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.     

Methadone‐Related Deaths – Epidemiological,Pathohistological, and Toxicological Traits in 10‐year Retrospective Study in Vojvodina,Serbia

The number of methadone‐related deaths (MRDs) during a 10‐year period (2002–2011) in the region of Vojvodina, Serbia, was increased. The cases were evaluated according to epidemiological parameters, pathohistological findings, and toxicological screening. The majority of victims were men, aged from 20 to 38. Pathohistologically, the signs of acute focal myocardial damage were present in the heart of victims with drug abuse history shorter than 2 years, while both signs of recent and chronic focal myocardial damage were developed among victims with longer drug abuse history (2–5 years). In postmortem blood samples of 54.84% of victims, methadone was detected in combination with diazepam, both in therapeutic range. Alcohol was absent in most cases. Other detected drugs were antipsychotics and antidepressants in therapeutic concentrations. These findings raise the attention to the concomitant use of methadone and benzodiazepines with the need for further studies to clarify the mechanism of death in such cases.     

Distribution of Enantiomers of Methadone and Its Main Metabolite EDDP in Human Tissues and Blood of Postmortem Cases

Knowledge concerning the distribution of methadone in postmortem human tissue and the effect of postmortem redistribution on methadone is today limited making the choice of a suitable substitute for femoral blood difficult when this is not available. Cardiac blood, femoral blood, muscle, and brain tissue concentrations of the enantiomers of methadone and its metabolite 2‐ethyl‐1,5‐dimethyl‐3,3‐diphenylpyrrolinium were recorded for 155 postmortem cases. Brain and muscle tissue concentrations exceeded the femoral blood concentrations with a median fold of 2.3 and 1.6, respectively, but both had a better correlation than cardiac blood to femoral blood concentrations. The Kruskal–Wallis test showed a significant dependency on time and body mass index for some of the matrix ratios over femoral blood. We conclude brain or muscle tissue may constitute a better alternative for measurement of methadone than cardiac blood for situations in which femoral blood is not available, despite concentrations in both matrices being systematically higher.     

Popliteal Vein Blood Sampling and the Postmortem Redistribution of Diazepam,Methadone, and Morphine

Postmortem redistribution (PMR) refers to the site‐ and time‐related blood drug concentration variations after death. We compared central blood (cardiac and subclavian) with peripheral blood (femoral and popliteal) concentrations of diazepam, methadone, and morphine. To our knowledge, popliteal blood has never been compared with other sites. Intracardiac blood (ICB), subclavian blood (SB), femoral blood (FB), and popliteal blood (PB) were sampled in 30 cases. To assess PMR, mean concentrations and ratios were compared. Influence of postmortem interval on mean ratios was also assessed. Results show that popliteal mean concentrations were lower than those for other sites for all three drugs, even lower than femoral blood; mean ratios suggested that the popliteal site was less subject to PMR, and estimated postmortem interval did not influence ratios except for diazepam and methadone FB/PB. In conclusion, our study is the first to explore the popliteal site and suggests that popliteal blood is less prone to postmortem redistribution.     

“Bath Salts” the New York City Medical Examiner Experience: A 3‐Year Retrospective Review

“Bath salts” are synthetic derivatives of cathinones, compounds found in the leaves of Catha edulis, which possesses amphetamine‐like properties. At the New York City Office of Chief Medical Examiner, we conducted a 3‐year retrospective analysis of deaths in which cathinones were detected. Two categories emerged; those in which cathinones were a contributory cause of death (15 cases) and those in which they were an incidental finding (15 cases). Of the former group, 13 were associated with additional intoxicants; two deaths were attributed solely to cathinone intoxication, both survived 10 h: a man whose postmortem blood methylone concentration was 0.71 mg/L and a woman whose postmortem blood ethylone concentration was 1.7 mg/L. In the latter category, there were several individuals who had higher concentrations of cathinones than the above two, the highest being a blood methylone of 4.8 mg/L. Based upon our data and the literature presented, lethal concentrations of cathinones cannot be established.     

Suicide by gabapentin overdose

Gabapentin is an antiepileptic drug that is prescribed for both FDA-approved and multiple off-label conditions, and has a relatively safe side-effect profile. Rare cases of overdose-related adverse effects have been reported in the literature. Described herein are the circumstances and autopsy findings of a 62-year-old woman with a history of depression, whose death was caused by intentional ingestion of excess gabapentin. The postmortem peripheral blood gabapentin concentration as determined by high-performance liquid chromatography/tandem mass spectroscopy was 88 μg/mL. Previously reported cases of individuals surviving gabapentin overdoses are discussed and compared with this case. Based on a review of the available literature, this appears to be the first published report of a death due solely to gabapentin toxicity.     

Toxicologic analysis in cases of possible sudden infant death syndrome: a worthwhile exercise?

The diagnosis of sudden infant death syndrome (SIDS) is one of exclusion. At the Department of Forensic Medicine, Westmead Hospital, toxicologic analysis is performed as part of the postmortem examination of all apparent SIDS deaths. The results for the 5-year period January 1, 1994, to December 31, 1999, were audited to determine whether such routine testing was worthwhile. During this time there were 117 cases with a history consistent with SIDS. Drugs were detected in 19 (16%) of these cases. In 1 case, death was attributed to the finding of methadone. The presence of methadone was regarded as a possible contributing factor to death in a further 2 cases. The presence of possible methadone toxicity had not been expected from the history given before the examination in these 3 cases. In 114 cases there was a suitable sample for alcohol testing; in no case was alcohol detected. In 13 cases the postmortem examination revealed an anatomic cause of death (including 3 cases consistent with whiplash/shaken baby/impact head injury), which excluded a diagnosis of SIDS. In conclusion, routine toxicologic testing in all possible cases of SIDS death supplements the postmortem examination in excluding cases of non-SIDS.     

Site‐, Technique‐, and Time‐Related Aspects of the Postmortem Redistribution of Diazepam,Methadone, Morphine,and their Metabolites: Interest of Popliteal Vein Blood Sampling

Sampling site, technique, and time influence postmortem drug concentrations. In 57 cases, we studied drug concentration differences as follows: subclavian vein‐dissection/clamping versus blind stick, femoral vein‐dissection/clamping versus blind stick, right cardiac chamber, and popliteal vein‐dissection and clamping only. Cases were distributed in group #1 (all cases with both techniques), group #2 (dissection/clamping), and group #3 (blind stick). Sampled drugs were diazepam, methadone, morphine, and their metabolites. To assess PMR, mean concentrations and ratios were calculated for each group. Time‐dependent variations of blood concentrations and ratios were also assessed. Results indicate that site, method, and time may influence postmortem distribution interpretation in different ways. Popliteal blood seems less subject to PMR. In conclusion, our study is the first to evaluate concurrently three main aspects of PMR and confirms that the popliteal vein may represent a site that is more resistant to the changes seen as a result of PMR.     

Ethanol production by Candida albicans in postmortem human blood samples: effects of blood glucose level and dilution

We present two cases in which the ethanol concentration in blood samples taken after death continued to increase in the absence of any remarkable increase in n-propanol concentration. Species of bacteria and yeasts, including Candida albicans were isolated from these samples. We then examined whether C. albicans, the most common yeast in the general environment, was able to produce ethanol in human blood stored at room temperature. Ethanol production increased as the glucose concentration increased, indicating that C. albicans produced ethanol from the glucose. Our results also suggested that C. albicans produced ethanol more easily in blood diluted by intravenous infusions that included glucose than in undiluted blood. These findings are useful for the evaluation of postmortem ethanol production in subjects whose blood has been diluted by infusions with glucose. Furthermore, there was no quantitative relationship between the amount of n-propanol detected and the amount of ethanol production: n-propanol appears to be an unreliable index of putrefaction and postmortem ethanol production by C. albicans. It is possible for the blood ethanol level to be high and n-propanol not to be detected, even if the subject has not been drinking alcohol. We reconfirmed the necessity of immediately adding sodium fluoride to samples for ethanol analysis to prevent postmortem ethanol production.     

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.     

Postmortem oxycodone and hydrocodone blood concentrations

There is limited data on postmortem oxycodone concentrations, consisting of three published reports with a total of 11 cases, many of which were polypharmacy cases. This report presents the results of a review of autopsy and coroner's reports from 10 counties for the years 2000 and 2001 to locate cases with oxycodone or hydrocodone exposure as a leading cause of death. Eighty-eight cases were located. Twenty-four deaths were attributed to oxycodone alone. Mean and median postmortem oxycodone blood concentrations were 1.23 mg/L and 0.43 mg/L, respectively. The range was 0.12 to 8.0 mg/L, with 13 cases (54%) < or = 0.5 mg/L. Seventeen deaths were attributed to hydrocodone alone. Mean and median postmortem hydrocodone blood concentrations were 0.53 mg/L and 0.40 mg/L, respectively. The range was 0.12 to 1.6 mg/L, with 11 cases (65%) < or = 0.5 mg/L. There were seven cases where the cause of death was attributed to the effects of a combination of hydrocodone and oxycodone. Mean oxycodone and hydrocodone blood concentrations were 0.34 mg/L and 0.14 mg/L, respectively. Forty cases involved polysubstance overdoses with significant involvement of other drugs and ethanol. Mean oxycodone and hydrocodone blood concentrations were 0.18 mg/L and 0.29 mg/L, respectively. The list of other substances involved was extensive but included ethanol, amitriptyline, methadone, codeine, propoxyphene, and acetaminophen. The findings of this study report oxycodone values associated with a fatality at blood concentrations lower than previously reported. This may represent enhanced information because of the larger sample group. Hydrocodone values associated with a fatality were similar to previously published values.     

Digoxin-like immunoreactive substance in postmortem blood of infants and children

A digoxin-like immunoreactive substance (DLIS) has been reported in the serum of infants not receiving digoxin. This study was undertaken to determine if DLIS is present in the postmortem blood and tissues of infants or children and whether the endogenous substance could interfere with forensic toxicological analysis in suspected overdose. Ninety blood specimens taken from the heart at autopsy of children or infants were screened for DLIS using commercial radioimmunoassay kits. The average age at death in these cases was 8.6 months, the median age was 2 months. DLIS equivalent to 0.25 to 2.0 ng/mL digoxin was found in one third of the cases. The incidence of positive findings was 5/6 stillborns, 10/45 Sudden Infant Death Syndrome (SIDS), 10/15 deaths as a result of infection, 4/7 homicides, 1/8 deaths caused by congenital defects, and 0/9 accidental deaths. The body distribution of DLIS was investigated and highest levels were found in the liver. Findings of DLIS in blood were correlated with renal failure, (elevated vitreous urea nitrogen), electrolyte imbalance, and liver trauma. Apparent concentrations were in the equivalent therapeutic range of digoxin and would not be confused with accidental or intentional overdose with digoxin.     

Morbus Fahr--considerations on a case of sudden death

This paper presents 21 cases related to cyanide intoxication by oral ingestion. Cyanide concentrations in biological specimens are especially different from the type of postmortem specimens, and very important in interpreting the cause of death in postmortem forensic toxicology. Besides the detection of cyanide in autopsy specimens, the autopsy findings were unremarkable. Biological samples (0.2mL or equal to less than 10μg of cyanide) were analyzed colorimetrically for cyanide. In a series of 21 cyanide fatalities, the concentration ranges (mean±SD) of cyanide in heart blood, peripheral blood and gastric contents were 0.1-248.6mg/L (38.1±56.6mg/L), 0.3-212.4mg/L (17.1±45.1mg/L) and 2.0-6398.0mg/kg (859.0±1486.2mg/kg), respectively. The ranges of the heart/peripheral blood concentration ratio and gastric contents/peripheral blood concentration ratio were 0.3-10.6 (mean 3.4) and 3.4-402.4 (mean 86.0), respectively. From the difference of cyanide concentration and the concentration ratio of cyanide in different types of postmortem specimens, the possibility of the postmortem redistribution of cyanide and death by oral ingestion of cyanide could be confirmed. We reported cyanide fatal cases along with a review of literature.     

Methanol Detected in a Subdural Hematoma as an Embalming Artifact

Analysis of subdural hematomata has been used to suggest antemortem drug concentrations, with the assumption that materials within the hematoma are less subject to metabolism or degradation during any survival period and postmortem interval. We report the case of an 87‐year‐old woman whose death had not been reported to the coroner's office until postembalming. Autopsy revealed a traumatic brain injury with subdural hematoma causing a mass effect. Testing of the clot indicated a methanol concentration of 51.8 mg%. No additional analyses were detected. These findings suggest that methanol can be present in a postmortem hematoma sample, yet not represent a poisoning. Our findings also suggest that while the interior of hematomata do not necessarily represent completely “protected space” from postmortem diffusion of some blood constituents, such diffusion is not facile, and analysis may still provide useful indications of antemortem drugs present, if not actual concentrations.     

Elevated morphine concentrations determined during infant death investigations: artifacts of withdrawal of care

Abstract:  Three cases are reported of elevated postmortem blood morphine concentrations (189–3036 ng/mL) that were observed during the course of death investigations involving three children ranging in age from 1 week to 2 years, all of whom underwent withdrawal of life support. In all three cases, the presence of opiates in postmortem blood was indicated by immunoassay (ELISA) and quantitative confirmatory analysis of free morphine concentrations in postmortem blood was performed by solid-phase extraction followed by gas chromatography/mass spectrometry (GC/MS) in the selected ion monitoring mode. While the practice of withdrawing life support from terminally ill patients, with the accompanying administration of narcotics/analgesics has been reported in the medical literature, it has not been adequately described in the forensic literature. The implications of this practice on the forensic toxicological interpretation of morphine findings are discussed. To our knowledge, this is the first report of postmortem morphine concentrations arising directly from administration in conjunction with withdrawal of care in pediatric patients.     

Methadone-related deaths in Hennepin County,Minnesota: 1992-2002

Methadone maintenance therapy (MMT) is the only currently established medical therapy for heroin addiction. However, MMT still remains controversial. In Hennepin County, Minnesota, methadone is one of the top ten drugs reported in medical examiner investigated deaths and one of the most commonly diverted pharmaceuticals. This report reviews the role of methadone in medical examiner deaths over a 10-year period, 1992-2002. We compare cause and manner of death (accidental, natural, suicide) and methadone blood concentrations for decedents who were members of MMT programs with illicit users and those prescribed methadone for chronic pain. Findings reveal that 65% of decedents with measurable blood methadone concentrations were not participating in MMT programs. A total of 96 cases were identified, with the majority white (90.5%) and male (76.8%). MMTP program members were the minority (34.7%) of the methadone positive deaths and 39% were illicit users. Fifteen percent were chronic pain patients with almost half of this group dying from overdose. Methadone concentrations of drug caused/related deaths (0.18-3.99 mg/L) overlapped with those of deaths not attributable to methadone (0.18-3.03 mg/L) with no definable lethal level. Interpretation of methadone blood concentrations must be done in the context of the clinical history for determining cause of death, and may be confounded by postmortem redistribution.     

Unusual characteristic patterns of postmortem injuries

Animal scavenging is one of the most significant causes of postmortem injuries. A large variety of scavenging animals have been reported on in previous papers. Although postmortem injuries attributable to birds are well known in the case of "aerial burial," the custom in Tibet, few cases of bird scavenging have been reported. In the two cases discussed herein, postmortem injuries were attributed to crows. Both cases, shared characteristic patterns of postmortem injuries, and in both cases death was attributed to fire. Although massive tissue loss by the crow scavenging made it difficult to determine the cause of the death and rendered personal identification difficult, 1 mL of blood drawn from the intracranial cavity and DNA analysis enabled this information to be determined, albeit with some difficulty.