Real or fake? Sourcing and marketing of non-prescribed benzodiazepines amongst two samples of people who regularly use illicit drugs in Australia.

INTRODUCTION: There is concern around non-prescribed benzodiazepine use, particularly with increasing detections of counterfeit products containing high-risk novel compounds. The aims of this study were to investigate how and which non-prescribed benzodiazepines are being sourced; forms, appearance and packaging; and awareness of risks associated with non-prescribed benzodiazepines. METHODS: Data were collected from a sample of Australians who inject drugs or use ecstasy and/or other illicit stimulants on a monthly or more frequent basis, and who reported past 6-month use of non-prescribed benzodiazepines (n = 235 and n = 250, respectively). Data were collected on source, diversion from a known/trusted prescription, product name and aesthetic characteristics for the last non-prescribed benzodiazepine obtained. RESULTS: Amongst participants who injected drugs, 71% reported that their last non-prescribed benzodiazepines were diverted from a known/trusted prescription, compared to 59% of participants who used ecstasy/other stimulants. Sourcing via cryptomarkets was rare. Across both samples, the majority reported last obtaining substances sold/marketed as diazepam or alprazolam. Participants sourcing via non-diverted means were twice as likely to obtain alprazolam. Known sourcing of novel compounds was rare. Amongst participants who used ecstasy/other stimulants, 36% reported confidence in the content/dose of non-prescribed benzodiazepines even when the source is unknown. DISCUSSION AND CONCLUSIONS: Most participants obtained substances sold as classic/registered benzodiazepines, mostly via diverted prescriptions, with a substantial minority potentially unaware of counterfeits circulating. While diverted use undeniably presents risks, tightening of prescriptions in Australia could inadvertently lead to greater supply of novel benzodiazepines as seen internationally, reinforcing prioritisation of demand and harm reduction strategies.

Assessment of 2-Year Neurodevelopmental Outcomes in Extremely Preterm Infants Receiving Opioids and Benzodiazepines.

Importance: Extremely preterm (EP) infants frequently receive opioids and/or benzodiazepines, but these drugs' association with neurodevelopmental outcomes is poorly understood. Objectives: To describe the use of opioids and benzodiazepines in EP infants during neonatal intensive care unit (NICU) hospitalization and to explore these drugs' association with neurodevelopmental outcomes at 2 years' corrected age. Design, Setting, and Participants: This cohort study was a secondary analysis of data from the Preterm Erythropoietin Neuroprotection (PENUT) Trial, which was conducted among infants born between gestational ages of 24 weeks, 0 days, and 27 weeks, 6 days. Infants received care at 19 sites in the United States, and data were collected from December 2013 to September 2016. Data analysis for this study was conducted from March to December 2020. Exposures: Short (ie, ≤7 days) and prolonged (ie, >7 days) exposure to opioids and/or benzodiazepines during NICU stay. Main Outcomes and Measures: Cognitive, language, and motor development scores were assessed using the Bayley Scales of Infant Development-Third Edition (BSID-III). Results: There were 936 EP infants (448 [48%] female infants; 611 [65%] White infants; mean [SD] gestational age, 181 [8] days) included in the study, and 692 (74%) had neurodevelopmental outcome data available. Overall, 158 infants (17%) were not exposed to any drugs of interest, 297 (32%) received either opioids or benzodiazepines, and 481 (51%) received both. Infants exposed to both had adjusted odds ratios of 9.7 (95% CI, 2.9 to 32.2) for necrotizing enterocolitis and 1.7 (95% CI, 1.1 to 2.7) for severe bronchopulmonary dysplasia; they also had a longer estimated adjusted mean difference in length of stay of 34.2 (95% CI, 26.2 to 42.2) days compared with those who received neither drug. After adjusting for site and propensity scores derived for each exposure category, infants exposed to opioids and benzodiazepines had lower BSID-III cognitive, motor, and language scores compared with infants with no exposure (eg, estimated difference in mean scores on cognitive scale: -5.72; 95% CI, -8.88 to -2.57). Prolonged exposure to morphine, fentanyl, midazolam, or lorazepam was associated with lower BSID-III scores compared with infants without exposure (median [interquartile range] motor score, 85 [73-97] vs 97 [91-107]). In contrast, BSID-III scores for infants with short exposure to both opioids and benzodiazepines were not different than those of infants without exposure. Conclusions and Relevance: In this study, prolonged combined use of opioids and benzodiazepines was associated with a risk of poorer neurodevelopmental outcomes as measured by BSID-III at 2 years' corrected age.

A nurse-driven analgesia and sedation protocol reduces length of PICU stay and cumulative dose of benzodiazepines after corrective surgery for tetralogy of Fallot.

PURPOSE: Analgesia and sedation protocols are reported to reduce the requirement of sedative and analgesic agents, duration of mechanical ventilation, and length of pediatric intensive care unit (PICU) stay. However, these studies often were conducted based on inhomogeneous cohorts. The aim of this study was the evaluation of a nurse-driven analgesia and sedation protocol in a homogenous population of infants following corrective surgery for tetralogy of Fallot (TOF). DESIGN AND METHODS: This retrospective analysis was conducted in a cardiac PICU of a tertiary referral center. Two cohorts of patients who underwent corrective surgery for TOF below the age of 7 months, were retrospectively evaluated before and after implementation of a nurse-driven analgesia and sedation protocol. We compared peak and cumulative doses of midazolam, morphine, and clonidine, length of PICU stay and time on mechanical ventilation. RESULTS: A total of 33 patients were included in the preimplementation period and 32 during the postimplementation period. Implementation of the nurse-driven analgesia and sedation protocol had no effect on time on mechanical ventilation (72 hr [24-141] vs. 49 hr [24-98]), but significantly on length of PICU stay (7 days [5-14] vs. 5 days [4-7]). Cumulative doses of midazolam (7.37 mg/kg [4.70-17.65] vs. 5.0 mg/kg [2.70-9.12]) as well as peak doses of midazolam (0.22 mg·kg-1 ·hr-1 [0.20-0.33] vs. 0.15 mg·kg-1 ·hr-1 [0.13-0.20]) and morphine (50.0 µg·kg-1 ·hr-1 [39.7-79.9] vs. 42.5 µg·kg-1 ·hr-1 [29.7-51.8]) were significantly reduced. The postimplemantation group showed no increase in postoperative complications and adverse events. PRACTICE IMPLICATIONS: The implementation of a nurse-driven analgesia and sedation protocol is safe in infants following corrective surgery for TOF. It reduces significantly the length of PICU stay, cumulative and peak doses of midazolam and peak doses of morphine.

Conformity in Prescription and Administration of Respiratory Distress Protocols in a Tertiary Care Hospital in the Province of Quebec: RELIEVE Study.

BACKGROUND: Respiratory distress protocols (RDPs) are protocolized prescriptions comprised of 3 medications (a benzodiazepine, an opioid, and an anticholinergic) administered simultaneously as an emergency treatment for respiratory distress in palliative care patients in the province of Quebec, Canada. However, data on appropriate use that justifies the combination of all 3 components is scarce and based on individual pharmacodynamic properties along with expert consensus. OBJECTIVES: Our study aimed to evaluate the conformity and the effectiveness of RDPs prescribed and administered to hospitalized adult patients. METHODS: This was a prospective and descriptive study conducted in a single center. Prescription and administration conformity were assessed based on predefined appropriateness criteria. RESULTS: A total of 467 adult patients were prescribed a RDP, 175 administrations were documented, and 78 patients received at least 1 RDP. Prescription conformity was assessed on 1473 separate occasions over the trial period. Overall prescription conformity was found to be 37% (95% confidence interval [CI]: 33.6-40.4), and administration conformity was 37.7% (95% CI: 26.2-50.7). Low administration conformity was primarily explained by incorrect indications for RDP use. Seemingly important determinants of higher conformity were prescriber's speciality in palliative care, use of preprinted orders, pharmacist involvement, and hospitalization in the palliative care unit. CONCLUSION: This study highlights important gaps in the use of RDPs in our institution. Health-care provider training appears necessary in order to ensure adequate conformity and allow for further evaluation of RDP effectiveness.

County and Physician Variation in Benzodiazepine Prescribing to Medicare Beneficiaries by Primary Care Physicians in the USA.

BACKGROUND: Physicians widely prescribe benzodiazepines (BZD) despite well-recognized harms. OBJECTIVE: To determine county and provider characteristics that predict high-intensity BZD prescribing by primary care physicians (PCPs) to Medicare beneficiaries. DESIGN: Cross-sectional analysis of the 2015 Medicare Part D Public Use Files (PUF). SUBJECTS: n = 122,054 PCPs who prescribed 37.3 billion medication days. MAIN MEASURES: Primary outcome was intensity of BZD prescribing (days prescribed/total medication days) at the county- and physician levels. PCP and county characteristics were derived from the Part D PUF, Area Health Resources Files, and County Health Rankings. Logistic regression determined the characteristics associated with high-intensity (top quartile) BZD prescribing. KEY RESULTS: Beneficiaries were prescribed over 1.2 billion days of BZD in 2015, accounting for 2.3% of all medication days prescribed in Part D. Top quartile counties had 3.1 times higher BZD prescribing than the lowest (3.4% vs. 1.1%; F = 3293.8, df = 3, p < 0.001). Adjusting for county-level demographics and health care system characteristics (including supply of mental health providers), counties with more adults with at least some college had lower odds of high-intensity prescribing (per 5% increase, adjusted odds ratio [AOR] 0.80, 99% confidence interval (CI) 0.73-0.87, p < 0.001), as did higher income counties (per US$1000 increase, AOR 0.93, CI 0.91-0.95, p < 0.001). Top quartile PCPs prescribed at 6.5 times the rate of the bottom (3.9% vs. 0.6%; F = 63,910.2, df = 3, p < 0.001). High-intensity opioid prescribing (AOR 4.18, CI 3.90-4.48, p < 0.001) was the characteristic most strongly associated with BZD prescribing. CONCLUSIONS: BZD prescribing appears to vary across counties and providers and is related to non-patient characteristics. Further work is needed to understand how such non-clinical factors drive variation.

Dispensación de benzodiacepinas y análogos en farmacias comunitarias de Valladolid / Dispensation of benzodiazepines and analogues in community pharmacies in Valladolid

Introducción: Las benzodiacepinas (BZD) son fármacos de consumo creciente, que se utilizan muy frecuentemente para los trastornos de ansiedad y del sueño, así como relajantes musculares. Muchos pacientes las usan de forma crónica a pesar de estar desaconsejadas y, en algunas ocasiones, de manera inadecuada, en especial la población anciana. Objetivos: Investigar las principales características de los usuarios, las BZD prescritas, si se tiene conocimiento y se hace un buen uso de ellas, las reacciones adversas, las posibles interacciones farmacológicas con la medicación y otros problemas relacionados con los medicamentos. Material y métodos: Se llevó a cabo un estudio transversal en 2 farmacias comunitarias de Valladolid desde septiembre de 2012 hasta febrero de 2013. Se utilizó un cuestionario cerrado y administrado por el farmacéutico. Se incluyeron todos los pacientes mayores de 16 años que solicitaron BZD prescritas por el médico. Resultados: En total, 104 pacientes consintieron ser entrevistados. La mayor parte utilizaba las BZD más tiempo del aconsejado. El 63,5% de los pacientes experimentó, al menos, una reacción adversa (dependencia, sedación, somnolencia, pérdida de memoria, etc.). El 13,2% de los usuarios mayores de 65 años estaba tomando dosis mayores de las recomendadas en la fi cha técnica, y el 27,7% de éstos utilizaba BZD de vida media larga. Conclusiones: Este estudio muestra un inadecuado uso de las BZD por parte de la población, en especial los ancianos. El farmacéutico comunitario junto con el médico desempeñan un papel clave en la mejora del uso de las BZD por parte de la población (AU)

Background: Benzodiazepines (BZD) are drugs of growing consumption, which are very often used for anxiety disorders, sleep and relaxing muscle. Many patients use them chronically despite being discouraged and sometimes misused, particularly in the elderly population. Aims: To investigate the main characteristics of the users, prescribed BZD, knowledge and if they make good use of them, adverse reactions, possible drug interactions with medication and other drug-related problems. Material and methods: A cross-sectional study in two community pharmacies in Valladolid was conducted during the months of September of 2012 through February of 2013. We used a closed questionnaire administered by the pharmacist. We included all patients older than sixteen years that requested BZD prescribed by the doctor. Results: In total, 104 patients consented to be interviewed. Most of the users took BZD longer than the recommended time. The 63.5% of the patients experienced at least one adverse reaction (dependence, sedation, sleepiness, loss of memory, etc.). The 13.2% of users over the age of 65 was taking doses higher than those recommended in the technical sheet and 27.7% of these used long half-life BZD. Conclusions: This study shows the inadequate use of BZD by the population, especially in the elderly population. The community pharmacist and the doctor play a key role in the improvement of the use of BZD by the population (AU)

Rapid LC-MS/MS quantification of the major benzodiazepines and their metabolites on dried blood spots using a simple and cost-effective sample pretreatment.

BACKGROUND: Dried blood spots (DBS) sampling has gained popularity in the bioanalytical community as an alternative to conventional plasma sampling, as it provides numerous benefits in terms of sample collection and logistics. The aim of this work was to show that these advantages can be coupled with a simple and cost-effective sample pretreatment, with subsequent rapid LC-MS/MS analysis for quantitation of 15 benzodiazepines, six metabolites and three Z-drugs. For this purpose, a simplified offline procedure was developed that consisted of letting a 5-µl DBS infuse directly into 100 µl of MeOH, in a conventional LC vial. RESULTS: The parameters related to the DBS pretreatment, such as extraction time or internal standard addition, were investigated and optimized, demonstrating that passive infusion in a regular LC vial was sufficient to quantitatively extract the analytes of interest. The method was validated according to international criteria in the therapeutic concentration ranges of the selected compounds. CONCLUSION: The presented strategy proved to be efficient for the rapid analysis of the selected drugs. Indeed, the offline sample preparation was reduced to a minimum, using a small amount of organic solvent and consumables, without affecting the accuracy of the method. Thus, this approach enables simple and rapid DBS analysis, even when using a non-DBS-dedicated autosampler, while lowering the costs and environmental impact.

Improving the use of benzodiazepines--is it possible? A non-systematic review of interventions tried in the last 20 years.

BACKGROUND: Benzodiazepines are often used on a long term basis in the elderly to treat various psychological disorders including sleep disorders, some neurological disorders and anxiety. This is despite the risk of dependence, cognitive impairment, and falls and fractures. Guidelines, campaigns and prescribing restrictions have been used to raise awareness of potentially inappropriate use, however long term use of benzodiazepine and related compounds is currently increasing in Australia and worldwide. The objective of this paper is to explore interventions aimed at improving the prescribing and use of benzodiazepines in the last 20 years. METHODS: Medline, EMBASE, PsychINFO, IPA were searched for the period 1987 to June 2007. RESULTS: Thirty-two articles met the study eligibility criteria (interventions solely focusing on increasing appropriate prescribing and reducing long term use of benzodiazepines) and were appraised. Insufficient data were presented in these studies for systematic data aggregation and synthesis, hence critical appraisal was used to tabulate the studies and draw empirical conclusions. Three major intervention approaches were identified; education, audit and feedback, and alerts. CONCLUSIONS: Studies which used a multi-faceted approach had the largest and most sustained reductions in benzodiazepines use. It appears that support groups for patients, non-voluntary recruitment of GPs, and oral delivery of alerts or feedback may all improve the outcomes of interventions. The choice of outcome measures, delivery style of educational messages, and requests by GPs to stop benzodiazepines, either in a letter or face to face, showed no differences on the success rates of the intervention.

Development and validation of an HPLC method for the determination of benzodiazepines and tricyclic antidepressants in biological fluids after sequential SPE.

A novel method for the simultaneous determination of six benzodiazepines (BZDs) and four tricyclic antidepressants (TCAs) in biological fluids by HPLC with UV detection at 240 nm has been developed. After a deproteinization step biological fluids were analyzed by direct injection. SPE on Nexus cartridges was also applied. Since two compounds, namely imipramine and diazepam, were coeluting, a sequential SPE protocol has been developed. BZDs were eluted by a mixture of methanol/ACN(1:1), followed by the elution of TCAs with methanol. Separation was performed on a Kromasil C8 column (250 x 64 mm(2) id, 5 microm) using a mobile phase of 0.05 MCH3COONH4/ACN/methanol (initial composition 55:15:30 v/v/v) at a flow rate of 1.0 mL/min delivered by a gradient program within 15 min. Colchicine was used as the internal standard (4 ng/microL). The method was linear for all analytes up to 20 ng/lL, with coefficients of regression between 0.996 and 0.99996. LODs and LOQs were 0.08-1.17 and 0.28-3.91 ng/lL, respectively. Recovery was in the range of 92.8-108.7% for within-day and 91.9-109.9% for between-day assays, with RSD values lower than 10.0% for all matrices.

Conscious sedation for dentistry: an update.

Despite its excellent safety record there remains disquiet about the provision of conscious sedation for dental care. This applies particularly to the use of 'alternative' sedation techniques which extend beyond the 'standard' techniques (intravenous midazolam for adults and nitrous oxide/oxygen) described in Conscious sedation in the provision of dental care (2003). New guidance from the Faculty of Dental Surgery of the Royal College of Surgeons of England and the Royal College of Anaesthetists develops the earlier guidance to encompass the use of alternative sedation drugs and techniques. It has been prepared for dental and medical practitioners (including anaesthetists) and their teams and defines the minimum standard for safe and effective patient care whatever the clinical setting.

Determination of Olanzapine in rat brain using liquid chromatography with coulometric detection and a rapid solid-phase extraction procedure.

A sensitive and selective method was developed for the determination of the antipsychotic drug Olanzapine levels in rat brain tissue, based on HPLC with electrochemical detection. The analyses were carried out on a C8 reversed phase column (150 mm x 4.6 mm, 5 microm), using a mobile phase composed of methanol and a phosphate buffer (44.0 mM, pH 3.5), containing triethylamine (21:79, v/v), flowing at 1.2 mL min(-1). A high sensitivity coulometric detection analytical cell containing two flow-through low volume working electrodes was used: electrode 1 was set at +0.350 V and electrode 2 at -0.200 V. Olanzapine, administered to rats in different doses or in different times, was extracted from tissue homogenate of either the whole brain or specific areas (cortex, hyppocampus, nucleus striatum) with a rapid solid phase extraction procedure (SPE) on Oasis HLB cartridges. The method provided a high extraction yield of Olanzapine and internal standard (2-methylolanzapine) from brain tissue homogenate with absolute recovery values higher than 90.0%. The detector response was linear over a concentration range of 0.2-100.0 ng mL(-1) of Olanzapine. The limit of quantification (LOQ) was 0.2 ng mL(-1). Precision results, expressed by the intra-day and the inter-day relative standard deviation values, were satisfactory, better than 4.6%. Accuracy was satisfactory as well. This method proved to be suitable for the analysis of Olanzapine in rat brain tissues and for the study of distribution and pharmacokinetics of Olanzapine in rat brain after a single treatment with the antipsychotic drug.

Management of alcohol withdrawal delirium. An evidence-based practice guideline.

BACKGROUND: Alcohol withdrawal delirium is the most serious manifestation of alcohol withdrawal. Evidence suggests that appropriate care improves mortality, but systematic reviews are unavailable. METHODS: Articles with original data on management of alcohol withdrawal delirium underwent structured review and meta-analysis. RESULTS: Meta-analysis of 9 prospective controlled trials demonstrated that sedative-hypnotic agents are more effective than neuroleptic agents in reducing duration of delirium and mortality, with a relative risk of death when using neuroleptic agents of 6.6. Statistically significant differences among various benzodiazepines and barbiturates were not found. No deaths were reported in 217 patients from trials using benzodiazepines or barbiturates. CONCLUSIONS: Control of agitation should be achieved using parenteral rapid-acting sedative-hypnotic agents that are cross-tolerant with alcohol. Adequate doses should be used to maintain light somnolence for the duration of delirium. Coupled with comprehensive supportive medical care, this approach is highly effective in preventing morbidity and mortality.

Chronic benzodiazepine use in nursing homes: effects of federal guidelines, resident mix, and nurse staffing.

OBJECTIVES: To assess the overall prescribing and chronic use of benzodiazepines (BZs) in nursing homes before and after implementation of BZ guidelines by the Health Care Finance Administration (HCFA). A second aim was to identify facility predictors of BZ prescribing and chronic use after guideline implementation. DESIGN: Nonexperimental, observational study design. SETTING: Drug use was assessed in 16 randomly selected skilled nursing facilities in Wisconsin before 1990 and again in 1993-1994. PARTICIPANTS: One thousand one hundred eighty-one Medicaid-funded residents at baseline and 1,650 Medicaid-funded residents at follow-up. MEASUREMENTS: Drug use measures included percentage of residents with prescribed BZs and percentage of residents with chronic BZ use (defined as >or=4 months of continuous use). A 4-month cutoff was used because HCFA guidelines consider this length of continuous use to be potentially excessive. Facility predictors of drug use included resident demographic and diagnostic mix, size, ownership, Medicaid per diem, and nurse staffing. RESULTS: Before 1990, one-fourth of all residents were prescribed a BZ and nearly one-tenth of all residents had chronic BZ use. Federal guidelines had nonsignificant effects on these measures; BZ prescribing declined only 3.6% (26.4-22.8%) and chronic use declined only 1.3% (9.2-7.9%). Regression results showed that overall prescribing at follow-up was higher in facilities with more female residents (beta= .52, P= .018) and residents with psychiatric disorders (beta= .41, P= .045). However, nurse staffing was the only significant predictor of chronic BZ use. As expected, better nurse staffing was associated with lower rates of chronic use (beta= -0.46, P= .037). CONCLUSION: Efforts to improve BZ use in nursing homes must address the need for better nurse staffing and better assessment and management of psychiatric disorders that can trigger BZ prescribing.