An epidemic of illicit fentanyl deaths in Cook County, Illinois: September 2005 through April 2007

Between September 2005 and April 2007, 350 fentanyl intoxication deaths were investigated and certified by the Cook County Medical Examiners Office. Investigations revealed that the majority of these fatalities were by intravenous injection of a white powder followed by a rapid collapse. The fentanyl was clandestinely produced in a lab in Toluca, Mexico and sold by the Mickey Cobra street gang. The term "Drop Dead" was coined for this "tainted heroin." Postmortem samples were screened by ELISA and confirmed by standard GC-MS methods. Fentanyl fatalities peaked at 47 per month in May and June 2006. Fifty-two percent were single fentanyl intoxications, with the remainder accompanied by either cocaine, morphine from heroin, or alcohol. This epidemic stressed the limited resources of the toxicology laboratory and autopsy service of the Medical Examiners Office. The clandestine lab was terminated, distributing gang members and leaders arrested, and the epidemic ceased in April 2007.     

Acetyl Fentanyl: Trends and Concentrations in Metro Detroit

Acetyl fentanyl (N‐[1‐phenethylpiperidin‐4‐yl]‐N‐phenylacetamide) is a potent opioid analgesic with no medicinal uses. We report deaths between 2016 and 2017 at the Medical Examiner's Office in Detroit, MI where acetyl fentanyl was found in the decedent's blood and compare them to previously published deaths between 2015 and 2016. The recent cases (cohort B) had a mean acetyl fentanyl concentration of 0.9 ng/mL (range: 0.1–5.3 ng/mL) and an associated higher concentration of fentanyl along with multiple other drugs present. The older cases (cohort A) had higher concentrations of acetyl fentanyl (mean: 8.9 ng/mL; range: 0.28–37 ng/mL) with lower, yet still toxic, concentrations of fentanyl. We conclude that the cause of death in these recent cases was likely multiple drug toxicity with fentanyl and that the consistently observed lower peripheral blood concentrations of acetyl fentanyl are most likely an artifact in the manufacture of the consumed illicit fentanyl.     

Prevalence of xylazine in overdose cases: An analysis of Miami-Dade County medical examiner case data

Xylazine sedative, muscle relaxant, and analgesic used in a veterinary setting. Although xylazine was never approved for therapeutic use in humans, it has become popular in the street drug market as a cutting or bulking agent in the fentanyl and heroin supply. Recently, there has been a significant increase in the detection of xylazine in postmortem forensic toxicology casework. Xylazine can be identified during routine toxicology screening utilizing instrumentation such as gas chromatography–mass spectrometry and liquid chromatography–mass spectrometry. Using the Miami-Dade Medical Examiner's LIMS system, all cases received between 2015 and 2022 in which xylazine was reported were reviewed. The cases studied include accidental drug overdose deaths in Miami-Dade County as well as Collier County (Naples), Florida. In total, there are 170 cases; the majority are accidental polydrug overdoses involving White males between the ages of 25 and 44 years old. Of the 170 cases, 37% listed xylazine as the cause of death. 13% of cases contained only xylazine and fentanyl while the remaining 87% of deaths were attributed to polydrug toxicity involving two or more substances. The prevalence of xylazine can be attributed to its increasing popularity rather than an increase in caseload. In 2019, xylazine was present in only 4% of all accidental fentanyl overdoses. By 2021, this percentage has increased sixfold, with xylazine present in 24% of all accidental fentanyl overdoses. Despite a decrease in fentanyl overdoses in 2022, the percentage of xylazine detection remained the same.     

The impact of fentanyl on DUIDs and traffic fatalities: Blood and oral fluid data

Fentanyl has emerged as the most prolific drug in the ongoing opioid epidemic and has greatly impacted traffic safety in recent years. This study aimed to evaluate fentanyl prevalence and concentrations in blood and oral fluid in driving under the influence of drugs (DUID) cases in three different regions (i.e., Alabama, Orange County, CA, and Houston, TX) from 2017 to 2022. Furthermore, traffic fatalities were evaluated for Alabama and Orange County, CA. Fentanyl positivity in DUID and traffic fatalities increased for most years in this study. In Alabama, the prevalence of fentanyl DUID cases increased 4-fold in 2022 compared to 2017. Orange County's increase from 2017 to 2022 was 14-fold. In Houston, the increase was approximately 2-fold from 2019 to 2022. The greatest increase for all laboratories coincided with the start of the COVID-19 pandemic. In 2022, the median fentanyl DUID blood concentrations were 4.7, 11, and 4.7 ng/mL in Alabama, Orange County, and Houston, respectively. Most fentanyl cases were polydrug cases (≥90%). Methamphetamine, THC, and alprazolam were the most frequently detected drugs in combination with fentanyl. Alabama has collected oral fluid and blood in DUID cases since 2018. The detection of fentanyl in oral fluid was comparable to blood. However, 59% and 8.7% of fentanyl-positive cases had concentrations of >20 ng/mL in oral fluid and blood, respectively. Therefore, oral fluid as an alternative or supplemental specimen to blood is an attractive approach for fentanyl in DUID cases. This study contributes to understanding recent fentanyl trends and their impact on traffic safety.     

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.     

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.     

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.     

Report of Increasing Overdose Deaths that include Acetyl Fentanyl in Multiple Counties of the Southwestern Region of the Commonwealth of Pennsylvania in 2015–2016

Acetyl fentanyl is a Schedule I controlled synthetic opioid that is becoming an increasingly detected “designer drug.” Routine drug screening procedures in local forensic toxicology laboratories identified a total of 41 overdose deaths associated with acetyl fentanyl within multiple counties of the southwestern region of the state of Pennsylvania. The range, median, mean, and standard deviation of blood acetyl fentanyl concentrations for these 41 cases were 0.13–2100 ng/mL, 11 ng/mL, 169.3 ng/mL, and 405.3 ng/mL, respectively. Thirty‐six individuals (88%) had a confirmed history of substance abuse, and all but one case (96%) were ruled multiple drug toxicities. This report characterizes this localized trend of overdose deaths associated with acetyl fentanyl and provides further evidence supporting an alarmingly concentrated opiate and opioid epidemic of both traditional and novel drugs within this region of the United States.     

Emergence of fentanyl-related deaths in Travis County,Texas and surrounding areas: A retrospective review of postmortem fentanyl-related drug toxicities from 2020 to 2022

The opioid epidemic has affected the United States (US) for decades with fentanyl and its analogs accounting for a recent surge in morbidity and mortality. Currently, there is a relative lack of information characterizing fentanyl-related fatalities specifically in the Southern US. A retrospective study was conducted to examine all postmortem fentanyl-related drug toxicities in Travis County, Texas, encompassing Austin (one of the fastest-growing cities in the US), from 2020 to 2022. Fentanyl contributed to 2.6% and 12.2% of deaths submitted for toxicology between 2020 and 2022, respectively, representing a 375% increase in fentanyl-related deaths over this 3-year period (n = 517). Fentanyl-related fatalities primarily occurred in males in their mid-30s. Fentanyl and norfentanyl concentrations ranged from 0.58 to 320 ng/mL and 0.53 to 140 ng/mL with mean (median) concentrations of 17.2 ± 25.0 (11.0) and 5.6 ± 10.9 (2.9) ng/mL, respectively. Polydrug use was present in 88% of cases, with methamphetamine (or other amphetamines) (25%), benzodiazepines (21%), and cocaine (17%) representing the most frequently identified concurrent substances. Co-positivity rates of various drugs and drug classes widely varied over time. Scene investigations reported illicit powder(s) (n = 141) and/or illicit pill(s) (n = 154) in 48% (n = 247) of fentanyl-related deaths. Illicit oxycodone (44%, n = 67) and illicit “Xanax” (38%, n = 59) pills were frequently reported on scene; however, toxicology only identified oxycodone and alprazolam in 2 and 24 of these cases, respectively. The results of this study provide a better understanding of the fentanyl epidemic in this region creating an opportunity to promote increased awareness, shift focus to harm reduction, and aid in minimizing public health risks.     

Medical examiner response to the drug overdose epidemic in King County Washington: “Real-time” surveillance,data science,and applied forensic epidemiology

As the overdose epidemic overwhelmed medicolegal death investigation offices and toxicology laboratories, the King County Medical Examiner's Office responded with “real-time” fatal overdose surveillance to expedite death certification and information dissemination through assembling a team including a dedicated medicolegal death investigator, an information coordinator, and student interns. In-house testing of blood, urine, and drug evidence from scenes was performed using equipment and supplies purchased for surveillance. Collaboration with state laboratories allowed validation. Applied forensic epidemiology accelerated data dissemination. From 2010 to 2022, the epidemic claimed 5815 lives in King County; the last 4 years accounted for 47% of those deaths. After initiating the surveillance project, in-house testing was performed on blood from 2836 decedents, urine from 2807, and 4238 drug evidence items from 1775 death scenes. Time to complete death certificates decreased from weeks to months to hours to days. Overdose-specific information was distributed weekly to a network of law enforcement and public health agencies. As the surveillance project tracked the epidemic, fentanyl and methamphetamine became dominant and were associated with other indicators of social deterioration. In 2022, fentanyl was involved in 68% of 1021 overdose deaths. Homeless deaths increased sixfold; in 2022, 67% of 311 homeless deaths were due to overdose; fentanyl was involved in 49% and methamphetamine in 44%. Homicides increased 250%; in 2021, methamphetamine was positive in 35% of 149 homicides. The results are relevant to the value of rapid surveillance, its impact on standard operations, selection of cases requiring autopsy, and collaboration with other agencies in overdose prevention.     

Organic impurity profiling of fentanyl samples associated with recent clandestine laboratory methods

Nearly a decade ago, fentanyl reappeared in the United States illicit drug market. In the years since, overdose deaths have continued to rise as well as the amount of fentanyl seized by law enforcement agencies. Research surrounding fentanyl production has been beneficial to regulatory actions and understanding illicit fentanyl production. In 2017, the Drug Enforcement Administration (DEA) began collecting seized fentanyl samples from throughout the United States to track purity, adulteration trends, and synthetic impurity profiles for intelligence purposes. The appearance of a specific organic impurity, phenethyl-4-anilino-N-phenethylpiperidine (phenethyl-4-ANPP) indicates a shift in fentanyl production from the traditional Siegfried and Janssen routes to the Gupta-patent route. Through a collaboration between the DEA and the US Army's Combat Capabilities Development Command Chemical Biological Center (DEVCOM CBC), the synthesis of fentanyl was investigated via six synthetic routes, and the impurity profiles were compared to those of seized samples. The synthetic impurity phenethyl-4-ANPP was reliably observed in the Gupta-patent route published in 2013, and its structure was confirmed through isolation and structure elucidation. Organic impurity profiling results for illicit fentanyl samples seized in late 2021 have indicated yet another change in processing with the appearance of the impurity ethyl-4-anilino-N-phenethylpiperidine (ethyl-4-ANPP). Through altering reagents traditionally used in the Gupta-patent route, the formation of this impurity was determined to occur through a modification of the route as originally described in the Gupta patent.     

Fatalities associated with fentanyl and co-administered cocaine or opiates

Fatalities associated with fentanyl hydrochloride are increasingly seen in Massachusetts. Between September 2005 and November 2006, 5009 medicolegal investigations associated 107 deaths with licit or illicit fentanyl use, along with a co-detection of an opiate/opioid or cocaine/benzoylecognine, or both. Deaths associated with illicit fentanyl use occur in younger people (39.4 vs. 61.5 years) with higher fentanyl (17.1 ng/mL vs. 4.4 ng/mL) and lower morphine (76.9 ng/mL vs. 284.2 ng/mL) postmortem blood concentrations, and more frequent cocaine co-intoxication (65% vs. 3%), than deaths associated with illicit fentanyl use. A wide range of postmortem blood concentrations of fentanyl was detected (trace-280 ng/mL), with a minimum concentration of 7 ng/mL of fentanyl strongly associated with illicit use of fentanyl in poly-drug cases. The most commonly detected opiates/opioids in illicit fentanyl users were: morphine (29%), oxycodone (14.5%), and methadone (14.5%). Ethanol, cannabinoids, diazepam, citalopram, and diphenhydramine were each detected in greater than 10% of the licit fentanyl cases. Most fentanyl abusers died at their own home and their deaths were most often classified as accidental. Mapping of primary residences of decedents revealed conspicuous clustering of the illicit fentanyl use cases, as opposed to the random pattern in licit use cases. Fentanyl misuse is a public health problem in Massachusetts.     

Investigation of Postmortem Absorption and Redistribution After the Application of a Fentanyl Patch

Fentanyl deaths have increased with availability of transdermal patches. Interpretation of postmortem fentanyl levels may be complicated by postmortem redistribution and absorption of fentanyl from a patch. We applied an unused 100‐μg/h fentanyl patch onto the lower abdomen of a decedent with no premortem fentanyl exposure. Ocular fluid, blood, and urine were collected prior to placement, and the decedent was refrigerated for 23 h. Prior to the autopsy, urine, subcutaneous tissue under the patch, and samples from the same anatomic sites were obtained. We observed no fentanyl in any postpatch placement samples (LOD: 0.1 ng/mL for blood and vitreous fluid, 1.0 ng/mL urine, 2.0 ng/g for tissues). Although we observed no postmortem absorption of fentanyl, this was only a single case; therefore, we recommend that patches be removed after receipt of a cadaver before initiation of an autopsy, with the location of removed patch documented.     

Characteristic Features of Pediatric Firearm Fatalities—Comparisons Between Australia and the United States

Abstract:  Gunshot deaths in children less than 17 years of age from Adelaide, SA, Australia (1969–2005) and from San Diego County, CA, United States (1988–2005) were compared. Forty-two pediatric gunshot fatalities occurred in South Australia (1.1 cases/year; M:F = 30:12). There were 6 accidents (14%), 14 suicides (33%), and 22 homicides (52%). In San Diego there were 185 cases ( c. 10 cases/year; M:F = 148:37). There were 6 accidents (3%), 42 suicides (23%), 130 homicides (70%), and 7 undetermined cases (4%). The incidence of homicide was significantly higher in San Diego County compared to Adelaide ( p  < 0.001), with a higher proportion of murder–suicides occurring in Adelaide. There were markedly more accidents and suicides involving males in Adelaide and a far higher number of male homicide victims in San Diego County compared to females. Rifles of 0.22-caliber were preferred weapons in South Australia, compared to handguns in San Diego County.     

Fentanyl-related deaths: demographics, circumstances, and toxicology of 112 cases

Since 1979, the potent narcotic analgesic fentanyl and its analogs have been synthesized in clandestine laboratories and sold as heroin substitutes. At least 112 overdose deaths have been associated with their use. In this study, toxicology data, autopsy findings, and coroners' investigative reports were reviewed in order to construct a profile of the typical fentanyl overdose victim and to identify any factors that might heighten the risk of death from fentanyl use. The "typical" fentanyl overdose victim was 32.5 +/- 6.7 years of age (range, 19 to 57 years), male (78%, compared with 22% female), and Caucasian (50%, compared with 29% Hispanic, 20% Black, and 0.9% Asian). With the exception of his or her age, the typical fentanyl overdose victim is quite similar to the typical heroin user. Nearly all the deaths (94%) occurred in California, yet within the state they were widely distributed throughout 17 counties and 44 cities. Pulmonary edema and congestion and needle puncture sites were consistent postmortem findings. No preexisting medical conditions were identified as possible risk factors. Although most of the fentanyl victims had a prior history of intravenous drug use, morphine or codeine were not commonly found, which suggests that the victims had little or no opiate tolerance. Ethanol was present in 38% of the cases and is thought to be a significant risk factor. Mean fentanyl concentrations in the body fluids were quite low: 3.0 +/- 3.1 ng/mL (0.3 +/- 0.31 micrograms/dL) in blood and 3.9 +/- 4.3 ng/mL (0.39 +/- 0.43 micrograms/dL) in urine, measured by radioimmunoassay. Although the potency of the analogs and the purity of street samples varies considerably, it is probably the general availability of the drug rather than the potency of a particular analog that determines the incidence of overdose deaths.     

Evaluating the sensitivity,stability, and cross-reactivity of commercial fentanyl immunoassay test strips

Illicit fentanyl has flooded the United States' drug market, increasing the risk of overdose and poisonings throughout the general population and accidental exposure among law enforcement officers confiscating the increasing number of seizures. Fentanyl test strips (FTS) are used to obtain presumptive information about the presence of fentanyl in a suspected sample. However, their adoption by law enforcement personnel and seized-drug analysts has been limited because most products are advertised for urine testing, not for assays using water solutions. This study presents an evaluation of four commercial FTS: Rapid Response from BTNX, Inc.; T-Dip Fentanyl (FTY) Urine Dip Cards obtained from Amazon.com ; Premier BioDip FYL10 from Premier Biotech Inc.; and MobileDetect Fentanyl strips from DetectaChem, Inc. Performance characteristics curves were used to compare the products' sensitivity, showing that all can reliably detect fentanyl in aqueous solutions at concentrations below 1 μg/mL, with some of the tests able to reliably detect the drug at 200 ng/mL. A stability study demonstrates the performance of all four FTS brands was only slightly affected after 30 days of storage at two extreme environmental conditions. Fentanyl-related substances are also evaluated using the Rapid Response FTS, which showed high cross-reactivity with para-fluorofentanyl and acetylfentanyl, but lower with ortho-chlorofentanyl, carfentanil, and 4-ANPP. Users should be aware that FTS may give false-negative results even when potentially dangerous levels of carfentanil are present. When testing other common drugs, adulterants, and diluents frequently encountered in seized tablets, concentration-dependent results were obtained and multiple instances of false positives were recorded.     

An Examination of the Postmortem Redistribution of Fentanyl and Interlaboratory Variability,

Fentanyl is a synthetic opioid agonist used for pain control. Often administered as a transdermal patch, it is an interesting drug for study of postmortem redistribution. We hypothesized that fentanyl concentrations would increase over time after death, as measured in blood drawn on the day prior to autopsy and in blood drawn at the time of autopsy in ten cases where fentanyl patches were identified at the scene. Concentrations were compared, and heart blood to femoral blood ratios were calculated as markers of postmortem redistribution. Fentanyl concentrations measured in peripheral blood drawn the day of autopsy (peripheral blood 2 [PB2]) were higher than those drawn the day prior to autopsy (peripheral blood 1 [PB1]) with a mean ratio (PB2/PB1) of 1.80. The ratio of heart blood concentrations (HB) to femoral blood concentrations drawn at autopsy (PB2) had a mean ratio (HB/PB2) of 1.08. Some cases had blood from the same source analyzed at two different laboratories, and concentrations of fentanyl in those samples showed inter‐ and intralaboratory differences up to 25 ng/mL. Postmortem fentanyl concentrations may be affected by antemortem factors, postmortem redistribution, and laboratory variability. Forensic pathologists must use caution in interpreting fentanyl levels as part of death investigation.