One hundred seventy two deaths involving the use of oxycodone in Palm Beach County

Oxycodone is a potent semi-synthetic narcotic prescribed for the management of pain. Previous investigators have reported that the abuse of oxycodone is most frequently seen in conjunction with the abuse of other drugs, although fatalities have been reported with oxycodone alone. We undertook a retrospective review of cases investigated by the Palm Beach County Medical Examiner's Office in which postmortem toxicologic studies indicated the presence of oxycodone. A total of 172 consecutive cases were studied, including 18 in which death was attributed to oxycodone toxicity, 117 to combined drug toxicity, 23 to trauma, 9 to natural causes and 5 to another drug or drugs. The postmortem blood concentrations of oxycodone overlapped among the groups. The mean blood oxycodone concentration among the cases of oxycodone toxicity was 0.69 mg/L, combined drug toxicity 0.72 mg/L and trauma 0.62 mg/L. Concentrations were lower in cases of deaths attributed to natural causes and to another drug or drugs (mean each 0.087 mg/L). Benzodiazepines, detected in 96 cases, were the most common co-intoxicants in the cases of combined drug toxicity, followed by cocaine, which was found in 41. The most frequently encountered benzodiazepine was alprazolam. This study confirms that deaths in which oxycodone is a factor are most commonly cases of combined drug toxicity. The high incidence of alprazolam as a co-intoxicant has not been previously recognized.     

Postmortem forensic toxicology of trazodone

Trazodone is a popular antidepressant medication that has been available for approximately 30 years. It has a reputation as a safe drug with relatively few reported fatalities attributed solely to it. We review the pharmacology and forensic toxicology of trazodone and report toxicology and cause and manner of death in a series of 37 deaths in which trazodone was detected. Although the normal upper therapeutic blood concentration for trazodone is about 2 mg/L, fatalities are rarely attributed solely to it at blood concentrations below 9 mg/L. Considering the pharmacology of the drug, potential interactions between other drugs with serotonin reuptake properties need to be considered, as does the increased susceptibility to the toxic effects in patients with pre-existing heart disease. In the cases reviewed, none were attributed solely to trazodone, although trazodone was frequently present together with other serotonergic drugs, such as the selective serotonin reuptake inhibitors like fluoxetine and sertraline. Ten cases had blood trazodone concentrations above 2 mg/L. Of these cases, trazodone played a primary role in the death of three subjects, with blood concentrations all greater than 9 mg/L. We confirm the conclusions of others that trazodone is a relatively safe drug except in massive overdose, although its toxicity may be influenced by the presence of other drugs and underlying pathophysiology.     

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.     

Death of an infant involving benzocaine

This report describes the death of a four-month-old Hispanic male which may be related to benzocaine toxicity. A toxicological evaluation revealed benzocaine at a concentration of 3.48 mg/L, and postmortem methemoglobin of 36% (normal 0.4-1.5). Methemoglobinemia is a complication of benzocaine toxicity. In light of the toxicology findings, the coroner investigated the source of the benzocaine and discovered that the child was treated with Zenith Goldline Allergen Ear Drops containing 0.25% w/v benzocaine and 5.4% w/v antipyrine. There was an admission by a caregiver that on the day prior to the child's death, he had been treated with three times the prescribed dose. Blood benzocaine concentrations in nine other unrelated cases were determined and concentrations ranged from <0.05-5.3 mg/L (mean 1.48 mg/L). Seven of the nine cases were positive for drugs of abuse, and one additional case was described as a known drug user. Methemoglobin in these benzocaine positive cases ranged from 6-69%; however, methemoglobin concentrations in postmortem cases are frequently elevated and should be interpreted with caution. The unknown significance of the benzocaine, and the circumstances of the case raise questions about the ultimate attribution of this death to SIDS.     

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.     

Flunitrazepam: an evaluation of use, abuse and toxicity.

The benzodiazepine flunitrazepam is extensively prescribed to patients with insomnia in many countries, but has also become popular among alcohol- and drug abusers. Several reports indicate that it is used as a date rape drug and suggest that it may precipitate violent behavior. Furthermore, flunitrazepam is involved in many fatal intoxications in Sweden. This study was designed and conducted to explore the negative consequences of flunitrazepam abuse in Sweden, and to assess the trends in its use and abuse. The occurrence of flunitrazepam in cases referred to the Department of Forensic Chemistry in Link?ping, Sweden 1992-1998, was investigated in detail. The detections were studied separately for different groups; medicolegal death investigations, drug abuse cases, driving under influence cases, and other medicolegal cases. These data were further compared with the sales, and seizures by the Swedish Customs and the Swedish Police. During 1992-1998, 641 fatalities occurred, where the cause of death was attributed to intoxication with flunitrazepam solely (130) or in combination with other drugs, or concomitant conditions (511). In 78% of all driving under influence cases, where flunitrazepam was detected, the analyses also disclosed the presence of illicit drugs. A similar association was seen in drug abuse cases. The seizures reported by the Swedish Customs revealed a substantial and increasing illegal trade. Cases, where flunitrazepam seemingly induced violent behavior were identified, and one of these is described in some detail. It is concluded that the abuse pattern and the toxicity of flunitrazepam should be kept in mind by forensic investigators and that this panorama also should be considered when decisions about the registration and classification of flunitrazepam are made in different countries.     

Fatal intoxications in a Swedish forensic autopsy material during 1992-2002

Compilations of substances detected in fatal intoxications are important in order to observe changes in intoxication patterns, to monitor effects of preventive work and to discover new trends in drug usage. The aim of the present study was to describe the current pattern of substances detected in fatal intoxications in Sweden. Fatal intoxications investigated at the Department of Forensic Chemistry, Link?ping, Sweden, during 1992-2002, were analysed. All suicides, uncertain cases and accidents where the cause of death were fatal intoxications (ICD-9: E950, E980 and E859) were included and substances detected in more than 50 fatal intoxications (in femoral blood) were listed. For each substance, a cut off value was set, above which concentrations were considered toxic. Fatal intoxications were detected by forensic-chemical analyses in 12% (6998/60,314) of the forensic autopsies during the study period. Among the suicides, an average of 3.8 substances were detected per case, the corresponding figure for uncertain cases and accidents were 3.5 and 4.1 substances, respectively. Ethanol was by far the most frequently detected substance, detected in 43% (3039) of the fatal intoxications, of which 32% (960) had toxic concentrations, followed by propoxyphene, detected in 27% (1863) of the fatal intoxications of which 74% (1370) had toxic concentrations. The number of cases where ethanol and propoxyphene were detected decreased during the study period. Moreover, other CNS-active drugs such as antidepressants, analgesics and anxiolytics were also frequently detected. The drugs with high proportions of cases with toxic concentrations detected were propoxyphene, amitriptyline, zolpidem, carisoprodol, alprazolam, thioridazine, methadone and ketobemidone. Selective serotonin reuptake inhibitors (SSRI) and tricyclic antidepressants (TCA) were detected in 12% (833) and 10% (665), respectively. A significantly (P <0.001) higher proportion of cases where TCA were detected had toxic concentrations when compared with cases where SSRI were detected (64% versus 31%).     

Increasing Methamphetamine Detection in Cases of Early Childhood Fatalities

Age and organ maturity can influence drug toxicity in children; however, most clinical data and literature are based on drug concentrations in adults. Therefore, the interpretation of drugs detected in children is often difficult or not possible. Retrospective reviewing of pathology and toxicology information from postmortem cases may assist in future interpretations or identify drug trends. A search of the Forensic Science SA case files was undertaken over 15 years from January 2002 to December 2016 for all children (<13 years). Of the 412 pediatric coronial cases, toxicological information was available on 373. At least one drug was detected in 94 cases with paracetamol, ibuprofen, codeine and hospital-administrated lignocaine and morphine among the most commonly detected agents. Methamphetamine, one of the most commonly abused illicit drugs in Australia, was found in seven cases. In the methamphetamine cases, deaths were associated with shared sleeping in three, pneumonia in one, and stillbirth in one. Methamphetamine was considered potentially contributory to death in two cases. The causes of death in the remaining two cases were undetermined. As six of the seven positive cases occurred in the 2012–2016 (n = 106) timeframe, an increase has occurred over recent years in the number of infants and young children presenting to forensic autopsy in South Australia who have detectable concentrations of methamphetamine. If this is an indication of a more generalized increased childhood exposure in the community there may be significant long-term physical and psychological effects.     

Postmortem investigation of lamotrigine concentrations

Lamotrigine is a relatively new anticonvulsant. Therapeutic plasma concentrations generally range from 1 to 4 mg/L, although several studies have shown that good control of epilepsy has been achieved with concentrations reaching 10 mg/L generally, with little toxicity. In overdose, however, the drug has been linked to ECG changes that may suggest a possible arrythmogenic effect and hence cardiac toxicity. Lamotrigine has also been shown to cause encephalopathy and thus neurotoxicity. There is no information concerning postmortem lamotrigine concentrations and their interpretation. We describe lamotrigine concentrations in postmortem specimens including blood, liver, bile, vitreous humour, and urine from eight cases. A high performance liquid chromatography (HPLC) method is described with extraction procedures for the various tissues. Two possible groups were identified. The first being the "broader therapeutic" group with blood concentrations ranging from 0.9 to 7.2 mg/L and corresponding liver concentrations ranging from 16 to 36 mg/kg. The second being a "supratherapeutic" group with blood concentrations ranging from 20 to 39 mg/L and corresponding liver concentrations ranging from 53 to 350 mg/kg. Although none of the eight cases described were attributed to overdose by lamotrigine alone, the cause of death for one of the three cases in the "supratherapeutic" group was given as mixed drug toxicity. Cause of death for the remaining two cases in this group was reported as epilepsy. However, both these cases showed elevated concentrations of lamotrigine and both were co-medicated with valproic acid. Such co-administration has been shown in the literature to lead to elevated lamotrigine concentrations and a reduction in lamotrigine dose has been recommended. With such data, we highlight the importance of monitoring lamotrigine concentrations in cases co-medicated, particularly with valproic acid.     

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.     

Drugged drivers in Norway with benzodiazepine detections

Norwegian drugged drivers with benzodiazepine (BZD) detections have been studied with regard to drug use pattern and rearrest rate. During 1995, 3343 drivers were apprehended by the police in Norway due to the suspicion of influence by drugs. Blood samples from all drivers were sent to the National Institute of Forensic Toxicology (NIFT). The samples were analysed using a standard program covering the most commonly abused drugs on the marked in Norway. BZDs, representing some of the most frequently detected drugs, were found in approximately 30% (n = 1051) of the cases, represented by 14% (n = 150) female and 86% (n = 901) male drivers. In 8% of the cases, one BZD only was detected, half of these cases with one BZD could reflect therapeutic use. One or more BZDs were combined with illegal drug(s) (73%), other prescribed drugs (10%), and/or alcohol (24%). 62% of the drivers with BZD detections, had earlier been arrested for the same offence, or six cases per rearrested driver. The frequency of earlier arrests were lower for female (34%) than for male (67%) drivers. Alcohol was most frequently found for those arrested for the first time before 1992, while BZD or illegal drugs were most frequently found for those with their first arrest during 1992-1995. Our study shows that apprehended drivers using BZD are mainly represented by drug abusers due to frequent multi-drug use, blood concentrations representing doses above therapeutic levels and high rearrest rate for the same offence. A treatment program or other reactions, are thus necessary in addition to fines, prison penalty and suspension of driving licence.     

Concentrations of Opiates and Psychotropic Agents in Polydrug Overdoses: A Surprising Correlation Between Morphine and Antidepressants

Abstract: The relationship between postmortem concentrations of morphine and co‐detected psychoactive drugs in fatal overdoses is examined. Morphine and other drugs were detected in 161 medicolegal autopsy cases. Subsets of these morphine‐positive cases based on drug class were established, including opioids, antidepressants, ethanol, benzodiazepines, and “other.” Each subset was split into high or low concentration groups based on median drug concentrations. Morphine concentrations of the [high] and [low] groups were compared, with no significant difference in morphine concentration identified in the opioid, ethanol, or benzodiazepine subsets. The “other” drug class was too heterogeneous for statistical assessment. Morphine concentrations did show a significant direct relationship (p = 0.01) with antidepressants, namely increased concentrations of antidepressant drugs are associated with an increased concentration of morphine. This trend probably remains even after excluding cocaine‐positive cases. The unsuspected finding that postmortem concentrations of antidepressants positively correlate with morphine levels may be important in the treatment of depression in drug addicts.     

The predictive value of history and scene investigation for toxicology results in a medical examiner population

Medical examiner offices vary in the extent to which they pursue postmortem toxicology. Our office routinely tests decedents for ethanol and drugs of abuse, and we decided to evaluate the usefulness of our practice. We reviewed 1180 medical examiner cases examined in 2002-2003. History and scene investigation indicated that alcohol or drugs of abuse were likely to be detected in 369 cases, yet toxicology testing revealed an intoxicating substance in 589 cases, a prevalence of 50%. Screening for toxicology testing based on investigative findings had a sensitivity of 0.47, a specificity of 0.84, and a positive predictive value of 0.74. Moreover, even in the 811 cases where initial investigation did not suggest substance abuse, toxicology testing revealed at least 1 substance that was pertinent to the subsequent investigation in one third of the cases (260), and the intoxicating substance was sufficiently important to merit inclusion as a cause of death or contributing factor in nearly half of those cases (113). We conclude that investigation alone is ineffective at predicting the presence of intoxicating substances within decedents.     

K2 Toxicity: Fatal Case of Psychiatric Complications Following AM2201 Exposure

Limited forensic and clinical experience and the lack of confirmatory testing strategies for synthetic cannabinoids (SC) prevent adequate characterization of SC toxicity and the potential impact on public health. A statewide surveillance system identified a fatality involving a 23‐year‐old man found with a large stab wound to the neck following use of a SC product suspected of containing AM2201. Analytical testing for common SCs, SC metabolites, routine drugs of abuse, and over‐the‐counter medications was performed on heart blood obtained at autopsy. Additionally, assays were performed on the SC raw material and drug paraphernalia found on the decedent. High concentrations of AM2201 were detected in all samples. AM2201 metabolites were detected in postmortem blood. Other than a trace amount of JWH‐073 found in smoke residue, no other substances were detected. Psychiatric complications including self‐induced, lethal trauma can occur after the use of SC products.     

Fatal unintentional intoxications with tramadol during 1995-2005

Tramadol is an extensively used centrally acting analgesic and is considered a safe drug devoid of many serious adverse effects of traditional opioids. However, recently, toxicity and an abuse potential of tramadol have been reported. This study examined fatal unintentional tramadol intoxications among Swedish forensic autopsy cases between 1995 and 2005. All fatal intoxications were selected, in which toxic concentrations of tramadol (>1 microg/g femoral blood) had been detected, and where the forensic pathologist considered the intoxication unintentional and the fatal outcome at least partly explained by tramadol. Toxicology analyses, police reports, autopsy protocols and medical records were scrutinized. A total of 17 cases (eleven men and six women) of fatal unintentional tramadol intoxications were identified. For these cases the median age was 44 years (range 18-78 years) and the median tramadol concentration was 2.0 microg/g (range 1.1-12.0 microg/g). Other pharmaceutical substances, illicit drugs or ethanol were detected in addition to tramadol in all of these cases. In fact, intoxication with multiple drugs was considered the cause of death in 10 (59%) cases. However, in seven cases tramadol was the only substance present in toxic concentrations. A history of substance abuse was identified in 14 (82%) subjects and a present tramadol abuse in 8 (47%). These results suggest that fatal intoxications with tramadol may occur unintentionally and that subjects with a history of substance abuse may be at certain risk. Precaution is therefore warranted when prescribing tramadol in such patients.     

Determining the Toxicological Significance of Pregabalin in Fatalities

Pregabalin has become more widely prescribed and abused in recent years but is still not always included in laboratory analysis. An LC‐MS‐MS method has been developed and applied to measure pregabalin in 93 postmortem cases, including drug‐related deaths, alternative causes of death, and fatalities where pregabalin was likely to have contributed to death. Other drugs or alcohol was detected, and the most common drug types (in decreasing frequency) were antidepressants, opioids, benzodiazepines, opiates, alcohol, antipsychotics, cocaine, cardiac drugs, amphetamines, cannabis, anticonvulsants, and antihistamines. New psychoactive substances (methoxphenidine and synthetic cannabinoids) were only found in two cases. The results provide further data to assist in evaluating the significance of postmortem pregabalin concentrations and a toxicologically significant concentration of 25 mg/L is proposed. Pregabalin, especially with concomitant use of other CNS depressant drugs, presents a significant toxicological risk and existing laboratory protocols should be reviewed for their suitability to detect pregabalin.