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.     

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.     

A fentanyl fatality involving midazolam

A case is presented of a 35-year-old black African male anesthesiology resident, found dead in his apartment. At the scene a syringe, butterfly intravenous line and a bottle of Versed (Midazolam) were recovered. A comprehensive screen for common drugs of abuse and therapeutic agents failed to detect any drugs in blood and urine. The blood ethanol concentration was 0.06 g/dl. A GC/MS SIM assay for midazolam was developed. A sub-therapeutic midazolam blood concentration of 7.5 ng/ml was detected and concentrations (ng/ml or ng/g) in bile, urine, and liver were 3.3, 7.5, and 96, respectively. The syringe fluid was then analyzed and found to contain only fentanyl, midazolam was absent. The blood fentanyl concentration was 4.9 ng/ml which is consistent with those reported in fentanyl fatalities. Fentanyl concentrations (ng/ml or ng/g) in bile, urine, and liver were 8.8, 5.0, and 5.9, respectively. The cause of death was ruled to be fentanyl intoxication and the manner of death undetermined.     

Concurrent detection of heroin, fentanyl, and xylazine in seven drug-related deaths reported from the Philadelphia Medical Examiner's Office

Recreational drugs, such as cocaine and heroin, are often adulterated with other pharmacological agents to either enhance or diminish the drug effects. Between April 21, 2006 and August 8, 2006, the Philadelphia Medical Examiner's Office detected xylazine (a veterinary sedative) and fentanyl (a synthetic opioid) in specimens taken from seven cases. Initial immunoassay screening was performed on urine and blood for fentanyl, opiate, cocaine, phencyclidine (PCP), and benzodiazepines. All tests reported positive were confirmed by gas chromatography-mass spectrometry. All seven xylazine positive cases tested positive for fentanyl and six cases tested positive for 6-acetylmorphine (a metabolite and definitive marker for heroin). The seventh case was positive for morphine and had a history of heroin abuse. Xylazine was present in urine in all seven cases and blood levels were detected in three cases. The blood concentrations ranged from trace to 130 ng/mL. Fentanyl was present in the blood and urine in each case and blood concentrations ranged from 4.7 to 47 ng/mL. Adulteration of illicit drugs has become an epidemic health concern for drug users. Healthcare professionals need to be aware of this issue, so the patients can be treated in an effective, timely manner.     

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.     

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.     

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.     

Abnormally high concentrations of amphetamine in blood of impaired drivers

We present a case series (N = 46) of individuals apprehended in Sweden for driving under the influence of drugs (DUID). These cases were selected because the concentrations of amphetamine in blood were abnormally high (> 5.0 mg/L), the highest being 17 mg/L. In comparison, the median blood-amphetamine concentration in a population of DUID offenders (N = 6,613) was 0.70 mg/L. Among the DUID suspects with extremely high blood-amphetamine concentrations there were 38 men (83%) with mean age of 37.8 y (SD 6.8 y) and 8 women (17%) with a mean age of 34.1 y (SD 4.3 y). All had previously been registered in our database (mean 12 times, median 9 times) for drug-related offences, including DUID. The concentration of amphetamine in blood of female offenders was slightly higher than the concentration in male offenders (6.6 mg/L vs. 5.8 mg/L), although this difference was not statistically significant (p > 0.05). The drugs other than amphetamine most frequently encountered in the blood samples were tetrahydrocannabinol and benzodiazepines (diazepam and nordiazepam). The commonest signs of drug use reported by the arresting police officers were bloodshot and glazed (watery) eyes, restlessness, talkativeness, exaggerated reflexes and slurred speech. Unsteady gait and dilated pupils were observed in some but not all individuals. These very high concentrations of amphetamine were tolerated without any fatalities indicating a pronounced adaptation to the pharmacologic effects of this central stimulant. Anecdotal information indicated that those with the very highest concentrations of amphetamine in blood had swallowed the drug to prevent being apprehended in possession of an illicit substance.     

Postmortem redistribution of fentanyl in the rabbit blood

Postmortem redistribution of fentanyl in the rabbit was investigated after application of the 50-μg/h Durogesic pain patch. Patches were applied for 48 hours. Two cycles of patch administration were used before characterization of the postmortem redistribution. Fentanyl showed marked redistribution into the femoral and pulmonary veins of the rabbit through 48 hours after the animals were humanely killed and the pain patches removed. The plasma concentration of 2.34 ng/mL in the femoral blood before killing the animals increased 5.6-fold by 48 hours after patch removal to 13.2 ng/mL. This postmortem concentration is approximately 3-fold the C(max) determined during antemortem pharmacokinetic analysis, 4 ng/mL, which was achieved 24 hours after the application of the second 50-μg/h Durogesic pain patch. After blood sampling for 48 hours after animal termination with patch removal compared with sampling for 48 hours from animals not terminated and with patch removal, the exposure ratios in the terminated animals were approximately 30-fold, indicating that between the postmortem redistribution of fentanyl and the cessation of hepatic clearance of fentanyl in the rabbit, the postmortem redistribution of fentanyl leads to an elevated measures of postmortem blood concentrations relative to antemortem blood concentrations.     

n‐Ethyl Pentylone‐Related Deaths in Alabama

n‐Ethyl pentylone (NEP) is a chemical substance derived from cathinone. Synthetic cathinones are an evolving group of drugs with stimulating, mind‐altering effects sometimes referred to as novel or new psychoactive substances (NPS). There is scarce information in the medical literature regarding forensic cases in which NEP is detected in toxicological testing. We present four fatalities involving NEP from Alabama in 2017. Deaths were attributed to NEP toxicity in two cases (peripheral blood concentrations of 0.121 and 0.953 mg/L) and injuries caused by gunshot wounds in two cases (peripheral blood concentrations of 0.045 and 0.031 mg/L). One case involving NEP described an individual who exhibited classic CNS‐stimulant induced erratic behavior before being found dead. These cases enhance the forensic literature regarding specific NPS like NEP and provide contextual reference for professionals considering the significance of NEP in toxicological interpretation.     

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.     

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.     

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.     

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.     

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.     

The Outbreak of Fentanyl‐Related Deaths in Cook County,Illinois, Between October 2015 and December 2017: A Retrospective Study and a Comparison with Previous Data

The National Institute on Drug Abuse has observed an increase in fentanyl deaths in the United States. One epidemic related to the abuse of fentanyl happened in Cook County in 2005–2007 (350 deaths). Another outbreak of fentanyl deaths occurred in 2015–2017 in the same area. The database of the Cook County Medical Examiner's Office was searched for cases of fentanyl deaths between 2015 and 2017: 1244 deaths were found. A comparison was performed with the previous data: an increase in the number of females was observed in 2015–2017. Also, in 2005–2007, the majority of deaths occurred among African American, while in 2015–2017, Caucasians were more involved. Within our population, some drug combinations were more common in specific demographic subgroups (male/females; Caucasian/African American; and certain age groups). The epidemiology and the most significant drug associations found at the toxicology are discussed, highlighting the usefulness of the knowledge about this outbreak for public health.     

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.     

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.