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JAMA Network Open Apr 2024Although insomnia guidelines recommend the use of several individual hypnotics, the most useful hypnotic for treating insomnia in a clinical setting remains unclear. (Observational Study)
Observational Study
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.
Topics: Adult; Female; Humans; Male; Middle Aged; Cohort Studies; Eszopiclone; Hypnotics and Sedatives; Indenes; Japan; Retrospective Studies; Sleep Initiation and Maintenance Disorders; Treatment Failure; Triazolam; Zolpidem
PubMed: 38630476
DOI: 10.1001/jamanetworkopen.2024.6865 -
Biological & Pharmaceutical Bulletin 2024Alzheimer's disease (AD) is accompanied by behavioral and psychological symptoms of dementia (BPSD), which is often alleviated by treatment with psychotropic drugs, such...
Alzheimer's disease (AD) is accompanied by behavioral and psychological symptoms of dementia (BPSD), which is often alleviated by treatment with psychotropic drugs, such as antidepressants, hypnotics, and anxiolytics. If these drugs also inhibit acetylcholinesterase (AChE) activity, they may contribute to the suppression of AD progression by increasing brain acetylcholine concentrations. We tested the potential inhibitory effects of 31 antidepressants, 21 hypnotics, and 12 anxiolytics on recombinant human AChE (rhAChE) activity. At a concentration of 10 M, 22 antidepressants, 19 hypnotics, and 11 anxiolytics inhibited rhAChE activity by <20%, whereas nine antidepressants (clomipramine, amoxapine, setiptiline, nefazodone, paroxetine, sertraline, citalopram, escitalopram, and mirtazapine), two hypnotics (triazolam and brotizolam), and one anxiolytic (buspirone) inhibited rhAChE activity by ≥20%. Brotizolam (≥10 M) exhibited stronger inhibition of rhAChE activity than the other drugs, with its pIC value being 4.57 ± 0.02. The pIC values of the other drugs were <4, and they showed inhibitory activities toward rhAChE at the following concentrations: ≥3 × 10 M (sertraline and buspirone), ≥10 M (amoxapine, nefazodone, paroxetine, citalopram, escitalopram, mirtazapine, and triazolam), and ≥3 × 10 M (clomipramine and setiptiline). Among these drugs, only nefazodone inhibited rhAChE activity within the blood concentration range achievable at clinical doses. Therefore, nefazodone may not only improve the depressive symptoms of BPSD through its antidepressant actions but also slow the progression of cognitive symptoms of AD through its AChE inhibitory actions.
Topics: Humans; Anti-Anxiety Agents; Acetylcholinesterase; Hypnotics and Sedatives; Sertraline; Clomipramine; Mirtazapine; Paroxetine; Citalopram; Escitalopram; Amoxapine; Buspirone; Triazolam; Antidepressive Agents
PubMed: 38296462
DOI: 10.1248/bpb.b23-00719 -
Journal of Analytical Toxicology Jul 2023Postmortem whole blood samples can differ greatly in quality where hyperlipemia is a frequent variable that can influence the results of analytical methods. The aim of...
Postmortem whole blood samples can differ greatly in quality where hyperlipemia is a frequent variable that can influence the results of analytical methods. The aim of this study was to investigate the influence of lipemia on postmortem analysis as well as demonstrate the usage of Intralipid in comparison to pooled postmortem lipids as matrix additives for meaningful evaluation and validation of hyperlipidemic postmortem samples. Hyperlipidemic blood samples were simulated by adding different concentrations of Intralipid or pooled authentic postmortem lipids to bovine whole blood. The hyperlipidemic blood samples were spiked with 14 benzodiazepines and five sedative and antianxiety drugs (alprazolam, clonazepam, 7-aminoclonazepam, diazepam, flunitrazepam, 7-aminoflunitrazepam, hydroxyzine, lorazepam, midazolam, nitrazepam, 7-aminonitrazepam, nordazepam, oxazepam, propiomazine, dihydropropiomazine, temazepam, triazolam, zolpidem and zopiclone). Samples were prepared with liquid-liquid extraction followed by ultra-high performance liquid chromatography-mass spectrometry. The effects of lipemia on the recovery of analytes and internal standards (ISs) were evaluated to determine the effect of, and any differences between, the two additives. Lipemia was found to cause major interference when quantifying the analytes. For most analytes, the ISs could compensate for analyte losses. However, the most hydrophilic analytes (7-amino metabolites), together with the most lipophilic analytes (propiomazine and dihydropropiomazine), were greatly affected by lipemia (<50% recovery), and the IS could not compensate for analyte losses. In general, lower analyte recoveries were observed for samples with Intralipid as a lipemic additive in comparison to those containing pooled postmortem lipids. Both Intralipid and pooled postmortem lipids showed marked effects on the analytical results. Intralipid gave a good indication of the effects of lipemia and could be a useful tool for making a meaningful evaluation of hyperlipidemic postmortem samples during the method development and validation.
Topics: Animals; Cattle; Tandem Mass Spectrometry; Benzodiazepines; Phospholipids; Hyperlipidemias
PubMed: 37130054
DOI: 10.1093/jat/bkad025 -
Neuropsychopharmacology Reports Apr 2024To investigate changes in the clinical characteristics of patients who abused benzodiazepine receptor agonists (BZRA) or over-the-counter (OTC) drugs before and after...
Comparison of patients with benzodiazepine receptor agonist-related psychiatric disorders and over-the-counter drug-related psychiatric disorders before and after the COVID-19 pandemic: Changes in psychosocial characteristics and types of abused drugs.
AIM
To investigate changes in the clinical characteristics of patients who abused benzodiazepine receptor agonists (BZRA) or over-the-counter (OTC) drugs before and after COVID-19 based on the 2018 and 2022 data of the "Nationwide Psychiatric Hospital (NPH) Survey on Drug-related Psychiatric Disorders."
METHOD
A total of 446 and 155 cases, and 435 and 273 cases, who mainly abused BZRAs or OTC drugs, respectively, were extracted from the database of the two NPH Surveys. Demographic variables, education, employment, criminal record, drug use during the previous year, psychiatric diagnosis, and types of abused drugs were compared between 2018 and 2022.
RESULT
A comparison of BZRA abusers revealed a decreased number of users during the previous year and an increase in the comorbidity rate of other disorders (F3 and F4 in ICD-10) in 2022. Etizolam, flunitrazepam, triazolam, and zolpidem were used most in both years, with an increase in zolpidem and a decrease in triazolam in 2022. A comparison of OTC drug abusers revealed a higher proportion of women and young patients in 2022. An increase in the comorbidity rate of F3 and F9 and a significant increase in the use of dextromethorphan products were observed in 2022, although codeine products were in the majority in both years.
CONCLUSION
By comparing NPH Surveys before and after the COVID-19 pandemic, both BZRA abusers and OTC drug abusers present complex pathologies, requiring tailor-made treatment. The younger OTC drug abusers were particularly evident among women, and the abuse of dextromethorphan-containing OTC drugs has increased alarmingly.
PubMed: 38622878
DOI: 10.1002/npr2.12440 -
Acta Obstetricia Et Gynecologica... Sep 2023Therapeutic rest refers to the usage of medication to relieve pain in women in the latent phase of labor. Very few data are available to evaluate the safety and effect...
INTRODUCTION
Therapeutic rest refers to the usage of medication to relieve pain in women in the latent phase of labor. Very few data are available to evaluate the safety and effect of its use. The objectives of this study were to compare perinatal and labor outcomes in women who were seeking hospital care during the latent phase of labor and who were treated either with or without therapeutic rest.
MATERIAL AND METHODS
Retrospective cohort study with inclusion of nulliparous singleton pregnant women in the latent phase of labor presenting at the labor ward at Aarhus University Hospital, Denmark from May 13, 2018 to June 1, 2021. We identified two groups: women who were treated with therapeutic rest and women who were not. The primary outcomes were neonatal admission and neonatal resuscitation. Secondary outcomes included use of cardiotocography during labor, nonreactive fetal heart rate, meconium-stained amniotic fluid, pediatric delivery room assistance, umbilical cord arterial pH and standard base excess, Apgar score at 5 minutes, interventions during labor and mode of delivery.
RESULTS
In our sample of 800 women in the latent phase of labor, 414 women (52%) were treated with therapeutic rest and 386 women (48%) were not. The most frequently used (n = 206) medication for therapeutic rest was a combination of paracetamol, triazolam and codeine. We found no significant difference in neonatal admission (9.2% vs 6.5%, adjusted odds ratio [aOR] 1.2, 95% confidence interval [CI] 0.4-3.1) or neonatal resuscitation (2.4% vs 3.1%, aOR 0.7, 95% CI 0.1-4.0) between women treated with or without therapeutic rest. There were no differences between the two groups in other perinatal adverse outcomes, interventions during labor or mode of delivery.
CONCLUSIONS
This study found no significant association between therapeutic rest and neonatal admission or resuscitation. Our findings indicate that therapeutic rest is a safe method for managing the latent phase of labor concerning neonatal health and does not increase the risk of labor complications.
Topics: Child; Pregnancy; Female; Infant, Newborn; Humans; Cohort Studies; Retrospective Studies; Resuscitation; Parturition; Labor, Obstetric
PubMed: 37452448
DOI: 10.1111/aogs.14635 -
Tremor and Other Hyperkinetic Movements... 2024In a recent survey of 16,694 people receiving treatment for Restless Legs Syndrome (RLS), approximately 25% were treated with benzodiazepines either singly or in... (Review)
Review
UNLABELLED
In a recent survey of 16,694 people receiving treatment for Restless Legs Syndrome (RLS), approximately 25% were treated with benzodiazepines either singly or in combination with other RLS treatments. Because of the large number of people receiving benzodiazepines for treatment of RLS, we conducted a historical overview of the therapeutic role of benzodiazepines in RLS and its associated condition Periodic Limb Movements in Sleep (PLMS). We found 17 articles on the use of clonazepam in RLS, PLMS, or both, 3 on triazolam and PLMS, 1 on alprazolam and RLS, 1 on temazepam and PLMS, and 1 on nitrazepam and PLMS. The order of benefit of benzodiazepines from the summarized literature is Sleep>RLS>PLMS and arousals > PLMS. Most of the studies on clonazepam employed dosages of 0.5-2.0 mg. Dosages of 3 or 4 mg caused lethargy, somnolence and confusion. An epidemiological study on the therapy of RLS suggests that treatment of RLS with most types of RLS medications including benzodiazepines in combination with other RLS therapies lowers the future cardiovascular risk associated with RLS. The major effect of benzodiazepines is through potentiation of the effect of GABA on the GABA A receptor. Neuroimaging studies suggest that GABA is altered either positively or negatively in various brain regions in RLS and genetic studies suggest that there are alterations in the GABA receptor in RLS. These results suggest that medications with different GABAergic mechanisms such as tiagabine (Gabitril) or others should be investigated in RLS for their possible therapeutic benefit.
HIGHLIGHTS
Benzodiazepines are frequently used as therapy in Restless Legs Syndrome (RLS) and Periodic Limb Movements in Sleep. The order of benefit is Sleep>RLS>PLMS and arousals > PLMS. For clonazepam dosages of 0.5 mg-2.0 mg/day are most frequently employed. Benzodiazepines exert their therapeutic effect through GABA-ergic mechanisms.
Topics: Restless Legs Syndrome; Humans; Clonazepam; Benzodiazepines; Nocturnal Myoclonus Syndrome; History, 20th Century; History, 21st Century; Adult
PubMed: 38708125
DOI: 10.5334/tohm.824 -
European Journal of Pharmaceutical... Mar 2024The concomitant administration of ritonavir and oxycodone may significantly increase the plasma concentrations of oxycodone. This study was aimed to simulate DDI between...
The concomitant administration of ritonavir and oxycodone may significantly increase the plasma concentrations of oxycodone. This study was aimed to simulate DDI between ritonavir and oxycodone, a widely used opioid, and to formulate dosing protocols for oxycodone by using physiologically based pharmacokinetic (PBPK) modeling. We developed a ritonavir PBPK model incorporating induction and competitive and time-dependent inhibition of CYP3A4 and competitive inhibition of CYP2D6. The ritonavir model was evaluated with observed clinical pharmacokinetic data and validated for its CYP3A4 inhibition potency. We then used the model to simulate drug interactions between oxycodone and ritonavir under various dosing scenarios. The developed model captured the pharmacokinetic characteristics of ritonavir from clinical studies. The model also accurately predicts exposure changes of midazolam, triazolam, and oxycodone in the presence of ritonavir. According to model simulations, the steady-state maximum, minimum and average concentrations of oxycodone increased by up to 166% after co-administration with ritonavir, and the total exposure increased by approximately 120%. To achieve similar steady-state concentrations, halving the dose with an unchanged dosing interval or doubling the dosing interval with an unaltered single dose should be practical for oxycodone, whether formulated in uncoated or controlled-release tablets during long-term co-medication with ritonavir. The results revealed exposure-related risks of oxycodone-ritonavir interactions that have not been studied clinically and emphasized PBPK as a workable method to direct judicious dosage.
Topics: Ritonavir; Oxycodone; Cytochrome P-450 CYP3A; Midazolam; Drug Interactions; Models, Biological
PubMed: 38199444
DOI: 10.1016/j.ejps.2024.106697 -
Clinical Ophthalmology (Auckland, N.Z.) 2024Long-term patient satisfaction may influence patients' perspectives of the quality of care and their relationship with their providers. This is a follow up to a...
PURPOSE
Long-term patient satisfaction may influence patients' perspectives of the quality of care and their relationship with their providers. This is a follow up to a comparative effectiveness study investigating oral to intravenous sedation (OIV study). The OIV study found that oral sedation was noninferior in patient satisfaction to standard intravenous (IV) sedation for anterior segment and vitreoretinal surgeries. This study aims to determine if patient satisfaction with oral sedation remained noninferior long term.
PATIENTS AND METHODS
Patients were re-interviewed using the same satisfaction survey given during the OIV study. Statistical analysis involved t-tests for noninferiority of the long-term mean satisfaction score of oral and IV sedation. We also compared the original mean satisfaction score and the follow-up mean satisfaction score for each type of sedation and for both groups combined.
RESULTS
Participants were interviewed at a median of 1225.5 days (range 754-1675 days) from their surgery. The original mean satisfaction score was 5.26 ± 0.79 for the oral treatment group (n = 52) and 5.27 ± 0.64 for the intravenous treatment group (n = 46), demonstrating noninferiority with a difference in mean satisfaction score of 0.015 (p < 0.0001). The follow-up mean satisfaction score was 5.23 ± 0.90 for oral sedation and 5.60 ± 0.61 for IV sedation, with a difference in the mean satisfaction score of 0.371 (p = 0.2071). Satisfaction scores did not differ between the original mean satisfaction score and the follow-up mean satisfaction score for the oral treatment group alone (p = 0.8367), but scores in the intravenous treatment group increased longitudinally (p = 0.0004).
CONCLUSION
In this study, long-term patient satisfaction with oral sedation was not noninferior to satisfaction with IV sedation, unlike our findings with short-term patient satisfaction in our original study. Patient satisfaction also remained unchanged over time for the oral treatment group, but patients in the intravenous treatment group reported higher long-term satisfaction with their anesthesia experience compared to the immediate post-operative period.
PubMed: 38476357
DOI: 10.2147/OPTH.S444999