Non-benzodiazepine Sedative-hypnotics Research Articles

Lifetime Psychotropic Medication Use Among Service Members and Veterans With and Without History of Mild Traumatic Brain Injury: A Pilot Study.

Military Service Members, Veterans, and other patient populations who experience traumatic brain injury (TBI) may have increased risk of early neurodegenerative diseases relative to those without TBI history. Some evidence suggests that exposure to psychotropic medications may play a role in this association. The Long-term Impact of Military-relevant Brain Injury Consortium-Chronic Effects of Neurotrauma Consortium (LIMBIC-CENC) prospective longitudinal study provides an ideal setting to examine the effects of psychotropic medication exposure on long-term neurological health of those with and without mild TBI history. In this study, we sought to develop and pilot test a self-report electronic survey instrument to measure participants' psychotropic medication histories for use across LIMBIC-CENC study sites. We developed a new survey instrument measuring psychotropic medication history and fielded it among Service Members and Veterans enrolled in a single site of the LIMBIC-CENC study to evaluate response rates and patterns, and to compare survey responses to prescription data extracted from participants' Veterans Affair (VA) records. Descriptive statistics estimated survey respondents' lifetime psychotropic medication exposures by their TBI history and other demographic and clinical characteristics of interest. We also compared survey responses to participants' VA outpatient prescription records to estimate sensitivity and negative predictive values (NPVs) for participants' self-reported medication exposures relative to this single prescription data source. Among 310 Veterans enrolled at the study site, 249 completed the survey (response rate = 80%), of whom 248 also had VA health records and were included in the analysis. Most (69%) had a history of mild TBI. Over three-fourths of survey respondents (78%) reported ever having used prescription opioids, 26% reported benzodiazepines, 50% reported muscle relaxants, 42% reported antidepressants, 13% reported non-benzodiazepine sedative-hypnotics, 15% reported stimulants, 7% reported mood stabilizers, and 6% reported antipsychotics. Veterans with, versus without, a history of mild TBI were more likely to self-report psychotropic medication history as well as have confirmed receipt of VA prescriptions for each medication class. Using VA records as a criterion standard, the sensitivity of the survey for detecting VA prescriptions ranged from 19% to 84%, while the NPVs ranged from 64% to 97%. Sensitivity and NPVs were similar for participants with, versus without, mild TBI history. Service Members and Veterans may receive psychotropic medications from multiple sources over their lifetimes. Valid methods to examine and quantify these exposures among those with a history of TBI are important, particularly as we evaluate causes of neurodegenerative disorders in this population over time. The measurement of Veterans' lifetime psychotropic medication exposures using a self-report survey, in combination with health care records, holds promise as a valid approach, but further testing and refinement are needed.

Managing insomnia in Elderly patients: Evidence-based treatment approaches

Elderly patients (EP) often have Chronic Sleep (CS). Although elders are among the categories with the highest need for therapy, these EP are often seen as challenging to treat. This study offers a thorough the studies on the therapy of persistent insomnia in EP with an emphasis on Evidence-Based (EB) therapeutic strategies. Meta-Analyses (MA), EB evaluations of therapy modalities, randomized controlled trials of Non-Pharmacologic (NP) treatment, and the features and treatment of insomnia were all criteria for selecting publications. MA, EB on solid, and studies including pertinent new data were given preference. When NP gets closer, the field is on their side. Among the medications used to treat insomnia include sedating antidepressants, barbiturates, OTC, prescription, and chloral hydrate antihistamines, as well as OTC and OTC nutritional supplements and cognitive behavioral therapy (CBT). SH drugs, including Benzodiazepine (BZD), Non-Benzodiazepine (NB), and melatonin agonists. NP therapies for insomnia in people of all ages have a large body of research supporting their efficacy and durability, yet still need to be addressed. With a few notable exceptions, the bulk of pharmacological trials found was of short length and did not just include EP as participants. The Non-benzodiazepine Sedative Hypnotics (NSH) proved to have minor, if any, substantial therapeutic benefits in effectiveness or tolerability in EP compared to BZD. Melatonin agonists are among the newer medicines with unique mechanisms of accomplishment and better security profiles that show promise for treating Chronic Insomnia (CI) in EP. There is no strong evidence base for the long-term use of sedative hypnotics (SH) to treat insomnia, and this practice has historically been discouraged because of concerns about possible adverse effects such as cognitive impairment, daytime sedation, motor incoordination, and an increased risk of falls and car accidents. The most effective management technique for senior people with CI will need more study to establish the extended-term consequences of therapy.

Comparative Risk of Harm Associated with Zopiclone or Trazodone Use in Nursing Home Residents: a Retrospective Cohort Study in Alberta, Canada.

There is growing evidence of harm associated with trazodone and nonbenzodiazepine sedative hypnotics (e.g., zopiclone); however, their comparative risk of harm is unknown. We conducted a retrospective cohort study with linked health administrative data, which enrolled older (≥66 years old) nursing home residents living in Alberta, Canada, between December 1, 2009, and December 31, 2018; the last follow-up date was June 30, 2019. We compared the rate of injurious falls and major osteoporotic fractures (primary outcome) and all-cause mortality (secondary outcome) within 180 days of first prescription of zopiclone or trazodone with cause-specific hazard models and inverse probability of treatment weights to control for confounding; primary analysis was intention-to-treat and secondary analysis was per-protocol (i.e., residents censored if dispensed the other exposure drug). Our cohort included 1,403 residents newly dispensed trazodone and 1,599 residents newly dispensed zopiclone. At cohort entry, the mean resident age was 85.7 (standard deviation [SD] 7.4), 61.6% were female, and 81.2% had dementia. New zopiclone use was associated with similar rates of injurious falls and major osteoporotic fractures (intention-to-treat-weighted hazard ratio 1.15, 95% confidence interval [CI] 0.90-1.48; per-protocol-weighted hazard ratio 0.85, 95% CI 0.60-1.21) and all-cause mortality (intention-to-treat-weighted hazard ratio 0.96, 95% CI 0.79-1.16; per-protocol-weighted hazard ratio 0.90, 95% CI 0.66-1.23) compared to trazodone. Zopiclone was associated with a similar rate of injurious falls, major osteoporotic fractures, and all-cause mortality compared to trazodone-suggesting one medication should not be used in lieu of the other. Appropriate prescribing initiatives should also target zopiclone and trazodone.

Identifying barriers and facilitators to deprescribing benzodiazepines and sedative hypnotics in the hospital setting using the Theoretical Domains Framework and the Capability, Opportunity, Motivation and Behaviour (COM-B) Model: a qualitative study

ObjectivesGeriatric guidelines strongly recommend avoiding benzodiazepines and non-benzodiazepine sedative hypnotics in older adults. Hospitalisation may provide an important opportunity to begin the process of deprescribing these medications, particularly as new...

New and Persistent Sedative-Hypnotic Use After Adjuvant Chemotherapy for Breast Cancer.

Sedative-hypnotic medications are used to treat chemotherapy-related nausea, anxiety, and insomnia. However, prolonged sedative-hypnotic use can lead to dependence, misuse, and increased health-care use. We aimed to estimate the rates at which patients who receive adjuvant chemotherapy for breast cancer become new persistent users of sedative-hypnotic medications, specifically benzodiazepines and nonbenzodiazepine sedative-hypnotics (Z-drugs). Using the MarketScan health-care claims database, we identified sedative-hypnotic-naïve patients who received adjuvant chemotherapy for breast cancer. Patients who filled 1 and more prescriptions during chemotherapy and 2 and more prescriptions up to 1 year after chemotherapy were classified as new persistent users. Univariate and multivariable logistic regression analyses were used to estimate odds of new persistent use and associated characteristics. We identified 22 039 benzodiazepine-naïve patients and 23 816 Z-drug-naïve patients who received adjuvant chemotherapy from 2008 to 2017. Among benzodiazepine-naïve patients, 6159 (27.9%) filled 1 and more benzodiazepine prescriptions during chemotherapy, and 963 of those (15.6%) went on to become new persistent users. Among Z-drug-naïve patients, 1769 (7.4%) filled 1 and more prescriptions during chemotherapy, and 483 (27.3%) became new persistent users. In both groups, shorter durations of chemotherapy and receipt of opioid prescriptions were associated with new persistent use. Medicaid insurance was associated with new persistent benzodiazepine use (odds ratio = 1.88, 95% confidence interval = 1.43 to 2.47) compared with commercial or Medicare insurance. Patients who receive sedative-hypnotic medications during adjuvant chemotherapy for breast cancer are at risk of becoming new persistent users of these medications after chemotherapy. Providers should ensure appropriate sedative-hypnotic use through tapering dosages and encouraging nonpharmacologic strategies when appropriate.

Use of Benzodiazepines and Z-Drugs in Multiple Sclerosis.

ObjectiveUse of benzodiazepines and Z-drugs (non-benzodiazepine sedative hypnotics) is controversial due to adverse health outcomes in the general population. However, little is known about their use in people with multiple sclerosis (MS). We estimated the incidence and prevalence of benzodiazepine and Z-drug use (jointly BZD) in the MS population as compared to an age-, sex- and geographically-matched population without MS, and examined the association of mood/anxiety disorders with the use of BZD over a twenty-year period.MethodsUsing administrative data from Manitoba, Canada, we identified 2,985 persons with incident MS and 14,891 persons without MS matched 5:1 on sex, birth year and region. We applied validated case definitions to identify persons with any mood/anxiety disorder. Dispensations of BZD were identified. To assess the association between MS, mood/anxiety disorders and BZD use we constructed generalized linear models adjusting for age, sex, index year, socioeconomic status, urban/rural residence, physical comorbidities, and health care use. We also examined patterns of BZD use.ResultsIn 2016, the crude incidence of benzodiazepine use in the MS cohort was 2.10% (95%CI: 1.43–2.98%), 1.49-fold higher than in the non-MS cohort (1.41%; 95%CI: 1.18–1.67%). The crude incidence of Z-drug use in the MS cohort was 1.77% (95%CI: 1.20–2.51%), 1.78-fold higher than in the non-MS cohort (0.99%; 95%CI: 0.81–1.21%). After adjusting for covariates, among individuals without an active mood/anxiety disorder, the MS cohort had a 39% increased incidence rate of benzodiazepine use and a 72% increased incidence rate of Z-drug use as compared to the non-MS cohort. Among individuals with an active mood/anxiety disorder, the incidence of BZD use did not differ between the MS and non-MS cohorts. A higher proportion of people with MS used BZD for ≥6 months than people without MS.ConclusionUse of BZD is more common in people with MS than in general population controls, and use of these agents is in persons with MS is often chronic.

Abstract PD5-08: New and persistent sedative hypnotic use after adjuvant chemotherapy for breast cancer

Abstract Introduction: Sedative-hypnotic medications, such as benzodiazepines (BZDs) and non-benzodiazepine sedative-hypnotics (Z-drugs), are used to treat chemotherapy-related nausea, anxiety and insomnia. While effective for these indications, prolonged use can lead to dependence, misuse and increased healthcare utilization. We aimed to estimate rates of new and persistent BZD and Z-drug use after adjuvant chemotherapy for breast cancer. Methods: We used the MarketScan health care claims database to identify patients who received adjuvant chemotherapy for breast cancer from 2008 to 2017. We categorized prescriptions for BZDs or Z-drugs into three periods: 365 days prior to chemotherapy to the start of chemotherapy (period 1); start of chemotherapy to 90 days after the end of chemotherapy (period 2); and 90 days to 365 days after chemotherapy (period 3). Patients who filled no BZD prescriptions in period 1 were considered BZD-naïve. Those who then filled at least one BZD prescription in period 2, and at least two BZD prescriptions in period 3, were classified as new persistent BZD users. The same definitions were used for Z-drugs. We used multivariable logistic regression to estimate associations between patient characteristics and new persistent use of BZDs and Z-drugs. Results: We identified 17,532 BZD-naïve patients and 21,863 Z-drug-naïve patients who received adjuvant chemotherapy for breast cancer. The median age was 57 for BZD-naïve patients (IQR = 13) and 56 for Z-drug-naïve patients (IQR = 13). The majority of patients had commercial or Medicare insurance (92.6% BZD-naïve, 92.7% Z-drug-naïve) versus Medicaid. A slight majority received lumpectomy (56.6% BZD-naïve, 55.1% Z-drug-naïve) versus mastectomy. Roughly half of patients received less than 4 months of chemotherapy (48.0% BZD-naïve, 48.6% Z-drug-naïve). Among BZD-naïve patients, 4,447 (25%) filled at least one BZD prescription during chemotherapy, and 1,192 (7% of all BZD-naïve patients, 27% of those filling at least one BZD prescription during chemotherapy) became new persistent BZD users after chemotherapy. Among Z-drug naïve patients, 2,160 (10%) filled at least one Z-drug prescription during chemotherapy, and 730 (3% of all Z-drug-naïve patients, 34% of those filling at least one prescription during chemotherapy) became new persistent Z-drug users afterwards. There were 115 patients who became new persistent users of both types of sedative-hypnotics. Several characteristics were associated with new persistent BZD use: age 50-65 (Table 1; OR = 1.23, p = 0.01) and age > 65 (OR = 1.38, p = 0.005) relative to age ≤ 49; as well as Medicaid insurance, relative to commercial and Medicare insurance (OR = 1.68, p < 0.0001). Chemotherapy duration of less than 4 months was associated with both new persistent BZD and Z-drug use relative to 4 or more months of chemotherapy (OR = 1.17, p = 0.03 for BZDs; OR = 1.58, p < 0.0001 for Z-drugs). Conclusion: Women who receive sedative-hypnotic medications during adjuvant chemotherapy for breast cancer are at risk of becoming persistent users of these medications after chemotherapy. With an awareness of this observation, providers can take steps to ensure appropriate use of these medications, through tapering dosages and encouraging non-pharmacologic strategies when appropriate. Associations between Patient Characteristics and New Persistent Sedative-Hypnotic UseNew Persistent BZD UseNew Persistent Z-Drug UseVariableOdds Ratio95% CIp valueOdds Ratio95% CIp valueAge (years)≤ 49ReferentReferent50-651.231.05 - 1.430.011.210.99 - 1.480.07> 651.381.10 - 1.720.0050.950.68 - 1.310.7InsuranceMedicaid1.681.31 - 2.16<0.00010.760.50 - 1.150.2OtherReferentReferentSurgeryMastectomy1.090.95 - 1.250.20.890.74 - 1.070.2LumpectomyReferentReferentChemotherapy duration< 4 months1.171.02 - 1.340.031.581.31 - 1.89<0.0001≥ 4 monthsReferentReferent Citation Format: Jacob C. Cogan, Rohit R. Raghunathan, Melissa P. Beauchemin, Melissa K. Accordino, Elena B. Elkin, Alexander Melamed, Jason D. Wright, Dawn L. Hershman. New and persistent sedative hypnotic use after adjuvant chemotherapy for breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD5-08.

Receipt of Concurrent VA and Non-VA Opioid and Sedative-Hypnotic Prescriptions Among Post-9/11 Veterans With Traumatic Brain Injury.

Receipt of concurrent psychotropic prescription medications from both US Department of Veterans Affairs (VA) and non-VA healthcare providers may increase risk of adverse opioid-related outcomes among veterans with traumatic brain injury (TBI). Little is known about patterns of dual-system opioid or sedative-hypnotic prescription receipt in this population. We estimated the prevalence and patterns of, and risk factors for, VA/non-VA prescription overlap among post-9/11 veterans with TBI receiving opioids from VA providers in Oregon. Oregon VA and non-VA outpatient care. Post-9/11 veterans in Oregon with TBI who received an opioid prescription from VA providers between the years of 2014 and 2019. Historical cohort study. Prescription overlap of VA opioids and non-VA opioids or sedative-hypnotics; proportions of veterans who received VA or non-VA opioid, benzodiazepine, and nonbenzodiazepine sedative-hypnotic prescriptions were also examined by year and by veteran characteristics. Among 1036 veterans with TBI receiving opioids from the VA, 210 (20.3%) received an overlapping opioid prescription from a non-VA provider; 5.3% received overlapping benzodiazepines; and none received overlapping nonbenzodiazepine sedative-hypnotics. Proportions of veterans with prescription overlap tended to decrease over time. Veterans with other than urban versus urban addresses (OR = 1.4; 95% CI, 1.0-1.8), high versus medium average annual VA visits (OR = 1.7; 95% CI, 1.1-2.6), and VA service connection of 50% or more versus none/0% to 40% (OR = 4.3; 95% CI, 1.3-14.0) were more likely to have concurrent VA/non-VA prescriptions in bivariable analyses; other than urban remained associated with overlap in multivariable models. Similarly, veterans with comorbid posttraumatic stress disorder diagnoses were more likely to have concurrent VA/non-VA prescriptions in both bivariable and multivariable (OR = 2.1; 95% CI, 1.0-4.1) models. Among post-9/11 veterans with TBI receiving VA opioids, a considerable proportion had overlapping non-VA prescription medications. Providers and healthcare systems should consider all sources of psychotropic prescriptions, and risk factors for overlapping medications, to help mitigate potentially unsafe medication use among veterans with TBI.

The effect of non-benzodiazepine sedative hypnotics on CPAP adherence in patients with OSA: a systematic review and meta-analysis.

This meta-analysis aimed to explore the effect of non-benzodiazepine sedative hypnotics (NBSH) on continuous positive airway pressure (CPAP) adherence in patients with obstructive sleep apnea (OSA). We conducted a systematic search through PubMed, Medline, the Cochrane Library, EMBASE, Scopus and ClinicalTrials (all searched from inception to August 15, 2020). Publications were limited to articles, clinical conferences and letters, including randomized controlled trials and retrospective studies. We used a random-effects model to calculate the odds ratio (OR) and mean difference (MD) with corresponding confidence interval (CI). Subgroup analyses were conducted to analyze the sources of heterogeneity. Eight studies fulfilled the inclusion and exclusion criteria for patients newly diagnosed with obstructive sleep apnea. Overall, the use of NBSH was associated with increased use of CPAP per night (MD = 0.62 h; 95% CI = 0.26-0.98) and use for more nights (MD = 12.08%; 95% CI = 5.27-18.88). When a study seriously affecting heterogeneity was removed, more patients adhered well with CPAP use (pooled OR = 2.48; 95% CI = 1.75-3.52) with good adherence defined as CPAP use for >4 h/night on >70% of nights. Among prescribed NBSHs, eszopiclone showed the most significant effect on CPAP adherence. CPAP adherence may increase in OSA patients treated with non-benzodiazepine sedative hypnotics especially eszopiclone. The effect of zolpidem and zaleplon on CPAP adherence requires further investigation by larger scale, randomized, controlled trials.

Vasorelaxant effects of benzodiazepines, non-benzodiazepine sedative-hypnotics, and tandospirone on isolated rat arteries

Benzodiazepines (BDZs) and non-BDZ sedative-hypnotics are effective for the management of chronic insomnia; however, they are associated with adverse effects such as headache, dizziness, and palpitations. Furthermore, long-term use of these medications is associated with decreased blood pressure (BP) or depressed baroreflex function. Therefore, here, we assessed whether BDZs and non-BDZs cause vasorelaxation directly. Vasorelaxation in response to 22 BDZs, 2 non-BDZs, and tandospirone was determined by myograph methods using isolated Wistar rat thoracic aortas. All the drugs relaxed phenylephrine-contracted rat aortas in a concentration-dependent manner. Zolpidem and tandospirone caused over 80% relaxation at a concentration of 10 μM; diazepam, estazolam, etizolam, and tofisopam caused 60–70% relaxation; whereas 18 other BDZs (alprazolam, bromazepam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepate, ethyl loflazepate, flunitrazepam, flurazepam, lorazepam, lormetazepam, midazolam, nimetazepam, nitrazepam, oxazepam, temazepam, and triazolam) and zaleplon caused less than 50% relaxation. The relaxation was partially but significantly inhibited to the same extent by a nitric oxide (NO) synthase antagonist and after endothelium removal. Binding assay of gamma-aminobutyric acid type A receptors was performed using [3H]flunitrazepam. No correlation was observed between vasorelaxation at a concentration of 10 μM and the binding affinities for 23 drugs. The study demonstrated that zaleplon, zolpidem, tandospirone, and many BDZs cause vasorelaxation to different extents via endothelial NO-dependent and endothelium-independent pathways. In conclusion, the direct vasodilatory effects of these drugs may be involved in the mechanisms underlying their adverse effects. Additionally, the decreased BP observed in persons who take BDZs or non-BDZs may be partly due to direct vasodilation.

Trends in Co-Prescribing of Opioids and Opioid Potentiators Among U.S. Adults, 2007–2018

Several factors influence the risk of harms associated with prescription opioids.1 One modifiable factor is the co-prescription of medications such as benzodiazepines, nonbenzodiazepine sedative hypnotics, and gabapentinoids, which potentiate opioids’ respiratory depressant effects,2,3 slowing breathing and increasing risk of accidental overdose.4 Co-prescribing of benzodiazepines and opioids decreased after the U.S. Food and Drug Administration (FDA) black box warning of 2016.5 However, it is unknown how the co-prescription of opioids with other respiratory depressant potentiators has changed recently.

The Physiology and Maintenance of Respiration: A Narrative Review.

Chronic pain is one of the most common reasons adults seek medical care and is often managed with opioid analgesics; however, opioids may cause respiratory depression by suppressing various components of respiration. Respiration is the physiological process that facilitates gas exchange and is mediated through the proper function of and communication among central neural control (respiratory drive), sensory input systems, the lungs, and the muscles involved in respiration. Normal respiratory function can be dampened with the use of central nervous system (CNS) depressants and/or underlying health conditions. Patients with chronic pain are often exposed to CNS depressants other than opioids, including benzodiazepines, barbiturates, nonbenzodiazepine sedative-hypnotics, and ethanol, which can function synergistically with opioids to increase the risk of respiratory depression. Some patients may also have underlying health issues, such as obstructive sleep apnea, that can be exacerbated with the use of opioids and other CNS depressants and further contribute to respiratory depression. Clinicians should have a thorough understanding of respiration, recognize how various CNS depressants suppress it, and take necessary steps to mitigate the risk of opioid-induced respiratory depression by collaborating with a multidisciplinary team (i.e., sleep and pain specialists), choosing appropriate medications, and educating patients on the proper use and storage of opioids.

Gender Differences in Prescribing of Zolpidem in the Veterans Health Administration (VHA)

Use of nonbenzodiazepine sedative hypnotics, especially zolpidem, has grown substantially, raising concerns about safety. Gender‐specific guidelines have been recommended for appropriate zolpidem prescribing to address patient safety concerns. In line with an FDA recommendation in 2013, the Veterans Health Administration (VHA) issued a similar directive to lower the doses of zolpidem in women in 2013. However, little is known about zolpidem prescribing patterns in the VHA in general. Therefore, the goal of this study was to examine utilization trends and inappropriate prescribing of zolpidem in accordance with VHA guidelines in male and female veterans in the VHA.A cross‐sectional study of veterans receiving zolpidem in the outpatient setting from October 1, 2011, to September 30, 2016. We examined 2 outcomes related to inappropriate zolpidem prescribing: high‐dose and overlap with benzodiazepines.The study population consisted of 500 332 zolpidem users (58 598 women and 441 734 men) and a random 10% sample (n = 631 449) of nonusers.Across the VHA, 7.1% of men and 10.0% of women received zolpidem at least once during the study period. In 2016, 29.7% of female veterans received an inappropriately high guideline‐discordant dosage compared with 0.1% of male veterans (P < .001 for all reported comparisons). Furthermore, more women than men had overlapping benzodiazepine and zolpidem prescriptions (18.8% vs 14.3%). In unadjusted trends in high‐dose zolpidem prescriptions by gender before and after the VHA 2013 recommendations for suggested lower dose in women, we found that the observed proportion of women receiving the higher dose decreased considerably from 75.9% in 2011 to 29.1% in 2016. For men also, there was a decline in observed receipt of high‐dose zolpidem from 1.7% in 2011 to 0.1% in 2016. In fully adjusted models, inappropriately high doses were more commonly received by younger women (adjusted odds ratios [AORs]: 2.75 for 21‐39 years and 2.97 for 40‐49 years compared with ≥ 80 years) and women with substance use disorder (AOR, 1.48). In the second inappropriateness outcome models, women with anxiety (AOR, 2.28) or schizophrenia (AOR, 2.05) and men with cancer (AOR, 1.42), anxiety (AOR, 2.66), or schizophrenia (AOR, 2.46) were more likely to receive an overlapping prescription of zolpidem and benzodiazepines.We found inappropriate prescribing of zolpidem, in terms of both guideline‐discordant dosage and coprescribing with benzodiazepines, with female Veterans affected more than male Veterans. Potential contributors to this inappropriate prescribing of zolpidem in women could include the fact that the majority of patients served by the VHA are men. Hence, providers may be less familiar with issues specific to treating female veterans.Findings have implications both for patient safety and promoting guideline‐concordant prescribing in female zolpidem users, specifically those with existing mental conditions. These findings may help guide and inform intervention efforts targeted toward these female Veterans to optimize zolpidem prescribing in the VHA. Greater understanding of the drivers of this inappropriate prescribing is necessary to develop interventions to promote safer, more guideline‐concordant prescribing.Department of Veterans Affairs.

Risk of Overdose with Exposure to Prescription Opioids, Benzodiazepines, and Non-benzodiazepine Sedative-Hypnotics in Adults: a Retrospective Cohort Study

Concurrent use of benzodiazepines in opioid users has been linked to a higher risk of an emergency room visit or inpatient admission for opioid overdose and death from drug overdose. Further research is needed to confirm the findings and analyze contributing risk factors for opioid overdoses in a large commercially insured population. To estimate the risk of opioid overdose associated with opioid users exposed to various combinations of opioid, benzodiazepine, and non-benzodiazepine sedative-hypnotic therapy. To identify other factors that are associated with increased risk for opioid overdose. Retrospective cohort study. New start adult users of opioids, defined as naïve to opioids for 6 months, in Kaiser Permanente California regions from January 2013 through September 2017. Inpatient or emergency department admissions due to opioid-related overdose. A total of 2,241,530 patients were included in this study. Patients exposed to opioids, benzodiazepines, and non-benzodiazepine sedative-hypnotics at any point during their follow-up were 60% more likely to overdose than those who were only exposed to opioids (p < 0.0001). Those exposed to opioids and benzodiazepines were 20% more likely to have an opioid-related overdose than those exposed to opioids only (p < 0.0001). Significant risk factors for opioid overdose included exposure to all three medication classes, higher opioid dosage strengths, elderly age (age ≥ 65 years), history of previous overdose, and substance use disorder. Results from this study demonstrate a significant increase in risk of opioid overdose in patients exposed to combinations of sedative-hypnotics with opioids compared to those only taking opioids. Findings from this study provide evidence that opioids should be avoided in combination with benzodiazepines and non-benzodiazepine sedative-hypnotics, used at the lowest dose possible, and used with caution in the elderly, those with previous history of overdose, and those with substance use disorder at baseline.

Тревожный пациент на приеме у невролога

The article presents a review of scientific publications devoted to the study of the problem of anxiety disorders. The authors present modern views on the etiology and main pathogenesis mechanisms of normal and pathological anxiety. The article describes the most characteristic mental and somatic symptoms of generalized anxiety disorder. It also highlights the symptoms that are commonly a somatic manifestation of unconscious pathological anxiety. Special attention is paid to the most frequent somatic symptom of generalized anxiety disorders — headache, the largest share in the structure of which is tension headache. Modern methods for the pharmacological treatment and drugs that optimally affect the main clinical manifestations of the disease are considered. The methods of rational and cognitive behavioral therapy used in the treatment of anxiety disorders are also described. Adding that, the article notes the features of communication between a doctor and a patient with anxiety. KEYWORDS: generalized anxiety disorder, somatic symptoms of anxiety, tension headache, dizziness, non-benzodiazepine sedative hypnotics, aminophenylbutyric acid. FOR CITATION: Chutko L.S., Surushkina S.Yu. Patient with anxiety at a neurologist’s appointment. Russian Medical Inquiry. 2020;4(9):590– 594. DOI: 10.32364/2587-6821-2020-4-9-590-594.

Developing an animal model to detect drug–drug interactions impacting drug-induced respiratory depression

Opioids and benzodiazepines were frequently co-prescribed to patients with pain and psychiatric or neurological disorders; however, co-prescription of these drugs increased the risk for severe respiratory depression and death. Consequently, the U.S. Food and Drug Administration added boxed label warnings describing this risk for all opioids and benzodiazepines. Sedating psychotropic drugs with differing mechanisms of action (e.g., antipsychotics, antidepressants, non-benzodiazepine sedative-hypnotics, etc.) may be increasingly prescribed in place of benzodiazepines. Despite being marketed for years, many sedating psychotropic drugs have neither human nor animal data that quantify or qualify the potential for causing respiratory depression, either alone or in combination with an opioid. In this study, diazepam was selected as the benzodiazepine to detect any additive or synergistic effects on respiratory depression caused by the opioid, oxycodone. Pharmacokinetic studies were conducted at three doses with oxycodone (6.75, 60, 150 mg/kg) and with diazepam (2, 20, 200 mg/kg). Dose dependent decrease in arterial partial pressure of oxygen and increase in arterial partial pressure of carbon dioxide were observed with oxycodone. Diazepam caused similar partial pressure changes only at the highest dose. Further decreases in arterial partial pressure of oxygen and increases in arterial partial pressure of carbon dioxide consistent with exacerbated respiratory depression were observed in rats co-administered oxycodone 150 mg/kg and diazepam 20 mg/kg. These findings confirm previous literature reports of exacerbated opioid-induced respiratory depression with benzodiazepine and opioid co-administration and support the utility of this animal model for assessing opioid-induced respiratory depression and its potential exacerbation by co-administered drugs.

Menopausal Symptoms and Higher Risk Opioid Prescribing in a National Sample of Women Veterans with Chronic Pain.

The greatest increases in long-term opioid use and opioid-related overdose mortality in recent years have been among women in midlife. Common menopausal symptoms broadly affect health and health care utilization in midlife, but their contribution to chronic pain management during this period is unknown. To examine relationships between menopausal symptoms and long-term opioid prescription patterns among midlife women with chronic pain. Cross-sectional analysis of national Veterans Health Administration medical and pharmacy records (2014-2015). Women Veterans aged 45-64 with ≥ 1 outpatient visit and chronic pain diagnoses spanning ≥ 90days. Long-term opioids (prescribed oral opioids for ≥ 90days), high-dose long-term opioids (> 50mg average morphine equivalent daily dose), and long-term opioids co-prescribed with central nervous system depressants (benzodiazepine and non-benzodiazepine sedative-hypnotics, gabapentin/pregabalin, muscle relaxants). Multivariable logistic regression models were used to examine associations between outcomes and menopausal symptoms (menopausal symptom-related diagnoses (i.e., "symptomatic menopausal states") on ≥ 2 encounters and/or menopausal hormone therapy, adjusting for race, age, body mass index, and mental health and substance use disorder diagnoses. In this national sample of 104,984 midlife women Veterans with chronic pain (mean age 54.5, SD 5.4years), 17% had evidence of menopausal symptoms, 51% were prescribed long-term opioids, 13% were prescribed high-dose long-term opioids, and 35% were co-prescribed long-term opioids and central nervous system depressants. In multivariable analyses, women with menopausal symptoms had increased odds of long-term opioids (OR 1.21, 95% CI 1.18-1.26), high-dose long-term opioids (OR 1.08, 95% CI 1.02-1.13), and long-term opioids co-prescribed with central nervous system depressants (sedative-hypnotics OR 1.25, 95% CI 1.22-1.30; gabapentin/pregabalin OR 1.23, 95% CI 1.20-1.27; muscle relaxants OR 1.24, 95% CI 1.20-1.28). Among midlife women Veterans with chronic pain, evidence of menopausal symptoms was associated with potentially risky long-term opioid prescription patterns, independent of known risk factors.

Psychoactive medication use among older community-dwelling Americans

BackgroundFalls are a common and serious health issue among older Americans. A common fall risk factor is the use of psychoactive medications. There is limited recent information on the national prevalence of psychoactive medication use among older Americans. ObjectivesTo estimate the prevalence of psychoactive medication use among community-dwelling older Americans and compare it with previous estimates from 1996. MethodsThe data source was the 2013 Cost and Use Data files combining Medicare claims data and survey data from the Medicare Current Beneficiary Survey, an in-person nationally representative survey of Medicare beneficiaries. Participants were included if they were 65 years of age and older, lived in the community, and had a complete year of prescription use data. Medication use was examined for 7 classes of psychoactive medications categorized by the 2015 American Geriatric Society Beers criteria as increasing fall risk. These include opioids, benzodiazepines, selective serotonin reuptake inhibitors, anticonvulsants, nonbenzodiazepine sedative hypnotics, antipsychotics, and tricyclic antidepressants. Data on participant demographic factors were also collected. ResultsAmong the 6959 community-dwelling older adults studied, representing 33,268,104 community-dwelling Medicare beneficiaries, 53.3% used at least 1 psychoactive medication linked to falls in 2013. The most frequently used medication classes were opioids (34.9%), benzodiazepines (15.4%), selective serotonin reuptake inhibitors (14.3%), and anticonvulsants (13.3%). These estimates are considerably higher for all classes except tricyclic antidepressants than previous reports from 1996 that used the same data source. Among most psychoactive medication classes observed, women had higher usage than men. ConclusionMore than half of all older Americans used at least 1 psychoactive medication in 2013. Health care providers, including pharmacists, play a vital role in managing older adults’ exposure to psychoactive medications. Medication management can optimize health and reduce older adult falls.

The medicalization of sleeplessness: Results of U.S. office visit outcomes, 2008-2015.

Previous analysis of U.S. physician office visits (1993–2007) indicated that the medicalization of sleeplessness was on the rise and had potentially negative implications for population health. Our study asks if the medicalization of sleeplessness at the level of patient-physician interaction has persisted over time. Using the most recent years available (2008–2015) of the National Ambulatory Medical Care Survey we calculated nationally representative estimates for four sleeplessness-related outcomes of physician office visits: sleeplessness complaint, insomnia diagnosis, and prescription of benzodiazepine and non-benzodiazepine sedative-hypnotics (NBSH). To test for the significance of the linear trajectory, we ran a series of bivariate linear models. We tested three hypotheses grounded in the medicalization framework: if the medicalization of sleeplessness at the interactional level is continuing at a rate comparable to previous analyses, sleeplessness-related outcomes will continue to increase significantly over time (Hypothesis 1); NBSH prescriptions and insomnia diagnoses will continue to outpace sleeplessness complaints (Hypothesis 2); and insomnia diagnoses and use of sedative-hypnotics will increase or remain concentrated among age groups who lack the changing sleep patterns and commonly occurring comorbidities associated with older age (Hypothesis 3). Support for these hypotheses was mixed. Unlike previous analyses wherein all sleeplessness-related outcome trends were positive and statistically significant over time, regression analyses revealed a significant negative NBSH prescription trend 2008–2015 (slope, b = −699,628, P < 0.05). No other associations were significant. Younger age groups were most likely to receive an insomnia diagnosis and NBSH prescription. These trends imply that the medicalization of sleeplessness at the level of patient-physician interaction may be on the decline. We suggest that increasingly negative portrayals of sedative-hypnotics, conservative practice recommendations, and decreased direct-to-consumer advertising for NBSH may decrease consumerism and physician compliance related to the medicalization of sleeplessness. We conclude with a discussion on non-pharmaceutical methods of reducing sleeplessness relevant to population health.

Patient Education and Pharmacist Consultation Influence on Nonbenzodiazepine Sedative Medication Deprescribing Success for Older Adults.

Use of nonbenzodiazepine sedative hypnotics or "Z-drugs"-including eszopiclone, zolpidem, or zaleplon-is discouraged for older adults; however, these medications commonly are prescribed to treat insomnia in this population. We evaluated the impact of direct-to-patient education, with or without a pharmacist consultation, on Z-drug discontinuation among Kaiser Permanente Northwest members age 64 years and older. We randomized 150 patients to usual care (UC), educational information only, or educational information and pharmacist consultation. Patients age 64 years and older who received 2 to 3 Z-drug fills in 2016 were included. Logistic regression was used to calculate odds of discontinuation at 6 months among patients who received either intervention, compared with those who received UC. Patients who received education only and education plus pharmacist consultation were significantly more likely to discontinue Z-drug use than those who received UC (28/50 of those who received education only and 27/49 of those who received education plus consultation vs 13/50 patients who received UC). After controlling for patient demographics, comorbidity, and antianxiety and antidepressant medication use, patients who received education only had greater odds of Z-drug discontinuation than those in the UC group (adjusted odds ratio = 4.02, 95% confidence interval = 1.66-9.77). Patients who received education and a pharmacist call also had greater odds of discontinuing use of these drugs than those in the UC group (adjusted odds ratio = 4.10, 95% confidence interval = 1.65-10.19). Patients who received direct-to-patient education with or without a pharmacist consultation were significantly more likely to discontinue Z-drug use than patients receiving UC. Providing evidence-based information about Z-drug use is an effective and low-resource method to encourage drug discontinuation.