Treatment Failure and Long-Term Prescription Risk for Guideline-Recommended Hypnotics in Japan.

Importance: Although insomnia guidelines recommend the use of several individual hypnotics, the most useful hypnotic for treating insomnia in a clinical setting remains unclear. Objective: To determine which guideline-recommended hypnotics have lower risks of monotherapy failure and which hypnotics have a higher risk of long-term prescription for insomnia treatment. Design, Setting, and Participants: This retrospective observational cohort study used data from the Japan Medical Data Center Claims Database from April 1, 2005, to March 31, 2021. Participants included adults whose first prescribed pharmaceutical treatment for insomnia was guideline-recommended hypnotic monotherapy. Data were analyzed from December 24, 2022, to September 26, 2023. Exposures: Suvorexant, ramelteon, eszopiclone, zolpidem, and triazolam monotherapy. Main Outcomes and Measures: The primary outcome was monotherapy failure, defined as a change in hypnotic or having an additional hypnotic prescribed for insomnia within 6 months of the first prescription of a guideline-recommended hypnotic monotherapy. The secondary outcome was monotherapy discontinuation, defined as no prescription of any hypnotic for 2 consecutive months within 6 months after prescribing a guideline-recommended hypnotic in patients for whom monotherapy did not fail. Monotherapy failure and discontinuation were compared using Cox proportional hazards and logistic regression models, respectively. Results: The study included 239 568 adults (median age, 45 [IQR, 34-55] years; 50.2% women) whose first prescription for insomnia was guideline-recommended hypnotic monotherapy. During the 6-month follow-up period, 24 778 patients (10.3%) experienced failure of monotherapy with a guideline-recommended hypnotic. In comparison with eszopiclone, there were more cases of monotherapy failure for ramelteon (adjusted hazard ratio [AHR], 1.23 [95% CI], 1.17-1.30; P < .001), fewer cases for zolpidem (AHR, 0.84 [95% CI, 0.81-0.87]; P < .001) and triazolam (AHR, 0.82 [95% CI, 0.78-0.87]; P < .001), and no significant difference between suvorexant and eszopiclone. Among those without monotherapy failure, monotherapy was discontinued in 84.6% of patients, with more discontinuations for ramelteon (adjusted odds ratio [AOR], 1.31 [95% CI, 1.24-1.40]; P < .001) and suvorexant (AOR, 1.20 [95% CI, 1.15-1.26]; P < .001) than for eszopiclone and no significant difference between zolpidem or triazolam and eszopiclone. Conclusions and Relevance: Due to uncontrolled confounding factors in this cohort study, no conclusions regarding the pharmacologic properties of guideline-recommended hypnotics can be drawn based on these results. Further studies accounting for confounding factors, including diagnoses of chronic vs acute insomnia disorder, insomnia and psychiatric symptom severity, and physician attitudes toward hypnotic prescription, are needed.

Intraventricular haemorrhage treated by extra ventricular drainage with catheter mistakenly penetrating the cisterna ambiens: A case report.

Intraventricular haemorrhage (IVH) is a severe and acute type of stroke with a complex pathophysiology and is a therapeutic challenge. This case report described a man in his early 50's diagnosed with IVH by computed tomography (CT). Although bilateral extraventricular drainage (EVD) was undertaken, a postoperative CT scan showed that while the left catheter was correctly positioned, the right catheter had been wrongly inserted into the cisterna ambiens. The procedure was equivalent to simultaneous EVD combined with cisternostomy. As a consequence, the haematoma was rapidly removed, the risk of infection and long-term hydrocephalus was reduced, and prognosis was improved. Large case-control studies or prospective studies are needed to evaluate the safety and effectiveness of this treatment modality.

A Patient With Minimally Conscious Syndrome Due to Cerebrovascular Accident Whose Symptoms Resolved With Zolpidem.

OBJECTIVE: In this report, we discuss the case of a patient with minimally conscious state (MCS) whose clinical condition significantly improved after Zolpidem therapy. We aim to provide supportive evidence for inclusion of zolpidem trials in patients with MCS. METHODS: Our team used electronic medical records, direct patient care experiences, and literature review to obtain information for this case report. RESULTS: Twice daily zolpidem therapy led to significant clinical improvement in our patient with MCS. In addition, this improvement was maintained throughout an increasingly arduous medical course. CONCLUSIONS: Minimally conscious state is a disorder with limited proven therapeutic options. Zolpidem administration has demonstrated immense benefit in a select population of patients, including ours. Given the potential for great improvement with limited downside, zolpidem trial presents an intriguing treatment option. Further clarification of prognostic features to stratify responders and nonresponders to therapy is needed.

Alleviating sleep disturbances and modulating neuronal activity after ischemia: Evidence for the benefits of zolpidem in stroke recovery.

AIMS: Sleep disorders are prevalent among stroke survivors and impede stroke recovery, yet they are still insufficiently considered in the management of stroke patients, and the mechanisms by which they occur remain unclear. There is evidence that boosting phasic GABA signaling with zolpidem during the repair phase improves stroke recovery by enhancing neural plasticity; however, as a non-benzodiazepine hypnotic, the effects of zolpidem on post-stroke sleep disorders remain unclear. METHOD: Transient ischemic stroke in male rats was induced with a 30-minute middle cerebral artery occlusion. Zolpidem or vehicle was intraperitoneally delivered once daily from 2 to 7 days after the stroke, and the electroencephalogram and electromyogram were recorded simultaneously. At 24 h after ischemia, c-Fos immunostaining was used to assess the effect of transient ischemic stroke and acute zolpidem treatment on neuronal activity. RESULTS: In addition to the effects on reducing brain damage and mitigating behavioral deficits, repeated zolpidem treatment during the subacute phase of stroke quickly ameliorated circadian rhythm disruption, alleviated sleep fragmentation, and increased sleep depth in ischemic rats. Immunohistochemical staining showed that in contrast to robust activation in para-infarct and some remote areas by 24 h after the onset of focal ischemia, the activity of the ipsilateral suprachiasmatic nucleus, the biological rhythm center, was strongly suppressed. A single dose of zolpidem significantly upregulated c-Fos expression in the ipsilateral suprachiasmatic nucleus to levels comparable to the contralateral side. CONCLUSION: Stroke leads to suprachiasmatic nucleus dysfunction. Zolpidem restores suprachiasmatic nucleus activity and effectively alleviates post-stroke sleep disturbances, indicating its potential to promote stroke recovery.

Effect of Psychological and Medication Therapies for Insomnia on Daytime Functions: A Randomized Clinical Trial.

Importance: Daytime functional impairments are the primary reasons for patients with insomnia to seek treatment, yet little is known about what the optimal treatment is for improving daytime functions and how best to proceed with treatment for patients whose insomnia has not remitted. Objectives: To compare the efficacy of behavioral therapy (BT) and zolpidem as initial therapies for improving daytime functions among patients with insomnia and evaluate the added value of a second treatment for patients whose insomnia has not remitted. Design, Setting, and Participants: In this sequential multiple-assignment randomized clinical trial conducted at institutions in Canada and the US, 211 adults with chronic insomnia disorder were enrolled between May 1, 2012, and December 31, 2015, and followed up for 12 months. Statistical analyses were performed on an intention-to-treat basis in April and October 2023. Interventions: Participants were randomly assigned to either BT or zolpidem as first-stage therapy, and those whose insomnia had not remitted received a second-stage psychological therapy (BT or cognitive therapy) or medication therapy (zolpidem or trazodone). Main Outcomes and Measures: Study outcomes were daytime symptoms of insomnia, including mood disturbances, fatigue, functional impairments of insomnia, and scores on the 36-item Short-Form Health Survey (SF-36) physical and mental health components. Results: Among 211 adults with insomnia (132 women [63%]; mean [SD] age, 45.6 [14.9] years), 104 were allocated to BT and 107 to zolpidem at the first stage. First-stage treatment with BT or zolpidem yielded significant and equivalent benefits for most of the daytime outcomes, including depressive symptoms (Beck Depression Inventory-II mean score change, -3.5 [95% CI, -4.7 to -2.3] vs -4.3 [95% CI, -5.7 to -2.9]), fatigue (Multidimensional Fatigue Inventory mean score change, -4.7 [95% CI, -7.3 to -2.2] vs -5.2 [95% CI, -7.9 to -2.5]), functional impairments (Work and Social Adjustment Scale mean score change, -5.0 [95% CI, -6.7 to -3.3] vs -5.1 [95% CI, -7.2 to -2.9]), and mental health (SF-36 mental health subscale mean score change, 3.5 [95% CI, 1.9-5.1] vs 2.5 [95% CI, 0.4-4.5]), while BT produced larger improvements for anxiety symptoms relative to zolpidem (State-Trait Anxiety Inventory mean score change, -4.1 [95% CI, -5.8 to -2.4] vs -1.2 [95% CI, -3.0 to 0.5]; P = .02; Cohen d = 0.55). Second-stage therapy produced additional improvements for the 2 conditions starting with zolpidem at posttreatment in fatigue (Multidimensional Fatigue Inventory mean score change: zolpidem plus BT, -3.8 [95% CI, -7.1 to -0.4]; zolpidem plus trazodone, -3.7 [95% CI, -6.3 to -1.1]), functional impairments (Work and Social Adjustment Scale mean score change: zolpidem plus BT, -3.7 [95% CI, -6.4 to -1.0]; zolpidem plus trazodone, -3.3 [95% CI, -5.9 to -0.7]) and mental health (SF-36 mental health subscale mean score change: zolpidem plus BT, 5.3 [95% CI, 2.7-7.9]; zolpidem plus trazodone, 2.0 [95% CI, 0.1-4.0]). Treatment benefits achieved at posttreatment were well maintained throughout the 12-month follow-up, and additional improvements were noted for patients receiving the BT treatment sequences. Conclusions and Relevance: In this randomized clinical trial of adults with insomnia disorder, BT and zolpidem produced improvements for various daytime symptoms of insomnia that were no different between treatments. Adding a second treatment offered an added value with further improvements of daytime functions. Trial Registration: ClinicalTrials.gov Identifier: NCT01651442.

High Prescribing and State-Level Variation in Z-Drug Use Among Medicare Patients.

BACKGROUND: Z-drugs are nonbenzodiazepine hypnotics used for sleep initiation and maintenance; these drugs increase the risk of fall-related injuries in older adults. The American Geriatrics Society's Beers criteria classifies Z-drugs as high-risk and strongly recommends avoiding prescribing Z-drugs to older adults due to adverse effects. The study objectives were to determine the prevalence of Z-drug prescribing among Medicare Part D patients and identify state or specialty-dependent prescribing differences. This study also aimed to determine prescribing patterns of Z-drugs to Medicare patients. METHODS: Z-drug prescription data was extracted from the Centers for Medicare and Medicaid Services State Drug Utilization Data for 2018. For all 50 states, the number of prescriptions per 100 Medicare enrollees and days-supply per prescription was determined. The percentage of total prescriptions prescribed by each specialty and the average number of prescriptions per provider within each specialty was also determined. RESULTS: Zolpidem was the most prescribed Z-drug (95.0%). Prescriptions per 100 enrollees were significantly high in Utah (28.2) and Arkansas (26.7) and significantly low in Hawaii (9.3) relative to the national average (17.5). Family medicine (32.1%), internal medicine (31.4%), and psychiatry (11.7%) made up the largest percentages of total prescriptions. The number of prescriptions per provider was significantly high among psychiatrists. DISCUSSION: Contrary to the Beers criteria, Z-drugs are prescribed to older adults at high rates.

Prescribing Z-drugs in Greece: an analysis of the national prescription database from 2018 to 2021.

BACKGROUND: The Z-drugs are indicated for the short-treatment of insomnia, but they are associated with abuse, dependence and side-effects. There are only sparse data about Z-drug prescribing in Greece. METHODS: We analyzed data from the Greek prescription database, considering prescriptions for the available Z-drugs in Greece, i.e., zolpidem and zopiclone, during the period from 01.10.2018 to 01.10.2021 in order to examine the prevalence, monthly number and characteristics of Z-drug prescriptions in Greece. RESULTS: There were 1,229,842 prescriptions for Z-drugs (zolpidem: 89.7%) during the investigated period from 2018 to 2021, which corresponded to 156,554 patients (73.1% ≥ 65 years, 64.5% female). More than half of the patients (65.8%) had more than one prescription with a median number of 8, interquartile range IQR [3, 17], prescriptions during the three-year study period. Most patients (76.1%) were prescribed by medical specialties other than psychiatrists and neurologists, despite a considerable frequency of psychiatric comorbidities (53.7%). About half of patients with anxiety/depression were not prescribed anxiolytics or antidepressants, a practice more frequently observed among medical specialties other than psychiatrists and neurologists. The average annual prevalence of at least one prescription for Z-drugs in the Greek population during 2019-2020 was approximately 0.9% (higher in females and older adults). The monthly number of prescriptions was relatively stable with a median number of 334.2 IQR [310.4; 351.6] prescriptions per 100,000 persons. CONCLUSIONS: A considerable number of patients are prescribed Z-drugs in Greece, more often older adults, females and patients with psychiatric comorbidities. The prescribing physicians were in the majority (70%) internists and general practitioners, while psychiatrists (10.9%) and neurologists (6.1%) accounted for a smaller proportion. Due to the limitations inherent to medical claims databases, further research is warranted in order to elucidate the potential abuse and misuse of Z-drugs.

Rapid resolution of catatonia secondary to post traumatic stress disorder with secondary psychotic features through scheduled zolpidem tartrate.

Catatonia is a complication of numerous psychiatric and medical conditions. The first-line treatment is typically management of the underlying primary condition as well as scheduled benzodiazepines or electroconvulsive therapy. Electroconvulsive therapy and benzodiazepines are not always tolerated or available when treating patients with catatonia. For this reason, other treatment regimens have been trialed in recent years, including the GABA-modulatory Z drugs such as zolpidem. Some alternative treatment modalities have shown great promise. However, which populaces these are most beneficial for is still unclear. In this article, we examine a case report of a woman who suffered from post-traumatic stress disorder with secondary psychotic features who experienced recurrent akinetic catatonia that was refractory to benzodiazepine therapy. She responded rapidly to scheduled zolpidem with minimal side effects. It is our author's belief that when managing catatonia in patients with post traumatic stress disorder with secondary psychosis, Z drugs may be preferable to benzodiazepines.

Complex regional pain syndrome after mRNA-based COVID-19 vaccination.

We describe the case of a 17-year-old woman diagnosed with complex regional pain syndrome (CRPS) at a pain clinic after the second dose of the COVID-19 vaccine. She was referred to our department for surgical treatment of movement disorder seven months after the second inoculation. Baclofen (50 µg), administered intrathecally, improved the involuntary movements of her right hand. After administration of zolpidem (5 mg), involuntary movements of the right index finger almost disappeared. However, neither zolpidem nor intrathecal baclofen improved the limited range of motion of the first joint of the left-hand finger. Despite various reports on CRPS development after vaccination, only one case post COVID-19 vaccination has been reported. Therefore, healthcare providers should keep in mind that CRPS can appear after the COVID-19 vaccination.

Evolution of benzodiazepine receptor agonist prescriptions in general practice: A registry-based study.

Background: Contrary to most European guidelines, benzodiazepine receptor agonists (BZRA) are often used continuously at a low dosage, being the most common form of long-term use. In Belgium, BZRA use is monitored by analyzing self-report data about medication use in the last 24 h. This method provides insufficient insight into the terms of use of these psychoactive drugs. Aim: To describe trends in BZRA prescribing in Flanders, Belgium, between 2000 and 2019. Design and setting: Population-based trend analysis and a case-control study for the year 2019 were done with data from a morbidity registry in general practice. Methods: Repeated cross-sectional and joinpoint regression analyses revealed trends in sex- and age-standardized prescription rates among adult patients (18+). Results: Overall, BZRA prescriptions increased. The highest overall increase was found among male patients 18-44 years old, with an average annual percentage change of 2.5 (95% CI: 0.9, 4.3). Among 65+ female patients, a decrease was found since 2006, with an annual percentage change of -0.7 (95% CI: -1.3, -0.1). In 2019, 12% of registered patients received minimally one prescription, long-term use was observed in 5%, back pain was the most common morbidity significantly associated with a rise in BZRA prescriptions, and zolpidem was the most prescribed BZRA (22%). Conclusion: Despite some statistically significant decreasing trends, an overall increase in BZRA prescriptions was observed throughout the 19-year study period, especially among long-term users of 18-44 years and 65-plus. Zolpidem became the most prescribed BZRA and warrants more attention.

Network meta-analysis comparing the effectiveness of a prescription digital therapeutic for chronic insomnia to medications and face-to-face cognitive behavioral therapy in adults.

OBJECTIVE: The purpose of this study was to compare the effectiveness of the only Food and Drug Administration-authorized prescription digital therapeutic (PDT) Somryst versus face-to-face cognitive behavioral therapy for insomnia (CBT-I), or FDA-approved prescription medications for insomnia. METHODS: A systematic literature review was undertaken to identify relevant studies. A Bayesian network meta-analysis (NMA) was conducted to examine (1) mean change in insomnia severity index (ISI); (2) proportional change in ISI remitters; (3) mean change in wake after sleep onset (WASO); and (4) mean change in sleep onset latency (SOL). RESULTS: Twenty studies provided data on the PDT, CBT-I, CBT-I in combination with self-help (SH), or two prescription medications (eszopiclone and zolpidem). The PDT was associated with significant mean change in ISI (-5.77, 95% Credible Interval [CrI] - 8.53, -3.07) and ISI remitters (OR 12.33; 95% CrI 2.28, 155.91) compared to placebo, and had the highest probability of being the most effective treatment overall for ISI mean change (56%), and ISI remitters (64%). All evaluated interventions significantly outperformed placebo for WASO but no significant differences were observed for SOL (five interventions). Sensitivity analyses excluding medications and meta-regression (assessing type, duration, delivery method for CBT-I) did not affect NMA results. CONCLUSIONS: This network meta-analysis demonstrated that a PDT delivering CBT-I had the highest probability of being most effective compared to face-to-face CBT-I, prescription sleep medications, or placebo, as measured by reductions in mean ISI score from baseline and ISI-determined remittance.

Chronic insomnia is the long-term inability to fall asleep easily or to stay asleep. This condition is much more serious than most people realize, raising the risk of many health problems including depression, heart disease, and injuries.Although sleep medications are commonly used to treat insomnia, these drugs may not be effective and can lead to harms such as accidents or clouded thinking. Clinical guidelines recommend a treatment called cognitive behavioral therapy for insomnia (CBT-I) that is safe and effective. Unfortunately, there is a shortage of clinicians trained to provide CBT-I.Prescription digital therapeutics (PDTs) are FDA-approved software programs available on mobile devices such as smartphones. A PDT for insomnia (Somryst) delivers CBT-I and can overcome barriers to access for this important type of therapy. To compare the effectiveness of this PDT with FDA-approved sleep medications and face-to-face CBT-I a special kind of study was conducted called a network meta-analysis. This is a statistical method of combining data from numerous studies in a way that allows the results to be fairly compared.This network meta-analysis of 20 studies found that the PDT was more effective at reducing insomnia symptoms than any of the sleep medications studied and was even more effective than face-to-face CBT-I as measured by scores on a clinically valid scale of insomnia symptoms. These results are encouraging because they suggest that digital delivery of CBT-I could help the millions of people who currently do not have access to this effective treatment.

Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis.

BACKGROUND: Behavioural, cognitive, and pharmacological interventions can all be effective for insomnia. However, because of inadequate resources, medications are more frequently used worldwide. We aimed to estimate the comparative effectiveness of pharmacological treatments for the acute and long-term treatment of adults with insomnia disorder. METHODS: In this systematic review and network meta-analysis, we searched the Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, Embase, PsycINFO, WHO International Clinical Trials Registry Platform, ClinicalTrials.gov, and websites of regulatory agencies from database inception to Nov 25, 2021, to identify published and unpublished randomised controlled trials. We included studies comparing pharmacological treatments or placebo as monotherapy for the treatment of adults (≥18 year) with insomnia disorder. We assessed the certainty of evidence using the confidence in network meta-analysis (CINeMA) framework. Primary outcomes were efficacy (ie, quality of sleep measured by any self-rated scale), treatment discontinuation for any reason and due to side-effects specifically, and safety (ie, number of patients with at least one adverse event) both for acute and long-term treatment. We estimated summary standardised mean differences (SMDs) and odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with Open Science Framework, https://doi.org/10.17605/OSF.IO/PU4QJ. FINDINGS: We included 170 trials (36 interventions and 47 950 participants) in the systematic review and 154 double-blind, randomised controlled trials (30 interventions and 44 089 participants) were eligible for the network meta-analysis. In terms of acute treatment, benzodiazepines, doxylamine, eszopiclone, lemborexant, seltorexant, zolpidem, and zopiclone were more efficacious than placebo (SMD range: 0·36-0·83 [CINeMA estimates of certainty: high to moderate]). Benzodiazepines, eszopiclone, zolpidem, and zopiclone were more efficacious than melatonin, ramelteon, and zaleplon (SMD 0·27-0·71 [moderate to very low]). Intermediate-acting benzodiazepines, long-acting benzodiazepines, and eszopiclone had fewer discontinuations due to any cause than ramelteon (OR 0·72 [95% CI 0·52-0·99; moderate], 0·70 [0·51-0·95; moderate] and 0·71 [0·52-0·98; moderate], respectively). Zopiclone and zolpidem caused more dropouts due to adverse events than did placebo (zopiclone: OR 2·00 [95% CI 1·28-3·13; very low]; zolpidem: 1·79 [1·25-2·50; moderate]); and zopiclone caused more dropouts than did eszopiclone (OR 1·82 [95% CI 1·01-3·33; low]), daridorexant (3·45 [1·41-8·33; low), and suvorexant (3·13 [1·47-6·67; low]). For the number of individuals with side-effects at study endpoint, benzodiazepines, eszopiclone, zolpidem, and zopiclone were worse than placebo, doxepin, seltorexant, and zaleplon (OR range 1·27-2·78 [high to very low]). For long-term treatment, eszopiclone and lemborexant were more effective than placebo (eszopiclone: SMD 0·63 [95% CI 0·36-0·90; very low]; lemborexant: 0·41 [0·04-0·78; very low]) and eszopiclone was more effective than ramelteon (0.63 [0·16-1·10; very low]) and zolpidem (0·60 [0·00-1·20; very low]). Compared with ramelteon, eszopiclone and zolpidem had a lower rate of all-cause discontinuations (eszopiclone: OR 0·43 [95% CI 0·20-0·93; very low]; zolpidem: 0·43 [0·19-0·95; very low]); however, zolpidem was associated with a higher number of dropouts due to side-effects than placebo (OR 2·00 [95% CI 1·11-3·70; very low]). INTERPRETATION: Overall, eszopiclone and lemborexant had a favorable profile, but eszopiclone might cause substantial adverse events and safety data on lemborexant were inconclusive. Doxepin, seltorexant, and zaleplon were well tolerated, but data on efficacy and other important outcomes were scarce and do not allow firm conclusions. Many licensed drugs (including benzodiazepines, daridorexant, suvorexant, and trazodone) can be effective in the acute treatment of insomnia but are associated with poor tolerability, or information about long-term effects is not available. Melatonin, ramelteon, and non-licensed drugs did not show overall material benefits. These results should serve evidence-based clinical practice. FUNDING: UK National Institute for Health Research Oxford Health Biomedical Research Centre.

Quetiapine Add-On Therapy May Improve Persistent Sleep Disturbances in Patients with PTSD on Stabile Combined SSRI and Benzodiazepine Combination: A One-Group Pretest-Posttest Study.

BACKGROUND: To assess potential benefits of quetiapine for persistent sleep disturbances in patients with posttraumatic stress disorder (PTSD) on stable combined SSRI and benzodiazepine therapy, who previously failed to respond to various benzodiazepine and non-benzodiazepine hypnotic adjuvant treatment as well as to first-generation antipsychotic add-on treatment. SUBJECTS AND METHODS: Fifty-two male PTSD outpatients on stable combination treatment with SSRI and benzodiazepines, with persistent sleep disturbances not responding to prescription of zolpidem, flurazepam, nitrazepam, promazine, and levopromazine, were assessed for sleep disturbances improvements after prescription of quetiapine in the evening. Each patient met both ICD-10 and DSM-IV criteria for PTSD. Psychiatric comorbidity and premorbidity were excluded using the Mini-International Neuropsychiatric Interview (MINI). Improvement on the CAPS recurrent distressing dream item, reduction in the amount of time needed to fall asleep, prolongation of sleep duration, and reduction in average number of arousals per night in the last 7 days before the assessment period were used as efficacy measures. RESULTS: All sleep-related parameters improved significantly at the end of a five-week follow-up: sleep duration increased by one hour (p<0.001), sleep latency decreased by 52.5 minutes (p<0.001), median number of arousals per night decreased from two to one (p<0.001), CAPS recurrent distressing dream item median decreased from five to four (p<0.001), and the number of patients dissatisfied with their sleep quality and quantity decreased from 45 to two (p<0.001). CONCLUSION: Quetiapine prescribed in the evening may be successful therapy for persistent sleep disturbances in patients with PTSD and generally good response to an SSRI and benzodiazepine combination, who previously failed to respond to some of the usual hypnotic medication or addition of first-generation antipsychotics: zolpidem, flurazepam, nitrazepam, promazine, and levopromazine.

Orthopedic sleep and novel analgesia pathway: a prospective randomized controlled trial to advance recovery after shoulder arthroplasty.

BACKGROUND: Lack of sleep is associated with adverse effects on postsurgical pain and recovery. We hypothesized that a multimodal sleep pathway, including nonpharmacologic sleep hygiene interventions and the use of zolpidem and melatonin, could improve patient analgesia and sleep after total shoulder arthroplasty. METHODS: We performed a prospective randomized controlled study in which patients undergoing anatomic and reverse total shoulder arthroplasty were treated with or without an interventional multimodal sleep pathway. This pathway included nursing-directed nonpharmacologic measures that promote sleep hygiene and pharmacologic interventions with low-dose zolpidem and melatonin at bedtime. All patients underwent a standardized multimodal analgesia protocol with scheduled acetaminophen, naproxen, and gabapentin, as well as a single-shot interscalene regional nerve block. RESULTS: This study enrolled 125 patients (64 in control group and 61 in interventional group) with similar demographic characteristics. The interventional group showed less oral morphine milligram equivalent (MME) consumption on postoperative day (POD) 0 (44.8 ± 36.1 MMEs vs. 60.9 ± 42.1 MMEs, P = .01) and showed a trend toward lower POD 0 visual analog scale pain scores (2.6 ± 1.8 vs. 3.3 ± 3.0, P = .06). Visual analog scale pain scores and MME consumption were similar on POD 1. The interventional group showed a longer objective sleep duration by quantitative wrist actigraphy (5.9 ± 3.1 hours vs. 4.6 ± 2.7 hours, P = .008), with better sleep quality assessed by the Leeds Sleep Evaluation Questionnaire (0-100 scale; 50.3 ± 26.8 vs. 38.5 ± 27.8, P = .01). The 2 groups showed similar satisfaction with pain management (89.2% vs. 79.6%, P = .16) and sleep management (82.1% vs. 76.8%, P = .48). There was no difference in the length of inpatient stay (32.2 ± 14.8 hours vs. 34.1 ± 12.8 hours, P = .44). CONCLUSION: In the setting of a regional and multimodal analgesia recovery plan for shoulder arthroplasty patients undergoing inpatient observation, the use of an interventional sleep pathway appears to be safe and beneficial, with improved analgesia, reduced opioid use, increased sleep duration, and improved reported sleep quality during the postoperative recovery period.

Incremental health care resource use and costs among adult patients with depression and treated for insomnia with zolpidem, trazodone, or benzodiazepines.

OBJECTIVE: To quantify health care resource utilization (HCRU) and costs associated with insomnia treated with commonly prescribed insomnia medications among patients with depression. METHODS: A retrospective cohort study was conducted using IBM MarketScan Commercial and Medicare Supplemental Databases to identify adults with: (1) ≥1 ICD-9/ICD-10 code for depression; (2) ≥1 commonly prescribed medication for insomnia (zolpidem immediate release [IR], zolpidem extended release [ER], trazodone, or benzodiazepines); and (3) ≥12 months of eligibility before and after initiating insomnia medication. A 1:1 age- and sex-matched control cohort with depression but without sleep-related disorders was identified. Adjusted HCRU and costs were compared using generalized linear models. RESULTS: A total of 21,027 patients (mean age = 48.3 years, 69.5% female) with depression and treated insomnia (D + TI; 1.9% zolpidem ER, 32.0% zolpidem IR, 50.0% trazodone, 16.1% benzodiazepines) were matched to controls. Although mean number of inpatient visits were similar (0.1 for both), relative to controls, D + TI had a higher mean number of ED (0.2 vs 0.1, p < .001) and outpatient visits (2.2 vs 1.3, p < .001). Adjusted total costs per patient per month were higher among D + TI patients ($2450 vs $1095, p < .001). Inpatient and ED costs were higher among patients prescribed zolpidem IR, trazodone, or benzodiazepines, but not zolpidem ER. CONCLUSIONS: Relative to controls with depression but without sleep disorders, overall, health care costs for adults with D + TI were 2.2-fold higher; costs and HCRU varied by insomnia medication. Further study of the impact of newer insomnia treatments on patient outcomes in depression and comorbid insomnia is warranted.

The Effect of Improving Preoperative Sleep Quality on Perioperative Pain by Zolpidem in Patients Undergoing Laparoscopic Colorectal Surgery: A Prospective, Randomized Study.

METHODS: A prospective, randomized study was conducted with 88 patients undergoing laparoscopic colorectal surgery. The experimental group (S group, n = 44) was given 10 mg of zolpidem tartrate one night before the surgical procedure, while no medication was given to the control group (C group, n = 44). The primary outcome was the intraoperative remifentanil consumption. Sufentanil consumption, average patient-controlled analgesia (PCA) effective press times, the visual analog scale (VAS) scores, and incidences of postoperative nausea and vomiting (PONV) were recorded at 6 h (T1), 12 h (T2), and 24 h (T3) postoperatively. RESULTS: The intraoperative remifentanil consumption was significantly lower in the S group than that in the C group (p < 0.01). Sufentanil consumption at 6 h and 12 h postoperatively was significantly lower in the S group than that in the C group (p < 0.05); average PCA effective press times and VAS scores, at 6 h and 12 h postoperatively, were significantly lower in the S group than those in the C group (p < 0.01); differences between groups 24 h postoperatively were not significant. No significant between-group difference was noted in the incidence of nausea and vomiting. CONCLUSION: Improving patients' sleep quality the night before surgical procedure by zolpidem can decrease the usage of intraoperative analgesics and reduce postoperative pain.

Fall Risk, Healthcare Resource Use, and Costs Among Adult Patients in the United States Treated for Insomnia with Zolpidem, Trazodone, or Benzodiazepines: A Retrospective Cohort Study.

INTRODUCTION: Falls are a common cause for morbidity and mortality among patients taking prescription insomnia medication. The objective of this study is to compare the risk of falls, all-cause healthcare resource utilization (HCRU), and costs among patients treated with commonly used, older generation insomnia medications and non-sleep-disordered controls. METHODS: This retrospective cohort study used the IBM® MarketScan® Commercial and Medicare Supplemental Databases to identify patients aged at least 18 years treated with commonly prescribed medications for insomnia (zolpidem, trazodone, benzodiazepines) between 1 January 2012 and 30 September 2017. The insomnia-treated cohort were age- and sex-matched (1:1) to non-sleep-disordered controls. Odds ratios (ORs) compared risk of falls in each cohort, adjusting for covariates. Costs were adjusted to 2018 dollars, the most recent year for the study data. RESULTS: Relative to matched controls (n = 313,086), the insomnia-treated cohort had a higher rate of falls (3.34% vs. 1.33%), and higher risk of falls [OR = 2.36 (95% confidence interval 2.27-2.44)]. Relative to other index treatments, patients treated with trazodone had the greatest risk of falls. Compared with matched controls, the estimated mean number of inpatient visits, emergency department visits, outpatient visits, and mean length of inpatient stay were all significantly higher among patients treated for insomnia. Such patients incurred greater total costs per patient per month than matched controls ($2100 versus $888; estimated mean ratio, 2.36; 95% CI 2.35-2.38; p < 0.0001). CONCLUSIONS: Relative to matched controls, the insomnia-treated cohort showed higher risk of falls with greater HCRU and costs. Each outcome measured was highest among patients treated with trazodone, relative to other index treatments. Findings suggest the need for new treatment options to optimize quality of care for patients with insomnia.

Long-term benzodiazepines and z-drug prescribing in Australian general practice between 2011 and 2018: A national study.

Despite reducing benzodiazepine prescribing, benzodiazepine-involving deaths have substantially increased in Australia. This study aimed to explore patterns in long-term prescribing of medications (benzodiazepine and z-drugs [BZD]) used for sleep-issues/insomnia in Australia to better understand these changes. Open cohort study using de-identified electronic health records of 1 414 593 adult patients regularly attending 404 Australian general practices from 2011 to 2018 (MedicineInsight). We used logistic regression adjusted for patient and practice characteristics to; (1) estimate long-term BZD prescribing prevalence (≥3 prescriptions in 6 months) and the associated sociodemographic factors, and (2) Poisson regression to compute annual changes in prescribing rates. Long-term BZD prescribing changed from 4.4% in 2011 to 5.8% in 2015, remaining relatively stable until 2018 (annual increase +2.5% [95% CI +2.0%;+3.0%]). Long-term BZD prescribing in any year was up to six times more likely in elderly rather than in younger patients and 30%-43% more prevalent in females, or patients living in or attending a practice located in more disadvantaged areas. The increase was more pronounced among males, adults aged 35-49 years, and individuals living in advantaged areas. The median duration among incident cases decreased from 1183 to 322 days between 2011 and 2017, and was up to 197 days longer among elderly females than males. Despite a slight increase and recent stability in long-term BZD prescribing, the higher rates and durations among elderly patients, women, or those living in more disadvantaged areas are concerning and highlights the need for interventions that reduce the potential harms of long-term BZD use in vulnerable groups.

Association between insomnia patients' pre-treatment characteristics and their responses to distinctive treatment sequences.

STUDY OBJECTIVES: It is common to provide insomnia patients a second treatment when the initial treatment fails, but little is known about optimal treatment sequences for different patient types. This study examined whether pre-treatment characteristics/traits predict optimal treatment sequences for insomnia patients. METHODS: A community sample of 211 adults (132 women; Mage = 45.6 ± 14.9 years) with insomnia were recruited. Patients were first treated with behavioral therapy (BT) or zolpidem (Zol). Non-remitting BT recipients were randomized to a second treatment with either Zol or cognitive therapy; non-remitting Zol recipients underwent BT or Trazodone as a second treatment. Remission rates were assessed at the end of the first and second 6-week treatments. We then compared the remission rates of dichotomous groups formed on the basis of gender, age, pretreatment scores on SF36 and Multidimensional Fatigue Scale, the presence/absence of psychiatric/medical comorbidities or pain disorders, and mean subjective sleep duration and efficiency within and across treatment sequences. RESULTS: Lower remission rates were noted for those: with a pain disorder, poor mental health perceptions, high MFI fatigue scores, and lower sleep times and efficiencies. Patients with a pain disorder responded best to the BT-to-Zol sequence, whereas patients with more mental impairment, severe fatigue, short sleep, and low sleep efficiency responded poorly to treatment starting with BT. CONCLUSIONS: Pain, fatigue, poor mental health status, and subjective sleep duration and efficiency all affect response to different insomnia treatment sequences. Findings may guide clinicians in matching insomnia treatments to their patients. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01651442, Protocol version 4, April 20, 2011, registered June 26, 2012, https://clinicaltrials.gov/ct2/show/NCT01651442?rslt=With&type=Intr&cond=Insomnia&cntry=US&state=US%3ACO&city=Denver&age=12&draw=2&rank=1.

Lemborexant for the Treatment of Insomnia: Direct and Indirect Comparisons With Other Hypnotics Using Number Needed to Treat, Number Needed to Harm, and Likelihood to Be Helped or Harmed.

Objective: To describe lemborexant for the treatment of insomnia (DSM-5) in adults using number needed to treat (NNT), number needed to harm (NNH), and likelihood to be helped or harmed (LHH).Methods: Lemborexant data were obtained from two Phase 3 trials conducted 2016-2018. Efficacy was assessed using different categorical definitions for response, and tolerability was assessed by evaluating rates of adverse events (AEs). Direct comparisons were made with zolpidem extended release (ER), and indirect comparisons were made with other hypnotic agents, including suvorexant, doxepin, ramelteon, zolpidem immediate release, eszopiclone, zaleplon, and selected benzodiazepines, using data from published reports and regulatory documents.Results: Lemborexant had a clinically relevant magnitude of therapeutic effect, as evidenced by NNT values versus placebo as robust as 3 (95% CI, 2-3). In general, NNH values for lemborexant versus placebo were ≥ 10, suggesting that lemborexant is relatively tolerable. Somnolence was the most common AE, with NNH estimates of 28 (95% CI, 18-61) and 15 (95% CI, 11-22) for lemborexant 5 mg and 10 mg, respectively. Rates of discontinuation of lemborexant because of an AE were low, and for lemborexant 5 mg the rate was lower than that for placebo. LHH contrasting the statistically significant endpoint efficacy measures versus discontinuation because of an AE ranged from 13 to 54. NNT values for lemborexant were generally more robust than for zolpidem ER for the polysomnography and sleep diary outcomes. In indirect comparisons, NNT data for the other hypnotics demonstrated effect sizes that were generally similar to those for lemborexant.Conclusions: In Phase 3 trials, the benefit-risk ratio for lemborexant is favorable as measured by NNT, NNH, and LHH.Trial Registration: ClinicalTrials.gov identifiers: NCT02783729, NCT02952820.