A review of methadone deaths in Jefferson County,Alabama

Interpretation of the concentration of a drug is more difficult when a combination of drugs is present in a decedent's blood. An increase in deaths resulting from co-intoxication with methadone and a benzodiazepine led the authors to perform a retrospective study of cases examined at the Jefferson County Coroner/Medical Examiner Office. They found 101 deaths wherein methadone was detected in the blood. Based on the drugs detected in the blood, these 101 cases were grouped into four categories: (1) pure methadone intoxication, (2) intoxication with methadone and benzodiazepine, (3) intoxication with methadone and other drugs excluding benzodiazepine, and (4) intoxication with methadone, benzodiazepines, and other drugs. Methadone was the sole intoxicant in 15 cases, with a mean concentration of 0.27 mg/L. Benzodiazepines were the most frequently detected co-intoxicant (60 of 101 cases). Benzodiazepine was the only co-intoxicant in 30 cases, and the mean methadone concentration in those 30 cases was 0.599 mg/L. Higher levels of methadone may occur in acute intoxication with methadone and benzodiazepine because benzodiazepines compete with methadone for methadone receptors. Higher levels of methadone may occur with chronic abuse of methadone and benzodiazepines because over time, benzodiazepines inhibit the hepatic enzymes that metabolize methadone.     

An unusual drug death involving maggots

Toxicologic analysis of decomposed specimens provides greater analytical challenges than those encountered with fresh postmortem specimens. Despite the difficulties involved, in cases in which the cause of death is not determined at autopsy or when there is a strong indication of drug intoxication, all reasonable steps must be undertaken to perform as comprehensive a drug screen as possible. An unidentified white male was found in a field near a river. The body was decomposed and skeletonized, and 3- to 4-mm maggots were present on the body. Near the body was an empty bottle of secobarbital that had been prescribed to a female. There was no evidence of injury. Calf muscle and maggots were sent for toxicologic analysis. No volatile substances or drugs were detected in the calf muscle. Because intoxication due to secobarbital was strongly suggested from the scene investigation, the only other specimen available, the maggots, were tested for acid-neutral drugs. Secobarbital was identified by retention time and was confirmed by full-scan electron ionization gas chromatography/mass spectrometry. Based on the available information, the medical examiner ruled that the cause of death was secobarbital intoxication and the manner of death was suicide.     

Acute intoxication with orphenadrine and clozapine.

This report describes a fatal intoxication with two different drugs: clozapine and orphenadrine. A 38-year-old man was found dead in the bedroom of his residence. Near the body were found various empty pharmaceutical boxes, employed in schizophrenic therapy, two of them containing clozapine and orphenadrine. High concentrations of clozapine and orphenadrine detected in blood, urine and gastric content were related to death. These compounds were identified and quantitated by liquid-liquid extraction followed by gas chromatographic/mass spectrometry (GC/MS) analysis.     

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.     

Fatality caused by a combined trimipramine-citalopram intoxication

A 53-year-old woman who was diagnosed as suffering from depression was found dead in her bed. The autopsy revealed no morphological changes sufficient to explain death. Toxicological analysis was performed and the drugs trimipramine (2.33 mg/l), citalopram (4.81 mg/l) and zolpidem (0.07 mg/l) were identified in the femoral blood. A combined drug intoxication resulting in synergistic effects to cardiovascular disorders was proposed as the cause of death. An acute overdose and suicide was suggested by calculation of the parent drug to main metabolite ratios in femoral blood and liver tissue. The trimipramine to desmethyltrimipramine ratios were calculated to be 2.06 and 3.18, the citalopram to desmethylcitalopram ratios were 1.96 and 2.02.     

Zolpidem distribution in postmortem cases

Zolpidem is the prototype of a class of sedative hypnotic drugs that are derivatives of imidazopyridine and is sold in the United States under the trade name Ambien. Over a four-year period, zolpidem was identified in eight cases investigated by the Office of the Chief Medical Examiner, State of Maryland. Zolpidem was identified by gas chromatography-nitrogen-phosphorus detection (GC-NPD) following an alkaline extraction and was confirmed by full-scan electron impact gas chromatography/mass spectrometry. Zolpidem was quantitated by GC-NPD in all specimens received. Five of the cases presented were deaths due to drug intoxication. In three of these cases, zolpidem was an incidental finding because the drug fatalities resulted from other drugs. In the other two cases of drug intoxication, zolpidem was present in elevated concentrations and was a contributing, but not exclusive cause of the drug intoxication. The remaining three cases were deaths that were not caused by drugs. The blood zolpidem concentrations in these cases were therapeutic (0.28, 0.12 and 0.19 mg/L, respectively). In six of the eight cases where both blood and urine were analyzed, the blood concentration was higher than the urine concentration. The distribution of zolpidem into the liver and kidney failed to identify any sequestration of the drug into either specimen.     

Production of intoxication states by actors--acoustic and temporal characteristics

This paper is the second of a series; the first has been published (J Forensic Sci, 1998;43:1153-62). The goal in the initial pair of experiments was to determine if speakers (actors) could effectively mimic the speech of intoxicated individuals and also volitionally reduce the degradation to their speech that resulted from severe inebriation. To this end, two highly controlled experiments involving 12 actor-speakers were carried out. It was found that, even when sober, nearly all of them were judged drunker (when pretending) than when they actually were severely intoxicated. In the second experiment, they tried to sound sober when highly intoxicated; here most were judged less inebriated than they were. The goal of this second paper is to identify some of the speech characteristics that allowed the subjects to achieve the cited illusions. The focus here is on four paralinguistic factors: fundamental frequency (F0), speaking rate, vocal intensity, and nonfluency level. For the simulation of intoxication study, it was found that F0 was raised along with increased intoxication but raised even more when this state was feigned. A slowing of speaking rate was associated with increasing intoxication, but this shift also was greater when the speaker simulated intoxication. The most striking contrast was found for the nonfluencies; they were doubled for actual intoxication, but quadrupled when intoxication was simulated. On the other hand, the shifts exhibited by the subjects when they attempted to sound sober were not as clear cut. Indeed, no systematic relationships were found here for either F0 or vocal intensity. Both speaking rate and the number of nonfluencies shifted appropriately, but these changes were not statistically significant. In sum, discernable suprasegmental relationships occurred for both studies (but especially the first); further, it is predicted that useful cues also will be found embedded in the segmentals (the sounds of speech).     

Cases of fatal poisoning in post-mortem examinations at the Institute of Forensic Medicine in Greifswald--analysis of five decades of post-mortems

Apparently, fatal poisoning as cause of death are still rarely found in unnatural deaths investigated in the institutes of forensic medicine. In the Institute of Forensic Medicine at the University of Greifswald, 10-15% of the post-mortem autopsies displayed an intoxication during the last several decades with a possible decreasing tendency. Thirteen thousand eight hundred and nineteen autopsies were carried out in our institute-situated in a low populated rural area-during the last 50 years with the confirmed death cause intoxication in 1,589 times. In this study, especially the intoxication causes and the substance classes of the poisonous agents have been investigated. In addition, we analyzed the frequency of intoxications as well as sex and age of the deceased. Surprisingly, CO-intoxications were found most frequently with an incidence of 49% followed by alcohol intoxications with 21%. The latter was not unexpected taking into account the habits of the local population. Medical drugs and narcotics take only the third place, although the abuse of modern narcotics drugs is already visible even in the far east of Germany. The spectrum of substances which are abused, taken accidentally or deliberately is continuously changing, reflecting scientific progress in the pharmaceutical industry as well as fashion tendencies. Therapeutic use is almost always followed by abuse. Our results confirm prior experience concentrating mostly on other poisons like heavy metals or herbicides, etc. In addition, we could demonstrate the influence of political conditions on use and distribution of illegal drugs in Germany. Our study clearly demonstrates that insufficient equipment or analytical methods are no longer the reason for any problems uncovering lethal intoxications. They are rather due to insufficient investigations of the corpses (without considering the possibility of an intoxication as differential diagnosis) and to frequent mistakes of the prosecutor's office in death without signs of physical violence. These facts may explain the above mentioned decreasing tendency of intoxications, but they also clarify that this tendency probably does not correspond to reality.     

Brain changes in parathion poisoning: observations in 42 cases

A total of 42 cases were examined neuropathologically to determine possible toxic changes occurring in the brain after parathion intoxication. Sporadic anoxic alterations were observed in 7% of 41 cases in which the cause of death was acute intoxication. Nearly all cases (93%), however, showed marked hyperemia, often coupled with small reactionsless, periventricular hemorrhages which occurred in 40% of the cases. In one third of the cases (33%) there was moderate swelling of the oligodendroglia. Whereas histological evidence of edema was found in nearly one third of the cases (30%), comparison of the brain weights in these subjects with those of a large comparative collective showed definite pathologic brain weights in only five cases (12%) with 95% confidence limits. It is true that in 18 cases (42%) the brain weight was above the normal value if the confidence limit is ignored. Pronounced anoxic alterations were observed in only one case in which the individual survived the acute intoxication for 4 weeks after initial respiratory arrest. Predominantly toxic changes, however, could not be detected in any of the cases examined. This negative morphologic finding does not agree with the physiologic alterations reported by other investigators using animal models; they considered the cause of death in cases of parathion intoxication to be the result of toxic paralysis of the respiratory center. The literature was discussed.     

Immunohistochemical investigation of pulmonary surfactant-associated protein A in fatal poisoning

To evaluate the immunohistochemical distribution of pulmonary surfactant-associated protein A (SP-A) in fatal poisoning in relation to the effects of drugs and poisons on respiratory function, 42 forensic autopsy cases were examined by scoring the staining intensity. The highest scores of SP-A staining, with dense granular deposits (aggregates) in the intra-alveolar space, were observed in fatalities from pancuronium bromide (muscle relaxant) injection and petroleum (butane) gas inhalation. Poisoning with organophosphate pesticides and arsenic (ingestion) showed a second grade SP-A score. However, The SP-A scores were relatively low in ethanol and sedative-hypnotic intoxication. Carbon monoxide intoxication showed a varied degree of SP-A score, and the aggregated SP-A score tended to be higher in cases of lower blood carboxyhemoglobin concentration. A varied SP-A score was also observed in methamphetamine fatalities, in which the score was relatively low in cases with a higher serum drug level. Increase of SP-A was not always associated with the intra-alveolar effusion or hemorrhages. The above-described observations suggested that the immunohistochemical score of SP-A may be a possible indication for intensity and duration of drug/poison-dependent respiratory distress.     

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.     

A sudden death with lung embolism after inadvertent infusion of zinc oxide shake lotion

A 74-year old woman in postoperative treatment after a colonic surgery died immediately after perfusion of about 1.5 mL of a white emulsion which was believed to contain 1% propofol via cardiac catheter into the right atrium. It was strongly suspected that a syringe with a zinc oxide shake lotion (consisting of 20% ZnO, 20% talc, 25% glycerol and 35% water) which was intended for external treatment had been mistaken for the propofol syringe. During autopsy, an anatomic cause of death could not be found. In order to exclude an intoxication and to determine the significance of the perfusion fluid in this context, toxicological and histological investigations were performed. Propofol and other drugs applied to the patient were found in therapeutic or sub-therapeutic range. However, in comparison to a control case, the zinc concentrations determined by AAS were about 200 times higher in lung tissue, 10 times higher in heart blood and 3–4 times higher in kidney and liver tissue. No increase was seen in venous blood. Histology showed a strong embolism of the lung tissue with birefingent sharp-edged crystals, which were identified as the talcum, and an amorphous component (ZnO). The same embolism was seen to a medium extent also in the brain sections and to a low extent in heart, liver, pancreas and kidney. Pulmonary embolism by talcum and zinc oxide was established as the cause of death which occurred by syringe swap due to insufficient security precautions in the drug administration. The results are discussed in context of pulmonary microembolism cases frequently described for drug addicts after injection of crashed talcum containing tablets.     

Ecstasy--deadly risk even outside rave parties

Fatalities due to 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") are rare in Austria, although the use of designer drugs has become quite common. This is the first published case of a fatal MDMA intoxication in Austria. A 19-year-old girl died after the consumption of ecstasy tablets in the apartment of a friend. Blood analysis gave a concentration of MDMA as 3.8 mg/L and traces of its metabolite MDA. Cannabinoids were found as well. This case shows that the consumption of MDMA, without physical stress, can lead to death.     

Detection of drugs using XAD-2 resin. I:Choice of resin, chromatographic conditions, and recovery studies

Amberlite XAD-2, a nonionic polystyrene divinylbenzene resin, was first used for the analysis of drugs in urine and a number of reports have described the development at optimal conditions for extraction, including type of resin columns, pH conditions, and eluting solvents. XAD-4 and XAD-7 resins were compared to the similarly structured XAD-2 resin and no significant advantage over the XAD-2 resin for drug screening was observed. A quantity of 5 to 6 g of resin was found to have sufficient capacity for the extraction of 200 ml of pentobarbital solution (1 mg/100ml). A column flow rate of approximately 15 ml/min (gravitational flow) was sufficient for analysis and slower rates were not more efficient. A mixture of ethyl acetate and 1,2-dichloroethane (3:2) was found to give best overall recovery (66 to 94%) of drugs, the resulting extracts being reasonably free of interfering substances. A pH value of 8.5 is recommended as optimum for comprehensive analysis of acidic and basic drugs. Recovery studies were conducted on spiked samples to determine drug losses occuring during various steps in the XAD-2 extraction procedure for four acidic (amobarbital, secobarbital, pentobarbital, and phenobarbital) and four basic (morphine, codeine, meperidine, and methadone) drugs. A relatively small amount (0 to 5%) of the drugs was not adsorbed by the resin and amounts varying from 6 to 40% failed to be desorbed by the eluting solvent. Additional losses occurred during the removal and analysis of TLC spots. Recovery of drugs from aqueous solutions analyzed with the XAD-2 resin were compared to recoveries reported in the literature with other XAD-2 resin methods for the extraction of drugs from urine. Recovery of phenobarbital, morphine, and codeine improved by 4 to 23% while recoveries of amobarbital, pentobarbital, secobarbital, methadone, and meperidine were 4 to 28% less efficient when compared to literature data.     

Acute intoxication with guaifenesin, diphenhydramine, and chlorpheniramine.

Mixed drug reactions are frequently encountered in emergency department overdose cases and also in fatal intoxications. Assessment of the relative contribution of each drug in producing adverse effects is often compounded by lack of case history and the paucity of cases reported in the literature. This report describes a fatal intoxication with three common over-the-counter medications: guaifenesin, diphenhydramine, and chlorpheniramine. A 48-year-old woman was found dead in the attic bedroom of her residence. Specimens obtained at autopsy for toxicologic analysis included heart blood, urine, bile, gastric contents, vitreous humor, and cerebrospinal fluid. The over-the-counter drugs were identified and quantitated by acid/neutral or basic liquid-liquid extraction followed by gas chromatographic analysis with nitrogen phosphorus detection. Concentrations of guaifenesin, diphenhydramine, and chlorpheniramine detected in the heart blood were 27.4, 8.8, and 0.2 mg/L, respectively. The cause of death was determined to be acute intoxication by the combined effects of guaifenesin, diphenhydramine, and chlorpheniramine, and the manner of death was determined to be suicide. To our knowledge, the blood guaifenesin concentration in this case is the highest reported concentration to date associated with an acute intoxication.     

The influence of hypnotics on the development of morphological and biochemical wound reaction (author's transl)]

The influence of hypnotics (barbital and carbromal) on the development of the early wound reactions in mechanically injured skin of guinea pigs was investigated: 1) The cellular reactions in incised wounds were retarded after moderate intoxication by hypnotics (300 mg/kg barbital; 3 g/kg carbromal). The histomorphological changes in wounds were inhibited by carbromal twice as much as by barbital. The hitherto published investigations had not shown any retardation of the early cellular inflammation by weakening influences such as loss of blood or alcohol without symptoms of shock (Berg et al., 1977) or local disturbances by acids and bases (Kampmann et al., 1978). 2). A moderate delay of the activity of structure bound enzymes was found in barbital intoxication, a stronger restriction under the influence of carbromal. 3) After barbital intoxication significant elevation of histamine or serotonin in wounds was not seen. Under the influence of carbromal there was also no increase of histamine but an increase of serotonin. Thus, although the cellular reactions seem to be the most reliable indicator among the methods for the determinations of wound age under devitalizing influences, their value is reduced in cases of intoxications by hypnotics needing treatment. Possible pathophysiological connections of the alterations of morphological and biochemical wound reaction with shock are discussed.     

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.     

A fatal doxepin poisoning associated with a defective CYP2D6 genotype

It has been suggested that the polymorphism of the CYP2D6 gene can contribute to occurrence of fatal adverse effects. We therefore investigated postmortem toxicology cases of fatal drug poisonings related to CYP2D6 substrates, with the manner of death denoted as accidental or undetermined. CYP2D6 genotypes were determined in 11 consecutive cases with samples available for DNA analysis. A case of fatal doxepin poisoning with an undetermined manner of death was found to coincide with a completely nonfunctional CYP2D6 genotype (*3/*4), indicating a total absence of CYP2D6 enzyme and suggesting a poor metabolizer phenotype. The doxepin concentration was 2.4 mg/L, the concentration of nordoxepin 2.9 mg/L, and the doxepin/nordoxepin ratio 0.83, the lowest found among the 35 nordoxepin-positive postmortem cases analyzed during the same year. No alcohols or other drugs were detected in the case. The CYP2C19 genotype was determined as that of an extensive metabolizer. The high N-desmethylmetabolite concentration is not consistent with acute intoxication. It is therefore probable that the defective genotype has contributed to the death, possibly involving repeated high dosage of doxepin. Our case strongly emphasizes that a pharmacogenetic analysis in postmortem forensic setting may reveal new insight to the cause or manner of death.     

The 'break enter and die' syndrome may involve significant injury to major neck vessels

Death from incised wounds of major vessels may occur during illegal entry of premises. Wounds are often relatively unimpressive having been caused by thin shards of glass. Alcohol and/or drugs have often been taken that have impaired coordination and contributed to a failure to take appropriate action. A 37-year-old man slipped and fell while attempting to enter a house through a window that he had just broken. He was found dead surrounded by a large amount of blood. At autopsy, a single horizontal, deeply incised wound of the anterior neck was present with transection of the internal jugular veins bilaterally and the right common carotid artery. Toxicological studies were negative for alcohol and common drugs. Death was due to exsanguination and air embolism. This case demonstrates that the injuries sustained during such activities may be quite extensive and involve major neck vessels. Alcohol and drug intoxication are not necessarily involved.     

Drug deposition in adipose tissue and skin: evidence for an alternative source of positive sweat patch tests

In a series of licit and illicit drug-related deaths, qualitative and quantitative analyses on extracts of adipose tissue and skin were performed by GC/MS. In all cases, the adipose tissue was found to contain drugs at concentrations lower than, approximately equal to, or even greater than the concentrations of the same analytes found in the blood, which may reflect a consequence of long-term chronic exposure, or acute intoxication, or some combination of both. Approximately one cubic inch of skin with adipose tissue was removed from the mid to lower abdominal region adjacent to the midline incision during autopsy. The drugs were recovered from the specimens following incubation and alkaline, acidic, and alkaline chloroform back extraction of one to three grams of tissue. Deuterated analogs of the analytes were added to the matrix at the beginning of the incubation period. Cocaine and free morphine (from heroin) were readily identified in several cases. The presence of these illicit drugs in adipose tissue raises significant forensic questions, especially the use of 'sweat patches' to monitor recent cocaine or heroin use in chronic drug users.