Position Paper: Recommendations for the Investigation, Diagnosis, and Certification of Deaths Related to Opioid and Other Drugs.

The National Association of Medical Examiners convened an expert panel to update the association's evidence-based recommendations for investigating and certifying deaths associated with opioids and other misused substances to improve death certificate and mortality data for public health surveillance. The recommendations are as follows:1. Autopsy provides the best information on a decedent's medical condition for optimal interpretation of toxicology results, circumstances surrounding death, medical history, and scene findings. The panel considers autopsy an essential component of investigating apparent overdose deaths.2. Scene investigation includes reconciling prescription information and medication counts. Investigators should note drug paraphernalia or other evidence of using intoxicating substances.3. Retain blood, urine, and vitreous humor whenever available. Blood from the iliofemoral vein is preferable to blood from more central sites.4. A toxicological panel should be comprehensive, including potent depressant, stimulant, and antidepressant medications. Detecting novel substances present in the community may require special testing.5. When death is attributed to a drug or combination of drugs (as cause or contributing factor), the certifier should list the drugs by generic name in the autopsy report and death certificate.6. The best classification for manner of death in an overdose without any apparent intent of self-harm is "accident."

Case report of a fatal intoxication by Nucynta.

Tapentadol (Nucynta) is a centrally acting opioid analgesic prescribed for the treatment of moderate to severe acute pain. Its efficacy is believed to be due to µ-opioid receptor agonist activity and inhibition of norepinephrine reuptake resulting in increased norepinephrine concentrations. There is only one other case in the literature relating to the toxicity of this agent or report of a fatality. This case report documents a case in which tapentadol was identified as the cause of death. The tapentadol concentration found in the heart blood submitted in this case was more than 20 times the upper limit of the therapeutic range. Possible mechanisms of death include respiratory depression, central nervous system depression, and serotonin syndrome. Based on the scene investigation and autopsy findings in this case, the medical examiner determined that the cause of death was narcotic (Nucynta) intoxication and the manner of death was undetermined.

Quantitation of amphetamine-type stimulants by LC-MS/MS.

Amphetamines or amphetamine-type stimulants (ATSs) refer to a group of pharmacological and -toxicological agents that have a common phenethylamine structural backbone and typically impart effects that include, but are not limited to, vasoconstriction, anorexia, central nervous system stimulation, and/or hallucinations. While differences in side chain chemistry can impart different pharmacological or toxicological effects, for some compounds, e.g., MDMA (Ecstasy), alterations of the phenyl part of the molecule impart other significant effects. ATSs are used both therapeutically and recreationally, with significant abuse and addiction potential. Therapeutically, these agents are mainly used to treat hyperactivity disorders or aid in weight loss. Toxicological effects include hypertension, arrhythmia, excitability, aggressiveness, psychoses, coma, and death.Traditional analytical methods to analyze amphetamines include gas chromatography-mass spectrometry where derivatization is often required to facilitate analysis. Besides sample preparation issues, it has been demonstrated that injection port chemistry in the GC can lead to misleading results with some members of the amphetamine class. To circumvent these issues, liquid chromatography-mass spectrometry (LC-MS/MS) offers the promise of a simpler sample preparation procedure and fewer analytical concerns. This chapter describes an LC-MS/MS technique for the analysis of 14 ATSs in blood, serum/plasma, and urine. The method is quantitative and has reporting limits in the low ng/mL range. Electrospray ionization is used in the positive ion mode. Two transitions for each compound are monitored along with ion ratios.

Qualitative identification of rodenticide anticoagulants by LC-MS/MS.

Rodenticide anticoagulants are used in the control of rodent populations. In addition to accidental ingestions in humans, such agents have also been used for homicidal and suicidal purposes. There are two major groups of rodenticide anticoagulants - hydroxycoumarins and indanediones. Before the advent of LC-MS/MS, analysis for such agents was relegated to such techniques as TLC and HPLC with nonspecific modes of detection. LC-MS/MS has been used to determine any given number of rodenticide anticoagulants in animal tissues, foods, plasma, etc. Use of this technique allows for the simultaneous identification of individual compounds within both classes of rodenticide anticoagulants. The LC-MS/MS method presented allows for simultaneous qualitative identification of brodifacoum, bromadiolone, chlorphacinone, dicumarol, difenacoum, diphacinone, and warfarin in blood, serum, and plasma using ESI in the negative mode. Two transitions are monitored for each analyte after a simple sample preparation. Chromatographic separation is accomplished using a gradient of ammonium hydroxide in water and ammonium hydroxide in methanol. Chloro-warfarin is used as internal standard.

LC-MS/MS method for the detection of common laxatives.

Laxatives refer to a group of diverse substances used to induce bowel movements. There exist various classes of laxatives, which work through different pharmacological means. Based on the potential medical cause of use, one particular class of laxative may be preferred over another. Additionally, abuse of laxatives in both adults and children occurs. Some of the signs and symptoms of excessive laxative use/abuse can not only mimic various pathological conditions, but cause such conditions. Based on the potential abuse of laxatives, as well as for compliance purposes, a test to identify the use of common laxatives is of significant value. While stool and stool water can be used for such analyses, isolation and identification of analytes can be difficult due to matrix constituents and potential interferences. Ideally, a sensitive urine test for detection of laxative use/abuse with specific detection would be preferable. Described is an LC-MS/MS procedure for the detection of four metabolites related to common laxatives-desacetylbisacodyl, aloe-emodin, emodin, and rhein. Deuterated internal standards for desacetylbisacodyl and emodin are employed while an analog internal standard, biochanin A is used for rhein and aloe-emodin. Sample preparation consists of deconjugation of analytes in urine followed by a simple organic solvent extraction. Analysis is carried out using a pentafluorophenyl column employing a gradient mobile phase of formic acid in water/methanol. Mass spectral ionization conditions employ both positive and negative ESI. Two transitions are monitored for each analyte of interest.

Multidisciplinary investigation of an unusual apparent homicide/suicide.

The investigation of deaths of individuals whose bodies are decomposed, mummified, or skeletonized is particularly difficult for medical examiners and medicolegal death investigators. Determination of the cause and manner of death in such cases frequently requires consultation with experts in a variety of disciplines in the forensic sciences and necessitates correlation of the autopsy results, scene investigation, medical and social history of the deceased, and laboratory studies. The authors report an unusual case of an apparent homicide/suicide involving 2 individuals and a canine that went undetected for almost 4 years. Determination of the cause and manner of death in these cases involved a multidisciplinary, intercontinental investigation and necessitated the performance of toxicologic studies on specimens not commonly analyzed. These cases illustrate the importance of the multidisciplinary approach to medicolegal death investigations and the necessity of considering nontraditional sources of potential information and specimens for laboratory analysis in selected cases.

Alprazolam-related deaths in Palm Beach County.

Alprazolam is a commonly prescribed benzodiazepine. The abuse of benzodiazepines is most frequently seen in conjunction with the abuse of other drugs. Only rare fatalities have been attributed to alprazolam 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 alprazolam, to further study the pattern of alprazolam abuse. Our review consisted of 178 cases, including 87 in which death was attributed to combined drug toxicity, 2 to alprazolam toxicity alone, 44 to trauma, 12 to natural causes, and 33 to another drug or drugs. Cocaine and methadone were the most common cointoxicants in the cases of combined drug toxicity, while heroin was less frequently detected. There was considerable overlap in the postmortem blood alprazolam concentrations among the groups. The overlapping ranges of concentrations of alprazolam detected indicate that it may be difficult to define a lethal alprazolam range, and that it may not be possible to determine the actual role of alprazolam as a causal factor in cases of combined drug toxicity. This study confirms that alprazolam alone is rarely a cause of death, and that alprazolam abuse usually occurs within a polydrug use pattern. The high incidence of cocaine as a cointoxicant has not been previously reported.