Male Predominance in West Virginia Unintentional Overdose Deaths is Influenced by Alcohol and Co-Intoxicants.

BACKGROUND: To examine sex differences in overdose (OD) mortality based upon substances involved. METHODS: A retrospective database analysis of West Virginia OD decedents (12,666 unintentional OD deaths, 2005-early 2023). Exposures were substances judged to contribute to death. The main outcome measure was determination of male to female death ratios with varying co-intoxicant involvement, particularly related to alcohol and fentanyl. Secondary outcomes included associations of fentanyl concentrations with alcohol concentrations and male sex, including fentanyl (F) and inactive metabolite norfentanyl (N) concentration variability between sexes. RESULTS: Alcohol co-intoxication in OD deaths was associated with higher male:female death ratios, from 2.0 (alcohol absent) to 3.3 (alcohol present). There was a greater increase over time in alcohol involvement in recent deaths involving females compared to males (relative increases of 52% vs. 6%, respectively). Male:female ratios with alcohol and fentanyl co-involvement ranged from 5.9:1 (only two drugs involved) to 2.4:1 (= 5 substances), with females significantly more likely to have multiple substances contributing to death. Overall, males had statistically significantly larger fentanyl (F) to norfentanyl (N) median concentration ratios compared to females (8.8 vs. 6.9, respectively). Multivariable analyses found alcohol presence was associated with a statistically significant 22% reduction in predicted fentanyl concentrations. CONCLUSIONS: Male:female ratios in unintentional OD deaths were higher with greater alcohol involvement and lower with fewer co-intoxicants. Fentanyl and norfentanyl concentration differences by sex were observed. It is important to determine possible contributors to sex differences in OD death rates to better target prevention and treatment initiatives.

Demographic, co-intoxicants and other characteristics of citalopram-involved overdose deaths.

Selective serotonin reuptake inhibitors (SSRIs) including citalopram are commonly used antidepressants that can be involved in drug-related deaths along with opioids and other substances. This study characterized citalopram involvement in West Virginia (WV) drug-related deaths compared to other SSRI and non-SSRI-related deaths. All 2005-2021 WV drug-related deaths were analyzed in this retrospective study. Demographics, other substances involved, and comorbidities in cases in which citalopram was listed on the death certificate were compared to other SSRI-related and total non-SSRI deaths. Citalopram concentrations and the association between citalopram presence with predicted fentanyl concentrations were determined. Citalopram was the most common antidepressant present in the deaths (4.5% of 14,363 total), with most (81%) unintentional. Male: female ratios in citalopram cases (0.9:1) were significantly lower than in non-SSRI deaths (2.3:1). Almost two-thirds of citalopram deaths had ≥ 4 substances involved compared to 26% of non-SSRI deaths. Overall, oxycodone was most frequently identified in citalopram deaths (fentanyl more commonly in recent years), followed by alprazolam and diazepam. Cardiovascular comorbidity was significantly more common in citalopram than non-SSRI deaths. No association was found between citalopram presence and predicted fentanyl concentrations. Most citalopram-related deaths were unintentional and involved proportionately more females, with larger numbers of concurrent substances present and more cardiovascular comorbidity compared to non-SSRI deaths. Citalopram is widely used and less toxic than many antidepressants. The extent to which it contributed to overdose deaths can be difficult to ascertain given the multiple substances usually present.

Quantifying a potential protective effect of buprenorphine on fatality risk during acute fentanyl exposures.

INTRODUCTION: Buprenorphine is an important therapy for opioid use disorder and may also reduce the risk of fatal overdoses in fentanyl exposures. However, the role of buprenorphine in reducing this risk has not been quantified. This cross-sectional study examined the association between buprenorphine presence, decedent characteristics, and other factors with the predicted fentanyl concentrations in overdose deaths. METHODS: The study identified unintentional fentanyl overdose decedents (n = 3036) from the West Virginia Forensic Drug Database, 2011 through mid-2020. The main outcome was fentanyl concentrations in overdose deaths in the presence and absence of buprenorphine. A multiple linear regression model examined the association of fentanyl concentrations with buprenorphine presence based on the concentrations of the parent drug buprenorphine (B) and its metabolite norbuprenorphine (N), adjusting for demographics, toxicological characteristics (presence of multiple opioids, benzodiazepines, stimulants, marijuana, and alcohol), and comorbidities. We used a B/N concentration ratio < 1 as an indirect indicator of longer-term buprenorphine exposure prior to drug overdose death. RESULTS: The median fentanyl concentration was 65 % higher when buprenorphine was present (N = 168) vs. absent (N = 2868) (0.028 vs. 0.017 µg/mL, p < 0.001). In the multivariable model, statistically significant associations occurred between buprenorphine presence and increased fentanyl concentrations (+28.7 %) with a B/N ratio < 1. Obesity, male sex, alcohol presence, and comorbid cardiovascular diseases were statistically significantly associated with lower (-11.3 % to -20.7 %) fentanyl concentrations, whereas marijuana presence and a history of substance use disorder were associated with statistically significant higher fentanyl concentrations (+8.8 % to +31.3 %). CONCLUSIONS: These findings suggest that sustained or longer-term buprenorphine intake might exert some protective effect on fatalities resulting from fentanyl exposure as documented by the association of higher fentanyl blood concentrations with buprenorphine presence among fatal drug overdoses. As fentanyl availability and overdose rates increase nationally, buprenorphine is a vital tool for effective opioid use disorder treatment that might also reduce the risk of fatality in an acute fentanyl exposure.

Characterization of Unintentional Deaths Among Buprenorphine Users.

OBJECTIVE: Medications used to treat opioid use disorder (OUD) reduce drug overdose risk. Buprenorphine is often the preferred treatment for OUD because of its high safety profile. Given expanding buprenorphine use, this study sought to examine buprenorphine-involved deaths (BIDs) and compare them with other drug-related deaths. METHOD: West Virginia drug-related deaths from 2005 to early 2020 were identified. Study data included decedent demographics, toxicology, autopsy findings, and medical and prescription histories. Characteristics of BIDs compared with other drug-related deaths were statistically analyzed. RESULTS: Among 11,764 drug-related deaths, only 564 (4.8%) involved buprenorphine. Buprenorphine alone was present in 32 deaths, of which 20 were considered the direct cause of death (0.2% of all drug-related deaths). Significantly more BIDs involved five or more drugs (23%) compared with other opioid deaths (14.9%). Co-intoxicants found most frequently in BIDs were benzodiazepines (47.3%), methamphetamine (27.1%), and fentanyl (22.9%). Cardiovascular and pulmonary comorbidities were identified in 43% and 21% of BIDs, respectively. Of the 564 BIDs, a current buprenorphine prescription was present in 132 deaths (23.4%). CONCLUSIONS: Despite increasing buprenorphine use, BIDs comprised less than 5% of overall West Virginia drug-related deaths. Seldom was it the only drug found, and most decedents did not have current prescriptions for buprenorphine. Although buprenorphine is effective, with a wide safety margin, clinicians and patients should be aware that buprenorphine can be involved in overdose deaths, especially when buprenorphine is taken in combination with drugs such as benzodiazepines, methamphetamine, or fentanyl, and in persons with underlying cardiovascular or pulmonary comorbidities.

Characteristics of xylazine-related deaths in West Virginia-Xylazine-related deaths.

BACKGROUND AND OBJECTIVES: The involvement of xylazine, a veterinary drug, in West Virginia (WV) human drug-related deaths was examined. METHODS: WV drug deaths from 2019 (when xylazine was first identified) to mid-2021. Characteristics including toxicology findings were compared between xylazine and nonxylazine deaths. RESULTS: Of 3292 drug deaths, 117 involved xylazine, and the proportions of deaths with it have increased (1% [2019] to 5% [mid-2021)]. Xylazine decedents had more cointoxicants, with fentanyl (98%) predominant followed by methamphetamine. Xylazine decedents had a significantly greater history of drug or alcohol misuse and hepatic disease. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: In one of the largest analyses of xylazine-involved deaths in a predominantly rural state, identification of xylazine was increasing with multiple cointoxicants (especially fentanyl), and was present in a few deaths with only one other substance involved. Health professionals should be aware of possible enhanced toxicity from xylazine ingestion especially since naloxone does not reverse xylazine's adverse effects.

Fentanyl and other opioid involvement in methamphetamine-related deaths.

Background: Methamphetamine-related deaths have been rising along with those involving synthetic opioids, mostly fentanyl and fentanyl analogs (FAs). However, the extent to which methamphetamine involvement in deaths differs from those changes occurring in synthetic opioid involvement is unknown.Objectives: To determine the patterns and temporal changes in methamphetamine-related deaths with and without other drug involvement.Methods: Data from all methamphetamine-related deaths in West Virginia from 2013 to 2018 were analyzed. Quasi-Poisson regression analyses over time were conducted to compare the rates of change in death counts among methamphetamine and fentanyl//FA subgroups.Results: A total of 815 methamphetamine-related deaths were analyzed; 572 (70.2%) were male and 527 (64.7%) involved an opioid. The proportion of methamphetamine only deaths stayed relatively flat over time although the actual numbers of deaths increased. Combined fentanyl/FAs and methamphetamine were involved in 337 deaths (41.3%) and constituted the largest increase from 2013 to 2018. The modeling of monthly death counts in 2017-2018 found that the average number of deaths involving fentanyl without methamphetamine significantly declined (rate of change -0.025, p < .001), while concomitant fentanyl with methamphetamine and methamphetamine only death counts increased significantly (rate of change 0.056 and 0.057, respectively, p < .001).Conclusions: Fentanyl and FAs played an increasingly significant role in methamphetamine-related deaths. The accelerating number of deaths involving fentanyl/FAs and methamphetamine indicates the importance of stimulants and opioids in unintentional deaths. Comprehensive surveillance efforts should continue to track substance use patterns to ensure that appropriate prevention programs are undertaken.

Quantifying enhanced risk from alcohol and other factors in polysubstance-related deaths.

BACKGROUND: To quantify how alcohol, polysubstance use and other factors influence opioid concentrations in drug-related deaths in West Virginia (WV), United States. METHODS: Multiple linear regression models were employed to identify relationships among alcohol, other factors, and the concentrations of four commonly identified opioids (fentanyl, hydrocodone, oxycodone, methadone), accounting for demographic, toxicological and comorbid characteristics in WV drug-related deaths from 2005 to 2018. RESULTS: Alcohol concentrations of 0.08% or above were associated with significant reductions in blood concentrations of fentanyl (27.5%), hydrocodone (30.5%) and methadone (32.4%). Significantly lower predicted concentrations of all opioids studied were associated with multiple opioid vs. single opioid presence, with predicted concentration reductions ranging from 13.7% for fentanyl to 65-66% for hydrocodone and oxycodone. Benzodiazepine presence was associated with small, non-statistically significant changes in opioid concentrations, while stimulant presence was associated with statistically significant reductions in hydrocodone and oxycodone concentrations. CONCLUSIONS: Co-ingestion of alcohol, multiple opioids or stimulants were associated with significantly decreased predicted concentrations of commonly identified opioids in drug deaths. Further evidence is provided for enhanced risks from polysubstance use with opioids, which has important public health implications.

Fentanyl and fentanyl-analog involvement in drug-related deaths.

BACKGROUND: To describe and analyze the involvement of fentanyl and fentanyl analogs (FAs) in drug-related deaths in West Virginia (WV), United States. METHODS: Retrospective analyses of all WV drug-related deaths from 2005 to 2017 were performed, including comparisons of demographic and toxicological characteristics among total deaths, deaths in which fentanyl/FAs were present, deaths in which they were absent, heroin-related deaths, and prescription opioid-related deaths. RESULTS: Most of the 8813 drug-related deaths were overdoses, with about 11% resulting from transportation/other injuries in which drugs were contributors. Prescription opioid presence (without fentanyl) decreased by 75% from 2005-14 to 2015-17 (3545 deaths to 859 deaths, respectively), while fentanyl involvement in the deaths increased by 122% between these periods (487 to 1082 deaths). Ten FAs were identified (427 instances) after 2015. Alprazolam and ethanol were among the top five most frequently identified substances across years. Fentanyl, heroin and cocaine replaced oxycodone, diazepam and hydrocodone in the top five beginning in 2015. Few decedents had a prescription for fentanyl after 2015, with fewer prescriptions also present for other controlled substances identified. CONCLUSIONS: Fentanyl, rapidly emerging FAs, and other illicit drugs in recent years pose a serious health threat even though prescription opioid-related deaths decreased over the same time period.

The Importance of Melatonin Detection in Pediatric Deaths.

Melatonin is an endogenous hormone that regulates sleep patterns. It is available in varying formulations and dosages and is marketed as a natural substance that can alleviate insomnia. Recent news reports indicate that melatonin has been administered without appropriate authorization in daycare settings. Even though lethal outcomes have not been solely attributed to exogenous melatonin overdose, it has been relevant to select police and postmortem investigations. A quantitative liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was developed for the analysis of biological specimens. Results of 22 positive blood samples were evaluated based upon gender, age, and melatonin concentration from cases submitted by clinical, police, and death investigation agencies. Two cases are described. In Case 1, a 9-month-old was found unresponsive after cosleeping with a sibling. Allegations included exposure to an unspecified pesticide and dextromethorphan, and consumption of half a cigarette. There was admitted use of melatonin. Melatonin was quantified in blood and gastric fluid at concentrations of 13 ng/mL and 1200 ng/mL, respectively. In Case 2, a 13-month-old was found nonresponsive in a shared room. Melatonin was found within some of the sippy cups. The infant was extremely warm to the touch. Resuscitative efforts were unsuccessful and death was pronounce3d. Analysis showed a result of 210 ng/mL in blood. The presented quantitative LC-MS/MS method can successfully be applied to evaluate exposure to exogenous melatonin. Toxicology testing can assist in the investigation of these case types by substantiating the purposeful administration of melatonin.