The Need to Rethink Harm Reduction for People Using Drugs Alone to Reduce Overdose Fatalities.

Background: During the ongoing opioid epidemic, Cuyahoga County (second largest in Ohio) reported overdose mortality rates (54/per 100,000) higher than the national average. Prior research demonstrates that people who use drugs often use alone but there is minimal research on people who died of overdose while using alone. The objective of this study is to examine sociodemographic, toxicologic, and injury characteristics, and emergency medical response to overdose decedents who died using drugs alone. Method: Data from the Cuyahoga County Medical Examiner's Office (2016-2020, N = 2944) on unintentional overdose deaths in adults was tabulated including socio-demographic, toxicologic, and injury-related information. Decedents using drugs alone were identified and compared to those not using alone via Chi-square and Fisher's exact tests. We further fit a multivariate logistic regression model to evaluate socio-demographic, toxicologic, and injury-related factors associated with increased odds of using alone. All results are reported with 95% confidence intervals. Result: Among decedents, 75% (n = 2205) were using drugs alone. Decedents using alone were more likely to be using drugs at home (p = 0.001) or be found dead at the scene (p < 0.001) and less likely to receive naloxone (p < 0.001) have other person/bystander, not using, present (p = 0.002). Using drugs at home (aOR = 1.61[1.19-2.20]) was associated with higher odds of using alone; and being married (aOR = 0.57[0.38-0.86]), having history of illicit drug use (aOR = 0.25[0.08-0.81]) and other person present, who was not using (aOR = 0.58[0.42-0.79]) were associated with lower odds of using alone. Conclusion: New harm reduction approaches targeting people using drugs alone are needed to reduce overdose deaths.

A case study for local data surveillance in opioid overdose fatalities in Cuyahoga County, OH 2016-2020.

Introduction: Fentanyl and fentanyl analogs have increased the overdose mortality rates in the United States, significantly impacting states like Ohio. We examined carfentanil overdose deaths, other contributing Cause of Death (COD) drugs, and drug seizure trends from 2016 to 2020 in Northeast Ohio. Materials and methods: We studied death investigation data from the Cuyahoga County, Ohio Medical Examiner's Office (CCMEO) of all fatal accidental opioid overdoses as well as drug seizure data from Cuyahoga County Regional Forensic Science Laboratory (CCRFSL). We also compared decedents' race, gender, age, residential locality, drugs contributing to the COD in opioid cases, and for carfentanil, fentanyl, and cocaine seizures in Cuyahoga County from 2016 to 2020 (N = 2948). Results: Decedents' had an average of three different drugs contributing to their COD. A bimodal carfentanil spike was observed in fatal accidental overdoses in Cuyahoga County for the years 2017 and 2019. Decedents in urban residency, who were Non-Hispanic, White and younger, significantly predicted the presence of carfentanil contributing to the COD. In 2020, decedents who were Black and older were significantly associated with cocaine contributing to the COD. Carfentanil and carfentanil-related overdoses were significantly correlated. Discussion: The pervasiveness of illicitly manufactured fentanyl and fentanyl analog (e.g., carfentanil) mixtures with other drugs are changing the demographics of persons who fatally overdose in Cuyahoga County, OH. Significant trending shifts can also be observed for the presence of carfentanil in decedent and seizure county data. Conclusions: Local data of drug-related overdose deaths and drug seizures from a medical examiner's office and affiliated forensic laboratory lab can be used for timely public health surveillance, and informing prevention, and intervention at the county level.

The Public Health Role of Medical Examiner Offices During COVID-19 and Other Mass Fatality Events.

ABSTRACT: The public health role of a medical examiner office (MEO) in a pandemic is largely undefined; however, death data may be useful in strategic planning. Deaths reportable to MEO are defined in statute, with discretion as to the assumption of jurisdiction. We analyzed the daily reported death numbers (DRDNs) in our jurisdiction from March 1, 2020, to March 31, 2021, and compared them with hospital admission and COVID-19 fatality data over the same period. The DRDN from an MEO is easily obtained and may be useful as a supplemental and surrogate metric in certain pandemic mass casualty decisions. Hospital admission data were analyzed in real time and with a 2-week time-shift, as deaths lag hospital admissions as a disease surveillance metric. Moderate correlation was observed between DRDN and hospital admissions (r = 0.570), and this improved to strong correlation (0.645) when the 2-week time-shift was incorporated into the analysis. Both evaluations were statistically significant (P < 0.0001). The DRDN also moderately correlated (r = 0.412) with the number of COVID-19 deaths. Because death certification and hospital diagnosis may be delayed, real-time trend recognition in a pandemic may benefit from use of DRDN from MEO.

Trends in opioid overdose fatalities in Cuyahoga County, Ohio: Multi-drug mixtures, the African-American community and carfentanil.

Background: Ohio's age-adjusted opioid overdose fatality rate is double the national average. In an ever-evolving epidemic, it is crucial to monitor trends to inform public health interventions. Methods: A retrospective study was conducted using the Medical Examiner's decedent case files for all accidental opioid-related adult overdose deaths in Cuyahoga County (Cleveland), Ohio in 2017. Characterization of trends was based on autopsy/toxicology and first responder reports, medical records and death scene investigations. Results: Of 543 accidental opioid-related adult overdose fatalities, 64.1% died from 3+ drugs. The most common cause of death (COD) drugs included fentanyl (63.4%), heroin (44.4%), cocaine (37.0%) and carfentanil (35.0%). There were four times as many African American decedents as two years prior. Three or more COD drugs was >50% more common in those with fentanyl (Prevalence Ratio (PR) = 1.56[1.34-1.70]; p<.001) or carfentanil (PR = 1.51[1.33-1.70]; p<.001) as a COD drug, more common with a history of prescription drug abuse (PR = 1.16[1.02-1.33]; p=.025), but less common in divorced/widowed decedents (PR = 0.83[0.71-0.97]; p=.022). Carfentanil was nearly 4 times as prevalent in those with previous illicit drug use (PR = 3.88[1.09-13.70]; p=.025), and less common in those with previous medical history (PR = 0.72[0.55-0.94]; p=.016) or age 50+ (PR = 0.72[0.53-0.97]; p=.031). Conclusions: Accidental opioid-related overdose fatalities in Cuyahoga County adults were dominated by 3+ COD drugs, with cocaine/fentanyl mixtures driving sharp increases in African American fatalities. Carfentanil was more prevalent in people fitting the profile of recreational drug use. This data can inform harm reduction interventions.

The fentanyl phase of the opioid epidemic in Cuyahoga County, Ohio, United States.

Since late 2014, fentanyl has become the major driver of opioid mortality in the United States. However, a descriptive analysis of fentanyl victims is limited. We studied the 2016 fentanyl and heroin overdose deaths and compared them to previously studied heroin-associated fatalities from 2012 over a wide range of demographic and investigative variables, including overdose scene findings, toxicology results, and prescription drug history. We observed a significant increase in fentanyl-related deaths (n = 421, 2016) versus heroin deaths (n = 160, 2012) but the baseline demographics between both cohorts remained similar. Victims were predominantly of ages 35-64 years (60%-64%), White (83%-85%), and male (73%-76%). 2016 fentanyl decedents were more likely to have naloxone administered upon overdose, and the majority still had a positive prescription history for a controlled substance. Toxicology data showed a decrease in mean morphine and 6-monoacetylmorphine concentrations when cointoxication with fentanyl occurred. Our study emphasizes the medical examiner's role as a public health data source and bridge between different stakeholders combating the opioid epidemic.

Position Paper: Recommendations for the Investigation, Diagnosis, and Certification of Deaths Related to Opioid and Other Drugs.

The National Association of Medical Examiners convened an expert panel to update the association's evidence-based recommendations for investigating and certifying deaths associated with opioids and other misused substances to improve death certificate and mortality data for public health surveillance. The recommendations are as follows:1. Autopsy provides the best information on a decedent's medical condition for optimal interpretation of toxicology results, circumstances surrounding death, medical history, and scene findings. The panel considers autopsy an essential component of investigating apparent overdose deaths.2. Scene investigation includes reconciling prescription information and medication counts. Investigators should note drug paraphernalia or other evidence of using intoxicating substances.3. Retain blood, urine, and vitreous humor whenever available. Blood from the iliofemoral vein is preferable to blood from more central sites.4. A toxicological panel should be comprehensive, including potent depressant, stimulant, and antidepressant medications. Detecting novel substances present in the community may require special testing.5. When death is attributed to a drug or combination of drugs (as cause or contributing factor), the certifier should list the drugs by generic name in the autopsy report and death certificate.6. The best classification for manner of death in an overdose without any apparent intent of self-harm is "accident."

Unique Structural/Stereo-Isomer and Isobar Analysis of Novel Fentanyl Analogues in Postmortem and DUID Whole Blood by UHPLC-MS-MS.

The presented analytical method enabled the Toxicology Department at the Cuyahoga County Medical Examiner's Office to identify 26 and quantitatively report 24 compounds in 500 µL of whole blood, including fentanyl analogues (fentalogues) such as methoxyacetyl fentanyl (MeOAF) and cyclopropyl fentanyl (CPF). This second-generation method (FG2) was developed with the objective to improve the existing analysis (FG1) by decreasing sample size, lowering limits of detection (LOD) and lower limit of quantitation, minimizing ion suppression and resolving chromatographic interferences. Interferences may occur in the analysis of fentanyl, MeOAF, CPF, 3-methylfentanyl (3MF), butyryl fentanyl and isobutyryl fentanyl due to isobars and structural or geometric isomerism with another analogue or metabolite. The isomeric and isobaric fentalogues were grouped into three sets. The LOD established for Set 1 [MeOAF, para-methoxyacetyl fentanyl, para-fluoro acryl fentanyl (isobar), fentanyl carbamate], 2-furanyl fentanyl, Set 2 [CPF, (E)-crotonyl fentanyl] and carfentanil was 0.0125 ng/mL. The LOD established for N-methyl norfentanyl, norfentanyl, norcarfentanil, despropionyl fentanyl (4-ANPP), acetyl fentanyl, ß-hydroxy fentanyl, benzyl fentanyl, acryl fentanyl, alfentanil, fentanyl, para-fluoro fentanyl, Set 3 [(±)-trans-3MF, (±)-cis-3MF, isobutyryl and butyryl fentanyl], para-fluoroisobutyryl fentanyl, sufentanil, phenyl fentanyl and cyclopentenyl fentanyl was 0.0625 ng/mL. Seven-point linear calibration curves were established between 0.025 and 4.0 ng/mL for the 8 analytes with the lower LOD and 0.125 and 20 ng/mL for the 18 analytes with the higher LOD. 4-ANPP and cyclopentenyl fentanyl met qualitative reporting criteria only. The results for five postmortem and two driving under the influence of drugs authentic case samples are presented. To the authors' knowledge, FG2 is the first published method that achieved baseline resolution of the nine structural/stereo isomers and one isobar by ultra-high performance liquid chromatography-MS-MS and provided quantitative validation data for nine compounds. FG2 may be used as the new baseline for future isomers that need to be chromatographically separated.

The Opioid Epidemic: Moving Toward an Integrated, Holistic Analytical Response.

In many jurisdictions, public safety and public health entities are working together to enhance the timeliness and accuracy of the analytical characterization and toxicology testing of novel synthetic opioids. The improved sharing and early detection of these analytical data are intended to inform surveillance, interdiction efforts, patient intervention and treatment, all of which are critical to curbing the opioid epidemic. Forensic practitioners working to identify novel synthetic opioids struggle to provide timely results when encountering new or unknown substances, such as the fentanyl analogs. These compounds, which mimic heroin in pharmacologic effect but can be far more potent, are inconsistently present in chemical identification libraries, and are currently largely unavailable as reference materials for analytical comparison. Additionally, federal, state and local governments as well as nongovernmental organizations require potency, toxicity and potential-for-abuse data to evaluate the potential health risks of emerging drug threats. Subsequent scheduling efforts and criminal prosecutions also require these thorough drug characterization studies. Pilot programs have demonstrated that early communication of real-time drug toxicity and analytical data significantly impacts the successful response to emerging opioids. High-quality, real-time, national-level data on chemical composition, toxicological test data, drug toxicity and overdoses, and analysis of seized materials by law enforcement are needed to track drug trends. However, the USA still lacks a national system to coordinate and communicate toxicology, medical and medical examiner and coroner data with the broader medical and law enforcement communities. Opportunities to address these gaps as well as recent advancements collected through interagency efforts and technical workshops in the toxicology and analytical chemistry communities are presented here. Opportunities for partnership, increased communication and expanding best practices to move toward an integrated, holistic analytical response are also explored.

An LC-MS-MS Method for the Analysis of Carfentanil, 3-Methylfentanyl, 2-Furanyl Fentanyl, Acetyl Fentanyl, Fentanyl and Norfentanyl in Postmortem and Impaired-Driving Cases.

In July of 2016, carfentanil (CF) emerged in Northeast Ohio resulting in over 25 deaths within a 30-day period. A total of 125 deaths have occurred in Summit County and Cuyahoga County has reported 40 deaths, relating to the presence of CF either alone, or in combinations with heroin and fentanyl. Prior to this surge in CF cases, positive fentanyl enzyme-linked immunosorbent assay (ELISA) screening results were increasing in number. Many were negative for fentanyl confirmation by gas chromatography-mass spectrometry. Fentanyl analogs such as CF, acetyl fentanyl (AF), 2-furanyl fentanyl (2-Fu-F) and 3-methylfentanyl (3-MF) may be present in these cases. Some fentanyl analogs like CF and 3-MF do not cross-react with the Immunalysis ELISA fentanyl assay. With the emergence of potent synthetic fentanyl analogs, questions arose as to how to interpret their very low concentrations or absence in the blood in relation to cause of death. Driving under the influence of drugs (DUID) blood specimens had also tested positive for CF by reference laboratories. A liquid chromatography-tandem mass spectrometry method was developed to identify and quantify fentanyl, norfentanyl (NF) and four analogs: AF, 2-Fu-F, 3-MF and CF. The method has been utilized to quantify these fentanyl analogs in blood and vitreous humor in authentic antemortem and postmortem cases. Calibration curves were established between 0.10-4.0 ng/mL (NF, AF, 3-MF, 2-Fu-F and CF) and 1.0-40 ng/mL for fentanyl. In total, 98 postmortem cases analyzed produced the following blood concentration ranges: CF (0.11-0.88 ng/mL), 3-MF (0.15-1.7 ng/mL), 2-Fu-F (0.15-0.30 ng/mL), AF (0.14-0.16 ng/mL), fentanyl (1.1-15 ng/mL) and NF (0.10-3.7 ng/mL). Only CF, fentanyl and NF were detected in a statistically significant subset DUID population of 26 cases producing concentration ranges between 0.11 and 0.47 ng/mL, 1.0 and 9.8 ng/mL, and 0.11 and 3.5 ng/mL, respectively.

The Evolution of the Opiate/Opioid Crisis in Cuyahoga County.

The United States continues to grapple with an epidemic of opiate/opioid drugs. This crisis initially manifested itself in the use and abuse of opioid pain relievers and has since seen an increase in illicit opiate/opioid drug use mortality. Cuyahoga County (metropolitan Cleveland) has been an area where the crisis has been particularly acute; this paper updates our previous experience. Most notable in the evolution of the drug epidemic has been an increase in mortality associated with fentanyl and an alarming rise in overall deaths, largely attributable to the emergence of fentanyl (a 64% increase in total overdose deaths from 2015 to 2016, with fentanyl increasing 324%). Fentanyl is a synthetic opioid with use in medical analgesia and anesthesia; however, most of the current supply is of clandestinely manufactured origin. Also of concern is the recent appearance of illicit fentanyl analogues, which are briefly described in this report. White males continue to be the most frequent overdose victims in the current crisis. A decrease of age appears to have taken place with the emergence of fentanyl with the most common age group being between 30 and 44 years of age. The majority of decedents are nonurban residents. Educationally, most of these decedents have a high school diploma or less schooling and a significant percentage consists of manual laborers. Medical examiners are an important source of information necessary to develop prevention and interdiction strategies. Challenges faced regarding adequate funding, instrumentation, and staffing are being felt.

Rules for Establishing Causation in Opiate/Opioid Overdose Prosecutions - The Burrage Decision.

As the opiate/opioid crisis has worsened in the United States, one of the law enforcement responses has involved increased efforts to prosecute the individuals responsible for the distribution of illicit drugs that result in overdoses. When mixed intoxications occur, the controlling decision for prosecution is Burrage v. United States (2014), which provides guidance on the types of evidence required for establishment of causation. In many types of legal proceedings, forensic pathologists are called to provide expert testimony, although they may be unaware of the burden of proof that is required in a given case. This paper seeks to elaborate upon the burden of proof in drug overdose prosecutions with the guidance of Burrage and offer insight into the expectations and limitations involved in these cases.

Synthetic cannabinoid drug use as a cause or contributory cause of death.

Adverse effects associated with synthetic cannabinoid use include agitation, psychosis, seizures and cardiovascular effects, all which may result in a lethal outcome. We report the collection of data from 25 medical examiner and coroner cases where the presence of synthetic cannabinoids was analytically determined. Participating offices provided case history, investigative and relevant autopsy findings and toxicology results along with the cause and manner of death determination. This information, with the agency and cause and manner of death determinations blinded, was sent to participants. Participants offered their opinions regarding the likely contribution of the toxicology findings to cause and manner of death. The results show that some deaths are being attributed to synthetic cannabinoids, with the highest risk areas being behavioral toxicity resulting in excited delirium, trauma or accidents and as contributing factors in subjects with pre-existing cardiopulmonary disease. While insufficient information exists to correlate blood synthetic cannabinoid concentrations to effect, in the absence of other reasonable causes, the drugs should be considered as a cause or contributory cause of death based on history and circumstances with supporting toxicological data.

Suicide in Jail: A Ten-Year Retrospective Study.

Suicide in jails, like all death in custody, may involve complicated investigation. Allegations of mistreatment and/or abuse may be raised and these possibilities need to be addressed. Apart from these investigative concerns, the occurrence of suicides in such a controlled environment raises additional questions about potential preventative measures. Between 2004 and 2014, there were ten deaths of incarcerated individuals in Cuyahoga County (metropolitan Cleveland) Ohio. Most (80%) were white and all were male. Similar to previous reviews, the majority of decedents hanged themselves (90%), with one case of asphyxiation by airway obstruction with a foreign body. Psychiatric disorders were noted in six of ten decedents while seven of ten had a history of substance abuse including alcoholism. Overall, nine of ten had at least one of these disorders. All suicide deaths occurred within one year of incarceration, which may reflect the absence of a long-term prison fatality in our county. It is noteworthy that 70% of deaths occurred within the first month of incarceration with four of ten events occurring in less than a day including two deaths in less than 30 minutes. Positive toxicology for abused substances was noted in 75% (three) of the four individuals who died in less than a day and only in one other suicide, which occurred on the second day of incarceration. Our data suggest that suicide in jail is predominantly a male phenomenon, with early incarceration being a particularly vulnerable period. The presence of another inmate in the same cell as the decedent was not seen to have an independent deterrent effect. Intoxication, particularly in individuals with a history of substance abuse and/or alcoholism, should raise concern for potential self-harm in recently jailed individuals. Possible interventions suggested by this study might include closer direct surveillance in the early incarceration period, earlier access to mental health services as well as design modifications in holding cells with possible dedicated short-term holding areas where self-harm risks are minimized and surveillance can be optimized.

In vitro formation of acetylmorphine from morphine and aspirin in postmortem gastric contents and deionized water.

Forensic toxicologists consider detection of 6-acetylmorphine (6-AM) definitive evidence of heroin abuse. This study investigated the possibility that aspirin, when in solution with morphine, may acetylate morphine to produce acetylmorphine (AM). Morphine sulfate-extended release tablets (15 mg) and aspirin (325 mg) tablets were incubated in 50 mL postmortem gastric contents or deionized water at 37°C. One-milliliter aliquots were taken at timed intervals, extracted by solid-phase extraction, derivatized and analyzed by the gas chromatograph with a mass selective detector. Both 3- and 6-AM were detected in samples containing morphine and aspirin in combination; no heroin was detected. Production of AM was pH dependent with optimal formation at pH ≥4. In gastric contents, concentrations of 3-AM exceeded that of 6-AM by ∼10-fold. Production of 3-AM in gastric contents was approximately twice as high as it was in water, while matrix did not appear to affect 6-AM production. Urine specimens (10,602) assayed at a pain management laboratory and postmortem cases (>6,000) were investigated for in vivo formation of AM. Three cases exhibited unexplained 6-AM results. These data indicate that in vivo formation of 6-AM from the co-administration of aspirin and morphine, if it happens, is quite rare. In instances where this is suspected, 3-AM should be monitored.

'Lingering' opiate deaths? Concentration of opiates in medulla and femoral blood.

'Lingering death' cases occur when the circumstances of death indicate an opiate overdose, but measured opiate blood levels are only in the therapeutic range; death results from cardiac and respiratory depression. This study examined the relative concentration of opiates in femoral blood and in the medulla oblongata (sites for cardiac and respiratory control) from 41 cases to determine whether a difference in opiate concentration might explain lingering deaths. Opiates from blood and medulla were analyzed using GC-EI-MS in selective ion monitoring mode. Results were correlated with gross and microscopic findings of the lungs and with cause and manner of death. Opiate concentrations for morphine, codeine and 6-acetylmorphine (6-AM) were higher in the medulla than in blood. The brain: blood ratio for the analytes demonstrated an increasing ratio from morphine, to codeine, to 6-AM (1.42, 2.48 and 4.86), which corresponds to the relative lipophilicity of these analytes. The average right and left lung weights were 762 and 668 g, respectively. Histologic examination showed edema, and/or polarizable microemboli, acute bronchopneumonia and acute bronchitis. The preferential distribution of opiates to medulla suggests that lingering opiate deaths may be explained, at least in part, because of higher relative concentrations of drug in brain, compared with femoral blood.