Concomitant Use Of Benzodiazepines Research Articles

Risk Factors for Respiratory Depression Associated with Tramadol Based on the Global Pharmacovigilance Database (VigiBase).

Tramadol, a weak μ-opioid receptor agonist, has been used worldwide for pain management. It is considered to have a favorable safety profile without serious adverse events; however, safety issues of respiratory depression were proposed by regulatory governments. We aimed to examine the risk and contributing factors associated with tramadol-related respiratory depression using a real-world database, VigiBase. Disproportionality analysis of tramadol and tramadol/paracetamol was performed using proportional reporting ratios, reporting odds ratios, and information components for all drugs and opioids. Factors related to respiratory depression, including sex, age, presence of abuse, death, and various concomitant medications, were evaluated. Among 140,721 tramadol reports, respiratory depression was reported in 1126 cases, 81.3% of which were deemed serious. Five adverse events were detected as signals of tramadol-related acute central respiratory depression (ACRD) in 882 reports. A higher proportion of ACRD cases in children and adolescents was observed than all adverse events cases of tramadol. Concomitant users of CYP2D6 inhibitors, opioids, benzodiazepines, and anti-depressant drugs showed a higher proportion in ACRD cases than non-ACRD cases. ACRD was related to drug abuse and death. This pharmacovigilance study, using VigiBase, confirmed a high risk of respiratory depression (a serious, potentially fatal adverse event) secondary to the use of tramadol, especially in pediatric patients, drug abusers, or during concomitant use of opioids, benzodiazepines, or antidepressants.

Do benzodiazepines reduce the efficacy of transcranial magnetic stimulation?

To investigate the effect of concomitant use of benzodiazepines on the efficacy of repetitive transcranial magnetic stimulation (rTMS) in patients with treatment-resistant major depressive disorder (TR-MDD). This is a retrospective study comparing rTMS treatment outcomes between patients taking benzodiazepines (n = 59) and those who were not (n = 136). Participants completed the HAM-A, HAM-D17, MADRS and ZUNG at baseline and at the end of treatment. Patients taking benzodiazepines during rTMS treatment did not show any difference in partial response, response or remission rates compared to patients not treated with benzodiazepines. There was a significant decrease (p < .0001) in depression and anxiety scores from baseline to post-treatment among both groups. Concomitant benzodiazepine treatment had no effect on the efficacy of rTMS treatment of TRD, contrary to previous research.

Take-Home Naloxone Access and Use among Older Adults Living with Pain: A Scoping Review.

Opioids are a common treatment for older adults living with pain. Given high rates of polypharmacy and chronic comorbidities, older adults are at risk of opioid overdose. Evidence is now available that take-home naloxone (THN) supports reduction of opioid-related harms. It is unknown what THN initiatives are available for older adults, especially those living with chronic pain. To summarize the literature regarding THN, with a focus on older adults using opioids for pain, including facilitators of and barriers to THN access, knowledge gaps, and pharmacist-led initiatives. A scoping review, guided by an established framework and PRISMA-ScR guidelines, was performed. Methods involved searching 6 bibliographic databases (MEDLINE, Embase, Scopus, APA PsycINFO, Web of Science Core Collection, and PubMed), reference harvesting, and citation tracking. Searches were conducted up to March 2023, with no date limits applied; only English publications were included. Study eligibility was determined according to preset criteria, including age; discrepancies were resolved by discussion and consensus. Data were extracted and categorized through thematic analysis. Four studies met the eligibility criteria. All 4 studies detailed THN programs in primary care settings involving older adults taking opioids for pain management. Two of the studies highlighted patient-specific risk factors for opioid overdose, including concomitant use of benzodiazepines and/or gabapentinoids, mean morphine milligram equivalents per day of at least 50, and previous opioid overdose. Two of the studies assessed patient knowledge of opioid overdose management and attitudes toward THN. Educational programs increased patients' interest in THN. The literature about THN for older adults living with pain is limited, and no literature was found on pharmacist-led initiatives in this area. Future research on THN provision for older adults, including pharmacist-led initiatives, could help to optimize care for older adults living with pain.

Productivity Loss Among Opioid and Benzodiazepine Users in the United States: A Medical Expenditure Panel Survey From 2010 to 2019.

The aim of the study is to estimate the association between productivity losses and the use of prescription opioids and benzodiazepines among employed US adults with painful conditions. Using Medical Expenditures Panel Survey (2010-2019), we used two-part (logistic regression and generalized linear model with zero-truncated negative binomial link) model to compare missed workdays due to illness or injury among employed adults with a painful condition. Of the eligible sample of 57,413 working US individuals, 14.65% were prescription opioid users, 2.95% were benzodiazepine users, and 1.59% were both opioid and benzodiazepine users. The predicted missed workdays were 5.75 (95% Confidence Limit [CL]: 5.58-5.92) days for benzodiazepine users, 13.06 (95% CL: 12.88-13.23) days among opioid users, and 15.18 (95% CL: 14.46-15.90) days for opioid and benzodiazepine concomitant users. Concomitant use of prescription opioids and benzodiazepines was significantly associated with having more missed workdays among employed adults with documented painful conditions.

Augmenting the efficacy of benzodiazepine taper with telehealth-delivered cognitive behavioral therapy for anxiety disorders in patients using prescription opioids: A pilot randomized controlled trial

The risks of concomitant benzodiazepine (BZ) and opioid use are significant. Despite the urgent need to reduce BZ use among patients taking opioids, no treatment intervention research to our knowledge has addressed treatment for this concurrent, high-risk use. The current study will evaluate the efficacy of augmenting BZ taper procedures with CBT for anxiety disorders that has been adapted specifically for patients with concomitant BZ and opioid use (either use as prescribed or misuse), a high-risk patient population. Research combining rapidly scalable behavioral interventions ancillary to pharmacological approaches delivered via telehealth in primary care settings is innovative and important given concerning trends in rising prevalence of BZ/opioid co-prescription, BZ-associated overdose deaths, and known barriers to implementation of behavioral health interventions in primary care. CBT delivery using telehealth has the potential to aid adherence and promote access and dissemination of procedures in primary care. Lastly, the current study will utilize an experimental therapeutics approach to preliminarily explore the mechanism of action for the proposed interventions. The overall aim of the present pilot randomized controlled trial is to examine the feasibility and preliminary efficacy of a BZ taper with CBT for anxiety disorders adapted for patients with concomitant BZ (BZT + CBT) and opioid use to a BZ taper with a control health education program (BZT + HE) in a sample of individuals (N = 54) who have been prescribed and are taking benzodiazepines and opioids for at least 3 months prior to baseline and experience anxious distress. Screening and outcome measures, methods, and implications are described.Trial Registration: ClinicalTrials.gov (NCT05573906).

Opioid and Benzodiazepine Co-Prescribing Trends from the Emergency Department from 2012 to 2019: A National Analysis

BackgroundIn 2016, the U.S. Food and Drug Administration (FDA) issued its strongest safety warning (“Black Box Warning”) for concomitant use of prescription opioids and benzodiazepines due to overdose deaths. ObjectiveOur objective was to look at trends of opioid and benzodiazepine co-prescribing in the emergency department (ED) using national data, because recent data are sparse. MethodsThis is a retrospective review of data collected by the National Hospital Ambulatory Medical Care Survey between 2012 and 2019. Our primary outcome was to determine whether there was a trend in ED visits when opioids and benzodiazepines were co-prescribed at discharge. We also compared the rate of visits when co-prescribing occurred before (2012–2015) and after (2017–2019) the 2016 FDA warning. We identified commonly co-prescribed benzodiazepines and opioids, and the rate of naloxone co-prescribing. We used descriptive statistics and bivariate tests to describe data. ResultsBetween 2012 and 2019, there were 4,489,613 ED visits (0.41% of ED visits) when benzodiazepines and opioids were co-prescribed. There was no trend in the rate of co-prescribing overall, but a decrease in visits after the 2016 FDA Black Box Warning (2012–2015: mean 0.49%; 2017–2019: mean 0.29%; p < 0.0001). There were 7980 ED visits (0.18%) when naloxone was co-prescribed for these visits within this time frame and an increase over time (p < 0.001). ConclusionsOur study found that between 2012 and 2019, there was no overall reduction in co-prescribing of opioids and benzodiazepines across EDs nationwide, but a decrease after the 2016 Black Box Warning.

Association between initial clozapine titration and pneumonia risk among patients with schizophrenia in a Korean tertiary hospital.

Pneumonia is a significant adverse drug reaction (ADR) associated with clozapine, characterized by high mortality and potential linkage with other inflammatory responses. Despite the critical nature, research regarding the development of pneumonia during initial clozapine titration remains limited. This retrospective study included 1408 Korean inpatients with schizophrenia spectrum disorders. Data were collected from January 2000 to January 2023. Pneumonia developed in 3.5% of patients within 8weeks of clozapine initiation. Patients who developed pneumonia were taking a greater number and higher dose of antipsychotics at baseline (2.14 vs. 1.58, p<0.001; 25.64 vs. 19.34, p=0.012). The average onset occurred 17.24days after initiation, on an average dose of 151.28mg/day. Titration was either paused or slowed in most of these patients, with no reported fatalities. The types of pneumonia included aspiration pneumonia, mycoplasma pneumonia, bronchopneumonia, and COVID-19 pneumonia. Myocarditis, drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, and urinary tract infections were also identified. Logistic regression analysis revealed that a greater number of concomitant antipsychotics (odds ratio [OR]=1.59, p=0.027) and concomitant benzodiazepine use (OR=2.33, p=0.005) at baseline were associated with an increased risk of pneumonia. Overall, pneumonia development during clozapine titration is linked with other inflammatory ADRs, suggesting a shared immunological mechanism. Close monitoring is recommended, especially for patients taking multiple antipsychotics and benzodiazepines. Further studies involving repeated measures of clozapine concentrations at trough and steady state, along with a more detailed description of pneumonia types, are warranted.

Prevalence and Risk Factors for Iatrogenic Opioid Withdrawal in Medical Critical Care Patients.

To identify the and risk factors for IWS in adult patients admitted to critical care medicine services who received greater than or equal to 24 hours of continuous opioid infusion therapy. A prospective, observational study was conducted in a tertiary care hospital in adult medical ICU patients. Ninety-two patients who received greater than or equal to 24 hours of continuous opioid infusions were included in the study. Patients were assessed daily after opioid infusion discontinuation using the Clinical Opiate Withdrawal Scale (COWS) and the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) opioid withdrawal criteria for a maximum of 5 days. The primary outcome was the prevalence of IWS of moderate severity or greater using COWS. Secondary outcomes included the prevalence of IWS diagnosis of any severity based on COWS, the prevalence of IWS diagnosis based on a positive DSM-V score, and the identification of potential risk factors for developing IWS of any severity. Four hundred forty-seven patients received greater than or equal to 24 hours of continuous opioid therapy. Of these, 385 were excluded, leaving 92 patients included in the final analysis. Except for a higher prevalence of psychiatric history in the IWS-positive group, baseline characteristics were similar. Overall, 11 patients (12%) developed IWS of moderate severity or greater, based on COWS. The IWS-positive group also had longer durations of opioid infusions, higher cumulative opioid infusion doses, higher mean daily doses, and higher infusion rates at any given time. The concomitant use of dexmedetomidine (38.3 vs 15.6%, p = 0.014) and benzodiazepines (63.8 vs 37.8%, p = 0.021) during or after the opioid infusion were significantly higher in the IWS-positive group compared with the IWS-negative group. No significant differences were found between the two groups for scheduled or as needed opioids after cessation of the opioid infusion. Continuous opioid infusions greater than or equal to 72 hours and total daily dose greater than or equal to 1,200 μg were found to be independent predictors for the development of iatrogenic opioid withdrawal via logistic regression. Approximately one in every eight patients receiving continuous infusion opioid for greater than 24 hours while mechanically ventilated in the medical ICU will develop IWS of moderate severity or greater; this increases to one in three patients diagnosed with DSM-V criteria or any level of IWS severity. Patients receiving opioid infusions greater than or equal to 72 hours, or a total daily fentanyl dose of greater than or equal to 1,200 μg (~ 50 μg/hr) are at a higher risk for developing IWS and should be monitored as part of clinical practice when opioid infusions are discontinued.

Benzodiazepine Dose Intensity among Patients Concurrently Prescribed Buprenorphine in Rhode Island

Background: The concomitant use of buprenorphine and benzodiazepines has been linked to patient fatalities, with greater risk occurring with higher doses of benzodiazepines. We assessed benzodiazepine dose intensity among patients who were concurrently prescribed buprenorphine, as compared with patients prescribed benzodiazepines who were not receiving buprenorphine. Methods : We conducted a cross-sectional analysis of adult patients who received at least a 30-day supply of benzodiazepines during 2018, using data from the Rhode Island (RI) Prescription Drug Monitoring Program. Mean daily diazepam milligram equivalents (DME) were calculated overall and according to patient sex, age group, payment type, and RI county. Multivariable logistic regression analyses were conducted to assess the odds of higher-dose benzodiazepine utilization among patients with concurrent use of buprenorphine, as compared with patients not prescribed buprenorphine, adjusting for patient demographics. Results : Compared to patients prescribed benzodiazepines who were not receiving buprenorphine, those with concurrent buprenorphine utilization had a significantly higher mean DME/day (19.22, 95% CI: 18.70-19.74; vs 10.94, 95% CI: 10.93-10.95; p < 0.001). Patients who were prescribed benzodiazepines with concurrent utilization of buprenorphine also had a comparatively higher odds of a DME/day ≥15 (aOR: 2.86, 95% CI: 2.63-3.10), ≥20 DME/day (aOR: 2.98, 95% CI: 2.75-3.24), and ≥25 DME/day (aOR: 2.99, 95% CI: 2.65-3.18). Conclusion : Compared to patients prescribed benzodiazepines for at least 30 days who were not receiving buprenorphine, patients concurrently utilizing benzodiazepines and buprenorphine had more than twice the odds of higher dose benzodiazepine utilization. Future studies are needed to assess the relationship between benzodiazepine dose intensity, overdose outcomes, and treatment retention among patients receiving buprenorphine.

Oral buprenorphine utilization, concomitant benzodiazepines and opioid analgesics, and payment source: Trends from 2015 to 2019

IntroductionThis study describes utilization patterns of oral buprenorphine products indicated for the treatment of opioid use disorder with a focus on patterns consistent with prescribing guidelines and the safe use conditions during induction and maintenance treatment outlined by the Risk Evaluation and Mitigation Strategy (REMS) Program, including trends over time. MethodsUsing an anonymized longitudinal patient-level dataset that captures information on medical and pharmacy claims in the United States (October 1, 2014 through March 31, 2020), buprenorphine prescriptions, days' supply, and daily dose were described overall and stratified by induction (month 1) vs. maintenance (month 2–6) treatment, along with duration of concomitant benzodiazepines or opioid analgesics. ResultsOverall, there were 1.5 million buprenorphine treatment episodes initiated between January 1, 2015 to September 30, 2019 (2015: 258,899; 2019: 351,378). Treatment episodes included an average of 6.8 buprenorphine prescriptions (standard deviation [SD] = 6.7), 16.8 days' supply per prescription (SD = 10.5), 94.2 total days' supply per treatment episode (SD = 71.4), and a mean daily dose of 13.6 mg (SD = 6.3), with the number of prescriptions and total days' supply per treatment episode declining over the study period. There was a lower mean number of days' supply per prescription in the first month of treatment compared to months 2–6 (month 1: 15.8 [SD = 11.0]; month 2–6: 19.0 [SD = 10.1]) and daily dose per prescription (month 1: 13.3 mg [SD = 6.4]; months 2–6: 14.3 mg [SD = 6.2]), and a higher mean number of prescriptions per month (month 1: 2.5 per month [SD = 1.7]; months 2–6: 1.8 per month [SD = 1.2]). From 2015 to 2019, there appeared to be a shift in payer mix, with increases in Medicaid/Medicare and declines in cash and commercial insurance. Concomitant benzodiazepine and opioid analgesic use declined over time; in 2019, 16.6 % and 14.3 % of treatment episodes had any concomitant benzodiazepine or opioid analgesic, respectively, and <5 % had chronic (>90 overlapping days) concomitant use (3.0 % and 0.4 %, respectively). ConclusionsThe number of oral buprenorphine treatment episodes increased over the study period, and prescribing was generally consistent with the REMS and other treatment guidelines. There was a decline in concomitant buprenorphine and benzodiazepine or opioid analgesics, and chronic concomitant use was rare.

The effect of opioid analgesics, benzodiazepines, gabapentinoids, and opioid agonist treatment on mortality risk among opioid-dependent people.

BackgroundAs dispensings for benzodiazepines and gabapentinoids have increased in recent years, risk of increased mortality has been identified, particularly when used with opioids. There is limited research examining use of these medicines among people with opioid dependence and whether mortality risk varies according to opioid agonist treatment (OAT) status. This study characterizes patterns of opioid analgesic utilization and concomitant use of benzodiazepines, gabapentinoids and OAT among people with opioid dependence initiating opioid analgesics. It also assesses mortality risk associated with exposure to these medicines.&#x0D; MethodsRetrospective cohort study in New South Wales, Australia, including 28,891 people with documented opioid dependence initiating opioid analgesics between July 2003 and December 2018. Linked administrative records provided data on prescription dispensings, sociodemographics, clinical characteristics, OAT and mortality. Generalised estimating equation models estimated incidence rate ratios (IRR) comparing periods in and out of OAT for the number of opioid analgesic dispensings. Periods of concomitant use of opioid analgesics, benzodiazepines, gabapentinoids, and OAT were identified. Cox models assessed associations between concomitant medicines use with mortality risk.&#x0D; ResultsAt the time of opioid analgesic initiation, 43.7% of the cohort were in OAT. The most commonly initiated opioid was codeine (67.8%). In the 90 days prior to the index opioid dispensing, benzodiazepines were more frequently dispensed than gabapentinoids, but rates varied over time. Between 2004 and 2018, benzodiazepine dispensings decreased (41.7% to 21.1%) while gabapentinoid dispensings increased (0.2% to 7.9%). Incidence of opioid analgesic dispensings was higher during periods out of OAT compared to in OAT (5.8 v. 2.3 per person-year; IRR 0.39, 95% CI 0.38, 0.41). Analyses investigating associations between medicine exposure and mortality are ongoing.&#x0D; ConclusionPeople with opioid dependence had high rates of recent benzodiazepine utilization and current OAT enrollment at the time of opioid analgesic initiation. OAT was associated with a significant reduction in opioid analgesic prescribing.

Concomitant medication use and its implications on the hazard pattern in pharmacoepidemiological studies: example of antidepressants, benzodiazepines and fracture risk

Background: Antidepressants and benzodiazepines are often co-prescribed and both associated with an increased fracture risk, albeit with distinctive hazard patterns. Timing of initiation of one with respect to the other and duration of use may influence the combined fracture hazard.&#x0D; The objective of our study was to describe patterns of concomitant use of benzodiazepine and antidepressants in terms of timing of initiation and duration and to illustrate the potential impact of various scenarios of timing of co-use on hip fracture hazard.&#x0D; Methods: Patients initiating antidepressant therapy (2002-2009) were identified from the Netherlands Primary Care Research Database. Concomitant benzodiazepine use was assessed according to the start time of benzodiazepine with respect to antidepressant therapy start. Duration of concomitant use was estimated relative to the length of antidepressant treatment episode. &#x0D; Results: Among 16,087 incident antidepressant users, 39.0% used benzodiazepines concomitantly during their first antidepressant treatment episode. The time of initiation of benzodiazepine use was variable (64.4% starting before, 13.7% simultaneous and 21.9% after antidepressants). Duration of concomitant use in the three groups varied. &#x0D; Conclusions: Co-prescribed medications with a common adverse event, may not only require accounting for concomitant use, but also the timing of start and duration of use as the overall hazard may vary accordingly.&#x0D;

Characteristics of and Experience Among People Who Use Take-Home Naloxone in Skåne County, Sweden.

BackgroundOpioid overdose related injury or death can be prevented by bystander naloxone administration. For naloxone to be present when and where overdoses occur, opioid prevention education and naloxone distribution (OPEND) must be established on a broad level. This is the 30-month follow-up of the first multi-site naloxone project in Sweden, implemented at 31 sites in the County of Skåne 2018.AimTo address participant characteristics and factors associated with returning for naloxone refill and with having used naloxone for overdose reversal. An additional aim was to describe self-reported reasons for naloxone refill and overdose experiences.MethodsData were collected during June 2018—December 2020 through questionnaires at baseline and upon naloxone refill of the initial and subsequent naloxone kit. Descriptive statistics was used to address participant characteristics, those returning for naloxone refill and reporting overdose reversal. Chi-2 test was used for variable comparison between groups. Factors associated with overdose reversals were examined by logistic regression analysis. Reasons for naloxone refill, overdose situation and management were presented descriptively.ResultsAmong 1,079 study participants, 22% (n = 235) returned for naloxone refill, of which 60% (n = 140) reported a total of 229 overdose reversals. Reversals were more likely to be reported by participants trained at needle exchange programs (NEPs) [adjusted odds ratio (AOR) = 5.18, 95% Confidence interval (CI) = 3.38–7.95)], with previous experience of own (AOR = 1.63, 95% CI = 1.03–2.58) or witnessed (AOR = 2.12, 95% CI = 1.05–4.29) overdose, or who had used sedatives during the last 30 days before initial training (AOR = 1.56, 95% CI = 1.04–2.33). A majority of overdoses reportedly occurred in private settings (62%), where the victim was a friend (35%) or acquaintance (31%) of the rescuer.ConclusionParticipants with own risk factors associated with overdose (e.g., injection use, concomitant use of benzodiazepines and previous experience of own overdose) were more likely to report administering naloxone for overdose reversal. Overdose management knowledge was high. The findings indicate that implementation of multi-site OPEND reaches individuals at particularly high risk of own overdose in settings with limited previous harm reduction strategies and favors a further scaling up of naloxone programs in similar settings.

Leveraging the Prescription Drug Monitoring Program to Curb Opioid Prescribing in Arkansas.

Effective means of accurately identifying problematic opioid prescribing are needed. Using an iterative approach with the Arkansas State Medical Board Pain Subcommittee, we modified existing opioid prescriber criteria to create seven metrics to be deployed in Arkansas. These included metrics of dose and days' supply, concomitant use of opioid and benzodiazepines, solid dosage units, and numbers of opioid patients and certain opioid prescriptions. Two of these metrics (average MME daily dose per prescription and total oxycodone 30mg or hydromorphone prescriptions) were weighted by 2, creating a maximum score of 9 of which each prescriber could receive. Twenty prescribers with a score of 7 or greater were identified and referred to the Arkansas State Medical Board Pain Subcommittee for review and subsequent investigation if deemed necessary. Of those 20 prescribers, four were previously investigated and under disciplinary action, and three were under current investigation for misconduct related to prescribing practices. Five prescribers had new investigations opened due to the findings from the metrics, and disciplinary action was taken. Therefore, 12 of the 20 prescribers referred to the Arkansas State Medical Board were deemed worthy of investigation and disciplinary action. The Arkansas opioid prescriber metrics are able to accurately identify prescribers with potentially problematic opioid prescribing.

Short-term, but not long-term, beneficial effects of concomitant benzodiazepine use on clinical course in patients with schizophrenia.

This study aims to examine possible differences in the effect on the course characteristics of the disease in cases of no use, short-term use and long-term use of benzodiazepines in patients with schizophrenia. In this retrospective observational study, the sample comprised patients with schizophrenia who were admitted to our psychiatric clinics from January 2015 to January 2019. Patients were also retrospectively tracked from the date of the first admission during the specified time until the end of the observation period (24 months) for clinical course characteristics. Data for 1710 patients with schizophrenia were included in the analyses. Patients with short-term benzodiazepines use had fewer psychiatric hospitalizations and shorter lengths of stay at psychiatric services than patients with no use or long-term use. Rates of antipsychotic drug discontinuation and suicidal behavior were also significantly lower among short-term benzodiazepines users than among those with no use or long-term use. In conclusion, our study indicates that short-term benzodiazepines use is associated with a better clinical course in patients with schizophrenia. Future studies should evaluate the effects of different benzodiazepines use patterns on disease prognosis with longer-term follow-up and prospective methodology and should concomitantly examine psychopathological variables.

The Safety of Benzodiazepines and Opioids in the Geriatric Population: An Analysis of Patient Safety Events Reported by Hospitals and Ambulatory Surgical Facilities

Benzodiazepines may increase the risk of cognitive impairment, delirium, falls, fractures, and motor vehicle crashes in patients 65 years and older. The concomitant use of benzodiazepines and opioids may also be inappropriate for older adults due to the increased risk of overdose. We searched the Pennsylvania Patient Safety Reporting System (PA-PSRS) for reports of patient safety events related to the concomitant use of benzodiazepines and opioids in older adults in order to gain a better understanding of the potential risks of using these medications in combination. We identified 80 reports in which a patient may have experienced an adverse drug reaction (ADR) to the combined use of a benzodiazepine and an opioid pain medication. Reports were reviewed to determine the ADR(s) experienced by the patient. Changes in mental status were most common, occurring in more than two-thirds of reports (68.8%; 55 of 80), followed by respiratory reactions (51.3%; 41 of 80) and cardiovascular reactions (25.0%; 20 of 80). In over two-thirds of reports (70.0%; 56 of 80), the patient received a reversal agent, either flumazenil (10.7%; 6 of 56) or naloxone (35.7%; 20 of 56), or both (53.6%; 30 of 56). The inappropriate use of benzodiazepines and opioid pain medications in combination among patients 65 years and older is a growing problem, and an increased awareness may be the first step for providers to begin addressing it.

Risk of fracture in antidepressant users with concurrent use of benzodiazepines: A self-controlled case-series analysis.

Despite the fracture risk associated with both antidepressant (AD) medication and benzodiazepines (BDZs), they are commonly prescribed simultaneously. However, studies elucidating the effects of concurrent use of BDZs and ADs on the risk fracture are scant. The objective of this study was to evaluate the risk of fracture associated with concurrent use of BDZs in AD users, using a self-controlled case-series analysis. A self-controlled case-series analysis, in which the participants act as their own control, was conducted using the Korean National Health Insurance Service-National Sample Cohort database (2002-2015). We studied AD users who were prescribed BDZs and diagnosed with a fracture. The risk periods were subdivided into consecutive periods (1-30, 31-60, and>60days) after receiving a BDZ. A 2-week pre-exposure period and a 2-week post-exposure period were also included. The incidence rate ratio (IRR) was estimated after adjusting for age and use of co-medications. A total of 3020 patients were identified during the study period. There was an increased fracture risk in the first 30days following BDZ use (IRR: 1.88, 95% confidence interval [CI] 1.66-2.12), in the 31-60-day period (1.73, 95% CI 1.48-2.02), and beyond the 60-day period (IRR: 1.68, 95% CI 1.47-1.91). The risks of fracture were greater in men and older patients. The concomitant use of BDZs and ADs was related to a significant increase in fracture risk. AD users should be aware of the fracture risk with concomitant BDZ use, especially for first-time BDZ users and for elderly patients.

Concomitant opioid and benzodiazepine use and risk of suicide attempt and intentional self-harm: Pharmacoepidemiologic study

BackgroundOverdose due to concomitant use of opioids and benzodiazepines has been raised as a major public health concern, although little research has examined whether this risk extends to intentional overdose or other self-harm. This study examined whether prescription opioids and benzodiazepines interact to increase the rate of suicide attempt and intentional self-harm. MethodsThe study analyzed 4,762,438 users of opioids, benzodiazepines, both drugs concomitantly, or neither drug from the MarketScan Commercial Claims and Encounters databases (2014–2016). The four groups were matched using inverse probability of treatment weighting and a difference in difference design was used to examine associations with risk of suicide attempt, intentional self-harm and drug overdose, including suicide death resulting in a medical claim. ResultsThere was a small association for opioids (HR=1.23; 95% CI 1.06–1.43) but a larger association for benzodiazepines (HR=2.55; 95% CI 2.12–3.05) with suicide attempt, intentional self-harm, and drug overdose. The medication interaction was opposite to the expected direction (HR=0.70; 95% CI 0.55–0.89), indicating that risk associated with concomitant use was lower than would be expected on an additive basis. Sensitivity analyses found no evidence of increased risk due to interaction between the two drug classes. ConclusionsIncreased risk of suicide attempt, intentional self-harm and drug overdose for concomitant use of opioids and benzodiazepines is in large part attributable to benzodiazepine use alone. In typically prescribed quantities, opioids and benzodiazepines may not represent a drug interaction in terms of yielding increased risk of suicide attempt and intentional self-harm resulting in medical care.

SY19-2 Delirium before the last days of life

Delirium occurs in approximately 90% of patients in the last days of life. Pharmacotherapy, mainly antipsychotics, has been generally recommended to palliate delirium-related symptoms. However, recent randomized placebo-controlled trials have questioned its effectiveness. For example, in terminally ill cancer patients with mild to moderate delirium and advanced cancer patients with hypoactive delirium, symptoms of delirium were rather more likely to deteriorate after starting pharmacotherapy (Agar M, et al. JAMA Intern Med 177(1):34-42, 2017; Okuyama T, et al. Oncologist. 24(7):e574-e582, 2019). From these results, for those with hypoactive delirium or mild to moderate delirium, comprehensive measure other than pharmacotherapy is recommended: 1) treatment of any potentially reversible causes such as infections, hypercalcemia, polypharmacy, and opioid neurotoxicity, 2) non-pharmacological measures including orientation cues, window light, efforts to minimize unnecessary stimuli, and caregiver education, and 3) total symptom management. On the other hand, in patients with severe agitated delirium, sedative neuroleptics such as chlorpromazine and concomitant use of benzodiazepine may reduce agitation in patients in the last days (Hui D, et al. Lancet Oncol. 21(7):989-998, 2020).

Effect of Concomitant Benzodiazepine Use on Efficacy and Safety of Esketamine Nasal Spray in Patients with Major Depressive Disorder and Acute Suicidal Ideation or Behavior: Pooled Randomized, Controlled Trials

PurposeThe impact of benzodiazepines on the efficacy and safety of esketamine as a rapid-acting antidepressant remains unclear.Materials and MethodsData from two identically designed, randomized double-blind studies were pooled and analyzed on a post-hoc basis. In both studies, adults with major depressive disorder with acute suicidal ideation or behavior were randomized to placebo or esketamine 84 mg nasal spray twice-weekly for 4 weeks, each with comprehensive standard-of-care (initial hospitalization and newly initiated or optimized oral antidepressant[s]). Efficacy and safety were analyzed in two groups based on whether patients used concomitant benzodiazepines, which were prohibited within 8 hours before and 4 hours after the first dose of esketamine and within 8 hours of the primary efficacy assessment at 24 hours. The primary efficacy endpoint – change from baseline to 24 hours post-first dose in Montgomery-Asberg Depression Rating Scale (MADRS) total score – was analyzed using ANCOVA.ResultsMost patients (309/451, 68.5%) used concomitant benzodiazepines. Greater decrease in MADRS total score was observed with esketamine (mean [SD]: −16.1 [11.73]) versus placebo (−12.6 [10.56]) at 24 hours (least-squares mean difference: −3.7, 95% CI: −5.76, −1.59). The differences between the esketamine and placebo groups were clinically meaningful, irrespective of benzodiazepine use (benzodiazepine: −4.3 [−6.63, −1.89]; no benzodiazepine: −3.1 [−6.62, 0.45]). Among patients taking esketamine, change in MADRS total score was not significantly different between patients taking benzodiazepines (−15.8 [11.27]) versus those not taking benzodiazepines (−16.8 [12.82]) (least-squares mean difference: 1.1, [−2.24, 4.45]). Among esketamine-treated patients, the incidence of sedation was higher with benzodiazepine use, whereas dissociation was similar.ConclusionBenzodiazepines do not meaningfully affect the rapid-acting antidepressant effect of esketamine at 24 hours post-first dose among patients with MDD and acute suicidal ideation or behavior.