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.

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 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.

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.

Relatively mild symptoms after chronic overdose with a double-dose encorafenib: a case report.

Encorafenib (Braftovi) is indicated for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation, in combination with binimetinib (Mektovi). According to the product label of encorafenib, there are no specific treatment recommendations in case of an overdose. We report on a 63-year-old man who ingested a double dose (900 mg) of encorafenib for 16 days. He developed overall minor chronic overdose symptoms such as nausea and vomiting grade 1 and muscle pain. Based on the most occurring adverse events of encorafenib, liver values, kidney function parameters and QTc interval were measured. Kidney function parameters were normal, whereas liver values were slightly increased (grade 1) and QTc slightly prolonged. The plasma concentration 3 h after the last dose was 2110 ng/mL. We describe the course of a case with a chronic overdose during 16 days of the double dose of encorafenib as well as the followed approach, which could be taken into account when observing an encorafenib overdose. Providing information in times of Covid-19 is challenging, but remains necessary for good clinical care.

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.

Opioid use and misuse in children, adolescents, and young adults with cancer: a systematic review of the literature.

Adolescents and young adults (AYAs) are at increased risk for negative opioid-related outcomes, including misuse and overdose. High-quality cancer care requires adequate pain management and often includes opioids for tumor- and/or treatment-related pain. Little is known about opioid use and misuse in children and AYAs with cancer, and we therefore conducted a systematic review of the literature using PRISMA guidelines to identify all relevant studies that evaluated opioid use and/or misuse among this population. Eleven studies were identified that met our inclusion criteria. The range of opioid use among the studies was 12-97%, and among the five studies that reported opioid misuse or aberrant behaviors, 7-90% of patients met criteria. Few studies reported factors associated with opioid misuse but included prior mental health and/or substance use disorders, and prior opioid use. In summary, opioid use is highly variable among children and AYAs with cancer; however, the range of use varies widely depending on the study population, such as survivors or end-of-life cancer patients. Few studies have examined opioid misuse and/or aberrant behaviors, and future research is needed to better understand opioid use and misuse among children and AYAs with cancer, specifically those who will be cured of their cancer and may subsequently experience adverse opioid-related outcomes.

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.

Are opioid receptor antagonists adequate for "Opioid" overdose in a changing reality?

WHAT IS KNOWN AND OBJECTIVE: Deaths due to opioid-induced respiratory depression (OIRD) continue to rise despite intense regulatory and professional actions. COVID-19 has only worsened this situation.1 An opioid receptor antagonist (ORA) such as naloxone is the most common intervention for OIRD. However, with increasing overdose from highly potent illicit opioids and polysubstance abuse, appraisal of the adequacy of ORA seems warranted and timely. COMMENT: OIRD results from the binding of an excess number of agonist molecules to opioid receptors. Mechanistically, it makes sense to reverse this by displacing agonist molecules by administering an ORA. But realistically, the trend to higher-potency agonists and polysubstance abuse diminishes the effectiveness of this approach. We are left facing a crisis without a solution. WHAT IS NEW AND CONCLUSION: For the increasingly common OIRD from highly potent illicit agonists and polysubstance overdose, ORAs are correspondingly less effective. Alternatives are needed-soon.

Mice deficient in pyruvate dehydrogenase kinase 4 are protected against acetaminophen-induced hepatotoxicity.

Though mitochondrial oxidant stress plays a critical role in the progression of acetaminophen (APAP) overdose-induced liver damage, the influence of mitochondrial bioenergetics on this is not well characterized. This is important, since lifestyle and diet alter hepatic mitochondrial bioenergetics and an understanding of its effects on APAP-induced liver injury is clinically relevant. Pyruvate dehydrogenase (PDH) is critical to mitochondrial bioenergetics, since it controls the rate of generation of reducing equivalents driving respiration, and pyruvate dehydrogenase kinase 4 (PDK4) regulates (inhibits) PDH by phosphorylation. We examined APAP-induced liver injury in PDK4-deficient (PDK4-/-) mice, which would have constitutively active PDH and hence elevated flux through the mitochondrial electron transport chain. PDK4-/- mice showed significant protection against APAP-induced liver injury when compared to wild type (WT) mice as measured by ALT levels and histology. Deficiency of PDK4 did not alter APAP metabolism, with similar APAP-adduct levels in PDK4-/- and WT mice, and no difference in JNK activation and translocation to mitochondria. However, subsequent amplification of mitochondrial dysfunction with release of mitochondrial AIF, peroxynitrite formation and DNA fragmentation were prevented. Interestingly, APAP induced a rapid decline in UCP2 protein levels in PDK4-deficient mice. These data suggest that adaptive changes in mitochondrial bioenergetics induced by enhanced respiratory chain flux in PDK4-/- mice render them highly efficient in handling APAP-induced oxidant stress, probably through modulation of UCP2 levels. Further investigation of these specific adaptive mechanisms would provide better insight into the control exerted by mitochondrial bioenergetics on cellular responses to an APAP overdose.

Situating the Continuum of Overdose Risk in the Social Determinants of Health: A New Conceptual Framework.

Policy Points This article reconceptualizes our understanding of the opioid epidemic and proposes six strategies that address the epidemic's social roots. In order to successfully reduce drug-related mortality over the long term, policymakers and public health leaders should develop partnerships with people who use drugs, incorporate harm reduction interventions, and reverse decades of drug criminalization policies. CONTEXT: Drug overdose is the leading cause of injury-related death in the United States. Synthetic opioids, predominantly illicit fentanyl and its analogs, surpassed prescription opioids and heroin in associated mortality rates in 2016. Unfortunately, interventions fail to fully address the current wave of the opioid epidemic and often omit the voices of people with lived experiences regarding drug use. Every overdose death is a culmination of a long series of policy failures and lost opportunities for harm reduction. METHODS: In this article, we conducted a scoping review of the opioid literature to propose a novel framework designed to foreground social determinants more directly into our understanding of this national emergency. The "continuum of overdose risk" framework is our synthesis of the global evidence base and is grounded in contemporary theories, models, and policies that have been successfully applied both domestically and internationally. FINDINGS: De-escalating overdose risk in the long term will require scaling up innovative and comprehensive solutions that have been designed through partnerships with people who use drugs and are rooted in harm reduction. CONCLUSIONS: Without recognizing the full drug-use continuum and the role of social determinants, the current responses to drug overdose will continue to aggravate the problem they are trying to solve.

Intersections of Firearm Suicide, Drug-Related Mortality, and Economic Dependency in Rural America.

BACKGROUND: Rural counties in the United States have higher firearm suicide rates and opioid overdoses than urban counties. We sought to determine whether rural counties can be grouped based on these "diseases of despair." METHODS: Age-adjusted firearm suicide death rates per 100,000; drug-related death rates per 100,000; homicide rate per 100,000, opioid prescribing rate, %black, %Native American, and %veteran population, median home price, violent crime rates per 100,000, primary economic dependency (nonspecialized, farming, mining, manufacturing, government, and recreation), and economic variables (low education, low employment, retirement destination, persistent poverty, and persistent child poverty) were obtained for all rural counties and evaluated with hierarchical clustering using complete linkage. RESULTS: We identified five distinct rural county clusters. The firearm suicide rates in the clusters were 5.9, 6.8, 6.4, 8.5, and 3.8 per 100,000, respectively. The counties in cluster 1 were poor, mining dependent, with population loss, cluster 2 were nonspecialized economies, with high opioid prescription rates, cluster 3 were manufacturing and government economies with moderate unemployment, cluster 4 were recreational economies with substantial veterans and Native American populations, high median home price, drug death rates, opioid prescribing, and violent crime, and cluster 5 were farming economies, with high population loss, low median home price, low rates of drug mortality, opioid prescribing, and violent crime. Cluster 4 counties were spatially adjacent to urban counties. CONCLUSIONS: More than 300 counties currently face a disproportionate burden of diseases of despair. Interventions to reduce firearm suicides should be community-based and include programs to reduce other diseases of despair.

Use of Amphetamine-Type Stimulants Among Emergency Department Patients With Untreated Opioid Use Disorder.

STUDY OBJECTIVE: Concurrent use of amphetamine-type stimulants among individuals with opioid use disorder can exacerbate social and medical harms, including overdose risk. The study evaluated rates of amphetamine-type stimulant use among patients with untreated opioid use disorder presenting at emergency departments in Baltimore, MD; New York, NY; Cincinnati, OH; and Seattle, WA. METHODS: Emergency department (ED) patients with untreated opioid use disorder (N=396) and enrolled between February 2017 and January 2019 in a multisite hybrid type III implementation science study were evaluated for concurrent amphetamine-type stimulant use. Individuals with urine tests positive for methamphetamine, amphetamine, or both were compared with amphetamine-type stimulant-negative patients. RESULTS: Overall, 38% of patients (150/396) were amphetamine-type stimulant positive; none reported receiving prescribed amphetamine or methamphetamine medications. Amphetamine-type stimulant-positive versus -negative patients were younger: mean age was 36 years (SD 10 years) versus 40 years (SD 12 years), 69% (104/150) versus 46% (114/246) were white, 65% (98/150) versus 54% (132/246) were unemployed, 67% (101/150) versus 49 (121/246) had unstable housing, 47% (71/150) versus 25% (61/245) reported an incarceration during 1 year before study admission, 60% (77/128) versus 45% (87/195) were hepatitis C positive, 79% (118/150) versus 47% (115/245) reported drug injection during 1 month before the study admission, and 42% (62/149) versus 29% (70/244) presented to the ED for an injury. Lower proportions of amphetamine-type stimulant-positive patients had cocaine-positive urine test results (33% [50/150] versus 52% [129/246]) and reported seeking treatment for substance use problems as a reason for their ED visit (10% [14/148] versus 19% [46/246]). All comparisons were statistically significant at P<.05 with the false discovery rate correction. CONCLUSION: Amphetamine-type stimulant use among ED patients with untreated opioid use disorder was associated with distinct sociodemographic, social, and health factors. Improved ED-based screening, intervention, and referral protocols for patients with opioid use disorder and amphetamine-type stimulant use are needed.

Acute intentional caffeine overdose treated preemptively with hemodialysis.

Caffeine is the most commonly used central nervous system stimulant. While it has a high LD50 (150-200 mg/kg), when ingested in significant quantity, caffeine can lead to severe and even lethal side effects. Manifestation of toxicity include tachyarrhythmias, seizures, and metabolic derangements which can eventually lead to cardiovascular collapse and death. Studies have shown that lethal doses of caffeine (80-100 µg/mL) can be seen with the ingestion of approximately 10 g of caffeine. Due to the low number of reported cases, there is no consensus on the standard of care for treatment of suspected caffeine overdose. This case details a 39-year-old male who presented to the emergency department (ED) after having ingested 50 g of caffeine. Despite a high dose esmolol infusion, the patient exhibited worsening tachyarrhythmias. Hemodialysis was started empirically given the known amount ingested and ongoing hemodynamic perturbations. Initial pre-dialysis caffeine level was found to be 254 µg/ml. After treatment with two sessions of hemodialysis the patient's caffeine level decreased dramatically. We believe this is the first case report to demonstrate the success of preemptive hemodialysis, prior to cardiovascular collapse and/or renal failure, in a case of caffeine overdose and should be considered very early in patients presenting with recent toxic ingestion.

Epidemiologic assessment of benzodiazepine exposure among suicide deaths in Colorado, 2015-2017.

BACKGROUND: Suicide rates have been climbing in the U.S., particularly in Rocky Mountain states such as Colorado. Benzodiazepines have been linked with suicidal ideation, but there have been few population level assessments of this link. We conducted a public health assessment to determine the epidemiology and prevalence of recent benzodiazepine exposure, among suicide deaths in Colorado from 2015 to 17. METHODS: This epidemiologic assessment linked Colorado's Prescription Drug Monitoring Program, death certificate data, and Violent Death Reporting System to determine patterns of benzodiazepine exposure among suicide deaths in Colorado between 2015 and 2017. Recent benzodiazepine exposure was defined as receiving a prescription within 30 days of death or having a positive toxicology screen post-mortem. RESULTS: Among the 3465 suicide deaths in Colorado between 2015 and 2017, 20% had recent benzodiazepine exposure, and nearly 50% of those also had recent opioid exposure. Recent benzodiazepine exposure was more common among females than males (34% versus 16%). Among suicide deaths, those who died via drug overdose were more likely to have had recent benzodiazepine exposure (48%), compared to suicides by firearm (17%), hanging/asphyxiation (13%) and all other methods (approximately 20%). CONCLUSIONS: Benzodiazepines have been linked to suicidal ideation, but population level assessments of benzodiazepine exposure among suicide deaths are rare. Our epidemiologic assessment indicates a relatively high prevalence of recent benzodiazepine exposure that warrants further investigation from both clinical and public health perspectives.

Dexmedetomidine infusion overdose during anesthesia: A case report.

A 12-kg infant was given intravenous dexmedetomidine 0.2 µg kg-1  min-1 as an adjunct for general anesthesia. The 60-fold increase in dexmedetomidine infusion rate caused a biphasic response with initial hypertension followed by bradycardia and hypotension requiring inotropic support. No postoperative or long-term sequelae were noted. Dexmedetomidine infusion is usually delivered as µg kg-1  h-1 .

Designers Drugs-A New Challenge to Emergency Departments-An Observational Study in Poland.

Background and Objective: In the last decade, the phenomenon of using new psychoactive substances (NPS), called designer drugs, has been on rise. Though their production and marketing in Poland is prohibited, reports of the Supreme Audit Office noted that young people are increasingly reaching for new intoxication agents in the form of designer drugs. There is a significant increase in the number of patients with NPS abuse admitted to the emergency departments. As NPS cannot be detected by standard tests for the presence of psychoactive substances, it is difficult to choose the appropriate therapeutic intervention. Therefore, the aim of the present study was to evaluate the patient characteristics in the population of adults and children suspected of using NPS and formulate the protocol for diagnosis and treatment. Materials and Method: The paper is based on a retrospective analysis of medical records of hospitalized patients in the Clinical Emergency Department of The Regional Specialist Hospital in Olsztyn (SKOR WSS, emergency department (ED)) and the Pediatric Emergency Department of the Provincial Specialist Children's Hospital in Olsztyn (SORD WSSD, pediatric emergency department (PED)) between years 2013 to 2018. The patient records related to their general symptoms at admission, mental state and laboratory diagnostic tests were evaluated. Results: The majority of patients hospitalized due to the suspected use of NPS were adolescents in 2013-2016 and a reversal of this trend was observed in 2017-2018 when number of adults admitted to the emergency department (ED) due to NPS use was higher. The NPS abuse was significantly higher among male patients, alcoholics, people using other psychoactive substances, patients suffering from mental disorders and teenagers in difficult socio-economic family situations. Whereas, the most common symptoms among pediatric patients were co-ordination disorder and aggression, in adults mainly tachycardia and aggression was observed. The laboratory tests in significant number of adult patients showed leukocytosis and ketonuria. Conclusions: In the present study, no unambiguous toxidrome or biochemical pattern characteristic for using NPS was observed. However, evaluation of blood morphology, coagulation parameters, liver and kidney function can be helpful in the diagnostic and therapeutic process. Symptomatic treatment of patients, fluid therapy and sedation was sufficient in most cases to resolve the patient symptoms in 48 h.

An Unexpected Role of Cholesterol Sulfotransferase and its Regulation in Sensitizing Mice to Acetaminophen-Induced Liver Injury.

Overdose of acetaminophen (APAP) is the leading cause of acute liver failure (ALF) in the United States. The sulfotransferase-mediated sulfation of APAP is widely believed to be a protective mechanism to attenuate the hepatotoxicity of APAP. The cholesterol sulfotransferase SULT2B1b is best known for its activity in catalyzing the sulfoconjugation of cholesterol to synthesize cholesterol sulfate. SULT2B1b can be transcriptionally and positively regulated by the hepatic nuclear factor 4α (HNF4α). In this study, we uncovered an unexpected role for SULT2B1b in APAP toxicity. Hepatic overexpression of SULT2B1b sensitized mice to APAP-induced liver injury, whereas ablation of the Sult2B1b gene in mice conferred resistance to the APAP hepatotoxicity. Consistent with the notion that Sult2B1b is a transcriptional target of HNF4α, overexpression of HNF4α sensitized mice or primary hepatocytes to APAP-induced hepatotoxicity in a Sult2B1b-dependent manner. We conclude that the HNF4α-SULT2B1b axis has a unique role in APAP-induced acute liver injury, and SULT2B1b induction might be a risk factor for APAP hepatotoxicity.

Prescription of benzodiazepines, z-drugs, and gabapentinoids and mortality risk in people receiving opioid agonist treatment: Observational study based on the UK Clinical Practice Research Datalink and Office for National Statistics death records.

BACKGROUND: Patients with opioid dependency prescribed opioid agonist treatment (OAT) may also be prescribed sedative drugs. This may increase mortality risk but may also increase treatment duration, with overall benefit. We hypothesised that prescription of benzodiazepines in patients receiving OAT would increase risk of mortality overall, irrespective of any increased treatment duration. METHODS AND FINDINGS: Data on 12,118 patients aged 15-64 years prescribed OAT between 1998 and 2014 were extracted from the Clinical Practice Research Datalink. Data from the Office for National Statistics on whether patients had died and, if so, their cause of death were available for 7,016 of these patients. We identified episodes of prescription of benzodiazepines, z-drugs, and gabapentinoids and used linear regression and Cox proportional hazards models to assess the associations of co-prescription (prescribed during OAT and up to 12 months post-treatment) and concurrent prescription (prescribed during OAT) with treatment duration and mortality. We examined all-cause mortality (ACM), drug-related poisoning (DRP) mortality, and mortality not attributable to DRP (non-DRP). Models included potential confounding factors. In 36,126 person-years of follow-up there were 657 deaths and 29,540 OAT episodes, of which 42% involved benzodiazepine co-prescription and 29% concurrent prescription (for z-drugs these respective proportions were 20% and 11%, and for gabapentinoids 8% and 5%). Concurrent prescription of benzodiazepines was associated with increased duration of methadone treatment (adjusted mean duration of treatment episode 466 days [95% CI 450 to 483] compared to 286 days [95% CI 275 to 297]). Benzodiazepine co-prescription was associated with increased risk of DRP (adjusted HR 2.96 [95% CI 1.97 to 4.43], p < 0.001), with evidence of a dose-response effect, but showed little evidence of an association with non-DRP (adjusted HR 0.91 [95% CI 0.66 to 1.25], p = 0.549). Co-prescription of z-drugs showed evidence of an association with increased risk of DRP (adjusted HR 2.75 [95% CI 1.57 to 4.83], p < 0.001) but little evidence of an association with non-DRP (adjusted HR 0.79 [95% CI 0.49 to 1.28], p = 0.342). There was no evidence of an association of gabapentinoid co-prescription with DRP (HR 1.54 [95% CI 0.60 to 3.98], p = 0.373) but evidence of an association with increased non-DRP (HR 1.83 [95% CI 1.28 to 2.62], p = 0.001). Concurrent benzodiazepine prescription also increased mortality risk after consideration of duration of OAT (adjusted HR for DRP with benzodiazepine concurrent prescription 3.34 [95% CI 2.14 to 5.20], p < 0.001). The main limitation of this study is the possibility that unmeasured confounding factors led to an association between benzodiazepine prescription and DRP that is not causal. CONCLUSIONS: In this study, co-prescription of benzodiazepine was specifically associated with increased risk of DRP in opioid-dependent individuals. Co-prescription of z-drugs and gabapentinoids was also associated with increased mortality risk; however, for z-drugs there was no evidence for a dose-response effect on DRP, and for gabapentinoids the increased mortality risk was not specific to DRP. Concurrent prescription of benzodiazepine was associated with longer treatment but still increased risk of death overall. Clinicians should be cautious about prescribing benzodiazepines to opioid-dependent individuals.

Concurrent use of opioids with benzodiazepines or nonbenzodiazepine sedatives among patients with cancer referred to an outpatient palliative care clinic.

BACKGROUND: The concurrent use of opioids with benzodiazepines (BZD) or nonbenzodiazepine sedatives (S) recently was found to be associated with an increased risk of overdose death compared with the use of opioids alone. In the current study, the authors examined the frequency and trend of concurrent opioid/BZD-S use and its associated risk factors among patients with cancer. METHODS: Data regarding the frequency and trend of concurrent opioid/BZD-S use were extracted for 1500 randomly selected patients referred to the outpatient palliative care clinic at The University of Texas MD Anderson Cancer Center between the calendar years of 2011 and 2016. To explore associated risk factors, the authors compared the demographic and clinical predictors of 418 patients each in the concurrent opioid/BZD-S group and opioids-only group. RESULTS: In 2011, at the time of referral to the palliative care clinic, 96 of 221 patients with cancer (43%) were prescribed concurrent opioids/BZD-S. This rate progressively declined to 67 of 217 patients (31%) by 2016 (P = .0008). Patients in the concurrent opioid/BZD-S group had a higher percentage of females (233 individuals; 55% [P = .007]) and whites (323 individuals; 77% [P = .002]), and patients reported higher scores regarding depression (P = .0001), anxiety (P ≤ .0001), drowsiness (P = .048), and worst feeling of well-being (P = .001). The morphine equivalent daily dose was significantly higher in concurrent opioid/BZD-S group (median of 67.5 mg/day [interquartile range (IQR), 30-135 mg/day] vs 60 mg/day [IQR, 30-105 mg/day]; P = .034). Multivariate analysis demonstrated that anxiety (P ≤ .0001), white race (P = .0092), and poor Eastern Cooperative Oncology Group performance status (P = .0017) were significantly associated with concurrent use. CONCLUSIONS: The concurrent use of opioids with BZD-S has declined but continues to be frequent among patients with cancer. Anxiety, white race, and poor Eastern Cooperative Oncology Group performance status were associated with its use. More research is needed to explore which medications can replace these agents.