Fatal intoxication due to tramadol alone: case report and review of the literature

Poisoning may also lead to both coma and multiple organ failure, also in youngsters without a known major medical history. As not all toxic agents are routinely screened when a poisoning is suspected, it is useful to consider less frequently encountered poisons in certain cases. We describe the occurrence of asystole and multiple organ failure which occurred in a young man after a suspected tramadol overdose. The tramadol concentration on admission in the ICU was indeed 8 microg/ml (mg/l), far above the therapeutic range. Subsequently, the patient developed severe acute liver failure, finally leading to death. Post-mortem toxicology did not reveal any other poison responsible for this unfavourable course as only very high serum and tissue tramadol and desmethyltramadol concentrations were found. Only a few fatal poisonings attributable to tramadol alone, as observed in our case, have been reported. An overview of these cases is presented.     

Fatality due to ingestion of tramadol alone

A rare case of a fatal intoxication in an adult with tramadol alone is reported. In the peripheral blood, tramadol was measured in a concentration of 9.6 mg/l exceeded at least 30-times the normal therapeutic range of 0.1-0.3 mg/l. The concentration of tramadol in liver and kidney, in relation to blood, failed to suggest a major sequestration of drug in either specimen which is consistent with the volume of distribution of 3 l/kg. The concentration of tramadol in the heart and peripheral blood specimens did not suggest a major difference (ratio of 1.36). Similar to morphine tramadol was accumulated significantly in the bile.     

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.     

Tramadol (Ultram) concentrations in death investigation and impaired driving cases and their significance

We reviewed a series of 66 deaths in Washington State between 1995-2000 in which tramadol (Ultram and Ultracet, Ortho-McNeil) was detected in the decedent's blood, in order to assess the role tramadol was determined to have played. Additionally, we reviewed a series of 83 impaired driving cases in which tramadol was detected in order to establish a non-lethal blood tramadol concentration reference range. In both populations, tramadol was consistently found together with other analgesic, muscle relaxant, and CNS depressant drugs. Death was rarely attributable to tramadol alone. However, tramadol may be a significant contributor to lethal intoxication when taken in excess with other drugs, via the potential interaction with serotonergic antidepressant medications, as well as the potential for increased CNS depression. Although the incidence of tramadol detection has increased consistently over the last eight years, there is no evidence of a corresponding increase in the number of cases in which death was attributed solely to tramadol. Blood drug concentrations in many deaths exceeded the therapeutic serum range of 0.28-0.61 mg/L; however, the concentrations overlapped almost completely with the range identified in living subjects arrested for impaired driving. These findings suggest caution in the interpretation of blood tramadol concentrations outside of the recognized therapeutic range. It also suggests that the drug, even when used in moderate excess, is not a principle cause of death in suicidal or accidental deaths.     

Multidrug poisoning involving nicotine and tramadol

A fatal case of multidrug poisoning by tramadol and nicotine is reported. Tramadol is a centrally acting analgesic used in the treatment of moderate to severe acute or chronic pain. Nicotine, a lipid-soluble alkaloid, is one of the most readily available drugs in modern society. A 46-year-old man was found dead in his bed, and a suicide note was discovered near the body. He had 25 transdermal nicotine patches attached to his thorax and abdomen. Two half emptied bottles were found on the bedside table; the toxicological examination revealed that they contained tobacco and nicotine as well as other drugs such as diphenhydramine. At autopsy, areas of fresh and old myocardial infarction as well as diffuse pulmonary congestion and edema were present. The tramadol concentration was 6.6 μg/mL in femoral venous blood, while levels of nicotine and its primary metabolite cotinine were determined to be 0.6 and 2.0 μg/mL in femoral venous blood. Based on these results, we determined the cause of death to be cardiorespiratory failure induced by the additive effects of tramadol and nicotine shortly after consumption.     

曲马多在家兔体内的死后分布研究

目的研究曲马多在中毒家兔体内死后分布规律,为曲马多中毒检材采取提供实验依据。方法家兔经口给予10倍LD50曲马多,待家兔死亡后迅速解剖取样,气相色谱／质谱联用和气相色谱-FTD法测定其体液、脏器、大脑及右上肢和右下肢肌肉中曲马多的含量,比较其变化规律。结果血液和肝脏中曲马多的最低检出限分别为0．05μg/mL和0．05μg/g,提取回收率为97．60％±0．65％～103．10％±1．24％。曲马多在家兔体内的死后分布为：肾〉胃〉肝〉脾〉肺〉脑〉心〉上肢肌肉〉下肢肌肉〉〉体液（尿〉胆汁、心血〉玻璃体液）。结论大剂量曲马多中毒致死后在体内分布不均匀,组织中曲马多含量明显高于心血、胆汁等体液。     

Tissue distribution of tramadol and metabolites in an overdose fatality

Tramadol (Ultram) is a centrally acting, synthetic analgesic agent. Although it has some affinity for the opiate receptors, tramadol is believed to exert its analgesic effect by inhibiting the re-uptake of norepinephrine and serotonin. There are several published cases of tramadol's involvement in drug-related deaths and impairment. Reports of deaths involving tramadol alone with associated tissue concentrations are rare. This report documents a case in which tramadol overdose was identified as the cause of death. The following tramadol concentrations were found in various tissues: blood, 20 mg/L; urine, 110.2 mg/L; liver, 68.9 mg/kg; and kidney, 37.5 mg/kg. Tissue distributions of the two primary metabolites, N-desmethyl and O-desmethyl tramadol, are also reported. In each tissue or fluid except urine, the tramadol concentration was greater than either metabolite, consistent with other reports of drug-impaired drivers and postmortem cases. The O-desmethyl metabolite concentration was greater than the N-desmethyl metabolite concentration in all tissues; this is in contrast to other postmortem reports, in which the majority of cases report concentrations of O-desmethyl as less than those of N-desmethyl. This may be useful as an indicator of time lapse between ingestion and death.     

Fatal venlafaxine overdose with acinar zone 3 liver cell necrosis

We present a case of fatal venlafaxine overdose in a 34-year-old male with a history of depression and previous suicide attempts. He presented unwell, and his condition deteriorated with the development of rhabdomyocytolysis and renal failure. Although treatment was provided, this was unsuccessful, and he died within a day of his admission. A postmortem examination was performed, and the findings included an acinar zone 3 pattern of liver cell necrosis and a very high level of serum venlafaxine in the deceased. No other elevated drug levels were detected. From this case, it is clear that venlafaxine overdose was the primary cause of a fatal acinar zone 3 pattern of liver cell necrosis. As far as we are aware, this is the first reported case of fatal acinar zone 3 liver necrosis caused by venlafaxine overdose alone.     

Lethal combination of tramadol and multiple drugs affecting serotonin

The death of a 36-year-old alcoholic man who died after developing seizure activity while being treated with tramadol, as well as with venlafaxine, trazodone, and quetiapine, all of which interact with the neurotransmitter serotonin, is reported. The decedent, who had a history of chronic back pain, alcoholism, depression, mild hypertensive cardiovascular disease, and gastritis, had just been discharged from the hospital after 4 days of alcohol detoxification treatment. During the admission, no withdrawal seizures were noted. The morning after discharge, a witness observed the decedent exhibiting seizure activity and then collapsing. An autopsy was performed approximately 6 hours after death, and the anatomic findings were consistent with seizure activity and collapse, which included biting injuries of the tongue and soft-tissue injuries of the face. Toxicologic analysis identified tramadol, venlafaxine, promethazine, and acetaminophen in the urine; tramadol (0.70 mg/L) and venlafaxine (0.30 mg/L) in the heart blood, and 0.10 mg of tramadol in 40 ml of submitted stomach contents. No metabolites, such as acetate, acetone, lactate, and pyruvate, were found in the specimens that would be characteristically found in a person with alcohol withdrawal syndrome. The threshold for seizures is lowered by tramadol. In addition, the risk for seizure is enhanced by the concomitant use of tramadol with selective serotonin reuptake inhibitors or neuroleptics, and its use in patients with a recognized risk for seizures, i.e., alcohol withdrawal. The cause of death in this individual was seizure activity complicating therapy for back pain, depression, and alcohol withdrawal syndrome. The data in Adverse Event Reporting System of the Food and Drug Administration from November 1, 1997 to September 8, 1999 was reviewed along with a MEDLINE search from 1966 to the present. This case appears to be the first reported death caused by seizure activity in a patient taking tramadol in combination with drugs that affect serotonin.     

Fatal overdoses of tramadol: is benzodiazepine a risk factor of lethality?

Tramadol is a centrally acting analgesic agent used in the treatment of mild to moderate pain. It has a low affinity to opioid receptors and inhibits the reuptake of norepinephrin and serotonin producing an analgesic action by blocking nociceptive impulses in the spine. Although 21 drug-combined fatalities including tramadol have been reported, only two fatal overdoses in adults with tramadol alone have been reported to date. We report four additional lethal intoxications, assess the toxicity of tramadol, the detection method and the possible interaction with other central nervous system (CNS) depressants, particularly benzodiazepines. Similarities between tramadol and buprenorphine are discussed, and a possible cytochrome P450-based interaction between tramadol and benzodiazepine is considered. To our knowledge, this relationship has never been reported in the literature.     

A fatal overdose of the ergot derivative cabergoline

A 79-year-old woman, with Parkinson's disease treated with cabergoline, was admitted to a hospital due to jaundice and weakness. She was found confused, absent minded, and died after 2 weeks. Autopsy showed an extrahepatic bile duct adenocarcinoma with spread to the gall bladder, the liver, and regional lymphnodes. While cleaning the hospital bed after her death, the nurses found several tablets hidden in the bed. Biological samples obtained at the autopsy were screened for common drugs and narcotics. Several drugs such as buprenorphine, codeine, paracetamol, and propranolol were detected in the blood at therapeutic levels. A method to determine cabergoline in whole blood and other forensic matrices was developed, and further investigations determined cabergoline concentrations in whole blood and liver tissue of 94 and 3100 microg/kg, respectively. The blood concentration was 100 times above the therapeutic level reported on cabergoline in plasma and in combination with her symptoms, suggest she took a fatal overdose of cabergoline.     

Post-mortem SNP analysis of CYP2D6 gene reveals correlation between genotype and opioid drug (tramadol) metabolite ratios in blood

Tramadol is an opioid drug metabolised in phase I by cytochrome P450 (CYP) enzymes, of which CYP2D6 is mainly responsible for the O-demethylation of tramadol, but is not involved in N-demethylation. Defects in the genes encoding drug metabolising enzymes (DMEs) may lead to adverse drug effects, even to death. To aid interpretation of the forensic toxicology results, we studied how the genetic variation of the CYP2D6 gene is reflected in tramadol metabolite ratios found in post-mortem samples. In 33 Finnish autopsy cases where tramadol was found, we analysed both the CYP2D6 genotype and the concentrations of tramadol and its metabolites O- and N-demethyltramadol. As expected, we found a correlation between the number of functional CYP2D6 alleles and the ratio of tramadol to O-demethyltramadol. We also found a correlation between the number of functional alleles and the ratio of tramadol to N-demethyltramadol. This can be explained by the complementary nature of the two main tramadol demethylation pathways. No known CYP2D6 inhibitors were associated with exceptional metabolic ratios. Furthermore, no accidental tramadol poisonings were associated with a defective CYP2D6 gene. Our results on the tramadol are among the first to demonstrate that genetic variation in drug metabolising enzymes can be analysed in post-mortem blood, and that it correlates well with the parent drug to metabolite ratios. The results also suggest that genetic factors play, in general, a dominant role over other factors in the metabolism of individual drugs.     

Myxoid heart disease: a review with special emphasis on sudden cardiac death

Myxoid heart disease (MHD), more commonly known as mitral valve prolapse, is a very common cardiac abnormality affecting 5-10% of the general population. This article reviews the history, symptoms, physical findings, pathology, associated conditions and complications of this entity. Special emphasis is given to sudden cardiac death, which occurs as a result of acute heart failure or due to a fatal arrhythmia. Theories regarding the origin of the arrhythmias are discussed. Once the origin is known, those at risk for this devastating complication can be identified and perhaps a preventative therapeutic regimen developed.     

Neonatal death following clozapine self-poisoning in late pregnancy: an unusual case report

The report presents a fatal poisoning of a neonate occurring in the final stage of gestational life and evoked by his mother, who, while 9 months pregnant, took a toxic dose of clozapine aiming at committing suicide. She was also severely poisoned, but ultimately was saved. The woman had been taking the medication due to schizophrenia and depression prior to conception, and the discontinuation of the drug in the course of pregnancy increased the risk of the woman attempting suicide. In the course of comprehensive toxicological analysis based on the developed analytical procedure with the use of LC-APCI-MS, clozapine and its two metabolites, norclozapine and clozapine-N-oxide, were determined in postmortem blood, liver and kidney in concentrations explaining the death of the neonate. The interpretation of the above-described case is complex and--apart from toxicological aspects--also involves issues associated with psychiatry, pharmacotherapy in pregnancy and medicolegal problems.     

Myxoid heart disease: A review with special emphasis on sudden cardiac death

Myxoid heart disease (MHD), more commonly known as mitral valve prolapse, is a very common caridac abnormality affecting 5–10% of the general population. This article reviews the history, symptoms, physical findings, pathology, associated conditions and complications of this entity. Special emphasis is given to sudden cardiac death, which occurs as a result of acute heart failure or due to a fatal arrhythmia. Theories regarding the origin of the arrhythmias are discussed. Once the origin is known, those at risk for this devastating complication can be identified and perhaps a preventative therapeutic regimen developed.     

盐酸曲马多在大鼠体内的分布特点

目的观察盐酸曲马多在大鼠体内的分布及其特点。方法大鼠以3倍和6倍LD50228mg/kg剂量盐酸曲马多灌胃染毒致死,取材,薄层色谱法检测其心、肺、肝、脾、肾、大脑和血内盐酸曲马多的浓度。结果3倍LD50剂量组大鼠肾、肺、血、肝、大脑、脾和心组织盐酸曲马多的浓度分别为112±15、59±17、53±31、32±19.7、22±11.5、20±20、16.7±8.3μg/g或μg/ml;6倍LD50剂量组大鼠血、肺、肝、心、肾、大脑和脾中盐酸曲马多的浓度分别为107.6±7.2、26.3±20、11.7±6.6、11.2±7.2、10.3±3.6、6.38±0.2、6.1±0.3μg/g或μg/ml。结论3倍LD50剂量组大鼠,肾、肺、血内盐酸曲马多浓度最高;6倍LD50剂量组大鼠血、肺、肝中盐酸曲马多的浓度最高。盐酸曲马多中毒时,血、肝、肺和肾可以作为法医毒物分析的检材。     

A case of sudden cardiac death in connection with Salmonella typhimurium infection

A case of fatal myocarditis in a 24-year-old otherwise healthy man is described. It was possible to cultivate Salmonella typhimurium from the alimentary tract, the blood, the liver and skeletal muscles. The possibility of a solitary myocarditis with fatal outcome due to Salmonella typhimurium infection is discussed. Such a case seems not to have been mentioned previously in the literature.The problems concerning the statistical registration of such a death are briefly discussed.     

Commotio cordis as a result of a fight: report of a case considered to be imprudent homicide

The report describes a fatal outcome in a 5-year-old male who died after drinking a fatal dose of ethanol at the party held by his parents. Urine and blood alcohol level of the deceased was 0.4 and 0.5 g/dL, what might explain the sudden death of the child. In addition, the analysis of the boy's hair demonstrated the presence of ethyl glucuronide (EtG), a marker of alcohol consumption; hair EtG concentration levels indicated that the boy might have occasionally imbibed alcohol prior to death. Pathological lesions of the liver observed in histopathology did not contradict such a hypothesis.     

Bloodstain pattern analysis in a case of fatal varicose vein rupture

Rupture of a varicose vein is a rare cause of sudden death. It occurs when the failure of venous valves causes an increase in venous pressure great enough to provoke rupture of the blood vessel. When it does happen, the victim is often found surrounded by a pool of blood, and the examination of the scene can mislead the forensic team to think of violent death. Until now, the bloodstain patterns in these fatal cases have not been described. An examination of the bloodstain pattern in a case of fatal varicose vein rupture in an 84-year-old man is here reported.