The impact of low-threshold methadone maintenance treatment on mortality in a Canadian setting
Introduction
In North America, the use of prescription and illicit opioids continues to increase with devastating consequences (Goodnough, 2015). Opioid dependence has become a serious public health concern as a result of these growing trends (Fullerton et al., 2014, King et al., 2014). Without treatment, the risk of premature death amongst illicit opioid users is significant with estimates ranging from 13 to 63 times higher than that of the general population (English et al., 1995, Gronbladh et al., 1990, Hulse et al., 1999).
While the benefits of methadone maintenance therapy (MMT) for the reduction of illicit opioid use and retention in treatment are well established, its effect on mortality is less clear. Several randomized controlled trials (Gunne and Gronbladh, 1981, Kinlock et al., 2007, Newman and Whitehill, 1979, Yancovitz et al., 1991) comparing MMT and non-pharmacological options were included in a 2009 Cochrane review; separately or pooled, they showed no significant difference in mortality (Mattick et al., 2009). These results are difficult to interpret, however, as the included studies had small sample sizes and low mortality rates. A number of observational and registry studies have demonstrated an association between methadone use and reduced mortality (Bell et al., 2009, Clausen et al., 2008, Degenhardt et al., 2009, Evans et al., 2015, Gibson et al., 2008). A 2008 Norwegian prospective, cross-registry study (Clausen et al., 2008) following 3789 opioid dependent patients who applied for opioid maintenance therapy (OMT) demonstrated a reduction in mortality using an intention to treat analysis (relative risk = 0.60, p = 0.004). Through data linkage, an Australian study by Degenhardt et al., in 2009 demonstrated an overall 29% reduction in mortality among 42,676 opioid-dependent participants entering OMT between 1985 and 2006. Lastly, a more recent longitudinal study published by Evans et al., in 2015 assessed mortality among opioid dependent individuals accessing MMT in the U.S. between 2006 and 2010 and found a decrease in mortality risk with MMT (hazard ratio = 0.30, 95% confidence interval [CI]: 0.25–0.37).
While these studies do demonstrate an association between MMT participation and improved mortality, the strength of this association may be understated given the comparison group is often in receipt of psychosocial treatments and those receiving no treatment are excluded. Often programmatic barriers such as limiting MMT administration to specialized clinics, long-wait lists for treatment entry and lack of universal medical insurance coverage restrict access to MMT (Peterson et al., 2010). Furthermore even when opioid users have access to MMT, limits on dosing and duration of maintenance may limit its potential (Strain et al., 1999). British Columbia, Canada, is a unique environment that overcomes these challenges as the provision of MMT always occurs through a low-threshold methadone program. Specifically, MMT is widely accessible through the setting's universal no-cost medical insurance plan and through the integration of prescribing and dispensation through community physicians and community pharmacies respectively (Nosyk et al., 2012). Furthermore, low-threshold methadone administration occurs without any restriction on the maximum dose needed for desired efficacy or duration of treatment and while abstinence is the ultimate goal, it is not a prerequisite for continuation with the program. Thus, in this setting we sought to determine the relationship between MMT enrolment and all-cause mortality amongst persons who inject drugs (PWID) over a 15 year follow-up period.
Section snippets
Study population
The present study derived data from the Vancouver Injection Drug Users Study (VIDUS) and the AIDS Care Cohort to Evaluate Access to Survival Services (ACCESS); two open prospective cohort studies of illicit drug users in Vancouver, British Columbia, Canada. Described in detail previously (Palepu et al., 2006, Strathdee et al., 1998), ACCESS and VIDUS comprise of HIV-positive and HIV-negative participants respectively. Beyond this, both cohorts follow identical recruitment and follow up
Results
Between May, 1996 and December, 2011, a total of 2595 PWID were recruited. Overall, 2335 (90.0%) participants were included in the study and 260 (10.0%) were excluded as a result of having no follow-up visit (and no confirmed death date) within 24 months of their baseline visit. Compared to the 260 (10.0%) individuals who were excluded, the participants included in these analyses were more likely to be younger, HIV negative or homeless in the preceding 6 months at baseline and were less likely
Discussion
In the present study, we observed a high mortality rate among PWID in our setting. At the same time, we found that enrollment in a low-threshold MMT program was associated with a protective effect against all-cause mortality, even after adjusting for confounders including age, HIV infection and heroin injection.
Though many previous reports demonstrate the increased mortality risk faced by those with an opioid use disorder (English et al., 1995, Gronbladh et al., 1990, Evans et al., 2015, Hulse
Role of funding source
The study was supported by the US National Institutes of Health (R25DA037756, VIDUS: R01DA011591, U01DA038886; ACCESS: R01DA021525) and the Canadian Institutes of Health Research through the Canadian Research Initiative on Substance Misuse (FMN-139148). This research was undertaken, in part, thanks to funding for a Tier 1 Canada Research Chair in Inner City Medicine, which supports Dr. Evan Wood. Dr. Kanna Hayashi is supported by the Canadian Institutes of Health Research. Dr. Julio Montaner is
Contributors
Seonaid Nolan and Evan Wood designed and prepared the first draft of the manuscript. Vivianne Dias Lima and Huiru Dong conducted the statistical analyses. All coauthors contributed to the drafting of the final manuscript.
Conflict of interest
JSGM has received limited unrestricted funding, paid to his institution, from Abbvie, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, and ViiV Healthcare. VDL has received limited unrestricted funding, paid to her institution, from GlaxoSmithKline. All other authors declare no competing interests.
Acknowledgments
The authors thank the study participants for their contribution to the research, as well as current and past researchers and staff.
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