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Excess all-cause mortality is a key indicator for assessing direct and indirect consequences of injection drug use and data are warranted to delineate sub-populations within people who inject drugs at higher risk of death. Our aim was to examine mortality and factors associated with mortality among people who inject drugs in Estonia. Retrospective cohort study using data from people who inject drugs recruited in the community with linkage to death records. Standardized mortality ratios were used to compare the cohort mortality to the general population and potential predictors of death were examined through survival analysis Cox regression. The cohort include a total of people who inject drugs recruited for cross-sectional surveys using respondent driven sampling between and in Estonia. A cohort with follow-up through was formed with linkage to national causes of death registry. The all-cause mortality rate in the cohort was Being HIV positive, injecting mainly opioids fentanyl , living in the capital region and the main source of income other than work were associated with greater mortality risk. While low-threshold services have been available for a long time for people who inject drugs, there is still a need to widen the availability and integration of services, particularly the integration of HIV and opioid treatment. Up-to-date data are needed on cause-specific mortality and identification of risk factors among people who use drugs to assess the effect of, and tailor prevention, care and harm reduction efforts for reducing morbidity and mortality. The most recent systematic review on this topic 2 located three cohorts from Central Europe and no studies were found from Eastern Europe. There, potent illicitly produced fentanyl derivatives have largely replaced prescription opioids and heroin, driving a widespread epidemic of opioid-related deaths. In Estonia, studies conducted among people who inject drugs PWID , highlight the strong connection between injection fentanyl use, 5—7 overdose risk 8 , 9 and HIV in this population, 10 but the cumulative impact remains unquantified. The widespread fentanyl injection in Estonia, which has resulted in a two-decade-long epidemic of high HIV seroprevalence 10 and significant overdose mortality, 8 , 9 predates the situation in North America by two decades. We report findings from a retrospective cohort study on all-cause mortality, causes of death and factors associated with mortality among community-recruited people who inject drugs in Estonia. These surveys used respondent driven sampling for subject recruitment. Participants received pre- and post-test HIV counselling. Data on the Estonian personal identification code PIC was collected. Demographic data for age and sex were collected. Variables for analysis were selected from those used in mortality studies of people who inject drugs which appear to be prognostic indicators. There were indicators concerning: educational attainment years of education ; main source of income work versus other, including social benefits, theft, etc. The primary outcome—survival time—was time since the first injection to death. Follow-up time person-years was calculated from the year of participating in the source studies to the date of death or at censoring if they remained alive until 4 April Dates and causes of death were obtained from the Estonian Causes of Death Registry ECD , a population-based registry that covers the entire country. ECD captures all deaths registered in Estonia and information collected includes a diagnostic code ICD for the underlying cause of death and the nature of injury. Causes of death among people who inject drugs were grouped into ICD code combinations recommended by Santo et al. PIC, as single unique identifier, was used to link source survey data with mortality data. For baseline characteristics, means were calculated for continuous variables and percentages for categorical variables using the data collected at the recruitment into respective cross-sectional studies. We used all-cause crude mortality rates to determine absolute risk of mortality and all-cause age and sex standardized mortality ratios to compare the cohort mortality to the general population. Mortality was calculated using person-time methods. To calculate crude mortality rates CMR , we summed the number of deaths by category and calculated a rate per person years. To compare the cohort mortality to the general population, we calculated standardized mortality ratios SMR using year age bands stratified by gender. Population data were obtained from Statistics Estonia, the Estonian government agency responsible for producing official statistics regarding the country. Summary statistics were used to describe people who inject drugs. Survival curves of the cohort were constructed using the Kaplan—Meier method for left-truncated data. We used the normal log-rank test to compare survival between groups of people who inject drugs i. The proportional hazard assumption was evaluated by Schoenfeld residuals. We used Cox regression to determine predictors of all-cause mortality. In multivariable Cox proportional hazard regression analysis, age was used as a time scale to account for left-truncation in the data. One of the predictor variables HIV status displayed evidence of violation of the proportional hazards assumption having a time-varying effect. Therefore, the multivariable model was stratified by this variable HIV status. Given that stratification by a non-proportional variable precludes estimation of its strength and its test within the Cox model, the follow-up time was spilt and fitted additional Cox models for two time-periods. The assumptions of the proportional hazards were tested and were not violated. A compilation of the final sample for this analysis is presented in Supplementary figure. From July to April , a total of people who inject drugs participated in the source studies. If there were duplicate entries, we kept the first occurrence. The resulting cohort included participants. Data on sociodemographic and behavioural characteristics are shown in Supplementary annex 1. The median follow-up duration per study subject was 3. Observed all-cause mortality rate in this cohort was Mortality among people who inject drugs significantly exceeded that of the Estonian general population SMR Excess mortality was particularly prominent in the younger age group aged 20— SMR The univariable analyses Supplementary annex 1 showed that being HIV positive was associated with the highest risk of death. Injecting opioids, living in the capital region, age and calendar time of first injection, prison experience and reporting other than paid work as the main source of income were associated with higher mortality risk Supplementary annex 1. Being a female was associated with a lower risk of death. The median survival time for people who inject drugs was Factors in the multivariable analysis independently associated with mortality are presented in figure 2. Causes of death and factors associated with all-cause death, multivariable stratified by injecting time analysis. Analyses on causes of death showed that there were more drug use-related deaths among those who had injected for less than fifteen years table 2. In this study, we show high risk of excess mortality and observed notable risk factors for all-cause mortality among people who inject drugs in Estonia. To the best of our knowledge, this is the first study investigating the risk of dying among people who inject drugs in countries in Europe that are witnessing explosive injection drug use, illicit fentanyl use and related HIV epidemics since the turn of the century. The crude all-cause mortality reported in this study In earlier studies, other than gender and HIV infection, higher mortality has also been attributed to increasing age among people who inject drugs. Mortality of PWID in Estonia was almost twelve times higher than the general population and remained elevated across all age groups. The excess mortality was higher among women and in the younger age-group. These findings reflect the age and gender differences in mortality of the general population younger age groups in comparison to older, and females in comparison to males have lower mortality in the general population. We saw a clear diverging pattern of factors contributing to all-cause death risk by the duration of injection drug use. Among people who inject drugs with a shorter injection career, injecting opioids was the sole significant contributor increasing risk of death. In studies from elsewhere in Europe, high mortality rates among people who inject drugs coincided with a reported high number of drug overdoses. Most of the overdose deaths have been caused by fentanyl and fentanyl derivates which have been the most common form of opioids used in Estonia. Since —, overdose deaths declined, potentially related to decreased availability of fentanyl derivates and a scaling-up of interventions e. Fentanyl use led to Estonia having the highest fatal drug overdose rate in Europe up to In Estonia, fentanyl emerged in , swiftly replacing heroin in the illicit drug market. Between and , 3-methylfentanyl dominated confiscations. Until , only fentanyl and 3-methylfentanyl were detected by the Estonian Forensic Science Institute. Although, there was a fentanyl drug market drought in , recent years have seen the emergence of a new type of synthetic opioids called nitazenes proto-, meto-, isotonitazen , not infrequently mixed with xylazine veterinary drug for sedation, anaesthesia, muscle relaxation, analgesia. These changes have led to a sharp increase in drug-related overdose mortality since A similar fentanyl-overdose situation has developed in the USA. Over the last several decades, the USA has experienced different waves of opioid-related overdose deaths. First was the opioid prescription analgesic wave roughly — , followed by a heroin wave roughly — , followed by the fentanyl wave roughly to the present. The similarity between the USA and Estonian situations indicates there are needs for greater treatment for opioid use disorder and for greater distribution of naloxone in the community in both countries. Although drug treatment is considered a protective measure against mortality among people who inject drugs, 2 , 32 the low coverage observed in our study and other studies from Estonia 33 , 34 do not show a population-based effect. This finding potentially indicates that the positive impact of ART remains largely inaccessible for people who inject drugs in Estonia. The argument is further confirmed by our subgroup analysis showing no difference in mortality among those on ART in comparison to those who are not. These results may indicate to stigmatization, lack of integrated services and suboptimal HIV care. Surveys have shown that ART adherence among people who inject drugs in Estonia is relatively high, based on self-reports. These results are similar to other studies where higher mortality risk among people who inject drugs was associated with unemployment and the inability to work due to disability. Living in the capital region was also a factor associated with a doubled mortality risk. Regional differences in risk structure among people who inject drugs are well known. Higher numbers of mortality of people who inject drugs may be driven by opioid use, higher age and lower drug treatment coverage. The main strengths of this study include its large sample size, long follow-up period, valid measurement laboratory confirmed for HIV verification and linkage to the national causes of death registry using personal identifiers. Our study benefits from rigorous measures for key variables, i. We were able to control for the relevant known confounders region, age, education, source of income, prison experience, receiving opioid agonist treatment OAT. We are aware of biases based on analysis on non-random samples. There are, however, limitations to our study. To minimize selection bias errors, we used the left truncation method to diminish the possibility of excluding from the sample people who had died before the source studies were conducted. Still, mortality among PWID who have been injecting for several decades may be overestimated, as our sample does not account for individuals who have ceased injecting. Secondly, some errors caused by self-reported questions may exist as people may give socially desirable answers. Thirdly, HIV coinfection, particularly coinfection with HCV, information was not available for all study participants; therefore, these factors could not be considered in the data analyses. However, these limitations seem unlikely to have caused the clear patterns observed in this study. Our findings show the impact of drug policy and practice. A SMR of 12 underscores the significant impact of illicit drug use on excess mortality, emphasizing it as a major public health concern. Although the low-threshold services for people who use drugs have been available for a long time in Estonia, there is a need to improve the services. To reduce harms caused by injecting illicit drugs, is important to make the services for people who inject drugs more accessible by integrating infectious disease care and substance use treatment. It is also important to increase the coverage of the services. Key points Illicit drug use influences on excess mortality. Being HIV positive and injecting mainly opioids were associated with greater mortality risk. To decrease mortality there is a need to integrate services provided to PWID, particularly the integration of HIV and opioid treatment. There are legal restrictions on sharing a de-identified data. According to legislative regulation and data protection law in Estonia, the authors cannot publicly release the data received from the health data registers in Estonia. More information about data availability: maris. 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Luxembourg: Publ Off Eur Union, , Worldwide prevalence and trends in unintentional drug overdose: a systematic review of the literature. Am J Public Health ; : e29 — Overdose mortality rates in Croatia and factors associated with self-reported drug overdose among persons who inject drugs in three Croatian cities. Int J Drug Policy ; 64 : 95 — Luxembourg: Publ Off Eur Union, , 4 — 6. Luxembourg: Publ Off Eur Union, The National institute for health development. Ciccarone D. The triple wave epidemic: supply and demand drivers of the US opioid overdose crisis. Int J Drug Policy ; 71 : — 8. Drug overdose deaths in the United States, — Association of opioid agonist treatment with all-cause mortality and specific causes of death among people with opioid dependence: a systematic review and meta-analysis. JAMA Psychiatry ; 78 : — Global, regional, and country-level coverage of interventions to prevent and manage HIV and hepatitis C among people who inject drugs: a systematic review. Lancet Glob Health ; 5 : e — Ongoing impact of HIV infection on mortality among persons who inject drugs despite free antiretroviral therapy. Addiction ; : — 9. Global epidemiology of injecting drug use and HIV among people who inject drugs: a systematic review. Lancet ; : — Drug overdose mortality is associated with employment status and occupation in the National Longitudinal Mortality Study. Am J Drug Alcohol Abuse ; 46 : — A Hazard analysis of risk factors of mortality in individuals who inject drugs in Denver CO. AIDS Behav ; 21 : — Macroeconomic conditions and opioid abuse. J Health Econ ; 56 : — Eur Addict Res ; 27 : — Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Advertisement intended for healthcare professionals. Sign in through your institution. Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents Abstract. Supplementary data. Data availability. Journal Article. Mortality among people who inject drugs — the interwoven roles of fentanyl and HIV: a community-based cohort study. Oxford Academic. Sigrid Vorobjov. Don Des Jarlais. Select Format Select format. Permissions Icon Permissions. Abstract Background. Figure 1. Open in new tab Download slide. Figure 2. Forest plot of hazard ratios of variables associated with mortality risk. Table 1 Open in new tab. Age 1. Table 2 Open in new tab. Causes of death stratified by injecting time. P -value a. Causes of death. HIV-related deaths 3 7. Google Scholar Crossref. Search ADS. Google Scholar PubMed. For commercial re-use, please contact journals. Issue Section:. Download all slides. Comments 0. Add comment Close comment form modal. I agree to the terms and conditions. You must accept the terms and conditions. Add comment Cancel. Submit a comment. Comment title. 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Drug Misuse as an Epidemic: A Focus on the Synthetic Opioid Fentanyl

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