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.     

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.     

Methadone-related deaths in Norway

IntroductionThe use of methadone in opioid maintenance treatment (OMT) is potentially associated with a number of adverse effects and the risk of fatal toxicity. Increased methadone availability may lead to an increase in methadone-related deaths. We have investigated methadone-related deaths in Norway over the period 2000–2006.Materials and methodsMethadone-positive samples over the period 2000–2006 were identified from forensic toxicological investigations, and demographic and toxicological data were retrieved. The cases were cross-linked with the Norwegian Cause of Death Registry and regional OMT registers.ResultsA total of 312 individuals had died after taking methadone over the period 2000–2006, predominantly men with a mean age of 36. In 85% of cases (n = 264), the deceased had died of a methadone-related intoxication, most often in combination with other drugs, including benzodiazepines, cannabis and other opioids. Only 22% of the deceased had been in OMT at the time of death. A larger proportion of OMT patients had died of causes other than intoxications compared to those not in OMT (30% vs. 8%, respectively), most commonly related to disease.ConclusionsOne methadone-related death occurred, on average, every week over the time period investigated. Only 22% of the deceased were registered in opioid maintenance treatment (OMT) programs. The findings underline the need to control diversion of medication from OMT programs.     

Prevalence of nicotine consumption in drug deaths

One hundred consecutive drug death victims autopsied at the Institute of Forensic Medicine, University of Freiburg, between 1995 and 1997 were studied retrospectively as to whether the drug users had also consumed nicotine. The study included histological examination of the lung tissue for smoker cells and radioimmunological as well as GC-MS assays of the urine for cotinine, the primary metabolite of nicotine. It was found that 98 out of 100 drug victims had consumed nicotine in addition to illicit drugs or replacements. Yellowish-brown discolorations on the middle and index fingers were discernible in 44 drug victims, whereas fresh or scarred burns due to glowing cigarettes were found in six deceased drug consumers. Diseases of the bronchial system typical of heavy smokers were seen in 35 cases. Siderophages could be demonstrated in 17 of the 100 drug deaths.     

Investigations on the cause of death in a polytoxicomanic patient treated with wires and intermaxillary fixation for a chronic, infected mandibular fracture

The case of a 36-year-old male and former patient is presented who died for initially unknown reasons, with intermaxillary wire fixation for the treatment of an infected mandibular fracture still in place. The combined investigation of forensic experts and maxillofacial surgeons excluded aspiration and asphyxia as cause of death. Evidence was found for lethal methadone concentrations after intravenous drug abuse and a broncho pneumonia. Despite the clear evidence of a fatal intoxication in this case, caution must be exercised when dealing with individuals carrying intermaxillary fixation.     

Forensic aspects of water intoxication: four case reports and review of relevant literature

Water intoxication (WI) is a rare condition that originates from over-consumption of water, with a potentially fatal outcome. Increased water intake (polydipsia) is followed by urination of high amount of diluted urine (polyuria) which are the main initial symptoms of WI. We present four case reports of WI. Two of them are unusual pediatric clinical cases using medical documentation and police case files, one of which is related to child abuse, and the other to a psychiatric disorder. The other two cases are fatal adult cases submitted to autopsy from a psychiatric hospital. Also, we present a diagnostic algorithm for polydipsia and polyuria before death. WI is usually seen in patients with psychiatric disorders, victims of child abuse or torture, drug abusers or it can be iatrogenically induced.     

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.     

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.     

Drug abuse in western Denmark during the eighties. II. Fatal poisonings among drug abusers.

Cases of fatal poisoning among drug addicts (n = 246) and abusers of medical drugs (n = 138) are discussed on the basis of the availability of illicit and medical drugs during the eighties. Propoxyphene was frequently the cause of death among both drug addicts and abusers of medical drugs. Deaths caused by analgesics and psychoactive drugs, mainly barbiturates and antidepressants, predominated among abusers of medical drugs. During the late eighties the number of deaths caused by barbiturates and propoxyphene declined as a result of changes in the distribution regulations for both drugs. Heroin/morphine accounted for only one-third of the poisonings in drug addicts. No trends concerning the prevalence of deaths caused by these drugs were observed throughout the decade. The number of deaths caused by the synthetic opiates methadone and ketobemidone, however, increased during the late eighties, probably due to an increased availability of these drugs in the illicit drug market. Alcohol was detected in half of all the poisoning cases and benzodiazepines in one-third.     

Trends and pattern of drug abuse deaths in Maryland teenagers

The Office of the Chief Medical Examiner of Maryland recorded a total of 149 drug abuse deaths of teenagers aged 13-19 years between 1991 and 2006. Of these deaths, 96 (64.4%) were caused by the use of narcotic drugs only, 29 (19.5%) by both narcotics and cocaine, four (2.7%) by both narcotics and methylenedioxymethamphetamine, six (4.0%) by cocaine only, and 14 (9.4%) by volatile substances (e.g., butane, Freon, nitrous oxide, and propane). The annual death rate from drug abuse for teenagers increased from 1.4 deaths per 100,000 population in 1991 to 2.7 deaths per 100,000 population in 2006 (chi-square test for time trend, p<0.01). The increase in teenager drug abuse deaths occurred in 1999 and since has remained at a higher rate. Further analysis revealed that the increase in drug abuse deaths was attributable to a large degree to narcotic drugs, particularly heroin/morphine and methadone, and was confined to teenagers residing in the suburban and rural areas.     

Fatal intoxications in the age group 15-34 years in Denmark in 1984 and 1985. A forensic study with special reference to drug addicts

This survey deals with the Danish part of a study on fatal intoxications conducted in the Nordic countries in 1984 and 1985 with special reference to drug addicts. There were 315 cases of fatal intoxications in people 15-34 years of age. These were examined at the Forensic Institutes in Denmark and described with reference to cause of death, sex, age and drug addiction. Of the deceased, 194 were drug addicts according to a specific definition of this term. Women accounted for 28% of all the fatalities investigated in the study and 24% of those in addicts. More than 90% of the deaths were caused by drugs, with ethanol as a contributory factor in approximately 40% of cases. Deaths caused by heroin/morphine predominated, causing 50% of the deaths among drug addicts, but legal drugs, such as dextropropoxyphene, methadone and ketobemidone were also frequent causes of death in this group. In half the cases the concentration of morphine in blood following injection of heroin/morphine was found to be equal to or less than 0.5 mumol/kg, and in only about one-tenth of cases was the blood concentration above 2.0 mumol/kg.     

Drugs and chronic alcohol abuse in drivers

Blood specimens from 210 drivers (179 male and 31 female) apprehended in Luxembourg from autumn 2001 to spring 2002 and requested for the determination of their blood alcohol concentration (BAC) were tested for medicinal drugs, illicit drugs, and chronic alcohol abuse (by quantification of the carbohydrate-deficient transferrin: CDT). These additional analyses were performed anonymously and with permission of state prosecutor. The 22.8% had consumed medicinal drugs, with benzodiazepines and antidepressants (10.9 and 7.6%, respectively) as main psychoactive classes. Cannabis was the most detected illicit drug (9.5%) but only one in three had THC detectable in their blood. Association of two or more psychoactive substances (poly-drug use) was observed in 27.6% of drivers (90.6% of drug consumers). On the basis of CDT values, 29.5% of drivers investigated were assumed to be chronic alcohol abusers. Statistical analysis revealed that chronic alcohol abuse and medicinal psychoactive drugs were associated with significantly higher BAC. Medicinal psychoactive drugs were clearly associated with poly-drug use, and were furthermore detected at supra-therapeutic levels in 34.9%.     

Toxicology and sudden infant death

One hundred thirty cases of sudden infant death occurring in Wayne County, Michigan, (population 2.7 million) were analyzed for possible drugs. The toxicological protocol has been outlined. Six cases were found to be positive, and in five of these the drugs found had been prescribed for a variety of illnesses. In one case methadone was found in the blood of an infant whose mother was undergoing methadone treatment for drug addiction, the drug being transmitted through breast milk. In none of the 102 cases of sudden infant death syndrome (SIDS) included in the study did the toxicological results affect the diagnosis. In our study, toxicological analyses never contradicted an initial diagnosis of SIDS, and, therefore, we feel that this diagnosis should be made promptly based on investigative and autopsy findings.     

Cause of death and drug use pattern in deceased drug addicts in Sweden, 2002-2003

Compared with their contemporaries, individuals abusing illicit drugs suffer a higher risk of premature death. In Sweden, a simple protocol for registration of fatalities among abusers of alcohol, pharmaceuticals, illicit drugs, or other substances, has been used by the forensic pathologists since 2001. This routine was introduced to allow for an evaluation of the cause and manner of death, and patterns of abuse among different groups of abusers. We explored the data on drug abusers (i.e. abusers of illicit drugs) subjected to a forensic autopsy 2002-2003. The Swedish forensic pathologists examined 10,273 dead victims during the study period and 7% (743/10,273) of the cases were classified as drug abusers. Toxicological analyses were carried out in 99% (736/743) and illicit drugs were detected in 70% (514/736) of these. On average, 3.8 substances (legal or illegal) were found per case. The most common substances were ethanol and morphine, detected in 43 and 35% of the cases, respectively. When exploring the importance of the different substances for the cause of death, we found that the detection of some substances, such as fentanyl and morphine, strongly indicated a poisoning, whereas certain other substances, such as benzodiazepines more often were incidental findings. In total, 50% (372/743) died of poisoning, whereas only 22% (161/743) died of natural causes. Death was considered to be directly or indirectly due to drug abuse in 47% (346/743), whereas evidence of drug abuse was an incidental finding in 21% (153/743) or based on case history alone in 33% (244/743). We believe that this strategy to prospectively categorize deaths among drug addicts constitutes a simple means of standardizing the surveillance of the death toll among drug addicts that could allow for comparisons over time and between countries.     

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.