Lipid emulsion treatment for local anesthetic systemic toxicity in pediatric patients: A systematic review.

BACKGROUND: Local anesthetic systemic toxicity (LAST) is rare, but fatal; the current widely used treatment is lipid emulsion (LE). The goal of this study was to analyze and review case reports on LE treatment for LAST in pediatric patients. METHODS: We performed a systematic review using case reports on LE treatment for LAST in pediatric patients, searching PubMed and Scopus databases to March 2023 using the following keywords: ("local anesthetic toxicity" OR "local anesthetic systemic toxicity" OR LAST") AND ("newborn" OR "infant" OR "child" OR "children" OR "adolescent" OR "pediatric") AND ("lipid emulsion" OR "Intralipid"). RESULTS: Our search yielded 21 cases, revealing that nearly 43% patients with LAST were less than 1 year old, and most cases were caused by bupivacaine (approximately 67% cases). "Inadvertent intravascular injection" by anesthesiologists and "overdose of local anesthetics" mainly by surgeons were responsible for 52% and 24% cases of LAST, respectively. LAST occurred in the awake state (52%) and under general anesthesia (48%), mainly causing seizures and arrhythmia, respectively. Approximately 55% of patients received LE treatment in <10 minutes after LAST, mainly improving cardiovascular symptoms. A 20% LE (1.5 mL/kg) dose followed by 0.25 mL/kg/minutes dose was frequently used. LE and anticonvulsants were mainly used in the awake state, whereas LE with or without vasopressors was mainly used under general anesthesia. LE treatment led to full recovery from LAST in 20 cases; however, 1 patient died due to underlying disease. CONCLUSION: Consequently, our findings reveal that LE is effective in treating pediatric LAST.

Evaluation of the relationship of xylazine and fentanyl blood concentrations among fentanyl-associated fatalities.

INTRODUCTION: Illicit fentanyl and fentanyl-analogs have produced a devastating increase in opioid fatalities in the United States. Increasingly, xylazine has been found in the illicit fentanyl supply. The role of xylazine in fentanyl intoxication remains unclear. We reviewed coroner records to evaluate trends and effects associated with xylazine in fentanyl-related fatalities. METHODS: This is a retrospective cohort study of all deaths reported to the Franklin County Coroner's Office in Ohio from 1 January 2019 to 16 March 2023, in which fentanyl was determined causative or contributory to death. Cases identified as fentanyl-associated fatalities were separated into two groups based on whether or not xylazine was also detected. RESULTS: There were 3,052 fentanyl-related fatalities during the study period. 4.8 percent of these decedents also tested positive for xylazine. There was no meaningful demographic difference between fentanyl-related fatalities in which xylazine was detected versus those without xylazine detected. There was a mean of 726 fentanyl-associated fatalities per year, with a peak of 846 deaths in 2020 and a decline thereafter. The percentage of fentanyl-related fatalities with xylazine detected increased in linear fashion from 2.7 percent in 2019 to 6.6 percent in 2022. The median fentanyl concentration was 17.0 µg/L (inter-quartile range: 7.9, 27.0) in cases with xylazine detected and 10.0 µg/L (inter-quartile range: 5.6, 18.0) without xylazine. The odds of a fentanyl concentration greater than 40 µg/L in cases with xylazine detected was more than twice as great (odds ratio: 2.41; 95 percent confidence interval: 1.58-3.64) than that in cases without xylazine detected. CONCLUSIONS: Postmortem fentanyl concentrations were greater in cases with xylazine detected than those without xylazine detected. Though it is unclear why patients who were exposed to xylazine tolerated higher opioid doses prior to succumbing to death, we postulate that xylazine may act to competitively antagonize some degree of mu-opioid receptor binding by opioids.

An individual segmented trajectory approach for identifying opioid use patterns using longitudinal dispensing data.

PURPOSE: The aim of this study is to use electronic opioid dispensing data to develop an individual segmented trajectory approach for identifying opioid use patterns. The resulting opioid use patterns can be used for examining the association between opioid use and drug overdose. METHODS: We retrospectively assembled a cohort of members on long-term opioid therapy (LTOT) between January 1, 2006 and June 30, 2019 who were 18 years and older and enrolled in one of three health care systems in the US. We have developed an individual segmented trajectory analysis for identifying various opioid use patterns by scanning over the follow-up and finding distinct opioid use patterns based on variability measured with coefficient of variation and trends of milligram morphine equivalents levels. RESULTS: Among 31, 865 members who were on LTOT between January 1, 2006 and June 30, 2019, 58.3% were female, and the average age was 55.4 years (STD = 15.4). The study population had 152 557 person-years of follow-up, with an average follow-up of 4.4 years per enrollment per person (STD = 3.4). This novel approach identified up to 13 distinct patterns including 88 756 episodes of "stable" pattern (42.1%) with an average follow-up of 11.2 months, 29 140 episodes of "increasing" pattern (13.8%) with an average follow-up of 6.0 months, 13 201 episodes of ≤10% dose reduction (6.3%) with an average follow-up of 10.4 months, 7286 episodes of 11%-20% dose reduction (3.5%) with an average follow-up of 5.3 months, 4457 episodes of 21%-30% dose reduction (2.1%) with an average follow-up of 4.0 months, and 9903 episodes of >30% dose reduction (4.7%) with an average follow-up of 2.6 months. CONCLUSIONS: A novel approach was developed to identify 13 distinct opioid use patterns using each individual's longitudinal dispensing data and these patterns can be used in examining overdose risk during the time that these patterns are ongoing.

Large variations in all-cause and overdose mortality among >13,000 patients in and out of opioid maintenance treatment in different settings: a comparative registry linkage study.

Background: Opioid maintenance treatment (OMT) has the potential to reduce mortality rates substantially. We aimed to compare all-cause and overdose mortality among OMT patients while in or out of OMT in two different countries with different approaches to OMT. Methods: Two nation-wide, registry-based cohorts were linked by using similar analytical strategies. These included 3,637 male and 1,580 female patients enrolled in OMT in Czechia (years 2000-2019), and 6,387 male and 2,078 female patients enrolled in OMT in Denmark (years 2007-2018). The direct standardization method using the European (EU-27 plus EFTA 2011-2030) Standard was employed to calculate age-standardized rate to weight for age. All-cause and overdose crude mortality rates (CMR) as number of deaths per 1,000 person years (PY) in and out of OMT were calculated for all patients. CMRs were stratified by sex and OMT medication modality (methadone, buprenorphine, and buprenorphine with naloxone). Results: Age-standardized rate for OMT patients in Czechia and Denmark was 9.7/1,000 PY and 29.8/1,000 PY, respectively. In Czechia, the all-cause CMR was 4.3/1,000 PY in treatment and 10.8/1,000 PY out of treatment. The overdose CMR was 0.5/1,000 PY in treatment and 1.2/1,000 PY out of treatment. In Denmark, the all-cause CMR was 26.6/1,000 PY in treatment and 28.2/1,000 PY out of treatment and the overdose CMR was 7.3/1,000 PY in treatment and 7.0/1,000 PY out of treatment. Conclusion: Country-specific differences in mortality while in and out of OMT in Czechia and Denmark may be partly explained by different patient characteristics and treatment systems in the two countries. The findings contribute to the public health debate about OMT management and may be of interest to practitioners, policy and decision makers when balancing the safety and accessibility of OMT.

A 2023 Agenda for Substance Use Prevention and Treatment in the US.

In this Viewpoint, officials from the White House Office of National Drug Control Policy describe 3 actions that health care personnel can take to expand prevention and treatment of substance misuse and overdose.

States' Methods for Capturing and Reporting Local Responses to Suspected Nonfatal Drug Overdoses.

This study examines the available data used to surveil state-level drug overdoses and characterizes them based on their timeliness, drug involvement, and specification of nonfatal outcomes.

Discontinuation and tapering of prescribed opioids and risk of overdose among people on long-term opioid therapy for pain with and without opioid use disorder in British Columbia, Canada: A retrospective cohort study.

BACKGROUND: The overdose crisis in North America has prompted system-level efforts to restrict opioid prescribing for chronic pain. However, little is known about how discontinuing or tapering prescribed opioids for chronic pain shapes overdose risk, including possible differential effects among people with and without concurrent opioid use disorder (OUD). We examined associations between discontinuation and tapering of prescribed opioids and risk of overdose among people on long-term opioid therapy for pain, stratified by diagnosed OUD and prescribed opioid agonist therapy (OAT) status. METHODS AND FINDINGS: For this retrospective cohort study, we used a 20% random sample of residents in the provincial health insurance client roster in British Columbia (BC), Canada, contained in the BC Provincial Overdose Cohort. The study sample included persons aged 14 to 74 years on long-term opioid therapy for pain (≥90 days with ≥90% of days on therapy) between October 2014 and June 2018 (n = 14,037). At baseline, 7,256 (51.7%) persons were female, the median age was 55 years (quartile 1-3: 47-63), 227 (1.6%) persons had been diagnosed with OUD (in the past 3 years) and recently (i.e., in the past 90 days) been prescribed OAT, and 483 (3.4%) had been diagnosed with OUD but not recently prescribed OAT. The median follow-up duration per person was 3.7 years (quartile 1-3: 2.6-4.0). Marginal structural Cox regression with inverse probability of treatment weighting (IPTW) was used to estimate the effect of prescribed opioid treatment for pain status (discontinuation versus tapered therapy versus continued therapy [reference]) on risk of overdose (fatal or nonfatal), stratified by the following groups: people without diagnosed OUD, people with diagnosed OUD receiving OAT, and people with diagnosed OUD not receiving OAT. In marginal structural models with IPTW adjusted for a range of demographic, prescription, comorbidity, and social-structural exposures, discontinuing opioids (i.e., ≥7-day gap[s] in therapy) was associated with increased overdose risk among people without OUD (adjusted hazard ratio [AHR] = 1.44; 95% confidence interval [CI] 1.12, 1.83; p = 0.004), people with OUD not receiving OAT (AHR = 3.18; 95% CI 1.87, 5.40; p < 0.001), and people with OUD receiving OAT (AHR = 2.52; 95% CI 1.68, 3.78; p < 0.001). Opioid tapering (i.e., ≥2 sequential decreases of ≥5% in average daily morphine milligram equivalents) was associated with decreased overdose risk among people with OUD not receiving OAT (AHR = 0.31; 95% CI 0.14, 0.67; p = 0.003). The main study limitations are that the outcome measure did not capture overdose events that did not result in a healthcare encounter or death, medication dispensation may not reflect medication adherence, residual confounding may have influenced findings, and findings may not be generalizable to persons on opioid therapy in other settings. CONCLUSIONS: Discontinuing prescribed opioids was associated with increased overdose risk, particularly among people with OUD. Prescribed opioid tapering was associated with reduced overdose risk among people with OUD not receiving OAT. These findings highlight the need to avoid abrupt discontinuation of opioids for pain. Enhanced guidance is needed to support prescribers in implementing opioid therapy tapering strategies with consideration of OUD and OAT status.

Association of Benzodiazepine Treatment for Sleep Disorders With Drug Overdose Risk Among Young People.

Importance: Benzodiazepines are prescribed for the treatment of adolescent sleep disorders; however, benzodiazepine overdoses occur, often in combination with opioids. Objective: To evaluate whether benzodiazepine treatment for sleep disorders, compared with alternative pharmacologic treatments (trazodone, hydroxyzine, zolpidem, zaleplon, and eszopiclone), is associated with increased risk of drug overdose for young people. Design, Setting, and Participants: This cohort study included privately insured people 10 to 29 years of age identified from a US commercial claims database (MarketScan), from January 1, 2009, to December 31, 2018. Young people with a sleep disorder diagnosis initiating benzodiazepine (n = 23 084) or comparator pharmacologic treatments (n = 66 706) were included in the study. Statistical analysis was performed from November 1, 2021, to May 16, 2022. Exposures: New use of benzodiazepine treatment or comparator pharmacologic treatments (defined as ≥1 year without a prescription for benzodiazepine or comparator medications). Main Outcomes and Measures: Incident diagnosed drug overdoses were identified from inpatient and emergency department records within 6 months of treatment initiation. The propensity score-adjusted cumulative incidence of overdose and hazard ratios (HRs) were estimated with intention-to-treat (analyzed based on initial treatment) and as-treated analyses (added censoring at treatment discontinuation). Results were stratified by prior prescription opioid fill. Results: The cohort included 23 084 young people initiating benzodiazepine treatment (14 444 female participants [62.6%]; mean [SD] age, 23 [4.1] years) and 66 706 initiating a comparator treatment (38 446 female participants [57.6%]; mean [SD] age, 22 [4.4] years). Six months after treatment initiation, 9.7% (95% CI, 9.3%-10.1%) of benzodiazepine users and 12.3% (95% CI, 12.1%-12.6%) of the comparator group were still receiving treatment. The crude incidence of drug overdose at 6 months was 0.9% for benzodiazepine initiators and 0.8% for comparator treatment initiators. In adjusted analyses, an increased risk of drug overdose was associated with benzodiazepines vs comparator treatments (intention-to-treat analysis: HR, 1.25 [95% CI, 1.03-1.51]; as-treated analysis: HR, 1.44 [95% CI, 1.14-1.80]). This association was stronger among young people with a recent prescription opioid fill vs those without a recent prescription opioid fill (as-treated analysis: adjusted HR, 2.01 [95% CI, 1.24-3.25] vs adjusted HR, 1.31 [95% CI, 1.00-1.70]). Conclusions and Relevance: The findings of this study suggest that benzodiazepines, compared with alternative pharmacologic treatments for common sleep disorders, were associated with an increased risk of drug overdose among young people during the following 6-month period, especially among those with a recent opioid prescription. Drug overdose is an important safety consideration when treating young people with benzodiazepines.

Prescribed opioid use is associated with adverse cardiovascular outcomes in community-dwelling older persons.

AIMS: Prescribed opioids are commonly used in the older community-dwelling population for the treatment of chronic pain. Although the harmful effects of opioid abuse and overdose are well understood, little is known about the long-term cardiovascular (CV) effects of prescribed opioids. The aim of this study was to investigate the CV effects associated with prescribed opioid use. METHODS AND RESULTS: A post hoc analysis of participants in the Aspirin in Reducing Events in the Elderly (ASPREE) trial was conducted. Participants in the ASPREE trial included community-dwelling older adults without a prior history of CV disease (CVD). Prescribed opioid use was defined as opioid use at baseline and/or at the first annual visit (AV1). Cox proportional hazards regression was used to calculate hazard ratios and 95% confidence intervals (95% CI) for associations between opioid use and CVD events following AV1. Of the 17 701 participants included (mean age 75.2 years, 58.2% female), 813 took opioids either at baseline or at AV1. Over a median follow-up period of 3.58 years (IQR 2.50-4.62), CVD events, most notably heart failure hospitalization, occurred in 7% (n = 57) amongst opioid users and 4% (n = 680) amongst non-opioid users. After adjustment for multiple covariates, opiate use was associated with a 1.67-fold (CI 1.26-2.23, P < 0.001) increase in the hazard ratio for CVD events. CONCLUSIONS: These findings identify opioid use as a non-traditional risk factor for CVD events in community-dwelling older adults.

Risk of non-medical drug overdose following prescription of opioids post-injury: A retrospective cohort study.

Background: There has been increasing scrutiny of opioid prescribing following injury because of concerns that prescribed opioids may contribute to addiction and overdose. This study aimed to better understand the relationship between injury, opioids prescribed before and after injury, and non-medical drug poisoning. Data and methods: Working age (15 to 65 years old) residents of British Columbia's Fraser Health region with an injury that involved an emergency department visit were included. Factors examined included the prescription of opioid and opioid agonist therapy (OAT) medications before and after injury, age, sex, work-related injuries, and socioeconomic status, as well as how they were associated with non-medical drug poisoning risk and post-injury prescriptions. Results: Opioid-naive individuals (those without an opioid prescription captured before their injury) who were prescribed OAT medication-a marker of opioid use disorder-following their injury had a higher risk of subsequent non-medical drug poisoning (Hazard ratio (HR): 21.4 to 22.4 compared with opioid-naive individuals without an opioid or OAT prescription). Post-injury opioid prescription in these individuals increased poisoning risk (HR: 1.27 compared with those without a prescription). Being of male sex (HR: 1.80), being younger (HR: 0.76 for every 10-year increase in age) and living in the lowest-income neighbourhoods (HR: 1.44 compared with the middle quintile) increased poisoning risk. Compared with injuries sustained outside of work, work-related injuries reduced risk (HR: 0.62). Interpretation: Among a cohort of British Columbians visiting emergency departments following an injury, opioid prescribing in patients who were opioid-naive appears to be a minor contributor to non-medical drug poisoning, particularly when compared with other patient factors, such as being male, being younger and having a low socioeconomic status.

Long-term Risk of Overdose or Mental Health Crisis After Opioid Dose Tapering.

Importance: Patients prescribed long-term opioid therapy are increasingly undergoing dose tapering. Recent studies suggest that tapering is associated with short-term risks of substance misuse, overdose, and mental health crisis, although lower opioid dose could reduce risks of adverse events over the longer term. Objective: To assess the longer-term risks of overdose or mental health crisis associated with opioid dose tapering. Design, Setting, and Participants: This is a cohort study using an exposure-crossover analysis. Data were obtained from the OptumLabs Data Warehouse, which includes deidentified medical and pharmacy claims and enrollment records for commercial insurance and Medicare Advantage enrollees, representing a diverse mixture of ages, races, ethnicities, and geographical regions across the US. Participants were US adults who underwent opioid dose tapering from 2008 to 2017 after a 12-month baseline period of stable daily dosing of 50 morphine milligram equivalents or higher and who had at least 1 month of long-term follow-up during a postinduction period beginning 12 months after taper initiation. Data analysis was performed from October 2021 to April 2022. Exposures: Opioid tapering, defined as 15% or more relative reduction in mean daily dose during any of 6 overlapping 60-day windows within a 7-month follow-up period after the stable baseline period. Main Outcomes and Measures: Emergency or hospital encounters for drug overdose or withdrawal and mental health crisis (depression, anxiety, or suicide attempt). Outcome counts were assessed in pretaper and postinduction periods (from 12 to 24 months after taper initiation). Results: The study included 21 515 tapering events among 19 377 patients with a mean (SD) of 9.1 (2.7) months of postinduction follow-up per event (median [IQR], 10 [8-11] months). Patients had a mean (SD) age of 56.9 (11.2) years, 11 581 (53.8%) were female, and 8217 (38.2%) had commercial insurance (vs Medicare Advantage). In conditional negative binomial regression analyses, adjusted incidence rate ratios for the postinduction period compared with the pretaper period were 1.57 (95% CI, 1.42-1.74) for overdose or withdrawal and 1.52 (95% CI, 1.35-1.71) for mental health crisis. Conclusions and Relevance: These findings suggest that opioid tapering was associated with increased rates of overdose, withdrawal, and mental health crisis extending up to 2 years after taper initiation.

Association between opioid therapy trajectories and potential opioid-related adverse health events.

PURPOSE: We identified associations between membership in seven group-based trajectories based on supply of filled opioid prescriptions and potential opioid-related adverse health events over a 720-day window. METHODS: We identified two veteran cohorts with chronic non-cancer pain who initiated treatment with long-term opioid therapy between 2008 and 2015, excluding those with prior substance use disorder (n = 373 941) or non-SUD, opioid-related adverse outcome (n = 405 631) diagnoses. Outcomes of interest included opioid use disorder, non-opioid drug use disorder, and alcohol use disorder for the first cohort; or accidents resulting in wounds or injuries, self-inflicted injuries, opioid-related accidents and overdoses, alcohol and non-opioid drug-related accidents and overdoses, and violence-related injuries for the second cohort. Using a cross-sectional design, Veterans were followed until the specific outcome of interest was diagnosed, they died, the study ended, or they were lost to follow up. Accelerated failure time models were estimated for each outcome. RESULTS: Membership in persistent moderate days covered and persistent modest days covered trajectories was associated with decreased risk of opioid use disorder (Moderate: θ = 0.59, 95%CI:0.54, 0.64; Modest: θ = 0.54, 95%CI:0.50, 0.59) and opioid overdose (Moderate: θ = 0.67,95%CI: 0.57, 0.79; Modest: θ = 0.72, 95%CI:0.61, 0.85) versus higher-utilizing persistent users. Rapid discontinuation was associated with decreased risk of opioid use disorder (θ = 0.86, 95% CI:0.77, 0.95) and opioid overdose (θ = 0.54, 95%CI:0.41, 0.71), but increased risk of alcohol use disorder (θ = 1.07, 95%CI:1.00, 1.15) and other substance use disorders. Delayed discontinuation or delayed reduction was associated with increased risk for most opioid related adverse health events. CONCLUSION: Persistent use trajectories with low levels of opioid utilization were associated with lower risks of potential opioid-related adverse health events.

Association of Opioid Dose Reduction With Opioid Overdose and Opioid Use Disorder Among Patients Receiving High-Dose, Long-term Opioid Therapy in North Carolina.

Importance: Rapid reduction or discontinuation of long-term opioid therapy may increase risk of opioid overdose or opioid use disorder (OUD). Current guidelines for chronic pain management caution against rapid dose reduction but are based on limited evidence. Objective: To characterize the association between rapid reduction or abrupt discontinuation of opioid therapy (vs maintained or gradual reduction) and incidence of opioid overdose and OUD among patients prescribed high-dose, long-term opioid therapy (HDLTOT). Design, Setting, and Participants: This retrospective cohort study was conducted among patients aged 18 to 64 years who were prescribed HDLTOT (≥90 daily morphine milligram equivalents for ≥90% of 90 days) from January 2006 to September 2018, with follow-up up to 4 years after cohort entry. Claims data were drawn from a large private health insurer in North Carolina and analyzed from March 1, 2006, to September 30, 2018. Exposures: Time-varying exposure of rapid dose reduction or discontinuation (>10% dose reduction/week) vs maintenance, increase, or gradual reduction or discontinuation. Main Outcomes and Measures: The main outcome was incident opioid overdose (fatal or nonfatal) or diagnosed OUD. Inverse probability-weighted cumulative incidence of outcomes were estimated using the cumulative incidence function and hazard ratios (HRs) using marginal structural Fine-Gray models as a function of rapid dose tapering or discontinuation (vs gradual reduction or discontinuation or maintained or increased), accounting for competing risks. Results: A total of 19 443 patients (median [IQR] age, 49 [41-55] years; 10 073 [51.8%] men) who received HDLTOT were identified. Rapid reduction or discontinuation was associated with higher risk of fatal and nonfatal overdoses compared with gradual reduction after the first year (year 1: HR, 1.43; 95% CI, 0.94-2.18; years 2-4: HR, 1.95; 95% CI, 1.31-2.90). There was no association between rapid reduction or discontinuation and diagnosed OUD through 2 years of follow-up; however, the hazard of incident OUD among patients exposed to rapid tapering or discontinuation was greater 25 to 48 months after the start of follow-up (HR, 1.28; 95% CI, 1.01-1.63). Conclusions and Relevance: In this cohort study, rapid dose reduction or discontinuation was associated with increased risk of opioid overdose and OUD during long-term follow-up. These findings reinforce prior concerns about safety of rapid dose reductions for patients receiving HDLTOT and highlight the need for caution when reducing opioid doses.

[Overdose from a patch]. / Überdosis durch ein Pflaster.

HISTORY AND CLINICAL FINDINGS: We present the case of an 89-year-old patient with impaired consciousness for whom the emergency services were called. She was soporose and showed a pronounced generalized muscle rigidity. Due to a third-party history the incorrect use of a fentanyl patch was found out to be at cause. TREATMENT AND CLINICAL COURSE: The antidote administration of naloxone led to restoration. The need for repetitive administration confirmed the clinical hypothesis. CONCLUSION: The application of fentanyl via the skin in the form of transdermal therapeutic systems (TTS) has become more popular over the years. Incorrect administration causes intoxication with the leading symptoms of loss of consciousness and respiratory depression. This case report extends the spectrum of symptoms to include skeletal muscle rigidity otherwise only described in connection with intravenous administration, especially in anaesthetic settings.

Association Between Receipt of Overlapping Opioid and Benzodiazepine Prescriptions From Multiple Prescribers and Overdose Risk.

Importance: The receipt of overlapping opioid and benzodiazepine prescriptions is associated with increased overdose risk. It is unknown whether this increase in risk varies when overlapping prescriptions are written by multiple prescribers vs 1 prescriber. Objective: To evaluate the association between receipt of overlapping opioid and benzodiazepine prescriptions from multiple prescribers and overdose risk. Design, Setting, and Participants: This cohort study was conducted using 2017 to 2018 claims from the Optum deidentified Clinformatics Data Mart. Participants were patients with private insurance or Medicare Advantage aged 12 years or older with overlapping opioid and benzodiazepine prescriptions. Data were analyzed from March through November 2020. Exposures: For each patient, person-days on which opioid and benzodiazepine prescriptions overlapped were identified. The exposure was whether these prescriptions were written by multiple prescribers vs 1 prescriber. Main Outcomes and Measures: The outcome was a treated overdose, defined as the occurrence of 1 or more claims containing a diagnosis code for opioid or benzodiazepine poisoning on a person-day of opioid-benzodiazepine overlap. The association between exposure and outcome at the person-day level was estimated using logistic regression, controlling for opioid and benzodiazepine prescribing patterns, demographics, and comorbidities. The average marginal effect (AME) of the exposure, defined as the absolute difference in the probability of a treated overdose if all person-days of overlap involved prescriptions from multiple prescribers vs 1 prescriber, was calculated. Results: Among 529 053 patients, the mean (SD) age was 61.2 (15.6) years and 350 857 (66.3%) were female patients. Mean (SD) follow-up was 198.7 (249.8) days. During follow-up, overdose occurred on 1 or more person-days of opioid-benzodiazepine overlap for 2288 patients (0.4%, or 1 in 231 patients). There were 52 989 316 person-days of opioid-benzodiazepine overlap. Among 19 895 457 person-days (37.5%) involving prescriptions from multiple prescribers, there were 1390 overdoses (7.0 per 100 000 person-days), and among 33 093 859 person-days (62.5%) involving prescriptions from 1 prescriber, there were 1302 overdoses (3.9 per 100 000 person-days). Overdose risk was increased 1.8-fold (95% CI, 1.6-1.9) on person-days of overlap involving prescriptions from multiple prescribers vs 1 prescriber. The association between multiple prescribers and increased risk of overdose persisted in adjusted analyses (adjusted odds ratio, 1.20; 95% CI, 1.10-1.31; AME, 0.91 per 100 000 person-days of overlap; 95% CI, 0.46-1.37). Conclusions and Relevance: This study found that among patients already at increased risk of overdose owing to concurrent treatment with opioids and benzodiazepines, overdose risk was increased further when multiple prescribers were responsible for this treatment regimen compared with 1 prescriber. This increased risk was not fully accounted for by differences in prescribing patterns, demographics, or comorbidities. This finding suggests that other factors, such as poor care coordination, may be associated with the increase in risk.

Extracorporeal treatment for poisoning to beta-adrenergic antagonists: systematic review and recommendations from the EXTRIP workgroup.

BACKGROUND: ß-adrenergic antagonists (BAAs) are used to treat cardiovascular disease such as ischemic heart disease, congestive heart failure, dysrhythmias, and hypertension. Poisoning from BAAs can lead to severe morbidity and mortality. We aimed to determine the utility of extracorporeal treatments (ECTRs) in BAAs poisoning. METHODS: We conducted systematic reviews of the literature, screened studies, extracted data, and summarized findings following published EXTRIP methods. RESULTS: A total of 76 studies (4 in vitro and 2 animal experiments, 1 pharmacokinetic simulation study, 37 pharmacokinetic studies on patients with end-stage kidney disease, and 32 case reports or case series) met inclusion criteria. Toxicokinetic or pharmacokinetic data were available on 334 patients (including 73 for atenolol, 54 for propranolol, and 17 for sotalol). For intermittent hemodialysis, atenolol, nadolol, practolol, and sotalol were assessed as dialyzable; acebutolol, bisoprolol, and metipranolol were assessed as moderately dialyzable; metoprolol and talinolol were considered slightly dialyzable; and betaxolol, carvedilol, labetalol, mepindolol, propranolol, and timolol were considered not dialyzable. Data were available for clinical analysis on 37 BAA poisoned patients (including 9 patients for atenolol, 9 for propranolol, and 9 for sotalol), and no reliable comparison between the ECTR cohort and historical controls treated with standard care alone could be performed. The EXTRIP workgroup recommends against using ECTR for patients severely poisoned with propranolol (strong recommendation, very low quality evidence). The workgroup offered no recommendation for ECTR in patients severely poisoned with atenolol or sotalol because of apparent balance of risks and benefits, except for impaired kidney function in which ECTR is suggested (weak recommendation, very low quality of evidence). Indications for ECTR in patients with impaired kidney function include refractory bradycardia and hypotension for atenolol or sotalol poisoning, and recurrent torsade de pointes for sotalol. Although other BAAs were considered dialyzable, clinical data were too limited to develop recommendations. CONCLUSIONS: BAAs have different properties affecting their removal by ECTR. The EXTRIP workgroup assessed propranolol as non-dialyzable. Atenolol and sotalol were assessed as dialyzable in patients with kidney impairment, and the workgroup suggests ECTR in patients severely poisoned with these drugs when aforementioned indications are present.

Big data and predictive modelling for the opioid crisis: existing research and future potential.

A need exists to accurately estimate overdose risk and improve understanding of how to deliver treatments and interventions in people with opioid use disorder in a way that reduces such risk. We consider opportunities for predictive analytics and routinely collected administrative data to evaluate how overdose could be reduced among people with opioid use disorder. Specifically, we summarise global trends in opioid use and overdoses; describe the use of big data in research into opioid overdose; consider the potential for predictive modelling, including machine learning, for prevention and monitoring of opioid overdoses; and outline the challenges and risks relating to the use of big data and machine learning in reducing harms that are related to opioid use. Future research for improving the coverage and provision of existing interventions, treatments, and resources for opioid use disorder requires collaboration of multiple agencies. Predictive modelling could transport the concept of stratified medicine to public health through novel methods, such as predictive modelling and emulated trials for evaluating diagnoses and prognoses of opioid use disorder, predicting treatment response, and providing targeted treatment recommendations.

Fentanyl contaminated "M30" pill overdoses in pediatric patients.

BACKGROUND: Fentanyl is a high potency opioid that has become an increasingly large proportion of the illicit drug supply. Fentanyl overdoses and deaths, including in pediatric patients, has concomitantly increased. PURPOSE: To describe two cases of pediatric fentanyl overdoses via "M30" pills illicitly sold as oxycodone. BASIC PROCEDURES: Two cases of pediatric opioid toxicity reportedly from oxycodone are presented in which mass spectrometry was used to confirm fentanyl and not oxycodone exposure. MAIN FINDINGS: Both pediatric patients required naloxone and admission to the intensive care unit following exposure. Both had urine drug screens that did not show the presence of opioids but mass spectrometry testing confirmed fentanyl exposure. CONCLUSIONS: Providers should be aware of these illicit tablets, know not to assume they are pharmaceutical, and consider the risk they pose to pediatric patients through exploratory ingestion or misuse. Further inquiry, including social investigation, should be considered for pediatric patients presenting with reported oxycodone ingestion, especially blue "M30" pills.