Abstract
IntroductionOpioid agonist treatment (OAT) is a safe and effective treatment for opioid use disorder (OUD). However, people commonly stop and start OAT and their risk of death is high immediately after stopping. The prevalence of illicitly manufactured fentanyl and other highly potent synthetic opioids have increased in the illicit drug supply globally. Yet, there is limited evidence examining the relationship between OAT and mortality when these contaminants are widely available in the illicit drug supply.
 Objectives and ApproachWe aimed to compare the risk of mortality on and off OAT in a setting with a high prevalence of illicitly manufactured fentanyl and other potent synthetic opioids in the illicit drug supply. We linked five health administrative datasets in British Columbia, Canada, creating a cohort of 55,347 people with OUD who received OAT during a 23-year period (1996 to 2018). We compared the risk of mortality on and off treatment over time, and according to time since starting or stopping treatment and by medication type.
 Results7,030 of 55,347 (12.7%) OAT recipients died during follow-up. All-cause SMR was substantially lower on OAT (4.6 [4.4 to 4.8]) compared to off OAT (9.7 [9.5 to 10.0]). In a period of increasing prevalence of fentanyl, the relative risk of mortality off OAT was 2.1 [1.8 to 2.4] times higher than on OAT prior to the introduction of fentanyl, and increased to 3.4 [2.8 to 4.3] at the end of the study period (65% increase in relative risk).
 Conclusion / ImplicationsThe protective effect of OAT on mortality increased as fentanyl and other synthetic opioids became common in the illicit drug supply, while the risk of mortality remained high off OAT. As fentanyl becomes more widespread globally, these findings highlight the importance of interventions that improve retention on opioid agonist treatment and prevent recipients from stopping treatment.
Highlights
The global burden of disease due to opioid use disorder continues to grow
Despite advances in opioid agonist treatment and a growing body of evidence showing the protective effects of engagement and retention on these medications,[14 47] mortality among people with opioid use disorder continues to increase in North America.[49]
This study provides strong evidence that opioid agonist treatment (OAT) is an effective intervention to reduce the risk of mortality in the presence of illicitly manufactured fentanyl and other potent synthetic opioids
Summary
The global burden of disease due to opioid use disorder continues to grow. Between 1990 and 2016, the total number (age standardised prevalence) of people dependent on opioids increased from 18.2 million (360.8 per 100 000) to 26.8 million (353.0 per 100 000), resulting in 86 200 deaths and 36.6 million years of life lost in 2016.1 In North America, the introduction of illicitly manufactured fentanyl and other highly potent, synthetic opioids in the drug supply has contributed to a rapidly worsening disease burden.[2,3,4,5,6,7] In Canada, an unprecedented 4614 opioid related deaths occurred in 2018, with nearly three quarters of these deaths involving fentanyl or other synthetic opioids.[8] People with opioid use disorder are at high risk of exposure to these contaminants,[9] which are up to 10 000 times more potent than morphine.[10 11] This is contributing to a mounting global public health concern as fentanyl and other synthetic opioids become more widespread internationally.[12].
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