Drug-related Mortality Research Articles

Real-world outcomes of rapid regional hepatitis C virus treatment scale-up among people who inject drugs in Tayside, Scotland.

SummaryBackgroundIn 2017, Tayside, a region in the East of Scotland, rapidly scaled‐up Hepatitis C Virus (HCV) outreach and treatment among People Who Inject Drugs (PWID) using novel community care pathways.AimsWe aimed to determine treatment outcomes for PWID during the scale‐up against pre‐determined targets; and assess re‐infection, mortality, and post‐treatment follow up.MethodsHCV treatment was delivered in community pharmacies, drug treatment centres, nurse‐led outreach clinics, prisons, and needle exchanges, alongside conventional hospital care. We retrospectively analysed clinical outcomes and compared pathways using logistic regression models.ResultsOf 800 estimated HCV‐infected PWID, 718 (90%) were diagnosed. 713 treatments commenced among 662 (92%) PWID, delivering 577 (81%) Sustained Virologic Responses (SVR). SVR was 91% among those who attended for testing. Forty‐six individuals were treated more than once. Needle exchanges and community pharmacies initiated 49% of all treatments. Regression analyses implied pharmacies had superior follow‐up, but there was no difference in likelihood of achieving SVR in community pathways relative to hospital care. Re‐infection occurred 39 times over 256.57 person years (PY), yielding a rate of 15.20 per 100 PY (95% CI 10.81‐20.78). 54 deaths occurred (29 drug related) over 1,553.04 PY, yielding a mortality rate of 3.48 per 100 PY (95% CI 2.61‐4.54). Drug‐related mortality was 1.87 per 100 PY (95% CI 1.25‐2.68).ConclusionsRapid HCV treatment scale‐up to PWID in community settings, whilst maintaining high SVR, is achievable. However, other interventions are required to minimise re‐infection; reduce drug‐related deaths; and improve post‐SVR follow‐up testing regionally.

Single-dose of adrecizumab versus placebo in acute cardiogenic shock (ACCOST-HH): an investigator-initiated, randomised, double-blinded, placebo-controlled, multicentre trial

Cardiogenic shock has a high mortality on optimal therapy. Adrenomedullin is released during cardiogenic shock and is involved in its pathophysiological processes. This study assessed treatment with the humanised, monoclonal, non-neutralising, adrenomedullin antibody adrecizumab, increasing circulating concentrations of adrenomedullin in cardiogenic shock. In this investigator-initiated, placebo-controlled, double-blind, multicentre, randomised trial (ACCOST-HH), patients were recruited from four university hospitals in Germany. Patients were eligible if they were 18 years old or older and hospitalised for cardiogenic shock within the last 48 h. Exclusion criteria were resuscitation for longer than 60 min and cardiogenic shock due to sustained ventricular tachycardia or bradycardia. Adult patients in cardiogenic shock were randomly assigned (1:1) to intravenous adrecizumab (8 mg/kg bodyweight) or placebo using an internet-based software. A block randomisation procedure was applied with stratification by age (older vs younger than 65 years), sex (male vs female), and type of underlying cardiogenic shock (acute myocardial infarction vs other entities). Investigators, patients, and medical staff involved in patient care were masked to group assignment. The primary endpoint was number of days up to day 30 without the need for cardiovascular organ support, defined as vasopressor therapy, inotropes, or mechanical circulatory support (or both) assessed in the intention-to-treat population. Safety outcomes included therapy-emergent serious adverse events, severe adverse events, adverse events, suspected unexpected serious adverse reactions, study drug-related mortality, and total mortality. The trial was registered at ClinicalTrials.gov, NCT03989531, and EudraCT, 2018-002824-17, and is now complete. Between April 5, 2019, and Jan 13, 2021, 150 patients were enrolled: 77 (51%) were randomly assigned to adrecizumab and 73 (49%) to placebo. All patients received the allocated treatment. The number of days without the need for cardiovascular organ support was not different between patients receiving adrecizumab or placebo (12·37 days [95% CI 9·80-14·94] vs 14·05 [11·41-16·69]; adjusted mean difference -1·69 days [-5·37 to 2·00]; p=0·37). Serious adverse events occurred in 59 patients receiving adrecizumab and in 57 receiving placebo (odds ratio 0·92 [95% CI 0·43-1·98]; p=0·83). Mortality was not different between groups at 30 days (hazard ratio 0·99 [95% CI 0·60-1·65]; p=0·98) or 90 days (1·10 [0·68-1·77]; p=0·71). Adrecizumab was well tolerated in patients with cardiogenic shock but did not reduce the need for cardiovascular organ support or improve survival at days 30 and 90. Adrenomed AG and University Hospital of Hamburg.

Assessing the impact of funding cuts to local housing services on drug and alcohol related mortality: a longitudinal study using area-level data in England

Since 2010 there have been large reductions in funding for local government services in England. This has led to reduced income to fund services, such as housing services, that potentially promote health. Housing services expenditure includes spending on housing advice services, homelessness relief and provision of temporary accommodation. During the same period there has been an increase in homelessness and drug related mortality. We carried out an ecological study by linking data on housing services expenditure to deaths from drug and alcohol abuse by local authority in England between 2013 and 2018, to assess whether those areas that experienced a greater decline in spending, also experienced more adverse trends in mortality rates. Our results demonstrate that spending cuts were associated with increased mortality rates due to drug misuse, however, we found no strong evidence of an association with alcohol-specific mortality. This study suggests that reduced fiscal support alongside the introduction of policies that changed how funds are distributed between areas may in part explain the recent adverse trends in drug-related mortality. Since housing expenditure decreased more in the most deprived areas of England compared to less deprived areas, such spending cuts may have contributed to the widening of health inequalities. KEYWORDS Housing services; spending; drug; alcohol; mortality

Bioactive chemical constituents, in vitro anti-proliferative activity and in vivo toxicity of the extract of Curcuma singularis Gagnep rhizomes

Ethnopharmacological relevanceCurcuma singularis Gagnep is a Vietnamese medicinal plant which has been commonly used as a medicinal remedy in traditional and folk medicines for improving health as well as for treating some diseases, like rheumatoid arthritis, kidney failure. However, pharmacological effects, including anti-cancer activity and the safety of this plant has not been fully investigated. Aim of the studyThis study aimed to investigate the in vitro anti-growth activity of an extract derived from Curcuma singularis rhizome extract (CSE) against cell lines as well as determine its phytochemical composition. The other goal of our study was to assess the safety of CSE in rats. Materials and methodsThe main constituents in the extract were identified and quantitatively analyzed. The in vitro cytotoxicity of CSE was evaluated in several cancer and normal cell lines. The apoptotic activity of CSE and the expression of the apoptosis-related genes were investigated in AGS cells to clarify the underlying molecular mechanisms. The in vivo toxicity of CSE was assessed via acute and subacute oral studies on Sprague-Dawley rats, respectively according to the guidelines 425 and 407 of the Organization for Economic Cooperation and Development (OECD). The drug-related toxicity signs, mortality, body and organ weights were recoreded during the experimental period. In addition, the selected hematological and biochemical parameters, and histological alterations were determined at the end of the subacute toxicity test. ResultsGermacrone, ar-turmerone, and curcumol were three sesquiterpene components found in the extract. CSE showed cytotoxic effects in different cancer cells, but had minimal effects on normal cells. Apoptosis in AGS cells was caused by CSE in a concentration-dependent pattern through increase of Bax/Bcl-2 ratio, and release of cytochrome c, which leads to activation of caspase-3/-7, caspase-9, as well as cleavage of PARP. In the acute toxicity test, no signs of toxicity and no mortality were recorded in rats at both doses of 1000 and 5000 mg/kg. In the subacute toxicity study, CSE showed no drug-related adverse effects on water and food consumption, body and organ weights. CSE at a dose of 1000 mg/kg slightly increased WBC and platelet values in female rats, while it increased WBC values in male rats in all tested doses. The decrease of total cholesterol and triglyceride levels were found in female rats treated CSE at doses of 250 or 500 mg/kg. In addition, the increase of serum ALT and AST levels in rats treated at the dose of 1000 mg/kg were noted. No significant changes in histopathological structures of kidneys, spleen, heart and lungs, except liver tissue with minor modifications was found. ConclusionsOur findings indicated that CSE exhibited in vitro anti-proliferative effects on AGS cells by mainly activating the caspase-dependent mitochondrial apoptotic pathway. CSE also showed in vivo toxicity signals at the dose of 1000 mg/kg with proven minor hepatic injuries, which should be avoided the high dose for prolonged use. Curcuma singularis rhizomes may be used as a chemotherapeutic agent for the treatment of gastric cancer with in vitro anti-cancer investigation and in vivo biological safety evaluation.

From the Editor’s desk…

From the Editor’s desk…

Designing and validating a Markov model for hospital-based addiction consult service impact on 12-month drug and non-drug related mortality.

Addiction consult services (ACS) engage hospitalized patients with opioid use disorder (OUD) in care and help meet their goals for substance use treatment. Little is known about how ACS affect mortality for patients with OUD. The objective of this study was to design and validate a model that estimates the impact of ACS care on 12-month mortality among hospitalized patients with OUD. We developed a Markov model of referral to an ACS, post-discharge engagement in SUD care, and 12-month drug-related and non-drug related mortality among hospitalized patients with OUD. We populated our model using Oregon Medicaid data and validated it using international modeling standards. There were 6,654 patients with OUD hospitalized from April 2015 through December 2017. There were 114 (1.7%) drug-related deaths and 408 (6.1%) non-drug related deaths at 12 months. Bayesian logistic regression models estimated four percent (4%, 95% CI = 2%, 6%) of patients were referred to an ACS. Of those, 47% (95% CI = 37%, 57%) engaged in post-discharge OUD care, versus 20% not referred to an ACS (95% CI = 16%, 24%). The risk of drug-related death at 12 months among patients in post-discharge OUD care was 3% (95% CI = 0%, 7%) versus 6% not in care (95% CI = 2%, 10%). The risk of non-drug related death was 7% (95% CI = 1%, 13%) among patients in post-discharge OUD treatment, versus 9% not in care (95% CI = 5%, 13%). We validated our model by evaluating its predictive, external, internal, face and cross validity. Our novel Markov model reflects trajectories of care and survival for patients hospitalized with OUD. This model can be used to evaluate the impact of other clinical and policy changes to improve patient survival.

Implementation of on-call clinical pharmacy service in an emergency department during COVID 19: New initiative in Hamad General Hospital, Qatar

Background: Throughout COVID-19, complex therapeutics and medication protocols left clinicians overwhelmed by contradicting information leading to drug-related problems (DRPs) potentially leading to ineffective pharmacotherapy and drug-related morbidity and mortality. DRPs queries are time consuming, utilize numerous resources, and require skills and experience to provide accurate answers. Quick answers are paramount in the Emergency Department (ED) especially during a pandemic period. Clinical pharmacists (CP) can identify and resolve DRPs but are only available in the ED during daytime hours. We set up an out-of-office CP service for ED DRPs. This study aimed to assess the capacity of the service to capture 100% of calls received and to measure the time taken to resolve DRP queries compared to the international standard. Methods: A dedicated ED CP on-call phone line and rota until 10 pm daily was arranged by the Hamad General Hospital Pharmacy (Doha, Qatar). Data was documented in a logbook and within the Electronic Medical Records (EMR) and analysed using predefined parameters. Results: Between March-September 2020, 133 DRPs calls were received and resolved by a CP. 38% were related to drug interaction/safety (often about medications used in COVID-19 treatment protocols), adverse drug reactions, dose-adjustments, drug allergies and drug in pregnancy. 30% were about medication administration, such as infusion rates, titration, and intravenous compatibility. Those questions were mostly from nurses. Appropriate dose selection and appropriate indication represented 21% and 11% respectively . Caller's acceptance rate to responses provided by CP was 100%. Responses were documented in the patients’ EMR. The call-history-log showed an average duration of 4.66 minutes per call which is below the average standard of 15-30 minutes. Conclusion: The availability of clinical pharmacists to provide quick, acceptable, responses to DRPs queries is crucial given the complexity and diversity of ED patients. During COVID-19, an on-call clinical pharmacy service has proven its capability to resolve DRPs and support the clinical decision-making process in a relatively short time.

Association between disability-related budget reductions and increasing drug-related mortality across local authorities in Great Britain

BackgroundDrug-related mortality in the UK rose markedly after 2012. Here we test the hypothesis that cuts to disability-related spending were associated with increased drug-related mortality across local governments in Great Britain. MethodsWe regressed changes in drug-related death rates (years 2010–12 versus 2015–17) on local government disability-related budget reductions, adjusting for a range of regional, demographic, and economic factors. Budget reductions are captured with a combined measure of financial losses due to Incapacity Benefit and Disability Living Allowance reforms, expressed in pounds sterling per capita, per year. 364 local authorities across England, Scotland, and Wales were included in the study. FindingsGreater budget reductions were associated with greater increases in drug-related death rates. In the unadjusted model, each £100 per capita budget reduction was associated with an increase in drug-related death rates of 3.30 per 100 000 population (95% CI: 2.43 to 4.17). The magnitude of the association increased after adjusting for region and demographic factors (b = 4.84; 95% CI: 3.26 to 6.43). The association remained statistically significant after adjusting for a full set of controls, including baseline and trends in unemployment rates, median hourly pay, and gross disposable household income per capita (b = 4.41; 95% CI: 2.57 to 6.24). ConclusionDeeper cuts to local government spending in Great Britain in the 2010s were associated with larger increases in drug-related deaths.

English

Drug-drug interaction or simply term drug interactions may be defined as the combining of two or more drugs such that the potency or efficiency of one drug is significantly modified by the presence of another. Potential drug-drug interactions (DDIs) are concern for patients and providers, as multiple medication use is becoming more common to manage complex diseases. The consequences of DDIs can range from no untoward effects to drug-related morbidity and mortality. The study was prospective conducted for a period of twelve months in Government Headquarters Hospital Ooty (GHQH) and four community pharmacies that were located in Southern India, Tamilnadu. A total number of 1,066 prescriptions were collected from the patients. A copy of prescription was taken from the patients and data collected included age and sex of the patients, their primary diagnoses presence or absence of comorbidities and the list of medications prescribed concurrently. The potential DDIs were determined through IBM Micromedex Database. However, 147 DDIs were followed up for clinically drug interactions which were found not to be significant. Among the total numbers of prescriptions analyzed 402 (38%) prescriptions showed 462 DDIs and 664 (62.2%) total number of prescriptions collected from inpatient department, GHQH showed 147 DDIs. The DDIs were classified based on the mechanism of interactions, severity of interactions, drug causing DDIs and top combination of drugs and which were determined. This study emphasized on understanding about the most prone age group and the common mechanism that can cause drug interactions which will help in the safety and efficacy of prescribed drugs followed by its management. Key words: Drug-Drug interactions, prescriptions, prevalence, severity, management.

Impact of direct-acting antivirals for HCV on mortality in a large population-based cohort study

We evaluated the effect of direct-acting antiviral (DAA)-induced sustained virologic response (SVR) on all-cause, liver- and drug-related mortality in a population-based cohort in British Columbia, Canada. We used data from the British Columbia Hepatitis Testers Cohort, which includes people tested for HCV since 1990, linked with data on medical visits, hospitalizations, prescription drugs and mortality. We followed people who received DAAs and people who did not receive any HCV treatment to death or December 31, 2019. We used inverse probability of treatment weighting to balance the baseline profile of treated and untreated individuals and performed multivariable proportional hazard modelling to assess the effect of DAAs on mortality. Our cohort comprised 10,851 people treated with DAAs (SVR 10,426 [96%], no-SVR: 425) and 10,851 matched untreated individuals. Median follow-up time was 2.2 years (IQR 1.3-3.6; maximum 6.2). The all-cause mortality rate was 19.5/1,000 person-years (PY) among the SVR group (deaths= 552), 86.5/1,000 PY among the no-SVR group (deaths= 96), and 99.2/1,000 PY among the untreated group (deaths= 2,133). In the multivariable model, SVR was associated with significant reduction in all-cause (adjusted hazard ratio [aHR] 0.19; 95% CI 0.17-0.21), liver- (adjusted subdistribution HR [asHR] 0.22, 95% CI 0.18-0.27) and drug-related mortality (asHR 0.26, 95% CI 0.21-0.32) compared to no-treatment. Older age and cirrhosis were associated with higher risk of liver-related mortality while younger age, injection drug use (IDU), problematic alcohol use and HIV/HBV co-infections were associated with a higher risk of drug-related mortality. DAA treatment is associated with a substantial reduction in all-cause, liver- and drug-related mortality. The association of IDU and related syndemic factors with a higher risk of drug-related mortality calls for an integrated social support, addiction, and HCV care approach among people who inject drugs. We assessed the effect of treatment of hepatitis C virus infection with direct-acting antiviral drugs on deaths from all causes, liver disease and drug use. We found that treatment with direct-acting antiviral drugs is associated with substantial lowering in risk of death from all causes, liver disease and drug use among people with hepatitis C virus infection.

Targeting Burkitt's Lymphoma Using Novel, Discrete Carbon Nanotubes

Burkitt's lymphoma is an incredibly aggressive B-cell derived non-Hodgkin lymphoma that is quickly fatal if left untreated. Doxorubicin (Doxo) provides one method of treatment for this cancer, but has numerous common side effects including significant weight loss, nausea, hair loss, bone marrow suppression, vomiting, rash, heart damage, allergic reaction, tissue damage at injection site, and treatment-related leukemia. Therefore, better therapies which deliver Doxo specifically to tumor cells hold great promise for a more effective therapy with reduced side-effect severity. Carbon nanotubes (CNTs) have long been of interest as drug delivery transporters because of their unique structure, high drug-binding surface area, and variety of customization options. Unfortunately, most CNTs have proven toxic during in vivo studies because of the presence of high residual contaminants and near-unavoidable aggregative properties. A novel form of clean, discrete CNT (dCNT) marketed as Medical Grade MOLECULAR REBAR® (MGMR®) lack the aggregative problems and high toxin levels of CNT before them and show promise as a drug delivery technology.We observed no toxicity of dCNTs in vitro across multiple cell types or in vivo in mice establishing a high MTD of at least 70 mg/kg by an i.v. route. Biodistribution studies of Lu-177 radioisotope labeled dCNTs (single tail vein injection into BALB/C female mice) demonstrated tolerability and clearance from various organs. Mice were sacrificed at 7 timepoints under 34d and many organs were analyzed for accumulation. The liver, spleen, and blood identified one route of clearance and distribution, but it was interesting to note that the bone retained ~10% of injected dCNTs at all time points, demonstrating potential for bone targeted therapies. Further targeting to the bone was possible by grafting commonly available bone chelators to the surface of the dCNT to create BT-dCNT as shown by significantly great adhesion (p<0.05) to ex vivo bone.Protocols were then developed to saturate the surface of the dCNT with therapeutic Active Pharmaceutical Ingredients (API) and then characterize their elution/release over time. We then optimized methods for drug-loading and observed a slow drug release profile for most drugs. Enhanced pharmacokinetic information was tested in cell culture and then confirmed by animal experimentation. In addition, cell penetration and delivery study of MGMR® in vitro showed that endocytosis is nontoxic and well tolerated and that small peptides can be delivered to cancer cells and retain their functionality. Zeta Potential measurements (-40 to -50 mV) and Dynamic Light Scattering validated the stability of different dCNTs over time.Lastly, in a Raji-Burkitt's lymphoma mouse model, we saw significant increases in survival, and decreases in tumor burden in mice treated with Doxo (free, in dCNTs, and in BT-dCNTs vs no drug control). SCID mice were inoculated via the tail vein with 2x105 Raji B. luc+ tumor cells and treated once a week with one of the following: Doxo (5 mg/kg), dCNTs (14.29 mg/kg), dCNTs (14.29 mg/kg) + Doxo (5 mg/kg), BT-dCNTs (14.29 mg/kg) + Doxo (5 mg/kg), or no treatment. Using whole body bioluminescence imaging (BLI), we saw that the groups receiving both the Doxo-loaded dCNTs and the Doxo-loaded BT-dCNTs had greatly reduced tumor burden over time compared to untreated groups, and a tumor burden similar to those that received free Doxo alone (Figure 1A). Both groups receiving Doxo-loaded dCNTs also showed increased survival compared to the Doxo alone group (Figure 1B). Importantly, the typical signs of Doxo toxicity in mice, characterized by rapid weight loss or drug-related mortality, were not seen in the groups that received Doxo-loaded CNTs (Figure 1C).In summary, dCNTs is a highly promising biomedical tool for drug delivery for clinical applications. Our dCNTs represent a promising platform for use in biomedical research as they have proven to be nontoxic, tunable, stable, and capable of drug delivery and organ-specific targeting. This novel technology gives great promise for the bone-targeting ability of novel carbon nanotubes in vivo as a bone-specific drug delivery mechanism for diseases that grow in bone or bone marrow specifically. [Display omitted] DisclosuresFalank:BioPact Ventures, LLC: Research Funding. Tassett:BioPact Ventures, LLC: Employment. Harris:BioPact Ventures, LLC: Research Funding. Farrell:BioPact Ventures, LLC: Research Funding. Everill:BioPact Ventures, LLC: Employment. Reagan:BioPact Ventures, LLC: Research Funding.

Association of Opioid Agonist Treatment With All-Cause Mortality and Specific Causes of Death Among People With Opioid Dependence

Mortality among people with opioid dependence is higher than that of the general population. Opioid agonist treatment (OAT) is an effective treatment for opioid dependence; however, there has not yet been a systematic review on the relationship between OAT and specific causes of mortality. To estimate the association of time receiving OAT with mortality. The Embase, MEDLINE, and PsycINFO databases were searched through February 18, 2020, including clinical trial registries and previous Cochrane reviews. All observational studies that collected data on all-cause or cause-specific mortality among people with opioid dependence while receiving and not receiving OAT were included. Randomized clinical trials (RCTs) were also included. This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Data on study, participant, and treatment characteristics were extracted; person-years, all-cause mortality, and cause-specific mortality were calculated. Crude mortality rates and rate ratios (RRs) were pooled using random-effects meta-analyses. Overall all-cause and cause-specific mortality both by setting and by participant characteristics. Methadone and buprenorphine OAT were evaluated specifically. Fifteen RCTs including 3852 participants and 36 primary cohort studies including 749 634 participants were analyzed. Among the cohort studies, the rate of all-cause mortality during OAT was more than half of the rate seen during time out of OAT (RR, 0.47; 95% CI, 0.42-0.53). This association was consistent regardless of patient sex, age, geographic location, HIV status, and hepatitis C virus status and whether drugs were taken through injection. Associations were not different for methadone (RR, 0.47; 95% CI, 0.41-0.54) vs buprenorphine (RR, 0.34; 95% CI, 0.26-0.45). There was lower risk of suicide (RR, 0.48; 95% CI, 0.37-0.61), cancer (RR, 0.72; 95% CI, 0.52-0.98), drug-related (RR, 0.41; 95% CI, 0.33-0.52), alcohol-related (RR, 0.59; 95% CI, 0.49-0.72), and cardiovascular-related (RR, 0.69; 95% CI, 0.60-0.79) mortality during OAT. In the first 4 weeks of methadone treatment, rates of all-cause mortality and drug-related poisoning were almost double the rates during the remainder of OAT (RR, 2.01; 95% CI, 1.55-5.09) but not for buprenorphine (RR, 0.58; 95% CI, 0.18-1.85). All-cause mortality was 6 times higher in the 4 weeks after OAT cessation (RR, 6.01; 95% CI, 4.32-8.36), remaining double the rate for the remainder of time not receiving OAT (RR, 1.81; 95% CI, 1.50-2.18). Opioid agonist treatment was associated with a lower risk of mortality during incarceration (RR, 0.06; 95% CI, 0.01-0.46) and after release from incarceration (RR, 0.09; 95% CI, 0.02-0.56). This systematic review and meta-analysis found that OAT was associated with lower rates of mortality. However, access to OAT remains limited, and coverage of OAT remains low. Work to improve access globally may have important population-level benefits.

Are drug consumption facilities an effective intervention to reduce drug related mortality? A critical review of the literature

AimsTo critically appraise the literature regarding the effect of Drug Consumption Facilities in reducing overdose mortalityDrug consumption facilities (DCF) are places where people can use illicit drugs in the presence of medically trained staff, they aim to reduce fatal overdose risk, reduce risky injecting practices, and to serve as a bridge for users into mainstream treatment, healthcare and social services. Increasing numbers of fatal overdoses due to illicit drug use are a significant public health concern. The UK's statutory independent advisory body (the Advisory Council on the Misuse of Drugs) has recommended DCFs as a mechanism to reduce fatal overdoses due to illicit drugs. However, current UK legislation prohibits their provision.MethodSystematic extraction of relevant literature from PubMed, using a search string with a focus on observational cohort studies with fatal overdose as the outcome. Appraisal of identified papers using the CASP toolResult184 papers were identified, two of these met the inclusion criteria. Quality was fair/good. Neither demonstrated a clear effect of DCFs in reducing overdose mortalityConclusionIt is difficult to draw firm conclusions due to design weaknesses and potential confounding variables. Robust design is difficult in this research area, due to lack of suitability for RCTs. Despite the lack of a clear effect on overdose mortality, DCFs may exert other positive effects and are a pragmatic and humane response to reducing risk in this target population

Deaths from ‘diseases of despair’ in Britain: comparing suicide, alcohol-related and drug-related mortality for birth cohorts in Scotland, England and Wales, and selected cities

BackgroundThe contribution of increasing numbers of deaths from suicide, alcohol-related and drug-related causes to changes in overall mortality rates has been highlighted in various countries. In Scotland, particular vulnerable cohorts...

Reduced mortality in patients with extended duration of methadone maintenance treatment: a five-year retrospective nationwide study.

The retention of patients under methadone maintenance treatment (MMT) is an indication for the effectiveness of the therapy. We aimed to explore the relation between mortality and the cumulative MMT duration. A retrospective cohort analysis was performed using Taiwan Illicit Drug Issue Database (TIDID) and National Health Insurance Research Database (NHIRD) during 2012-2016. We included 9149 and 11 112 MMT patients as the short and long groups according to the length of their cumulative MMT duration, 1-364 and ⩾365 days, respectively. The risk of mortality was calculated by Cox proportional hazards regression model with time-dependent exposure to MMT, and the survival probability was plotted with the Kaplan-Meier curve. The mortality rates were 2.51 and 1.51 per 100 person-years in the short and long cumulative MMT duration groups, respectively. After adjusting for on or off MMT, age, sex, marital status, education level, maximum methadone dose, and comorbidities (human immunodeficiency virus, depression, hepatitis C virus, hepatitis B virus, alcoholic liver disease, and cardiovascular disease), the long group had a lower risk of death (hazard ratio = 0.67; 95% confidence interval 0.60-0.75) than the short group. Increased risk was observed in patients with advanced age, being male, unmarried, infected by HIV, HCV, and HBV, and diagnosed with depression, ALD, and CVD. Causes of death were frequently related to drug and injury. Longer cumulative MMT duration is associated with lower all-cause and drug-related mortality rate.

Increasing drug-related mortality rates over the last decade in Scotland are not just due to an ageing cohort: A retrospective longitudinal cohort study.

In Europe, North America, and Australia, mortality due to drug-related (DR) causes amongst people who inject drugs (PWID) is a major issue. Our objective was to characterise temporal trends in DR mortality rates in a large cohort of PWID in Scotland over the past decade, all of whom had been diagnosed with hepatitis C virus (HCV) infection, and to investigate factors associated with DR mortality. Retrospective longitudinal cohort study linking Scotland's national HCV Diagnosis Database and deaths registry. The study cohort consisted of all individuals with likely injection drug use-related route of HCV acquisition, who had been diagnosed with HCV between 1991 and 2018, and were alive and aged under 65 years on 1 January 2009. We used Lexis expansion to adjust for ageing cohort effects and calculated the mortality rate from an underlying/contributing DR cause over the period 2009-2018. We fitted Poisson regression models to estimate the temporal trend adjusting for attained age, sex, referral setting, region, and viraemic status at baseline. Amongst the study population (n=35,065; 236,914 person-years), a total of 1900 DR deaths occurred; the DR mortality rate increased from 5.6/1000 [101 deaths] in 2009 to 12.4/1000 [342] person-years in 2018. Increasing trends were observed for all age-groups except 55-64 years. The overall DR mortality rate was highest for referrals for HCV testing from prison (11.0/1000) and hospital settings (10.0/1000). Mortality increased with calendar time period, with significantly raised adjusted rate ratios (RRs) from 2015 (RR=1.40, 95% CI:1.16-1.69) to 2018 (RR=2.23, 95% CI:1.88-2.64), compared with 2011-2012, for older age (35-44: RR=1.37, 95% CI:1.20-1.56; 45-54: RR=1.32, CI:1.14-1.53) compared with <35 years, for persons diagnosed with HCV since 2009 (RR=1.34, 95% CI:1.21-1.49), and for prison and hospital referrals (RRs of 1.30, 1.37) compared with GP referrals. Increasing DR mortality rates in Scotland over the past decade are not just due to an ageing cohort. Harm reduction services will likely need to expand and adapt to reverse the recent upward trends in DR mortality in PWID.

The identification of artefacts in reporting of drug‐induced deaths using structural breaks analysis of time series statistics

Drug-related mortality is a key epidemiological indicator that is collected nationally and internationally. Significant efforts were made in 2006-2007 to improve the quality of data concerning drug-related mortality in the Czech Republic. The aim of this article is to identify the effect of a quality improvement project on the drug-induced mortality data reported in the General Mortality Registry (GMR), and to demonstrate how to identify, quantify and interpret changes in drug-induced mortality based on the example of the Czech Republic. We extracted data on illicit drug-induced deaths from the Czech Republic GMR and Special Mortality registry (SMR) for the years between 2004 and 2012, and aggregated monthly and quarterly time series. We applied a new procedure to identify structural breakpoints in time series based on dating structural changes in standard linear regression models. In the GMR, breakpoints were identified in three time series: (i) opioid-related deaths; (ii) other stimulant-related deaths; and (iii) total drug-induced deaths. In the SMR, the structural breaks were identified for opioids, volatile substances and selection D time series. In each of these time series, the analysis identified a decrease in the intercepts in the different segments. The structural breaks identified and quantified in the GMR time series were plausibly caused by the quality improvement efforts that started in 2006. These results demonstrate that it is critical for the analysis and use of drug mortality data collected in the registries to identify practice changes in the relevant registries, to quantify their influence and to adjust mortality estimates accordingly.

COVID-19 and the Drug Overdose Crisis: Uncovering the Deadliest Months in the United States, January‒July 2020.

Objectives. To determine the magnitude of increases in monthly drug-related overdose mortality during the COVID-19 pandemic in the United States. Methods. We leveraged provisional records from the Centers for Disease Control and Prevention provided as rolling 12-month sums, which are helpful for smoothing, yet may mask pandemic-related spikes in overdose mortality. We cross-referenced these rolling aggregates with previous monthly data to estimate monthly drug-related overdose mortality for January through July 2020. We quantified historical errors stemming from reporting delays and estimated empirically derived 95% prediction intervals (PIs). Results. We found that 9192 (95% PI = 8988, 9397) people died from drug overdose in May 2020-making it the deadliest month on record-representing a 57.7% (95% PI = 54.2%, 61.2%) increase over May 2019. Most states saw large-magnitude increases, with the highest in West Virginia, Kentucky, and Tennessee. We observed low concordance between rolling 12-month aggregates and monthly pandemic-related shocks. Conclusions. Unprecedented increases in overdose mortality occurred during the pandemic, highlighting the value of presenting monthly values alongside smoothed aggregates for detecting shocks. Public Health Implications. Drastic exacerbations of the US overdose crisis warrant renewed investments in overdose surveillance and prevention during the pandemic response and postpandemic recovery efforts.

CDC's Efforts to Quantify Prescription Opioid Overdose Deaths Fall Short.

In a 2018 report titled, Quantifying the Epidemic of Prescription Opioid Overdose Deaths, four senior analysts of the Centers for Disease Control and Prevention (CDC), including the head of the Epidemiology and Surveillance Branch, acknowledged for the first time that the number of prescription opioid overdose deaths reported by the CDC in 2016 was erroneous. The error, they said, was caused by miscoding deaths involving illicitly manufactured fentanyl (IMF) as deaths involving prescribed fentanyl. To understand what caused this error, the authors examined the CDC’s methodology for compiling drug-related mortality data, beginning with the source data obtained from approximately 2.8 million death certificates received each year from state vital statistics registrars. Systemic problems often begin outside the CDC, with a surprisingly high rate of errors and omissions in the source data. Using the CDC’s explanation for what caused the error, the authors show why an international program used by the CDC for reporting mortality is ill-suited for compiling and reporting drug overdose deaths. Except for heroin, methadone, and opium, each of which has an individual program code, all other opioids are separated in just two program codes according to whether they are synthetic or semisynthetic/opiates. Methadone-involved deaths pose a special problem for the CDC because methadone has dual indications for treating pain and for treating opioid use disorder (OUD). In 2019, more than seven times more methadone was administered or dispensed for OUD treatment than was prescribed for pain, yet all methadone-involved deaths are coded by the CDC as involving the prescribed form of the drug. The authors conclude that the CDC was at fault for failing to recognize and correct this problem before 2016. Public policy consequences of this failure are briefly mentioned.

Buprenorphine Treatment Intake and Critical Encounters following a Nonfatal Opioid Overdose

Background Individuals with prior opioid-related overdose events have an increased risk for opioid-related mortality. Buprenorphine is a partial agonist that has shown to be an effective medication for opioid use disorder (MOUD). Yet, few studies have investigated whether buprenorphine reduces the risk of opioid-related mortality following a nonfatal opioid-related overdose. Methods A retrospective study was conducted on all overdose cases in Indiana between January 1, 2017 and December 31, 2017. Data were linked from multiple administrative sources. Cases were linked to vital records to assess mortality. Bivariate analyses were conducted to assess group differences between survivors and decedents. A series of multiple logistic regression models were used to determine main and interaction effects of opioid-related mortality. Results Among the 10,195 nonfatal overdoses, 2.4% (247) resulted in a subsequent fatal overdose. Overdose decedents were on average 36.4 years-old, 66.8% male, 91.1% White, and 83.8% did not receive a buprenorphine dispensation. Incremental increases in the number of buprenorphine dispensations decreased the likelihood of fatal overdose by 94% (95% CI = 0.88-0.98, p = .001). Incremental increases in arrest encounters were found to significantly increase the likelihood of a fatal overdose (AOR = 2.16; 95% CI = 1.13-3.55). Arrest encounters were a significant moderator of the relationship between buprenorphine uptake effectiveness and drug-related mortality. Conclusions Analysis of linked data provided details of risk and protective factors of fatal overdose. Buprenorphine reduced the risk of death; however, criminal justice involvement remains an area of attention for diversion and overdose death prevention interventions.