Use of sedative-hypnotic medications and risk of dementia: A systematic review and meta-analysis.

AIMS: Growing evidence suggests an association between the use of sedative-hypnotic medications and risk of dementia. The aim of this study is to examine this association using a meta-analysis approach. METHODS: MEDLINE (PubMed) and Scopus were systematically searched for studies published in English only. The quality of studies was evaluated using the Newcastle-Ottawa scale, and an overall odds ratio was pooled using a random-effects model. RESULTS: A total of 35 articles were included in the analysis. Pooled odds ratios (ORs) for dementia from all records were (OR; 1.33, 95% CI 1.19-1.49) for benzodiazepine (BZD) combined use (Subgroup-1), (OR: 1.46, 95% CI 1.23-1.73) for short-acting BZD use (Subgroup-2), (OR: 1.72, 95% CI 1.48-1.99) for long-acting BZD use (Subgroup-3), (OR: 1.13, 95% CI 0.97-1.32) for BZDs without specification of duration of action (Subgroup-4), (OR: 1.64, 95% CI 1.13-2.38) for the combined BZDs and Z-drugs, (OR: 1.43, 95% CI 1.17-1.74) for Z-drugs only, (OR: 1.14, 95% CI 0.88-1.46) for antidepressant use, (OR: 0.97, 95% CI 0.68-1.39) for antipsychotic use and (OR: 0.98, 95% CI 0.85-1.13) for anticonvulsant use. When sensitivity analysis was performed, association between overall use of BZDs and short-acting BZDs with the increased risk of dementia disappeared after exclusion of studies that were not adjusted for age covariate (OR: 1.2, 95% CI 1.0-1.44) and (OR: 1.22, 95% CI 0.75-2.01), respectively. Adjustment for protopathic bias by introduction of a lag period showed no evidence of increased risk of dementia with the use of BZDs (Subgroup-1) (OR: 1.14, 95% CI 0.82-1.58), Z-drugs (OR: 1.29, 95% CI 0.78-2.13), and combined BZDs and Z-drugs (OR: 1.51, 95% CI 0.91-2.53). Combined use of BZDs and Z-drugs showed more positive association when only studies of non-user design were analysed (OR: 2.75, 95% CI 2.23-3.39). CONCLUSIONS: All the investigated sedative-hypnotics showed no association with increased risk of dementia except for BZDs. However, the observed association with BZDs did not persist after exclusion of studies with potential reverse causation and confounding by indication. Therefore, this association needs to be assessed carefully in future research.

Abuse of Pharmaceutical Drugs and Its Prevention.

Abuse of pharmaceutical drugs is a major public health and social problem worldwide. Mostly abused drugs mainly include opioids such as morphine, tramadol, methadone and fentanyl, sedative-hypnotics such as benzodiazepines and non-benzodiazepines, and central stimulants such as Ritalin (methylphenidate), Adderall (amphetamine and dextroamphetamine) and modafinil. Abuse of pharmaceutical drugs not only causes direct damage to multiple systems of the body, but also significantly increases risks of mental and physical diseases, imposing a heavy burden on individuals, families and society. Therefore, the prevention and control of pharmaceutical drug abuse are of vital importance. The Chinese government has taken strict administration measures for pharmaceutical drugs with abuse risk. However, confronting endless new drugs and changing abuse trends, it is necessary to further strengthen management and prevention of pharmaceutical drugs, monitor the trend of abuse, establish rapid response mechanisms, popularize relevant knowledge, and develop specific therapeutic drugs and intervention means, in order to promote prevention and treatment of pharmaceutical drug abuse.

Effects of sedative-hypnotics on sleep quality among patients with insomnia: evidence from an observational, pre-post study in India.

BACKGROUND: Insomnia continues to be neglected globally, despite its high prevalence. Guidelines by the health regulatory agencies call for studies to evaluate the effect of sedative-hypnotics on sleep quality. METHODS: We conducted a pre-post observational study to evaluate sleep quality among 186 inpatients receiving short-term oral sedative-hypnotic therapy in a tertiary care teaching hospital in Kozhikode (Kerala), India. Using Pittsburgh Sleep Quality Index_Past-Week (PSQI_PW) questionnaire, patients were interviewed upon hospital admission and at follow up after ≥1-week of sedative-hypnotic therapy. Additionally, we interviewed 36 physicians to understand the current clinical perception about sedative-hypnotics. RESULTS: Mean (SD) age of the study patients was 59 (7.5) years. Majority (63.4%) of the patients were men. Of the various primary diagnoses for hospitalization, cardiovascular disease was the most common (22.6%, n = 49). Sedative-hypnotic therapy improved the mean (SD) PSQI_PW overall score by 6.79 points (pre: 12.70 (3.5) vs. post: 5.91 (2.8); p < 0.0001). Statistically significant improvements in sleep duration, latency, efficacy, and day dysfunction were observed. Higher proportion of study patients were prescribed benzodiazepines (73.7%) compared to zolpidem (26.3%). Patients treated with zolpidem reported higher improvements in mean overall PSQI_PW scores compared to those treated with benzodiazepines, however these differences were not statistically significant upon adjusting for age, gender and primary diagnosis for hospitalization. Qualitative interviews indicate that that physicians consider zolpidem to be safer and more efficacious. CONCLUSIONS: In our study, sedative-hypnotic therapy helped improve sleep quality among the hospitalized patients. More studies evaluating the comparative efficacy and safety of zolpidem vs. benzodiazepines - including among patient groups with varying demographic and clinical characteristics - are needed. India must develop evidence-based treatment guidelines to inform the clinical practice around the use of sedative-hypnotics.

Trends in the consumption rates of benzodiazepines and benzodiazepine-related drugs in the health region of Lleida from 2002 to 2015.

BACKGROUND: The high prevalence and long-term use of benzodiazepines (BZDs) treatment are debated topics because of the risk they can cause to the patients. Despite the current information on the risk-benefit balance of these drugs, their consumption remains particularly high. We determined the trend in the consumption prevalence of benzodiazepines (BZDs) and drugs related to BZDs (Z-drugs) in the population of the Health Region of Lleida to explore patterns of use and the associated characteristics associated between 2002 and 2015. METHODS: An analysis of secular trends was carried out between 2002 and 2015; the databased included all individuals from the Health Region of Lleida, which had 358,157 inhabitants in 2015, that consumed BZDs. The consumption of BZDs was evaluated using prescription billing data from the Public Health System. All types of BZDs and BZD analogues that had been approved by the drug agency were included. Trends by age and sex were investigated. RESULTS: Over the whole study period, a total of 161,125 individuals accounted for 338,148 dispensations. Overall, 59% were women, and the mean age was 56 years. The dispensing prevalence of BZDs use in 2015 was 14.2% overall -18.8% in women and 9.6% in men-and was 36% in those over 65 years. According to the half-life of BZDs, the prevalence of short-intermediate BZD use, intermediate-long BZD use, and Z-drugs use was 9.7, 5.5 and 0.8%, respectively. The evolution of the annual prevalence of BZD dispensing showed a progressive decline, from 15.3% in 2002 to 14.2% in 2015, which was attributed to a decrease in the consumption of intermediate-long half-life BZDs (8.0% vs. 5.5%) and Z-drugs (1.4% vs. 0.8%). CONCLUSION: The dispensing prevalence of BZDs and Z-drugs was high, although a small reduction was observed during this time period. The dispensing prevalence was especially high in the population over 65, despite the risk of cognitive decline and falls. Integral actions are required to lower the BZD prescription rate.

Pre-operative hemoglobin level and use of sedative-hypnotics are independent risk factors for post-operative delirium following total knee arthroplasty.

BACKGROUND: Delirium is a well-known complication following surgery, especially with the increasing age of patients undergoing surgery. The increasing demands resulting from a prolonged healthy life expectancy has resulted in more arthroplasties despite their age and existing comorbidities. The purpose of this study is to explore the various risk factors that may contribute to delirium in unilateral and bilateral total knee arthroplasties in the elderly population. METHODS: 170 patients who underwent unilateral or bilateral total knee arthroplasties were analyzed retrospectively for delirium. Age, sex, comorbidities, use of sedative-hypnotics, peri-operative blood loss, pre- and post-operative laboratory blood test results were investigated and analyzed. RESULTS: The incidence of post-operative delirium was 6.5% (11 out of 170 patients) with a mean age of 79.5 (± 6.9) years, compared to 73.0 (± 9.0) years in the non-delirium group. Higher age, use of sedative-hypnotics, low pre-operative Hb and Ht, low post-operative Hb, Ht and BUN were observed in the delirium group. Multivariate logistic regression analysis identified that the use of sedative-hypnotics and pre-operative Hb level were independent risk factors for post-operative delirium after TKA. The odds ratios for the use of sedative-hypnotics and pre-operative Hb level were 4.6 and 0.53, respectively. Receiver operating characteristic curve analysis showed that pre-operative Hb of less than 11.1 g/dL was a predictor for the development of delirium, with a sensitivity of 54.6% and a specificity of 91.6%. CONCLUSION: Patients with a pre-operative Hb level of < 11.1 g/dL or those using sedative-hypnotics are associated with post-operative delirium. Peri-operative management and preventative measures are therefore needed to reduce the risks of post-operative delirium in such patients.

Sedative-hypnotic initiation and renewal at discharge in hospitalized older patients: an observational study.

BACKGROUND: Sedative-hypnotics (SHs) are widely used in France but there are no available data addressing their prescription specifically in hospitalized older patients. The objective is thus to determine the cumulative incidence of sedative-hypnotic (SH) medications initialized during a hospital stay of older patients, the proportion of SH renewal at discharge among these patients and to study associated risk factors. METHODS: We conducted a retrospective observational study in six internal medicine units and six acute geriatric units in eight hospitals (France). We included 1194 inpatients aged 65 and older without SH medications prior to hospitalization. Data were obtained from patients' electronic pharmaceutical records. Primary outcome was the cumulative incidence of SH initiation in the study units. Secondary outcomes were the proportion of SH renewal at discharge and risk factors for SH initiation and renewal at discharge (patient characteristics, hospital organization). A Cox regression model was used to study risk factors for SH initiation. A mixed effects logistic regression was used to study risk factors for SH renewal at discharge. RESULTS: SH initiation occurred in 21.5% of participants 20 days after admission. SH renewal at discharge occurred in 38.7% of patients who had initiated it during their stay and were discharged home and in 56.0% of patients discharged to rehabilitation facilities. Neither patients' characteristics nor hospital organization patterns was associated with SH initiation. SH initiation after the first six days after admission was associated with a lower risk of SH renewal in patients discharged to rehabilitation facilities (OR = 0.19, 95% CI: [0.04-0.80]). CONCLUSIONS: Hospitalization is a period at risk for SH initiation. The implementation of interventions promoting good use of SHs is thus of first importance in hospitals. Specific attention should be paid to patients discharged to rehabilitation facilities.

Insomnia management in prisons in England and Wales: a mixed-methods study.

Insomnia in prison is common; however, research is limited regarding the management strategies that prison establishments employ. To address this knowledge gap, we conducted a survey to identify how insomnia is detected, diagnosed and treated in adult prisons in England and Wales. Telephone interviews with a purposive sample of health-care managers were then conducted. The survey was sent to all establishments holding adult prisoners, covering screening and assessment methods to detect insomnia; treatment options, both pharmacological and non-pharmacological; the importance of insomnia as a treatable condition; and staff training available. Eighty-four (73%) prisons completed the survey. Few had a stepped approach to insomnia management, as recommended by National Institute for Health and Care Excellence (NICE) guidelines. The most common treatments available were sleep hygiene education and medication, offered by 94 and 88% of respondents, respectively. Analysis of telephone interviews revealed four main themes: insomnia as a normal occurrence in prison; the problem of medication in prison; the negative impact of the prison environment; and effective management of insomnia in prison. The current findings suggest that logistical, ethical and security barriers and a lack of staff knowledge and training impact negatively on the management of insomnia in prison.

Simultaneous analysis by Quadrupole-Orbitrap mass spectrometry and UHPLC-MS/MS for the determination of sedative-hypnotics and sleep inducers in adulterated products.

Adulterated products are continuously detected in society and cause problems. In this study, we developed and validated a method for determining synthetic sedative-hypnotics and sleep inducers, including barbital, benzodiazepam, zolpidem, and first-generation antihistamines, in adulterated products using Quadrupole-Orbitrap mass spectrometry and ultrahigh performance liquid chromatography with tandem mass spectrometry. In Quadrupole-Orbitrap mass spectrometry analysis, target compounds were confirmed using a combination of retention time, mass tolerance, mass accuracy, and fragment ions. For quantification, several validation parameters were employed using ultrahigh performance liquid chromatography with tandem mass spectrometry. The limit of detection and limit of quantitation was 0.05-53 and 0.17-177 ng/mL, respectively. The correlation coefficient for linearity was more than 0.995. The intra- and interassay accuracies were 86-110 and 84-111%, respectively. Their precision values were evaluated as within 4.0 (intraday) and 10.7% (interday). Mean recoveries of target compounds in adulterated products ranged from 85 to 116%. The relative standard deviation of stability was less than 10.7% at 4°C for 48 h. The 144 adulterated products obtained over 3 years (2014-2016) from online and in-person vendors were tested using established methods. After rapidly screening with Quadrupole-Orbitrap mass spectrometry, the detected samples were quantified using ultrahigh performance liquid chromatography with tandem mass spectrometry. Two of them were adulterated with phenobarbital.

Emergency department visits involving benzodiazepines and non-benzodiazepine receptor agonists.

OBJECTIVE: Sedative-hypnotic medications (e.g., Benzodiazepines [BZDs] and non-benzodiazepine receptor agonists [nBZRAs]) are associated with adverse events, especially in the elderly, that may require emergency department (ED) treatment. This study assessed outcomes from ED visits attributed to BZDs and/or nBZRAs, and variations in these associations by age group. METHODS: Data came from the 2004-2011 waves of the Drug Abuse Warning Network (DAWN). Visits were categorized as involving: (1) BZDs-only, (2) nBZRAs-only, (3) combination of BZDs and nBZRAs, or (4) any other sedative-hypnotic medication. DAWN also recorded the disposition (i.e., outcome) of the visit. Analyses focused on outcomes indicating a serious disposition defined as hospitalization, patient transfer or death. Using logistic regression, the association of BZD and nBZRA use with visit disposition was assessed after applying sample weights so as to be nationally representative of ED visits in the United States involving medications or illicit substances. RESULTS: Nineteen percent of visits involving other sedative-hypnotics, 28% involving BZDs-only, 20% involving nBZRAs-only and 48% involving a combination of BZDs and nBZRAs resulted in a serious disposition. Compared to visits involving other sedative-hypnotics, visits involving BZDs-only had 66% greater odds (Odds Ratio [OR]=1.66, 95% Confidence Interval [CI]=1.37-2.01), and visits involving a combination of BZDs and nBZRAs had almost four times increased odds of a serious disposition (OR=3.91, 95% CI=2.38-6.41). Results were similar across age groups. CONCLUSIONS: Findings highlight the need for clinical and regulatory initiatives to reduce BZD use, especially in combination with nBZRAs, and to promote treatment with safer alternatives to these medications.

Drugs & the Brain: Case-based Instruction for an Undergraduate Neuropharmacology Course.

In order to transform a traditional large non-majors general education (GE) neurobiology lecture (Drugs & the Brain) into an active learning course, we developed a series of directed mini-cases targeting major drug classes. Humorous and captivating case-based situations were used to better engage and motivate students to solve problems related to neuropharmacology and physiology. Here we provide directed cases, questions and learning outcomes for our opiates mini-cases. In addition, we describe how case studies were incorporated into our course and assessed using peer review and online quizzing. An in-depth analysis of the overall course transformation on student exam performance, opinions and instructor evaluations can be found in the JUNE article Don't Believe the Gripe! Increasing Course Structure in a Large Non-majors Neuroscience Course.

Trends in prescribing of sedative-hypnotic medications in the USA: 1993-2010.

PURPOSE: Non-benzodiazepine receptor agonists (nBZRAs) were developed as an alternative to benzodiazepines (BZDs) to treat insomnia. Little is known about how the introduction of nBZRAs influenced trends in BZD prescribing. We examined BZD and nBZRA prescribing trends from 1993 to 2010. METHODS: We used the National Ambulatory Medical Care Survey to examine 516,118 patient visits between 1993 and 2010. We categorized visits as BZD, nBZRA, or BZD + nBZRA visits based on medications prescribed in each visit and applied linear probability regression models to assess trends in visits. RESULTS: Increases were observed in proportions of visits that were BZD (2.6% in 1993 to 4.4% in 2010, p < 0.001) and nBZRA (0% to 1.4%, p < 0.001). Increases in BZD visits were primarily after 2002, with prescribing in the preceding years remaining relatively stable. We also found increases in BZD + nBZRA visits (0% to 0.4%, p < 0.001). Among patients with sleep disorders, there was an increase in nBZRA visits (2.3% to 13.7%, p < 0.001), and decline in BZD visits (23.5% to 10.8%, p = 0.015). Just under a third (30.8%) of any sedative-hypnotic visits were for adults aged 65+ years, among whom increases in BZD, nBZRA, and BZD + nBZRA visits were observed across the study period. CONCLUSIONS: There were increases in prescribing of nBZRAs between 1993 and 2010. Increases in prescribing of BZDs were also observed, especially after 2002. The introduction of nBZRAs likely resulted in declines in BZD prescribing among those with a sleep disorder, but not other groups. Delivery of behavioral treatments should be encouraged to avert adverse outcomes associated with sedative-hypnotic use. Copyright © 2015 John Wiley & Sons, Ltd.

Sedative-hypnotics and osteoporotic fractures: A systematic review of observational studies with over six million individuals.

We reviewed and meta-analyzed 20 observational studies to examine the relationship between sedative-hypnotic use and osteoporotic fractures. We searched PubMed, Embase, APA PsycINFO, and Web of Science™ for studies that used cohort, case-control, case-crossover, and self-controlled case series designs. We further assessed the quality of each study and performed meta-analyses of association estimates, e.g., odds ratios (ORs). The analysis included 6,084,083 participants and found a slight association between the use of sedative-hypnotics and osteoporotic fractures, with differing strength of associations between different classes of drugs and greater sedative-hypnotics exposure. The pooled estimates ORs for case-control studies were 1.33 (95% CI 0.98-1.80) with benzodiazepines (BZD) and any fractures, 1.32 (95% CI 1.05-1.66) with BZDs and hip fractures, and case-crossover studies were 1.15 (95% CI 0.95-1.41) with BZDs and any fractures, 1.41 (95% CI 1.08-1.85) with Z-drugs and any fractures. The study suggests that more research is needed to aid medical professionals in balancing this potential risk of osteoporotic fractures associated with sedative-hypnotic use against other reported adverse events and anticipated therapy outcomes.

Edward O. Bixler, PhD: from the Apollo project and chimpanzees to sleep epidemiology.

What an honor to write about Dr. Edward O. Bixler's contributions to the sleep field. In 1967, Dr. Bixler published a case report on a chimpanzee with implanted brain electrodes while working at an Air Force base in New Mexico. A few years later, in 1971, he published on the sleep effects of flurazepam in individuals with insomnia together with Dr. Anthony Kales, data that he had collected when the Sleep Research & Treatment Center (SRTC) was housed at the University of California Los Angeles. Dr. Bixler, a meticulous scientist, learned from Dr. Kales, a devoted clinician, to study "the whole patient, and all aspects of sleep," a legacy that continued when the SRTC moved to Penn State in Hershey. Indeed, Dr. Bixler's tenure at Penn State from 1971 until 2019 kept the science of the SRTC focused on that premise and helped translate scientific evidence into clinical care. He not only contributed early to the pharmacology of sleep and the effects of hypnotics, but he was also a pioneer in "sleep epidemiology." His "Prevalence of sleep disorders in the Los Angeles metropolitan area" study of 1979 was the first rigorous epidemiological study on sleep disturbances. Starting in 1990, he established the Penn State Adult Cohort to estimate the prevalence and natural history of sleep-disordered breathing and other sleep disorders in adults. Inspired by life-course epidemiology, he established in 2001 the Penn State Child Cohort to estimate the same phenomena in children. This Living Legend paper captures and highlights Dr. Bixler's enduring legacy to sleep science.

Effects of High-altitude Hypoxia on Drug Metabolism and Pharmacokinetics of Sedative-hypnotic Drugs and Regulatory Mechanism.

Sedative hypnotics effectively improve sleep quality under high-altitude hypoxia by reducing central nervous system excitability. High-altitude hypoxia causes sleep disorders and modifies the metabolism and mechanisms of drug action, impacting medication therapy's effectiveness. This review aims to provide a theoretical basis for the treatment of central nervous system diseases in high-altitude areas by summarizing the progress and mechanism of sedative-hypnotics in hypoxic environments, as well as the impact of high-altitude hypoxia on sleep.

Adult Medical Cannabinoid Use and Changes in Prescription Controlled Substance Use.

Introduction: Nonopioid-based strategies for managing chronic noncancer pain are needed to help reduce overdose deaths. Although lab studies and population-level data suggest that cannabinoids could provide opioid-sparing effects, among medical cannabis participants they may also impact overdose risk by modifying other controlled substance use such as sedative hypnotics. However, no study has combined observational data at the individual level to empirically address interactions between the use of cannabinoids and prescribed controlled substances. Methods: Electronic health records, including prescription drug monitoring program data, from a large multisite medical cannabis program in New York State were abstracted for all participants with noncancer pain and recently prescribed noncannabinoid controlled substances who completed a new intake visit from April 15, 2018-April 14, 2019 and who remained actively in treatment for >180 days. Participants were partitioned into two samples: those with recent opioid use and those with active opioid use and co-use of sedative hypnotics. A patient-month level analysis assessed total average equivalent milligrams by class of drug (i.e., cannabinoid distinguishing tetrahydrocannabinol [THC] vs. cannabidiol [CBD], opioids, and sedative-hypnotics) received as a time-varying outcome measure across each 30-day "month" period postintake for at least 6 months for all participants. Results: Sample 1 of 285 opioid users were 61.1 years of age (±13.5), 57.5% female, and using an average of 49.7 (±98.5) morphine equivalents daily at intake. Unadjusted analyses found a modest decline in morphine equivalents to 43.9 mg (±94.1 mg) from 49.7 (±98.5) in month 1 (p=0.047) while receiving relatively low doses of THC (2.93 mg/day) and CBD (2.15 mg/day). Sample 2 of 95 opioid and sedative-hypnotic users were 60.9 years of age (±13.1), 63.2% female, and using an average of 86.6 (±136.2) morphine equivalents daily, and an average of 4.3 (±5.6) lorazepam equivalents. Unadjusted analyses did not find significant changes in either morphine equivalents (p=0.81) or lorazepam equivalents (p=0.980), and patients similarly received relatively low doses of THC (2.32 mg/day) and CBD (2.24 mg/day). Conclusions: Findings demonstrated minimal to no change in either opioids or sedative hypnotics over the 6 months of medical cannabis use but may be limited by low retention rates, external generalizability, and an inability to account for nonprescribed substance use.

Sedative-hypnotic Co-prescribing with Opioids in a Large Network of Community Health Centers.

OBJECTIVE: When prescribed with opioids, sedative-hypnotics substantially increase the risk of overdose. The objective of this paper was to describe characteristics and trends in opioid sedative-hypnotic co-prescribing in a network of safety-net clinics serving low-income, publicly insured, and uninsured individuals. METHODS: This retrospective longitudinal analysis of prescription orders examined opioid sedative-hypnotic co-prescribing rates between 2009 and 2018 in the OCHIN network of safety-net community health centers. Sedative-hypnotics included benzodiazepine and non-benzodiazepine sedatives (eg, zolpidem). Co-prescribing patterns were assessed overall and across patient demographic and co-morbidity characteristics. RESULTS: From 2009 to 2018, 240 587 patients had ≥1 opioid prescriptions. Most were White (65%), female (59%), and had Medicaid insurance (43%). One in 4 were chronic opioid users (25%). During this period, 55 332 (23%) were co-prescribed a sedative-hypnotic. The prevalence of co-prescribing was highest for females (26% vs 19% for males), non-Hispanic Whites (28% vs 13% for Hispanic to 20% for unknown), those over 44 years of age (25% vs 20% for <44 years), Medicare insurance (30% vs 21% for uninsured to 22% for other/unknown), and among those on chronic opioid therapy (40%). Co-prescribing peaked in 2010 (32%) and declined steadily through 2018 (20%). Trends were similar across demographic subgroups. Co-prescribed sedative-hypnotics remained elevated for those with chronic opioid use (27%), non-Hispanic Whites (24%), females (23%), and those with Medicare (23%) or commercial insurance (22%). CONCLUSIONS: Co-prescribed sedative-hypnotic use has declined steadily since 2010 across all demographic subgroups in the OCHIN population. Concurrent use remains elevated in several population subgroups.

Suspected suicides and suicide attempts involving antipsychotic or sedative-hypnotic medications reported to America's Poison Centers, 2000-2021.

OBJECTIVE: To investigate the patterns and trends of suspected suicides and suicide attempts involving antipsychotic or sedative-hypnotic medications reported to United States poison centers. METHODS: Data from the National Poison Data System for 2000 through 2021 were retrospectively analyzed. RESULTS: There were 972,975 suspected suicides and suicide attempts with antipsychotics or sedative-hypnotics ranked as the primary substance reported to poison centers from 2000-2021, averaging 44,226 cases annually. Most (85.6%) cases occurred among individuals >19 years old, females accounted for 63.5% of cases, and 51.8% were single-substance exposures. The rate of reported exposures per 100,000 United States population increased significantly from 27.2 in 2000 to 49.1 in 2008 (P < 0.0001), then plateaued to 49.6 in 2016 (P = 0.1497), followed by a significant decrease to 38.7 in 2021 (P < 0.0001). Individuals 13-19 years old demonstrated the greatest increase in rate from 28.4 in 2000 to 79.6 in 2021 (P < 0.0001). Approximately half (48.8%) of primary substance exposures were benzodiazepines, followed by antipsychotic medications (36.7%) and other types of sedative/hypnotic/anti-anxiety or antipsychotic medications (14.6%). Most primary substance exposures were admitted to a critical care or non-critical care unit (43.3%) or directly to a psychiatric facility (27.9%), and 36.1% were associated with in a serious medical outcome, including 1,330 deaths. Individuals >49 years old were more likely to experience a serious medical outcome (relative risk = 1.25, 95% CI: 1.24-1.26), including death (relative risk = 3.06, 95% CI: 2.74-3.41), or be admitted to a critical care or non-critical care unit (relative risk = 1.24, 95% CI: 1.23-1.24) than younger individuals. CONCLUSIONS: Suspected suicides and suicide attempts involving antipsychotic or sedative-hypnotic medications increased during the 22-year study period, especially among individuals 13-19 years old, and these cases often had severe clinical consequences. Based on the characteristics and trends identified in this study, increased prevention efforts are warranted to help prevent these suspected suicides and suicide attempts.

A health-system-embedded deprescribing intervention targeting patients and providers to prevent falls in older adults (STOP-FALLS trial): study protocol for a pragmatic cluster-randomized controlled trial.

BACKGROUND: Central nervous system (CNS) active medications have been consistently linked to falls in older people. However, few randomized trials have evaluated whether CNS-active medication reduction reduces falls and fall-related injuries. The objective of the Reducing CNS-active Medications to Prevent Falls and Injuries in Older Adults (STOP-FALLS) trial is to test the effectiveness of a health-system-embedded deprescribing intervention focused on CNS-active medications on the incidence of medically treated falls among community-dwelling older adults. METHODS: We will conduct a pragmatic, cluster-randomized, parallel-group, controlled clinical trial within Kaiser Permanente Washington to test the effectiveness of a 12-month deprescribing intervention consisting of (1) an educational brochure and self-care handouts mailed to older adults prescribed one or more CNS-active medications (aged 60 + : opioids, benzodiazepines and Z-drugs; aged 65 + : skeletal muscle relaxants, tricyclic antidepressants, and antihistamines) and (2) decision support for their primary health care providers. Outcomes are examined over 18-26 months post-intervention. The primary outcome is first incident (post-baseline) medically treated fall as determined from health plan data. Our sample size calculations ensure at least 80% power to detect a 20% reduction in the rate of medically treated falls for participants receiving care within the intervention (n = 9) versus usual care clinics (n = 9) assuming 18 months of follow-up. Secondary outcomes include medication discontinuation or dose reduction of any target medications. Safety outcomes include serious adverse drug withdrawal events, unintentional overdose, and death. We will also examine medication signetur fields for attempts to decrease medications. We will report factors affecting implementation of the intervention. DISCUSSION: The STOP-FALLS trial will provide new information about whether a health-system-embedded deprescribing intervention that targets older participants and their primary care providers reduces medically treated falls and CNS-active medication use. Insights into factors affecting implementation will inform future research and healthcare organizations that may be interested in replicating the intervention. TRIAL REGISTRATION: ClinicalTrial.gov NCT05689554. Registered on 18 January 2023, retrospectively registered.

Trends in Stimulant and Sedative/Hypnotic Dispensing: An Exploratory Study.

OBJECTIVE: To investigate patterns and trends of co-prescriptions of stimulants and sedatives within the last 6 years at a tertiary care center. METHOD: Patients 18 years of age and older who were dispensed at least one stimulant prescription from an institutional pharmacy between 1/1/2015 and 7/1/2021 were included. Prescription data for any co-prescribed sedative/hypnotic were collected. RESULTS: Both the number of stimulant dispenses and the number of patients with stimulant dispenses increased significantly with yearly incidence rate ratios of 1.115 (95% CI [1.110, 1.119]) and 1.090 (95% CI [1.084, 1.096]), respectively. The number of patients with a stimulant dispensed who also had a benzodiazepine or "Z-drug" sedative-hypnotic dispensed at any point in the search timeframe increased significantly with incidence rate ratios of 1.077 and 1.092, respectively. The number of stimulant dispenses, number of patients with stimulant dispenses, and number of patients with a stimulant dispensed who also had both a benzodiazepine and Z-drug dispensed at any point in the search timeframe increased significantly more in Non-White than in White patients. CONCLUSIONS: The results confirm previous findings of increases in dispensing of stimulants over the past 6 years and report increased polypharmacy of stimulants and sedative-hypnotics.

Quantification of sedative-hypnotics in human urine and plasma via polystyrene-based solid phase extraction-LC-MS/MS analysis.

Owing to the adverse effects of the overuse of common sedative-hypnotics on human health, the development of an efficient analytical method for the detection of drugs in clinical emergencies and forensic science is significant. Although conventional analytical methods, such as immunoassay, liquid chromatography (LC), gas chromatography, and mass spectrometry (MS) are reliable, they exhibit drawbacks such low-throughput screening and high costs. Thus, in this study, we developed a novel high-throughput method consisting of a polystyrene-based solid phase extraction (SPE) and an LC with tandem MS analysis for the detection of drugs in biological samples and investigated its precision and reliability via the detection of twelve sedative-hypnotics in human urine and plasma samples. Good linear relationship (r ≥ 0.99) were achieved within the concentration range of 0.1-20 ng/mL for the 12 analytes in urine samples. Whereas, in the plasma samples, the correlation coefficient was greater than 0.99 in the concentration range 1-100 ng/mL for lorazepam and clonazepam and in the range 0.5-100 ng/mL for the remaining analytes. The intra- and inter-day precision, autosampler and freeze-thaw stabilities, and lower limit of quantitation (LLOQ) for all twelve analytes in the urine and plasma samples were favorable. Furthermore, sedative-hypnotics were detected in clinical samples obtained from the Hebei General Hospital using this method. These results indicated that the analytical method proposed in this study can be effectively applied in toxicology screening and drug abuse monitoring.The method developed in this study could be applied in clinical and forensic toxicology laboratories for sedative-hypnotic drug screening, providing support for drug abuse monitoring and clinical diagnosis.