Mary M. Doyle-Waters

Background: Patients who experience harms from alcohol and other substance use often seek care in the emergency department (ED). ED visits related to alcohol withdrawal have increased across the world during the COVID-19 pandemic. ED clinicians are responsible for risk-stratifying patients under time and resource constraints and must reliably identify those who are safe for outpatient management versus those who require more intensive levels of care. Published guidelines for alcohol withdrawal are largely limited to the primary care and outpatient settings, and do not provide specific guidance for ED use. The purpose of this review was to synthesize published evidence on the treatment of alcohol withdrawal syndrome in the ED. Methods: We conducted a rapid review by searching MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials (1980 to 2020). We searched for grey literature on Google and hand-searched the conference abstracts of relevant addiction medicine and emergency medicine professional associations (2015 to 2020). We included interventional and observational studies that reported outcomes of clinical interventions aimed at treating alcohol withdrawal syndrome in adults in the ED. Results: We identified 13 studies that met inclusion criteria for our review (7 randomized controlled trials and 6 observational studies). Most studies were at high/serious risk of bias. We divided studies based on intervention and summarized evidence narratively. Benzodiazepines decrease alcohol withdrawal seizure recurrence and treat other alcohol withdrawal symptoms, but no clear evidence supports the use of one benzodiazepine over another. It is unclear if symptom-triggered benzodiazepine protocols are effective for use in the ED. More evidence is needed to determine if phenobarbital, with or without benzodiazepines, can be used safely and effectively to treat alcohol withdrawal in the ED. Phenytoin does not have evidence of effectiveness at preventing withdrawal seizures in the ED. Conclusions: Few studies have evaluated the safety and efficacy of pharmacotherapies for alcohol withdrawal specifically in the ED setting. Benzodiazepines are the most evidence-based treatment for alcohol withdrawal in the ED. Pharmacotherapies that have demonstrated benefit for treatment of alcohol withdrawal in other inpatient and outpatient settings should be evaluated in the ED setting before routine use.

North America is in the midst of an unabated opioid overdose epidemic due to the increasing non-medical use of fentanyl and ultra-potent opioids. Naloxone is an effective antidote to opioid toxicity, yet its optimal dosing in the context of fentanyl and ultra-potent opioid overdoses remains unknown. This review aims to determine the relationship between the first empiric dose of naloxone and reversal of toxicity, adverse events, and the total cumulative dose required among patients with undifferentiated opioid overdoses and those with suspected toxicity from ultra-potent opioids. Secondary objectives include evaluating the relationship between the cumulative naloxone dose and toxicity reversal and adverse events, among patients with undifferentiated opioid overdoses and those with suspected toxicity from ultra-potent opioids. To identify studies, we will search MEDLINE, Embase, CENTRAL, DARE, CDAG, CINAHL, Science Citation Index, multiple trial registries, and the gray literature. Included studies will evaluate patients with suspected or confirmed opioid toxicity from undifferentiated opioids and ultra-potent opioids, who received an empiric and possibly additional doses of naloxone. The main outcomes of interest are the relationship between naloxone dose and toxicity reversal and adverse events. We will include controlled and non-controlled interventional studies, observational studies, case reports/series, and reports from poison control centers. We will extract data and assess study quality in duplicate with discrepancies resolved by consensus or a third party. We will use the Downs and Black and Cochrane risk of bias tools for observational and randomized controlled studies. If we find sufficient variation in dose, we will fit a random effects one-stage model to estimate a dose-response relationship. We will conduct multiple subgroup analyses, including by type of opioid used and by suspected high and low prevalence of ultra-potent opioid use based on geographic location and time of the original studies. Our review will include the most up-to-date available data including ultra-potent opioids to inform the current response to the opioid epidemic, addressing the limitations of recent reviews. We anticipate limitations relating to study heterogeneity. We will disseminate study results widely to update overdose treatment guidelines and naloxone dosing in Take Home Naloxone programs.

Opioid addiction prevention has become an urgent public health priority, with several countries declaring a state of emergency due to rising death tolls from opioid abuse. Reducing the risk of developing addiction among opioid-naïve patients exposed to prescribed opioids during the process of medical care may be an important primary prevention strategy. Our objective is to synthesize the available evidence about factors associated with the development of addiction among patients first exposed to prescribed opioids, with a focus on opioid-naïve patients. We will perform a systematic search of MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and other databases in collaboration with a health information specialist using a comprehensive search strategy. We will also supplement our search with a scan of the grey literature to identify relevant ongoing and unpublished studies. We will include studies reporting on risk factors for opioid addiction in patients prescribed opioid analgesic therapy through a prescription from a licensed medical professional, with a focus on opioid-naïve patients. We will exclude studies focusing on patients who are first exposed to illicit opioids, those who use prescription opioids for cancer pain, and/or who are palliative. Two reviewers will independently review titles, abstracts, and full texts for inclusion and exclusion criteria. They will then extract data from included full texts using standardized piloted data extraction forms and assess study quality through risk of bias assessment. We will synthesize the effect sizes of risk factors derived from clinically homogenous studies with similar designs and the remaining ones qualitatively. Understanding risk factors for opioid addiction among patients who require analgesia has the potential to inform clinical care and opioid prescribing guidelines aiming to reduce opioid addiction. We will also use this information as a starting point for developing interventions for primary prevention.

Cerebral small vessel disease (CSVD) is a common cause of stroke, dementia, and functional decline. In recent years, neuroradiologic correlates of CSVD have been identified. These imaging findings, best characterized on magnetic resonance imaging (MRI), include some combination of white matter hyperintensities, lacunes, cerebral microbleeds, enlarged perivascular spaces, and cerebral atrophy. Though some cohorts have reported that participants with type 2 diabetes mellitus (T2DM), an important risk factor for CSVD, may have a distinct neuroradiologic phenotype, this relationship is not well-characterized. Adults with diabetes mellitus have a two- to threefold higher incidence of ischemic stroke compared to controls and are an increasingly important population given global trends of increasing diabetes prevalence. This study aims to determine if adults with CSVD and T2DM have a distinct neuroradiologic phenotype. A systematic search of the literature will be conducted to find articles that report the MRI features of CSVD in a cohort of participants including those with and without type 2 diabetes mellitus (T2DM). A number of databases will be searched including MEDLINE, Embase, CINAHL, and Web of Science. Proceedings and abstracts from key conferences will also be reviewed and relevant journals hand searched for additional papers. The references from selected papers will be scanned. Screening of potential articles, data extraction, and quality appraisal will be performed in duplicate by independent reviewers. Odds ratios and 95% confidence intervals for the presence versus absence of each neuroradiologic correlate of interest from each included study will be calculated. If sufficient homogeneity exists among studies, a meta-analysis will be performed for each neuroradiologic correlate of CSVD. If heterogeneity of studies precludes data pooling, results will be presented in narrative form. Determining whether a distinct neuroradiologic phenotype of CSVD exists in adults with T2DM will provide insight into the underlying mechanisms of CSVD and guide future research on therapeutic targets. PROSPERO CRD42016046669