Treatment of cholinergic-induced status epilepticus with polytherapy targeting GABA and glutamate receptors.

Despite new antiseizure medications, the development of cholinergic-induced refractory status epilepticus (RSE) continues to be a therapeutic challenge as pharmacoresistance to benzodiazepines and other antiseizure medications quickly develops. Studies conducted by Epilepsia. 2005;46:142 demonstrated that the initiation and maintenance of cholinergic-induced RSE are associated with trafficking and inactivation of gamma-aminobutyric acid A receptors (GABAA R) thought to contribute to the development of benzodiazepine pharmacoresistance. In addition, Dr. Wasterlain's laboratory reported that increased N-methyl-d-aspartate receptors (NMDAR) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR) contribute to enhanced glutamatergic excitation (Neurobiol Dis. 2013;54:225; Epilepsia. 2013;54:78). Thus, Dr. Wasterlain postulated that targeting both maladaptive responses of reduced inhibition and increased excitation that is associated with cholinergic-induced RSE should improve therapeutic outcome. We currently review studies in several animal models of cholinergic-induced RSE that demonstrate that benzodiazepine monotherapy has reduced efficacy when treatment is delayed and that polytherapy with drugs that include a benzodiazepine (eg midazolam and diazepam) to counter loss of inhibition, concurrent with an NMDA antagonist (eg ketamine) to reduce excitation provide improved efficacy. Improved efficacy with polytherapy against cholinergic-induced seizure is demonstrated by reduction in (1) seizure severity, (2) epileptogenesis, and (3) neurodegeneration compared with monotherapy. Animal models reviewed include pilocarpine-induced seizure in rats, organophosphorus nerve agent (OPNA)-induced seizure in rats, and OPNA-induced seizure in two mouse models: (1) carboxylesterase knockout (Es1-/- ) mice which, similarly to humans, lack plasma carboxylesterase and (2) human acetylcholinesterase knock-in carboxylesterase knockout (KIKO) mice. We also review studies showing that supplementing midazolam and ketamine with a third antiseizure medication (valproate or phenobarbital) that targets a nonbenzodiazepine site rapidly terminates RSE and provides further protection against cholinergic-induced SE. Finally, we review studies on the benefits of simultaneous compared with sequential drug treatments and the clinical implications that lead us to predict improved efficacy of early combination drug therapies. The data generated from seminal rodent studies of efficacious treatment of cholinergic-induced RSE conducted under Dr. Wasterlain's guidance suggest that future clinical trials should treat the inadequate inhibition and temper the excess excitation that characterize RSE and that early combination therapies may provide improved outcome over benzodiazepine monotherapy.

Management of Phenibut Use Disorder and Withdrawal in a Geriatric Patient.

Phenibut is a misused substance which has shown an increase in use over the past decade. Marketed as a "dietary supplement," it is not approved in the United States for use and is not regulated by the Food and Drug Administration. The substance, however, is readily available for purchase through online markets. It has a similar drug profile as alcohol, gabapentin and benzodiazepines. Clinical effects of this drug include physiologic dependence, euphoria, anxiolysis, antispasticity, sedation, and possible nootropic properties. While there are emerging new cases of managing phenibut withdrawal, no cases currently feature phenibut addiction and withdrawal management in the geriatric population. Here we discuss such a case of phenibut addiction and withdrawal in a 68-year-old male who initially began misusing phenibut to alleviate anxiety and insomnia precipitated by worsening affective disorder, sedative, hypnotic, or anxiolytic use disorder, and alcohol use disorder.

Use of benzodiazepines is the risk factor for infection in patients aged 80 years or older with diffuse large B-cell lymphoma: A single-institution retrospective study.

BACKGROUND: The number of patients aged 80 years or older with diffuse large B-cell lymphoma (DLBCL) is increasing, and the incidence rate of the disease in this population group reaches up to 20%. The risk of infection is higher in older patients than in other patients. Although hypnotic drugs are frequently detected as potentially inappropriate medications, it is unclear whether hypnotic drugs affect the occurrence of infection during chemotherapy. Here, we investigated whether the use of hypnotic drugs is associated with infection during first-line chemotherapy in patients with diffuse large B-cell lymphoma (DLBCL) aged 80 years or older. METHODS: Japanese patients aged 80 years or older with diffuse large B-cell lymphoma who had received first-line chemotherapy at Fujita Health University Hospital from January 2005 to March 2020 were enrolled in this retrospective cohort study. The primary study outcome was the identification of the risk factor for infection during first-line chemotherapy. RESULTS: This study included 65 patients received first-line chemotherapy. The proportion of patients with National Comprehensive Cancer Network-international prognostic index ≥ 6 was higher in the infection group than in the non-infection group. The relative dose intensity of each anticancer drug (cyclophosphamide, adriamycin, and vincristine) and dose of prednisolone did not significantly differ between the two groups. Multivariate analysis showed that the use of benzodiazepines was a risk factor for infection (odds ratio, 4.131 [95% confidence interval: 1.225-13.94], P = 0.022). CONCLUSION: DLBCL patients using benzodiazepines should be monitored for infection symptoms during chemotherapy.

The negative impact of vitamin D on antipsychotic drug exposure may counteract its potential benefits in schizophrenia.

AIMS: Patients with schizophrenia frequently show insufficient vitamin D levels, which are associated with somatic comorbidity and may contribute to psychopathology. For many reasons, vitamin D supplementation may be indicated for this patient cohort. However, there is growing evidence for a vitamin D-mediated increase of drug metabolism by induction of cytochrome P450 (CYP) 3A4. Hence, this study aimed to assess vitamin D's impact on both antipsychotic drug concentrations and psychopathology in a non-interventional manner. METHODS: Totals of 107 serum concentrations of different antipsychotic drugs (amisulpride, aripiprazole, clozapine, olanzapine, quetiapine and risperidone), 80 serum concentrations of vitamin D and psychopathological assessments were obtained from 80 patients with schizophrenia. The impact of Vitamin D on antipsychotic drug concentrations and symptomatology was assessed using a generalized linear model, path and correlation analyses. RESULTS: We observed a negative relationship between vitamin D and dose-adjusted antipsychotic drug concentrations, which was particularly pronounced for drugs which are predominantly metabolized via CYP3A4 (i.e., aripiprazole and quetiapine). A path analysis suggested a relieving effect of vitamin D on symptomatology which was, however, counteracted by its negative impact on antipsychotic drug levels. Finally, patients with vitamin D levels above the median exhibited a significantly higher proportion of therapeutically insufficient dose-normalized drug concentrations of aripiprazole and quetiapine. CONCLUSION: Despite vitamin D's potential benefits on physical and mental health, clinicians should be aware of its negative impact on blood concentrations of antipsychotics metabolized by CYP3A4 in patients with schizophrenia. Therefore, when considering its supplementation, therapeutic drug monitoring should be applied to guide dose adjustment.

A Case of Phenibut Directed Detoxification Leading to Toxicity During the COVID-19 Pandemic.

BACKGROUND: Phenibut is a non-Food and Drug Administration-approved gamma-aminobutyric acid analog marketed in the United States as an anxiolytic, cognitive enhancer, and alcohol withdrawal treatment through online supplement vendors. In this case report, we describe a woman's self-directed detoxification with phenibut used to manage withdrawal symptoms from fentanyl and benzodiazepines in March 2020 during the height of the COVID-19 pandemic. CASE: A 38-year-old woman with severe opioid, benzodiazepine, gabapentin, stimulant use disorders developed altered mental status after oral phenibut ingestion intended to help self-manage opioid and benzodiazepine withdrawal. She chose self-directed detoxification as she feared COVID-19 exposure in detoxification facilities. Her altered mental status drove her to jump out a third-story window causing multiple spinal fractures. After a long hospitalization, she self-directed her discharge home due to concerns about COVID-19. Her premature discharge disrupted opioid and benzodiazepine use disorder treatment plans. CONCLUSION: This case highlights the risks of phenibut use for selfdirected detoxification. With COVID-19 related changes in the drug supply, people may be more likely to use online pharmaceuticals, therefore, substance use assessments should inquire about the online acquisition of new psychoactive drugs. Public health messaging regarding the risks of infectious disease transmission in addiction care settings is needed to guide addiction treatment choices among people who use substances.

Outcomes After Implementation of a Benzodiazepine-Sparing Alcohol Withdrawal Order Set in an Integrated Health Care System.

Importance: Alcohol withdrawal syndrome (AWS) is a common inpatient diagnosis managed primarily with benzodiazepines. Concerns about the adverse effects associated with benzodiazepines have spurred interest in using benzodiazepine-sparing treatments. Objective: To evaluate changes in outcomes after implementation of a benzodiazepine-sparing AWS inpatient order set that included adjunctive therapies (eg, gabapentin, valproic acid, clonidine, and dexmedetomidine). Design, Setting, and Participants: This difference-in-differences quality improvement study was conducted among 22 899 AWS adult hospitalizations from October 1, 2014, to September 30, 2019, in the Kaiser Permanente Northern California integrated health care delivery system. Data were analyzed from September 2020 through November 2021. Exposures: Implementation of the benzodiazepine-sparing AWS order set on October 1, 2018. Main Outcomes and Measures: Adjusted rate ratios for medication use, inpatient mortality, length of stay, intensive care unit admission, and nonelective readmission within 30 days were calculated comparing postimplementation and preimplementation periods among hospitals with and without order set use. Results: Among 904 540 hospitalizations in the integrated health care delivery system during the study period, AWS was present in 22 899 hospitalizations (2.5%), occurring among 16 323 unique patients (mean [SD] age, 57.1 [14.8] years; 15 764 [68.8%] men). Of these hospitalizations, 12 889 (56.3%) used an order set for alcohol withdrawal. Among hospitalizations with order set use, any benzodiazepine use decreased after implementation from 6431 hospitalizations (78.1%) to 2823 hospitalizations (60.7%) (P < .001), with concomitant decreases in the mean (SD) total dosage of lorazepam before vs after implementation (19.7 [38.3] mg vs 6.0 [9.1] mg; P < .001). There were also significant changes from before to after implementation in the use of adjunctive medications, including gabapentin (2413 hospitalizations [29.3%] vs 2814 hospitalizations [60.5%]; P < .001), clonidine (1476 hospitalizations [17.9%] vs 2208 hospitalizations [47.5%]; P < .001), thiamine (6298 hospitalizations [76.5%] vs 4047 hospitalizations [87.0%]; P < .001), valproic acid (109 hospitalizations [1.3%] vs 256 hospitalizations [5.5%]; P < .001), and phenobarbital (412 hospitalizations [5.0%] vs 292 hospitalizations [6.3%]; P = .003). Compared with AWS hospitalizations without order set use, use of the benzodiazepine-sparing order set was associated with decreases in intensive care unit use (adjusted rate ratio [ARR], 0.71; 95% CI, 0.56-0.89; P = .003) and hospital length of stay (ARR, 0.71; 95% CI, 0.58-0.86; P < .001). Conclusions and Relevance: This study found that implementation of a benzodiazepine-sparing AWS order set was associated with decreased use of benzodiazepines and favorable trends in outcomes. These findings suggest that further prospective research is needed to identify the most effective treatments regimens for patients hospitalized with alcohol withdrawal.

Effects of Berberine on Gut Microbiota in Patients with Mild Metabolic Disorders Induced by Olanzapine.

Secondary metabolic disturbances in patients with schizophrenia or bipolar disorder may be attributed to olanzapine. It is important to prevent mild metabolic disorders progressing to metabolic syndrome. This study aims to investigate the effects of berberine on intestinal flora in patients with mild metabolic disorders induced by olanzapine. A total of 132 patients with schizophrenia, bipolar disorder, or schizoaffective psychosis that had been treated with olanzapine for at least 9 months were randomly assigned ([Formula: see text] = 66 each) to receive berberine or placebo tablets for 12 weeks. Metabolic assessments and intestinal flora were quantified at baseline and after 4, 8, and 12 weeks of treatment. Incidence rates of adverse reactions were recorded. FPG, FPI, HOMA-IR, HbA1, TG, BMI, and WC were significantly lower in patients who received berberine compared to placebo after 12 weeks of treatment ([Formula: see text]< 0.05). The abundance of firmicutes and coliform were significantly lower and the abundance of bacteroides significantly higher in patients who received berberine compared to placebo after 12 weeks of treatment ([Formula: see text]< 0.05). In patients who received berberine, the abundance of firmicutes was significantly decreased, and the abundance of bacteroides was significantly increased, and in patients who received placebo, the abundance of firmicutes was significantly increased post-treatment, compared to baseline (both [Formula: see text]< 0.05). In conclusions, berberine may regulate intestinal flora and metabolism in patients with schizophrenia or bipolar disorder and mild metabolic disturbances induced by olanzapine.

Profiles of polypharmacy in older adults and medication associations with signs of aspiration.

BACKGROUND: Polypharmacy and specific medication classes are prevalent in older adults. Their relationships with swallowing disorders are not well explored, which would best be managed holistically, with consideration of medication profiles. This study aimed to establish profiles of polypharmacy in older adults and investigate the associations of polypharmacy and medication class with signs of aspiration during swallowing. METHODS: This was a secondary retrospective analysis of data from 291 adults aged 60 years and older. Polypharmacy was profiled numerically and described. Multivariate logistic regression was used to identify associations between medication classes with signs of aspiration, while controlling for independent variables of demographics, functional status, and medical history. RESULTS: Three distinct profiles of polypharmacy were described. Higher numbers of medications were associated with higher age, lower functional status, nursing home residency, multimorbidity, and showing signs of aspiration. Thirty-four classes of medications were found in this study, benzodiazepines were the only class independently associated with signs of aspiration. CONCLUSIONS: Different profiles of polypharmacy can be observed in older adults, but none were independently associated with signs of aspiration. In addition to known demographic and functional status variables, benzodiazepine-use was found to be independently associated with signs of aspiration (p = .005, B = 7.94).

Hyperphosphorylated tau aggregation and cytotoxicity modulators screen identified prescription drugs linked to Alzheimer's disease and cognitive functions.

The neurodegenerative Alzheimer's disease (AD) affects more than 30 million people worldwide. There is thus far no cure or prevention for AD. Aggregation of hyperphosphorylated tau in the brain correlates with the cognitive decline of patients of AD and other neurodegenerative tauopathies. Intracerebral injection of tau aggregates isolated from tauopathy brains causes similar pathology in the recipient mice, demonstrating the pathogenic role of abnormally phosphorylated tau. Compounds controlling the aggregation of hyperphosphorylated tau therefore are probable modulators for the disease. Here we report the use of recombinant hyperphosphorylated tau (p-tau) to identify potential tauopathy therapeutics and risk factors. Hyperphosphorylation renders tau prone to aggregate and to impair cell viability. Taking advantage of these two characters of p-tau, we performed a screen of a 1280-compound library, and tested a selective group of prescription drugs in p-tau aggregation and cytotoxicity assays. R-(-)-apomorphine and raloxifene were found to be p-tau aggregation inhibitors that protected p-tau-treated cells. In contrast, a subset of benzodiazepines exacerbated p-tau cytotoxicity apparently via enhancing p-tau aggregation. R-(-)apomorphine and raloxifene have been shown to improve cognition in animals or in humans, whereas benzodiazepines were linked to increased risks of dementia. Our results demonstrate the feasibility and potential of using hyperphosphorylated tau-based assays for AD drug discovery and risk factor identification.

Efficacy, acceptability, and tolerability of all available treatments for insomnia in the elderly: a systematic review and network meta-analysis.

OBJECTIVES: Symptoms of insomnia are highly prevalent in the elderly. A significant number of pharmacological and non-pharmacological interventions exist, but, up-to-date, their comparative efficacy and safety has not been sufficiently assessed. METHODS: We integrated the randomized evidence from every available treatment for insomnia in the elderly (>65 years) by performing a network meta-analysis. Several electronic databases were searched up to May 25, 2019. The two primary outcomes were total sleep time and sleep quality. Data for other 6 efficacy and 8 safety outcomes were also analyzed. RESULTS: Fifty-three RCTs with 6832 participants (75 years old on average) were included, 43 of which examined the efficacy of one or more drugs. Ten RCTs examined the efficacy of non-pharmacological interventions and were evaluated only with pairwise meta-analyses because they were disconnected from the network. The overall confidence in the evidence was very low primarily due to the small amount of data per comparison and their sparse connectedness. Several benzodiazepines, antidepressants, and z-drugs performed better in both primary outcomes, but few comparisons had data from more than one trial. The limited evidence on non-pharmacological interventions suggested that acupressure, auricular acupuncture, mindfulness-based stress reduction program, and tart cherry juice were better than their control interventions. Regarding safety, no clear differences were detected among interventions due to large uncertainty. CONCLUSIONS: Insufficient evidence exists on which intervention is more efficacious for elderly patients with insomnia. More RCTs, with longer duration, making more direct interventions among active treatments and presenting more outcomes are urgently needed.

Benzodiazepine Use and Risk of Acute Angle-Closure Glaucoma: A Population-Based Case-Crossover Study.

INTRODUCTION: Theoretically, benzodiazepines (BZDs) can narrow the iridocorneal angle and induce acute angle-closure glaucoma (AACG). However, little evidence exists regarding this association. OBJECTIVE: The objective of this study was to assess whether the use of BZDs is associated with the risk of AACG. METHODS: We conducted a population-based case-crossover study using the nationwide claims database of the National Health Insurance Service in Korea. Patients with newly diagnosed AACG-between 1 January 2013 and 31 December 2016-who had received at least one BZD prescription prior to AACG diagnosis were enrolled. The date of AACG diagnosis was set as the index date. We assessed BZD use by each patient during a 30-day case period prior to the index date and three consecutive control periods that preceded this date. We used conditional logistic regression that adjusted for concomitant medications to determine the odds ratio for the use of BZDs in the case period compared with that in the control period in patients with incident AACG. RESULTS: Of the 11,093 patients with incident AACG, 6709 received a prescription for BZD prior to diagnosis. BZD use was associated with an increased risk of AACG [adjusted odds ratio (aOR) = 1.40; 95% confidence interval (CI) 1.27-1.54]. AACG risk was similar for short-acting (aOR = 1.40, 95% CI 1.24-1.57) and long-acting BZDs (aOR = 1.33, 95% CI 1.18-1.50). CONCLUSION: We found that BZD use was associated with AACG risk in the Korean population. Clinicians should carefully monitor the occurrence of visual disturbance in BZD-treated patients.

Complicated Withdrawal Phenomena During Benzodiazepine Cessation in Older Adults.

The cause of prolonged or recurrent symptoms following the cessation of long-term benzodiazepine use is proposed to be related to downregulation and allosteric decoupling of the γ-aminobutyric acid/benzodiazepine receptor complex. This case series describes 2 patients with prolonged (>2 weeks) recurrent complications during attempted tapering of benzodiazepine doses after long-term treatment. Excited catatonia developed in a 90-year-old woman, and prolonged delirium developed in a 69-year-old woman. Both patients showed improvement of symptoms after resumption of higher doses of benzodiazepine treatment and recurrence of symptoms when the dose was again lowered. Caution should be exercised regarding the long-term use of benzodiazepines in older adults (aged ≥65 years). Tapering of benzodiazepines in older patients after long-term treatment may require slow decreases in dose over long periods. Psychotherapeutic interventions, such as brief cognitive therapy with psychoeducation and motivational enhancement, and osteopathic manipulative treatment to decrease paravertebral muscle tension may be beneficial during the tapering process.

Economic impact of potentially inappropriate prescribing and related adverse events in older people: a cost-utility analysis using Markov models.

OBJECTIVES: To determine the economic impact of three drugs commonly involved in potentially inappropriate prescribing (PIP) in adults aged ≥65 years, including their adverse effects (AEs): long-term use of non-steroidal anti-inflammatory drugs (NSAIDs), benzodiazepines and proton pump inhibitors (PPIs) at maximal dose; to assess cost-effectiveness of potential interventions to reduce PIP of each drug. DESIGN: Cost-utility analysis. We developed Markov models incorporating the AEs of each PIP, populated with published estimates of probabilities, health system costs (in 2014 euro) and utilities. PARTICIPANTS: A hypothetical cohort of 65 year olds analysed over 35 1-year cycles with discounting at 5% per year. OUTCOME MEASURES: Incremental cost, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios with 95% credible intervals (CIs, generated in probabilistic sensitivity analysis) between each PIP and an appropriate alternative strategy. Models were then used to evaluate the cost-effectiveness of potential interventions to reduce PIP for each of the three drug classes. RESULTS: All three PIP drugs and their AEs are associated with greater cost and fewer QALYs compared with alternatives. The largest reduction in QALYs and incremental cost was for benzodiazepines compared with no sedative medication (€3470, 95% CI €2434 to €5001; -0.07 QALYs, 95% CI -0.089 to -0.047), followed by NSAIDs relative to paracetamol (€806, 95% CI €415 and €1346; -0.07 QALYs, 95% CI -0.131 to -0.026), and maximal dose PPIs compared with maintenance dose PPIs (€989, 95% CI -€69 and €2127; -0.01 QALYs, 95% CI -0.029 to 0.003). For interventions to reduce PIP, at a willingness-to-pay of €45 000 per QALY, targeting NSAIDs would be cost-effective up to the highest intervention cost per person of €1971. For benzodiazepine and PPI interventions, the equivalent cost was €1480 and €831, respectively. CONCLUSIONS: Long-term benzodiazepine and NSAID prescribing are associated with significantly increased costs and reduced QALYs. Targeting inappropriate NSAID prescribing appears to be the most cost-effective PIP intervention.

Opioid Adjuncts: Optimizing Opioid Therapy With Nonopioid Medications.

In this article, we describe a variety of medications that physicians managing outpatient chronic pain should familiarize themselves with to better aid their approach to multimodal pain therapy. Physicians should always consider the use of an adjuvant or coanalgesic drug as first-line treatments. Although many of these medications are not primarily analgesics, in clinical practice they have independent analgesic effects or synergistic analgesic properties when used with opioids. The use of adjunct analgesics reduces opioid-related adverse effects and optimizes pain management. Although there may be some medication overlap with this section and the ERAS section, the purpose of this article is to understand prolonged use in the outpatient setting to reduce opioid use or limit opioid dose with adjuvant therapy.

Prescription of Benzodiazepines and Related Drugs in Patients with Mild Cognitive Deficits and Alzheimer's Disease.

INTRODUCTION: Benzodiazepines and related drugs (BZDR) should be avoided in patients with cognitive impairment. We evaluated the relationship between a BZDR treatment and the health status of patients with Alzheimer's disease (AD). METHODS: Cross-sectional study in 395 AD patients using bivariate and multiple logistic analyses to assess correlations between the prescription of BZDR and patients' characteristics (cognitive and functional capacity, health-related quality of life (HrQoL), neuropsychiatric symptoms). RESULTS: BZDR were used in 12.4% (n=49) of all participants. In bivariate analyses, the prescription was associated with a lower HrQoL, a higher need of care, and the presence of anxiety. Multivariate models revealed a higher risk of BZDR treatment in patients with depression (OR 3.85, 95% CI: 1.45 - 10.27). Community-dwelling participants and those treated by neurologists/psychiatrists had a lower risk of receiving BZDR (OR 0.33, 95% CI: 0.12 - 0.89 and OR 0.16, 95% CI: 0.07 - 0.36). DISCUSSION: The inappropriate use of BZDR conflicts with national and international guidelines. We suggest evaluating indications and treatment duration and improving the knowledge of alternative therapies in healthcare institutions.

Correlates of Benzodiazepine Use and Adverse Outcomes Among Patients with Chronic Pain Prescribed Long-term Opioid Therapy.

OBJECTIVE: To examine the correlates and odds of receiving overlapping benzodiazepine and opioid prescriptions and whether co-prescription was associated with greater odds of falling or visiting the emergency department. DESIGN: Cross-sectional study. SETTING: A large private integrated health system and a Veterans Health Administration integrated health system. SUBJECTS: Five hundred seventeen adults with musculoskeletal pain and current prescriptions for long-term opioid therapy. METHODS: A multivariate logistic regression model examined correlates of having overlapping benzodiazepine and opioid prescriptions in the year before enrollment in the cross-sectional study. Negative binomial models analyzed the number of falls in the past three months and past-year emergency department visits. In addition to propensity score adjustment, models controlled for demographic characteristics, psychiatric diagnoses, medications, overall comorbidity score, and opioid morphine equivalent dose. RESULTS: Twenty-five percent (N = 127) of participants had co-occurring benzodiazepine and opioid prescriptions in the prior year. Odds of receiving a benzodiazepine prescription were significantly higher among patients with the following psychiatric diagnoses: anxiety disorder (adjusted odds ratio [AOR] = 4.71, 95% confidence interval [CI] = 2.67-8.32, P < 0.001), post-traumatic stress disorder (AOR = 2.24, 95% CI = 1.14-4.38, P = 0.019), and bipolar disorder (AOR = 3.82, 95% CI = 1.49-9.81, P = 0.005). Past-year overlapping benzodiazepine and opioid prescriptions were associated with adverse outcomes, including a greater number of falls (risk ratio [RR] = 3.27, 95% CI = 1.77-6.02, P = 0.001) and emergency department visits (RR = 1.66, 95% CI = 1.08-2.53, P = 0.0194). CONCLUSIONS: Among patients with chronic pain prescribed long-term opioid therapy, one-quarter of patients had co-occurring prescriptions for benzodiazepines, and dual use was associated with increased odds of falls and emergency department visits.

Problematic Medication With Benzodiazepines, "Z-drugs", and Opioid Analgesics.

BACKGROUND: An estimated 1.4 to 2.6 million people in German suffer from drug dependence. Most of them are long-term users of benzodiazepines (BZD), Z drugs (ZD), or opioid analgesics (OA). METHODS: This analysis is based on prescription data from patients of the national statutory health insurance system in the German federal states of Schleswig-Holstein, Hamburg, Bremen, and Lower Saxony. Drug-taking trends, duration, dosage, and long-term use of BZD, ZD, and OA in the years 2006 to 2015 are analyzed; prevalences are estimated for the years 2006 to 2016. RESULTS: In 2006, 7.7% of patients received at least one prescription for a BZD, ZD, or OA; in 2016, 7.0% did. Over the period of analysis, a marked drop was seen in prescriptions of BZD and a slight fall in prescriptions of ZD (2006: BZD 3.5%, ZS 1.1%; 2016: BZD 2.0%, ZS 0.8%), but there was also an increase in prescriptions of OA, from 4.2% to 4.9%. The number of defined daily doses (DDD) prescribed per year fell for both BZD and ZD. For OA, the number of DDD prescribed per year rose from 2006 to 2009 and decreased by a small amount in subsequent years. The proportions of BZD and ZD patients who had long-term prescriptions fell over time, while the corresponding percentage of OA patients rose. CONCLUSION: Nearly one-fifth of all prescriptions for BZD were long-term prescriptions for an entire year, in violation of the relevant guidelines. The rising prevalence of OA use was in the expected range in view of the aging population, but the number of prescriptions rose among younger patients as well. This trend toward more common treatment with opioid analgesics should be critically examined.

Engaging Integrated Health Teams to Decrease the Risk of Controlled Substance Use for Individuals With Serious Mental Illness.

The United States is facing an opioid epidemic that is virulent in its lethality and includes morbidity and mortality related to prescription opioids. Overuse of another class of drugs- benzodiazepines-has received less media attention, but also poses the threat of tolerance, dependence, and death, especially in combination with opioids or alcohol. These negative outcomes are not distributed evenly over the population but are especially prevalent in vulnerable populations. One such vulnerable population comprises individuals with serious mental illness. Professionals who serve this population are challenged by an often-fragmented health care system to collaborate with patients and other professionals to reduce risks and improve outcomes. This article examines strategies for addressing risks associated with the use of benzodiazepines and opioids in this population within the context of an integrated interprofessional team. Recommendations include (a) building consensus on the team, (b) providing education for all stakeholders, and (c) enhancing care coordination and patient access to effective treatments. [Journal of Psychosocial Nursing and Mental Health Services, 56(12), 11-15.].