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Alcohol withdrawal syndrome (AWS) is defined as the cessation or reduction in heavy and prolonged alcohol use within several hours to a few days of cessation. The recommended first-line therapy for AWS ranging from mild to severe or complicated remains benzodiazepines; in cases where benzodiazepines are not adequate in controlling persistent autonomic hyperactivity or anxiety, dexmedetomidine could be utilized. The possible advantage of dexmedetomidine compared to benzodiazepines is that it does not cause respiratory depression, thus reducing the risk of intubation and hospitalization in the ICUs, with the potential reduction in healthcare costs. The purpose of this systematic review and meta-analysis (PROSPERO CRD42018084370) is to evaluate the effectiveness and safety of dexmedetomidine as adjunctive therapy to the standard of care for the treatment of AWS. We retrieved literature from PubMed, EMBASE, and CENTRAL until 10 January 2024. Eligible studies were both randomized trials and nonrandomised studies with a control group, published in the English language and peer-reviewed journals. The primary outcome was tracheal intubation; secondary outcomes were (i) bradycardia and (ii) hypotension. A total of 3585 papers were retrieved: 2635 from EMBASE, 930 from Medline, and 20 from CENTRAL. After eliminating duplicates, 2960 papers were screened by title and abstract; 75 out of the 2960 papers were read in full text. The qualitative synthesis included nine of all manuscripts read in full text. The quantitative synthesis included eight studies for the primary outcome (tracheal intubation), seven for the secondary outcome bradycardia, and six for the secondary outcome hypotension. The meta-analysis showed that Dexmedetomidine, as adjunctive therapy, is not more effective than standard therapy in reducing the risk of tracheal intubation in AWS [RR: 0.57, 95% CI: 0.25–1.3, p = 0.15]. It also appears to be less safe than sedative therapy as it significantly increases the risk of bradycardia [RR: 2.68, 95% CI: 1.79–4.16, p = 0.0016]. Hypotension was not significantly different in patients who received dexmedetomidine [RR: 1.5, 95% CI: 0.69–3.49, p = 0.21]. [ABSTRACT FROM AUTHOR]

Alcohol use disorder (AUD) is a significant contributor to morbidity and mortality in the United States. It contributes to over 140,000 annual deaths, to over 200 related diseases and health conditions globally, and accounts for 5.1% of the global disease burden. Despite its substantial impact, AUD remains undertreated, marked by a scarcity of approved medications. This paper explores the current treatment landscape and novel strategies for both alcohol withdrawal syndrome and AUD. Promising results, including the use of psychedelics alongside psychotherapy, noninvasive neural-circuit-based interventions, phosphodiesterase-4 inhibitors, and GLP-1 receptor agonists, have emerged from recent studies. While these advancements show potential, further research is crucial for a comprehensive understanding of their effectiveness. The clear shortage of approved medications and other treatment modalities underscores the pressing need for ongoing research. [ABSTRACT FROM AUTHOR]

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This article discusses the use of optimal control in both therapeutics and epidemiology. Optimal control is a valuable tool for optimizing drug infusion protocols in cancer therapy and has gained attention in epidemiology due to the Covid-19 pandemic. The article highlights the similarities between these two contexts, such as the use of models and the need for ad-hoc techniques to implement optimal control strategies. The special issue discussed in the article includes papers on both epidemiology and therapeutics, with controls related to social distancing measures and vaccination in the former, and doses of drugs in the latter. The papers propose various approaches to dealing with model uncertainty and implement optimal controls using different techniques. Overall, this article provides an overview of the applications of optimal control in therapeutics and epidemiology. [Extracted from the article]

Alcohol withdrawal syndrome (AWS) is defined as the cessation or reduction in heavy and prolonged alcohol use within several hours to a few days of cessation. The recommended first-line therapy for AWS ranging from mild to severe or complicated remains benzodiazepines; in cases where benzodiazepines are not adequate in controlling persistent autonomic hyperactivity or anxiety, dexmedetomidine could be utilized. The possible advantage of dexmedetomidine compared to benzodiazepines is that it does not cause respiratory depression, thus reducing the risk of intubation and hospitalization in the ICUs, with the potential reduction in healthcare costs. The purpose of this systematic review and meta-analysis (PROSPERO CRD42018084370) is to evaluate the effectiveness and safety of dexmedetomidine as adjunctive therapy to the standard of care for the treatment of AWS. We retrieved literature from PubMed, EMBASE, and CENTRAL until 10 January 2024. Eligible studies were both randomized trials and nonrandomised studies with a control group, published in the English language and peer-reviewed journals. The primary outcome was tracheal intubation; secondary outcomes were (i) bradycardia and (ii) hypotension. A total of 3585 papers were retrieved: 2635 from EMBASE, 930 from Medline, and 20 from CENTRAL. After eliminating duplicates, 2960 papers were screened by title and abstract; 75 out of the 2960 papers were read in full text. The qualitative synthesis included nine of all manuscripts read in full text. The quantitative synthesis included eight studies for the primary outcome (tracheal intubation), seven for the secondary outcome bradycardia, and six for the secondary outcome hypotension. The meta-analysis showed that Dexmedetomidine, as adjunctive therapy, is not more effective than standard therapy in reducing the risk of tracheal intubation in AWS [RR: 0.57, 95% CI: 0.25–1.3, p = 0.15]. It also appears to be less safe than sedative therapy as it significantly increases the risk of bradycardia [RR: 2.68, 95% CI: 1.79–4.16, p = 0.0016]. Hypotension was not significantly different in patients who received dexmedetomidine [RR: 1.5, 95% CI: 0.69–3.49, p = 0.21].

Background: Understanding the interplay between psychopathology of alcohol withdrawal syndrome (AWS) in alcohol use disorder (AUD) patients may improve the effectiveness of relapse interventions for AUD. Network theory of mental disorders assumes that mental disorders persist not of a common functional disorder, but from a sustained feedback loop between symptoms, thereby explaining the persistence of AWS and the high relapse rate of AUD. The current study aims to establish a network of AWS, identify its core symptoms and find the bridges between the symptoms which are intervention target to relieve the AWS and break the self-maintaining cycle of AUD. Methods: Graphical lasso networkwere constructed using psychological symptoms of 553 AUD patients. Global network structure, centrality indices, cluster coefficient, and bridge symptom were used to identify the core symptoms of the AWS network and the transmission pathways between different symptom clusters. Results: The results revealed that: (1) AWS constitutes a stable symptom network with a stability coefficient (CS) of 0.21-0.75. (2) Anger (Strength = 1.52) and hostility (Strength = 0.84) emerged as the core symptom in the AWS network with the highest centrality and low clustering coefficient. (3) Hostility mediates aggression and anxiety; anger mediates aggression and impulsivity in AWS network respectively. Conclusions: Anger and hostility may be considered the best intervention targets for researching and treating AWS. Hostility and anxiety, anger and impulsiveness are independent but related dimensions, suggesting that different neurobiological bases may be involved in withdrawal symptoms, which play a similar role in withdrawal syndrome. [ABSTRACT FROM AUTHOR]

Alcoholism presents a significant health concern with notable socioeconomic implications. Alcohol withdrawal syndrome (AWS) can manifest when individuals cease or drastically reduce their alcohol consumption after prolonged use. Non-alcoholic fatty liver disease (NAFLD) is characterized by substantial lipid accumulation in the liver cells of individuals with no history of alcohol consumption. There is evidence suggesting an association between cognitive impairment and both conditions. This study aimed to evaluate cognitive impairment in patients with NAFLD and AWS using the Mini-Mental State Examination (MMSE). This study involved 120 patients admitted to two hospitals in Craiova, Romania. Results indicated that patients with NAFLD did not exhibit cognitive impairment as measured by MMSE (Mean = 29.27, SD = 0.785). Conversely, patients with AWS showed more pronounced cognitive dysfunction, with a mean MMSE score at admission of 16.60 ± 4.097 and 24.60 ± 2.832 after 2 weeks under treatment with Vitamins B1 and B6 and Cerebrolysin. Additionally, our findings suggested that cognitive dysfunction among alcohol consumers was correlated with the severity of clinical symptoms, as demonstrated by the severity of tremors in our study. The two-week period under treatment and alcohol withdrawal was insufficient for cognitive function to return to normal levels. Observational studies on longer periods of time are advised. [ABSTRACT FROM AUTHOR]

Background: Alcohol use disorder (AUD) is related to mental and somatic disorders that result in alcohol withdrawal syndrome (AWS), with 30% of AWS cases leading to life-threatening delirium tremens (DTs). Currently, studies do not support using any one biomarker in DTs. Neurotrophins affect neuromodulation, playing a role in the pathogenesis of AUD, AWS, and DTs. Methods: This review aims to summarize experimental and clinical data related to neurotrophins and S100B in neuroplasticity, as well as neurodegeneration in the context of AUD, AWS, and DTs. This work used publications that were selected based on the protocol consistent with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. Results: The BDNF level could be a good candidate biomarker for relapse susceptibility, as it is significantly reduced during consumption and gradually increases during abstinence. GDNF influences AUD through its integral role in the function of dopaminergic neurons and ablates the return to alcohol-drinking behavior. NGF protects neurons from ethanol-induced cytotoxic damage and affects recovery from cognitive deficits after brain damage. The NT-3 level is decreased after alcohol exposure and is involved in compensatory mechanisms for cognitive decline in AUD. NT-4 affects oxidative stress, which is associated with chronic alcohol consumption. S100B is used as a biomarker of brain damage, with elevated levels in serum in AUD, and can protect 5-HT neurons from the damage caused by alcohol. Conclusions: BDNF, GDNF, NT-3, NT-4, NGF, and S100B may be valuable markers for withdrawal syndrome. In particular, the most relevant is their association with the development of delirium complications. However, there are few data concerning some neurotrophins in AWS and DTs, suggesting the need for further research. [ABSTRACT FROM AUTHOR]

Background: Delirium Tremens (DT) is known to be a serious complication of alcohol withdrawal syndrome (AWS). Neurotransmitter abnormalities, inflammation, and increased permeability are associated with the pathogenesis of AWS and DT. However, the biomarkers of these conditions are still poorly understood. Methods: In this work, biochemical, hematologic, inflammatory, and gut permeability biomarkers were investigated in the following three groups: healthy controls (n = 75), severe AWS patients with DT (n = 28), and mild/moderate AWS without DT (n = 97). Blood sampling was performed after resolution of the acute condition (on 5 ± 1 day after admission) to collect clinical information from patients and to investigate associations with clinical scales. Biomarker analysis was performed using automated analyzers and ELISA. Inflammatory biomarkers included the erythrocyte sedimentation rate (ESR), high-sensitivity C-reactive protein (hsCRP), and platelet-to-lymphocyte ratio (PLR). Results: Among the biochemical biomarkers, only glucose, total cholesterol, and alanine aminotransferase (ALT) changed significantly in the analyzed groups. A multiple regression analysis showed that age and ALT were independent predictors of the CIWA-Ar score. Hematologic biomarker analysis showed an increased white blood cell count, and the elevated size and greater size variability of red blood cells and platelets (MCV, RDWc, and PDWc) in two groups of patients. Gut permeability biomarkers (FABP2, LBP, and zonulin) did not change, but were associated with comorbid pathologies (alcohol liver disease and pancreatitis). The increase in inflammatory biomarkers (ESR and PLR) was more evident in AWS patients with DT. Cluster analysis confirmed the existence of a subgroup of patients with evidence of high inflammation, and such a subgroup was more frequent in DT patients. Conclusions: These findings contribute to the understanding of biomarker variability in AWS patients with and without DT and support the heterogeneity of patients by the level of inflammation. [ABSTRACT FROM AUTHOR]

Objective: Alcohol‐related seizures (ARS) are one of the most important consequences of alcohol withdrawal syndrome (AWS). However, demographic and clinical characteristics, and furthermore, the relationship of ARS with delirium tremens (DT), have not yet been evaluated in detail. Therefore, the aim of the present study was to reveal the correlates of ARS and examine the interaction of ARS with the occurrence of DT and with the severity of AWS. Methods: In the retrospective study (Study 1) 2851 medical charts of inpatient admissions characterized by AWS and DT were listed. Demographic and clinical variables of ARS were assessed. In the follow‐up study (Study 2), patients admitted with AWS without (N = 28) and with (N = 18) ARS were enrolled. Study 1 was performed between 2008 and 2023, and Study 2 was performed in 2019 in Hungary. To determine the severity of AWS, the Clinical Institute Withdrawal Assessment Scale for Alcohol, Revised (CIWA‐Ar) was used. ARS is a provoked, occasional seizure; therefore, patients with epilepsy syndrome were excluded from the two studies. Statistical analyses were performed by the means of chi‐square tests, multinomial logistic regressions, mixed ANOVA, and derivation. Results: The occurrence of DT, the history of ARS, and somatic co‐morbidities were found to be risk factors for the appearance of ARS. ARS was proved to be a risk factor for the development of DT. In the follow‐up study, there was no difference in the decrease of CIWA‐Ar scores between the groups. Significance: Our present findings support the likelihood of kindling, which is one of the most important mechanisms underlying the development of ARS, but do not directly prove its presence. Additionally, our results revealed that the severity of AWS is not influenced by the presence of ARS. Plain Language Summary: Provoked, occasional seizures during AWS are defined as ARS. In the present study, predictors and interactions of these seizures with DT—the most severe form of withdrawal—and with the severity of withdrawal were examined in retrospective and follow‐up studies. The present study shows that a history of withdrawal seizures, the occurrence of DT, and somatic comorbidities are predictors of the development of seizures. Furthermore, our findings suggest that the presence of seizures does not influence the severity of withdrawal. [ABSTRACT FROM AUTHOR]

Background: Evidence-based research indicates that subjective questionnaires should be eliminated in screening for alcohol use disorder and management of alcohol withdrawal syndrome in critical care patients. However, transitioning clinicians away from these screening tools remains challenging. Objective: To improve screening for alcohol use disorder and management of alcohol withdrawal syndrome in the critical care setting by implementing an evidence-based alcohol use disorder screening tool and alcohol withdrawal syndrome protocol for critical care patients. Methods: The project site was a 17-bed adult medical intensive care unit in a large, southeastern US teaching hospital. Interventions consisted of the elimination of previously used tools such as the Clinical Institute Withdrawal Assessment for Alcohol–Revised and implementation of the Prediction of Alcohol Withdrawal Severity Scale for alcohol use disorder screening and the Richmond Agitation-Sedation Scale and symptom-triggered benzodiazepine administration for alcohol withdrawal syndrome management. Results: Alcohol use disorder screening among the critical care patient population increased by 49% from before to after the intervention. Of the patients at risk for withdrawal, 79% had an order for monitoring with the new intensive care unit alcohol withdrawal protocol in the postintervention group, compared with 35% who had an order for monitoring with the Clinical Institute Withdrawal Assessment for Alcohol–Revised in the preintervention group. Conclusion: The elimination of previously used tools and the implementation of the Prediction of Alcohol Withdrawal Severity Scale and the new intensive care unit alcohol withdrawal protocol improved alcohol use disorder screening and alcohol withdrawal syndrome management among critical care patients. [ABSTRACT FROM AUTHOR]

Aim: Phenobarbital, a long‐acting barbiturate, presents an alternative to conventional benzodiazepine treatment for alcohol withdrawal syndrome (AWS). Currently, existing research offers only modest guidance on the safety and effectiveness of phenobarbital in managing AWS in hospital settings. The study objective was to assess if a phenobarbital protocol for the treatment of AWS reduces respiratory complications when compared to a more traditionally used benzodiazepine protocol. Methods: A retrospective cohort study analyzing adults who received either phenobarbital or benzodiazepine‐based treatment for AWS over a 4‐year period, 2015–2019, in a community teaching hospital in a large academic medical system. Results: A total of 147 patient encounters were included (76 phenobarbital and 71 benzodiazepine). Phenobarbital was associated with a significantly decreased risk of respiratory complications, defined by the occurrence of intubation (15/76 phenobarbital [20%] vs. 36/71 benzodiazepine [51%]) and decreased incidence of the requirement of six or greater liters of oxygen when compared with benzodiazepines (10/76 [13%] vs. 28/71 [39%]). There was a significantly higher incidence of pneumonia in benzodiazepine patients (15/76 [20%] vs. 33/71 [47%]). Mode Richmond Agitation Sedation Scale (RASS) scores were more frequently at goal (0 to −1) between 9 and 48 h after the loading dose of study medication for phenobarbital patients. Median hospital and ICU length of stay were significantly shorter for phenobarbital patients when compared with benzodiazepine patients (5 vs. 10 days and 2 vs. 4 days, respectively). Conclusion: Parenteral phenobarbital loading doses with an oral phenobarbital tapered protocol for AWS resulted in decreased risk of respiratory complications when compared to standard treatment with benzodiazepines. [ABSTRACT FROM AUTHOR]

Alcohol use disorders (AUDs) are prevalent in intensive care units (ICUs). Alcohol abuse and/or dependence, leading to alcohol withdrawal syndrome (AWS), is as high as 10% or more. There seem to be wide variations in management strategies used to manage these patients, prompting an evaluation of the knowledge gap as well as finding the barriers. Noting lack of such literature in the Indian setting, a survey is undertaken to evaluate practice patterns surrounding the identification and management of alcohol dependence/abuse and AWS in the Indian critical care scenario. The main respondents of the survey are independent practitioners with anesthesia as their base specialty and overwhelmingly practice in multidisciplinary ICUs. They estimated AUD prevalence to be under 10%. The reason most expressed for lack of AUD documentation is fear of insurance rejection. Very few used risk assessment tool in evaluation of AUDs and AWS. Awareness of ICD 10/DSM-V components of AWS diagnosis was negligible. Chlordiazepoxide and lorazepam were used either in a fixed- or symptom-based therapy. Compared to available literature, haloperidol use is excessive, while barbiturates rarely. The wide variation is seen with the dose and frequency of thiamine in AWS without neurological complications. The impact on mortality and morbidity is poorly understood. In conclusion, the survey reported a lower prevalence compared to international literature. Insurance rejection is one of the main factors in limiting adequate history taking or documenting AUDs. Alcohol withdrawal syndrome risk assessment, monitoring, and management is variable and suboptimal. Variability in all aspects of AUDs is attributable to the knowledge gap. Further studies are needed to bridge the research gap. [ABSTRACT FROM AUTHOR]

Introduction: Patients with alcohol use disorder (AUD) exhibit symptoms such as alcohol withdrawal, depression, and cravings. The gut-immune response may play a significant role in manifesting these specific symptoms associated with AUD. This study examined the role of gut dysfunction, proinflammatory cytokines, and hormones in characterizing AUD symptoms. Methods: Forty-eight AUD patients [men (n = 34) and women (n = 14)] aged 23-63 years were grouped using the Clinical Institute Withdrawal Assessment of Alcohol Scale (CIWA) as clinically significant (CS-CIWA [score > 10] [n = 22]) and a clinically not-significant group (NCS-CIWA [score ≤ 10] [n = 26]). Clinical data (CIWA, 90-day timeline followback [TLFB90], and lifetime drinking history [LTDH]) and blood samples (for testing proinflammatory cytokines, hormones, and markers of intestinal permeability) were analyzed. A subset of 16 AUD patients was assessed upon admission for their craving tendencies related to drug-seeking behavior using the Penn-Alcohol Craving Score (PACS). Results: CS-CIWA group patients exhibited unique and significantly higher levels of adiponectin and interleukin (IL)-6 compared to NCS-CIWA. In the CS group, there were significant and high effects of association for the withdrawal score with gut-immune markers (lipopolysaccharide [LPS], adiponectin, IL-6, and IL-8) and for withdrawal-associated depression with gut-immune markers (scored using MADRS with LPS, soluble cells of differentiation type 14 [sCD14], IL-6, and IL-8). Craving (assessed by PACS, the Penn-Alcohol Craving Scale) was significantly characterized by what could be described as gut dysregulation (LBP [lipopolysaccharide binding protein] and leptin) and candidate proinflammatory (IL-lβ and TNF-α) markers. Such a pathway model describes the heavy drinking phenotype, HDD90 (heavy drinking days past 90 days), with even higher effects (R² = 0.955, p = 0.006) in the AUD patients, who had higher ratings for cravings (PACS > 5). Discussion: The interaction of gut dysfunction cytokines involved in both inflammation and mediating activity constitutes a novel pathophysiological gut-brain axis for withdrawal symptoms and withdrawal-associated depression and craving symptoms in AUD. AUD patients with reported cravings show a significant characterization of the gut-brain axis response to heavy drinking. Trial registration: ClinicalTrials.gov, identifier: NCT# 00106106. [ABSTRACT FROM AUTHOR]

Benzodiazepines are commonly used medications which are clinically useful towards the treatment of alcohol withdrawal, seizures, anxiety disorders, among other indications. Benzodiazepine use is also known to cause the rare phenomenon of paradoxical excitation whose mechanism has many postulated theories. We report this rare presentation of paradoxical excitation with the use of lorazepam in a 50-year-old male being treated for alcohol withdrawal. We also review the underlying pathophysiology, pharmacology, and current literature as it relates to this excitation. An inability to recognize this adverse effect and to appropriately withhold the agent may adversely affect a patient's course of treatment in the inpatient setting. [ABSTRACT FROM AUTHOR]

Baclofen may reduce the symptoms of alcohol withdrawal, as an alternative or as an adjuvant for benzodiazepines, but the available data are insufficient to support baclofen-assisted alcohol withdrawal. This study investigated the need for diazepam during acute alcohol withdrawal in patients receiving baclofen. In a single-blind, dose-dependent randomized controlled trial with three study arms, 63 patients with alcohol use disorder, starting in-patient benzodiazepine-assisted alcohol detoxification, were randomly assigned to receive placebo (n  = 18), baclofen 30 mg/day (N  = 20), or baclofen 60 mg/day (N  = 25) for 7 days. Diazepam was provided as needed based on the withdrawal symptoms stated by Clinical Institute Withdrawal Assessment for Alcohol-revised. The primary outcome measure was the number of patients in need of diazepam during alcohol detoxification. Secondary outcome measure included the between-group difference in the amount of diazepam needed during alcohol detoxification. Using baclofen 60 mg/day, 32% of patients needed additional diazepam compared to 35% on baclofen 30 mg/day and compared to 72% on placebo (P  = .013). The median total amount of diazepam needed was significantly lower in patients receiving baclofen 60 mg/day (0 ± 10 mg diazepam) and baclofen 30 mg/day (0 ± 10 mg diazepam) compared to placebo (10 ± 43 mg diazepam; P  = .017). Adverse events were comparable between patients on baclofen and placebo. Baclofen can reduce the withdrawal symptoms during alcohol detoxification. Baclofen was well tolerated and may be considered for the management of alcohol withdrawal syndrome, especially useful in situations where benzodiazepines should be withheld, such as patients with liver impairment. [ABSTRACT FROM AUTHOR]

Acute alcoholic hallucinosis is a psychotic disorder characterized by a predominance of auditory hallucinations with delusions and affective symptoms in the clinical picture. Classically, it develops as part of the alcohol withdrawal syndrome. The prevalence of acute alcoholic hallucinosis ranks second among alcohol-related psychoses after alcohol delirium. The study aimed to systematize the scientific data on the history of alcoholic hallucinosis, its pathogenesis, clinical presentation, and treatment approaches. A literature search was performed in PubMed, Scopus, Google Scholar, and eLibrary. The following words and combinations were used as search strings: (alcoholic hallucinosis OR alcoholic psychosis OR alcohol-related psychosis OR alcohol-induced psychosis OR alcohol-induced psychotic disorder OR complicated alcohol withdrawal syndrome) NOT (animal OR rat OR mouse). The relevant information concerning the history of acute alcoholic hallucinosis, its pathogenesis, clinical picture, and treatment approaches was systematized and summarized. This review presents relevant findings regarding acute alcoholic hallucinosis. Limitations of the review include the use of heterogeneous and mostly descriptive studies and studies on small cohorts of patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Here, we introduce a reliable, inexpensive, and versatile method for high-throughput kinetic assays of drug metabolism based on fluorometric quantification of formaldehyde (FA) formed in cytochrome P450-dependent demethylation reactions. We describe the implementation of this technique for automatized assays of cytochrome P450-dependent drug metabolism in human liver microsomes. We also report the use of our new approach for re-evaluating the pathways of metabolism of the NMDA-receptor antagonist ketamine, which is increasingly used as an antidepressant in the treatment of alcohol withdrawal syndrome. Probing the kinetic parameters of ketamine demethylation by 10 major cytochrome P450 (CYP) enzymes, we demonstrate that in addition to CYP2B6 and CYP3A enzymes, which were initially recognized as the primary metabolizers of ketamine, an important role is also played by CYP2C19 and CYP2D6. At the same time, the involvement of CYP2C9 suggested in the previous reports is insignificant. In a search for a reliable, inexpensive, and versatile technique for high-throughput kinetic assays of drug metabolism, we elected to rehire an old-school approach based on the determination of formaldehyde (FA) formed in cytochrome P450-dependent demethylation reactions. After evaluating several fluorometric techniques for FA detection, we chose the method based on the Hantzsch reaction with acetoacetanilide as the most sensitive, robust, and adaptable to high-throughput implementation. Here we provide a detailed protocol for using our new technique for automatized assays of cytochrome P450-dependent drug demethylations and discuss its applicability for high-throughput scanning of drug metabolism pathways in the human liver. To probe our method further, we applied it to re-evaluating the pathways of metabolism of ketamine, a dissociative anesthetic and potent antidepressant increasingly used in the treatment of alcohol withdrawal syndrome. Probing the kinetic parameters of ketamine demethylation by ten major cytochrome P450 (CYP) enzymes, we demonstrate that in addition to CYP2B6 and CYP3A enzymes, which were initially recognized as the primary metabolizers of ketamine, an important role is also played by CYP2C19 and CYP2D6. At the same time, the involvement of CYP2C9 suggested in the previous reports was deemed insignificant. [ABSTRACT FROM AUTHOR]

Background: Assessment and immediate surgical management of laryngotracheal injuries is essential to minimize the risk of perioperative and long term complications [1]. The present study was conducted at tertiary care centre to assess the proportions of complications following neck injuries. Methodology: The study was conducted as a prospective study on 19 patients presenting with laryngotracheal injuries at Emergency department in NSCB Medical College, Jabalpur, India during the study period of 2 years. History was obtained in detail and depending upon the extent and nature of injury, patients were managed. Patients were followed up till discharge for assessment of any postoperative complications. Results: A total of 19 cases with neck trauma were enrolled during our study period with mean age of 27.37±8.88 years. Tracheal breach was noted in 78.9% cases. The most common site of airway injury was tracheal wall (47.3%), followed by Laryngeal trauma with unilateral or bilateral thyroid cartilage (15.8%). Major vessels injury was noted in 26.3% cases and injury to minor blood vessels was observed in 68.4% cases. Wound exploration followed by wound repair was done in 36.8% of the cases whereas emergency tracheostomy along with wound repair was done in 31.6% of the cases. During surgery, brachial plexus injury and surgical site infection were the surgical complications in 1 case each. However, anemia psychiatric tendency and symptoms due to alcohol withdrawal were the complications in 1 case each. Among postoperative complications, persistence of psychiatric symptoms, recurrent laryngeal nerve palsy, withdrawal symptoms, and complications due to brachial plexus injury persisted. Conclusion: Neck injuries and laryngotracheal injuries are rare but life threatening injuries, timely management of which is essentially important to avoid the occurrence of complications. Management often requires multidisciplinary approach due to associated complications. The complications may be immediate or remote which can be prevented if patients are managed timely. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether dexmedetomidine (DEX), as adjunctive therapy to benzodiazepine (BZD), is superior to BZD alone in critically ill patients with alcohol withdrawal syndrome (AWS). Data Sources: PubMed Central, Cochrane CENTRAL, ClinicalTrials.gov and Google Scholar were used as search databases. Specific keywords and MeSH terms were "dexmedetomidine," "benzodiazepine," and "alcohol withdrawal syndrome." The last search was on September 16, 2022. Study Selection and Data Extraction: Randomized controlled trials (RCTs) and nonrandomized/cohort studies exploring the use of DEX in the management of AWS were included. A total of 12 studies were included in the systematic review and 7 in the meta-analysis. Data Synthesis: The intensive care unit length of stay (ICU LOS) was found to have a mean difference (MD) of 48.06 [37.48, 58.64], P = <0.001 for the cohort subgroup, significantly favoring the DEX arm, but, in contrast, pooled RCT data showed a result of –20.07 [–36.86, –3.28], P = 0.02, a shorter ICU LOS for the DEX arm. Bradycardia and hypotension incidence significantly favored the BZD arm in both subgroups. This study compares the effectiveness of adjunctive DEX in clinical practice and aims to help providers in critical decision-making by compiling and analyzing the best current available evidence of its use in AWS. Conclusions: Based on low to very low level of evidence, adjunctive DEX showed no significant difference for ICU LOS when compared with BZD alone. Pooled randomized trials potentially show a benefit but are similarly limited by their low quality of evidence. [ABSTRACT FROM AUTHOR]

Introduction: Alcohol use disorder (AUD) is the most prevalent substance use disorder (SUD) globally. In 2019, AUD affected 14.5 million Americans and contributed to 95,000 deaths, with an annual cost exceeding 250 billion dollars. Current treatment options for AUD have moderate therapeutic effects and high relapse rates. Recent investigations have demonstrated the potential efficacy of intravenous ketamine infusions to increase alcohol abstinence and may be a safe adjunct to the existing alcohol withdrawal syndrome (AWS) management strategies. Methods: We followed Preferred Reporting Items for Systematic Reviews (PRISMA) guidelines to conduct a scoping review of two databases (PubMed and Google Scholar) for peer-reviewed manuscripts describing the use of ketamine in AUD and AWS. Studies that evaluated the use of ketamine in AUD and AWS in humans were included. We excluded studies that examined laboratory animals, described alternative uses of ketamine, or discussed other treatments of AUD and AWS. Results: We identified 204 research studies in our database search. Of these, 10 articles demonstrated the use of ketamine in AUD or AWS in humans. Seven studies investigated the use of ketamine in AUD and three studies described its use in AWS. Ketamine used in AUD was beneficial in reducing cravings, alcohol consumption and longer abstinence rates when compared to treatment as usual. In AWS, ketamine was used as an adjunct to standard benzodiazepine therapy during severe refractory AWS and at signs of delirium tremens. Adjunctive use of ketamine demonstrated earlier resolution of delirium tremens and AWS, reduced ICU stay, and lowered likelihood of intubation. Oversedation, headache, hypertension, and euphoria were the documented adverse effects after ketamine administration for AUD and AWS. Conclusion: The use of sub-dissociative doses of ketamine for the treatment of AUD and AWS is promising but more definitive evidence of its efficacy and safety is required before recommending it for broader clinical use. [ABSTRACT FROM AUTHOR]

Aim Proving the Severity of Ethanol Withdrawal Scale (SEWS) significantly reduces Alcohol Withdrawal Syndrome (AWS) treatment Time on Medication Protocol (TOMP). Method Head-to-head Quality Assurance outcome compared separate cohorts of SEWS or Clinical Institute Withdrawal Assessment Alcohol Scale, Revised (CIWA-Ar) data using Student's t and Wilcoxon tests. Results SEWS-driven treatment (n  = 244) reduced TOMP to 2.2 days versus 3.4 days for CIWA-Ar (n  = 137); P  < 0.0001. Conclusion The SEWS is the superior measure of AWS symptoms. [ABSTRACT FROM AUTHOR]

Candida lipolytica is an uncommon Candida species causing invasive fungemia. This yeast is mainly associated with the colonisation of intravascular catheters, complicated intra-abdominal infections, and infections in the paediatric population. Here, we report a case of C. lipolytica bloodstream infection in a 53-year-old man. He was admitted for an alcohol withdrawal syndrome and mild COVID-19. Among the primary risk factors for candidemia, only the use of broad-spectrum antimicrobials was reported. The empiric treatment was commenced with caspofungin and then targeted with intravenous fluconazole. Infective endocarditis was ruled out using echocardiography, and PET/TC was negative for other deep-seated foci of fungal infection. The patient was discharged after blood culture clearance and clinical healing. To the best of our knowledge, this is the first case of C. lipolytica candidemia in a patient with COVID-19 and alcohol use disorder. We performed a systematic review of bloodstream infections caused by C. lipolytica. Clinicians should be aware of the possibility of C. lipolytica bloodstream infections in patients with alcohol use disorder, especially in a COVID-19 setting. [ABSTRACT FROM AUTHOR]

(1) Background: The assessment of mortality and rebleeding rate in upper gastrointestinal bleeding (UGIB) is essential, and several prognostic scores have been proposed. Some patients with UGIB did not undergo endoscopy, either because they refused the procedure, suffered from alcohol withdrawal symptoms or altered general status, or because the bleeding was severe enough to cause death before the endoscopy. The mortality risk in the subgroup of patients without endoscopy is poorly evaluated in the literature. (2) Methods: The purpose of the study was to identify the most useful scores for the assessment of in-hospital mortality in patients with UGIB with no endoscopy performed and no known etiology. A total of 198 patients with UGIB and no endoscopy performed were admitted between January 2017 and December 2021 and the accuracy of 12 prognostic scores and the Charlson comorbidity index for in-hospital mortality prediction were analyzed, as well as Child–Pugh Turcotte (CPT) and Meld scores in patients with cirrhosis. (3) Results: The mortality rate was 37.9%, higher than in variceal (21.9%, p < 0.0001) and non-variceal bleeding (7.4%, p < 0.0001). The most accurate scores by AUC were the International Bleeding score (INBS, 0.844), Glasgow Blatchford (0.783), MAP score (0.78), Iino (0.766), AIM65 and modified N-score (0.745 each), modified Glasgow-Blatchford (0.73), H3B2 and N-score (0.701); Rockall, Baylor, and T-score had an AUC below 0.7. MELD score was superior to CPT in patients with cirrhosis (AUC 0.811 versus 0.670). (4) Conclusions: The mortality rate in UGIB with no endoscopy was higher than in both variceal and non-variceal bleeding and was higher in the pandemic period but with no statistical significance (45.3% versus 32.14%, p = 0.0586), mainly because of positive cases. Only one case of rebleeding was noted; the hospitalization period was significantly shorter. The most accurate score was International Bleeding Score; the MELD score had a higher but moderate accuracy compared with CPT in patients with cirrhosis. [ABSTRACT FROM AUTHOR]

Aims The amount and pattern of cigarette and alcohol consumption are highly associated with cardiovascular risk. The aim of the present study was the assessment of changes in arterial stiffness and classical risk factors for cardiovascular disease after alcohol withdrawal and detoxification in persons with alcohol use disorder. Methods Two hundred and forty-one individuals (men and women) participated in the investigation. The photoplethysmographic method was applied to assess arterial stiffness in three stages within 6 weeks. Participants were divided into subgroups based on age and sex. Analyses were performed using analysis of variance with repeated measures. Results Different variations in time of stiffness index (SI) and reflection index (RI) values were recorded. Some increases in triglycerides, total cholesterol, low-density lipoprotein and a decrease in high-density lipoproteins were observed in all analyzed groups. Both systolic and diastolic blood pressure (DP) changed significantly during the 3 weeks of the study only in a group of younger men. The SI is correlated with age and gender. No correlation of RI with sex was found; however, RI was strongly correlated with age, pulse and DP. Conclusions The presented study shows that some groups of patients (older women and younger men) after detoxification may be particularly vulnerable to vascular system disorders, i.e. arterial stiffness, making it suggested to include additional observation during therapy. [ABSTRACT FROM AUTHOR]

Background: Management of alcohol withdrawal syndrome (AWS) requires bedside assessments of symptom severity to guide therapies. Commonly used assessment tools are the Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar), the modified Minnesota Detoxification Scale (mMINDS) and the Severity of Ethanol Withdrawal Scale (SEWS). Objective: To determine strength of correlation between the CIWA-Ar, mMINDS, and SEWS for bedside assessment of severe AWS and to survey nurses regarding ease of use of each tool. Methods: A single-center prospective correlation study of the three assessment tools performed by bedside nurses on patients with AWS followed by a questionnaire assessing ease of use of each tool (1 being the easiest and 9 being the hardest). Results: A total of 66 correlation assessments were performed by 49 nurses in 21 patients with AWS. Bedside CIWA-Ar, mMINDS, and SEWS were 14 ± 8.3, 13.9 ± 6.5, and 10.1 ± 4.5, respectively. The Pearson correlation coefficients were 0.814 (95% CI, 0.714-0.881) between CIWA-Ar and mMINDS; 0.722 (95% CI, 0.585-0.820) between CIWA-Ar and SEWS; and 0.658 (95% CI, 0.498-0.775) between SEWS and mMINDS. Nurse ratings for ease of use were 4 ± 2.3 for CIWA-Ar, 2.9 ± 2 for mMINDS (p=0.0044 vs. CIWA-Ar), and 4.8 ± 2.1 for SEWS (p=0.036 vs. CIWA-Ar, p<0.0001 vs. mMINDS). Forty-six (69.7%) respondents preferred mMINDS versus 14 (21.2%) and 6 (9.1%) respondents favored CIWA-Ar and SEWS, respectively. Conclusion: Correlations between the three scoring tools in severe AWS are robust. Only mMINDS was considered easy to use by nurses. It was the preferred tool. [ABSTRACT FROM AUTHOR]

Objective To undertake a double blinded randomised placebo-controlled trial to assess the efficacy of vigabatrin, a GABA-transaminase inhibitor, as a benzodiazepine sparing agent in the management of acute alcohol withdrawal syndrome in a residential setting. Methods We enrolled 120 patients with alcohol use disorder who were randomly assigned to either treatment with vigabatrin (2g/day for 4 days) or placebo. The primary outcome was defined as the number of participants in each treatment arm needing diazepam for withdrawal management. A secondary outcome prespecified was the total dose of diazepam received by participants in each treatment arm. Participants were recruited on admission to a residential withdrawal unit at St Vincent's Hospital Melbourne from December 2014 to April 2019. Results No significant difference was observed in the number of participants requiring benzodiazepines during their residential withdrawal stay with 44 participants (78.6%) in placebo arm requiring at least one dose of diazepam compared to 38 (66.7%) in vigabatrin arm (p  = .156). An 18.1% difference was observed between the proportion of participants who received a total dose of >100mg of diazepam during their residential withdrawal stay in placebo arm (32.1%), compared to vigabatrin arm (14.0%, p  = .022). There were higher rates of reported adverse events in placebo arm with nine (15.0%) participants reporting adverse events compared with two (3.3%) participants in vigabatrin arm (p = .027). Conclusion Vigabatrin significantly reduced the number of participants requiring >100mg diazepam over the course of their alcohol withdrawal and was associated with a reduction in adverse effects when compared to placebo. [ABSTRACT FROM AUTHOR]

Background: High alcohol intake is associated with increased mortality. We aimed to identify factors affecting mortality in people drinking extreme amounts of alcohol. Methods: We obtained information from the UK Biobank on approximately 500,000 participants aged 40–70 years at baseline assessment in 2006–2010. Habitual alcohol intake, lifestyle and physiological data, laboratory test results, and hospital diagnoses and death certificate data (to June 2020) for 5136 men (2.20% of male participants) and 1504 women (0.60%) who reported consuming ≥80 or ≥50 g/day, respectively, were used in survival analysis. Results: Mortality hazard ratios for these excessive drinkers, compared to all other participants, were 2.02 (95% CI 1.89–2.17) for all causes, 1.89 (1.69–2.12) for any cancer, 1.87 (1.61–2.17) for any circulatory disease, and 9.40 (7.00–12.64) for any liver disease. Liver disease diagnosis or abnormal liver function tests predicted not only deaths attributed to liver disease but also those from cancers or circulatory diseases. Mortality among excessive drinkers was also associated with quantitative alcohol intake; diagnosed alcohol dependence, harmful use, or withdrawal syndrome; and current smoking at assessment. Conclusions: People with chronic excessive alcohol intake experience decreased average survival, but there is substantial variation in their mortality, with liver abnormality and alcohol dependence or other alcohol use disorders associated with a worse prognosis. Clinically, patients with these risk factors and high alcohol intake should be considered for early or intensive management. Research can usefully focus on the factors predisposing to dependence or liver abnormality. [ABSTRACT FROM AUTHOR]

Aims The goal of this study was to develop a standard measure of AUD severity that includes multiple dimensions and can be used in clinical settings to inform treatment selection. Methods A large sample (n  = 1939) of moderate to heavy drinkers was amassed from six psychopharmacology studies. The severity factor was comprised of four dimensions: withdrawal, craving, AUD symptoms and alcohol-related consequences. First, a confirmatory factor analysis (CFA) was conducted to examine model fit. Next, a comprehensive item list from the four measures (i.e. CIWA, DrinC, PACs and SCID-5 AUD criteria) was reduced through exploratory factor analysis (EFA). Once the final items were merged into a preliminary assessment, an EFA was run to observe the factor structure. Initial validation of the measure was obtained via associations with clinical endpoints. Results The chi-square test statistic (⁠|${\chi}^2(2)=2.432\ P=0.297$|⁠) for a single-factor model of severity demonstrated good fit. Additional goodness-of-fit indices from the CFA revealed similar support for the single-factor model of severity (i.e. SRMSR = 0.011; RMSEA = 0.011; CFI = 0.999). Next, nine items from the individual EFAs were selected based on factor loading. The final EFA conducted on the 9-item scale demonstrated that a single factor model of severity best fit the data. Analysis of the psychometric properties revealed good internal consistency (⁠|$\alpha$| = 0.79). Conclusions The current study extends upon the measurement of severity and supports a brief severity measure. This brief 9-item scale can be leveraged in future studies as a screening instrument and as a tool for personalized medicine. [ABSTRACT FROM AUTHOR]

Background: Alcohol use disorder (AUD) commonly occurs in patients with chronic pain, and a major barrier to achieving abstinence and preventing relapse is the emergence of hyperalgesia during alcohol withdrawal. Elucidating novel therapeutic approaches to target hyperalgesia associated with alcohol withdrawal could have important implications for treating AUD. Here, we examined the role of 2‐arachidonoylglycerol (2‐AG)‐mediated endocannabinoid (eCB) signaling in the regulation of hyperalgesia associated with alcohol withdrawal in mice. We tested the hypothesis that pharmacological augmentation of 2‐AG signaling could reduce hyperalgesia during withdrawal. Methods: Male and female C57BL/6J mice were tested during withdrawal from a continuous access two‐bottle choice (2BC) paradigm to investigate how eCB signaling modulates mechanical and thermal sensitivity during withdrawal. Mice were pretreated with the monoacylglycerol lipase (MAGL) inhibitor JZL184 to elevate levels of 2‐AG. Rimonabant or AM630 were given to block CB1 and CB2 receptor activity, respectively. DO34 was given to reduce 2‐AG by inhibiting the 2‐AG synthetic enzyme diacylglycerol lipase (DAGL). Results: After 72 h of withdrawal, male and female mice exhibited increased mechanical, but not thermal, hypersensitivity, which normalized by 7 days. This effect was reversed by pretreatment with JZL184. The effects of JZL184 were prevented by coadministration of either the CB1 or the CB2 antagonist. DO34, Rimonabant, and AM630 exacerbated mechanical hypersensitivity during alcohol withdrawal, causing an earlier onset and persistent hypersensitivity even 1 week into withdrawal. Conclusions: Our findings demonstrate the critical role of 2‐AG signaling in the bidirectional regulation of mechanical sensitivity during alcohol withdrawal, with enhancement of 2‐AG levels reducing sensitivity, and inhibition of 2‐AG signaling exacerbating sensitivity. These data suggest that 2‐AG augmentation represents a novel approach to the treatment of alcohol withdrawal‐associated hyperalgesia and AUD in patients with comorbid pain disorders. [ABSTRACT FROM AUTHOR]

Benzodiazepines and medications acting on benzodiazepine receptors that do not have a benzodiazepine structure (z-drugs) have been viewed by some experts and regulatory bodies as having limited benefit and significant risks. Data presented in this article support the use of these medications as treatments of choice for acute situational anxiety, chronic anxiety disorders, insomnia, alcohol withdrawal syndromes, and catatonia. They may also be useful adjuncts in the treatment of anxious depression and mania, and for medically ill patients. Tolerance develops to sedation and possibly psychomotor impairment, but not to the anxiolytic effect of benzodiazepines. Sedation can impair cognitive function in some patients, but assertions that benzodiazepines increase the risk of dementia are not supported by recent data. Contrary to popular opinion, benzodiazepines are not frequently misused or conduits to misuse of other substances in patients without substance use disorders who are prescribed these medications for appropriate indications; most benzodiazepine misuse involves medications that are obtained from other people. Benzodiazepines are usually not lethal in overdose except when ingested with other substances, especially alcohol and opioids. Benzodiazepines comprise one of the few classes of psychotropic medication the mechanisms of action of which are clearly delineated, allowing for greater precision in their clinical use. These medications, therefore, belong in the therapeutic armamentarium of the knowledgeable clinician. [ABSTRACT FROM AUTHOR]

Alcohol use disorder is a highly significant medical condition characterized by an impaired ability to stop or control alcohol use, compulsive alcohol seeking behavior, and withdrawal symptoms in the absence of alcohol. Understanding how alcohol modulates neurocircuitry critical for long term and binge-like alcohol use, such as the central amygdala (CeA), may lead to the development of novel therapeutic strategies to treat alcohol use disorder. In clinical studies, reduction in the volume of the amygdala has been linked with susceptibility to relapse to alcohol use. Preclinical studies have shown the involvement of the CeA in the effects of alcohol use, with lesions of the amygdala showing a reduction in alcohol drinking, and manipulations of cells in the CeA altering alcohol drinking. A great deal of work has shown that acute alcohol, as well as chronic alcohol exposure via intake or dependence models, alters glutamatergic and GABAergic transmission in the CeA. The CeA, however, contains heterogeneous cell populations and distinct subregional differences in neurocircuit architecture which may influence the mechanism by which alcohol modulates CeA function overall. The current review aimed to parse out the differences in alcohol effects on the medial and lateral subregions of the CeA, and what role neuroinflammatory cells and markers, the endocannabinoid system, and the most commonly studied neuropeptide systems play in mediating these effects. A better understanding of alcohol effects on CeA subregional cell type and neurocircuit function may lead to development of more selective pharmacological interventions for alcohol use disorder. [ABSTRACT FROM AUTHOR]

Postoperative head and neck cancer patients are at increased risk for alcohol withdrawal syndrome. Literature has shown that in this patient population, alcohol withdrawal is associated with an increase in postoperative medical and surgical complications, length of hospitalization, and hospital‐related costs. Harm reduction and addiction medicine philosophies can reduce morbidity and mortality, but have not been fully validated in perioperative surgical management for head and neck cancer. This commentary synthesizes key principles of addiction medicine and current strategies that Otolaryngology–Head and Neck Surgery surgeons can consider in their perioperative assessment and management of alcohol withdrawal syndrome in their patients. [ABSTRACT FROM AUTHOR]

Aims The purpose of this review is to evaluate microdialysis studies where alterations in the dopaminergic system have been evaluated after different intoxication states, in animals showing preference or not for alcohol, as well as during alcohol withdrawal. Methods Ethanol administration induces varying alterations in dopamine microdialysate concentrations, thereby modulating the functional output of the dopaminergic system. Results Administration of low doses of ethanol, intraperitoneally, intravenously, orally or directly into the nucleus accumbens, NAc, increases mesolimbic dopamine, transmission, as shown by increases in dopamine content. Chronic alcohol administration to rats, which show alcohol-dependent behaviour, induced little change in basal dopamine microdialysis content. In contrast, reduced basal dopamine content occurred after ethanol withdrawal, which might be the stimulus to induce alcohol cravings and consumption. Intermittent alcohol consumption did not identify any consistent changes in dopamine transmission. Animals which have been selectively or genetically bred for alcohol preference did not show consistent changes in basal dopamine content although, exhibited a significant ethanol-evoked dopamine response by comparison to non-preference animals. Conclusions Microdialysis has provided valuable information about ethanol-evoked dopamine release in the different animal models of alcohol abuse. Acute ethanol administration increases dopamine transmission in the rat NAc whereas chronic ethanol consumption shows variable results which might reflect whether the rat is prior to or experiencing ethanol withdrawal. Ethanol withdrawal significantly decreases the extracellular dopamine content. Such changes in dopamine surges will contribute to both drug dependence, e.g. susceptibility to drug withdrawal, and addiction, by compromising the ability to react to normal dopamine fluctuations. [ABSTRACT FROM AUTHOR]

Aim To examine the efficacy and safety of antiepileptic drugs (AED) for the inpatient treatment of patients with moderate to severe alcohol withdrawal syndrome (AWS). Methods We searched in databases and gray literature to include randomized controlled clinical trials in adults that compare the use of AED versus placebo or any other medication. Studies that did not specify severity or were performed on an outpatient basis were excluded. The outcomes were improvement of symptoms, delirium tremens, seizures and adverse events. Two researchers independently selected the references, extracted the data and assessed the risk of bias. A qualitative synthesis was made and, when the heterogeneity was mild or moderate, a meta-analysis was performed. The quality of the evidence obtained was evaluated with the Grading of Recommendations Assessment, Development and Evaluation tool. Results In total, 26 studies with 1709 patients were included. No benefit is described in withdrawal syndrome severity measured by scales or in the development of delirium tremens. The only possible meta-analysis showed that there are no differences in the incidence of seizures (risk ratio [RR] = 1.0; confidence interval (CI) 95% 0.76–1.33), even when compared with placebo (RR = 0.95; CI95% 0.57–1.57). There were also no differences in adverse events, although a higher proportion of some mild cases were described with the use of carbamazepine and valproic acid. Conclusions The routine use of AED is not suggested in the treatment of patients with moderate or severe AWS unless indicated for comorbidity (weak recommendation against using moderate quality of evidence). [ABSTRACT FROM AUTHOR]

Chronic alcohol use increases risk of alcohol withdrawal symptoms (AW) and disrupts stress biology and resilient coping, thereby promoting excessive alcohol intake. Chronic alcohol intake and multiple alcohol detoxifications are known to impair brain medial prefrontal cortex (mPFC) and striatal functioning, regions involved in regulating stress, craving and alcohol intake. In two related studies, we examined whether AW predicts this functional brain pathology and whether Prazosin versus Placebo treatment may reverse these effects. In Study 1, patients with Alcohol Use Disorder (AUD) (N = 45) with varying AW levels at treatment entry were assessed to examine AW effects on corticostriatal responses to stress, alcohol cue and neutral visual images with functional magnetic resonance imaging (fMRI). In Study 2, 23 AUD patients entering a 12‐week randomised controlled trial (RCT) of Prazosin, an alpha1 adrenergic antagonist that decreased withdrawal‐related alcohol intake in laboratory animals, participated in two fMRI sessions at pretreatment and also at week 9–10 of chronic treatment (Placebo: N = 13; Prazosin: N = 10) to assess Prazosin treatment effects on alcohol‐related cortico‐striatal dysfunction. Study 1 results indicated that higher AW predicted greater disruption in brain mPFC and striatal response to stress and alcohol cues (p < 0.001, family‐wise error [FWE] correction) and also subsequently greater heavy drinking days (HDD) in early treatment (p < 0.01). In Study 2, Prazosin versus Placebo treatment reversed mPFC‐striatal dysfunction (p < 0.001, FWE), which in turn predicted fewer drinking days (p < 0.01) during the 12‐week treatment period. These results indicate that AW is a significant predictor of alcohol‐related prefrontal‐striatal dysfunction, and Prazosin treatment reversed these effects that in turn contributed to improved alcohol treatment outcomes. [ABSTRACT FROM AUTHOR]

Background: Despite its potential to produce serious adverse outcomes, DSM‐5 alcohol withdrawal syndrome (AWS) has not been widely studied in the general population. Methods: We used cross‐sectional data from 36,309 U.S. adults from the 2012–2013 National Epidemiologic Survey on Alcohol and Related Conditions‐III to examine the past‐year prevalence of AWS and its correlates. We focused on an important clinical population–past‐year drinkers with unhealthy alcohol use–i.e., those with a positive score on the Alcohol Use Disorders Identification Test–Consumption (AUDIT‐C) questionnaire. We also examined the association of AWS with sociodemographic measures, psychiatric disorders, alcohol‐related measures, and healthcare utilization. Results: Approximately one‐third (n = 12,634) of respondents reported unhealthy alcohol use (AUDIT‐C+). Of these, 14.3% met criteria for a DSM‐5 AWS diagnosis. The mean (SE) number of withdrawal symptoms among individuals with AWS was 2.83 (1.88), with the most common being nausea/vomiting and insomnia (19.8% and 11.6%, respectively). Among AUDIT‐C+ respondents, the odds of AWS were significantly higher among males (adjusted odds ratio [aOR] = 1.17 [95% CI, 1.02–1.33]), unmarried participants (aOR = 1.55 [95% CI, 1.25–1.92]), and those at the lowest (vs. highest) income levels (aOR = 1.62 [95% CI, 1.37–1.92]). Among AUDIT‐C+ respondents, AWS was also associated with psychiatric disorders (with aORs that ranged from 2.08 [95% CI, 1.79–2.41]) for major depressive disorder to 3.14 (95% CI, 1.79–2.41) for borderline personality disorder. AUDIT‐C+ respondents with AWS also had higher odds of past‐year alcohol use disorder (aOR = 11.2 [95% CI, 9.66–13.07]), other alcohol‐related features (e.g., binge drinking), and healthcare utilization. Conclusions: Among individuals with unhealthy alcohol use, AWS is prevalent, highly comorbid, and disabling. Given the risk of AWS among unhealthy drinkers, a comparatively large segment of the general population, clinicians should seek to identify individuals with AWS and intervene with them to prevent serious adverse outcomes. [ABSTRACT FROM AUTHOR]

In recent years, alcohol abuse and dependence have become topics of increasing concern in Uganda, but the chronic relapsing brain disease model of addiction remains only one of many ways of understanding and addressing alcohol-related problems there. For many Ugandan Pentecostals and spirit mediums to be addicted is to be under the control of a being that comes from outside the self. Where these two groups differ, and here they differ strongly, is in regard to the moral valence of these external spirits and what ought to be done about them. This article draws on four years of collaborative ethnographic fieldwork to explore the affordances of these ways of viewing and experiencing addiction and recovery for Ugandans attempting to leave alcohol behind. While the idioms of bondage, dedication, and possession are at times severe, this article argues that they contain within them concepts and practices that point away from models of addiction as a chronic relapsing brain disease and towards the possibility of release. [ABSTRACT FROM AUTHOR]

Aims: The coronavirus disease 2019 (COVID-19) pandemic and ensuing restrictions have negatively affected the mental health and well-being of the general population, and there is increasing evidence suggesting that lockdowns have led to a disruption of health services. In March 2020, South Africa introduced a lockdown in response to the COVID-19 pandemic, entailing the suspension of all non-essential activities and a complete ban of tobacco and alcohol sales. We studied the effect of the lockdown on mental health care utilisation rates in private-sector care in South Africa. Methods: We conducted an interrupted time-series analysis using insurance claims from 1 January 2017 to 1 June 2020 of beneficiaries 18 years or older from a large private sector medical insurance scheme. We calculated weekly outpatient consultation and hospital admission rates for organic mental disorders, substance use disorders, serious mental disorders, depression, anxiety, other mental disorders, any mental disorder and alcohol withdrawal syndrome. We calculated adjusted odds ratios (OR) for the effect of the lockdown on weekly outpatient consultation and hospital admission rates and the weekly change in rates during the lockdown until 1 June 2020. Results: 710 367 persons were followed up for a median of 153 weeks. Hospital admission rates (OR 0.38; 95% confidence interval (CI) 0.33–0.44) and outpatient consultation rates (OR 0.74; 95% CI 0.63–0.87) for any mental disorder decreased substantially after the introduction of the lockdown and did not recover to pre-lockdown levels by 1 June 2020. Health care utilisation rates for alcohol withdrawal syndrome doubled after the introduction of the lockdown, but the statistical uncertainty around the estimates was large (OR 2.24; 95% CI 0.69–7.24). Conclusions: Mental health care utilisation rates for inpatient and outpatient services decreased substantially after the introduction of the lockdown. Hospital admissions and outpatient consultations for alcohol withdrawal syndrome increased after the introduction of the lockdown, but statistical uncertainty precludes strong conclusions about a potential unintended effect of the alcohol sales ban. Governments should integrate strategies for ensuring access and continuity of essential mental health services during lockdowns in pandemic preparedness planning. [ABSTRACT FROM AUTHOR]

Background and Aims: Anti‐seizure medications (ASMs) have been used historically as treatment options in alcohol withdrawal syndrome (AWS). In the past 10 years, there have been no large‐scale meta‐analyses comparing ASMs with placebo or the current AWS treatment standard, benzodiazepines. We aimed to evaluate the efficacy and tolerability of ASMs in AWS. Methods: Systematic review and meta‐analysis of randomised controlled trials (RCTs) via searching Medline, Embase and PsychINFO from database inception to March 2020 involving adults age >18 years with AWS. We included 24 RCTs reporting on a total of 2223 participants. Efficacy outcomes included the number of participants experiencing AWS related seizures or delirium, Clinical Institute Withdrawal Assessment for Alcohol–Revised (CIWA‐Ar) score reduction and rescue medication requirements. Tolerability outcomes included adverse event rate and dropout because of adverse events, alongside severe and life‐threatening adverse event rates. Quality was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE). Results: There was no evidence of significant improvements in any efficacy outcomes when comparing ASMs with placebo or benzodiazepines. When compared with benzodiazepines, ASMs demonstrated significantly increased odds of requiring rescue medications (OR = 3.50, 95% CI = 1.32, 9.28; P = 0.012). When comparing ASMs with placebo, there were significantly more dropouts because of adverse events (OR = 1.86, 95% CI = 1.05, 3.28; P = 0.034). Most results were of very low quality with the majority of included studies conducted before 2000. Conclusions: This systematic review and meta‐analysis found no evidence to support general first line clinical use of anti‐seizure medications in alcohol withdrawal syndrome treatment. [ABSTRACT FROM AUTHOR]

Introduction: Phenobarbital has been successfully used in the emergency department (ED) to manage symptoms of alcohol withdrawal, but few studies have reported outcomes for ED patients who receive phenobarbital and are discharged. We compared return encounter rates in discharged ED patients with alcohol withdrawal who were treated with benzodiazepines and phenobarbital. Methods: This is a retrospective cohort study conducted at a single academic medical center utilizing chart review of discharged ED patients with alcohol withdrawal from July 1, 2016, to June 30, 2019. Patients were stratified according to ED management with benzodiazepines, phenobarbital, or a combination of both agents. The primary outcome was return ED encounter within three days of the index ED encounter. Multivariate logistic regression identified significant covariates of an ED return encounter. Results: Of 470 patients who were discharged with the diagnosis of alcohol withdrawal, 235 were treated with benzodiazepines, 133 with phenobarbital, and 102 with a combination of both. Baseline characteristics were similar among the groups. However, patients who received phenobarbital were provided significantly more lorazepam equivalents compared to patients who received benzodiazepines alone. Treatment with phenobarbital, alone or in combination with benzodiazepines, was associated with significantly lower odds of a return ED visit within three days compared with benzodiazepines alone [AOR 0.45 (95% CI 0.23, 0.88) p = 0.02 and AOR 0.33 (95% CI 0.15, 0.74) p = 0.007]. Conclusions: Patients who received phenobarbital for alcohol withdrawal were less likely to return to the ED within three days of the index encounter. Despite similar baseline characteristics, patients who received phenobarbital, with or without benzodiazepines, were provided greater lorazepam equivalents the ED. [ABSTRACT FROM AUTHOR]

Background: Patients who experience harms from alcohol and other substance use often seek care in the emergency department (ED). ED visits related to alcohol withdrawal have increased across the world during the COVID-19 pandemic. ED clinicians are responsible for risk-stratifying patients under time and resource constraints and must reliably identify those who are safe for outpatient management versus those who require more intensive levels of care. Published guidelines for alcohol withdrawal are largely limited to the primary care and outpatient settings, and do not provide specific guidance for ED use. The purpose of this review was to synthesize published evidence on the treatment of alcohol withdrawal syndrome in the ED.Methods: We conducted a rapid review by searching MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials (1980 to 2020). We searched for grey literature on Google and hand-searched the conference abstracts of relevant addiction medicine and emergency medicine professional associations (2015 to 2020). We included interventional and observational studies that reported outcomes of clinical interventions aimed at treating alcohol withdrawal syndrome in adults in the ED.Results: We identified 13 studies that met inclusion criteria for our review (7 randomized controlled trials and 6 observational studies). Most studies were at high/serious risk of bias. We divided studies based on intervention and summarized evidence narratively. Benzodiazepines decrease alcohol withdrawal seizure recurrence and treat other alcohol withdrawal symptoms, but no clear evidence supports the use of one benzodiazepine over another. It is unclear if symptom-triggered benzodiazepine protocols are effective for use in the ED. More evidence is needed to determine if phenobarbital, with or without benzodiazepines, can be used safely and effectively to treat alcohol withdrawal in the ED. Phenytoin does not have evidence of effectiveness at preventing withdrawal seizures in the ED.Conclusions: Few studies have evaluated the safety and efficacy of pharmacotherapies for alcohol withdrawal specifically in the ED setting. Benzodiazepines are the most evidence-based treatment for alcohol withdrawal in the ED. Pharmacotherapies that have demonstrated benefit for treatment of alcohol withdrawal in other inpatient and outpatient settings should be evaluated in the ED setting before routine use. [ABSTRACT FROM AUTHOR]