Benzodiazepine Exposure Research Articles

Prescribing Cascades of Loop Diuretics and Anti-vertigo Drugs Following Treatment with Gabapentinoids and Benzodiazepines: Prescription Sequence Symmetry Analysis of a Large-Scale Claims Database Including Japanese Older Adults.

Gabapentinoids (GBP) and benzodiazepines (BZ) are commonly prescribed in older adults and their package inserts list edema and vertigo as adverse drug reactions. These adverse drug reactions may be treated with symptomatic drug therapies without discontinuing the culprit drugs or decreasing their dose, thereby initiating a prescribing cascade and often resulting in polypharmacy. Whether prescribing cascades occur in the treatment of edema and dizziness among Japanese patients treated with GBP and BZ has not been investigated, including treatment with mirogabalin, a class drug of GBP marketed in Japan. We aimed to investigate prescribing cascades with GBP-induced and BZ-induced edema and dizziness treated with loop diuretics (LD) and anti-vertigo drugs (AVD), respectively, among older adults. A prescription sequence symmetry analysis design was used to detect signals of prescribing cascades associated with edema and dizziness induced by GBP and BZ (exposure drugs). Loop diuretics and AVD were the outcome drugs used to identify prescribing cascades following the initiation of exposure drugs. The study population consisted of enrollees of a large-scale health claims database provided by DeSC Healthcare, Inc., between April 2014 and March 2021. Subjects eligible for a prescription sequence symmetry analysis were patients aged ≥65 years prescribed an outcome drug within 90 days before and after exposure drug initiation. A signal of a prescribing cascade was detected if secular trend-adjusted sequence ratios were statistically significant on comparison of the frequencies of outcome drug initiation before and after exposure drug initiation. We identified 2671 patients with prescriptions of a GBP-LD combination, 4009 with a GBP-AVD combination, 8675 with a BZ-LD combination, and 9462 with a BZ-AVD combination. The adjusted sequence ratios for GBP-LD and BZ-LD cascades were significantly larger than one (adjusted sequence ratio [95% confidence interval], 1.69 [1.56-1.83]; 1.35 [1.29-1.41], respectively), indicating positive signals of prescribing cascades. No signal was detected for the GBP-AVD or BZ-AVD cascade (0.89 [0.83-0.94]; 0.90 [0.87-0.94], respectively). The adjusted sequence ratio for the mirogabalin cascade was higher than that for pregabalin (2.23 [1.84-2.71] vs 1.59 [1.46-1.73]). Our study provides good evidence that LD-prescribing cascades associated with edema would be a class effect of GBP and BZ. Edema emerging around 1 month after GBP initiation should be carefully differentiated from pathological edema, and undue LD prescription as a prescribing cascade should be avoided.

Prenatal exposure to benzodiazepine and z-hypnotics and fifth-grade scholastic skills – emulating target trials using data from the Norwegian Mother, Father and Child Cohort Study

Abstract Evidence is limited regarding the effect of prenatal benzodiazepine and z-hypnotic exposure and long-term neurodevelopment in childhood. The objective of this study was to investigate the effects of initiating benzodiazepine or z-hypnotic treatment in early, mid and late pregnancy on fifth-grade numeracy and literacy scholastic skills in children, by emulating three target trials. The trials are identical except for the timing of enrollment and the number of eligible individuals. Eligibility to the trials required a history of anxiety and/or depression prior to pregnancy. We used data from the Norwegian Mother, Father and Child Cohort Study, linked to the Medical Birth Registry of Norway, to emulate the trials. We adjusted for baseline covariates that were available at time 0 for each trial by inverse probability of treatment weighting using the propensity score. The findings of this study did not show any effect of mothers’ initiation of treatment with benzodiazepines or z-hypnotics in early, mid or late pregnancy on the children’s 5th grade test scores in numeracy and literacy. The study results provide reassurance for patients in need of benzodiazepines and z-hypnotics during pregnancy; however, these findings need to be interpreted with caution due to low study power in some of the analyses.

Gabapentin as a novel adjunct for postoperative irritability after superior cavopulmonary connection operation in children.

Describing our institution's off-label use of gabapentin to treat irritability after superior cavopulmonary connection surgery and its impact on subsequent opiate and benzodiazepine requirements. This is a single-center retrospective cohort study including infants who underwent superior cavopulmonary connection operation between 2011 and 2019. Gabapentin was administered in 74 subjects (74/323, 22.9%) during the observation period, with a median (IQR) starting dose of 5.7 (3.3, 15.0) mg/kg/day and a maximum dose of 10.7 (5.5, 23.4) mg/kg/day. Infants who underwent surgery in 2015-19 were more likely to receive gabapentin compared with those who underwent surgery in 2011-14 (p < 0.0001). Infants prescribed gabapentin were younger at surgery (137 versus 146 days, p = 0.007) and had longer chest tube durations (1.8 versus 0.9 days, p < 0.001), as well as longer postoperative intensive care (5.8 versus 3.1 days, p < 0.0001) and hospital (11.5 versus 7.0 days, p < 0.0001) lengths of stays. The year of surgery was the only predisposing factor associated with gabapentin administration in multivariate analysis. In adjusted linear regression, infants prescribed gabapentin on postoperative day 0-4 (n = 64) had reduced benzodiazepine exposure in the following 3 days (-0.29 mg/kg, 95% CI -0.52 - -0.06, p = 0.01) compared with those not prescribed gabapentin, while no difference was seen in opioid exposure (p = 0.59). Gabapentin was used with increasing frequency during the study period. There was a modest reduction in benzodiazepine requirements associated with gabapentin administration and no reduction in opioid requirements. A randomised controlled trial could better assess gabapentin's benefits postoperatively in children with congenital heart disease.

Effects of Benzodiazepine Exposure on Real-World Clinical Outcomes in Individuals at Clinical High Risk for Psychosis.

Animal models indicate GABAergic dysfunction in the development of psychosis, and that benzodiazepine (BDZ) exposure can prevent the emergence of psychosis-relevant phenotypes. However, whether BDZ exposure influences real-world clinical outcomes in individuals at clinical high risk for psychosis (CHR-P) is unknown. This observational cohort study used electronic health record data from CHR-P individuals to investigate whether BDZ exposure (including hypnotics, eg, zopiclone) reduces the risk of developing psychosis and adverse clinical outcomes. Cox proportional-hazards models were employed in both the whole-unmatched sample, and a propensity score matched (PSM) subsample. 567 CHR-P individuals (306 male, mean[±SD] age = 22.3[±4.9] years) were included after data cleaning. The BDZ-exposed (n = 105) and BDZ-unexposed (n = 462) groups differed on several demographic and clinical characteristics, including psychotic symptom severity. In the whole-unmatched sample, BDZ exposure was associated with increased risk of transition to psychosis (HR = 1.61; 95% CI: 1.03-2.52; P = .037), psychiatric hospital admission (HR = 1.93; 95% CI: 1.13-3.29; P = .017), home visit (HR = 1.64; 95% CI: 1.18-2.28; P = .004), and Accident and Emergency department attendance (HR = 1.88; 95% CI: 1.31-2.72; P < .001). However, after controlling for confounding-by-indication through PSM, BDZ exposure did not modulate the risk of any outcomes (all P > .05). In an analysis restricted to antipsychotic-naïve individuals, BDZ exposure reduced the risk of transition to psychosis numerically, although this was not statistically significant (HR = 0.59; 95% CI: 0.32-1.08; P = .089). BDZ exposure in CHR-P individuals was not associated with a reduction in the risk of psychosis transition or adverse clinical outcomes. Results in the whole-unmatched sample suggest BDZ prescription may be more likely in CHR-P individuals with higher symptom severity.

Restrictive use of Restraints and Delirium Duration in the Intensive Care Unit (R2D2-ICU): protocol for a French multicentre parallel-group open-label randomised controlled trial

IntroductionPhysical restraint (PR) is prescribed in patients receiving invasive mechanical ventilation in the intensive care unit (ICU) to avoid unplanned removal of medical devices. However, it is associated with an...

Prescription opioid use among people with opioid dependence and concurrent benzodiazepine and gabapentinoid exposure: An analysis of overdose and all-cause mortality

BackgroundStudies investigating mortality risk associated with use of opioid analgesics, benzodiazepines, gabapentinoids, and opioid agonist treatment (OAT) among people with opioid dependence (PWOD) are lacking. This study addresses this gap using a cohort of 37,994 PWOD initiating opioid analgesics between July 2003 and July 2018 in New South Wales, Australia. MethodsLinked administrative records provided data on dispensings, sociodemographics, clinical characteristics, OAT, and mortality. Cox proportional hazards models assessed associations between time-varying measures of individual and concurrent medicine use and OAT with all-cause mortality, accidental opioid overdose, non-drug induced accidents, and non-drug-induced suicide. Opioid analgesic dose effects, expressed as oral morphine equivalents (OMEs) per day, were also examined. OutcomesDuring the study period, 3167 individuals died. Compared with no use, all medicines of interest were associated with increased accidental opioid overdose risk; hazard ratios (HR) ranged from 1.33 (95 % CI: 1.05–1.68) for opioid analgesic use to 6.10 (95 % CI: 4.11–9.06) for opioid analgesic, benzodiazepine and gabapentinoid use. Benzodiazepine use was associated with increased non-drug-induced accidents and non-drug-induced suicides. For all-cause mortality, all combinations of benzodiazepines and gabapentinoids with opioid analgesics were associated with increased risk (aHRs ranged from 1.35 to 2.73). For most medicines/medicine combinations, all-cause mortality risk was reduced when in OAT compared to out of OAT. Higher opioid analgesic doses were associated with increased all-cause mortality (e.g., 90–199 mg vs 1–49 mg OME per day: HR 1.90 [95 % CI: 1.52–2.40]). InterpretationThe increased mortality risk associated with benzodiazepines and gabapentinoids among PWOD appear to be reduced when engaged in OAT. A greater focus on encouraging OAT engagement, providing overdose prevention education, and access and coverage of overdose antidotes is necessary to minimise the unintended consequences of medicines use in this population.

Using Risk Scores to Estimate Lower Extremity Fragility Fracture Risk among Individuals with Chronic Spinal Cord Injury: A Preliminary Model.

To develop SCI-FX, a risk score to estimate 5-year lower extremity fragility fracture risk among patients living with chronic spinal cord injury (cSCI). Adults with traumatic cSCI (n = 90) participated in a 2-year prospective longitudinal cohort study describing bone mineral density (BMD) change and fracture incidence conducted at the Lyndhurst Centre (University Health Network), University of Waterloo, and Physical Disability Rehabilitation Institute of Québec City. Prior publication and clinical intuition were used to identify fragility fracture risk factors including prior fragility fracture, years post-injury, motor complete injury (AIS A/B), benzodiazepine use, opioid use, and parental osteoporosis. We conducted bivariate analyses to identify variables associated with fracture. Multiple logistic regressions were performed using fragility fracture incidence as the dependent variable and all variables from the univariate analyses with a highly liberal p value at 0.2. Using the odds ratios (ORs) from the multiple logistic regression model, a point system for fragility fracture risk score was developed, and the odds of fracture for each point was estimated. All initial variables, with the exception of benzodiazepine exposure, were included in the final model. We identified a simple preliminary model for clinicians to estimate 5-year fracture risk among patients with cSCI based on their total score.

Letter to the Editor on 'Baseline benzodiazepine exposure is associated with greater risk of transition in clinical high-risk for psychosis (CHR-P): a meta-analysis'.

Letter to the Editor on 'Baseline benzodiazepine exposure is associated with greater risk of transition in clinical high-risk for psychosis (CHR-P): a meta-analysis'.

Baseline benzodiazepine exposure is associated with greater risk of transition in clinical high-risk for psychosis (CHR-P): a meta-analysis.

Emerging meta-analytical evidence indicates that baseline exposure to antipsychotics and to antidepressants in individuals at clinical high-risk for psychosis (CHR-P) have opposite prognostic effects as regards imminent transition to psychosis, with antipsychotics associated with higher risk and antidepressants associated with a lower risk in comparison to not-exposed individuals. Despite their common use, baseline exposure to benzodiazepines (BDZ) in CHR-P has surprisingly received poor attention as a potential risk modulator for transition to psychosis. The current systematic review and meta-analysis were performed to fix such a knowledge gap. Systematic scrutiny of Medline and Cochrane library, performed up to 31 December 2022, searching for English-language studies on CHR-P reporting numeric data about the sample, the transition outcome at a predefined follow-up time and raw data on BDZ baseline exposure in relation to such outcome. Of 1893 identified records, five studies were included in the systematic review and meta-analysis. The proportion of participants with exposure to BDZ at baseline ranged from 5.5% (one study) to 46.2%, with an average of 16.8%. At the end of the period of observation, i.e., the follow-up as reported in the study, 28.4% [95% confidence interval (CI) 19.7-39.1%] participants developed psychosis among the BDZ-exposed against 9.3% (7.3 to 11.9%) among the controls. CHR-P participants who were already under BDZ treatment at baseline had more than double chance of transition to psychosis than CHR-P participants who were BDZ-naïve. The risk ratio (RR) was 2.42 (95% CI 1.38-4.23) in the common effects model (z = 3.09; p = 0.002), and 2.40 (1.53 to 3.77) in the random-effects model (z = 5.40; p = 0.006; tau-squared = 0.0). There was no relevant heterogeneity: Cochran's Q = 1.49; df = 4; p = 0.828; I2 = 0.0% (95% CI 0.0-79%). Quality was good in four studies. Ongoing BDZ exposure at inception in CHR-P is associated with a higher risk of transition to psychosis at follow up. This meta-analytic association, which echoes a similar effect of baseline antipsychotic exposure, plausibly indicates that the clinicians' prescription of pharmacological intervention captures some form of prognostically-relevant information (e.g. an anxiety permeated mental state requiring BDZ prescription) that are not adequately encompassed by current CHR-P categorical criteria.

Assessment of a modified MINDS-based protocol for management of alcohol withdrawal syndrome on an inpatient medical service.

To determine if a novel symptom-based alcohol withdrawal syndrome (AWS) protocol in a US Veterans cohort leads to significant clinical improvements in patient outcomes and safety. Prior studies of AWS management, oftentimes using the revised version of the Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) index, have demonstrated the effectiveness of symptom-triggered therapy for AWS. The Minnesota Detoxification Scale (MINDS) is an alternative to the CIWA-Ar index but remains unevaluated outside of the intensive care unit (ICU) setting. This study assesses outcomes in AWS management prior to and after the implementation of a novel MINDS-based AWS protocol (SDAWP) utilizing a revised MINDS index (MINDS-rev) in an inpatient medical ward setting. Retrospective cohort study including encounters prior to (n = 342) and after (n = 338) the implementation of the protocol. Pre- and post-protocol encounters were selected by combinations of diagnostic codes and charting elements. Outcome measures of AWS management were obtained in both groups. The primary endpoint was median total benzodiazepine exposure. Secondary outcomes included median length of hospitalization, median duration of benzodiazepine administration, and the incidence of complications. The median total benzodiazepine exposure in the post-SDAWP group was significantly lower than the pre-SDAWP group (21.2 vs. 12.0 mg, p < 0.0001) and for a significantly shorter median duration of time (4.0 vs. 3.0 days, p < 0.0001). There was no significant difference in the median length of stay (4.0 vs. 4.0 days, p = 0.50). The incidence of delirium tremens (21 vs. 7, p = 0.01) and need for transfer to a higher level of care (33 vs. 12, p = 0.002) was significantly lower in the post-SDAWP group. The SDAWP has provided significant improvements in AWS management in our institution and may potentially serve as a template for wider use in other inpatient settings.

The Effect of Preoperative Exposure to Benzodiazepines on Opioid Consumption After One and Two-level Anterior Cervical Discectomy and Fusion.

Retrospective cohort. Investigate the relationship between preoperative benzodiazepine exposure and postoperative opioid use in patients undergoing primary 1 or 2-level anterior cervical discectomy and fusion (ACDF). Little is known about the effect of preoperative benzodiazepine exposure on postoperative opioid use in spine surgery. Patients undergoing primary 1 or 2-level ACDF at a single institution from February 2020 to November 2021 were identified through electronic medical records. The prescription drug monitoring program was utilized to record the name, dosage, and quantity of preoperative benzodiazepines/opioids filled within 60 days before surgery and postoperative opioids 6 months after surgery. Patients were classified as benzodiazepine naïve or exposed according to preoperative usage, and postoperative opioid dose and duration were compared between groups. Regression analysis was performed for outcomes that demonstrated statistical significance, adjusting for preoperative opioid use, age, sex, and body mass index. Sixty-seven patients comprised the benzodiazepine-exposed group whereas 90 comprised the benzodiazepine-naïve group. There was no significant difference in average daily morphine milligram equivalents between groups (median: 96.0 vs 65.0, P = 0.11). The benzodiazepine-exposed group received postoperative opioids for a longer duration (median: 32.0 d vs 12.0 d, P = 0.004) with more prescriptions (median: 2.0 vs 1.0, P = 0.004) and a greater number of pills (median: 110.0 vs 59.0, P = 0.007). On regression analysis, preoperative benzodiazepine use was not significantly associated with postoperative opioid duration [incidence rate ratio (IRR): 0.93, P = 0.74], number of prescriptions (IRR: 1.21, P = 0.16), or number of pills (IRR: 0.89, P = 0.58). While preoperative benzodiazepine users undergoing primary 1 or 2-level ACDF received postoperative opioids for a longer duration compared with a benzodiazepine naïve cohort, preoperative benzodiazepine use did not independently contribute to this observation. These findings provide insight into the relationship between preoperative benzodiazepine use and postoperative opioid consumption. Level III.

Diazepam-Induced Down-Regulation of the GABAA receptor α1 Subunit, as mediated by the activation of L-Type Voltage-Gated calcium Channel/Ca2+/Protein kinase a signaling cascade

Benzodiazepines are among the most prescribed drug class worldwide to treat disorders such as anxiety, insomnia, muscle spasticity, and convulsive disorders, and to induce presurgical sedation. Although benzodiazepines exhibit a high therapeutic index and low toxicity in short-term treatments, prolonged administration induces tolerance to most of their therapeutic actions. The mechanism of this tolerance remains unclear. The central actions of benzodiazepines are mediated by binding to GABAA receptors, which mediate most fast inhibitory transmission in the brain. The majority of GABAA receptors are composed of two α-(1–6), two β-(1–3) and one γ-subunits (1–3). In a previous report, we demonstrated that the prolonged exposure of cerebrocortical neurons to diazepam produces a transcriptional repression of the GABAA receptor α1 subunit gene via a mechanism dependent on the activation of L-type voltage-gated calcium channels (L-VGCCs). The results reported here confirm that the diazepam-induced downregulation of the α1 subunit is contingent upon calcium influx from extracellular space. In addition, this regulatory mechanism involves the activation of protein kinase A (PKA) and is accompanied by the activation of two transcription factors, the cAMP-response element-binding protein (CREB) and the inducible cAMP early repressor (ICER). Together, our results suggest that diazepam s activation of an L-VGCC/Ca2+/PKA/CREB-ICER signaling pathway is responsible for the regulation of GABAA receptors. This elucidation of the intracellular signaling cascade activated by a prolonged benzodiazepine exposure, itself potentially involved in the development of tolerance, may contribute to locating molecular targets for future therapeutic interventions.

Safety of benzodiazepine or Z-hypnotic exposure in early pregnancy

Safety of benzodiazepine or Z-hypnotic exposure in early pregnancy

Maternal and neonatal outcomes after benzodiazepine and benzodiazepine agonist exposure during pregnancy in women with mental disorders.

To compare the gestational age of neonates in utero exposed to benzodiazepines (BDZs) with nonexposed controls. Secondary objectives were birth weight, presence of congenital malformations, APGAR score and the need for >3 months (prolonged) maternal psychiatric care. A retrospective cohort study of women and neonates from 2013 to 2021 with univariate and multivariable analysis to study the associations between BDZ exposure and gestational age compared to nonexposed women with mental health problems. We found that BDZ exposure was not associated with a lower gestational age. We found that women in the exposed group had an increased risk of psychiatric care (adjusted odds ratio 2.58 [95% confidence interval 1.71-3.91], P< .001). We found that in utero BDZ exposure was not associated with a significantly lower gestational age of the neonates and was associated with prolonged psychiatric care of their mothers.

Prescription characteristics associated with drug overdose risk among adults prescribed benzodiazepines: a cohort study

BackgroundDrug overdose (OD) deaths in the U.S. continue to rise. After opioids, benzodiazepines (BZD) are the medication most commonly involved in prescription overdoses, yet OD risk factors among those prescribed BZD are not well understood. Our objective was to examine characteristics of BZD, opioid, and other psychotropic prescriptions associated with increased drug OD risk following a BZD prescription.MethodsWe completed a retrospective cohort study using a 20% sample of Medicare beneficiaries with prescription drug coverage. We identified patients with a BZD prescription (“index”) claim between 1 April 2016 and 31 December 2017. In the 6 months pre-index, those without and with BZD claims comprised incident and continuing cohorts, which were split by age (incident < 65 [n = 105,737], 65 + [n = 385,951]; continuing < 65 [n = 240,358], 65 + [n = 508,230]). Exposures of interest were: average daily dose and days prescribed of the index BZD; baseline BZD medication possession ratio (MPR) for the continuing cohort; co-prescribed opioids and psychotropics. Our primary outcome was a treated drug OD event (including accidental, intentional, undetermined, or adverse effect) within 30 days of the index BZD, examined using Cox proportional hazards.ResultsAmong incident and continuing BZD cohorts, 0.78% and 0.56% experienced an OD event. Compared to 14–30 days, a < 14-day fill corresponded to higher OD risk in incident (< 65 adjusted hazard ratio [aHR] 1.16 [95% CI 1.03–1.31]; 65 + : aHR 1.21 [CI 1.13–1.30]) and continuing (< 65: aHR 1.33 [CI 1.15–1.53]; 65 + : aHR 1.43 [CI 1.30–1.57]) cohorts. Among continuing users, lower baseline exposure (i.e., MPR < 0.5) was associated with increased OD risk for those < 65 (aHR 1.20 [CI 1.06–1.36]); 65 + (aHR 1.12 [CI 1.01–1.24]). Along with opioids, concurrent antipsychotic use and antiepileptic use were associated with elevated risk of OD in all 4 cohorts (e.g., aHRs for the continuing 65 + cohort: opioid, 1.73 [CI 1.58–1.90]; antipsychotic, 1.33 [CI 1.18–1.50]; antiepileptic, 1.18 [1.08–1.30]).ConclusionsIn both the incident and continuing cohorts, patients dispensed fewer days' supply were at increased OD risk; those in the continuing cohort with more limited baseline BZD exposure were also at elevated risk. Concurrent medication exposures including opioids, antipsychotics, and antiepileptics were associated with short-term elevated OD risk.

Gestational Exposure to Benzodiazepines and Z-Hypnotics and the Risk of Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder in Offspring

Two recent cohort studies, one from Norway and the other from Taiwan, examined for perhaps the first time whether gestational exposure to benzodiazepines and to z-hypnotics was associated with a clinical diagnosis of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) in offspring. The studies had important methodological strengths that are not often seen; these included actual assessment during pregnancy of whether drugs prescribed were used, and, if so, when; adjustment of analyses for postbaseline time-varying covariates; inclusion of discordant sibling pair and paternal exposure analyses; inclusion of pre-pregnancy vs intrapregnancy analyses; and others. The studies also had important limitations; these included inadequate statistical power resulting in a failure to identify potential associations in even unadjusted analyses; lack of information on intermittent use vs daily dosing; and others. The strengths and limitations are identified and explained to empower readers to identify similar issues in other studies. Important findings apparent in these studies are that benzodiazepine exposure may be associated with an increased risk of both ASD and ADHD, regardless of the trimester of exposure. The magnitude of increased risk is small and diminishes to statistical nonsignificance in adjusted analyses. The risks appear elevated in association with paternal exposure. In discordant sibling pair analyses, risks do not appear to be significantly higher in the exposed sib relative to the unexposed sib. These findings imply that observed associations, if any, between gestational exposure to benzodiazepines and ASD or ADHD in offspring may be due to maternal and paternal genetic factors, to family environmental variables, and to confounding by indication, rather than to benzodiazepine exposure itself. Nevertheless, decision-making should be tailored to individual context and shared between prescriber and patient. Finally, no conclusions can be drawn regarding the neurodevelopmental safety of z-drug exposure during pregnancy.

Trends in concomitant and single opioid and benzodiazepine exposures reported to the California Poison Control System following the Centers for Disease Control and Prevention release of opioid guidelines in 2016

Introduction In March 2016, the Centers for Disease Control and Prevention released the Guideline for Prescribing Opioids for Chronic Pain, intended for primary care clinicians. One recommendation advised against concurrent prescription of opioids and benzodiazepines. Although existing research suggests a reduction in co-prescribing of these drug classes by clinicians after guideline release, there are limited data assessing its possible effect on patient medical outcomes, such as overdoses. Methods This retrospective observational study analyzed opioid and benzodiazepine exposures, alone or in combination, reported to the California Poison Control System from January 2012 to June 2021. Interrupted time series analyses identified the difference in monthly call volume between pre- and post-guideline release. For exposures resulting in serious medical outcomes, additional analyses assessed trends and identified associated variables. Results There was no significant change in concomitant opioid and benzodiazepine exposures reported to California Poison Control System between pre- and post-guideline release. Compared to pre-guideline release, exposures to a single opioid or to a single benzodiazepine significantly decreased by 1.07 (95% CI: −1.62, −0.51) and 1.82 (95% CI: −2.33, −1.31) calls per month, respectively, after the guideline release. For exposure calls associated with serious medical outcomes, there was a significant increase of 0.11 (95% CI: 0.04, 0.18) and 0.2 (95% CI: 0.05, 0.34) calls per month for concomitant opioid and benzodiazepine and single opioid exposures, respectively, following guideline release. Discussion The guideline release appeared to have a variable association with exposures to single opioid, single benzodiazepines, and concomitant opioid and benzodiazepine cases reported to California Poison Control System. Although exposures to opioids or benzodiazepines alone significantly decreased after guideline release, there was no significant change in concomitant exposures. Additionally, for exposures associated with serious medical outcomes, concomitant exposures, and single opioid exposures significantly increased following guideline release. Conclusion Our results suggest that the guideline was not associated with a corresponding decrease in the number of concomitant poisoning exposures reported to California Poison Control System. Additional interventions may be needed to reduce concomitant exposures to opioids and benzodiazepines.

Maternal Benzodiazepines and Z-Drugs Use during Pregnancy and Adverse Birth and Neurodevelopmental Outcomes in Offspring: A Population-Based Cohort Study

Introduction: The use of benzodiazepines and/or z-drugs in women of childbearing age has increased. Objective: The aim of the study was to evaluate whether gestational benzodiazepine and/or z-drug exposure is associated with adverse birth and neurodevelopmental outcomes. Methods: A population-based cohort including mother-child pairs from 2001 to 2018 in Hong Kong was analysed to compare gestationally exposed and nonexposed children on the risk of preterm birth, small for gestational age, autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD) through logistic/Cox proportional hazards regression with a 95% confidence interval (CI). Sibling-matched analyses and negative control analyses were applied. Results: When comparing gestationally exposed with gestationally nonexposed children, the weighted odds ratio (wOR) was 1.10 (95% CI = 0.97–1.25) for preterm birth and 1.03 (95% CI = 0.76–1.39) for small for gestational age, while the weighted hazard ratio (wHR) was 1.40 (95% CI = 1.13–1.73) for ASD and 1.15 (95% CI = 0.94–1.40) for ADHD. Sibling-matched analyses showed no association between gestationally exposed children and their gestationally nonexposed siblings for all outcomes (preterm birth: wOR = 0.84, 95% CI = 0.66–1.06; small for gestational age: wOR = 1.02, 95% CI = 0.50–2.09; ASD: wHR = 1.10, 95% CI = 0.70–1.72; ADHD: wHR = 1.04, 95% CI = 0.57–1.90). Similarly, no significant differences were observed when comparing children whose mothers took benzodiazepines and/or z-drugs during pregnancy to children whose mothers took benzodiazepines and/or z-drugs before but not during pregnancy for all outcomes. Conclusions: The findings do not support a causal relationship between gestational benzodiazepines and/or z-drugs exposure and preterm birth, small for gestational age, ASD, or ADHD. Clinicians and pregnant women should carefully balance the known risks of benzodiazepines and/or z-drugs use against those of untreated anxiety and sleep problems.

Study suggests little risk of childhood ADHD from benzodiazepine exposure

The Brown University Psychopharmacology UpdateVolume 34, Issue 4 p. 8-8 Research Roundup Study suggests little risk of childhood ADHD from benzodiazepine exposure First published: 03 March 2023 https://doi.org/10.1002/pu.31003Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume34, Issue4April 2023Pages 8-8 RelatedInformation

Relationship between clock gene expression and CYP2C19 and CYP3A4 with benzodiazepines.

The present study aimed to clarify the expressions and roles of clock genes involved in drug metabolism in patients taking benzodiazepines (BZDs), as well as the drug metabolism regulators controlled by clock genes for each BZD type. The relationships between the expressions of the clock genes BMAL1, PER2, and DBP and the drug-metabolizing enzymes CYP3A4 and CYP2C19 were investigated using livers from BZD-detected autopsy cases. In addition, the effect of BZD exposure on various genes was examined in HepG2 human hepatocellular carcinoma cells. The expressions of DBP, CYP3A4, and CYP2C19 in the liver were lower in the diazepam-detected group than in the non-detected group. Furthermore, BMAL1 expression correlated with CYP2C19 expression. Cell culture experiments showed that the expressions of DBP and CYP3A4 decreased, whereas those of BMAL1 and CYP2C19 increased after diazepam and midazolam exposure. The results of the analyses of autopsy samples and cultured cells suggested that DBP regulates CYP3A4 when exposed to BZD. Understanding the relationship between these clock genes and CYPs may help achieve individualized drug therapy.