CNS drugs最新文献

Traumatic brain injury (TBI) is a prevalent cause of morbidity and mortality worldwide. A focus on neuroprotective agents to prevent the secondary injury cascade that follows moderate-to-severe TBI has informed the field greatly but has not yielded any viable therapeutic options to date. New strategies and pharmacotherapy options for neuroprotection continue to be evaluated, including tranexamic acid, progesterone, cerebrolysin, cyclosporin A, citicholine, memantine, and lactate. Biomarkers of injury that can aid in diagnosis and prognosis have also been elucidated and are incrementally being used in clinical practice. The spectrum of TBI severity has also gained increasing attention as it relates to mild TBI or concussion, blast injury, and subacute or chronic subdural hematomas. In this review, we review the pathophysiology, recent clinical trials, and future directions for acute TBI.

Background: Opioid prescribing to injured workers has increased despite evidence demonstrating that risks often outweigh the benefits. High-risk prescribing and persistent opioid use are often associated with harm. However, there are limited data on what predicts early high-risk and persistent opioid prescribing in Australian workers with back and neck-related injuries or disorders.

Objective: The purpose of this study was to determine the prevalence and identify determinants of early high-risk and persistent opioid prescribing in Australian workers with back and neck conditions.

Methods: A retrospective cohort study was carried out with injured workers with workers' compensation claims for back and neck conditions who filled at least one opioid prescription within the first 90 days after injury from 1 January 2010 to 31 December 2019. High-risk opioid prescribing practices in the first 90 days were measured using one of four indicators of risk (high-total opioid volume on first dispensing occasion-exceeding 350 mg oral morphine equivalent in the first week, average high-dose over 90 days-higher than 50 mg oral morphine equivalent, early supply with long-acting opioids, and concurrent psychotropic prescriptions). Persistent opioid use was determined using group-based trajectory modeling over the subsequent 1-year. Multivariable logistic regression was used to identify predictors of high-risk opioid prescribing in the first 90 days and persistent opioid use in the subsequent year.

Results: A total of 6278 injured workers prescribed opioids were included. At least one indicator of high-risk opioid prescribing was identified in 67.1% of the sample in the first 3 months. Persistent opioid use was identified in 22.8% of the sample over the subsequent year. Early high-risk opioid prescribing was associated with double the odds of persistent use (aOR 2.19, 95% CI 1.89-2.53). Injured workers residing in rural areas (inner regional and outer regional/remote Australia) had higher odds of high-risk prescribing (aOR 1.26, 95% CI 1.11-1.44) and (aOR 1.43, 95% CI 1.10-1.87), respectively, compared with those in major cities. Similarly, workers residing in areas with most disadvantaged and advantaged socioeconomic quintile had higher (aOR 1.18, 95% CI 1.01-1.39) and lower (aOR 0.68, 95% CI 0.56-0.82) odds of persistent opioid use, respectively, compared with those in the middle socioeconomic quintiles.

Conclusions: A total of two-thirds of injured workers receiving opioids in the first 90 days show evidence of high-risk prescribing, with nearly one-quarter exhibiting persistent opioid use over the subsequent year. Early high-risk opioid prescribing doubles the odds of opioid persistence. There is a need for further research and careful scrutiny of opioid prescribing in this population.

Background: Opioids are prescribed for postsurgical pain management, but a balance between achieving adequate pain control and minimising opioid-related harm is required. This study aimed to investigate the effectiveness of different opioid regimens, in daily dose or treatment duration, prescribed at surgical discharge.

Methods: A systematic search of MEDLINE, EMBASE, CENTRAL, and ICTRP was performed from inception to 12 January 2025. Randomised controlled trials (RCTs) and non-RCTs comparing different daily doses or treatment durations of opioid analgesics were included. All surgeries were included, except those related to cancer treatment or palliative care. Eligible populations were adults (≥ 18 years) or individuals classified as adults according to the criteria of the respective studies. Data were extracted at immediate-term (≤ 3 days), short-term (> 3 to ≤ 7 days), medium-term (> 7 to ≤ 30 days), and long-term (> 30 days). Data from RCTs were pooled using a random-effects model. Risk of bias was assessed. Certainty of evidence from RCTs was evaluated with Grading of Recommendations, Assessment, Development, and Evaluations (GRADE). The primary outcome was pain intensity. Adverse events were also measured.

Results: A total of 8432 records were identified. In total, 12 RCTs with 7128 patients and 24 non-RCTs with 118,849 patients were included. Studies included orthopaedic, gynaecology and obstetric surgeries, ranging from minor to major procedures. Higher-doses of opioids were more effective than lower-doses in reducing immediate pain intensity (mean difference (MD) 4.36, 95% confidence interval (CI) 0.50-8.23, n = 364, three studies, I² = 0%, high certainty). No difference in pain was found between higher-doses and lower-doses at other time points (moderate to high certainty). Longer-durations of opioid treatment showed no difference in pain at any time point (low to moderate certainty). More adverse events were reported with higher doses of opioids.

Conclusions: Higher-dose opioids provide a slight reduction in immediate post-discharge pain intensity but may lead to more adverse events. Longer durations of opioid treatment are probably not more effective in reducing pain than shorter treatment durations. Our findings suggest that clinicians may choose to prescribe lower doses of opioids or shorter durations of opioids without compromising pain control, even for major surgery.

Trauma is prevalent, with lifetime estimates of traumatic exposure ranging from 70% for a single event to 31% for multiple events. While many recover, a subset develop post-traumatic stress disorder (PTSD), a debilitating condition characterized by distressing memories, avoidance behaviors, hyperarousal, and mood disturbances. The National Comorbidity Survey reports a lifetime PTSD prevalence of 6.8%, with higher rates among women and veterans. PTSD is strongly associated with suicidality, depression, and substance use, and its chronic nature can cause significant functional impairment. Despite extensive research, only two US Food and Drug Administration (FDA)-approved medications, the selective serotonin reuptake inhibitors paroxetine and sertraline, are available for PTSD. Psychotherapy, including trauma-focused cognitive behavioral therapy, prolonged exposure therapy, and eye movement desensitization and reprocessing (EMDR), has shown efficacy. Recent interest has grown in using psychedelics and entactogens such as 3,4-methylenedioxymethamphetamine (MDMA) for PTSD. Early-phase clinical trials of MDMA-assisted therapy (MDMA-AT) showed promising results, leading the FDA to grant breakthrough therapy status to MDMA-AT in 2017. Phase 3 randomized controlled trials demonstrated significant reductions in PTSD symptoms, with nearly 70% of participants no longer meeting diagnostic criteria. However, in 2024, the FDA voted against MDMA approval, citing concerns about trial design (including blinding failure and lack of certain safety assessments including QT prolongation and abuse liability assessments), as well as concerns about allegations of potential misconduct. Ongoing research must address key challenges, including blinding, long-term safety, and variability in psychotherapy, to better understand the therapeutic potential of MDMA in PTSD treatment. The FDA's recent guidance on psychedelic trials provides a framework for future research. The objective of this article is to explore the potential of MDMA-AT in PTSD treatment, evaluate regulatory challenges following the FDA's recent decision, and highlight the need for ongoing research to address safety, efficacy, and therapeutic implementation.

Antiseizure medications (ASMs) are the primary treatment for epilepsy. However, adverse cardiac effects of ASMs can occur, related to their effects on lipid metabolism, raising ischemic heart disease risk; or specific actions on cardiac ion channels, increasing cardiac arrhythmia risk. Select ASMs, particularly enzyme inducers used at higher doses or for longer durations, can adversely affect lipids or cause metabolic changes, and thereby increase the risk for ischemic heart disease. These metabolic and potentially proarrhythmic actions may contribute to the increased cardiovascular morbidity and mortality that occur in epilepsy. Many ASMs block sodium channels or affect the QT interval, which can lead to proarrhythmia, particularly when used in combination with other medications or given to vulnerable populations. While ASMs are rarely reported to cause cardiac arrhythmias directly, population data raise concerns that cardiac arrhythmias and sudden cardiac death may be more common in epilepsy, and that sodium channel blocking ASMs in particular, might contribute. It is also possible that some cases of sudden cardiac death could be misclassified as sudden unexpected death in epilepsy (SUDEP), leading to an underestimation of the cardiovascular risk in this population. Cardiovascular risk factors, such as smoking and a sedentary lifestyle, are also associated with epilepsy, and should also be addressed. This summary is a narrative review of the literature, clarifies which ASMs tend to have more cardiovascular effects, and provides practical suggestions for medication management and monitoring from neurology and cardiology perspectives.

Background: In relapsing-remitting multiple sclerosis (RRMS), extended exposure to high-efficacy disease modifying therapy may increase the risk of side effects, compromise treatment adherence, and inflate medical costs. Treatment de-escalation, here defined as a switch to a lower efficacy therapy, is often considered by patients and physicians, but evidence to guide such decisions is scarce. In this study, we aimed to compare clinical outcomes between patients who de-escalated therapy versus those who continued their therapy.

Methods: In this retrospective analysis of data from an observational, longitudinal cohort of 87,239 patients with multiple sclerosis (MS) from 186 centers across 43 countries, we matched treatment episodes of adult patients with RRMS who underwent treatment de-escalation from either high- to medium-, high- to low-, or medium- to low-efficacy therapy with counterparts that continued their treatment, using propensity score matching and incorporating 11 variables. Relapses and 6-month confirmed disability worsening were assessed using proportional and cumulative hazard models.

Results: Matching resulted in 876 pairs (de-escalators: 73% females, median [interquartile range], age 40.2 years [33.6, 48.8], Expanded Disability Status Scale [EDSS] 2.5 [1.5, 4.0]; non-de-escalators: 73% females, age 40.8 years [35.5, 47.9], and EDSS 2.5 [1.5, 4.0]), with a median follow-up of 4.8 years (IQR 3.0, 6.8). Patients who underwent de-escalation faced an increased hazard of future relapses (hazard ratio 2.36 and 95% confidence intervals [CI] [1.79-3.11], p < 0.001), which was confirmed when considering recurrent relapses (2.43 [1.97-3.00], p < 0.001). It was also consistent across subgroups stratified by age, sex, disability, disease duration, and time since last relapse.

Conclusions: On the basis of this observational analysis, de-escalation may not be recommended as a universal treatment strategy in RRMS. The decision to de-escalate should be considered on an individual basis, as its safety is not clearly guided by specific patient or disease characteristics evaluated in this study.

Background: Reperfusion therapies, such as intravenous thrombolysis (IVT) and endovascular thrombectomy (EVT), are crucial for improving outcomes in patients with acute ischemic stroke (AIS). However, access to these treatments can vary significantly due to ethnicity, socioeconomic status (SES), and geographical location, impacting patient outcomes.

Objectives: The Disparities in Access to Reperfusion Therapy for Acute Ischemic Stroke (DARTS) study aims to systematically assess disparities in access to IVT and EVT on the basis of ethnicity, SES, and geographical location.

Methods: A comprehensive meta-analysis was conducted, incorporating data from 38 studies involving 5,256,531 patients with AIS. The analysis evaluated IVT and EVT utilization rates across ethnic groups, SES levels, and geographical locations.

Results: The findings reveal substantial disparities in access to reperfusion therapies. IVT and EVT utilization rates varied significantly by ethnicity (9% ethnic, 11% non-ethnic for IVT; 7% ethnic, 6% non-ethnic for EVT), SES (13% low SES, 16% high SES for IVT; 7% low SES, 10% high SES for EVT), and geography (9% rural, 12% urban for IVT; 1% rural, 4% urban for EVT). Black patients had significantly lower odds of receiving IVT (OR 0.69, p = 0.001) and EVT (OR 0.87, p = 0.005) compared with white patients. Similarly, patients with low SES and those from rural areas faced reduced odds of receiving IVT (OR 0.74, p < 0.001; OR 0.72, p = 0.002) and EVT (OR 0.74, p < 0.001; OR 0.39, p < 0.001). Rural patients also had significantly lower odds of timely hospital arrival (p < 0.001), posing a barrier to accessing reperfusion therapies.

Conclusions: The DARTS study (and this meta-analysis) reveals significant access disparities in AIS treatment related to ethnicity, geography, and SES, particularly affecting Black communities, low SES individuals, and rural populations. Despite advances in reperfusion therapies, suboptimal implementation rates persist. To address these issues, we recommend the EQUITY framework: Educate, Ensure Quality, provide Universal Access, Implement Inclusive Policy Reforms, Enhance Timely Data Collection, and Yield Culturally Sensitive Care Practices. Adopting these recommendations will improve access, reduce disparities, and enhance stroke management and outcomes globally. Equitable access is essential for all eligible patients to fully benefit from reperfusion treatments.

Background and objectives: The efficacy and safety of modified-release methylphenidate (MPH-MR) in the treatment of attention-deficit/hyperactivity disorder (ADHD) have been shown in both pediatric and adult Caucasian patients. The objective of this study was to assess the efficacy and safety of MPH-MR in Chinese children and adolescents with ADHD.

Methods: MICCA was a randomized, double-blind, placebo-controlled trial conducted at 19 sites in China from September 2018 to July 2021. The study enrolled children and adolescents aged 6 to < 18 years with a primary diagnosis of ADHD according to the Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition (DSM-5). Patients were randomized 1:1 to once-daily MPH-MR (10-60 mg) or placebo. The study included an up-titration phase of up to 5 weeks and a dose maintenance phase of 4 weeks. The primary efficacy endpoint was the change in the ADHD Rating Scale-IV (ADHD-RS-IV) total score from baseline to the end of the maintenance phase (EoM). Secondary endpoints included the change from baseline to EoM in Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P) total score, and Clinical Global Impression-Improvement (CGI-I) scores at EoM. Safety assessments included treatment-emergent adverse events (TEAEs) and vital signs.

Results: A total of 221 patients were randomized (MPH-MR: n = 110; placebo: n = 111). The change in the ADHD-RS-IV total score from baseline to EoM was significantly greater for MPH-MR versus placebo, with a least squares (LS) mean (95% confidence interval [CI]) treatment difference of - 4.6 (- 6.92, - 2.30) (p < 0.001). The mean (95% CI) treatment difference for the WFIRS-P total score change from baseline to EoM also significantly favored MPH-MR over placebo (- 6.46 [- 10.57, - 2.34]; p = 0.002). The CGI-I score at EoM was significantly lower in the MPH-MR group compared to the placebo group (2.2 vs 2.5; p = 0.002). Treatment-emergent adverse events were reported for 74 (67.3%) patients in the MPH-MR group and 55 (49.1%) patients in the placebo group. Most TEAEs were mild to moderate in severity. The most common TEAEs for MPH-MR were decreased appetite, nausea and upper respiratory tract infection. Treatment-emergent adverse events leading to study drug discontinuation/study withdrawal were reported in 4 (3.6%) patients in the MPH-MR group and 1 (0.9%) patient in the placebo group. No clinically relevant changes in vital signs were observed during the study.

Conclusions: Modified-release methylphenidate was superior to placebo in improving ADHD symptoms and functioning in Chinese pediatric patients with ADHD. Modified-release methylphenidate had a good safety and tolerability profile. Trial Registration http://www.chinadrugtrials.org.cn/ Identifier: CTR20180056 (registered on 21 May 2018).