Cognitive effects, pharmacokinetics, and safety of zuranolone administered alone or with alprazolam or ethanol in healthy adults in a phase 1 trial.

BACKGROUND: Zuranolone is an oral, once-daily, 14-day treatment course approved for adults with postpartum depression in the United States. AIMS: To assess cognitive effects, pharmacokinetics, and safety of zuranolone, alone or with alprazolam/ethanol. METHODS: This was a phase 1, two-part, two-period, randomized, double-blind, placebo-controlled crossover trial. Participants received zuranolone 50 mg or placebo once daily for 9 days, and additionally received alprazolam (1 mg, Part A), ethanol (males: 0.7 g/kg; females: 0.6 g/kg, Part B), or corresponding placebo on days 1, 5, and 9. Within each part, participants received all treatment combinations. Cognition was assessed using a computerized test battery; pharmacokinetics and safety were also evaluated. RESULTS: All participants (Part A, N = 24; Part B, N = 25) received ⩾1 dose of zuranolone/placebo. Compared to placebo, zuranolone produced small-to-moderate cognitive decline (Cohen's |d| = 0.126-0.76); effects were larger with alprazolam (Cohen's |d| = 0.523-0.93) and ethanol (Cohen's |d| = 0.345-0.88). Zuranolone coadministration with alprazolam (Cohen's |d| = 0.6-1.227) or ethanol (Cohen's |d| = 0.054-0.5) generally worsened cognitive decline when compared with zuranolone alone. Maximal pharmacodynamic effects occurred at approximately 5 h and were resolved by 12 h postbaseline. No pharmacokinetic interactions were observed. Incidence of adverse events was similar between groups; most events were mild or moderate in severity. CONCLUSION: A general small-to-moderate magnitude decline in cognition occurred with zuranolone alone. Coadministration with alprazolam/ethanol increased the magnitude, but not the duration, of effects compared with single-agent administration. Zuranolone prescribers and patients should be aware of the potential for increased central nervous system-depressant effects if coadministered with GABAergic active compounds such as alprazolam and ethanol.

Increased sexual function after intake of clomethiazole.

An octogenarian woman showed increased sexual function after replacing alprazolam with clomethiazole, a sedative-hypnotic drug commonly prescribed in French-speaking Switzerland for the treatment of anxiety and insomnia in elderly patients. The patient's sexual symptoms did not improve after resuming alprazolam, but disappeared after interrupting clomethiazole, and did not reappear when alprazolam was discontinued. Considering the chronology of the events, increased sexual function was likely a manifestation of the introduction of clomethiazole. However, because alprazolam was interrupted when clomethiazole was introduced, we cannot exclude an association between increased sexual function and alprazolam interruption.

Signal mining and risk analysis of Alprazolam adverse events based on the FAERS database.

This study aims to evaluate the safety of Alprazolam by analyzing the FAERS database, provide data analysis for monitoring adverse drug reactions. This research encompasses adverse event (AE) reports related to Alprazolam from the first quarter of 2004 to the second quarter of 2023. Four signal mining and analysis methods were utilized, including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayesian Geometric Mean (EBGM). Further exploration was conducted regarding patient characteristics and types of AEs. A total of 23,575 AE reports in which Alprazolam was the primary suspect drug were collected, identifying 347 Preferred Term (PT) signals and 27 System Organ Classes (SOCs). The number of AE reports increased annually, especially in 2015, 2018, 2019, and 2020. The main affected groups were females and the age range of 18 to 45. Psychiatric disorders, Nervous system disorders, and Gastrointestinal disorders were the most common the organ system in which the AEs occurred. There is a certain risk of drug abuse and suicide with Alprazolam. Most notably, several AEs not recorded in the Alprazolam leaflet appeared among the top 30 PTs in signal strength, including but not limited to Benzodiazepine drug level abnormal, Acquired amegakaryocytic thrombocytopenia, Cutaneous T-cell dyscrasia, and Coronary No-reflow Phenomenon. For the first time, AEs related to the cardiovascular system and platelet function were unveiled. The severe AE reports that resulted in "hospitalization" and "death" accounted for 30.96% and 21.86%. This study highlights the risks of suicide and misuse of Alprazolam. Other potential severe or fatal AEs, such as those related to the cardiovascular system, platelet function, and others, require further research to determine their precise mechanisms and risk factors.

Risk of suicide attempts and intentional self-harm on alprazolam.

BACKGROUND: From 2000-2021, U.S. suicide deaths have risen 36 %. Identification of pharmacological agents associated with increased suicide risk and safer alternatives may help reduce this trend. METHODS: An exposure-only within-subject time-to-event pharmacoepidemiologic study of the dynamic association between alprazolam treatment and suicide attempts over 2-years. Parallel analyses were conducted for diazepam, lorazepam and buspirone. Data for 2,495,520 patients were obtained from U.S. private insurance medical claims MarketScan from 2010 to 2019. FINDINGS: Alprazolam was associated with over a doubling of risk of suicide attempts (HR=2.21, 95 % CI=2.06,2.38). A duration-response analysis for the modal dose (0.5 mg) revealed a 5 % increase in suicidal events per additional month of treatment (HR=1.05, 95 % CI=1.04,1.07). Parallel analyses with long-acting (diazepam) and short-acting (lorazepam), found similar associations (diazepam HR=2.87, 95 % CI=2.56,3.21; lorazepam HR=1.83, 95 % CI=1.69,2.00), whereas the non-benzodiazepine anxiolytic, buspirone, showed significantly less risk (HR=1.25, 95 % CI=1.13,1.38), and no increased risk in patients with an attempt history (HR=1.05, 95 % CI=0.70,1.59). INTERPRETATION: This study confirmed an earlier signal linking alprazolam to increased suicide attempt risk. The increased risk extends to benzodiazepines in general, regardless of half-life and risk of withdrawal seizure. Buspirone appears to be a safer treatment than benzodiazepines, particularly in patients at increased risk for suicide.

Evolving Trends and Economic Burden of Benzodiazepine Use: Insights From a 10-Year Predictive Model.

OBJECTIVES: Benzodiazepines (BZDs) are widely prescribed in Croatia to treat anxiety, insomnia, mood disorders, and epileptic seizures. Long-term BZD use is associated with memory loss, Alzheimer's disease, dependence, addiction, falls in elderly populations, and increased traffic accident risk. METHODS: Drug consumption data were obtained from the Agency for Medicinal Products and Medical Devices of Croatia website. Autoregressive integrated moving average models, constructed using R programming language, forecasted diazepam, alprazolam, and overall BZD utilization and financial costs at a national level over 10 years. RESULTS: BZD consumption increased by up to 18.6% between 2012 and 2020. During the same period, diazepam utilization rose by 29.1%, and alprazolam consumption increased by 19.4%. Our model predicts that, by 2032, BZD, diazepam, and alprazolam utilization will increase substantially. The total projected financial expenditure for BZDs in 2032 is estimated at 14.22 million euros, with diazepam and alprazolam expenditures at 7.39 and 4.12 million euros, respectively. These increases will result in significant growth in healthcare spending and a rise in adverse effects related to long-term use. CONCLUSIONS: National healthcare decision makers should consider implementing regulatory and legislative measures to quantify, specify, and limit monthly BZD use for each patient. This would help control the negative side effects of prolonged BZD use while continuing to provide treatment for patients who genuinely need it.

Severe Alprazolam Withdrawal With Delirium and Psychosis: A Case Report and Literature Review.

ABSTRACT: In our report, and review of the literature, we present an important clinical lesson for the recognition and treatment of alprazolam withdrawal with complicated delirium and psychosis, and present a strong case for future treatment algorithms. Our case is unique due to the severity of behavioral disturbance associated with acute psychosis secondary to alprazolam withdrawal and the significant quantity of alprazolam consumed. The use of high cumulative doses of longer-acting benzodiazepines resulted in rapid improvement in symptoms with full resolution of psychosis. Within 4 days of treatment in hospital, delirium and psychosis had fully resolved. Detoxification continued in the community and the patient was followed up in clinic for monitoring of mental state. There was no recurrence of psychotic symptoms.

Efficacy and Safety of Anxiolytics in Mohs Micrographic Surgery: A Randomized, Double-Blinded, Placebo-Controlled Trial.

BACKGROUND: Patient anxiety can complicate surgical outcomes by elevating blood pressure, increasing the need for postoperative pain management, and reducing overall patient satisfaction. Despite the use of anxiolytic medications in outpatient procedures, there is limited comparative evidence on the efficacy and safety of these agents in Mohs micrographic surgery. OBJECTIVE: To compare the effectiveness and safety of different preprocedural anxiolytic agents in Mohs surgery on perioperative patient anxiety and patient satisfaction. MATERIALS AND METHODS: A double-blinded, randomized, placebo-controlled trial was conducted of 6 different preprocedural anxiolytic agents (lorazepam, diazepam, alprazolam, gabapentin, pregabalin, and melatonin) in 350 patients undergoing Mohs surgery. Anxiety and vital signs were recorded. RESULTS: Diazepam demonstrated a statistically significant, sustained reduction in anxiety levels compared with placebo ( p = .03). Gabapentin significantly reduced early anxiety ( p = .02). Alprazolam showed a trend to early anxiety reduction ( p = .08). Lorazepam ( p = .73), pregabalin ( p = .53), and melatonin ( p = .24) failed to reduce patient anxiety compared with placebo at any time point. No anxiolytic significantly impacted any patient vital sign or cognition. CONCLUSION: Although short-acting benzodiazepines and gamma-aminobutyric acid medications may have transient anxiolytic effects, a single oral dose of 5 mg of diazepam can provide a sustained anxiolytic effect in Mohs surgery, with excellent patient safety.

Alprazolam: Good for Some, Not Good for All!

BACKGROUND: Although alprazolam is approved only for use in panic disorder and generalized anxiety disorder, it is used for numerous other conditions, not only by psychiatrists but also by medical professionals in general. This commentary critically analyzes the use of alprazolam. METHODS: A narrative review approach was adopted, using relevant articles and textbooks, to compile pertinent literature for the aforementioned topic. RESULTS: Among all its adverse reactions, the most bothersome concern about the use of alprazolam is its potential for abuse and dependence. This can be attributed to certain unique pharmacokinetic and pharmacodynamic properties of this benzodiazepine. Also, the withdrawal triggered by use of alprazolam is challenging to treat. Alternate pharmacological and non-pharmacological strategies for use in anxiety and insomnia are available, which might be safer than alprazolam. Also, policy changes can serve as an answer to curb alprazolam abuse to some extent. Alprazolam might still be a good choice for individuals who do not have a history of abuse of other substances, with adequate psychoeducation and close monitoring of their usage pattern. CONCLUSION: There is a need to reconsider the need for long-term use of benzodiazepines in general, and alprazolam in particular. However, they still might be an appropriate choice in individuals where abuse and dependence are less likely.

Alprazolam misuse: Analysis of French Addictovigilance Network data from 2011 to 2020.

OBJECTIVES: Alprazolam, a high-potency and short-acting anxiolytic benzodiazepine, is one of the most misused benzodiazepines in France. In the context of various reports on alprazolam misuse during the COVID-19 pandemic, the objective of this study was to assess alprazolam abuse potential by analyzing French addictovigilance and international data. METHODS: Data collected from 2011 to 2020 using the following epidemiological tools of the French Addictovigilance Network were analyzed: spontaneous reports (SRs), OPPIDUM (addiction care center data), OSIAP (falsified prescriptions), DRAMES (substance-related deaths), and chemical submission surveys. Moreover, the VigiBase™ database was analyzed to evaluate alprazolam abuse liability worldwide. RESULTS: During the study period, 675 SRs concerning alprazolam misuse were recorded (sex ratio: Ì´1; median age: 39 years). The desired effects were intensification of the therapeutic anxiolytic effect, euphoric effect, and management of substance withdrawal. Alprazolam was the third and first benzodiazepine listed in OPPIDUM and OSIAP surveys. Analysis of the SR and OPPIDUM data showed a recent increase in the alprazolam-opioid combination. In DRAMES data, alprazolam was directly linked to 11 deaths (associated with opioids in 10/11). VigiBase™ data analysis highlighted that France was the third country with the most cases of alprazolam misuse. The disproportionality analysis showed that in France, alprazolam was associated with higher risk of misuse and dependence compared with other benzodiazepines: reporting odds ratio=1.43, (95% CI: 1.04-1.95) and=1.97 (95% CI:1.50-2.59), respectively. CONCLUSIONS: This study highlighted an increase in various signals of alprazolam abuse in France, and an increased use of the alprazolam-opioid combination that was also linked to most of the recorded alprazolam-linked deaths. These signals have been reported also in the international literature, and should be thoroughly investigated.

Alprazolam-related deaths in Scotland, 2004-2020.

BACKGROUND: The benzodiazepine drug alprazolam, a fast-acting tranquiliser, cannot be prescribed on the National Health Service in the United Kingdom. Illicit alprazolam supply and consumption have increased. Concern about increasing numbers of alprazolam-related fatalities started circulating in 2018. However, statistics on this issue are very limited. This study examined patterns in such mortality in Scotland. METHODS: Statistics on deaths where alprazolam was mentioned in the 'cause of death' were obtained from official mortality registers. Anonymised Scottish case-level data were obtained. Data were examined in respect of the characteristics of decedents and deaths using descriptive statistics. RESULTS: Scotland registered 370 deaths in 2004-2020; 366 of these occurred in 2015-2020: most involved males (77.1%); mean age 39.0 (SD 12.6) years. The principal underlying cause of death was accidental poisoning: opiates/opioids (77.9%); sedatives/hypnotics (15.0%). Two deaths involved alprazolam alone. Main drug groups implicated: opiates/opioids (94.8%), 'other benzodiazepines' (67.2%), gabapentinoids (42.9%), stimulants (30.1%), antidepressants (15.0%). Two-thirds (64.2%) involved combinations of central nervous system (CNS) depressants. DISCUSSION: Alprazolam-related deaths are likely due to an increasing illicit supply. The fall in deaths in 2019-2020 is partially due to increased use of designer benzodiazepines. Treatment for alprazolam dependence is growing. Clinicians need to be aware of continuing recreational alprazolam use. When such consumption occurs with CNS depressants, overdose and death risks increase. CONCLUSIONS: More awareness of alprazolam contributing to deaths, especially in conjunction with other CNS depressants, is needed by consumers and clinicians. Improved monitoring of illicit supplies could identify emerging issues of medicines' abuse.

[Transient hyperprolactinemia secondary to benzodiazepines: a case report]. / Hyperprolactinémie transitoire secondaire aux benzodiazépines : à propos d'un cas.

Hyperprolactinemia is common and accounts for 20 to 25% of secondary amenorrhea causes. Here, we report a case of moderate hyperprolactinemia observed in a 40-year-old patient consulting for spaniomenorrhea and inguinal pain during a bartholinitis episode. After eliminating all known causes of hyperprolactinemia, alprazolam intake is finally assumed. This hyperprolactinemia is found in a few bibliographic studies and is also noted in the summary of product characteristics. However, benzodiazepines are not known as hyperprolactinemia-inducing drugs by the endocrinologists and do not appear in the list of drugs established by a consensus of experts from the French Society of Endocrinology. This article aims to increase awareness of prescribing physicians and biologists of the possible occurrence of hyperprolactinemia in patients treated by benzodiazepines, especially since the intake of this molecule is particularly common in France, whether it is a medical prescription or self-medication.

Association of alprazolam with major cardiovascular events in patients with hypertension.

RATIONALE: Anxiety is a mediator for emotional reactivity and acute blood pressure elevations, which are associated with an increased risk of cardiovascular death. Alprazolam is a common medication for anxiolysis. We hypothesized that alprazolam usage can reduce the risk of major adverse cardiovascular events (MACEs) in patients with hypertension. METHODS: A retrospective cohort study was performed using datasets from Taiwanese Health and Welfare Data. Patients with hypertension were divided into exposed (Alprazolam-exposed) and control groups (non-Alprazolam-exposed) with 1:1 propensity score matching. The study endpoint was the occurrence of MACE. Adjusted hazard ratio (aHR) of MACE risk was estimated using the multiple Cox proportional hazard model. Age-stratified analysis was performed to evaluate the interaction of age and alprazolam use with MACEs. RESULTS: The study cohort consisted of 335 517 alprazolam-exposed patients and 1:1 PSM controls. The mean age was 63.62 ± 12.71 years in the Alprazolam-exposed population. Alprazolam exposure was significantly associated with reduced risk of MACEs (aHR = 0.965, 95% CI = 0.954-0.977), including ischemic stroke (aHR = 0.958, 95% CI = 0.940-0.976), hemorrhagic stroke (aHR = 0.856, 95% CI = 0.821-0.892), myocardial infarction (aHR = 0.933, 95% CI = 0.900-0.968), sudden cardiac death (aHR = 0.955, 95% CI = 0.916-0.996), and all-cause mortality (aHR = 0.921, 95% CI = 0.909-0.932). In the age-subgroup analysis, alprazolam showed the greatest risk reduction effect in hemorrhagic stroke for patients aged <65 years (aHR = 0.779, 95% CI = 0.727-0.835). CONCLUSION: Alprazolam usage in patients with hypertension was associated with a slightly reduced risk of MACEs and all-cause mortality, and up to 22% reduced risk of hemorrhagic stroke was observed in alprazolam users aged <65 years.

Abuse Potential of Lasmiditan: A Phase 1 Randomized, Placebo- and Alprazolam-Controlled Crossover Study.

Lasmiditan is a centrally penetrant, highly selective 5-hydroxytryptamine (serotonin) receptor 1F (5HT1F ) agonist under development as a novel therapy for acute treatment of migraine. A phase 1 randomized, placebo- and positive-controlled crossover study assessed the abuse potential of lasmiditan in adult recreational polydrug users. Following a qualification phase, subjects were randomized into treatment sequences, each consisting of 5 study treatments: placebo, alprazolam 2 mg, lasmiditan 100, 200 (lasmiditan 100 and 200 mg are proposed therapeutic doses), and 400 mg (supratherapeutic). The abuse potential of lasmiditan was investigated and compared with alprazolam and with placebo using the maximal effect score (Emax ) of the Drug-Liking Visual Analog Scale as the primary end point. Lasmiditan was not similar to placebo in drug-liking scores at all doses tested, with a maximum difference observed with the lasmiditan 400-mg dose (upper 90% confidence limit on difference in least-squares [LS] means > 14 for all lasmiditan doses). Drug-liking scores for lasmiditan 400 mg were not significantly different from alprazolam (lower 90% confidence limit on difference in LS means < 5), but drug-liking scores at lower doses (100 and 200 mg) were significantly different from alprazolam. During the treatment phase, the incidence of treatment-emergent adverse events (TEAEs) increased with increasing dose of lasmiditan; all TEAEs reported with lasmiditan treatment were mild. Subjective drug-liking effects for lasmiditan versus placebo and versus alprazolam, and the safety and tolerability profile of lasmiditan suggest that lasmiditan has a low potential for abuse.

Awake Sedation With Propofol Attenuates Intraoperative Stress of Carotid Endarterectomy in Regional Anesthesia.

BACKGROUND: Carotid endarterectomy in regional anesthesia is often associated with increased perioperative stress. We assumed that carotid endarterectomy performed under awake sedation with propofol is more beneficial to prevent such stress than alprazolam premedication only. METHODS: A total of 47 consecutive patients with significant carotid artery stenosis were enrolled into this investigation and followed up for 5 years to explore vascular complications. All operations were performed under regional anesthesia. As premedication, all patients took 0.5 mg of alprazolam 30 minutes before the procedure. After randomization, 22 patients had awake sedation with target controlled propofol infusion, and the other 25 had only premedication. Cortisol plasma levels were serially analyzed: before surgery (T1), before (T2) and after release of carotid clamp (T3), and at 2 (T4) and 24 postoperative hours (T5). Alprazolam levels were also measured before and after the surgery. RESULTS: The plasma concentration of cortisol was significantly lower in the propofol sedation group at T2 (P < 0.001), T3 (P = 0.001), and T4 (P < 0.001) than in the alprazolam-only group. Alprazolam levels did not correlate with cortisol levels at any time point. A significant positive correlation was found between the clamp time and plasma cortisol level at T3 (P = 0.018), similarly between the degree of contralateral carotid stenosis and plasma cortisol level at T3 (P = 0.03). Plasma cortisol concentration 2 hours after the operation (T4) proved to be an independent predictor of carotid restenosis during the 5-year follow-up (odds ratio: 1.67, 95% confidence interval: 1.02-2.73, P = 0.04). CONCLUSIONS: An additional intraoperative propofol sedation provides better stress relief than alprazolam-only premedication during awake carotid endarterectomy.

A Medical Review of Fatal High-G U.S. Aerobatic Accidents.

INTRODUCTION: Exposure to high G force is a known safety hazard in military aviation as well as civilian aerobatic flight. Tolerance to high G forces has been well studied in military pilots, but there is little research directed at civilian pilots who may have medications or medical conditions not permitted in military pilots.METHODS: In this case-control study, we identified 89 fatal high-G aerobatic accidents and 4000 fatal control accidents from 1995 through 2018 from the NTSB accident database and the FAA autopsy database. We retrieved medications and medical conditions from the FAA's pilot medical databases. Logistic regression models were used to explore the associations of drugs, medical conditions, height, and medical waivers with high-G accidents.RESULTS: Seven drugs (alprazolam, clonidine, ethanol, meclizine, phentermine, triamterene, and zolpidem) reached statistical significance in our models, but had such small case counts that we consider these findings to be uncertain, except for ethanol, which was found in seven cases. Of these, only triamterene was known to the FAA. Statistically significant medical predictors included only alcohol abuse (seven cases) and liver disease (only two cases).DISCUSSION: Our analysis found that the drug ethanol and the condition alcohol abuse are significantly associated with high-G accidents. Seven other factors were statistically significant, but should only be considered as hypothesis generating due to very low case counts. Our study does not suggest that restricting pilots with otherwise permissible medications or medical conditions from aerobatics is warranted.Mills WD, Greenhaw RM, Wang JMP. A medical review of fatal high-G U.S. aerobatic accidents. Aerosp Med Hum Perform. 2019; 90(11):959-965.

Pharmacokinetic assessment of alprazolam-induced neonatal abstinence syndrome using physiologically based pharmacokinetic model.

Sustained benzodiazepine use during pregnancy can induce neonatal abstinence syndrome (NAS). In this study, the association between NAS and plasma alprazolam concentration was examined using the measured neonatal concentrations in the time series as well as simulated plasma concentrations of pregnant woman and neonate by physiologically based pharmacokinetic (PBPK) modeling. A neonate born to a mother taking alprazolam daily throughout pregnancy exhibited symptoms such as apnea and vomiting from 9 h to 4 days after birth. Finnegan score was 7 at birth and decreased to 0 by day 4. Apnea improved by 24 h post-delivery and gastrointestinal symptoms disappeared by day 4. The plasma alprazolam concentration in the neonate was 15.2 ng/mL immediately after birth and gradually decreased over 3 days. Measured neonate and estimated maternal plasma alprazolam concentrations were within the 90% prediction intervals of each concentration by PBPK simulation using "pregnancy" and "pediatrics" population parameters including in Simcyp population-based ADME simulator. In conclusion, NAS symptoms such as apnea and digestive events disappeared in parallel with the decrease of the neonate's plasma alprazolam concentrations. Moreover, PBPK modeling and simulation is a useful methodology for toxicological assessment in special characteristics populations lacking specific experimental data.