Factors associated with opioid overdose during medication-assisted treatment: How can we identify individuals at risk?

BACKGROUND: Due to the loss of tolerance to opioids during medication-assisted treatment (MAT), this period may represent a time of heightened risk for overdose. Identifying factors associated with increased risk of overdose during treatment is therefore paramount to improving outcomes. We aimed to determine the prevalence of opioid overdoses in patients receiving MAT. Additionally, we explored factors associated with opioid overdose during MAT and the association between length of time enrolled in MAT and overdose. METHODS: Data were collected prospectively from 2360 participants receiving outpatient MAT in Ontario, Canada. Participants were divided into three groups by overdose status: no history of overdose, any lifetime history of overdose, and emergency department visit for opioid overdose in the last year. We used a multivariate multinomial regression model to assess demographic and clinical factors associated with overdose status. RESULTS: Twenty-four percent of participants reported a lifetime history of overdose (n = 562), and 8% reported an emergency department (ED) visit for opioid overdose in the last year (n = 179). Individuals with a recent ED visit for opioid overdose were in treatment for shorter duration. Individuals with a lifetime or recent history of overdose were more likely to be younger in age, report more physical symptoms, and had higher rates of non-prescription benzodiazepine use compared to individuals with no history of overdose. CONCLUSIONS: A considerable number of patients enrolled in MAT have experienced overdose. Our study highlights that there are identifiable factors associated with a patient's overdose status that may represent areas for intervention. In particular, longer duration in MAT is associated with a decreased risk of overdose

Assessing fragility of statistically significant findings from randomized controlled trials assessing pharmacological therapies for opioid use disorders: a systematic review

Abstract Background The fragility index is a statistical measure of the robustness or “stability” of a statistically significant result. It has been adapted to assess the robustness of statistically significant outcomes from randomized controlled trials. By hypothetically switching some non-responders to responders, for instance, this metric measures how many individuals would need to have responded for a statistically significant finding to become non-statistically significant. The purpose of this study is to assess the fragility index of randomized controlled trials evaluating opioid substitution and antagonist therapies for opioid use disorder. This will provide an indication as to the robustness of trials in the field and the confidence that should be placed in the trials’ outcomes, potentially identifying ways to improve clinical research in the field. This is especially important as opioid use disorder has become a global epidemic, and the incidence of opioid related fatalities have climbed 500% in the past two decades. Methods Six databases were searched from inception to September 25, 2021, for randomized controlled trials evaluating opioid substitution and antagonist therapies for opioid use disorder, and meeting the necessary requirements for fragility index calculation. Specifically, we included all parallel arm or two-by-two factorial design RCTs that assessed the effectiveness of any opioid substitution and antagonist therapies using a binary primary outcome and reported a statistically significant result. The fragility index of each study was calculated using methods described by Walsh and colleagues. The risk of bias of included studies was assessed using the Revised Cochrane Risk of Bias tool for randomized trials. Results Ten studies with a median sample size of 82.5 (interquartile range (IQR) 58, 179, range 52–226) were eligible for inclusion. Overall risk of bias was deemed to be low in seven studies, have some concerns in two studies, and be high in one study. The median fragility index was 7.5 (IQR 4, 12, range 1–26). Conclusions Our results suggest that approximately eight participants are needed to overturn the conclusions of the majority of trials in opioid use disorder. Future work should focus on maximizing transparency in reporting of study results, by reporting confidence intervals, fragility indexes, and emphasizing the clinical relevance of findings. Trial registration PROSPERO CRD42013006507. Registered on November 25, 2013

A call for consensus in defining efficacy in clinical trials for opioid addiction: combined results from a systematic review and qualitative study in patients receiving pharmacological assisted therapy for opioid use disorder

Abstract Background Given the complex nature of opioid addiction treatment and the rising number of available opioid substitution and antagonist therapies (OSAT), there is no ‘gold standard’ measure of treatment effectiveness, and each successive trial measures a different set of outcomes which reflect success in arbitrary or opportune terms. We sought to describe the variation in current outcomes employed across clinical trials for opioid addiction, as well as determine whether a discrepancy exists between the treatment targets that patients consider important and how treatment effectiveness is measured in the literature. Methods We searched nine commonly used databases (e.g., EMBASE, MEDLINE) from inception to August 1, 2015. Outcomes used across trials were extracted and categorized according to previously established domains. To evaluate patient-reported goals of treatment, semi-structured interviews were conducted with 18 adults undergoing methadone treatment. Results We identified 60 trials eligible for inclusion. Once outcomes were categorized into eight broad domains (e.g., abstinence/substance abuse), we identified 21 specific outcomes with furthermore 53 subdomains and 118 measurements. Continued opioid use and treatment retention were the most commonly reported measures (46%, n = 28). The majority of patients agreed that abstinence from opioids was a primary goal in their treatment, although they also stressed goals under-reported in clinical trials. Conclusions There is inconsistency in the measures used to evaluate the effectiveness of OSATs. Individual and population level decision making is being guided by a standard of effect considered useful to researchers yet in direct conflict with what patients deem important. Trial registration PROSPERO, CRD42013006507