Fatal Drug Research Articles

Evaluation of isatuximab in patients with soft-tissue plasmacytomas: An analysis from ICARIA-MM and IKEMA

The Phase 3 ICARIA-MM (NCT02990338) and IKEMA (NCT03275285) studies demonstrated that isatuximab (Isa) plus pomalidomide (P) and dexamethasone (d; Isa-Pd) or carfilzomib (K) and d (Isa-Kd) improved progression-free survival (PFS) versus Pd or Kd in patients with relapsed and/or refractory multiple myeloma. In this post hoc analysis of patients with soft-tissue plasmacytomas, we evaluated Isa-Pd/Isa-Kd efficacy using central radiology and central laboratory assessments. Given the low incidence of soft-tissue plasmacytomas (7.8 %, ICARIA-MM; 6.3 %, IKEMA), efficacy data were pooled across the two studies. PFS (HR, 0.47; 95 % CI, 0.21–1.08), overall response rate (50.0 % vs 17.7 %), and very good partial response or better rate (26.9 % vs 11.8 %) were improved with Isa-Pd/Isa-Kd versus Pd/Kd, with consistent improvements within individual studies. Patients with soft-tissue plasmacytomas who received Isa-Pd/Isa-Kd had similar median PFS compared with those without soft-tissue plasmacytomas and received Pd/Kd. Safety is reported individually per study. Longer median treatment duration and more Grade ≥ 3 treatment-emergent adverse events occurred in the Isa versus control arms in ICARIA-MM (36.9 vs 8.4 weeks; 85.7 % vs 70.0 %) and IKEMA (41.9 vs 29.9 weeks; 100.0 % vs 57.1 %); however, Isa did not increase the percentage of patients with fatal events or drug discontinuation. Isa-Pd or Isa-Kd is a potential new treatment option and partially overcomes the poor prognosis associated with soft-tissue plasmacytomas in relapsed and/or refractory multiple myeloma.

Demographic and Geographic Variation in Fatal Drug Overdoses in the United States, 1999-2020.

The U.S. drug overdose crisis has been described as a national disaster that has affected all communities. But overdose rates are higher among some subpopulations and in some places than they are in others. This article describes demographic (sex, racial/ethnic, age) and geographic variation in fatal drug overdose rates in the United States from 1999 to 2020. Across most of that timespan, rates were highest among young and middle-age (25-54 years) White and American Indian males and middle-age and older (45+ years) Black males. Rates have been consistently high in Appalachia, but the crisis has spread to several other regions in recent years, and rates are high across the urban-rural continuum. Opioids have been the main contributor, but overdoses involving cocaine and psychostimulants have also increased dramatically in recent years, demonstrating that our problem is bigger than opioids. Evidence suggests that supply-side interventions are unlikely to be effective in reducing overdoses. I argue that the U.S. should invest in policies that address the upstream structural drivers of the crisis.

The impact of opioid agonist treatment on fatal and non-fatal drug overdose among people with a history of opioid dependence in NSW, Australia, 2001-2018: findings from the OATS retrospective linkage study.

ObjectivesThere are critical periods of mortality risk at onset and cessation of opioid agonist treatment. We aim to determine whether non-fatal overdose followed the same pattern as fatal overdose, comparing the first 4 weeks of treatment and treatment cessation and the remainder time off treatment, with the remainder treatment time, to determine intervention markers. ApproachRetrospective cohort study of people with a history of opioid agonist treatment using linked New South Wales data. The incidence of non-fatal overdose hospitalization; emergency department presentation; and fatal overdose from national death records were compared. Rates were calculated using generalized estimating equations adjusting for demographics, year, and recent health and incarceration events. ResultsThe rate of an emergency department drug overdose presentation was highest. It was more than three-fold the rate of opioid non-fatal overdose hospitalisation and 14 times higher than fatal opioid overdose. It was also twice the rate of non-opioid non-fatal overdose hospitalisation. Fatal overdose was lowest while in treatment. This differed from the measures of non-fatal overdose, the overdose rate was elevated in the first four weeks in treatment as well as the first four weeks post treatment. ConclusionsRetention on opioid agonist treatment is protective against drug related overdose. There is elevated risk of non-fatal overdose at treatment initiation that is not evident for fatal overdose, however the first month of treatment cessation is a critical period for both non-fatal and fatal overdose. These findings emphasize the importance of treatment retention and interventions for polysubstance overdose at cessation.

Fatal adverse drug reactions in children: A descriptive study in the World Health Organization pharmacovigilance database, 2010-2019.

Adverse drug reactions (ADRs) represent a significant public health burden. There are few data on fatal ADRs in children. This population is particularly at risk due to metabolic and physiological immaturity, frequent off-label drug use and limited paediatric clinical pharmacology studies. The study investigated the main characteristics of drug-related deaths registered in World Health Organization pharmacovigilance database, during the past decade. Fatal outcomes registered between 2010 and 2019 in children (<18 y) and reported by physicians were investigated. Age, sex and suspected drugs were described and disproportionality analyses investigated differences according to sex, age and continents with calculation of reporting odds ratio and its 95% confidence interval. Among the 1 198 560 reports registered in children, 1585 (0.13%) were fatal. They occurred mainly in boys, aged 28 days-23 months. Reports mostly came from the Americas and Europe and involved, besides anti-infectious drugs (mainly vaccines), central nervous system (vigabatrin, paracetamol, methylphenidate…) and antineoplastic/immunomodulating (mainly thalidomide) and cardiovascular (mainly bosentan) drugs without major differences between boys and girls. Large differences were found according to continents and age. The risk of reporting was higher in boys, in children aged <23 months, in the Americas and Africa. Fatal ADRs represented a small part (around 1/1000) of total registered ADRs, occurred more frequently in boys and during the first 2 years of life. Beside anti-infectious drugs (vaccines), neuropsychiatric drugs were the most frequently involved, with large differences according to continents and classes of age.

Coroner county systems are associated with a higher likelihood of unclassified drug overdoses compared to medical examiner county systems

ABSTRACT Background: There is a striking geographic variation in drug overdose deaths without a specific drug recorded, many of which likely involve opioids. Knowledge of the reasons underlying this variation is limited. Objectives: We sought to understand the role of medicolegal death investigation (MDI) systems in unclassified drug overdose mortality. Methods: This is an observational study of 2014 and 2018 fatal drug overdoses and U.S. county-level MDI system type (coroner vs medical examiner). Mortality data are from the CDC’s National Center for Health Statistics. We estimated multivariable logistic regressions to quantify associations between MDI system type and several outcome variables: whether the drug overdose was unclassified and whether involvement of any opioid, synthetic opioid, methadone, and heroin was recorded (vs unclassified), for 2014 (N = 46,996) and 2018 (N = 67,359). Results: In 2018, drug overdose deaths occurring in coroner counties were almost four times more likely to be unclassified (OR 3.87, 95% CI 2.32, 6.46) compared to medical examiner counties. These odds ratios are twice as large as in 2014 (difference statistically significant, P < .001), indicating that medical examiner counties are improving identification of opioids in drug overdoses faster than coroner counties. Conclusions: Accurate reporting of drug overdose deaths depends on MDI systems. When developing state policies and local interventions aimed to decrease opioid overdose mortality, decision-makers should understand the role their MDI system is playing in underestimating the extent of the opioid overdose crisis. Improvements to state and county MDI systems are desirable if accurate reporting and appropriate policy response are to be achieved.

Fatal drug poisonings in an industrial region of the Far North of Russia

IntroductionDrug poisonings is a continuous public health problem in Russia and worldwide.ObjectivesThe objective of the study was to provide characteristics of lethal drug poisonings in a northern Russian region.MethodsThe data on deaths from drug poisoning that occurred between 2018 and September 2021, systematically collected by the Regional Center on the Organization of the Narcological and Psychiatric service of the Khanty-Mansi Autonomous Okrug of Russia, was analyzed.ResultsAmong 220 cases of fatal drug poisoning the overwhelming majority (90.4%) occurred among males. The number of cases increased annually from 27 in 2018 to 71 in 2020. The average age of death increased from 33.6 years in 2018 to 38.2 years in 2021. Over two thirds of deceased (70.9%) had complete secondary or vocational secondary level of education, almost one third (30.0%) were skilled workers, and slightly less than half (44.1%) were unemployed. The most common causes of death were methadone poisoning (34.5%), poisoning with other opioids (21.8%), other synthetic drugs (17.3%), other unspecified drugs (11.8%), and psychostimulants (10.0%). Alcohol intoxication was identified as a concomitant cause of death in every fourth case (26.0%), of which 98% were among males. Most often, alcohol was present in the blood at a concentration of 120 mg/ml and above. Every fourth deceased (23.6%) was registered with narcology health service for drug addiction.ConclusionsFatal poisonings with narcotic drugs and psychotropic substances is a growing public health problem in a northern industrial region of Russia, which affects predominantly working-age males and requires comprehensive multisectoral response.DisclosureNo significant relationships.

Contesting Deaths’ Despair: Local Public Religion, Radical Welcome and Community Health in the Overdose Crisis, Massachusetts, USA

Abstract In the United States, the first decades of the twenty-first century have been marked by a worsening fatal drug overdose epidemic leading life expectancy to decline for the first time in a century. Often termed deaths of despair, this development is attributed to declines in civic life, including lessening religious participation, wrought by long-term deindustrialization. Despite this, civil society has responded by contesting despair and the conditions hastening fatal overdose trends. This article examines faith-based community responses to the American overdose crisis through an extended case study of a church-led campaign in Massachusetts. In the summer of 2017, the state of Massachusetts released its fatal overdose numbers to the public: 2,069 people died of fatal overdose in 2016. In response, Trinity Church of Wrentham, Massachusetts, launched the #2069 campaign resulting in over 2,000 billboards and lawn signs emblazoned with #2069 displayed across the state. The memorial project fostered conversation, but also forged new community active in its work of social support, public health outreach and nonpartisan political engagement. The article considers the role of faith-based public health efforts and the potential for further interfaith and interracial collaboration on public health issues and the role of public religion in contesting conditions of despair.

Identifying behaviours for survival and wellness among people who use methamphetamine with opioids in British Columbia: a qualitative study

BackgroundBritish Columbia (BC) has been in a state of public health emergency since 2016, due to the unprecedented numbers of fatal and non-fatal drug toxicity (i.e. overdose) events. Methamphetamine detection in illicit drug toxicity deaths increased from 14% in 2012 to 43% in 2020 suggesting a concerning trend of concurrent methamphetamine and opioid use in BC, consistent with rising patterns identified across North America. People who use methamphetamine concurrently with opioids face an elevated risk of harm. This study aimed to identify behaviours for survival and wellness practiced by people who concurrently use methamphetamine and opioids.MethodsOne-on-one semi-structured interviews were conducted by peer research assistants in person and by telephone. Thematic analysis was carried out to identify patterns in behaviours participants described as important to their safety in the context of concurrent use of methamphetamine and opioids.ResultsParticipants (n = 22) were distributed across the province with at least four participants from each of the five geographic health regions: 64% self-identified as men, and 50% self-identified as Indigenous. Daily methamphetamine use was reported by 72.7% of participants, and 67.3% reported using alone either often or always. Participants made several considerations and adaptations in order to balance the perceived benefits and risks of their use of methamphetamine with opioids. Two overarching themes were identified to describe how participants adapted their use for survival and wellness. The first was personal safety behaviours which included self-regulation and self-care behaviours. The second was interpersonal safety behaviours which included using alongside peers, and engaging with peer-led services (e.g. community outreach organizations) and public health-led services (e.g. overdose prevention sites) to reduce the risk of harm. Participants identified many gaps in available services to meet their diverse needs.ConclusionsThis manuscript identified diversity in participants’ methamphetamine and opioid use (i.e. frequency, route of administration), and a range of behaviours that were performed to improve wellness and survival while using methamphetamine and opioids. Harm reduction and treatment responses must be robust and adaptable to respond to the diversity of patterns of substance use among people who use methamphetamine and opioids concurrently, so as to not perpetuate harm and leave people behind.

Multivalent Vaccine Strategies against Polydrug Use in Opioid Use Disorders

The number of annual fatal drug overdoses reached more than 100,000 between April 2020 to 2021, of which the majority involved individual opioids or polydrug mixtures containing opioids. A series of conjugate vaccines targeting fentanyl, carfentanil, oxycodone, heroin, and their analogs or metabolites have shown preclinical proof of efficacy, selectivity, and safety. Individual vaccines consist of haptens, small molecules that mimic the structure of the targeted drug, conjugated to carrier proteins, such as detoxified diphtheria toxin (CRM) or keyhole limpet hemocyanin (KLH). These studies identified lead haptens based on fentanyl (Fen), carfentanil (Carf), oxycodone (Oxy), and heroin (Her). Preclinical studies showed the efficacy of each vaccine (Fen‐CRM, Carf‐CRM, Oxy‐KLH, and Her‐KLH) in blocking their respective target drug distribution to the brain and their behavioral effects in mice and rats. While multivalent vaccine formulations are commonly used as a safe and effective strategy against infectious diseases, multivalent vaccination strategies against polydrug use have not yet been fully explored at treating substance use disorders. In the current study, the balb/c mice were vaccinated with a combination of Fen‐CRM, Carf‐CRM, Oxy‐KLH, and Her‐KLH as a quadrivalent vaccine. ELISA showed that quadrivalent vaccine increased fentanyl‐, carfentanil‐, oxycodone‐, and heroin‐specific IgG titers in the immunized mice. Correspondingly, this simultaneous immunization prevented the distributions of fentanyl, carfentanil, oxycodone, and heroin to the brain when the mice were challenged by the mixture of these drugs. These data demonstrate that individual efficacy of monovalent vaccine was preserved in a multivalent formulation without interference. Amid opioid epidemics, multivalent vaccine strategies will provide a broad spectrum of protection against multiple opioids with a single vaccination.

Pharmacology and pharmacokinetics of fentanyl toxicity reversal by anti‐fentanyl monoclonal antibodies in combination with naloxone

AIMWidespread access to illicit fentanyl has contributed to an ongoing epidemic of fatal drug overdoses in the United States. The incidence of fatal overdoses in the United States accelerated during the COVID‐19 pandemic, with over 100,000 deaths recorded by April 2021. Fentanyl‐specific monoclonal antibodies (mAb) offer a prophylactic and therapeutic intervention against opioid overdose by binding and sequestering fentanyl in serum, and reducing distribution to the brain. Here, the kinetics of overdose reversal by anti‐fentanyl mAb alone or in combination with naloxone were explored, and the dose‐response relationship between naloxone and high doses of fentanyl in the presence of mAb was evaluated.METHODSTo evaluate the kinetics of fentanyl reversal, fentanyl 0.1 mg/kg was administered to male Sprague‐Dawley rats, and mAb or naloxone was administered fifteen minutes after exposure. Oxygen saturation was monitored constantly for ten minutes following administration of reversal agent. To evaluate duration and extent of protection from further fentanyl exposures, rats were pre‐treated with mAb, naloxone, or a combination, and challenged with increasing doses of fentanyl up to 0.5 mg/kg. Finally, to determine whether the presence of mAb would increase efficacy of naloxone against a lethal dose of fentanyl, 2.25 mg/kg fentanyl was administered, followed by naloxone 0.01 to 1.0 mg/kg.RESULTSThe most rapid reversal of fentanyl toxicity was achieved by intravenous administration of a combination of anti‐fentanyl mAb and naloxone (&lt;1 min). Intravenous naloxone reversed fentanyl toxicity more quickly than subcutaneous naloxone, and intravenous mAb was effective against fentanyl within 4 minutes, similar to subcutaneous NLX. Against further challenges of fentanyl, both mAb and 0.1 mg/kg naloxone were effective against 0.1‐0.2 mg/kg fentanyl, and the combination of mAb and naloxone was effective against doses of 0.5 mg/kg fentanyl or higher. Prophylactic administration of mAb enhanced efficacy of naloxone in reversing a potentially lethal challenge of 2.25 mg/kg fentanyl. Finally, mAb sequestered high concentrations of both fentanyl and its metabolite norfentanyl in serum, and reduced brain concentrations of fentanyl in pre‐exposure scenarios.CONCLUSIONSThese results support translation of mAb as medical countermeasures to prevent and reverse opioid overdose related to fentanyl and its analogs.

The impact of opioid agonist treatment on fatal and non-fatal drug overdose among people with a history of opioid dependence in NSW, Australia, 2001–2018: Findings from the OATS retrospective linkage study

BackgroundThere are critical periods of mortality risk at onset and cessation of opioid agonist treatment. We aim to determine whether non-fatal overdose followed the same pattern as fatal overdose, comparing the first 4 weeks of treatment and treatment cessation and the remainder time off treatment, with the remainder treatment time, to determine intervention markers. MethodsRetrospective cohort study of people with a history of opioid agonist treatment using linked New South Wales data. The incidence of non-fatal overdose hospitalization; emergency department presentation; and fatal overdose from national death records were compared. Rates were calculated using generalized estimating equations adjusting for demographics, year, and recent health and incarceration events. ResultsThe remainder time in OAT had the lowest incidence of overdose for all outcomes and is the reference level for the adjusted incident rate ratios (aIRR). Fatal overdose was lowest in treatment and highest in the first four weeks out of treatment, aIRR of 12.83 (95% CI 10.0–16.4). Whereas the highest overdose rate for non-fatal opioid overdose was in the first four weeks in treatment, aIRR of 3.11 (95% CI 2.19–4.42). ConclusionsRetention on opioid agonist treatment is protective against drug related overdose. There is elevated risk of non-fatal overdose at treatment initiation that is not evident for fatal overdose, but the first month of treatment cessation is a critical period for both non-fatal and fatal overdose. These findings emphasize the importance of treatment retention and interventions for polysubstance overdose at cessation.

Variation in US drug overdose mortality within and between Hispanic/Latine subgroups: A disaggregation of national data

This study examined differences across Latine heritage groups (i.e., Mexican, Puerto Rican, Cuban, Dominican, Central American, South American) in rates of US drug overdose mortality.The study utilized 2015–2019 mortality data from the National Center for Health Statistics for 29,137 Hispanic individuals who died of drug overdose. We used population estimates from the American Community Survey to calculate age-standardized drug overdose mortality rates by specific Latine heritage and sex, nativity, educational attainment, and geographic region. We also calculated standardized rate ratios (SRRs), incidence rate ratios (IRRs) from negative binomial regression models, and 95% Confidence Intervals (CIs), using multiple imputation for missing Latine heritage group in select models.Drug overdose mortality rates in the Puerto Rican heritage group were more than three times as high as in the Mexican heritage group (IRR 3.61 [95% CI 3.02–4.30] in unadjusted model; IRR 3.70 [95% CI 3.31–4.15] in model adjusted for age, sex, nativity, educational attainment, and region; SRR 3.23 [95% CI, 3.15–3.32] in age-standardized model with missing Hispanic heritage imputed). Higher age-standardized rates of drug overdose mortality were observed in males than females across all Latine groups, yet the magnitude of the sex differential varied by Latine heritage. The relationship between drug overdose mortality and nativity differed by Latine heritage; in all groups except Puerto Rican, overdose mortality rates were significantly higher in the US-born than those not US-born. In contrast, overdose mortality rates were significantly lower for US-born Puerto Ricans than for Puerto Ricans who were not US-born (e.g., born in Puerto Rico; SRR, 0.84 [95% CI 0.80–0.88]). The relationship between drug overdose mortality and educational attainment (for ages 25+) also varied between Latine groups.The diverse subgroups comprising the US Latine population vary not only in rates of drug overdose mortality, but also in demographic risk factors for fatal drug overdose.

Identifying bright spot communities: Socioecological, workforce, and healthcare delivery factors influencing opioid mortality.

There were 50,000 U.S. opioid overdose deaths in 2019. Millions suffer from opioid addiction. Identifying protective factors for low community opioid mortality may have important implications for addressing the opioid epidemic. This study was funded through the Virginia (VA) Department of Medical Assistance Services (DMAS) through a SUPPORT Act Grant. To identify "Bright Spot" communities in Virginia with protective factors associated with reduced opioid mortality and morbidity. Ecologic study. Virginia All Payer Claims Database (APCD), Virginia Department of Health (VDH) statewide medical examiner registry, and American Community Survey (ACS). 2016-2019; 2019 data cited here. APCD includes VA residents with medical claims through commercial, Medicaid, and Medicare coverage. VDH data includes fatal drug overdoses. ACS surveys all VA residents. Primary outcome: fatal opioid overdoses. Secondary outcomes: emergency room visits for overdoses and opioid-related diagnoses, outpatient diagnoses for opioid-related disorder, prescription rate for opioids, and prescription rate for buprenorphine. Opioid mortality was associated with higher rates of community poverty (r=.38, p<.0001) and disability (r=.52, r<.0001). Opioid mortality was associated with inequality, with higher Gini index associated with higher opioid mortality (r=.23, p<.0001). A higher percentage of black residents was associated with increased fatal opioid overdoses (r=.37, p<.0001) and ED visits for overdoses (r=.30, p<.0001). A higher percentage of white residents correlated with increased outpatient visits for opioid use disorder (r=.24, p<.0001) and higher rates of buprenorphine (r=.34, p<.0001) and opioid prescriptions (r=.31, p <.0001). These findings suggest significant racial disparities in opioid outcomes. Communities with a higher percentage of black residents are more likely to have higher opioid mortality and a lower rate of outpatient treatment. This association may be affected by the time period used in the analysis (2015-2019), as nationally there has been an increasing rate of synthetic opioid deaths in Black communities. These measures have been incorporated into a multivariate analysis to identify Bright Spot communities, which will be discussed during the presentation.

Opioid and Benzodiazepine Substitutes: Impact on Drug Overdose Mortality in Medicare Population

IntroductionGabapentinoids (GABAs) and serotonergic drugs (selective serotonin reuptake inhibitors [SSRIs]/serotonin and norepinephrine reuptake inhibitors [SNRIs]) are increasingly being prescribed as potential substitutes to opioids and benzodiazepines (benzos), respectively, to treat co-occurring pain and anxiety disorders. The toxicities of these drug classes and their combinations are not well understood. MethodsWe conducted a matched case-control study using 2013-2016 Medicare files linked to the National Death Index. Cases were enrollees who died from drug overdose. Controls were enrollees who died from other causes. Cases and controls were matched on patient characteristics and prior chronic conditions. Possession of any opioids, GABAs, benzos, and SSRIs/SNRIs in the month prior to death was defined as drug use. Combination drug use was defined as possessing at least 2 types of these prescriptions for an overlapping period of at least 7 days in the month prior to death. ResultsAmong 4323 matches, benzo possession was associated with twice the risk for drug overdose death in cases vs controls. Compared with opioid-benzo co-prescribing, combinations involving SSRIs/SNRIs and opioids (or GABAs) were associated with decreased risk (adjusted odds ratio 0.55; 95% confidence interval, 0.44-0.69 for opioids and SSRIs/SNRIs; adjusted odds ratio 0.59; 95% confidence interval, 0.44-0.79 for GABAs and SSRIs/SNRIs). Fatal drug overdose risk was similar in users of GABA-opioid, GABA-benzo, and opioid-benzo combinations. ConclusionsBenzodiazepines, prescribed alone or in combination, were associated with an increased risk of drug overdose death. SSRIs/SNRIs were associated with lower risk of overdose death vs benzodiazepines. GABAs were not associated with decreased risk compared with opioids, raising concerns for GABAs’ perceived relative safety.

Sociodemographic and geographic disparities in excess fatal drug overdoses during the COVID-19 pandemic in California: A population-based study

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic is co-occurring with a drug addiction and overdose crisis.MethodsWe fit overdispersed Poisson models, accounting for seasonality and secular trends, to estimate the excess fatal drug overdoses (i.e., deaths greater than expected), using data on all deaths in California from 2016 to 2020.FindingsBetween January 5, 2020 and December 26, 2020, there were 8605 fatal drug overdoses—a 44% increase over the same period one year prior. We estimated 2084 (95% CI: 1925 to 2243) fatal drug overdoses were excess deaths, representing 5·28 (4·88 to 5·68) excess fatal drug overdoses per 100,000 population. Excess fatal drug overdoses were driven by opioids (4·48 [95% CI: 4·18 to 4·77] per 100,000), especially synthetic opioids (2·85 [95% CI: 2·56 to 3·13] per 100,000). The non-Hispanic Black and Other non-Hispanic populations were disproportionately affected with 10·1 (95% CI: 7·6 to 12·5) and 13·26 (95% CI: 11·0 to 15·5) excess fatal drug overdoses per 100,000 population, respectively, compared to 5·99 (95% CI: 5.2 to 6.8) per 100,000 population in the non-Hispanic white population. There was a steep, nonlinear educational gradient with the highest rate among those with only a high school degree. There was a strong spatial patterning with the highest levels of excess mortality in the southernmost region and consistently lower levels at progressively more northern latitudes (7·73 vs 1·96 per 100,000).InterpretationFatal drug overdoses disproportionately increased in 2020 among structurally marginalized populations and showed a strong geographic gradient. Local, tailored public health interventions are urgently needed to reduce growing inequities in overdose deaths.FundingUS National Institutes of Health and Department of Veterans Affairs.

Toxicological Analysis of Fluorofentanyl Isomers in Postmortem Blood.

The opioid epidemic continues to evolve in the USA, with fentanyl the most prevalent synthetic opioid in fatal drug overdoses. Following the scheduling of fentanyl's core structure in 2018, there was a notable decline in the prevalence of fentanyl analogs in decedents; however, fluorofentanyl began being reported in casework in the winter of 2020. Fluorofentanyl has three positional isomers (para-fluorofentanyl (p-FF), ortho-fluorofentanyl (o-FF) and meta-fluorofentanyl (m-FF)), with the most predominant isomer that has recently emerged in the USA being p-FF. The goal of this study was to identify p-FF in postmortem cases between October 2020 and April 2021. Urine and blood were extracted using UCT Clean Screen® extraction columns and then screened using an Agilent 1290 Infinity liquid chromatograph (LC) coupled to an Agilent 6545 accurate mass time-of-flight mass spectrometer (TOF-MS) and quantified using an Agilent 6890N GC system coupled with an Agilent 5973 MS. The limit of quantitation (LOQ) for fentanyl, acetyl fentanyl, butyryl fentanyl, p-FF, o-FF and m-FF was 2.5 ng/mL. The screening method could not differentiate the three positional isomers of fluorofentanyl. Suspected overdose cases (n = 370) received from October 2020 through April 2021 from four Medical Examiner Districts in the state of Florida were analyzed for the presence of fluorofentanyl. The LC-QTOF-MS screen yielded 27 decedents positive for fluorofentanyl, with a majority being Caucasian (93%) and male (70%) with ages ranging from 27 to 63 years. Analysis of the blood and urine by GC-MS yielded 14 decedents positive for p-FF, nine of which were positive in the blood. The blood concentrations (n = 9) for p-FF ranged from <LOQ to 30 ng/mL, with an average and median of 9.9 ng/mL and 5.5 ng/mL, respectively. p-FF was identified in the blood of 33% of the cases, and the concentration of p-FF was generally higher than previously reported.

Impact of the COVID-19 pandemic on temporal patterns of mental health and substance abuse related mortality in Michigan: An interrupted time series analysis

BackgroundThe emergence of SARS-CoV2 (COVID-19) had wide impacts to health and mortality and prompted unprecedented containment efforts. The full impact of the COVID-19 pandemic and resulting responses on mental health and substance abuse related mortality are unknown.MethodsWe obtained records for deaths from suicide, alcohol related liver failure, and overdose from the Michigan Department of Health and Human Services (MDHHS) for 2006 to 2020. We compared mortality within sex, age, marital, racial and urban/rural groups using basic statistical methods. We compared standardized mean daily mortality incidence before and after the onset of the pandemic using t-tests. We used an interrupted time series approach, using generalized additive Poisson regression models with smoothed components for time to assess differences in mortality trends before and after the onset of the pandemic within demographic groups.FindingsThere were 19,365 suicides, 8,790 deaths from alcohol related liver failure, and 21,778 fatal drug overdoses. Compared with 2019, suicides in 2020 declined by 17.6%, overdose mortality declined by 22.5%—while alcohol deaths increased by 12.4%. Crude comparisons suggested that there were significant declines in suicides for white people, people 18 to 65 and increases for rural decedents, overdoses increased for Black people, females and married/widowed people, and alcohol mortality increased for nearly all groups. ITS models, however, suggested increased suicide mortality for rural residents, significantly increased alcohol related mortality for people ≥65 and increased overdose mortality in men.InterpretationThe onset of the pandemic was associated with mixed patterns of mortality between suicide, alcohol and overdose deaths. Patterns varied within demographic groups, suggesting that impacts varied among different groups, particularly racial and marital groups.FundingThis work was supported by the United States National Institute of Environmental Health Sciences [K99/R00ES026198] and their Michigan Center on Lifestage Environmental Exposures and Disease [grant number P30ES017885]; and the Institute for Global Biological Change at the University of Michigan.

Anaphylaxis to Ciprofloxacin Requiring Emergent Surgical Cricothyrotomy.

Although allergies to antibiotics are commonly stated, anaphylactic reactions are uncommonly reported. This is especially the case with reactions to fluoroquinolone antibiotics. Furthermore, airway emergencies are rare. We present a case of ciprofloxacin-induced acute airway obstruction and anaphylaxis, necessitating emergent surgical cricothyrotomy following respiratory distress.LEARNING POINTSAnaphylactic reactions to fluoroquinolone antibiotics are extremely rare.There are currently no standardized diagnostic tests, making the diagnosis of anaphylaxis challenging and largely based on history alone.Treating clinicians should be aware of this rare, but potentially rapidly fatal adverse drug reaction.

Pharmacological Profiling of Antifentanyl Monoclonal Antibodies in Combination with Naloxone in Pre- and Postexposure Models of Fentanyl Toxicity.

The incidence of fatal drug overdoses in the United States is an alarming public health threat that has been exacerbated by the COVID-19 pandemic, resulting in over 100,000 deaths between April 2020 and April 2021. A significant portion of this is attributable to widespread access to fentanyl and other synthetic opioids, alone or in combination with heroin or psychostimulants, such as cocaine or methamphetamine. Monoclonal antibodies (mAb) offer prophylactic and therapeutic interventions against opioid overdose by binding opioids in serum, reducing distribution of drug to the brain and other organs. Here, we investigated the efficacy of a leading antifentanyl mAb, clone HY6-F9, in reversal and prevention of fentanyl-induced toxicity compared with the opioid receptor antagonist naloxone (NLX) in rats. In postexposure models, rats were challenged with fentanyl, followed by HY6-F9, NLX, or both. HY6-F9 reversed fentanyl-induced antinociception, respiratory depression, and bradycardia, and rats retained protection against additional challenges for at least 1 week. Although intravenous NLX reversed fentanyl-induced respiratory depression more rapidly than mAb alone, kinetics of reversal by intravenous mAb were similar to subcutaneous NLX. Coadministration of mAb and NLX provided greater protection than individual treatments against high doses of fentanyl. Prophylactic administration of mAb reduced the ED50 of NLX approximately twofold against 2.25 mg/kg of fentanyl. Finally, mAb sequestered fentanyl and its metabolite norfentanyl in serum and reduced brain concentrations of fentanyl. These results support the translation of mAb as medical interventions alone or in combination with NLX to prevent and reverse fentanyl-related overdose. SIGNIFICANCE STATEMENT: Fentanyl-related overdoses have increased dramatically in the US and worldwide. Currently, approved pharmacotherapies for treatment of opioid use disorder and reversal of overdose are not sufficient to curb the incidence of opioid-related deaths. Additionally, fentanyl and its potent analogs present a potential risk from use in deliberate poisoning or chemical attacks. This study demonstrates the use of monoclonal antibodies as a countermeasure to fentanyl-induced toxicity in pre- and postexposure scenarios, supporting their use in combination with the opioid antagonist naloxone.

Suicidal and accidental drug poisoning mortality among older adults and working-age individuals in Spain between 2000 and 2018

BackgroundAlthough medication poisoning in older adults is considered an increasingly important, but preventable cause of death, it has received relatively little attention. We explored recent trends and correlates of suicidal and accidental fatal drug poisonings among older and working-age individuals using nationwide data from Spain.MethodsWe identified all 15,353 fatal drug poisonings involving decedents aged ≥15 years in Spain between 2000 and 2018 and divided them by age into older adults (≥65 years) and working-age (15-64 years) individuals. For each age group, we analyzed time trends in suicidal and accidental fatal drug poisoning rates (overall and by ICD-10 drug categories) using joinpoint regressions. To understand the specific drugs classified as “Non-psychotropic/non-specified”, we used 2018 data including substance-specific ICD-10 supplementary codes. We explored relevant sociodemographic correlates of suicidal and accidental fatal poisoning rates using multivariable negative binomial regressions.ResultsBetween 2000 and 2018, suicidal fatal poisonings increased faster among older (from 0.19 to 0.63 per 100,000 – average annual change: 7.7%) than working-age individuals (from 0.40 to 0.72 per 100,000 – average annual change: 3.8%). Accidental fatal poisonings increased among older adults (from 0.25 to 2.67 per 100,000 – average annual change: 16.2%) but decreased among working-age counterparts (from 2.38 to 1.42 per 100,000 – average annual change: − 1.9%). Anticoagulants and cardiac-stimulants glycosides accounted for 70% of the 223 accidental fatal poisonings due to non-psychotropic/non-specified drugs registered among older adults in 2018. Roles of gender and urban dwelling in suicidal and accidental poisonings were heterogeneous across age groups.ConclusionIncreases in suicidal drug poisonings were faster among older than working-age individuals. Accidental fatal poisonings increased only among older adults. Our findings that (i) sociodemographic correlates were heterogeneous across age groups and (ii) anticoagulant and cardiac-stimulant glycosides were particularly salient drivers of accidental poisonings among older adults have implications for prevention.