Postmortem Blood Concentrations of R‐ and S‐Enantiomers of Methadone and EDDP in Drug Users: Influence of Co‐Medication and P‐glycoprotein Genotype

Abstract: We investigated toxicological and pharmacogenetic factors that could influence methadone toxicity using postmortem samples. R‐ and S‐methadone were measured in femoral blood from 90 postmortem cases, mainly drug users. The R‐enantiomer concentrations significantly exceeded that of the S‐enantiomers (Wilcoxon’s test, p < 0.001). The samples were divided into four groups according to other drugs detected (methadone only, methadone and strong analgesics, methadone and benzodiazepines, or methadone and other drugs). There was no significant difference in any of the R‐methadone/total methadone ratios among the four groups. The median R/S ratio was 1.38, which tends to be higher than that reported for the plasma of living subjects. In addition, we investigated whether small nucleotide polymorphisms in the MDR1 gene that encode the drug transporter P‐glycoprotein were associated with the concentrations of R‐ and S‐methadone and its metabolite 2‐ethylidene‐1,5‐dimethyl‐3,3‐diphenylpyrrolidine. No significant association was detected.     

Prison Suicides in South Australia: 1996–2010

Forty‐eight deaths occurring in prisons in South Australia were identified between January 1996 and December 2010, including 25 cases of suicide (mean age = 37 years; median age = 34 years; age range = 24–70 years). Most suicides were due to hanging (23/25; 92.0%) with victims using bedding, belts, or shoelaces attached to cell shelves, air vents, doors, or other accessible projections. There were no suicides attributed to drug overdose or sharp force injury. Over a third of all suicides (39.1%) occurred during the first month of confinement, with 26.1% of cases occurring within the first week. There was one suicide reported after 2 years of imprisonment. Given that suicide in state prisons currently occurs at a rate approximately eight times that of the general South Australian community, it appears that the subset of incarcerated individuals represents a group in need of effective preventive strategies to enable more appropriate provisions of existing prisoner resources.     

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.     

Fatal Intoxications in a Forensic Autopsy Material from Epirus,Greece, During the Period 1998‐2010

In this retrospective study, we report the epidemiological characteristics of all poisoning deaths in Epirus, Greece, from 1998 to 2010; we present the toxicological findings and the statistical evaluation of the results. This is the first detailed scientific report on all the officially certified poisoning deaths concerning part of the Greek population. A total of 126 poisoning fatalities were recorded, 67 of them being mono‐intoxications (53.2%). The cause of poisoning was as follows: drugs of abuse (60%); carbon monoxide (19.8%); pesticides (9.5%); corrosives (4.8%); pharmaceuticals (4.8%); and spider bite (0.8%). The most frequently detected poisonous substances were as follows: heroin (65 cases), ethanol (55), benzodiazepines (42), carbon monoxide (25), cocaine (17), cannabinoids (17) and pesticides (12). Increasing tendency in poisoning death rates was recorded, due to an increase in accidental poisoning deaths attributed mainly to drugs of abuse (total, accidental, and drugs‐of‐abuse poisoning death rates per 100,000 inhabitants per year were 1.87, 1.19, and 0.79, respectively, in the period 1998–2002 and 3.97, 3.41, and 2.55, respectively, in the period 2007–2010).     

The Toxicology of Methadone‐Related Death in Infants Under 1 Year: Three Case Series and Review of the Literature

Methadone‐related fatalities occur rarely in infants under 1 year, with five confirmed cases in the literature. The interpretation of pediatric postmortem toxicology relies on adult data; however, infants have crucial physiological differences that may impact interpretation of results. Retrospective case review included scene investigation, interviews, autopsy, and NIH/CDC Sudden Unexplained Infant Death Investigation Reporting Form. Methadone levels were confirmed by liquid chromatography/tandem mass spectrometry (LC‐MS/MS). The fatal blood methadone levels in this case series ranged from 69 to 700 ng/mL. This review of the literature adds toxicological findings of three methadone‐related infant fatalities and reviews the current literature on methadone‐related death in infants under 1 year. With opioid use on the rise in today's society, forensic experts should have a high index of suspicion for the possibility of intentional or unintentional poisoning in infants.     

Fatality of 33‐Year‐Old Man Involving Kratom Toxicity

Kratom is an herbal product commonly used for its effects which are similar to opioids and stimulants. Few studies demonstrate the dangers and lethality of Kratom, and most fatalities from Kratom involve other abused substances. In the current case report, a 33‐year‐old white man with a known history of opioid abuse and mental illnesses was found unresponsive in his basement with no obvious signs of trauma. After resuscitative efforts, he was pronounced dead and taken for autopsy evaluation. Blood from the inferior vena cava was analyzed for common abused substances. The laboratory toxicology work‐up revealed positive findings of caffeine, cotinine, and naloxone with low levels of Δ‐9 tetrahydrocannabinol. However, a marked level of mitragynine at 1.9 mg/L was observed, the highest reported to date. Given the facts and evidence, the medical examiner certified the cause of death as “mitragynine toxicity” and the manner of death was classified as an “accident.”     

Homicide–Suicide in Cuyahoga County,Ohio, 1991–2016

Research on homicides followed by suicides has relied heavily on small samples and relatively short time spans of data. This study helps to fill this gap by examining 26 years of homicide–suicide data from Cuyahoga County, Ohio, between 1991 and 2016. The main data source for the study is medical examiner files. Analyses of the data indicate the rate of homicide–suicide in Cuyahoga County is consistent with other studies but fluctuates considerably across years studied. The majority of victims are female while perpetrators are overwhelmingly male. Black people are overrepresented as victims and offenders. Use of drugs and/or alcohol leading up to the incident is common among perpetrators. Both the homicides and suicides were overwhelming committed with firearms. When comparing our results to the typology of murder–suicides developed by Marzuk, Tardiff, and Hirsch (JAMA 1992;267:3179), we find amorous jealousy is a significant motivating factor in a many cases, including those involving nonintimate partners. Our findings underscore the importance of widespread use of lethality assessment instruments.     

Alleged Biological Father Incest: A Forensic Approach

Paternal incest is one of the most serious forms of intrafamilial sexual abuse with clinical, social, and legal relevance. A retrospective study was performed, based on forensic reports and judicial decisions of alleged cases of biological paternal incest of victims under 18 years old (n = 215) from 2003 to 2008. Results highlight that in a relevant number of cases: victims were female; the abuse begun at an early age with reiteration; the alleged perpetrator presented a history of sexual crimes against children; sexual practices were physically poorly intrusive, which associated with a forensic medical evaluation performed more than 72 h after the abuse, explain partially the absence of physical injuries or other evidence—these last aspects are different from extrafamilial cases. In conclusion, observations about paternal incest are likely to exacerbate the psychosocial consequences of the abuse and may explain the difficulty and delay in detect and disclose these cases. Few cases were legally prosecuted and convicted.     

Increased risk of fatal intoxication and polypharmacy among psychiatric patients at death

Patients suffering from psychiatric disorders have an excess mortality and a shorter life span expectancy compared to the general population. Furthermore, they are treated with multiple drugs and are known to have an increased risk of drug abuse. In this study, we aimed at investigating the pharmaceutical drug and drug of abuse profiles of the deceased included in the Danish prospective autopsy‐based forensic study on psychiatric patients, SURVIVE. Using the postmortem systematic toxicological analysis results, we identified 129 different consumed compounds in our population (n = 443). Polypharmacy (≥5 compounds) was detected in 39.5% of the deceased. Deceased with a psychiatric diagnosis or who died from a fatal intoxication had significantly more compounds at the time of their death compared to having either no psychiatric diagnosis or another cause of death, respectively. Evidence of drug abuse was present, as 29.8% of our total population had consumed either methadone or illicit drugs of abuse, excluding tetrahydrocannabinol. Of those deceased with a psychiatric diagnosis, 33.6% had either consumed methadone or illicit drugs of abuse, a greater number than those without a psychiatric diagnosis. Fatal intoxication was the most frequent cause of death (40.6%) with methadone as the major intoxicant. Here, we found that those without a psychiatric diagnosis had fewer fatal pharmaceutical drug intoxications compared to the psychiatric diagnosis groups. Our findings add further context to understanding the excess mortality of psychiatric patents, since there is an increased occurrence of fatal intoxication, polypharmacy, and drug abuse in this population.     

Fatal Case of a 27‐Year‐Old Male After Taking Iboga in Withdrawal Treatment: GC‐MS/MS Determination of Ibogaine and Ibogamine in Iboga Roots and Postmortem Biological Material

We report the case of a man who died twelve hours after ingesting powdered iboga root, commonly taken for its stimulant and hallucinogenic properties. Ibogaine and ibogamine were quantified in the powder ingested and the victim's body fluids by GC‐MS/MS after liquid–liquid extraction (Toxi‐tubes A^®). The concentrations of ibogaine measured in the blood samples taken at the scene and in the peripheral blood, urine, and gastric fluid samples taken during the autopsy were 0.65, 1.27, 1.7, and 53.5 μg/mL, while the iboga content in the powder was 7.2%. Moreover, systematic toxicological analyses of biological samples showed the presence of diazepam and methadone in therapeutic concentrations. Death was attributed to the ingestion of a substantial quantity of iboga in the context of simultaneous methadone and diazepam consumption.     

Criminal Behavior in Opioid‐Dependent Patients Before and During Maintenance Therapy: 6‐year Follow‐Up of a Nationally Representative Cohort Sample

Lifetime prevalence of opioid dependence is about 0.4% in western countries. Opioid‐dependent patients have high morbidity and mortality and a high risk of criminal behavior. Few studies have addressed the long‐term impact of opioid maintenance therapy on convictions and criminal behavior. The PREMOS study is a prospective, longitudinal, naturalistic clinical study of a nationally representative sample of 2694 opioid‐dependent patients to investigate convictions and criminal behavior at baseline and after 6 years of maintenance treatment. At follow‐up, 2284 patients still were eligible (84.7%). A comprehensive assessment including a patient and doctor questionnaire, and the EuropASI was completed at baseline and follow‐up. Data on criminality at follow‐up had been received for 1147 (70.6%) patients. A large number (84.5%) of them had been charged or convicted at any time before baseline assessment, most frequently with drug‐related offenses (66.8%), acquisitive crime (49.1%), or acts of violence (22.0%). Reported charges and convictions had declined to 17.9% for the last 12 months before follow‐up, which was also reflected by a significant decrease in the EuropASI subscore “legal problems” from 1.52 at baseline to 0.98 after 6 years. These data indicate a significant and clinically relevant reduction in criminal behavior in opioid‐dependent patients in long‐term maintenance treatment. Maintenance therapy is effective in the reduction in both narcotics‐related and acquisition crime.     

Methylenedioxypyrovalerone (“Bath Salts”),Related Death: Case Report and Review of the Literature,

Cathinone derivatives (bath salts) have emerged as the latest drugs of abuse. 3,4‐methylenedioxypyrovalerone (MDPV) is the primary active ingredient in bath salts used in this country. This article presents the second reported cause of death by MDPV intoxication alone. In April 2011, a delusional man was emergently brought to a hospital, where he self‐reported bath salt usage. He became agitated, developed ventricular tachycardia, hyperthermia, and died. Comprehensive alcohol and drug testing was performed. Using the alkaline drug screen, heart blood contained 0.7 mg/L MDPV and peripheral blood contained 1.0 mg/L MDPV. His bizarre behavior with life‐threatening hyperthermia was consistent with an MDPV‐induced excited delirium state. MDPV is not yet found by routine immunoassay toxicology screens. Testing for MDPV should be considered in cases with a history of polysubstance abuse with stimulant type drugs, report of acute onset of psychogenic symptoms, excited delirium syndrome, or presentation in a hyperthermic state.     

Unexpected Serotonin Syndrome,Epileptic Seizures,and Cerebral Edema Following 2,5‐dimethoxy‐4‐bromophenethylamine Ingestion

4‐bromo‐2,5‐dimethoxyphenethylamine (2C‐B) is a designer drug. In Europe, 2C‐B is easily obtained and used for recreational purposes. It is known for its stimulating effects similar to those of 3,4‐methylenedioxymethamphetamine, although in higher doses it has more hallucinogenic effects. Here, we report a case of 2C‐B ingestion, confirmed by liquid chromatography‐tandem mass spectrometry, in an 18‐year‐old man. The neurological consequences were severe, including the development of serotonin syndrome and severe brain edema. Supportive therapy resulted in a stable condition, although, after several months, the patient still suffered from severe neurological impairment due to the drug‐induced toxicity. This case showed that 2C‐B could not be identified with the drugs of abuse screening routinely used in Dutch hospitals. The use of 2C‐B carries many risks, with potentially profound neurological damage, that both consumers and healthcare physicians are unaware of.     

Sudden Death Due to Hydatid Disease: A Six‐Year Study in the Northern Part of Tunisia

Human ecchinococcosis also known as hydatid disease is a zoonotic infection caused by the tapeworm Ecchinococcus with 2–3 Million cases worldwide. We hereby report a 6 years period study of Sudden death due to hydatidosis aiming to analyze the epidemiological criteria, death circumstances, and autopsy observations attributed to hydatid disease. During the past 6 years, 26 death cases were due to hydatid disease. Our analysis shows that the sex ratio (M/F) was 1.6, the mean age was 31‐year old, and 65% of the subjects lived in rural places. In 17 cases, death occurred in the victim's place, five victims died after a heavy exercise, and in two cases, death occurred immediately after trauma. At autopsy, 91% of the cysts were found in the liver. In three cases, death followed a septic state, and in two cases, it followed an acute respiratory failure. Death was attributed to anaphylaxis in 17 cases.