Prior use of medications for opioid use disorder in ED patients with opioid overdose: prevalence, misuse and overdose severity.

OBJECTIVES: Medications for opioid use disorder (MOUD) reduce opioid overdose (OD) deaths; however, prevalence and misuse of MOUD in ED patients presenting with opioid overdose are unclear, as are any impacts of existing MOUD prescriptions on subsequent OD severity. METHODS: This was a prospective observational cohort of ED patients with opioid OD at two tertiary-care hospitals from 2015 to 19. Patients with confirmed opioid OD (via urine toxicology) were included, while patients with alternate diagnoses, insufficient data, age < 18, and prisoners were excluded. OD severity was defined using: (a) hospital LOS (days); and (b) in-hospital mortality. Time trends by calendar year and associations between MOUD and study outcomes were calculated. RESULTS: In 2829 ED patients with acute drug OD, 696 with confirmed opioid OD were included. Overall, 120 patients (17%) were previously prescribed any MOUD, and MOUD prevalence was significantly higher in 2018 and 2019 compared to 2016 (20.1% and 27.8% vs. 8.8%, p < 0.05). Odds of MOUD misuse were significantly higher for methadone (OR 3.96 95% CI 2.57-6.12) and lowest for buprenorphine (OR 1.16, p = NS). Mean LOS was over 50% longer for methadone (3.08 days) compared to buprenorphine and naltrexone (both 2.0 days, p = NS). Following adjustment for confounders, buprenorphine use was associated with significantly shorter LOS (IRR -0.44 (95%CI -0.85, -0.04)). Odds of death were 30% lower for patients on any MOUD (OR 0.70, 95%CI 0.09-5.72), but highest in the methadone group (OR 0.82, 95%CI 0.10-6.74). CONCLUSIONS: While MOUD prevalence significantly increased over the study period, MOUD misuse occurred for patients taking methadone, and OD LOS overall was lower in patients with any prior buprenorphine prescription.

Effects of medication-assisted treatment on mortality among opioids users: a systematic review and meta-analysis.

Opioid use disorder (OUD) is associated with a high risk of premature death. Medication-assisted treatment (MAT) is the primary treatment for opioid dependence. We comprehensively assessed the effects of different MAT-related characteristics on mortality among those with OUD by a systematic review and meta-analysis. The all-cause and overdose crude mortality rates (CMRs) and relative risks (RRs) by treatment status, different type, period, and dose of medication, and retention time were pooled using random effects, subgroup analysis, and meta-regression. Thirty cohort studies involving 370,611 participants (1,378,815 person-years) were eligible in the meta-analysis. From 21 studies, the pooled all-cause CMRs were 0.92 per 100 person-years (95% CI: 0.79-1.04) while receiving MAT, 1.69 (1.47-1.91) after cessation, and 4.89 (3.54-6.23) for untreated period. Based on 16 studies, the pooled overdose CMRs were 0.24 (0.20-0.28) while receiving MAT, 0.68 (0.55-0.80) after cessation of MAT, and 2.43 (1.72-3.15) for untreated period. Compared with patients receiving MAT, untreated participants had higher risk of all-cause mortality (RR 2.56 [95% CI: 1.72-3.80]) and overdose mortality (8.10 [4.48-14.66]), and discharged participants had higher risk of all-cause death (2.33 [2.02-2.67]) and overdose death (3.09 [2.37-4.01]). The all-cause CMRs during and after opioid substitution treatment with methadone or buprenorphine were 0.93 (0.76-1.10) and 1.79 (1.47-2.10), and corresponding estimate for antagonist naltrexone treatment were 0.26 (0-0.59) and 1.97 (0-5.18), respectively. Retention in MAT of over 1-year was associated with a lower mortality rate than that with retention ≤1 year (1.62, 1.31-1.93 vs. 5.31, -0.09-10.71). Improved coverage and adherence to MAT and post-treatment follow-up are crucial to reduce the mortality. Long-acting naltrexone showed positive advantage on prevention of premature death among persons with OUD.

A comparison of blood toxicology in fatalities involving alcohol and other drugs in patients with an opioid use disorder treated with methadone, buprenorphine, and implant naltrexone.

Background: Methadone, buprenorphine, and implant naltrexone have comparable efficacy in preventing death from drug intoxication during treatment, but there may be differences between treatments in the specific drugs contributing to death and in the risk of death during different phases of treatment.Objective: The objective of this study was to compare concentrations of individual drugs in decedents for evidence that the three medications use to treat opioid use disorders differed in the protection they offered against fatal overdose.Methods: Fatalities with a primary or co-diagnosis of alcohol or other drug poisoning in patients treated with methadone (n = 66, 74.2% male), buprenorphine (n = 54, 74.1% male), or naltrexone (n = 28, 85.7% male) were identified by combining treatment (Monitoring of Drugs of Dependence System and clinical records) and mortality records (Western Australian Death Registry). Quantitative postmortem blood drug analysis data were obtained for drug-related deaths. The presence/absence of drugs were compared between the three medication groups and between phases of treatment (on-treatment/off-treatment).Results: Opioids (89.8%) and benzodiazepines (76.2%) were most commonly identified in postmortem blood. The three medication groups did not differ materially in the drugs present postmortem, except that alcohol was less prevalent in naltrexone-treated cases. Morphine or heroin intoxication was implicated in more patients dying off-treatment than on-treatment but levels of morphine and other drugs were comparable across the two phases.Conclusion: Comparisons of postmortem concentrations of specific drugs indicated that patients treated with methadone, buprenorphine, and implant naltrexone had comparable susceptibilities to lethal co-intoxication and that similar drug mixtures contributed to death.

Mortality and causes of death among patients with opioid use disorder receiving opioid agonist treatment: a national register study.

BACKGROUND: Mortality rates and causes of death among individuals in opioid agonist treatment (OAT) vary according to several factors such as geographical region, age, gender, subpopulations, drug culture and OAT status. Patients in OAT are ageing due to effective OAT as well as demographic changes, which has implications for morbidity and mortality. Norway has one of the oldest OAT populations in Europe. Because of the varying mortality rates and causes of death in different subgroups and countries, research gaps still exist. The aims of this study were to describe the causes of death among OAT patients in Norway, to estimate all-cause and cause-specific crude mortality rates (CMRs) during OAT and to explore characteristics associated with drug-induced cause of death compared with other causes of death during OAT. METHODS: This was a national, observational register study. Data from the Norwegian Cause of Death Registry and the Norwegian Patient Registry were combined with data from medical records. We included all patients in the Norwegian OAT programme who died not more than 5 days after the last intake of OAT medication, between 1 January 2014 and 31 December 2015. RESULTS: In the 2-year observation period, 200 (1.4%) of the OAT patients died. A forensic or medical autopsy was performed in 63% of the cases. The mean age at the time of death was 48.9 years (standard deviation 8.4), and 74% were men. Somatic disease was the most common cause of death (45%), followed by drug-induced death (42%), and violent death (12%). In general, CMRs increased with age, and they were higher in men and in patients taking methadone compared with buprenorphine. Increasing somatic comorbidity, measured by the Charlson comorbidity index, reduced the odds of dying of a drug-induced cause of death compared with other causes of death. CONCLUSIONS: Both somatic and drug-induced causes of death were common during OAT. Improved treatment and follow-up of chronic diseases, especially in patients aged > 40 years, and continuous measures to reduce drug-induced deaths appear to be essential to reduce future morbidity and mortality burdens in this population.

Medication for Opioid Use Disorder After Nonfatal Opioid Overdose and Association With Mortality: A Cohort Study.

Background: Opioid overdose survivors have an increased risk for death. Whether use of medications for opioid use disorder (MOUD) after overdose is associated with mortality is not known. Objective: To identify MOUD use after opioid overdose and its association with all-cause and opioid-related mortality. Design: Retrospective cohort study. Setting: 7 individually linked data sets from Massachusetts government agencies. Participants: 17 568 Massachusetts adults without cancer who survived an opioid overdose between 2012 and 2014. Measurements: Three types of MOUD were examined: methadone maintenance treatment (MMT), buprenorphine, and naltrexone. Exposure to MOUD was identified at monthly intervals, and persons were considered exposed through the month after last receipt. A multivariable Cox proportional hazards model was used to examine MOUD as a monthly time-varying exposure variable to predict time to all-cause and opioid-related mortality. Results: In the 12 months after a nonfatal overdose, 2040 persons (11%) enrolled in MMT for a median of 5 months (interquartile range, 2 to 9 months), 3022 persons (17%) received buprenorphine for a median of 4 months (interquartile range, 2 to 8 months), and 1099 persons (6%) received naltrexone for a median of 1 month (interquartile range, 1 to 2 months). Among the entire cohort, all-cause mortality was 4.7 deaths (95% CI, 4.4 to 5.0 deaths) per 100 person-years and opioid-related mortality was 2.1 deaths (CI, 1.9 to 2.4 deaths) per 100 person-years. Compared with no MOUD, MMT was associated with decreased all-cause mortality (adjusted hazard ratio [AHR], 0.47 [CI, 0.32 to 0.71]) and opioid-related mortality (AHR, 0.41 [CI, 0.24 to 0.70]). Buprenorphine was associated with decreased all-cause mortality (AHR, 0.63 [CI, 0.46 to 0.87]) and opioid-related mortality (AHR, 0.62 [CI, 0.41 to 0.92]). No associations between naltrexone and all-cause mortality (AHR, 1.44 [CI, 0.84 to 2.46]) or opioid-related mortality (AHR, 1.42 [CI, 0.73 to 2.79]) were identified. Limitation: Few events among naltrexone recipients preclude confident conclusions. Conclusion: A minority of opioid overdose survivors received MOUD. Buprenorphine and MMT were associated with reduced all-cause and opioid-related mortality. Primary Funding Source: National Center for Advancing Translational Sciences of the National Institutes of Health.

Opioid substitution therapy for people living in German prisons-inequality compared with civic sector.

BACKGROUND: The above-average proportion of people with opioid use disorder living in prisons is a worldwide reality, and the need to treat these people was recognized internationally more than 20 years ago. Studies have shown that substitution therapies are best suited to treat opioid use disorder and reduce the risk of HIV and hepatitis C transmission and overdose. However, huge health inequalities exist in and outside of prison due to the different implementation of opioid substitution therapy (OST). People living in prisons are entitled to the best possible health care. This is established by the Universal Declaration of Human Rights and by the International Convention on Economic, Social and Cultural Rights. Solely the imprisonment, and not the loss of fundamental human rights, constitutes the punishment. METHODS: A qualitative literature search using PubMed and Google Scholar was performed in order to identify relevant publications. RESULTS: This review shows the inequality in availability of opioid substitution therapy for people living in prison compared with people outside of prison in Germany. It also gives possible reasons and evidence for this inequality, showing that continuing or initiating OST in prison is more beneficial for the health of people living in prison than abstinence-oriented treatment only. CONCLUSION: It is important that drug use disorder is treated as a serious illness also in prison. Joint efforts are needed to provide people living in prison with the best possible treatment and to minimize the adverse effects of drug use. Therefore, with laws, policies, and programs that conform to international human rights standards, each state must ensure that people living in prison receive the same health care as people outside of prison.

Methadone maintenance treatment and mortality in people with criminal convictions: A population-based retrospective cohort study from Canada.

BACKGROUND: Individuals with criminal histories have high rates of opioid dependence and mortality. Excess mortality is largely attributable to overdose deaths. Methadone maintenance treatment (MMT) is one of the best evidence-based opioid substitution treatments (OSTs), but there is uncertainty about whether methadone treatment reduces the risk of mortality among convicted offenders over extended follow-up periods. The objective of this study was to investigate the association between adherence to MMT and overdose fatality as well as other causes of mortality. METHODS AND FINDINGS: We conducted a retrospective cohort study involving linked population-level administrative data among individuals in British Columbia (BC), Canada with a history of conviction and who filled a methadone prescription between January 1, 1998 and March 31, 2015. Participants were followed from the date of first-dispensed methadone prescription until censoring (date of death or March 31, 2015). Methadone was divided into medicated (methadone was dispensed) and nonmedicated (methadone was not dispensed) periods and analysed as a time-varying exposure. Hazard ratios (HRs) with 95% CIs were estimated using multivariable Cox regression to examine mortality during the study period. All-cause and cause-specific mortality rates were compared during medicated and nonmedicated methadone periods. Participants (n = 14,530) had a mean age of 34.5 years, were 71.4% male, and had a median follow-up of 6.9 years. A total of 1,275 participants died during the observation period. The overall all-cause mortality rate was 11.2 per 1,000 person-years (PYs). Participants were significantly less likely to die from both nonexternal (adjusted HR [AHR] 0.27 [95% CI 0.23-0.33]) and external (AHR 0.41 [95% CI 0.33-0.51]) causes during medicated periods, independent of sociodemographic, criminological, and health-related factors. Death due to infectious diseases was 5 times lower (AHR 0.20 [95% CI 0.13-0.30]), and accidental poisoning (overdose) deaths were nearly 3 times lower (AHR 0.39 [95% CI 0.30-0.50]) during medicated periods. A competing risk regression demonstrated a similar pattern of results. The use of a Canadian offender population may limit generalizability of results. Furthermore, our observation period represents community-based methadone prescribing and may omit prescriptions administered during hospital separations. Therefore, the magnitude of the protective effects of methadone from nonexternal causes of death should be interpreted with caution. CONCLUSIONS: Adherence to methadone was associated with significantly lower rates of death in a population-level cohort of Canadian convicted offenders. Achieving higher rates of adherence may reduce overdose deaths and other causes of mortality among offenders and similarly marginalized populations. Our findings warrant examination in other study centres in response to the crisis of opiate-involved deaths.

The Role of Preterm Birth in the Association Between Opioid Maintenance Therapy and Neonatal Abstinence Syndrome.

BACKGROUND: Pregnant women treated with methadone as opioid maintenance therapy are more likely than women treated with buprenorphine to deliver preterm. Preterm birth is associated with less risk of neonatal abstinence syndrome (NAS). We sought to assess the role of preterm birth as a mediator of the relationship between in utero exposure to methadone and NAS compared with buprenorphine. METHODS: We studied 716 women receiving methadone or buprenorphine and delivering liveborn infants at Magee-Womens Hospital, Pittsburgh, Pennsylvania (2013-15). We implemented inverse probability weighted marginal structural models to isolate the role of preterm birth (<37 weeks' gestation). Weights accounted for confounding by maternal age, race, insurance, parity, delivery year, marital, employment, hepatitis C, and smoking status. RESULTS: Approximately 57% of the cohort were treated with methadone. Preterm birth was more common in methadone-exposed pregnancies (25% versus 14%). The incidence of NAS treatment was higher in methadone compared with buprenorphine-exposed infants (65% vs 49%), and term compared with preterm births (64% vs 36%). For every 100 infants liveborn to mothers treated for opioid dependence, there were 13 excess cases of NAS among infants exposed to methadone compared with buprenorphine (adjusted risk difference [RD] 13.3, 95% confidence interval [CI] 5.7, 20.9). Among term births, this increased to 17 excess cases of NAS in methadone- compared with buprenorphine-exposed (RD 16.7, 95% CI 9.3, 24.0). CONCLUSION: The further increased risk of NAS associated with methadone use vs buprenorphine in term deliveries emphasises the utility of buprenorphine in clinical settings aimed at decreasing NAS.

Morbidity and mortality in opioid dependent patients after entering an opioid pharmacotherapy compared with a cohort of non-dependent controls.

Aims: To compare morbidity and mortality in opioid dependence patients following the commencement of treatment with the general population. Methods: Morbidity and mortality in all patients treated with methadone, buprenorphine or implant naltrexone for opioid dependence for the first time between 2001 and 2010 in Western Australia was compared to a cohort of age and gender matched controls using state health records. Results: Compared to community controls rates of all-cause mortality, hospital admissions and Emergency Department attendances are significantly elevated in opioid dependent persons following the commencement of their first treatment. Not surprisingly, rates of opioid and non-opioid drug poisoning, and intentional self-harm/suicide mortality and hospital admissions were significantly elevated in opioid dependent patients compared with non-dependent controls. However, significant increases in mortality and hospital admissions for conditions which are not generally associated with opioid use were also identified including cardiovascular, respiratory and traffic accidents. Life-time prevalence of both HBV and HCV were significantly elevated in opioid dependent patients compared with non-dependent patients. Conclusions: Even after the commencement of treatment, opioid dependent patients are at a high risk of morbidity and mortality compared with non-dependent age and gender matched controls.

Self-Harm, Methadone Use and Drug-Related Deaths amongst Those Registered As Being of No Fixed Abode or Homeless in Ireland.

This work aims to contribute to the evidence base regarding the health of those who experience homelessness in Ireland by collating data on methadone use, drug-related deaths and emergency department presentations due to self-harm. Data from the Central Methadone Treatment List (CTL), National Self-Harm Registry Ireland and the National Drug-Related Deaths Index were analysed. The percentage on the CTL registered as being of no fixed abode (NFA) or homeless increased from 2% to 7% from 2011-2014. The absolute number of presentations with deliberate self-harm from those of NFA increased by 49% from 2007-2014. The number of drug-related deaths amongst those of NFA or homeless and who died in Dublin fluctuated from 2004-13 with an overall upward trend. There is an urgent need to adequately resource and coordinate those services which aim to address factors (social and health inequalities, mental ill-health and addiction) which lead people into - and prevent them exiting from - homelessness.

CYP2B6 and OPRM1 gene variations predict methadone-related deaths.

The largest proportion of methadone-associated deaths occurs during the drug induction phase. We analysed methadone-related fatalities for gene variations linked with methadone action. A significant association between high methadone concentrations and the CYP2B6*6 allele characteristic of the slow metabolizer phenotype was identified. We suggest that the risk of methadone fatality may be predetermined in part by the CYP2B6*6 allele. A significant correlation was also observed between post-mortem benzodiazepine concentrations and the OPRM1 A118G allele GA in methadone-related fatalities. Screening for these susceptibility variations prior to methadone prescription could assist in reducing the potential for serious adverse effects.

Methadone deaths: risk factors in pain and addicted populations.

Methadone is highly effective in treating opioid dependence, and it is also used as an analgesic for second-line management of chronic pain. However, recent increases in methadone-related deaths have instigated controversy about the use of this medication. In this paper, we evaluate risk factors for methadone mortality in opioid dependent and pain populations and present guidelines for initiating methadone treatment in these two populations to minimize the risk of death. Early research with methadone-maintained patients revealed that methadone fatalities occur primarily due to respiratory arrest during methadone induction and in the context of polysubstance use. Recent reports of methadone deaths emphasize chronic pain populations, methadone-related QTc prolongation, and the possibility of inducing Torsade de pointes (TdP), a potentially fatal ventricular arrhythmia. Retrospective analyses of these deaths show that patients who develop TdP often present with multiple risk factors, including high methadone doses, use of other medications that cause QTc prolongation, and electrolyte abnormalities. To minimize fatalities, guidelines are presented for initiating methadone in opioid treatment and pain populations that consider the drug's pharmacology along with behavioral, medical and psychiatric risk factors.

Do interruptions to the continuity of methadone maintenance treatment in specialist addiction settings increase the risk of drug-related poisoning deaths? A retrospective cohort study.

AIMS: To examine the risk of mortality associated with interruptions to the continuity of methadone maintenance treatment (MMT), including transfers between services, in opioid-dependent individuals attending specialist addiction services. DESIGN: Retrospective cohort study using addiction services and primary care dispensing records, the National Methadone Register and National Drug-Related Death Index (NDRDI). SETTING: Geographically defined population in Dublin, Ireland. PARTICIPANTS: A total of 2899 people prescribed and dispensed methadone in specialist addiction services between January 2010 and December 2015. There were five exposure groups: weeks 1-4 following transfer between treatment providers; weeks 1-4 out of treatment; weeks 5-52 out of treatment; weeks 1-4 of treatment initiation; and weeks 5+ of continuous treatment (reference category). MEASUREMENTS: Primary outcome: drug-related poisoning (DRP) deaths. Secondary outcome: all-cause mortality (ACM). Mortality rates calculated by dividing number of deaths (DRP; ACM) in exposure groups by person-years exposure. Unadjusted and adjusted Poisson regression (covariates age, sex, incarceration, methadone dose and comorbidities) estimated differences in mortality rates. FINDINGS: There were 154 ACM deaths, 55 (35.7%) identified as DRP deaths. No deaths were observed in the first month following transfer between treatment providers. The risk of DRP mortality was highest in weeks 1-4 out of treatment [adjusted relative risk (aRR = 4.04, 95% confidence interval (CI) = 1.43-11.43, P = 0.009] and weeks 1-4 of treatment initiation (ARR = 3.4, 95% CI = 1.2-9.64, P = 0.02). Similarly, risk of ACM was highest in weeks 1-4 out of treatment (ARR = 11.78, 95% CI = 7.73-17.94, P < 0.001), weeks 1-4 of treatment initiation (aRR = 5.11, 95% CI = 2.95-8.83, P < 0.001) and weeks 5-52 off treatment (aRR = 2.04, 95% CI = 1.2-3.47, P = 0.009). CONCLUSIONS: Interruptions to the continuity of methadone maintenance treatment by treatment provider do not appear to be periods of risk for drug-related poisoning or all-cause mortality deaths. Risk of drug related poisoning and all-cause mortality deaths appears to be greatest during the first 4 weeks of treatment initiation/re-initiation and after treatment cessation.

Opioid agonist treatment and fatal overdose risk in a state-wide US population receiving opioid use disorder services.

BACKGROUND AND AIMS: Evidence from randomized controlled trials establishes that medication treatment with methadone and buprenorphine reduces opioid use and improves treatment retention. However, little is known about the role of such medications compared with non-medication treatments in mitigating overdose risk among US patient populations receiving treatment in usual care settings. This study compared overdose mortality among those in medication versus non-medication treatments in specialty care settings. DESIGN: Retrospective cohort study using state-wide treatment data linked to death records. Survival analysis was used to analyze data in a time-to-event framework. SETTING: Services delivered by 757 providers in publicly funded out-patient specialty treatment programs in Maryland, USA between 1 January 2015 and 31 December 2016. PARTICIPANTS: A total of 48 274 adults admitted to out-patient specialty treatment programs in 2015-16 for primary diagnosis of opioid use disorder. MEASUREMENTS: Main exposure was time in medication treatment (methadone/buprenorphine), time following medication treatment, time exposed to non-medication treatments and time following non-medication treatment. Main outcome was opioid overdose death during and after treatment. Hazard ratios were calculated using Cox proportional hazard regression. Propensity score weights were adjusted for patient information on sex, age, race, region of residence, marital and veteran status, employment, homelessness, primary opioid, mental health treatment, arrests and criminal justice referral. FINDINGS: The study population experienced 371 opioid overdose deaths. Periods in medication treatment were associated with substantially reduced hazard of opioid overdose death compared with periods in non-medication treatment [adjusted hazard ratio (aHR) = 0.18, 95% confidence interval (CI) = 0.08-0.40]. Periods after discharge from non-medication treatment (aHR = 5.45, 95% CI = 2.80-9.53) and medication treatment (aHR = 5.85, 95% CI = 3.10-11.02) had similar and substantially elevated risks compared with periods in non-medication treatments. CONCLUSIONS: Among Maryland patients in specialty opioid treatment, periods in treatment are protective against overdose compared with periods out of care. Methadone and buprenorphine are associated with significantly lower overdose death compared with non-medication treatments during care but not after treatment is discontinued.

Mortality of treatment-seeking men and women with alcohol, opioid or other substance use disorders - A register-based follow-up study.

BACKGROUND: Alcohol (AUD), opioid (OUD) and other substance use disorders (SUD) are associated with an increased risk of premature death. The aim of this register-based follow-up study was to compare the risk of death between individuals who had sought treatment for AUDs, OUDs and other SUDs in Finland. DESIGN, SETTING, PARTICIPANTS: Data included 10,888 individuals who had sought help from three clinics at some point between 1990 and 2009. Treatment data were linked to national register data concerning education, hospitalizations and death by the year 2018. MEASUREMENTS: Individuals were categorized into four groups: only alcohol (AUD-only), all OUDs (OUD-all), other or multiple SUDs (SUD-other) and outpatients without substance-related diagnoses or hospitalizations (SU-NAS); in mortality analyses, those who had started in opioid substitution treatment (OST) were analyzed separately. COX regression analyses were used to calculate the risk of death by the year 2018 or up to 15 years after seeking treatment. RESULTS: Among the 10,888 treatment-seeking individuals the cumulative mortality rates during 1-, 5- and 15-year follow-up were 2.5% (n = 271), 10.9% (n = 1191) and 28.4% (n = 3096), respectively. The mean age at death varied according to substance of use (55.0 years for AUD-only, 35.8 OUD-all, 45.8 SUD-other and 55.6 SU-NAS). The patients who had started in OST had a lower risk of death compared to the other groups, as did the SU-NAS group that likely included individuals with a less severe course of AUDs/SUDs. There were no differences between the AUD-only, OUD-other and SUD-other groups for the risk of death during the 15-year follow-up period when gender and year of birth were included as covariates. CONCLUSIONS: The mortality rates were very high; however, most of the deaths occurred several years after seeking treatment. The lower mortality amongst the patients who had initiated OST solidifies previous knowledge on the benefits of OST and efforts should be made to improve access to treatment. These results show that treatment plays a role in lowering the risk of death among individuals with AUDs/SUDs.

Non drug-related and opioid-specific causes of 3262 deaths in Scotland's methadone-prescription clients, 2009-2015.

BACKGROUND: Opioid drug use is a major cause of premature mortality, with opioid substitution therapy the leading intervention. As methadone-clients age, non-drug-related deaths (non-DRDs) predominate and DRD-risks increase differentially, quadrupling at 45+ years for methadone-specific DRDs. METHODS: 36,606 methadone-prescription-clients in Scotland during 2009-2015 were linked to mortality records to end-2015 by their Community Health Index (CHI). Cohort-entry, also baseline quantity of prescribed methadone, were defined by clients' first CHI-identified methadone-prescription during 2009-2015. National Records of Scotland identified non-DRDs from DRDs; and provided ICD10 codes for underlying and co-present causes of death. Methadone-specific DRD means methadone was implicated in DRD but neither heroin nor buprenorphine. RESULTS: During 193,800 person-years of follow-up, 1939 non-DRDs (59%) and 1323 DRDs occurred, of which 546 were methadone-specific. Predominant underlying ICD10 chapters for non-DRDs were: neoplasm (377); external causes (341); diseases of digestive (303), circulatory (286) or respiratory (212) system. As methadone-clients aged, the non-DRD proportion of their deaths increased from 54% (717/1318) at 35-44 years to 89% (372/417) at 55+ years. After allowing for DRDs' opioid-specificity, age-group and quintile for last-prescribed methadone, there was a significant, positive interaction for co-present circulatory disease between top-quintile for prescribed methadone and 45+ years at death (p = 0.033 after Bonferroni); not for digestive or respiratory co-presence. CONCLUSIONS: Circulatory disease is the co-morbidity most likely implicated in the quadrupling of methadone-specific DRD-risk at 45+ years; followed by digestive disease. Cultural shift is needed in treatment-services because degenerative non-DRDs predominate as methadone-clients age. Future linkage-studies should access hospitalizations and methadone-daily-dose.

Forensic Toxicology Perspectives of Methadone-associated Deaths in Tehran, Iran, a 7-year Overview.

Methadone has a long history of pain relief and successful substitute for maintenance treatment in heroin and narcotic addiction. The aim of the study was to assess the trends of methadone-associated deaths in Tehran, Iran, in 2009-2015, from a forensic toxicology point of view. All methadone-associated deaths during this 7-year study period were evaluated according to demographic parameters and forensic toxicology analysis results. Results showed that 1274 cases of methadone-associated deaths were investigated during the study period. The incidence rate of methadone-associated deaths had risen 7.7 times in 2015 in comparison with 2009 (p < 0.05). The majority of cases were men (90.35%), aged from 20 to 40 years. About 80% of cases had shown positive results for other drugs and poisons in combination with methadone. Methamphetamine and tramadol were the most drugs detected in post-mortem samples. Death rates among methadone users in Tehran, Iran, increased year by year during 2009-2015. These findings raise the attention to the concomitant use of drugs with the need for changes in regulation and regulatory policy to restrict access and use of controlled drugs.

Death from liver disease in a cohort of injecting opioid users in a Swedish city in relation to registration for opioid substitution therapy.

INTRODUCTION AND AIMS: Injecting opioid users are at elevated risk of death. Although liver disease (especially hepatitis C) is common, its impact on mortality is low in active injectors. Because opioid substitution therapy (OST) reduces the risk of death from directly drug related causes, we hypothesised that the proportion of liver-related deaths would increase in subjects receiving OST. We investigated liver-related mortality in a cohort of injecting opioid users attending a needle exchange program (NEP) in a Swedish city in relation to OST exposure. DESIGN AND METHODS: Participants enrolled in the NEP between 1987 and 2011 with available national identity numbers, and registered use of opioids, were included. Linkage based on national identity numbers was performed with national registers for death, emigration and prescription of OST. Participants were categorised as non-OST recipients until the registered date of first OST prescription, and hence as OST recipients. Hazard ratios were calculated by Cox regression for overall and liver-related mortality in relation to OST, with OST as a time-dependent variable. RESULTS: Among 4494 NEP participants, 1488 opioid users were identified; 711/1488 had been prescribed OST. During a follow-up period of 15 546 person-years 368 deaths occurred. Sixteen deaths were caused by liver disease; 10 of these occurred in OST recipients. The risk of liver-related death was significantly increased in OST receiving participants (hazard ratio 3.08, 95% confidence interval [1.09, 8.68], P = 0.03). CONCLUSIONS: Liver related mortality among opioid users was significantly elevated in OST recipients, showing the long-term importance of chronic liver disease in this population. [Jerkeman A, Håkansson A, Rylance R, Wagner P, Alanko Blomé M, Björkman P. Death from liver disease in a cohort of injecting opioid users in a Swedish city in relation to registration for opioid substitution therapy. Drug Alcohol Rev 2017;36:424-431].

Impact of treatment for opioid dependence on fatal drug-related poisoning: a national cohort study in England.

AIMS: To compare the change in illicit opioid users' risk of fatal drug-related poisoning (DRP) associated with opioid agonist pharmacotherapy (OAP) and psychological support, and investigate the modifying effect of patient characteristics, criminal justice system (CJS) referral and treatment completion. DESIGN: National data linkage cohort study of the English National Drug Treatment Monitoring System and the Office for National Statistics national mortality database. Data were analysed using survival methods. SETTING: All services in England that provide publicly funded, structured treatment for illicit opioid users. PARTICIPANTS: Adults treated for opioid dependence during April 2005 to March 2009: 151,983 individuals; 69% male; median age 32.6 with 442,950 person-years of observation. MEASUREMENTS: The outcome was fatal DRP occurring during periods in or out of treatment, with adjustment for age, gender, substances used, injecting status and CJS referral. FINDINGS: There were 1499 DRP deaths [3.4 per 1000 person-years, 95% confidence interval (CI) = 3.2-3.6]. DRP risk increased while patients were not enrolled in any treatment [adjusted hazard ratio (aHR) = 1.73, 95% CI = 1.55-1.92]. Risk when enrolled only in a psychological intervention was double that during OAP (aHR = 2.07, 95% CI = 1.75-2.46). The increased risk when out of treatment was greater for men (aHR = 1.88, 95% CI = 1.67-2.12), illicit drug injectors (aHR = 2.27, 95% CI = 1.97-2.62) and those reporting problematic alcohol use (aHR = 2.37, 95% CI = 1.90-2.98). CONCLUSIONS: Patients who received only psychological support for opioid dependence in England appear to be at greater risk of fatal opioid poisoning than those who received opioid agonist pharmacotherapy.