Blood Fentanyl Research Articles

Antemortem and postmortem fentanyl concentrations: a case report

Opinions currently differ in regard to the potential for fentanyl to exhibit postmortem redistribution (PMR). While some work has reported that it is prone to substantial postmortem concentration increase [1–3], other studies have disputed such a conclusion [4]. The more recent investigations have found that, in postmortem cases where it has been administered therapeutically and undergone complete distribution, fentanyl exhibits only minimal PMR. Central to peripheral blood fentanyl ratios of about 1.0 demonstrate minimal tendency towards PMR; fentanyl exhibits an average ratio of about 0.95–1.2 [4–6].Moreover, consideration of the fentanyl liver to peripheral blood (L/P) ratio corroborates the lack of fentanyl distribution or PMR; the average literature L/P ratio of 5.6 [4]. In view of the premise that drugs with an L/P ratio of about 5 have little to no propensity towards PMR [7, 8], it has been concluded that fentanyl is a compound with only minimal potential for PMR [4]. In the case reported here, we provide further evidence for a lack of significant fentanyl PMR by presenting a comparison of an antemortem fentanyl concentration (determined in a sample collected shortly before death) to postmortem peripheral and central blood fentanyl concentrations.

Physiologically-based pharmacokinetic model for Fentanyl in support of the development of Provisional Advisory Levels

Provisional Advisory Levels (PALs) are tiered exposure limits for toxic chemicals in air and drinking water that are developed to assist in emergency responses. Physiologically-based pharmacokinetic (PBPK) modeling can support this process by enabling extrapolations across doses, and exposure routes, thereby addressing gaps in the available toxicity data. Here, we describe the development of a PBPK model for Fentanyl – a synthetic opioid used clinically for pain management – to support the establishment of PALs. Starting from an existing model for intravenous Fentanyl, we first optimized distribution and clearance parameters using several additional IV datasets. We then calibrated the model using pharmacokinetic data for various formulations, and determined the absorbed fraction, F, and time taken for the absorbed amount to reach 90% of its final value, t90. For aerosolized pulmonary Fentanyl, F=1 and t90<1min indicating complete and rapid absorption. The F value ranged from 0.35 to 0.74 for oral and various transmucosal routes. Oral Fentanyl was absorbed the slowest (t90~300min); the absorption of intranasal Fentanyl was relatively rapid (t90~20–40min); and the various oral transmucosal routes had intermediate absorption rates (t90~160–300min). Based on these results, for inhalation exposures, we assumed that all of the Fentanyl inhaled from the air during each breath directly, and instantaneously enters the arterial circulation. We present model predictions of Fentanyl blood concentrations in oral and inhalation scenarios relevant for PAL development, and provide an analytical expression that can be used to extrapolate between oral and inhalation routes for the derivation of PALs.

Superiority of postmortem liver fentanyl concentrations over peripheral blood influenced by postmortem interval for determination of fentanyl toxicity

ObjectiveThe current study was undertaken to determine the relationship between postmortem (PM) peripheral blood (PB) and liver fentanyl concentrations and the role of measuring liver fentanyl concentrations in cause of death investigations in medical examiner cases in which fentanyl was identified. Design and methodsFB and liver tissue were routinely collected at autopsy from 4 Minnesota medical examiners' offices in 2010–2011. Samples were analyzed by gas chromatography–mass spectrometry (GC–MS). ResultsPB fentanyl ranged from <2–15μg/L in non-drug related deaths (n=5), <2–22μg/L from mixed drug toxicity (n=26) and 3.7–56μg/L from fentanyl toxicity (n=33). Liver fentanyl ranged from 11 to 104μg/kg, 6 to 235μg/kg, and 18 to 365μg/kg, respectively. PB and liver fentanyl showed a modest correlation (r=0.67). PM interval to the liver/blood ratio showed a decreasing ratio over increasing PM interval in cases from fentanyl and mixed drug toxicity. Liver fentanyl concentrations best define therapeutic use at <23μg/kg and fatal toxicity at >56μg/kg, without substantial overlap as found in blood fentanyl concentrations. ConclusionDiscriminatory liver fentanyl concentrations suggestive of therapeutic or toxic drug levels may better assist cause of death determination in cases of suspected fentanyl toxicity than postmortem PB concentrations. Peripheral blood fentanyl concentrations appear to undergo postmortem redistribution, associated with an increasing PM interval.

Determination of Buprenorphine, Fentanyl and LSD in Whole Blood by UPLC-MS-MS

A sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS-MS) method has been developed and validated for the quantification of buprenorphine, fentanyl and lysergic acid diethylamide (LSD) in whole blood. Sample preparation was performed by liquid-liquid extraction (LLE) with methyl tert-butyl ether. UPLC-MS-MS analysis was performed with a mobile phase consisting of ammonium formate (pH 10.2) and methanol. Positive electrospray ionization MS-MS detection was performed with two multiple reaction monitoring transitions for each of the analytes and the deuterium labeled internal standards. Limit of detection values of buprenorphine, fentanyl and LSD were 0.28, 0.044 and 0.0097 ng/mL and limit of quantification values were 0.94, 0.14 and 0.036 ng/mL, respectively. Most phospholipids were removed during LLE. No or only minor matrix effects were observed. The method has been routinely used at the Norwegian Institute of Public Health since September 2011 for qualitative and quantitative detections of buprenorphine, fentanyl and/or LSD in more than 400 whole blood samples with two replicates per sample.

A physiologically-based recirculatory meta-model for nasal fentanyl in man

Pharmacokinetic (PK) and pharmacodynamic (PD) data were available from a study of a nasal delivery system for the opioid analgesic fentanyl, together with data on the kinetics of fentanyl in arterial blood in man, and in the lung and brain of sheep. Our aim was to reconcile these data using a physiologically-based population recirculatory PK-PD model, with emphasis on achieving a meta-model that could simultaneously account for the arterial and venous (arm) concentrations of fentanyl, could relate PD effects (pain scores) to the CNS concentrations of fentanyl, and could account for the effect of body size and age on fentanyl kinetics. Data on the concentration gradients of fentanyl across brain, lung and muscle were used to develop sub-models of fentanyl kinetics in these organs. The sub-models were incorporated into a "whole body" recirculatory model by adding additional sub-models for a venous mixing compartment, the liver and gut, the kidney and the "rest of the body" with blood flows and organ volumes based on values for a Standard Man. Inter-individual variability was achieved by allometric scaling of organ size and blood flows, evidence-based assumptions about the effect of weight and age on cardiac output, and inter-individual variability in the free fraction in plasma and hepatic extraction of fentanyl. Post-operative pain scores were found to be temporally related to the predicted brain concentrations of fentanyl. We conclude that a physiologically-based meta-modelling approach was able to describe clinical PK-PD studies of fentanyl whilst providing a mechanistic interpretation of key aspects of its disposition.

Reliability of Postmortem Fentanyl Concentrations in Determining the Cause of Death

Transdermal fentanyl, an opioid used for management of marked pain, also is abused and may cause death. We reviewed medical examiner reports of 92 decedents who had one or more fentanyl transdermal patches on their body and had fentanyl detected in their postmortem toxicology analysis. The manners of death included 40 accidents, 36 natural, 8 suicides, 5 therapeutic complications, and 3 undetermined deaths. Among the accidental fentanyl intoxication deaths, 32 of 37 involved substance abuse. The majority (95 %) of the 37 accidental deaths involving fentanyl were multi-drug intoxications. The substance abuse deaths had a mean fentanyl blood concentration (26.4 ng/ml or μg/L) that was over twice that of the natural group (11.8 ng/ml). Our analysis suggests a relationship between total patch dosage and mean postmortem fentanyl concentration up to the 100-μg/h dose. The very wide and overlapping ranges of postmortem fentanyl concentrations effectively nullify the utility of correlating the dose and expected postmortem concentration for any particular death. Based on the variable relationship between dose and blood concentration, the antemortem dose cannot be reliably predicted based on the postmortem concentration. This does not, however, render the medical examiner/coroner unable to determine the cause and manner of death because the toxicology results are only one datum point among several that are considered. Although there was a weakly positive relationship between body mass index and fentanyl concentration, further research is needed to determine whether adipose tissue represents a significant depot for postmortem release of fentanyl.

Fentanyl: Toxic or Therapeutic? Postmortem and Antemortem Blood Concentrations After Transdermal Fentanyl Application

In forensic toxicology, several fatal intoxications with fentanyl have occurred in the recent past, but there are rare discussions in the literature of postmortem fentanyl blood concentrations subsequent to lethal and non lethal applications. To study this problem, we analyzed postmortem blood concentrations (vena femoralis) of 118 cases with therapeutic use of fentanyl and compared them with serum levels of 27 living persons after therapeutic administration of fentanyl patches (Durogesic). Basically, blood concentrations in postmortem specimens cannot be directly compared with in vivo serum levels: in our study, we observed that postmortem fentanyl blood concentrations were on average up to nine times higher than in vivo serum levels at the same dose. These differences could be explained by postmortem redistribution, but they were higher than expected on the basis of the physical and chemical properties of fentanyl alone. The special pharmacokinetics of the drug after long term transdermal application seem to play an important role in this phenomenon. In addition, there was no clear correlation between transdermal fentanyl dose and blood or serum concentrations, either antemortem or postmortem. Our study provides extensive data for postmortem peripheral blood concentrations after therapeutic non-fatal fentanyl patch application and demonstrates once more that in forensic toxicology, blood concentrations must be holistically interpreted with respect to all aspects of a case.

A low blood volume LC‐MS/MS assay for the quantification of fentanyl and its major metabolites norfentanyl and despropionyl fentanyl in children

Preterm and term neonates often require surgical procedures and analgesia. However, our knowledge about neonatal pharmacokinetics of fentanyl, the most commonly used drug for these procedures, and its metabolites is still incomplete. To facilitate pharmacokinetic studies of fentanyl and its metabolites in neonates and other children, we developed and validated an LC-MS/MS method based on minimally invasive, low blood volume sampling. LC-MS/MS was used for the simultaneous analysis of fentanyl, despropionyl fentanyl (DPF), and norfentanyl from dried blood samples (DBS) collected on filter paper. Positive ions were monitored using multiple reaction monitoring. Since the standard matrix for measuring fentanyl blood concentrations is plasma, the assay was developed and validated in plasma, whole blood, and then DBS. Our method was able to measure clinically relevant levels of fentanyl and its metabolites. In DBS, the lower limits of quantification were 100 pg/mL for fentanyl with a range of reliable response from 0.1 to 100 ng/mL (r(2)>0.99) and 250 pg/mL for both DPF and norfentanyl with a range of reliable response from 0.25 to 100 ng/mL (r(2)>0.99). In plasma and in DBS inter-day accuracy and precisions of fentanyl met predefined acceptance criteria and also indicated comparable assay performance in both matrices.

Effect of expression of P-glycoprotein in tumor tissue on analgesic efficacy of fentanyl and lornoxicam in patients with cancer pain

Objective To evaluate the effect of the expression of P-glycoprotein (P-gp) in the tumor tissue on the analgesic efficacy of fentanyl and lornoxicam in patients with cancer pain. Methods One hundred advanced cancer patients with pain aged 49-64 yr weighing $$-65 kg were included in this study. The expression of Pgp was positive in the tumor tissue in 50 patients (groups F1 and L1, n = 25 each) and negative in 50 patients (groups F2 and L2, n = 25 each). The patients in 4 groups received 48 h of pstient-controlled intravenous analgesia (PCIA). A loading dose of fentanyl 0.05 mg was administered before PCIA was started in groups F1 and F2 .The PCIA solution contained fentanyl 1 mg and droperidol 5 mg in 100 ml of normal saline in groups Ft and F2, or lomoxicam 64 mg and droperidol 5 mg in 100 ml of normal saline in groups L1 and L2. The PCA pump was set to deliver a background infusion of 2 ml/h and a bolus dose of 0.5 ml at 15 min lockout interval. Pain was assessed with VAS scores (0 = no pain, 10 = worst pain), and VAS score was maintained at ≤3 during PCIA. Flurbiprofen 50 mg was injected intravenously when VAS score≥4 and the consumption of flurbiprofen was recorded. The consumption of fentanyl and lornoxicam during PCIA was recorded. Blood samples from the internal jugular vein were taken at the beginning of PCIA (T0), and at 4, 12, 24, 48 h of PCIA (T1-4) for determination of blood fentanyl and lornoxicam concentrations. Results Flurbiprofen was not used in groups F2, L1 and L2. The consumption of flurbiprofen was ( 184 ± 41 ) mg in group F1 . There was no significant difference in the consumption of fentanyl during PCIA between groups F1 and F2 ( P ＞ 0.05). Blood fentanyl concentrations were not detected at all the time points in groups F1 and F2 . The VAS score during PCIA ≤ 3 in groups L1 and L2, and there was no significant difference in blood concentrations of lornoxicam at each time point and the consumption of lornoxicam during PCIA between groups L1 and L2 ( P ＞ 0.05). Conclusion Positive P-gp expression in the tunor tissue can decrease the analgesic efficacy of fentanyl, but exerts no effect on the analgesic efficacy of lornoxicam in patients with cancer pain. Key words: Glycoproteins; Fentanyl; Cyclooxygenase inhibitors; Neoplasms; Analgesia

Homicides Using Muscle Relaxants, Opioids, and Anesthetic Drugs

Homicides Using Muscle Relaxants, Opioids, and Anesthetic Drugs

Development and validation of a sensitive UPLC–MS/MS method for the analysis of narcotic analgesics in urine and whole blood in forensic context

Narcotic analgesics are widely (ab) used and sometimes only occur in low concentrations in biological samples. Therefore, a highly sensitive liquid chromatography tandem mass spectrometry method was developed for simultaneous analysis of 9 narcotic analgesics and metabolites (buprenorphine, O-desmethyltramadol, fentanyl, norbuprenorphine, norfentanyl, pethidine, piritramide, tilidine and tramadol) in urine and whole blood. Sample preparation was performed on a mixed-mode cation exchange solid phase extraction cartridge with an additional alkaline wash step to decrease matrix effects and thus increase sensitivity. Ionization with electrospray ionization was found to be more efficient than atmospheric pressure chemical ionization. The use of a mobile phase of high pH resulted in higher electrospray ionization signals than the conventional low pH mobile phases. In the final method, gradient elution with 10mM ammonium bicarbonate (pH 9) and methanol was performed on a small particle column (Acquity C18, 1.7 μm, 2.1 mm × 50 mm). Selectivity, matrix effects, recovery, linearity, sensitivity, precision, accuracy and stability were validated in urine and whole blood. All parameters were successfully evaluated and the method showed very high sensitivity, which was the major aim of this study. The applicability of the method was demonstrated by analysis of several forensic cases involving narcotic analgesics.

DEVELOPMENT AND VALIDATION OF A SOLID-PHASE EXTRACTION GAS CHROMATOGRAPHY-MASS SPECTROMETRY METHOD FOR THE SIMULTANEOUS QUANTIFICATION OF OPIOID DRUGS IN HUMAN WHOLE BLOOD AND PLASMA

A rapid, selective, sensitive, and specific method is presented to simultaneously quantify morphine, 6-monoacetylmorphine (6-MAM), codeine, heroin, fentanyl, and methadone in human whole blood and plasma. The drugs were extracted with phosphate buffer at pH 6, followed by solid-phase extraction (SPE) and quantification by GC/MS with electron impact ionization using helium as carrier gas. Quantification was performed based on nalorphine as internal standard (IS). The specificity, linearity, intra- and inter-assay precision and accuracy, and extraction recovery were fully evaluated. The limits of detection (LODs) were 0.40 – 7.63 ng/mL for whole blood and 0.80 – 32.00 ng/mL for plasma. The method is fast, simple, and accurate, with the sensitivity and specificity required in forensic and clinical toxicology.

Fentanyl in postmortem forensic toxicology

Context. Fentanyl is a powerful opioid used for the induction of anesthesia as well as for the management of severe pain. In recent years, transdermal fentanyl “patches” have become popular for outpatient management of chronic pain. The high potency and outpatient availability of fentanyl has also made it a highly sought-after drug of abuse. Deaths in which fentanyl is detected challenge medical examiners who must decide whether a given case represents therapeutic administration or overdose. Objectives. The current review seeks to present data about fentanyl that are relevant to the interpretation of postmortem blood and tissue fentanyl concentrations as well as to highlight areas which can be helpful or misleading in the evaluation of deaths potentially related to fentanyl exposure. Methods. Standard searching of the PubMed database for studies, case series, and case reports involving fentanyl kinetics, chemistry, and postmortem behavior was performed. Search terms typically included “postmortem” and “fentanyl,” as well as “kinetics” and “analysis,” where appropriate. Additional references were located as citations from reviewed papers or as conference abstracts. Results and Conclusions. The postmortem behavior of fentanyl is influenced heavily by pH changes and the antemortem kinetic behavior of the drug, especially, by its distribution. Postmortem blood fentanyl concentrations do not correlate directly with antemortem blood concentrations. Without adequate evaluation of kinetic data, investigative information and consideration of postmortem changes, misinterpretation of postmortem fentanyl results is likely.

Pharmacokinetics of fentanyl administered transdermally and intravenously in sheep

To investigate the pharmacokinetics of fentanyl administered transdermally and IV in sheep. 21 adult female sheep. Fentanyl was administered IV to 6 healthy sheep. Transdermal fentanyl patches (TFPs) were applied to 15 sheep 12 hours prior to general anesthesia and surgery. Seria blood samples were collected for 18 hours after IV injection and 84 hours after TFP application. Fentanyl concentrations were quantified via liquid chromatography-mass spectrometry, and pharmacokinetic values were estimated. All sheep completed the study without complications. Following a dose of 2.5 g/kg administered IV, the half-life was 3.08 hours (range, 2.20 to 3.36 hours), volume of distribution at steady state was 8.86 L/kg (range, 5.55 to 15.04 L/kg), and systemic clearance was 3.62 L/kg/h (range, 2.51 to 5.39 L/kg/h). The TFPs were applied at a mean dose of 2.05 g/kg/h. Time to maximum plasma concentration and maximal concentration were 12 hours (range, 4 to 24 hours) and 1.30 ng/mL (range, 0.62 to 2.73 ng/mL), respectively. Fentanyl concentrations were maintained at >0.5 ng/mL for 40 hours after TFP application. IV administration of fentanyl resulted in a short half-life. Application of a TFP resulted in stable blood fentanyl concentrations in sheep.

Development and validation of a sensitive ultra performance liquid chromatography tandem mass spectrometry method for the analysis of fentanyl and its major metabolite norfentanyl in urine and whole blood in forensic context

Fentanyl and its major metabolite norfentanyl often occur in low doses in biological samples. Therefore, a highly sensitive liquid chromatography tandem mass spectrometry (LC–MS/MS) method has been developed and fully validated. Sample preparation was performed on a mixed-mode cation exchange solid phase extraction (SPE) cartridge with an additional alkaline wash step to decrease matrix effects and thus increase sensitivity. Ionization of fentanyl and norfentanyl with electrospray ionization (ESI) was more efficient than atmospheric pressure chemical ionization (APCI). The use of a mobile phase of high pH resulted in higher ESI signals than the conventional low pH mobile phases. In the final method, gradient elution with 10 mM ammonium bicarbonate (pH 9) and methanol was performed. A comparison of columns with different internal diameter and/or smaller particles showed optimal resolution and sensitivity when an Acquity C18 column (1.7 μm, 2.1 mm × 50 mm) was used. Deuterium labeled internal standards were used, but with careful evaluation of their stability since loss of deuteriums was seen. With limits of detection of 0.25 pg/ml for fentanyl and 2.5 pg/ml for norfentanyl in urine and 5 pg/ml for fentanyl and norfentanyl in whole blood the presented method is highly appropriate for the analysis of fentanyl and norfentanyl in forensic urine and blood samples.

Fentanyl Transdermal Analgesia During Pregnancy and Lactation

This report describes an infant who was born to a mother with chronic pain treated with fentanyl 100 microg/h transdermal patch throughout her pregnancy and during lactation. On day of life 27, when the baby was feeding and gaining weight on maternal milk, samples of the baby's blood and maternal milk were sent for analysis. The mother's milk fentanyl level was 6.4 ng/ mL. The infant's blood fentanyl level was undetectable. This preliminary report suggests that fentanyl transdermal patch treatment might be a viable option for managing chronic pain during lactation.

A new transmucosal drug delivery system for patients with breakthrough cancer pain: the fentanyl effervescent buccal tablet

Breakthrough pain, a transitory severe pain with the background of otherwise controlled persistent pain has a prevalence between 52% and 67% in outpatients with cancer. Medications for such sudden-onset pain require non-invasive delivery of a potent and short-acting opioid for rapid pain relief. Although oral transmucosal delivery of fentanyl citrate (OTFC) has been shown to provide better pain relief than a typical oral opioid administration such as morphine sulfate immediate release (MSIR) in the management of breakthrough pain in patients with cancer-related pain, newer delivery systems offer a potential for further enhancement of pain relief. The fentanyl effervescent buccal tablet (FBT) formulation employs a novel drug delivery system that relies on an effervescence reaction to improve buccal fentanyl absorption. Using the effervescence reaction results in the production and dissipation of carbon dioxide with a dynamic shift in pH as the tablet dissolves. The induced low pH favors dissolution of fentanyl citrate in saliva (higher water solubility). The subsequent increase in pH thereafter favors the buccal absorption of non-ionized fentanyl across the buccal mucosa. Such a pH "pumping" mechanism increases the permeation of fentanyl into and through the buccal to the vascular system from where the agent is transported to the specific opioid receptor sites in the CNS. Compared with OTFC, data in healthy volunteers show that the effervescence reaction employed in FBT increases the total amount and the speed of absorption of fentanyl being absorbed. Compared with OTFC there is an increase in peak fentanyl blood concentrations, and an enhancement of the amount of buccal delivery of fentanyl. Such favorable data are underlined by the results of clinical studies where the FBT technology was studied in patients with breakthrough pain in chronic malignant pathologies.

Fentanyl Postmortem Redistribution: Preliminary Findings Regarding the Relationship Among Femoral Blood and Liver and Heart Tissue Concentrations

Postmortem redistribution refers to the process of drugs diffusing from tissues into blood along a concentration gradient between death and time of specimen collection at autopsy. Anatomical site-to-site variation can exist for drug concentrations. The purpose of this study was twofold. First femoral blood, liver, and heart fentanyl concentrations were compared in medical examiner cases to assist in determining which specimen most appropriately should be used for interpretation. Nine fentanyl-positive cases were identified by history of drug use over a 15-month period (2007-2008). Femoral blood fentanyl concentrations (n = 9) ranged from 2.7 to 52.5 microg/L, liver fentanyl tissue (n = 9) ranged from 37.0 to 179 microg/kg, and heart fentanyl tissue (n = 3) ranged from 52.8 to 179 microg/kg. Liver tissue to femoral blood ratios ranged from 0.85 to 35.8, and heart tissue to femoral blood ratios ranged from 1.9 to 5.4. Second, utilizing a published compendium of multiple postmortem drugs, liver and heart tissues to femoral blood drug ratios were compared to known volumes of distribution, solubilities, and pKa. No significant relationships were observed. In conclusion, establishing a larger evidence-based database using liver fentanyl concentrations may be more optimal than blood concentrations for interpretation of postmortem fentanyl concentrations in medical examiner and coroner cases.

Oral Abuse of Fentanyl Patches (Duragesic®): Seven Case Reports

In order to increase the understanding regarding the oral abuse and potential toxicity of fentanyl patches seven cases were identified over a 3-year period where fentanyl, either alone or in combination with other factors, contributed to death following the oral abuse of Duragesic patches. The decedents comprised three females and four males with ages ranging from 20 to 51 years. Postmortem blood fentanyl concentrations were determined in all cases and ranged from 7 to 97 ng/mL. Two deaths were classified as a fentanyl overdose, three deaths were classified as a fentanyl and ethanol overdose, one death was considered a mixed drug intoxication and the remaining death was determined to be a combination of fentanyl and medical causes. These cases represent the largest reported series of deaths following the oral administration of transdermal fentanyl patches and provide detailed information on the potential for the abuse of transdermal Duragesic patches via this route. The postmortem blood fentanyl concentrations detected for each of the decedents demonstrate the potentially fatal blood concentrations that can arise after this relatively rare route of administration.

Fentanyl Concentrations in 23 Postmortem Cases from the Hennepin County Medical Examiner’s Office*

The purpose of this study was to compare blood fentanyl concentrations in fentanyl-related deaths with fentanyl concentrations found incidentally at autopsy, as well as with fentanyl concentrations found in hospitalized patients receiving fentanyl. Between the years 1997 to 2005, 23 fentanyl-positive postmortem cases were identified. Nineteen of 23 (82.6%) cases were deemed to be drug overdoses. Fentanyl alone was responsible for 8 of the 19 (42.1%) overdose deaths. Mean and median fentanyl concentrations were 36 (SD 38) microg/L and 22 microg/L, respectively, range 5-120 microg/L. Seven of the cases were accidental, one undetermined. The remaining 11 of the 19 (57.9%) cases were mixed drug overdoses. Fentanyl concentrations in these cases were 31 (SD 46) microg/L, range 5-152 microg/L. All of the mixed drug overdoses were determined to be accidental. Four cases where fentanyl was considered an incidental postmortem finding were determined to be natural deaths. In hospitalized inpatients (n = 11) receiving fentanyl 2 of the patients receiving fentanyl for chronic pain for more than 3 months had concentrations of 8.5 microg/L and 9.9 microg/L. The other nine inpatient concentrations were less than 4 microg/L. In conclusion, blood fentanyl concentrations found in cases where fentanyl alone was determined to be the cause of death were similar to cases where fentanyl was part of a mixed drug overdose. There was also considerable overlap between fentanyl concentrations in fentanyl-related overdose deaths compared to hospitalized patients being treated for chronic pain. Fentanyl concentrations in postmortem cases must be interpreted in the context of the deceased's past medical history and autopsy findings.