Drug-related Deaths Research Articles

Suicide in people prescribed opioid-agonist therapy in Scotland, United Kingdom, 2011-2020: A national retrospective cohort study.

Opioid dependence is associated with an increased risk of suicide. Drug-related mortality among people with opioid dependence in Scotland has more than tripled since 2010; less is known about changes in suicide risk. We aimed to determine if opioid agonist therapy (OAT) in Scotland is protective against suicide and to measure trends in suicide rates in those with opioid dependence over time. Retrospective cohort study. Scotland, UK. 46 453 individuals in Scotland who received at least one prescription for OAT between 2011 and 2020 with over 304 000 person-years (pys) of follow-up. We calculated standardised mortality ratios (SMR) using the age- and sex-specific suicide rates in Scotland for years 2011-2020. We fitted multivariable competing-risk regression models to estimate suicide rates by OAT exposure and to estimate trends over time, adjusting for potential confounders. There were 575 deaths classed as suicide among the cohort and the overall suicide rate was 1.89 (95% confidence interval [CI] = 1.74-2.05) per 1000 pys. Age and sex SMR for suicide was 7.05 times (95% CI = 6.50-7.65) higher than in the general population. After adjustment, OAT was shown to be highly protective against suicide, with rates more than three times greater (adjusted hazard ratio: 3.07; 95% CI = 2.60-3.62) off OAT compared with on OAT. Suicide rates decreased over time, falling from 2.57 (95% CI = 2.19-3.02) per 1000 pys in 2011-12 to 1.48 (95% CI = 1.21-1.82) in 2019-20. People with opioid dependence in Scotland appear to have a greater risk of suicide than the general population. Treatment is protective, with rates of suicide lower among those on opioid agonist therapy. Suicide rates have decreased over time, during a period in which drug-related death rates in Scotland have risen to globally high levels.

Systematic review: The relationship between gabapentinoids, etizolam, and drug related deaths in Scotland.

In recent years Scotland has been experiencing a disproportionally high number of drug related deaths compared to other European countries, causing significant individual, societal and economic burden. A possible cause of this is the increase in average number of substances involved in Scottish drug related deaths, as well as the changing pattern of substances involved. Opioids, cocaine, and alcohol have been consistently involved in the culture of drug use in Scotland, however recently National Records Scotland have identified that designer benzodiazepines such as etizolam, and prescription drugs such as gabapentinoids are increasingly being detected in Scottish toxicology reports. A systematic literature review following PRISMA guidelines was conducted through searching PubMed and Google Scholar to identify peer-reviewed articles published in English between 2013 and 2023 that investigated Scottish population data on gabapentinoids and etizolam to establish their contribution to the rise in Scottish drug related deaths. 18 studies were included in the review. A high use prevalence of etizolam and gabapentinoids in Scotland has been identified, with both substance-related deaths showing recent increase, marked since 2015. This pattern is replicated in the Scottish prison system. There has also been a significant increase of gabapentinoids prescriptions in Scotland. Polydrug use was identified as the most common determinant of both etizolam and gabapentinoids related adverse effects and fatality in Scotland, especially concurrent opioid use. The results indicate the literature on individual characteristics of Scottish at-risk users of gabapentinoids and etizolam is limited, however the data shows both substances are being used by older cohort, with adverse effects seen more in older women.

Access and care for people with opioid use disorder in U.S. skilled nursing facilities: A policy commentary

Referrals for people with opioid use disorder (OUD) to skilled nursing facilities (SNFs) are increasing in the United States (U.S.). Further, legal guidance from the U.S. Department of Justice states that people with OUD cannot be discriminated against by health care institutions because of OUD or treatment with medications for OUD (MOUD). As such, SNFs are an important touchpoint for initiating or continuing MOUD, particularly amid rising drug-related overdose deaths among older adults and because people with OUD experience frailty and other geriatric syndromes at younger chronological ages. Informed by research, clinical expertise, and lived experience, this commentary describes policy and practice opportunities to help address challenges faced by people with OUD in gaining access to care and MOUD in SNFs. We propose opportunities to intervene against barriers that impede SNF placement and access to MOUD for people with OUD, including further revisions to 42 CFR Part 8 regulations to extend waivers for certification as opioid treatment programs (OTPs) to SNFs, allowing them to administer and dispense methadone in the same way as hospitals. If passed, proposed federal changes under the Modernizing Opioid Treatment Act would eliminate the requirement for methadone to be dispensed through OTPs, offering another opportunity to improve access to methadone for SNF residents. Also, we propose national and state-level investment in mobile substance use disorder services and partnerships with OTPs and hospital-based addiction consult services. We also recognize the need for more compassionate attitudes toward people with OUD in healthcare settings and discuss opportunities to address stigma. Although people with OUD are referred to SNFs for skilled care needs and not specifically for OUD care, it is essential for SNFs to be prepared to continue MOUD. It is both legally mandated and imperative that people with OUD have access to high quality and equitable SNF care.

Exploring unified methods of killing and storing insect samples for forensic entomotoxicology using diazepam in Lucilia sericata (Meigen, 1826) (Diptera: Calliphoridae) larvae

Forensic entomologists use the maturity of necrophagous larvae to estimate the minimum post-mortem interval (PMImin), ideally taking account of effects that xenobiotics in the corpse may have on insect maturation. Forensic toxicologists may employ larvae to detect drugs in drug-related deaths when human samples are unavailable. Yet current pre-analytical practices of these two professions differ significantly, impeding the successful use of the same samples. Potential benefits of shared pre-analytical practices and opportunities for enhanced collaboration have yet to be fully explored. We employed Lucilia sericata (Meigen, 1826) (Diptera: Calliphoridae) larvae, grown in the presence of diazepam, to investigate the effects of two standard investigative practices on larvae for drug detection and for quantifying mass and length as proxies of age. Specimens were killed by either blanching or freezing and stored at -20℃ for either intermediate or long periods. Blanched larvae showed smaller changes in size and body integrity during storage, thereby producing the most reproducible estimates of PMImin. Consequently, data obtained from blanched larvae were used to evaluate the impact of diazepam on larval development. Diazepam exerted no significant effect on larval mass, and a weak effect on length. Diazepam recovery was significantly higher from blanched larvae, suggesting that freeze-killing causes drug loss. This model system demonstrates the value to forensic entomologists of the standard technique of blanching larvae, followed by storage at -20℃ for toxicological analysis. We recommend that forensic toxicologists consider blanching to kill larvae before storage at low temperatures, at least for certain drugs. This approach offers the dual benefit of high-quality specimens for both PMI estimation and drug detection.

DRAMES and DTA databases: complementary tools to monitor drug-related deaths in France

DRAMES and DTA databases: complementary tools to monitor drug-related deaths in France

From Digital Inclusion to Digital Transformation in the Prevention of Drug-Related Deaths in Scotland: Qualitative Study.

Globally, drug-related deaths (DRDs) are increasing, posing a significant challenge. Scotland has the highest DRD rate in Europe and one of the highest globally. The Scottish Government launched the Digital Lifelines Scotland (DLS) program to increase the provision of digital technology in harm reduction services and other support services. Digital technology responses to DRDs can include education through digital platforms, improved access to treatment and support via telehealth and mobile apps, analysis of data to identify risk factors, and the use of digital tools for naloxone distribution. However, digital technology should be integrated into a comprehensive approach that increases access to services and addresses underlying causes. Digital transformation could enhance harm reduction service and support, but challenges must be addressed for successful implementation. The DLS program aims to enhance digital inclusion and improve health outcomes for people who use or are affected by drug use to reduce the risk of DRDs. This study aims to explore the role of digital technology as an enabler and supporter in enhancing existing services and innovating new solutions, rather than being a stand-alone solution. Specifically focusing on individuals who use drugs, the research investigates the potential of digital inclusion and technology provision for preventing DRDs within the context of the DLS program. Semistructured interviews were conducted with 47 people: 21 (45%) service users, 14 (30%) service providers, and 12 (26%) program staff who were all involved in DLS. Interviews were audio recorded, transcribed, and then coded. Analysis was done in three phases: (1) thematic analysis of interview data to identify the benefits of digital technologies in this sector; (2) identification of the challenges and enablers of using digital technologies using the Technology, People, Organizations, and Macroenvironment conceptual framework; and (3) mapping digital technology provision to services offered to understand the extent of digital transformation of the field. Participants identified increased connectivity, enhanced access to services, and improved well-being as key benefits. Digital devices facilitated social connections, alleviated loneliness, and fostered a sense of community. Devices enabled engagement with services and support workers, providing better access to resources. In addition, digital technology was perceived as a preventive measure to reduce harmful drug use. Lack of technical knowledge, organizational constraints, and usability challenges, including device preferences and security issues, were identified. The study found that digital inclusion through the provision of devices and connections has the potential to enhance support in the harm reduction sector. However, it highlighted the limitations of existing digital inclusion programs in achieving comprehensive digital transformation. To progress, there is a need for sustained engagement, cultural change, and economic considerations to overcome barriers.

Impact of ante-mortem fluoxetine administration on estimation of post-mortem interval and insect activity in rabbit carcasses

BackgroundIncreasing the number of drug-related deaths has affected medico-legal death investigations. Drugs within a corpse have a great impact on the insects’ development rate which in turn will affect the rate of post-mortem decomposition and the estimation of the post-mortem interval. This explains the importance of the application of forensic entomotoxicology, which studies the impact of drugs and toxins on the development and succession patterns of insects. The current study aimed to determine the impact of fluoxetine, one of the selective serotonin reuptake inhibitors (SSRIs), on post-mortem decomposition, insects’ attraction, and its pattern of succession on carcasses. Sixteen healthy male and female Oryctolagus cuniculus rabbits were chosen to be included in this study. They were divided into a treated group of eight rabbits received oral fluoxetine for 28 days and a control group of eight rabbits received oral distilled water for 28 days. After oral administration of 10 mg/kg/day of fluoxetine and distilled water for 28 days, rabbits were sacrificed, and carcasses were transmitted to the roof of Research and Training Centre on Vectors of Diseases at faculty of Sciences, Ain Shams University, for following up the post-mortem decomposition process and insect’s attraction to carcasses for 60 days. Carcasses were put in two outdoor sites that differ in temperature to assess the effect of temperature on decomposition process.ResultsFluoxetine administration has accelerated the rate of post-mortem decomposition in the treated carcasses by 3–9 days compared to the control ones and affected the numbers and species of attracted insects, while it had no effect on the insects’ succession patterns. Exposure of carcasses to direct sunlight has accelerated the rate of decomposition in comparison to that of carcasses put in shade in the overall period of decomposition by about 14 to 16 days.ConclusionsFluoxetine has an important and effective role in post-mortem decomposition and estimation of post-mortem interval (PMI) and has a great impact on attracted insects to the treated carcasses. Temperature has a great effect on the rate of decomposition of carcasses. Higher temperature accelerates the rate of post-mortem decomposition.

All-cause and cause-specific mortality amongst individuals with substance misuse: A population-based linked data study in Wales

ObjectiveSubstance misuse has a detrimental impact on an individual’s health and the wider society, as well as elevated mortality. Here, we analysed the association between substance misuse events across several healthcare service providers and risk of mortality. ApproachIn this retrospective population-based cohort study, we identified substance misuse amongst a cohort in Wales, aged ≥10 years old between 2010 and 2019 using the Secure Anonymised Linkage (SAIL) Databank. Cox regression and Kaplan-Meier survival curves were used to calculate risk for all-cause and cause-specific mortality. ResultsDuring the study period 16,229 (9.7%) individuals with a substance misuse event died. A high proportion of these individuals died prematurely (<75 years, 66.7%), and nearly half were from the most deprived areas at time of death (46.8%). Alongside alcoholic liver disease and alcohol hepatic failure, cardiovascular and respiratory diseases were the most common underlying causes of death. Those in receipt of specialist substance misuse treatment for alcohol-use were at greatest risk of suicide (hazard ratio: 1.83) and drug-related deaths (hazard ratio: 1.98). Risk of suicide was also higher for those with a drug-use health event recorded during a hospital admission (hazard ratio: 1.89). ConclusionsSubstance misuse was associated with elevated mortality risk, in particular, amongst those with substance misuse recorded during inpatient hospital admissions. These findings highlight the need for early interventions such as increased screening and monitoring of substance use to prevent premature mortality. ImplicationsOur results provide a clear indication of service needs to support planning and provisioning of health services.

Characteristics of drug-related deaths where individuals are found submerged in a bath or hot tub in the United Kingdom, 1997-2023.

Recent media reports highlight that drug-related fatalities can occur while individuals are immersed in water in domestic settings. We aimed to determine the case characteristics, circumstances of death and type of implicated drugs among individuals dying due to unintentional drug-related causes found immersed in a bath or hot tub. Retrospective cohort study in the United Kingdom using coronial records from the National Programme on Substance Abuse Deaths, 1997-2023. Information was available on decedent socio-demographics, characteristics of death and drugs implicated in death. One hundred fifty-six decedents were found immersed in the bath and six in a hot tub, a mean of 6.4 deaths per year (SD 3.7; range 1-13). Overall decedents were predominantly male (n = 94, 58.0%), of White ethnicity (n = 98, 60.5%) with a mean age of 40 years (SD 13; range 19-74). Only 12 decedents had any physical contributory factor to death other than poisoning or drowning. The median number of drugs detected at post-mortem was 3 (interquartile range 2, 5) with multiple drug toxicity implicated in the majority of cases (n = 90, 55.6%). The most common implicated drugs were heroin (n = 53, 32.7%), alcohol (n = 46, 28.4%) and cocaine (n = 33, 20.4%). Over the last two decades in the United Kingdom there have been consistent numbers of unintentional drug-related deaths each year where individuals were found in a bath or hot tub. Polysubstance, opioid and alcohol use are overrepresented. Targeted advice to avoid bathing while intoxicated would appear to be an appropriate harm reduction message.

Pregnancy-Associated Mortality During the Pandemic: Disparities by Rurality

IntroductionIn the US, rural areas experience higher rates of adverse maternal health outcomes, but little data exists on rural/urban differences in pregnancy-associated deaths (PAD, all deaths during pregnancy and postpartum) or rural/urban differences in those deaths during the COVID-19 pandemic. MethodsCross-sectional US vital statistics mortality data from 2018 to 2021 was used to identify PAD (analyzed in 2024). PAD ratios (deaths per 100,000 live births) and 95% confidence intervals (CIs) were calculated by year, cause, and rurality (urban, suburban, rural). The percent change in PAD ratios between the pre-pandemic (2018 and 2019) and pandemic (2020 and 2021) time periods was calculated by rurality. ResultsDuring the pandemic, rural—compared to suburban and urban—areas had the highest pregnancy-associated death ratios due to obstetric causes (53.9 deaths/100,000 live births, 95%CI: 48.8, 59.4), drug-related causes (19.0, 95%CI: 16.0, 22.4), suicide (4.4., 95%CI: 3.0, 6.2), and other causes (the majority of which are motor vehicle accidents, 16.4, 95%CI: 14.0, 19.6). Rural areas experienced increases in all causes of pregnancy-associated death from pre-pandemic (2018 and 2019) to pandemic (2020 and 2021) with increases of 48.1% in obstetric deaths, 115.9% in drug-related deaths, 17.8% in homicide, 25.7% in suicide, and 11.6% in other causes. Rural areas experienced the largest (compared to urban and suburban) increase in drug-related deaths, and only rural areas experienced an increase in suicide during the pandemic. ConclusionsRural areas experience a high burden of pregnancy-associated death, and this inequity was exacerbated during the COVID-19 pandemic.

Deaths involving novel benzodiazepines in Victoria, Australia from 2018-2022.

Novel benzodiazepine (NBz) detections in Victorian coronial cases started early in 2018 and have continued to increase in number and type up to December 2022. The eleven different NBz detections included etizolam (n=82), flualprazolam (n=43), clonazolam or 8-aminoclonazolam (n=30), bromazolam (n=15), clobromazolam (n=13), phenazepam (n=13), flubromazolam (n=12), flubromazepam (n=8), desalkylflurazepam (n=6), diclazepam (n=2), and estazolam (n=1). The pattern of detections varied over the 5-year period, with different compounds appearing over different time frames. The most recent NBz to appear were bromazolam, clobromazolam, flubromazepam and phenazepam; whereas etizolam had been seen regularly in case work since 2018. Of the total 133 deaths, 95 were considered drug related deaths by forensic pathologists with at least one additional CNS depressant also present capable of contributing to death. All deaths involved other (non-benzodiazepine) CNS active drugs, although many involved multiple NBz, with five or more different benzodiazepines detected in eight cases.

The Internalization of Stigma and the Shaping of the Grief Experience for Peers Bereaved by a Drug-Related Death.

People who use drugs form a significant part of the community who are impacted by drug-related deaths, but their stigmatized positioning in society yields implications for their access to support and the social recognition of their grief. This project explores how the internalization of drug-related stigmas shapes the grief experience for peers bereaved by a DRD. Six individuals who experienced the drug death of a peer during their own time in active addiction participated in semi-structured interviews, analyzed by interpretative phenomenological analysis. Three superordinate themes are reported in this paper: (i) Forged Connections; (ii) The Condemnation Script; and (iii) Nowhere Left to Turn. Participants reported grief responses such as survivor's guilt, shame, and increased drug use against the wider social invalidation of their close peer bonds. This paper appeals for a more health-based approach to supporting people in active addiction that recognizes and validates their grief experiences.

An exploratory investigator-initiated trial via intrathecal or intracerebroventricular delivery of B7H3-specific allogeneic universal CAR-T cells in patients with recurrent high-grade gliomas.

23 Background: The MT027, developed by T-Maximum, is a B7-H3 (CD276)-directed genetically modified allogeneic T cell, targeting CD276-overexpressed tumor cells. Here, we reported a first-in-human, single-center, open-label investigator-initiated trial (IIT) via intrathecal or Intracerebroventricular delivery targeting recurrent high-grade glioma (ChiCTR2100047968). Methods: As of March 7, 2024, a total of 50 adult patients with recurrent high-grade glioma, B7H3+ expression, and KPS ≥40 were enrolled and administered at least one dose of MT027 (FAS), of whom, 32 received at least 3 doses (PPS1), 15 subjects with ≥3 doses and at least 1 efficacy visit (PPS2). 4 dose levels of 1.0, 1.5, 2.0, 2.5×107 cells per injection were administered once every 4 weeks. Results: The overall results demonstrated the favorable tolerability, safety, PK/PD characteristics, and preliminary efficacy. In FAS, the most common AE were fever and headache, without any CRS, ICANS, GvHD, or drug-related death. There were 4 cases (8%) of grade 3 AE or greater and 3 cases (6%) of SAEs. The copies of CAR in all groups reached 10000-100000 copy/ug, and persisted for > 60 days after a single dose. After multiple doses, the MT027 CAR-T cell numbers maintained at a high level (median 8850 copies /μg (range: 200-385900)) and for a long time. The levels of IL6, TNF-α and IFN-γ in CSF increased significantly and maintained for a long time. The mOS was 13.54 m (95% CI: 7.45; 19.63) and 20.73 m (95% CI: 16.12; 25.34) in PPS1 and PPS2, respectively. The 12-month OS rate was 53.30% (95%CI: 37.5%-75.7%) and 84.60% (95%CI: 67.1%-100%) in PPS1 and PPS2, respectively (historical data: 14%). The objective response rate (ORR) was 33% and the disease control rate (DCR) was 80% in PPS2. Conclusions: In patients with relapsed high-grade glioma, the intrathecal or ICV administration of MT027 cell therapy was found to be safe and well-tolerated. The toxicity of grade 3 or above was 1/5 of similar products. The pharmacokinetics and pharmacodynamics of single-dose and multiple-dose treatments were stable. MT027 exhibited longer persistence in the body of the patients, and the cell numbers and cytokine responses induced in vivo were 1-2 orders of magnitude higher than those of similar products. MT027 cell therapy demonstrated the excellent efficacy in treating relapsed high-grade glioma, with significantly prolonged overall survival and higher objective response rate compared to the historical data and similar product data. Currently, we are preparing for the IND filing in US (expected in 2024) with the recurrent glioblastoma as the first indication. Clinical trial information: ChiCTR2100047968 .

Xylazine in the Unregulated Drug Market: An Integrative Review of Its Prevalence, Health Impacts, and Detection and Intervention Challenges in the United States.

Xylazine, a veterinary sedative, has emerged as a concerning element in the landscape of substance use in the United States. This integrative review synthesizes evidence from a systematic examination of 14 selected studies conducted between 2008 and 2023. The primary objective is to comprehensively understand the epidemiology and prevalence of xylazine use, particularly its involvement in drug-related deaths, regional variations, national impact, co-occurrence with opioids, and challenges associated with detection and intervention. The results underscore stark regional disparities in xylazine prevalence. West Virginia and Miami-Dade County have experienced alarming surges in xylazine-involved drug-related deaths. Nationally, its influence extends beyond regional boundaries, predominantly affecting white males in the Northeast. The co-occurrence of xylazine with opioids, especially fentanyl and heroin, significantly amplifies the risks of fatal overdoses. Detecting xylazine presents formidable challenges due to its frequent presence alongside other substances, necessitating enhanced surveillance and more effective detection methods. User perspectives emerge as pivotal, emphasizing the importance of user-informed harm reduction strategies. In conclusion, this review has significant policy implications. Tailored, region-specific strategies are imperative to address the diverse prevalence of xylazine use. A nationwide response is indispensable, prioritizing harm reduction initiatives, enhanced detection methods, and active user engagement. The multifaceted nature of the xylazine issue requires comprehensive approaches to mitigate its profound risks effectively. Policymakers are urged to consider regional disparities and the co-occurrence of xylazine with opioids when crafting targeted interventions. Immediate, user-informed harm reduction is vital to address the evolving landscape of xylazine use in the United States.

Trends in toxicological findings in unintentional opioid or stimulant toxicity deaths in Québec, Canada, 2012-2021: Has Québec entered a new era of drug-related deaths?

We aimed to describe rates and toxicological findings of unintentional opioid and stimulant toxicity deaths, 2012-2021. The dataset included accidental deaths determined by the Coroner to be due to opioids or stimulants. We calculated annual crude mortality rates and described combinations of drugs identified in toxicological examinations of these deaths. We described temporal trends in the detection of specific opioids, stimulants, benzodiazepines (including novel benzodiazepines), gabapentinoids and z-drugs in deaths due to opioids and stimulants. Mortality rates increased over time, reaching their peak in 2020 and remaining high in 2021. In deaths due to opioids, there was a decline in the proportion of deaths involving pharmaceutical opioids after 2019, and a corresponding increase in the proportion of deaths with fentanyl detected. Benzodiazepines were often present in deaths due to opioids, with novel benzodiazepines increasing rapidly from 2019 onwards. Cocaine was the most frequently detected drug in deaths due to stimulants, but amphetamine/methamphetamine was detected in around half of all stimulant deaths from 2016 onwards. Despite availability of a multitude of overdose prevention interventions, mortality rates due to drug toxicity have increased in Québec. Toxicological findings of these deaths suggest concerning shifts in the illicit drug market, with Québec potentially having entered a new era of elevated overdose mortality. Intervention scale-up is essential, but unlikely to be sufficient, to reduce drug-related mortality. Policy reform to address the root causes of drug toxicity deaths, including an unpredictable drug supply, strained health systems and socio-economic precarity, is essential.

A pilot study on post-mortem determination of drug abuse on dental tissues

BackgroundPost-mortem toxicology constantly deals with the research of reliable alternative matrices to be applied in case of highly damaged corpses (such us carbonized, skeletonized, human remains, etc.). Teeth represent a promising alternative matrix since dental tissues are endowed by different features, resistance and stability after death. ScopeSince scant literature reported on the pharmacokinetics and mechanism of incorporation of xenobiotics into dental tissues, this pilot research aims to investigate whether in the pulp can be detected the same substances found in blood in drug related death cases. Secondly, the study is addressed to disclose the possible deposit of drugs in dental hard tissues (dentine and/or enamel), thus contributing to reconstruct the drug abuse history (timing, e.g.). Materials and methodsThe study experimented with a novel method to separately analyse dental enamel, dentin, and pulp, applied to 10 teeth collected during autopsies of drug-related deaths along with blood and hair samples for classic toxicological analyses. Each tooth was prepared by “pulverization technique” and then analysed by gas chromatography paired with mass spectrometry (GC-MS) and ultra high performance liquid chromatography coupled to high resolution mass spectrometry (UHPLC/HR-MS) for searching cocaine, opiates, and metabolites. The results were then compared with those obtained from blood and hair samples. ResultsPreliminary results demonstrated that teeth differ from any other classic matrix (blood and hairs) since the qualitative correspondence of the detected substances between pulp and blood as well as dental hard tissues and hair suggests that they can be useful in post-mortem evaluation as a unique matrix for both acute and chronic assumptions of drugs. The mechanism of accumulation of substances in mineralized dental tissues emerged the most significant result, being influenced by the type of molecule and the method of assumption. The main limitation of this study is the limited availability of the sample and the absence of anamnestic information of the time, rates and method of drug assumption during life. Further research is necessary to systematically investigate the distribution of different substances within the different tissues of the tooth.

8 Nivolumab plus ipilimumab vs sunitinib for first-line treatment of advanced renal cell carcinoma: 8-year follow-up with analyses in favorable risk patients from the phase 3 CheckMate 214 trial

Abstract Background First-line nivolumab plus ipilimumab (NIVO+IPI) has provided substantial long-term survival benefits over sunitinib (SUN) in patients with advanced renal cell carcinoma (aRCC) in CheckMate 214. With a median follow-up of 8 years, the longest follow-up to date for any phase 3 trial of immune checkpoint inhibitor combination therapy in patients with aRCC, we report survival, response per independent radiology review committee (IRRC), and safety in all randomized patients (intent-to-treat [ITT] population) and in patients with International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) favorable risk. Methods Patients with clear cell aRCC were randomized 1:1 to NIVO 3 mg/kg plus IPI 1 mg/kg Q3W×4 doses, followed by NIVO (3 mg/kg or 240 mg Q2W or 480 mg Q4W); or SUN 50 mg once daily for 4 weeks on, 2 weeks off. Key study endpoints included overall survival (OS), IRRC-assessed progression-free survival (PFS) and objective response rate (ORR) in intermediate/poor-risk (primary), ITT (secondary), and favorable-risk (exploratory) patients. Cancer-specific survival was evaluated in ITT patients by censoring all causes of death other than RCC. Post hoc exploratory analyses in patients with favorable risk were performed. Results With 8 years (99.1 months) median follow-up, OS with NIVO+IPI versus SUN remained superior in ITT patients (hazard ratio [HR], 0.72; Table). The HR for PFS with NIVO+IPI versus SUN was 0.88. ORR was higher with NIVO+IPI versus SUN (Table), with more complete responses (12% vs 3%) and a longer median duration of response (DOR) in the combination arm versus SUN. In patients with favorable risk, OS benefits were similar between arms (HR, 0.82; Table). The HR for PFS favored SUN (HR, 1.76). ORR was lower with NIVO+IPI versus SUN, yet more patients achieved complete responses (13% vs 6%, respectively) and median DOR was longer with NIVO+IPI. Median cancer-specific survival (95% CI) in ITT patients was 73.7 (62.8-91.2) months with NIVO+IPI versus 45.1 (37.8-53.3) months with SUN (HR, 0.69; 95% CI 0.59-0.82). In exploratory post hoc analyses of patients with favorable risk, 75/125 (60.0%) patients in the NIVO+IPI arm and 85/124 (68.5%) patients in the SUN arm died over 8 years of follow-up. Of these patients, 31 in the NIVO+IPI arm and 27 in the SUN arm died within 3 years of randomization; the primary reason for death was disease in either arm (71.0% and 85.2%, respectively). Furthermore, among 27 patients in the NIVO+IPI arm with favorable risk who died after disease progression within 3 years, 12 patients did not receive second-line systemic therapy. Beyond 3 years, only 2 of 43 patients who died after disease progression did not receive subsequent systemic therapy. Among all treated patients, incidence of any-grade and grade 3-4 treatment-related adverse events remained largely unchanged. No new drug-related deaths occurred in either arm since the previous database lock. Table Conclusions With a median follow-up up of 8 years, NIVO+IPI continues to demonstrate sustained survival and more durable response benefits versus SUN in the ITT population, including a further reduction in the risk of death with NIVO+IPI as measured by cancer-specific survival. Long-term exploratory data in patients with favorable risk have shown a steady improvement in the HR for OS, and a marked improvement in median DOR and complete response rates with NIVO+IPI versus SUN, thus contributing to the survival and response benefits reported in the ITT population. Furthermore, the disproportionate number of patients with favorable risk who died within 3 years of randomization after documented progression without receiving subsequent therapy may have affected the HR for OS in this patient population early on. NIVO+IPI offers the potential for positive long-term outcomes, regardless of IMDC risk, and with no emergence of new safety signals.

Determination of indirect heroin biomarkers in biological samples of heroin users

Heroin use is responsible for many drug-related deaths, so the determination of its biomarkers, except for 6-acetylmorphine, in biological samples, is of particular concern in toxicological laboratories worldwide, for a better investigation of these cases. Th use of 6-acetylmorphine as a heroin biomarker has some limitations due to its rapid bioconversion to morphine within a few hours, especially in blood samples. The need for new indirect biomarkers, like the ones that come from the processing of opium during the clandestine production of heroin, becomes imperative. A GC/MS method was developed and validated for the determination of meconin, thebaine, papaverine, acetylcodeine and noscapine, along with morphine, codeine and 6-acetylmorphine, in different biological samples of heroin users. For all analytes and all individual biological samples, the LOD and LOQ were 2.00 and 5.00 ng/mL, respectively, the calibration curves were linear (R2≥0.991) from 5.00 to 500.0 ng/mL, and absolute recoveries were higher than 91.9 %. The method was applied during the toxicological investigation of 34 forensic cases after positive immunoassay screening for opiates. The results indicate that meconin is the most frequently detected indirect biomarker of heroin use, as it was found in 91.2 % of all cases, whilst in 23.5 % of them no 6-acetylmorphine was detected. Papaverine was found in 67.6 % of all cases and is considered to be the second most important indirect biomarker of heroin use. The establishment of detecting meconin and papaverine in biological materials in parallel with the detection of morphine, codeine and 6-acetylmorphine can contribute to more conclusive results concerning heroin use in forensic cases.

In vitro metabolism study of ADB-P-5Br-INACA and ADB-4en-P-5Br-INACA using human hepatocytes, liver microsomes, and in-house synthesized references.

Synthetic cannabinoids (SCs) remain a major public health concern, as they continuously are linked to severe intoxications and drug-related deaths worldwide. As new SCs continue to emerge on the illicit drug market, an understanding of SC metabolism is needed to identify formed metabolites that may serve as biomarkers in forensic toxicology screening and for understanding the pharmacokinetics of the drugs. In this work, the metabolism of ADB-4en-P-5Br-INACA and ADB-P-5Br-INACA ((S)-N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-5-bromo-1-(pent-4-en-1-yl)-1H-indazole-3-carboxamide, (S)-N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-5-bromo-1-pentyl-1H-indazole-3-carboxamide respectively) were investigated using human hepatocytes in vitro and in-house synthesized references. Both SCs were incubated with pooled human hepatocytes over 3h, with the aim to identify unique and abundant metabolites using liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QTOF-MS). In total nine metabolites were identified for ADB-4en-P-5Br-INACA and 10 metabolites for ADB-P-5Br-INACA. The observed biotransformations included dihydrodiol formation, terminal amide hydrolysis, hydroxylation, dehydrogenation, carbonyl formation, glucuronidation, and combinations thereof. The major metabolites were confirmed by in-house synthesized references. Recommended biomarkers for ADB-P-5Br-INACA and ADB-4en-P-5Br-INACA are the terminal hydroxy and dihydrodiol metabolite respectively.

What do Professional Helpers Describe as Important Competence when Supporting Persons Bereaved by a Drug-Related Death.

Bereaved persons following a drug-related death (DRD) experience significant stress, an increased risk of health-related problems, complicated grief reactions and a risk of higher mortality. Despite the support received from professional helpers being important, research has yet to examine their perspectives to understand and meet the bereaved's needs and increase the helpers' competence. Hence, this qualitative study explored professional helpers' perspectives on essential skills and competencies when supporting bereaved following DRD. We conducted focus group interviews with 29 professional helpers from diverse health and welfare services across six Norwegian municipalities. Reflexive thematic analysis generated three main themes: Diversity of competence, Basic human competence and Balancing act between different considerations. It is crucial that municipal services explicitly define the needs of bereaved persons following a DRD and determine the necessary professional competencies and appropriate intervention levels required.