih.go.kr, KCT0002221).

Opioid responsiveness of nociceptive versus mixed pain in clinical cancer patients.

OBJECTIVE: To investigate whether clinical cancer patients with mixed nociceptive-neuropathic pain are less responsive to opioids than patients with nociceptive pain. BACKGROUND: Pain is common in advanced cancer patients. Pain driven by neuropathic mechanisms is considered to be resistant to opioids. This hypothesis is mainly based on animal studies and single-dose opioid studies in humans but has not been confirmed in clinical practice. METHODS: Data were prospectively collected from 240 clinical cancer pain patients using opioids. Multiple linear regression was used for assessing the associations between the logarithm of the morphine equivalent dose (MED) at three days after admission (T = 3d) relative to admission (T = 0d) (logRMED) and type of pain (nociceptive versus mixed pain), corrected for gender, age, primary cancer site and use of non-opioid and adjuvant analgesics. As secondary outcome measures, associations between logMED and logPFent (fentanyl plasma level) at T = 3d and type of pain were assessed. RESULTS: Pain intensity between T = 0d and T = 3d was significantly and evenly reduced in patients with nociceptive pain (n = 173) and mixed pain (n = 67). Median (interquartile range) MED was 20 (10-52) and 20 (20-80) mg (T = 0d), 40 (10-67) and 40 (20-100) mg (T = 3d), median PFent (T = 3d) was 1.59 (0.58-3.19) and 1.38 (0.54-4.39) ng/ml, none of them significantly different, in patients with nociceptive and mixed pain, respectively. Neither logRMED, logMED (T = 3d), or logPFent (T = 3d) was significantly associated with type of pain, after correction for confounding factors. CONCLUSIONS: We conclude that, at least in clinical cancer patients, mixed pain is as responsive to opioids as nociceptive pain.

Sensitive Determination of Fentanyl in Low-Volume Serum Samples by LC-MS/MS.

Fentanyl is a widely used drug in the management of pain. Present LC-MS/MS methods for analysis of fentanyl require a large volume of serum, but yet the sensitivity was at about 50 pg/mL. Here, we report a modified liquid-liquid extraction method for the analysis of fentanyl in serum. The method is very sensitive with a LLOQ of 5 pg/mL while using only 0.175 mL of serum for analysis. The separation was performed on a Zorbax XDB-C18 column (4.6 × 50 mm, 1.8 µm, 600 bar) using a mobile phase of water: acetonitrile (70:30 v/v) with 0.1% formic acid that was pumped isocratically at a flow rate of 0.5 mL per minute. The calibration curve was found to be linear over a range of 5-10,000 pg/mL. The inter-day and intra-day accuracy and precision were tested using low (20 pg/mL), medium (1000 pg/mL), and high (5000 pg/mL) quality control samples of fentanyl prepared in blank human serum and were within ± 15% of the nominal value. Fentanyl was also found to be stable in various storage and sample preparation conditions, including short-term bench-top storage (for 5 h), freeze-thaw cycling (three cycles), long-term frozen condition (4.5 months at - 70°C), and post-preparative storage (for 48 h).

P-Glycoprotein on Blood-Brain Barrier Plays a Vital Role in Fentanyl Brain Exposure and Respiratory Toxicity in Rats.

Fentanyl is a rapid-acting, short duration opioid analgesic agent. In recent years, increased prescription and illicit use of fentanyl drugs have led to major safety concerns and a growing death toll. However, the causes of fentanyl-induced fatal adverse effects have not been thoroughly researched. This study investigated P-glycoprotein (P-gp) modulated blood-brain barrier penetration of fentanyl and its resulting toxicity in vitro and in vivo. ATPase assays were performed together with bi-directional transport assays using Caco-2 cells in the presence and absence of tariquidar, a P-gp inhibitor, to confirm the P-gp substrate property of fentanyl. In vivo determinations of brain pharmacokinetic profile, duration of loss of righting reflex, and respiratory function were further conducted following intravenous administration of low and high doses of fentanyl with and without tariquidar in rats. Fentanyl significantly increased the ATPase activity of P-gp membrane. The efflux ratio of fentanyl on Caco-2 cells was >2, which was remarkably reduced when co-incubated with tariquidar. Using concomitant tariquidar with fentanyl (40 µg/kg) in rats, the unbound brain-to-plasma concentration ratio in rats increased 2.9- fold. The duration of loss of righting reflex was significantly extended, and fentanyl-induced respiratory depression was aggravated. At high fentanyl doses (80 µg/kg), inhibition of P-gp resulted in severe respiratory toxicity in the rats and even death. Collectively, these results gave strong evidence that P-gp plays a vital role in fentanyl blood-brain barrier penetration and the resulting toxicity. Fentanyl requires close monitoring in clinic when administered concomitantly with P-gp inhibitors.

Time-Dependent Postmortem Redistribution of Opioids in Blood and Alternative Matrices.

Forensic postmortem case interpretation can be challenging, in particular due to postmortem redistribution (PMR) phenomena. Recent studies have shown that computed tomography (CT)-guided collection of biopsy samples using a robotic arm (virtobot) provides a valuable tool for systematic studies on time-dependent PMR. Utilizing this strategy, several cases involving opioid use such as methadone, fentanyl, tramadol, codeine, oxycodone and hydrocodone were evaluated for time-dependent concentration changes and potential redistribution mechanisms. Upon admission to the institute (t1), blood (femoral and right ventricle heart blood) and tissue biopsy samples (lung, kidney, liver, spleen, thigh muscle and adipose tissue) were collected utilizing CT-guided biopsy. Approximately 24 h later (t2; mean 28 ± 15 h), during the autopsy, samples from the same body regions were collected manually and in addition brain tissue, gastric content, urine and left ventricle heart blood. Analysis was conducted with liquid chromatography tandem mass spectrometry. Significant time-dependent methadone concentration increases in femoral blood (pB) indicate the occurrence of PMR, however, ultimately not relevant for forensic interpretation. The main metabolite of methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), showed a less significant trend for PMR. Redistribution by passive diffusion along the muscle-to-pB concentration gradient seems likely for methadone, but not for EDDP. Results for fentanyl suggest extensive PMR. Other opioids such as tramadol, codeine, hydrocodone and oxycodone showed no consistent trend for significant PMR. Overall, CT-guided biopsy sampling proved to be a valuable tool for the investigation of PMR mechanisms.

A Series of Deaths Involving Carfentanil in the UK and Associated Post-mortem Blood Concentrations.

The potent opioid and veterinary drug, carfentanil has recently entered the illicit drug market, especially in relation to heroin and cocaine. Recent publications have reported carfentanil concentrations found in fatalities occurring in the USA. This article presents the toxicological findings in seven heroin/cocaine cases occurring in the UK within a short period of time where carfentanil was detected and measured. Carfentanil was detected along with other drugs in all cases with no alcohol detected in the post-mortem blood in any of the cases. Of the other drugs detected, of particular note, cannabinoids were detected in three, cocaine in four, other opioids (methadone, dihydrocodeine and tramadol) in four and benzodiazepines were detected in four of the seven fatalities. A high concentration of ketamine and norketamine was found in one case. Morphine and its glucuronide metabolites were also measured where detected in six of the seven cases. The carfentanil concentrations were found to be between 0.22 and 3.3 ng/mL (mean 0.93, median 0.66 ng/mL) in post-mortem femoral blood. In one case where aortic and ventricular post-mortem blood was submitted for analysis in addition to femoral blood, comparative concentrations of 1.05 (aortic), 0.57 (ventricular) and 0.50 (femoral) ng/mL were found. The concentrations support the necessity to ensure laboratory detection methods for carfentanil and subsequent measurement are appropriate as concentrations below 0.3 ng/mL may be present in post-mortem blood. The concentrations also support the notion that there is no particular "toxic" or "fatal" post-mortem blood carfentanil concentration associated with its use.

The uptake of transdermal fentanyl in a pregnant sheep model.

OBJECTIVE: To evaluate the maternal and foetal uptake of transdermal fentanyl patch applied to the groin of pregnant sheep following surgery. STUDY DESIGN: Prospective series. ANIMALS: A group of 16 singleton pregnant sheep underwent anaesthesia for laparotomy, hysterotomy and instrumentation of the foetus. Of these ewes 10 (101 ± 12 days of gestation) were used to evaluate the maternal uptake of transdermal fentanyl, and the efficacy of the drug in the postoperative period (n = 10). To determine the extent of transplacental transfer of fentanyl, six ewes from the group of 10, and six other ewes (92 ± 1 days' gestation) were studied. METHODS: A 75 µg hour-1 fentanyl patch was placed onto the woolless skin of the medial thigh close to the groin at the end of surgery. Maternal blood samples were collected from the cephalic or jugular vein, and pain and sedation scores were determined, prior to application of the patch (time 0) and at 3, 6, 12, 24, 36 and 48 hours after. A commercial Fentanyl ELISA kit was used to determine the concentration of fentanyl. Paired maternal and foetal blood samples were collected 48 hours after surgery. Animals were euthanized at the end of the study. Data were tested for normality and compared with Student t test or one-way anova and are expressed as mean ± standard deviation or median (range). RESULTS: Recovery from anaesthesia and surgery was uneventful in all ewes. The dose of fentanyl was 1.4 ± 0.2 µg kg-1 hour-1. The maximum maternal plasma concentration of fentanyl was 0.547 ng mL-1 (range, 0.349-0.738 ng mL-1) at 12 hours. After 48 hours, the concentration of fentanyl was 0.381 ng mL-1 (range, 0.211-0.487 ng mL-1; maternal) and 0.295 ng mL-1 (range, 0.185-0.377 ng mL-1; foetal; p = 0.175). The placental transfer rate of fentanyl was 77%. CONCLUSIONS AND CLINICAL RELEVANCE: The uptake of fentanyl varied between animals. The placental transfer rate of fentanyl was 77%.

Plasma Concentrations of Fentanyl Achieved With Transdermal Application in Chickens.

Providing appropriate analgesia is an important concern in any species. Fentanyl, a µ-receptor specific opioid, use is common in mammalian species but has been incompletely evaluated for this purpose in avian species. Transdermal fentanyl patches were applied to domestic chickens (n = 10) of varying breeds for 72 hours. Repeated blood samples were collected from the birds to assess time-concentration of fentanyl and norfentanyl in plasma, as assayed by liquid chromatography-mass spectrometry, throughout patch application and for 48 hours after patch removal. Compartmental modeling was used to characterize the elimination profiles. Evaluation as a large bolus, followed by slower elimination rates over the remaining time, best fit the data as a one-compartment open model. Although maximum plasma fentanyl concentrations varied substantially by individual birds, chickens trended into 2 general groups of maximum plasma concentration, clearance, and volume of distribution, which was attributed to absorption variability. For all birds, harmonic mean of elimination half-life was 7.2 ± 3.7 hours and showed less individual variation than the other pharmacokinetic parameters. Because the application of transdermal fentanyl patches in the chickens achieved plasma fentanyl concentrations considered therapeutic in people, this approach could provide an additional analgesic option for avian patients.

Identification and physicochemical characterization of 4-fluorobutyrfentanyl (1-((4-fluorophenyl)(1-phenethylpiperidin-4-yl)amino)butan-1-one, 4-FBF) in seized materials and post-mortem biological samples.

During the last decade, a substantial growth in new psychoactive substances (NPS) has been recorded. Within this group, a considerably fast-growing sub-group is represented by the opioids, which are based on modifications of the fentanyl structure. In this study, identification and analytical characterization of a new fentanyl derivative, 4-fluorobutyrfentanyl (1-((4-fluorophenyl)(1-phenethylpiperidin-4-yl)amino)butan-1-one, 4-FBF), is described. Apart from the seized powder, 4-FBF was also identified in the e-cigarette liquid secured in Case 1. The concentration of the compound in the liquid was 35 mg/mL. The main component of the liquid was glycerol, and nicotine was also present. This substance was detected in seized material that originated from the illegal drug market in Poland. To the best of the authors' knowledge, this report presents the first two analytically confirmed cases of fatal intoxication associated with 4-FBF. Case 1 was a 26-year-old male drug user who was found dead at home. Case 2 was a 25-year-old female, occasional user of NPS and drugs, who was also found dead at home. The concentrations of 4-FBF in blood were 91 and 112 ng/mL and in urine 200 and 414 ng/mL. The concentrations of 4-FBF in liver and kidney were 902 and 411 ng/g, and 136 and 197 ng/g, for Case 1 and Case 2, respectively. Copyright © 2016 John Wiley & Sons, Ltd.

Time-dependent postmortem redistribution of butyrfentanyl and its metabolites in blood and alternative matrices in a case of butyrfentanyl intoxication.

A fatal case of butyrfentanyl poisoning was investigated at the Zurich Institute of Forensic Medicine. At admission at the institute approx. 9h after death (first time point, t1), femoral and heart blood (right ventricle) was collected, as well as samples from the lung, liver, kidney, spleen, muscle and adipose tissue using computed tomography (CT)-guided biopsy sampling. At autopsy (t2), samples from the same body regions were collected manually. Additionally, urine, heart blood (left ventricle), gastric content, brain samples and hair were collected. Butyrfentanyl concentrations and relative concentrations of the metabolites carboxy-, hydroxy-, nor-, and desbutyrfentanyl were determined by LC-MS/MS and LC-QTOF. At t1, butyrfentanyl concentrations were 66ng/mL in femoral blood, 39ng/mL in heart blood, 110ng/g in muscle, 57ng/g in liver, 160ng/g in kidney, 3100ng/g in lung, 590ng/g in spleen and 550ng/g in adipose tissue. At t2, butyrfentanyl concentration in urine was 1100ng/mL, in gastric content 2000ng/mL, in hair 11,000pg/mg and brain concentrations ranged between 200-340ng/g. Carboxy- and hydroxybutyrfentanyl were identified as most abundant metabolites. Comparison of t1 and t2 showed a concentration increase of butyrfentanyl in femoral blood of 120%, in heart blood of 55% and a decrease in lung of 30% within 19h. No clear concentration changes could be observed in the other matrices. Postmortem concentration changes were also observed for the metabolites. In conclusion, butyrfentanyl seems to be prone to postmortem redistribution processes and concentrations in forensic death cases should be interpreted with caution.

Relationship between the plasma fentanyl and serum 4ß-hydroxycholesterol based on CYP3A5 genotype and gender in patients with cancer pain.

This study aimed to evaluate the relationship between the concentrations of plasma fentanyl and serum 4ß-hydroxycholesterol based on CYP3A5 genotype and gender in cancer patients. Thirty-three Japanese cancer patients treated with transdermal fentanyl were enrolled. The concentrations of plasma fentanyl and norfentanyl, and serum 4ß-hydroxycholesterol and total cholesterol were determined at day 8 or later after starting the medication. The plasma fentanyl concentration was significantly higher in the CYP3A5*3/*3 group than in the *1 allele carrier group. The *3/*3 group had a lower metabolic ratio of fentanyl. The serum 4ß-hydroxycholesterol concentration and its ratio to total cholesterol were significantly lower in the CYP3A5*3/*3 group than in the *1 allele carrier group. The concentrations of plasma fentanyl and serum 4ß-hydroxycholesterol were significantly higher in women than in men. Gender did not affect the metabolic ratio of fentanyl or the concentration ratio of 4ß-hydroxycholesterol. The plasma fentanyl concentration was not correlated with the serum 4ß-hydroxycholesterol concentration, while the metabolic ratio of fentanyl was slightly correlated with the serum concentration ratio of 4ß-hydroxycholesterol. In conclusion, CYP3A5*3 and gender affected the plasma fentanyl and serum 4ß-hydroxycholesterol concentrations in cancer patients. However, the plasma disposition of fentanyl was not determined using the serum 4ß-hydroxycholesterol concentration.

Pragmatic pharmacology: population pharmacokinetic analysis of fentanyl using remnant samples from children after cardiac surgery.

AIMS: One barrier contributing to the lack of pharmacokinetic (PK) data in paediatric populations is the need for serial sampling. Analysis of clinically obtained specimens and data may overcome this barrier. To add evidence for the feasibility of this approach, we sought to determine PK parameters for fentanyl in children after cardiac surgery using specimens and data generated in the course of clinical care, without collecting additional blood samples. METHODS: We measured fentanyl concentrations in plasma from leftover clinically-obtained specimens in 130 paediatric cardiac surgery patients and successfully generated a PK dataset using drug dosing data extracted from electronic medical records. Using a population PK approach, we estimated PK parameters for this population, assessed model goodness-of-fit and internal model validation, and performed subset data analyses. Through simulation studies, we compared predicted fentanyl concentrations using model-driven weight-adjusted per kg vs. fixed per kg fentanyl dosing. RESULTS: Fentanyl clearance for a 6.4 kg child, the median weight in our cohort, is 5.7 l h(-1) (2.2-9.2 l h(-1) ), similar to values found in prior formal PK studies. Model assessment and subset analyses indicated the model adequately fit the data. Of the covariates studied, only weight significantly impacted fentanyl kinetics, but substantial inter-individual variability remained. In simulation studies, model-driven weight-adjusted per kg fentanyl dosing led to more consistent therapeutic fentanyl concentrations than fixed per kg dosing. CONCLUSIONS: We show here that population PK modelling using sparse remnant samples and electronic medical records data provides a powerful tool for assessment of drug kinetics and generation of individualized dosing regimens.

Exposure to Fentanyl After Transdermal Patch Administration for Cancer Pain Management.

This study aimed to describe exposure after fentanyl transdermal patch administration in patients with advanced cancer to quantify variability around the exposure. Patients (n  =  56) with advanced cancer who received transdermal fentanyl (Durogesic®; median dose, 50 µg/h; range, 12-200 µg/h) provided venous blood samples (n  =  163) at various times (0.5-72 hours) during several patch application intervals. Plasma fentanyl concentration was determined (median, 0.9 µg/L; range, 0.04-9.7 µg/L) by high-performance liquid chromatography coupled to tandem mass spectrometry. Pharmacokinetic analysis was performed using nonlinear mixed-effects modeling with NONMEM. A 1-compartment distribution model with first-order absorption and elimination described fentanyl exposure after transdermal patch administration. Fentanyl apparent clearance (between-subject variability [BSV], %) was estimated at 122 L/h/70 kg and 38.5%, respectively. The absorption rate constant was 0.013 h(-1) . Between-occasion variability on apparent clearance was 22.0%, which was lower than BSV, suggesting predictable exposure within the same patient and justifying therapeutic drug monitoring. Except for weight-based dosing, no other patient characteristic could be identified to guide initial fentanyl dose selection in patients with advanced cancer.