Changes in Opioid and Benzodiazepine Poisoning Deaths After Cannabis Legalization in the US: A County-level Analysis, 2002-2020.

BACKGROUND: Cannabis legalization for medical and recreational purposes has been suggested as an effective strategy to reduce opioid and benzodiazepine use and deaths. We examined the county-level association between medical and recreational cannabis laws and poisoning deaths involving opioids and benzodiazepines in the US from 2002 to 2020. METHODS: Our ecologic county-level, spatiotemporal study comprised 49 states. Exposures were state-level implementation of medical and recreational cannabis laws and state-level initiation of cannabis dispensary sales. Our main outcomes were poisoning deaths involving any opioid, any benzodiazepine, and opioids with benzodiazepines. Secondary analyses included overdoses involving natural and semi-synthetic opioids, synthetic opioids, and heroin. RESULTS: Implementation of medical cannabis laws was associated with increased deaths involving opioids (rate ratio [RR] = 1.14; 95% credible interval [CrI] = 1.11, 1.18), benzodiazepines (RR = 1.19; 95% CrI = 1.12, 1.26), and opioids+benzodiazepines (RR = 1.22; 95% CrI = 1.15, 1.30). Medical cannabis legalizations allowing dispensaries was associated with fewer deaths involving opioids (RR = 0.88; 95% CrI = 0.85, 0.91) but not benzodiazepine deaths; results for recreational cannabis implementation and opioid deaths were similar (RR = 0.81; 95% CrI = 0.75, 0.88). Recreational cannabis laws allowing dispensary sales was associated with consistent reductions in opioid- (RR = 0.83; 95% CrI = 0.76, 0.91), benzodiazepine- (RR = 0.79; 95% CrI = 0.68, 0.92), and opioid+benzodiazepine-related poisonings (RR = 0.83; 95% CrI = 0.70, 0.98). CONCLUSIONS: Implementation of medical cannabis laws was associated with higher rates of opioid- and benzodiazepine-related deaths, whereas laws permitting broader cannabis access, including implementation of recreational cannabis laws and medical and recreational dispensaries, were associated with lower rates. The estimated effects of the expanded availability of cannabis seem dependent on the type of law implemented and its provisions.

Trends in Nonfatal and Fatal Overdoses Involving Benzodiazepines - 38 States and the District of Columbia, 2019-2020.

Nonfatal and fatal drug overdoses increased overall from 2019 to 2020 (1).* Illicit benzodiazepines (e.g., etizolam, flualprazolam, and flubromazolam)† were increasingly detected among postmortem and clinical samples in 2020, often with opioids,§ and might have contributed to overall increases in drug overdoses. Availability of recent multistate trend data on nonfatal benzodiazepine-involved overdoses and involvement of illicit benzodiazepines in overdoses is limited. This data gap was addressed by analyzing annual and quarterly trends in suspected benzodiazepine-involved nonfatal overdoses¶ treated in emergency departments (EDs) (benzodiazepine overdose ED visits) during January 2019-December 2020 (32 states and the District of Columbia [DC]) and benzodiazepine-involved overdose deaths (benzodiazepine deaths), which include both illicit and prescription benzodiazepines, during January 2019-June 2020 (23 states) from CDC's Overdose Data to Action (OD2A) program. From 2019 to 2020, benzodiazepine overdose ED visits per 100,000 ED visits increased (23.7%), both with opioid involvement (34.4%) and without (21.0%). From April-June 2019 to April-June 2020, overall benzodiazepine deaths increased 42.9% (from 1,004 to 1,435), prescription benzodiazepine deaths increased 21.8% (from 921 to 1,122), and illicit benzodiazepine deaths increased 519.6% (from 51 to 316). During January-June 2020, most (92.7%) benzodiazepine deaths also involved opioids, mainly illicitly manufactured fentanyls (IMFs) (66.7%). Improving naloxone availability and enhancing treatment access for persons using benzodiazepines and opioids and calling emergency services for overdoses involving benzodiazepines and opioids, coupled with primary prevention of drug use and misuse, could reduce morbidity and mortality.

Sex differences in US emergency department non-fatal visits for benzodiazepine poisonings in adolescents and young adults.

BACKGROUND: Benzodiazepine (BZD)-related overdose deaths have risen in the past decade and BZD misuse contributes to thousands of emergency department (ED) visits annually, with the highest rates in adolescents and young adults. Because there are gaps in understanding BZD poisoning in youth and whether differences occur by sex, we aimed to characterize BZD poisoning ED visits in young people by sex. METHODS: BZD poisoning visits were identified in the Nationwide Emergency Department Sample, among adolescents (12-17 years) and young adults (18-29 years). Stratified by sex and age, we described ED visits for BZD poisonings in 2016, including poisoning intent, concurrent substances involved, and co-occurring mental health disorder diagnoses. With logistic regression we examined the association between intent and concurrent substance. RESULTS: There were approximately 38,000 BZD poisoning ED visits by young people nationwide with annual population rates per 10,000 of 2.9=adolescents and 5.8=young adults. Depression was diagnosed in 40 % of female and 23 % of male BZD visits (p < 0.01). Over half of BZD poisonings in females and a third in males were intentional (p < 0.01). Male BZD visits were more likely to involve opioids or cannabis and less likely to involve antidepressants than females (p-values<0.01). In males and females, BZD poisonings concurrent with antidepressants and other psychotropic medications were more likely to be intentional than unintentional (OR range:2.1-6.3). CONCLUSIONS: The high proportion of BZD poisonings that are intentional and include mental health disorder diagnoses, especially among young females, underscore the importance of ED mental health and suicide risk assessment with appropriate follow-up referral.

Epidemiology of acute poisoning by substances of abuse in the Emergency Department. Descriptive study in District IV of Asturias. / Epidemiología de las intoxicaciones agudas por sustancias de abuso en Urgencias. Estudio descriptivo en el área IV de Asturias.

The incidence of acute poisonings has increased in recent years and constitutes approximately 2% of the services provided by the Emergency Department currently. The objective of this study is to describe the frequency and characteristics of the intoxications treated at the Central University Hospital of Asturias during 2015 from biochemical-analytical, epidemiological and medical-legal perspectives. We conducted a retrospective study and a descriptive analysis of the clinical and sociodemographic variables included in the acute intoxication (AI) protocol at the national level. This hospital treated 2,478 cases of acute poisoning, representing 2.3% of the emergencies treated and corresponding to an incidence of 764 cases/100,000 inhabitants/year with an age ranging from under 1 year to over 80 years. The average age of the patients was 43.6 (SD = 16.6) years. Of these patients, 59.4% were males with an average age of 44 (SD = 16.8) years, and women represented 43.1% with an average age of 42.8 (SD = 16.5) years. These intoxications have a frequency of 47.2% during the weekend, while 37.4% occur between June and September. Acute voluntary intoxication is the most frequent intentionality, corresponding to 83.2% of the cases. We must point out that the medical records register 16.8% of the cases as suicide attempts. Ethanol and benzodiazepines are the most commonly-used toxics. These intoxications are treated in the Emergency Department without requiring hospitalization and have a very low mortality rate.

La incidencia de las intoxicaciones agudas ha aumentado en los últimos años, y actualmente constituye aproximadamente el 2% de las atenciones sanitarias llevadas a cabo por los Servicios de Urgencias. El objetivo de este estudio es describir la frecuencia y características de las intoxicaciones atendidas en el Hospital Universitario Central de Asturias durante el año 2015 desde la perspectiva bioquímica-analítica, epidemiológica y médico-legal. Se realizó un estudio retrospectivo y un análisis descriptivo de las variables clínicas y sociodemográficas incluidas en el protocolo de intoxicación aguda a nivel nacional. Este hospital atendió 2478 casos de intoxicaciones agudas representando el 2,3% de las urgencias atendidas y que corresponde a una incidencia de 764 casos/100000 habitantes/año con un rango de edad de menores de 1 año a mayores de 80 años. La edad media de los pacientes atendidos fue de 43,6 (DE = 16,6) años. El 59,4% de los pacientes eran varones con una edad media de 44 (DE = 16,8) años, las mujeres representaban el 43,1% y su edad media era de 42,8 (DE = 16,5) años. El 47,2% de estas intoxicaciones ocurren durante el fin de semana y el 37,4% se dan entre junio y septiembre. La intencionalidad más frecuente es la intoxicación aguda voluntaria correspondiente al 83,2% de los casos. Cabe destacar que el 16,8% de los casos están referenciados en su historia clínica como intentos de suicidio. Los tóxicos más empleados son el etanol y las benzodiacepinas. Estas intoxicaciones son resueltas en el Servicio de Urgencias sin requerir ingreso hospitalario y poseen una tasa de mortalidad muy baja.

Supramolecular solvent (SUPRASs) extraction method for detecting benzodiazepines and zolpidem in human urine and blood using gas chromatography tandem mass spectrometry.

OBJECTIVE: A high-throughput and sensitive method using supramolecular solvent (SUPRASs) for detecting 9 benzodiazepines and zolpidem in human urine and blood by gas chromatography-tandem mass spectrometry (GC-MS/MS) was newly established and applied to authentic human urine and blood samples in this study. METHODS: Urine and blood samples were subjected to liquid-liquid extractions with supramolecular solvent mixture which consists of tetrahydrofuran and 1-hexanol. The solvent layer was evaporated to dryness by stream of nitrogen. The residue was reconstituted with methanol, and subjected to analysis by GC-MS/MS in multiple reaction monitoring (MRM) mode; internal standard method was employed for quantifying of each targeted compound. RESULTS: The regression equation has a good linear relationship with correlation coefficients for all tested compounds were not lower than 0.9991. The lower limits of the quantification ranged from 0.20 to 5 ng/mL for tested compounds in urine; Meanwhile, the lower limits of the quantification in this method ranged from 1 to 50 ng/mL for tested compounds in blood. These results showed that excellent reproducibility and satisfactory extraction recovery rates could be obtained for the established analytical method for 10 drugs in both blood and urine samples. CONCLUSION: The established method in this study was high-throughput, simple and sufficiently sensitive for determining of benzodiazepinesand zolpidem in human urine and blood. Therefore, this newly established method could be of use for qualitative and quantitative determination of such drugs in urine and blood samples either for clinical poisoning monitoring or for forensic identification.

Violence against women and drug-facilitated sexual assault (DFSA): A review of the main drugs.

Sexual violence is a universal phenomenon without restriction to sex, age, ethnicity or social class that causes devastating effects in the physical and mental health spheres, in the short-term and long-term, such as pregnancy, sexually transmitted infections (STI) and greater susceptibility to psychiatric symptoms, especially depression. Some cases of sexual assault and rape are based on the use of so-called drug-facilitated sexual assault (DFSA), which cause victims' loss of consciousness and inability to defend, making them vulnerable to violence. Thus, this article aimed to review the literature on gender violence and the drugs used to facilitate sexual assault, addressing their mechanism of action and pharmacokinetics, as well as drug detection times in human body and types of forensic identification. It is understood that the knowledge of these drugs and their pharmacological and diagnostic mechanisms should be widely disseminated, especially about sensitivity tests and the time the drug remains in the body, which would validate the promotion of evidence to prove abuse, and, thus, being able to give a promising outcome to cases of aggression, which is extremely beneficial for women.

Non-Opioid Substances Acute Poisonings with Suicidal Intent in Patients with Opioid Use Disorder.

INTRODUCTION: Several epidemiological studies have evaluated the role of illicit drug use in suicide behaviour. AIM: To assess patients with opioid use disorder and suicidal intent related to behavior, severity of acute poisoning and the most commonly used non-opioid substances. MATERIALS AND METHODS: This cross sectional study included 67 patients diagnosed with opioid use disorder. The study was conducted at the University Clinic of Toxicology in Skopje over a 5-year period (2013-2017). The following variables were examined: gender, age, duration and route of opioid administration, duration of hospitalization, and types of substances used in acute poisoning. Assessment of patients' behavior and severity of poisoning was made by using the Suicide Behaviours Questionnaire-Revised and the Poison severity score. RESULTS: The majority of patients were male (88.1%). The mean age of patients was 30±6.1 years. The average duration of opioid use disorder was 8.5±3.9. A single poisoning was found in 62.7%, double poisoning in 25.4%, and triple poisoning in 11.9% of participants. Benzodiazepines were most commonly used by the patients (55.2%). The largest number of patients (32.8%) had minor Poison severity score (PSS), and only 17.9% had severe PSS. None of the patients had a fatal suicide attempt. 86.6% of patients had a score of ≥7 indicating a high risk of repeat suicide attempts. CONCLUSION: Benzodiazepines were most commonly used as a single or combined substance in patients with opioid use disorder. PSS indicated that most of the participants were with minor PSS and with high risk of a repeat suicide attempt.

Rates and Costs of Dispensing Naloxone to Patients at High Risk for Opioid Overdose in the United States, 2014-2018.

INTRODUCTION: Clinical practice guidelines recommend co-prescribing naloxone to patients at high risk of opioid overdose, but few such patients receive naloxone. High costs of naloxone may contribute to limited dispensing. OBJECTIVE: The aim of this study was to evaluate rates and costs of dispensing naloxone to patients receiving opioid prescriptions and at high risk for opioid overdose. METHODS: Using claims data from a large US commercial insurance company, we conducted a retrospective cohort study of new opioid initiators between January 2014 and December 2018. We identified patients at high risk for overdose defined as a diagnosis of opioid use disorder, prior overdose, an opioid prescription of ≥ 50 mg morphine equivalents/day for ≥ 90 days, and/or concurrent benzodiazepine prescriptions. RESULTS: Among 5,292,098 new opioid initiators, 616,444 (12%) met criteria for high risk of overdose during follow-up, and, of those, 3096 (0.5%) were dispensed naloxone. The average copayment was US$24.83 for naloxone (standard deviation [SD] 67.66) versus US$9.74 for the index opioid (SD 19.75). The average deductible was US$6.18 for naloxone (SD 27.32) versus US$3.74 for the index opioid (SD 25.56), with 94% and 88% having deductibles of US$0 for their naloxone and opioid prescriptions, respectively. The average out-of-pocket cost was US$31.01 for naloxone (SD 73.64) versus US$13.48 for the index opioid (SD 34.95). CONCLUSIONS: Rates of dispensing naloxone to high risk patients were extremely low, and prescription costs varied greatly. Since improving naloxone's affordability may increase access, whether naloxone's high cost is associated with low dispensing rates should be evaluated.

Clonazolam a new designer benzodiazepine intoxication confirmed by blood concentration.

BACKGROUND: Recently the number of new psychoactive substances have significantly increased, becoming popular among experienced users of designer drugs. A significant group includes benzodiazepine derivatives, which have not been introduced as medications but are abused by people experimenting with new and classical psychoactive substances. CASE PRESENTATION: The aim of this paper was to present the case of a clonazolam ingestion by a person who was not habituated to benzodiazepines. The intake caused only prolonged coma, decreased muscle tone, and deep tendon reflexes without any other concomitant toxicity and cardio-respiratory failure. CONCLUSIONS: Clonazolam concentrations in patient's blood, measured three times were 0.077 mg/L, 0.015 mg/L, 0.009 mg/L after 4, 8 and 12 h, respectively. Clonazolam's human toxicity has not been well established, so any case of poisoning should be closely monitored.

A case of local anesthetic toxicity that wasn't: lipid rescue from self-administered benzodiazepine overdose in labor.

A 32-year-old G2P1 woman presented for induction of labor at term. Her past medical history included polysubstance use disorder and methadone maintenance, scant prenatal care, morbid obesity, and intimate partner violence. Her induction was progressing smoothly until the acute onset of altered mental status near to the time of delivery, several minutes after a clinician-administered epidural local anesthetic bolus for significant pain. Given concern about local anesthetic systemic toxicity, lipid emulsion was administered and resulted in an immediate and drastic clinical response. The epidural infusion bag and pump system were evaluated and found to be correct and there was no clinical suspicion of an intravascular epidural catheter. The woman remained stable and was transferred to the postpartum unit, where she experienced a similar episode of altered mental status approximately 12 h postpartum. This episode self-resolved and she was managed conservatively. Shortly after this event, it was discovered that the patient had been self-administering benzodiazepines throughout the course of her labor, in addition to her hospital staff-administered medications. Presumably, her intrapartum altered mental status was a result of self-administered benzodiazepine that was then "rescued" with lipid emulsion. This case illustrates the potential for lipid emulsion as a reversal agent for medications other than local anesthetics.

Hospital-treated deliberate self-poisoning in the older adult: Identifying specific clinical assessment needs.

BACKGROUND: Hospital-treated deliberate self-poisoning is common, with a median patient age of around 33 years. Clinicians are less familiar with assessing older adults with self-poisoning and little is known about their specific clinical requirements. OBJECTIVE: To identify clinically important factors in the older-age population by comparing older adults (65+ years) with middle-aged adults (45-64 years) during an index episode of hospital-treated deliberate self-poisoning. METHODS: A prospective, longitudinal, cohort study of people presenting to a regional referral centre for deliberate self-poisoning (Calvary Mater Newcastle, Australia) over a 10-year period (2003-2013). We compared older-aged adults with middle-aged adults on demographic, toxicological and psychiatric variables and modelled independent predictors of referral for psychiatric hospitalisation on discharge with logistic regression. RESULTS: There were (n = 157) older-aged and (n = 925) middle-aged adults. The older-aged group was similar to the middle-aged group in several ways: proportion living alone, reporting suicidal ideation/planning, prescribed antidepressant and antipsychotic drugs, and with a psychiatric diagnosis. However, the older-aged group were also different in several ways: greater proportion with cognitive impairment, higher medical morbidity, longer length of stay, and greater prescription and ingestion of benzodiazepines in the deliberate self-poisoning event. Older age was not a predictor of referral for psychiatric hospitalisation in the multivariate model. CONCLUSION: Older-aged patients treated for deliberate self-poisoning have a range of clinical needs including ones that are both similar to and different from middle-aged patients. Individual clinical assessment to identify these needs should be followed by targeted interventions, including reduced exposure to benzodiazepines.

Potential undercounting of overdose deaths caused by specific drugs in vital statistics data: An analysis of Florida.

INTRODUCTION: Due largely to ambiguous or incomplete information provided on death certificates, the widely cited Multiple Cause of Death (MCOD) data reported by the U.S. Centers for Disease Control and Prevention has been shown to undercount the number of fatal overdoses caused by specific drugs. However, the extent of the undercounts is unclear. METHODS: We obtained the number of fatal overdoses from 2003 to 2017 in Florida caused by the three drug groups (amphetamines, benzodiazepines, and opioids) and three drugs (methadone, cocaine, and heroin) that we could map across the MCOD data and data reported by the Florida Medical Examiners Commission (FMEC). The FMEC data are based on state-mandated reporting of the causal drugs in overdose deaths. We analyzed the differences across all deaths and by gender, age group, and race. RESULTS: Depending on the drug, the numbers of deaths across all individuals reported in the FMEC data ranged from 19 %-39 % higher than the counts in the MCOD data. The differences varied over time and by some demographic factors. CONCLUSIONS: The MCOD data appear to undercount the number of fatal overdoses caused by the drugs we investigated. Our analysis did not identify a cause or pattern to explain the differences. Efforts to improve the reporting of fatal overdoses may enhance our understanding of and subsequently may improve the response to the drug overdose epidemic.

Little Helpers No More: A Framework for Collaborative Deprescribing of Benzodiazepines in Older Adults.

Benzodiazepines are a class of medications that tend to fly "under the radar" within the general population but nonetheless post a significant risk to older adults when not used appropriately. The current article aims to shine a spotlight on this medication class along with a framework for a team-based approach to successfully de-escalate use when clinically appropriate. [Journal of Psychosocial Nursing and Mental Health Services, 58(1), 23-28.].

Child and adolescent benzodiazepine exposure and overdose in the United States: 16 years of poison center data.

Background: Recently, there has been an increase in prescription drug abuse and related fatalities. Although opioid analgesics are commonly implicated, there have been significant increases in the prevalence of benzodiazepine exposures and overdoses.Objective: To describe national trends in pediatric benzodiazepine exposures from 2000 to 2015.Methods: A retrospective database analysis was conducted. Data regarding benzodiazepine exposures in children ages 0 to <18 years reported to participating United States poison centers from January 2000 through December 2015 were obtained from the National Poison Data System. Population data were obtained from the US Census Bureau to determine annual population estimates. Data were analyzed using chi-square tests.Results: A total of 296,838 pediatric benzodiazepine exposures were identified during the study period. The rate of pediatric benzodiazepine exposure increased 54% between 2000 and 2015. The severity of medical outcomes also increased, as did the prevalence of co-ingestion of multiple drugs, especially in children ages 12 to <18 years. Nearly half of all reported exposures in 2015 were documented as intentional abuse, misuse, or attempted suicide, reflecting a change from prior years. The most commonly identified pediatric benzodiazepines of exposures were alprazolam, clonazepam, and lorazepam.Conclusions: The rate and severity of reported pediatric benzodiazepine exposure is increasing over time. Adolescent exposures are of specific concern, as co-ingestion and intentional abuse were found to be more common in this group. Medical providers and caretakers should be cognizant of this growing epidemic to avoid preventable harm to adolescents, young children, and infants.

The Effect of Methylphenidate on Reed Scaling in Benzodiazepine Poisoning: A Prospective Trial.

BACKGROUND: Benzodiazepine is one of the most important causes of substance abuse and intoxication throughout the world and Iran. OBJECTIVE: The aim of our study is to determine the role of stimulants in reversing CNS level in acute Benzodiazepine poisoning patients who were hospitalized at referral poison center. METHOD: This was a randomized double-blind placebo-controlled trial study on 32 cases with pure acute Benzodiazepine poisoning from March 2016 to February 2017. Diagnosis of pure acute poisoning was based on history, and laboratory confirmation. We gathered the demographics, clinical data, laboratory data, hospitalization and outcome. Participants were randomized into two groups: Methylphenidate Group (MPH) and Placebo Group (PBO). RESULTS: The randomized sample consisted of 32 participants who were predominately female (83%). The majority of the PBO group and the MPH group reported improvement in their consciousness with a significant difference between the two groups (p = .005). Paired sample t-test analyses on Reed Scale data revealed an increase in the probability of improvement during the trial for the MPH group compared to the PBO group. Furthermore, the HCo3 (bicarbonate) level has a significant p-value with respect to age groups (p = .02). None of our cases required either the ICU facility or intubation. CONCLUSION: Our study provided the MPH superiority over PBO in reversing CNS symptoms in loss of consciousness in acute BZD poisoned patients. Thus, this trial provides concrete evidence that improvement in consciousness levels (Reed Scale rated) among those patients receiving MPH was associated with a methylphenidate use.

Triptan and ergotamine overdoses in the United States: Analysis of the National Poison Data System.

OBJECTIVE: To examine the clinical outcomes of intentional overdoses involving triptans and ergotamines with a retrospective review of the National Poison Data System (NPDS). METHODS: This was a 5-year retrospective cross-sectional study (2014-2018) using the NPDS. Demographics, exposure characteristics, and outcomes were described. Univariate logistic regression was used to estimate the odds ratio (OR) for major effect or death. A multivariable logistic regression model with inclusion criteria of p < 0.1 in univariate analysis was implemented with backwards selection. RESULTS: In this population (n = 1,489), multiple exposure was most common (n = 1,145). The mean age was 31.2 years and 1,197 (80.4%) participants were female. Major effects from a single exposure were seen in <1% with no recorded deaths. Triptan ingestion (n = 328) resulted in hypertension (14%), tachycardia (10.7%), drowsiness (11%), nausea (6.4%), vomiting (4.6%), vertigo (4%), chest pain (3.7%), and diaphoresis (2.4%). Ergotamine ingestion (n = 16) resulted in abdominal pain (16%), vomiting (12.5%), numbness (12.5%), nausea (6.3%), diarrhea (6.3%), and vertigo (6.3%). No clinical effect was seen in 90 (26.2%). No cases met Hunter criteria for serotonin syndrome. There is risk of major event or death due to age (OR 1.02; 95% confidence interval [CI] 1.01-1.04; p = 0.004), multiple product exposure (OR 9.50; 95% CI 2.29-39.48; p = 0.002), and concomitant overdose with benzodiazepines (OR 1.71; 95% CI 1.05-2.78; p = 0.032) or tricyclic antidepressants (OR 3.16; 95% CI 1.88-5.31; p < 0.001). CONCLUSION: The risk of major effect or death was low and predicted by age, multiple product exposure, and concomitant benzodiazepine or tricyclic antidepressant. The triptan toxidrome consists of hypertension, tachycardia, and drowsiness. The toxic effects of ergotamine are acute gastrointestinal syndrome with vertigo and numbness. No cases of serotonin syndrome were seen.