Characteristics of alprazolam-related deaths compiled by a centralized state medical examiner.

BACKGROUND AND OBJECTIVE: Unintentional drug poisoning deaths represent a major health concern, particularly in rural areas. Although alprazolam is frequently detected in drug-related deaths, characterization of its involvement is limited. Our objective was to compare the characteristics of alprazolam-related deaths with nonalprazolam deaths in a predominantly rural state. METHODS: A comprehensive forensic drug database (FDD) was developed in 2005 to compile demographic, toxicology, and co-morbidity information from all West Virginia (WV) drug-related deaths. All FDD data from 2005 to mid-November 2007 were analyzed. RESULTS: Alprazolam contributed to 204 (17.0%) of the 1,199 drug-related deaths and was identified in 7.2% of the 363 deaths occurring during 2005 and in 27.5% of the 422 deaths entered in the database during 2007. At least one other drug, predominantly an opioid, was identified in 97.5% of the alprazolam cases, with concurrent benzodiazepines also found. Compared to nonalprazolam deaths, alprazolam decedents were significantly more likely to be obese and to have preexisting cardiovascular disease, but were less likely to have documented substance abuse. An alprazolam prescription existed in 52.5% of the alprazolam deaths, with 77.6% having a prescription for all drugs identified. CONCLUSIONS: Alprazolam was a contributing cause of death in a substantial and increasing number of drug-related deaths. Prescriptions for alprazolam and the other drugs detected were often present in these cases. SCIENTIFIC SIGNIFICANCE: Controlled substance monitoring programs should be routinely used as one mechanism to help prevent potential drug misuse/abuse. Our findings provide a baseline for ongoing alprazolam-related death surveillance.

Patterns of abuse among unintentional pharmaceutical overdose fatalities.

CONTEXT: Use and abuse of prescription narcotic analgesics have increased dramatically in the United States since 1990. The effect of this pharmacoepidemic has been most pronounced in rural states, including West Virginia, which experienced the nation's largest increase in drug overdose mortality rates during 1999-2004. OBJECTIVE: To evaluate the risk characteristics of persons dying of unintentional pharmaceutical overdose in West Virginia, the types of drugs involved, and the role of drug abuse in the deaths. DESIGN, SETTING, AND PARTICIPANTS: Population-based, observational study using data from medical examiner, prescription drug monitoring program, and opiate treatment program records. The study population was all state residents who died of unintentional pharmaceutical overdoses in West Virginia in 2006. MAIN OUTCOME MEASURES: Rates and rate ratios for selected demographic variables. Prevalence of specific drugs among decedents and proportion that had been prescribed to decedents. Associations between demographics and substance abuse indicators and evidence of pharmaceutical diversion, defined as a death involving a prescription drug without a documented prescription and having received prescriptions for controlled substances from 5 or more clinicians during the year prior to death (ie, doctor shopping). RESULTS: Of 295 decedents, 198 (67.1%) were men and 271 (91.9%) were aged 18 through 54 years. Pharmaceutical diversion was associated with 186 (63.1%) deaths, while 63 (21.4%) were accompanied by evidence of doctor shopping. Prevalence of diversion was greatest among decedents aged 18 through 24 years and decreased across each successive age group. Having prescriptions for a controlled substance from 5 or more clinicians in the year prior to death was more common among women (30 [30.9%]) and decedents aged 35 through 44 years (23 [30.7%]) compared with men (33 [16.7%]) and other age groups (40 [18.2%]). Substance abuse indicators were identified in 279 decedents (94.6%), with nonmedical routes of exposure and illicit contributory drugs particularly prevalent among drug diverters. Multiple contributory substances were implicated in 234 deaths (79.3%). Opioid analgesics were taken by 275 decedents (93.2%), of whom only 122 (44.4%) had ever been prescribed these drugs. CONCLUSION: The majority of overdose deaths in West Virginia in 2006 were associated with nonmedical use and diversion of pharmaceuticals, primarily opioid analgesics.

Identification of N,N-dimethylamphetamine formed by methylation of methamphetamine in formalin-fixed liver tissue by multistage mass spectrometry.

Methamphetamine is methylated in the presence of unbuffered formalin solutions within hours at room temperature. The product, N,N-dimethylamphetamine, is also found in human liver exposed to methamphetamine followed by incubation with formalin. In the present study, a direct mass spectrometric method was developed to identify N,N-dimethylamphetamine in human liver before and after treatment with formalin. Human liver samples were obtained from four deaths that were investigated by the West Virginia Office of Chief Medical Examiner. Full toxicological analysis was conducted on samples from the decedents and methamphetamine was among the positive findings in each case. The method used to expose liver tissue to formaldehyde involved treating a small piece of liver from each case with formalin solution (20% v/v) for 24 h at room temperature. The formalin treated tissues were homogenized and the resulting suspension was sonicated for 5 min, and then centrifuged. Supernatant aliquots were directly analyzed by electrospray ionization (ESI) mass spectrometry without chromatographic isolation. Positive ion multistage mass spectra recorded in MS, MS/MS and MS/MS/MS (MS3) modes were used to confirm the presence of N,N-dimethylamphetamine and methamphetamine in the mixture. Liver tissue not treated with formalin did not contain a detectable level of N,N-dimethylamphetamine. Decreases in methamphetamine concentrations in liver tissue resulting from treatment with formalin were measured using deuterium-labeled methamphetamine as internal standard. The method can be completed in less than 2 h on thawed tissue. The results suggest that the process of fixing tissues with formalin may lead to false negative findings for methamphetamine.

Additive Effects of Cointoxicants in Single-Opioid Induced Deaths.

A forensic drug database (FDD) was used to capture comprehensive data from all drug-related deaths in West Virginia, with deaths also included from the northern New England states of Maine, Vermont, and New Hampshire. All four states serve predominantly rural populations under two million and all have similar state medical examiner systems that employ statewide uniform death certification policies and practices. This study focused on 1482 single opioid deaths (fentanyl, hydrocodone, methadone, and oxycodone) in the FDD from 2007-2011. We modeled relationships between the opioid concentrations and the presence or absence of the following commonly occurring non-opioid cointoxicants: benzodiazepines (alprazolam and diazepam), alcohol, tricyclic antidepressants, selective serotonin reuptake inhibitors, and diphenhydramine. Additional covariates of state, age, body mass index, and sex were included. Results showed that the presence of alcohol, benzodiazepines, and antidepressants were each associated with statistically significant lower concentrations of some but not all of the opioids studied, which may obscure the interpretation of postmortem toxicology results alone. Fentanyl concentrations appeared to be the least associated with the presence or absence of the variables studied, and cointoxicant alcohol appeared to be associated with lower concentrations in opioid concentrations than were most of the other factors in the model studied. These findings underscore the importance of documenting all potential cointoxicants in opioid-related deaths.

Methylation of 3,4-methylenedioxymethamphetamine in formalin-fixed human liver tissue.

3,4-Methylenedioxymethamphetamine (MDMA or ecstasy) is a commonly consumed recreational drug. As is the case with most secondary amines, MDMA reacts with formaldehyde under acidic conditions to form tertiary amines. This reaction is likely to occur in formalin-fixed tissue. In formalin solutions, MDMA is methylated producing 3,4-methylenedioxy-N,N-dimethylamphetamine (MDDA). MDDA standard was synthesized by treating methylenedioxyamphetamine HCl in formaldehyde solution. Structure confirmation was by electrospray ionization-mass spectrometry (MS) and MS-MS. Randomly chosen human liver pieces (100-200 mg) were injected with 2 microg of MDMA HCl. The liver pieces in centrifuge tubes were covered with 200 microL of formalin solution (20% v/v), held at room temperature for 24 h, and then homogenized. The resulting suspension was sonicated for 5 min and then centrifuged. Controls consisted of substitution of 200 microL of water in place of formalin solution. Supernatant aliquots (10 mciroL) were added to 500 microL of 0.1% formic acid in acetonitrile for MS analysis. Positive ion electrospray spectra recorded in MS, MS2, and MS3 modes were used to confirm the presence of methylated MDMA. Liver tissue containing added MDMA HCl but not treated with formalin did not show a detectable level of methylated MDMA.

Mental illness and psychotropic drug use among prescription drug overdose deaths: a medical examiner chart review.

OBJECTIVE: Between 1999 and 2006, there was a 120% increase in the rate of unintentional drug overdose deaths in the United States. This study identifies the prevalence of mental illness, a risk factor for substance abuse, and chronic pain among prescription drug overdose deaths in West Virginia and ascertains whether psychotropic drugs contributing to the deaths were used to treat mental illness or for nonmedical purposes. METHOD: In 2007, we abstracted data on mental illness, pain, and drugs contributing to death from all unintentional prescription drug overdose deaths in 2006 recorded by the West Virginia Office of the Chief Medical Examiner. Decedent prescription records were obtained from the state prescription drug monitoring program. RESULTS: Histories of mental illness and pain were documented in 42.7% and 56.6% of 295 decedents, respectively. Psychotropic drugs contributed to 48.8% of the deaths, with benzodiazepines involved in 36.6%. Benzodiazepines contributing to death were not associated with mental illness (adjusted odds ratio [AOR] = 1.1; 95% CI, 0.6-1.8), while all other psychotropic drugs were (AOR = 3.9; 95% CI, 2.0-7.6). Of decedents with contributory benzodiazepines, 46.3% had no prescription for the drug. CONCLUSIONS: Mental illness may have contributed to substance abuse associated with deaths. Clinicians should screen for mental illness when prescribing opioids and recommend psychotherapy as an adjunct or an alternate to pharmacotherapy. Benzodiazepines may have been used nonmedically rather than as a psychotropic drug, reflecting drug diversion. Restricting benzodiazepine prescriptions to a 30-day supply with no refills might be considered.

Fatal all-terrain vehicle crashes: injury types and alcohol use.

BACKGROUND: Since the 1990s, West Virginia has led the U.S. in the per-capita death rate from all-terrain vehicle (ATV) crashes, with rates eight times the national average and continually increasing. A comprehensive assessment was conducted of ATV fatalities to provide critical guidance for community interventions and public health policy to prevent further deaths. METHODS: In 2007, death certificates for 2004 to 2006 with ICD-10 codes correlating to ATV crashes were used to identify decedents involved in crashes occurring in West Virginia. Data were abstracted from medical examiner records regarding crash circumstances, sustained injuries, and toxicology. RESULTS: During 2004-2006, a total of 112 fatal ATV crashes were identified. Nearly all (92%) decedents were the ATV operator, and only 15% were known to have worn helmets. Among 54 traffic crashes, collisions (56%) and head injuries (65%) predominated, whereas the majority of 58 nontraffic crashes were rollovers (55%) and were most commonly associated with compression injuries of the thorax and abdomen (36%). Regardless of crash class (i.e., traffic versus nontraffic), alcohol was detected in the blood of 50% of decedents; of those, 88% had blood alcohol concentrations >OR=0.08% (mean=0.17%), West Virginia's legal limit. Drugs of abuse were identified in 21% of decedents, including marijuana (11%); opioid analgesics (7%); diazepam (6%); cocaine (2%); and methamphetamine (1%). CONCLUSIONS: Fatal crash and injury types differ significantly depending on the location of ATV use, although alcohol and drug abuse are frequent risk factors in all types of ATV crashes. In addition to promoting helmet use, interventions are needed to address alcohol use among ATV users.

A comparison of drug overdose deaths involving methadone and other opioid analgesics in West Virginia.

AIMS: To describe all people dying from unintentional overdoses of methadone or other opioid analgesics (OOA) in West Virginia in 2006. DESIGN: We analyzed medical examiner data supplemented by data from the state prescription drug monitoring program. We compared people whose deaths involved methadone with those whose deaths involved OOA. FINDINGS: The methadone group included 87 decedents, and the OOA group included 163 decedents. Most were male. Decedents in the methadone group were significantly younger than those in the OOA group: more than a quarter were 18-24 years of age. For both groups, approximately 50% had a history of pain, and 80% had a history of substance abuse. There was no intergroup difference in the prevalence of benzodiazepines at post-mortem. Methadone was significantly less likely to have ever been prescribed than OOA. Among those with prescriptions, the proportion prescribed within 30 days of death was significantly greater for methadone than for hydrocodone, but not for oxycodone. Ten (11.5%) of the methadone decedents were enrolled in an opiate treatment program (OTP) at the time of death. CONCLUSIONS: The high prevalence of a substance abuse history and lack of prescriptions suggest that most of the deaths in both groups are related to substance abuse. There was no indication of a harmful effect from methadone's metabolic interaction with benzodiazepines, but provider or patient unfamiliarity with methadone may have been a risk factor. Prescribing methadone, especially to young males, requires extra care. Providers, OTPs and coroners/medical examiners should use state prescription drug monitoring programs to monitor the use of controlled substances by their patients.

Asphyxial deaths caused by automobile exhaust inhalation not attributable to carbon monoxide toxicity: study of 2 cases.

The authors report two suicides that resulted from the intentional inhalation of automobile exhaust gases in which death occurred without the formation of physiologically significant amounts of carboxyhemoglobin. These circumstances are correlated with measurements of the involved vehicles' exhaust gases, which showed reduced concentrations of carbon monoxide present, reflecting improvements in automobile engine technology. In the absence of carbon monoxide toxicity, the authors attribute death in these cases to asphyxia caused by carbon dioxide intoxication and diminished atmospheric oxygen concentrations.

Shaken infant syndrome: developmental neuropathology, progressive cortical dysplasia, and epilepsy.

This study describes the developmental neuropathology of two infants who survived 7 and 9 years, respectively, an episode of violent shaking (shaken infant syndrome) early in their lives. The shaking injuries include cortical and subcortical contusions, hemorrhages, hypoxic/ischemic and axonal damage, and severe edema. The types, distribution, and resolution of these shaking injuries are detailed by sequential radiographic studies and by pathologic examination at postmortem. Despite their severity and extent, these injuries resolved in a relatively short period of time. By 6 months, the original injuries are repaired and the resultant encephaloclastic encephalopathies (e.g., multicystic encephalomalacia, porencephaly, generalized white matter attenuation, diffuse cortical atrophy, microgyria, ulegyria, and hydrocephalus ex vacuo) are well established. No appreciable pathologic differences are detected when radiographic findings at 6 months of age are compared to postmortem observations. On the other hand, undamaged and/or partially damaged cortical regions survive the original insult and undergo post-injury reorganization that transforms the residual cortex structural and presumably functional organization. Prominent features of this post-injury reorganization include progressive cortical dysplasia with cytoarchitectural disorganization, laminar obliteration, morphologic and functional (synaptic reorganization) transformation of some neurons, preservation of layer 1 intrinsic fibers and Cajal-Retzius cells, and the presence of large (hypertrophic) intrinsic neurons with intense neurofilament immunoreactivity. We propose that this progressive dysplastic process modifies the residual cortex structural and functional organization, influences the child's neurological and psychological maturation, and may play a significant role in the pathogenesis of ensuing neurological and/or psychological sequelae.