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OBJECTIVES: Alcohol consumption affects sleep both in healthy populations and in patients with alcohol use disorder (AUD). However, sleep has typically not been considered within AUD pharmacotherapy trials. We used data from a completed gabapentin clinical treatment trial to explore the medication's effect on patient-rated insomnia measured by a standard insomnia rating (Insomnia Severity Index [ISI]) and whether this influenced gabapentin's effects on alcohol consumption. METHODS: This study included 90 individuals with current Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition AUD criteria reporting current or past alcohol withdrawal. Participants were assigned to placebo or gabapentin (up to 1200 mg/day) for a 16-week randomized controlled trial with percent heavy drinking days (PHDD) and percent abstinent days (PDA) as outcomes. Utilizing mixed-effects models, this study assessed medication effects on ISI over the trial. We then examined the interaction of baseline ISI and medication on drinking. Finally, given our previous finding of alcohol withdrawal influencing gabapentin efficacy, we added change in ISI as a potential "moderator" of the interaction of medication effects and alcohol withdrawal on drinking. RESULTS: Sleep (ISI) improved more in those treated with gabapentin (60.6% reduction) compared with placebo (37.8% reduction; P = 0.013). Higher baseline ISI predicted drinking in gabapentin-treated individuals (lower PHDD [P = 0.026] and higher (PDA [P = 0.047]). ISI was an independent predictor of PHDD decrease and PDA increase (P < 0.001; P = 0.002), but this did not significantly moderate gabapentin's effectiveness. CONCLUSIONS: Although gabapentin positively impacts both alcohol use and sleep, its effect on drinking is not fully dependent on sleep improvement, implying a direct biological mechanism on alcohol use.
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OBJECTIVES: This study aimed to evaluate the validity of World Health Organization (WHO) risk drinking level reductions as meaningful endpoints for clinical practice and research. This study examined whether such reductions were associated with a lower likelihood of a current alcohol use disorder (AUD) diagnosis and fewer AUD criteria. METHODS: We conducted a secondary data analysis to address these objectives using data from a multisite randomized controlled trial of gabapentin enacarbil extended release in treating moderate to severe AUD among adults (N = 346). Participants received gabapentin enacarbil extended release or placebo for 6 months. The timeline follow-back was used to assess WHO risk drinking level reductions, and the Mini-International Neuropsychiatric Interview was used to assess Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) AUD diagnosis and criteria at baseline (past year) and end of treatment (past month). RESULTS: Most participants (80.1%) achieved at least a 1-level reduction in the WHO risk drinking levels from baseline to end of treatment, and nearly half of participants (49.8%) achieved at least a 2-level reduction. At least a 1-level reduction or at least a 2-level reduction in WHO risk drinking level predicted lower odds of an active AUD diagnosis (1-level: odds ratio, 0.74 [95% confidence interval (CI), 0.66-0.84]; 2-level: odds ratio, 0.71 [95% CI, 0.64-0.79]) and fewer AUD criteria (1-level: B , -1.66 [95% CI, -2.35 to -0.98]; 2-level: B , -1.76 [95% CI, -2.31 to -1.21]) at end of treatment. CONCLUSIONS: World Health Organization risk drinking level reductions correlate with Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) AUD diagnosis and criteria, providing further evidence for their use as endpoints in alcohol intervention trials, which has potential implications for broadening the base of AUD treatment.
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Alcoolismo , Organização Mundial da Saúde , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Alcoolismo/diagnóstico , Alcoolismo/tratamento farmacológico , Consumo de Bebidas Alcoólicas , Resultado do Tratamento , Preparações de Ação RetardadaRESUMO
AIMS: Among individuals with alcohol use disorder (AUD), sleep disturbances are pervasive and contribute to the etiology and maintenance of AUD. However, despite increased attention toward the relationship between alcohol use and sleep, limited empirical research has systematically examined whether reductions in drinking during treatment for AUD are associated with improvements in sleep problems. METHODS: We used data from a multisite, randomized, controlled trial that compared 6 months of treatment with gabapentin enacarbil extended-release with placebo for adults with moderate-to-severe AUD (N = 346). The Timeline Follow-back was used to assess WHO risk drinking level reductions and the Pittsburgh Sleep Quality Index was used to assess sleep quality over the prior month at baseline and the end of treatment. RESULTS: Sleep problem scores in the active medication and placebo groups improved equally. Fewer sleep problems were noted among individuals who achieved at least a 1-level reduction (B = -0.99, 95% confidence interval (CI) [-1.77, -0.20], P = .014) or at least a 2-level reduction (B = -0.80, 95% CI [-1.47, -0.14], P = .018) in WHO risk drinking levels at the end of treatment. Reductions in drinking, with abstainers excluded from the analysis, also predicted fewer sleep problems at the end of treatment (1-level: B = -1.01, 95% CI [-1.83, -0.20], P = .015; 2-level: B = -0.90, 95% CI [-1.59, -0.22], P = .010). CONCLUSIONS: Drinking reductions, including those short of abstinence, are associated with improvements in sleep problems during treatment for AUD. Additional assessment of the causal relationships between harm-reduction approaches to AUD and improvements in sleep is warranted.
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Alcoolismo , Adulto , Humanos , Consumo de Bebidas Alcoólicas/terapia , Alcoolismo/complicações , Alcoolismo/tratamento farmacológico , Organização Mundial da Saúde , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: Poor inhibitory control and enhanced subjective response to alcohol are interrelated risk factors for alcohol use disorder (AUD) that share underlying neural substrates, including dopamine signaling in the right prefrontal cortex, a potential target for pharmacological intervention. Cortical dopamine inactivation is primarily regulated by catechol-O-methyltransferase (COMT), an enzyme with large variation in activity as a function of the COMT rs4680 (val158met) single nucleotide polymorphism. In a previous randomized, placebo-controlled trial of the COMT inhibitor tolcapone (200 mg TID) in non-treatment-seeking participants with AUD, we found that tolcapone, relative to placebo, reduced alcohol self-administration only among rs4680 val-allele homozygotes, whose COMT activity is higher than in met-allele carriers. METHODS: We conducted secondary analyses of the effects of tolcapone and baseline COMT activity, as indexed by both rs4680 genotype and an enzymatic activity assay, on the subjective response to alcohol in a bar-laboratory paradigm among 60 participants in the previous trial. RESULTS: Tolcapone did not affect alcohol-induced stimulation or sedation more than placebo. However, baseline COMT activity moderated the effects of the drug on both outcomes, such that tolcapone-treated participants with higher baseline COMT activity had less stimulation (p = 0.008) and sedation (p = 0.053) than participants with lower baseline COMT activity and those treated with placebo. Additionally, alcohol-induced stimulation significantly mediated the interacting effects of baseline COMT activity and tolcapone on bar-laboratory self-administration. CONCLUSIONS: Tolcapone may reduce subjective response to alcohol more effectively among individuals with preexisting high COMT activity an effect that could account for the drug's reduction of alcohol consumption among these individuals.
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BACKGROUND: Abstinence has historically been considered the preferred goal of alcohol use disorder (AUD) treatment. However, most individuals with AUD do not want to abstain and many are able to reduce their drinking successfully. Craving is often a target of pharmacological and behavioral interventions for AUD, and reductions in craving may signal recovery. Whether reductions in drinking during AUD treatment are associated with reductions in craving has not been well examined. METHODS: We conducted secondary analyses of data from three AUD clinical trials (N's= 1327, 346, and 200). Drinking reductions from baseline to the end of treatment were measured as changes in World Health Organization (WHO) risk drinking levels; alcohol craving was measured using validated self-report measures. Regression analyses tested whether drinking reductions were associated with end-of-treatment craving reductions; moderation analyses tested whether associations between drinking reduction and end-of-treatment craving differed across AUD severity. RESULTS: Reductions of at least 1 or at least 2 WHO risk drinking levels were associated with lower craving (all p's < 0.05). Results were substantively similar after removing abstainers at the end-of-treatment. Associations between drinking reductions and craving were generally not moderated by AUD severity. CONCLUSIONS: Individuals with WHO risk drinking level reductions reported significantly lower craving, as compared to those who did not achieve meaningful reductions in drinking. The results demonstrate the utility of WHO risk drinking levels as AUD clinical trial endpoints and provide evidence that drinking reductions mitigate craving.
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Importance: Reward circuitry dysfunction is a candidate mechanism of co-occurring bipolar disorder and alcohol use disorder (BD + AUD) that remains understudied. This functional magnetic resonance imaging (fMRI) research represents the first evaluation of alcohol cue reward processing in BD + AUD. Objective: To determine how alcohol cue processing in individuals with BD + AUD may be distinct from that of individuals with AUD or BD alone. Design, Setting, and Participants: This cross-sectional case-control study (April 2013-June 2018) followed a 2 × 2 factorial design and included individuals with BD + AUD, AUD alone, BD alone, and healthy controls. A well-validated visual alcohol cue reactivity fMRI paradigm was administered to eligible participants following their demonstration of 1 week or more of abstinence from alcohol and drugs assessed via serial biomarker testing. Study procedures were completed at the Medical University of South Carolina. Analysis took place between June and August 2022. Main Outcomes and Measures: Past-week mood symptoms were rated by clinicians using the Montgomery-Åsberg Depression Rating Scale and Young Mania Rating Scale. The Alcohol Dependence Scale, Obsessive-Compulsive Drinking Scale, and Barratt Impulsiveness Scale were included questionnaires. Functional MRI whole-brain data were analyzed along with percent signal change within a priori regions of interest located in the ventral striatum, dorsal striatum, and ventromedial prefrontal cortex. Exploratory analyses of associations between cue reactivity and select behavioral correlates (alcohol craving, impulsivity, maximum number of alcohol drinks on a single occasion, and days since last alcohol drink) were also performed. Results: Of 112 participants, 28 (25.0%) had BD + AUD, 26 (23.2%) had AUD alone, 31 (27.7%) had BD alone, and 27 (24.1%) were healthy controls. The mean (SD) age was 38.7 (11.6) years, 50 (45.5%) were female, 33 (30%) were smokers, and 37 (34.9%) reported recent alcohol consumption. Whole-brain analyses revealed a BD × AUD interaction (F = 10.64; P = .001; η2 = 0.09) within a cluster spanning portions of the right inferior frontal gyrus and insula. Region of interest analyses revealed a main association of BD (F = 8.02; P = .006; η2 = 0.07) within the dorsal striatum. In each instance, individuals with BD + AUD exhibited reduced activation compared with all other groups who did not significantly differ from one another. These hypoactivations were associated with increased impulsivity and obsessive-compulsive alcohol craving exclusively among individuals with BD + AUD. Conclusion and Relevance: The findings of this study suggest conceptualizing reward dysfunction in BD + AUD by the potential interaction between blunted reward responsivity and deficient inhibitory control may help guide treatment development strategies. To this end, reduced right inferior frontal gyrus and insula alcohol cue reactivity represents a novel candidate biomarker of BD + AUD that may respond to pharmacological interventions targeting impulsivity-related neural mechanisms for improved executive control.
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Alcoolismo , Transtorno Bipolar , Humanos , Feminino , Adulto , Masculino , Alcoolismo/tratamento farmacológico , Transtorno Bipolar/diagnóstico por imagem , Estudos Transversais , Estudos de Casos e Controles , Sinais (Psicologia) , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Etanol , Biomarcadores , Imageamento por Ressonância Magnética/métodosRESUMO
Alcohol Use Disorder (AUD) is characterized by loss of control over drinking. Behavioral control is mediated, in part, by cortical dopamine signaling. Inhibition of catechol-O-methyltransferase (COMT), the enzyme primarily responsible for cortical dopamine inactivation, may increase cortical dopamine, especially among individuals with genetically mediated lower dopaminergic tone, such as COMT rs4680 (val158met) val-allele homozygotes. This study was a randomized, placebo-controlled, pharmacogenetic trial of the COMT inhibitor tolcapone. Ninety non-treatment-seeking AUD individuals were prospectively genotyped for rs4680 and randomized to tolcapone (200 mg t.i.d.) or placebo for 8 days. At baseline and on day 7, peripheral COMT activity was assayed, and participants completed an fMRI alcohol cue-reactivity task; on day 8, they completed a bar-lab paradigm. Primary outcomes were: (1) natural drinking during the medication period; (2) alcohol self-administration in the bar lab; and (3) alcohol cue-elicited cortical (right inferior frontal gyrus [rIFG]) and ventral striatal activation. At baseline, the rs4680 val-allele had an additive effect on COMT activity. Tolcapone, relative to placebo, reduced COMT activity in all genotype groups. COMT genotype moderated tolcapone's effect on drinking during the medication period and in the bar lab, such that tolcapone, relative to placebo, reduced drinking only among val-allele homozygotes. Tolcapone did not affect cue-elicited ventral striatal activation but reduced rIFG activation; less rIFG activation on day 7 was associated with less drinking during the medication period. Taken together, these data suggest that COMT inhibition may reduce drinking specifically among individuals genetically predisposed to excessive COMT activity and potentially low cortical dopamine tone.ClinicalTrials.gov identifier: NCT02949934 https://clinicaltrials.gov/ct2/show/NCT02949934.
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Alcoolismo , Catecol O-Metiltransferase , Alcoolismo/diagnóstico por imagem , Alcoolismo/tratamento farmacológico , Alcoolismo/genética , Catecol O-Metiltransferase/genética , Inibidores de Catecol O-Metiltransferase/farmacologia , Inibidores de Catecol O-Metiltransferase/uso terapêutico , Dopamina , Etanol , Humanos , Tolcapona/farmacologiaRESUMO
Cue reactivity is one of the most frequently used paradigms in functional magnetic resonance imaging (fMRI) studies of substance use disorders (SUDs). Although there have been promising results elucidating the neurocognitive mechanisms of SUDs and SUD treatments, the interpretability and reproducibility of these studies is limited by incomplete reporting of participants' characteristics, task design, craving assessment, scanning preparation and analysis decisions in fMRI drug cue reactivity (FDCR) experiments. This hampers clinical translation, not least because systematic review and meta-analysis of published work are difficult. This consensus paper and Delphi study aims to outline the important methodological aspects of FDCR research, present structured recommendations for more comprehensive methods reporting and review the FDCR literature to assess the reporting of items that are deemed important. Forty-five FDCR scientists from around the world participated in this study. First, an initial checklist of items deemed important in FDCR studies was developed by several members of the Enhanced NeuroImaging Genetics through Meta-Analyses (ENIGMA) Addiction working group on the basis of a systematic review. Using a modified Delphi consensus method, all experts were asked to comment on, revise or add items to the initial checklist, and then to rate the importance of each item in subsequent rounds. The reporting status of the items in the final checklist was investigated in 108 recently published FDCR studies identified through a systematic review. By the final round, 38 items reached the consensus threshold and were classified under seven major categories: 'Participants' Characteristics', 'General fMRI Information', 'General Task Information', 'Cue Information', 'Craving Assessment Inside Scanner', 'Craving Assessment Outside Scanner' and 'Pre- and Post-Scanning Considerations'. The review of the 108 FDCR papers revealed significant gaps in the reporting of the items considered important by the experts. For instance, whereas items in the 'General fMRI Information' category were reported in 90.5% of the reviewed papers, items in the 'Pre- and Post-Scanning Considerations' category were reported by only 44.7% of reviewed FDCR studies. Considering the notable and sometimes unexpected gaps in the reporting of items deemed to be important by experts in any FDCR study, the protocols could benefit from the adoption of reporting standards. This checklist, a living document to be updated as the field and its methods advance, can help improve experimental design, reporting and the widespread understanding of the FDCR protocols. This checklist can also provide a sample for developing consensus statements for protocols in other areas of task-based fMRI.
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Lista de Checagem , Imageamento por Ressonância Magnética , Sinais (Psicologia) , Técnica Delphi , Humanos , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Abstinence has historically been considered the target outcome for alcohol use disorder (AUD) treatment, yet recent work has found drinking reductions after AUD treatment, as measured by World Health Organization (WHO) risk drinking levels, are associated with meaningful improvements in functioning, physical health, and quality of life. OBJECTIVES: This study extends previous analyses of AUD treatment outcomes by estimating the association between changes in WHO risk drinking levels (very high, high, medium, and low, based on average daily alcohol consumption) and healthcare costs. METHODS: Secondary data analysis of the COMBINE study, a multisite randomized clinical trial of acamprosate, naltrexone and behavioral interventions for AUD. Generalized gamma regression models were used to estimate relationships between WHOrisk drinking level reductions over the course of treatment and healthcare costs in the year after treatment (N = 964) and up to 3 years following treatment (N = 651). RESULTS: SustainedWHOrisk drinking reductions of 2 or more levels throughout treatment were associated with 52.0% lower healthcare costs ( P < 0.001) in the year following treatment, and 44.0% lower costs ( P < 0.0025) over 3 years. A reduction of exactly 1 level was associated with 34.8% lower costs over 3 years, which was not significant ( P = 0.05). Cost reductions were driven by lower inpatient behavioral health and emergency department utilization. CONCLUSIONS: Reduction in WHO risk drinking levels of at least 2 levels was associated with lower healthcare costs over 1 and 3 years. Our results add to literature showing drinking reductions are associated with improvement in health.
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Alcoolismo , Qualidade de Vida , Consumo de Bebidas Alcoólicas , Alcoolismo/terapia , Custos de Cuidados de Saúde , Humanos , Resultado do Tratamento , Organização Mundial da SaúdeRESUMO
Polymorphisms in genes associated with opioid signaling and dopamine reuptake and inactivation may moderate naltrexone efficacy in Alcohol Use Disorder (AUD), but the effects of epigenetic modification of these genes on naltrexone response are largely unexplored. This study tested interactions between methylation in the µ-opioid receptor (OPRM1), dopamine transporter (SLC6A3), and catechol-O-methyltransferase (COMT) genes as predictors of naltrexone effects on heavy drinking in a 16-week randomized, placebo-controlled trial among 145 treatment-seeking AUD patients. OPRM1 methylation interacted with both SLC6A3 and COMT methylation to moderate naltrexone efficacy, such that naltrexone-treated individuals with lower methylation of the OPRM1 promoter and the SLC6A3 promoter (p = 0.006), COMT promoter (p = 0.005), or SLC6A3 3' untranslated region (p = 0.004), relative to placebo and to those with higher OPRM1 and SLC6A3 or COMT methylation, had significantly fewer heavy drinking days. Epigenetic modification of opioid- and dopamine-related genes may represent a novel pharmacoepigenetic predictor of naltrexone efficacy in AUD.
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Alcoolismo/tratamento farmacológico , Alcoolismo/genética , Epigênese Genética/genética , Naltrexona/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Adulto , Proteína de Matriz Oligomérica de Cartilagem/genética , Metilação de DNA , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Receptores Opioides mu/genética , Resultado do TratamentoRESUMO
OBJECTIVE: Although gabapentin has demonstrated efficacy in mitigating alcohol withdrawal symptoms and preventing relapse drinking in individuals with alcohol use disorder (AUD), the neurobiological mechanisms of action underlying these therapeutic effects remain unknown. The present study evaluated changes in GABA and glutamate levels in the dorsal anterior cingulate cortex (dACC) as candidate mechanisms of action. METHODS: In a 16-week randomized clinical trial, 68 adults with AUD, including a history of alcohol withdrawal syndrome, received 1,200 mg/day of gabapentin (N=37) or placebo (N=31) and nine medical management visits after ≥72 hours of abstinence. Proton MR spectroscopy (1H-MRS) estimates of dACC levels of GABA (N=67) and glutamate (N=64) were acquired before start of treatment and again approximately 14 days after randomization. Percent days abstinent was reported via timeline followback interview. RESULTS: The effects of gabapentin on GABA and glutamate levels were significantly associated with participants' percent days abstinent during early treatment. Specifically, gabapentin was associated with greater increases in glutamate and greater decreases in GABA levels in participants who remained mostly or entirely abstinent, and yet the opposite in participants who drank on more than half of the days preceding the second scan. Furthermore, gabapentin-treated participants with greater increases in glutamate levels during early treatment had significantly more percent days abstinent across the remainder of the study, relative to placebo-treated participants. CONCLUSIONS: In addition to providing insight into the mechanisms through which gabapentin may promote abstinence in individuals with AUD, this study also provides evidence for a biomarker of efficacious treatment that may be used to evaluate other glutamatergic or GABAergic medications for AUD and related conditions.
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Alcoolismo/tratamento farmacológico , Gabapentina/uso terapêutico , Ácido Glutâmico/metabolismo , Giro do Cíngulo/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismo , Adulto , Método Duplo-Cego , Feminino , Gabapentina/farmacologia , Giro do Cíngulo/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Espectroscopia de Prótons por Ressonância Magnética , Síndrome de Abstinência a Substâncias/tratamento farmacológicoRESUMO
OBJECTIVE: Little is known about change over time in the prevalence of World Health Organization (WHO) risk drinking levels (very high, high, moderate, low) and their association with health conditions, overall and by gender. The authors used two sets of nationally representative U.S. survey data to determine whether changes over time varied by gender and to examine whether health conditions related to alcohol were associated with WHO risk drinking level within each survey, and whether these associations differed by gender. METHODS: Data on current drinkers from the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC; N=26,655) and the 2012-2013 NESARC-III (N=25,659) were analyzed using logistic regression. Prevalence differences between surveys were estimated for each drinking level overall and by gender. Within each survey, prevalence differences by WHO risk drinking level were estimated for alcohol use disorder (AUD), drug use disorders, functional impairment, liver disease, and depressive and anxiety disorders. RESULTS: In the 2012-2013 survey, the prevalences of moderate, high, and very high risk drinking were 5.9%, 3.2%, and 3.5%, respectively, representing significant increases from the prevalences in the 2001-2002 survey, which were 1.0%, 0.6%, and 0.9%, respectively. The increase for very high risk drinking among men (0.5%) was smaller than the increase among women (1.4%). Within both surveys, compared with low risk, health conditions were significantly associated with very high risk (range of prevalence differences, 2.2%-57.8%), high risk (2.6%-41.3%), and moderate risk (0.6%-29.8%) drinking. Associations were similar by gender, except that there were stronger effects for AUD in men and for functional impairment and depressive and anxiety disorders in women. CONCLUSIONS: The increase in potentially problematic drinking levels among U.S. adults emphasizes the need for better prevention and treatment strategies. The study results support the validity of the WHO risk drinking levels, which show clinical utility as nonabstinent drinking reduction treatment goals. Such goals could engage more people in treatment, improving public health by decreasing personal and societal consequences of risk drinking.
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Consumo de Bebidas Alcoólicas/tendências , Alcoolismo/epidemiologia , Consumo Excessivo de Bebidas Alcoólicas/tendências , Adolescente , Adulto , Idoso , Consumo de Bebidas Alcoólicas/epidemiologia , Transtornos de Ansiedade/epidemiologia , Consumo Excessivo de Bebidas Alcoólicas/epidemiologia , Transtorno Depressivo/epidemiologia , Feminino , Estado Funcional , Humanos , Hepatopatias/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Risco , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Inquéritos e Questionários , Estados Unidos/epidemiologia , Organização Mundial da Saúde , Adulto JovemRESUMO
BACKGROUND: Alcohol use remains abundant in patients with traumatic injury. Previous studies have suggested that serum carbohydrate-deficient transferrin (%dCDT) levels, relative to blood alcohol levels (BALs), may better differentiate episodic binge drinkers from sustained heavy consumers in admitted patients with traumatic injury. We characterized %dCDT levels and BAL levels to differentiate binge drinkers from sustained heavy consumers in admitted trauma patients and their associations with outcomes. METHODS: This prospective, cross-sectional, observational study assessed %dCDT and BAL levels in admitted male and female patients with traumatic injury (≥18 y) at an American College of Surgeons Committee on Trauma level-1 center from July 2014 to June 2016. We designated patients with %dCDT levels ≥1.7% (CDT+) as chronic alcohol users and dichotomized acutely intoxicated patients using three different BAL-level thresholds. Primary outcomes included in-hospital complications, along with prolonged ventilation and intensive care unit length of stay, both defined as the top decile. Secondary outcomes included rates of drug or alcohol withdrawal and all-cause mortality. Analyses were adjusted for clinical factors. RESULTS: We studied 715 patients (77.5% men, 60.6% ≤ 40 y of age, median Injury Severity Score: 14, 41.7% motor vehicle crashes, 17.9% gunshot wounds, 11.1% falls). While 31.0% were CDT+, 48.7% were BAL>0. After adjusting for CDT levels, BAL levels >0, >100, or >200 were not associated with adverse outcomes. However, CDT+ relative to patients with CDT were associated with complications (adjusted odds ratio: 1.96 [1.24-3.09]), prolonged ventilation days (3.23 [1.08-9.65]), and prolonged intensive care unit stays (2.83 [1.20-6.68]). CONCLUSIONS: In this 2-year prospective, cross-sectional, and observational study, we found that %dCDT levels, relative to BAL levels, may better stratify admitted patients with traumatic injury into acute versus chronic alcohol users, identifying those at higher risk for in-hospital complications.
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Transtornos Relacionados ao Uso de Álcool/sangue , Transtornos Relacionados ao Uso de Álcool/epidemiologia , Concentração Alcoólica no Sangue , Transferrina/análogos & derivados , Ferimentos e Lesões/sangue , Acidentes de Trânsito , Adolescente , Adulto , Alcoolismo/sangue , Alcoolismo/epidemiologia , Consumo Excessivo de Bebidas Alcoólicas/sangue , Consumo Excessivo de Bebidas Alcoólicas/epidemiologia , Estudos Transversais , Diagnóstico Diferencial , Feminino , Humanos , Escala de Gravidade do Ferimento , Unidades de Terapia Intensiva , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Transferrina/análise , Resultado do Tratamento , Ferimentos e Lesões/epidemiologia , Ferimentos e Lesões/terapia , Ferimentos por Arma de Fogo/sangue , Adulto JovemRESUMO
BACKGROUND: Substance use during adolescence can have a number of negative consequences and interfere with normal brain development. Given limited time and resources, brief group- and school-based prevention programs are an efficient strategy for educating youth about the effects of substance use on health outcomes. OBJECTIVES: To determine if a science-based, interactive substance prevention program could improve student knowledge and influence students' attitudes toward future substance use behaviors. METHODS: The Just Say Know program was given to 1,594 middle and high school students. The facilitator engaged students in an interactive, hour-long session covering brain basics and effects of substance use. Students completed an eight-item pre- and post-knowledge-based test to measure learning outcomes along with feedback questions about youths' attitudes toward substance use and the program. RESULTS: After the program, 94% of students reported that it provided helpful information; 92% reported it may influence their approach to substance use, with 76% specifying that they would delay or cut back on substance use. Knowledge-based test performance increased by 78%, with high schoolers displaying significantly higher scores than middle schoolers, but both showing similar improvements in scores. Students who reported higher levels of friends' substance use had smaller improvements from pre- to posttest. CONCLUSION: Results suggest Just Say Know, a scientifically-based prevention program, is effective in increasing adolescents' program based-knowledge, has the potential to affect youths' attitudes toward substance use, and is well-received. These findings provide preliminary evidence that a cost-effective, neuroscience-informed group prevention program might reduce or delay adolescents' future substance use.
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Comportamento do Adolescente , Estudantes/psicologia , Transtornos Relacionados ao Uso de Substâncias/prevenção & controle , Adolescente , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Masculino , Projetos Piloto , Avaliação de Programas e Projetos de Saúde , Serviços de Saúde EscolarRESUMO
BACKGROUND: The World Health Organization (WHO) categorizes alcohol consumption according to grams consumed into low-, medium-, high-, and very-high-risk drinking levels (RDLs). Although abstinence has been considered the ideal outcome of alcohol treatment, reductions in WHO RDLs have been proposed as primary outcomes for alcohol use disorder (AUD) trials. OBJECTIVE: The current study examines the stability of WHO RDL reductions and the association between RDL reductions and long-term functioning for up to 3 years following treatment. DESIGN AND PARTICIPANTS: Secondary data analysis of patients with AUD enrolled in the COMBINE Study and Project MATCH, two multi-site, randomized AUD clinical trials, who were followed for up to 3 years post-treatment (COMBINE: n = 694; MATCH: n = 806). MEASURES: Alcohol use was measured via calendar-based methods. We estimated all models in the total sample and among participants who did not achieve abstinence during treatment. KEY RESULTS: One-level RDL reductions were achieved by 84% of patients at the end of treatment, with 84.9% of those individuals maintaining that reduction at a 3-year follow-up. Two-level RDL reductions were achieved by 68% of patients at the end of treatment, with 77.7% of those individuals maintaining that reduction at a 3-year follow-up. One- and two-level RDL reductions at the end of treatment were associated with significantly better mental health, quality of life (including physical quality of life), and fewer drinking consequences 3 years after treatment (p < 0.05), as compared to no change or increased drinking. CONCLUSION: AUD patients can maintain WHO RDL reductions for up to 3 years after treatment. Patients who had WHO RDL reductions functioned significantly better than those who did not reduce their drinking. These findings are consistent with prior reports suggesting that drinking reductions, short of abstinence, yield meaningful improvements in patient health, well-being, and functioning.
Assuntos
Alcoolismo , Consumo de Bebidas Alcoólicas/epidemiologia , Alcoolismo/epidemiologia , Alcoolismo/terapia , Humanos , Saúde Mental , Qualidade de Vida , Resultado do Tratamento , Organização Mundial da SaúdeRESUMO
BACKGROUND: While the opiate antagonist, naltrexone, is approved for treating alcohol use disorder (AUD), not everyone who receives the medication benefits from it. This study evaluated whether the OPRM1 SNP rs1799971 interacts with the dopamine transporter gene DAT1/SLC6A3 VNTR rs28363170 or the catechol-O-methyltransferase (COMT) gene SNP rs4680 in predicting naltrexone response. METHODS: Individuals who met DSM-IV alcohol dependence were randomly assigned to naltrexone (50 mg/d) or placebo based on their OPRM1 genotype (75 G-allele carriers and 77 A-allele homozygotes) and also genotyped for DAT1 VNTR (9 vs. 10 repeats) or COMT SNP (val/val vs. met carriers). Heavy drinking days (%HDD) were evaluated over 16 weeks and at the end of treatment. Effect sizes (d) for naltrexone response were calculated based on genotypes. RESULTS: Naltrexone, relative to placebo, significantly reduced %HDD among OPRM1 G carriers who also had DAT1 10/10 (p = 0.021, d = 0.72) or COMT val/val genotypes (p = 0.05, d = 0.80), and to a lesser degree in those OPRM1 A homozygotes who were also DAT1 9-repeat carriers (p = 0.09, d = 0.70) or COMT met carriers (p = 0.03, d = 0.63). All other genotype combinations showed no differential response to naltrexone. Diarrhea/abdominal pain was more prominent in OPRM1 A homozygotes who were also DAT 9 or COMT met carriers. CONCLUSIONS: These results suggest that individuals with AUD with a more opioid-responsive genotype (OPRM1 G carriers) respond better to naltrexone if they have genotypes indicating normal/less dopamine tone (DAT1 10,10 or COMT val,val), while those with a less responsive opioid-responsive genotype (OPRM1 A homozygotes) respond better to naltrexone if they have genotypes indicating greater dopamine tone (DAT1 9-repeat or COMT met carriers). These results could lead to more personalized AUD treatments.
Assuntos
Alcoolismo/tratamento farmacológico , Catecol O-Metiltransferase/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Naltrexona/uso terapêutico , Receptores Opioides mu/genética , Alcoolismo/genética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Resultado do TratamentoRESUMO
Importance: Although an estimated 30 million people meet criteria for alcohol use disorder (AUD), few receive appropriate pharmacotherapy. A more personalized, symptom-specific, approach might improve efficacy and acceptance. Objective: To examine whether gabapentin would be useful in the treatment of AUD, especially in those with the most alcohol withdrawal symptoms. Design, Setting, and Participants: This double-blind randomized clinical trial conducted between November 2014 and June 2018 evaluated gabapentin vs placebo in community-recruited participants screened and treated in an academic outpatient setting over a 16-week treatment period. A total of 145 treatment-seeking individuals who met Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) criteria for AUD and were not receiving other AUD intervention were screened, and 96 who also met recent alcohol withdrawal criteria were randomized to treatment after 3 abstinent days. Daily drinking was recorded, and percentage of disialo carbohydrate-deficient transferrin in the blood, a heavy drinking marker, was collected at baseline and monthly during treatment. Interventions: Gabapentin up to 1200 mg/d, orally, vs placebo along with 9 medical management visits (20 minutes each). Main Outcomes and Measures: The percentage of individuals with no heavy drinking days and those with total abstinence were compared between treatment groups and further evaluated based on prestudy alcohol withdrawal symptoms. Results: Of 96 randomized individuals, 90 were evaluable (44 in the gabapentin arm and 46 in the placebo arm), with a mean (SD) age of 49.6 (10.1) years; 69 were men (77%) and 85 were white (94%). The evaluable participants had 83% baseline heavy drinking days (4 or more drinks/day for women, 5 or more for men) and met 4.5 alcohol withdrawal criteria from the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition). More gabapentin-treated individuals had no heavy drinking days (12 of 44 participants [27%]) compared with placebo (4 of 46 participants [9%]), a difference of 18.6% (95% CI, 3.1-34.1; P = .02; number needed to treat [NNT], 5.4), and more total abstinence (8 of 44 [18%]) compared with placebo (2 of 46 [4%]), a difference of 13.8% (95% CI, 1.0-26.7; P = .04; NNT, 6.2). The prestudy high-alcohol withdrawal group had positive gabapentin effects on no heavy drinking days (P < .02; NNT, 3.1) and total abstinence (P = .003; NNT, 2.7) compared with placebo, while within the low-alcohol withdrawal group, there were no significant differences. These findings were similar for other drinking variables, where gabapentin was more efficacious than placebo in the high-alcohol withdrawal group only. Gabapentin caused more dizziness, but this did not affect efficacy. Conclusions and Relevance: These data, combined with others, suggest gabapentin might be most efficacious in people with AUD and a history of alcohol withdrawal symptoms. Future studies should evaluate sleep changes and mood during early recovery as mediators of gabapentin efficacy. Trial Registration: ClinicalTrials.gov Identifier: NCT02349477.
Assuntos
Abstinência de Álcool , Alcoolismo/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Gabapentina/uso terapêutico , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Adulto , Alcoolismo/complicações , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome de Abstinência a Substâncias/etiologia , Resultado do TratamentoRESUMO
AIMS: To examine whether World Health Organization (WHO) risk-level reductions in drinking were achievable, associated with improved functioning and maintained over time among patients at varying initial alcohol dependence severity levels. Design and setting Secondary data analysis of multi-site randomized clinical trials: the US Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) study and the UK Alcohol Treatment Trial (UKATT). PARTICIPANTS: Individuals with alcohol dependence enrolled in COMBINE (n = 1383; 68.8% male) and seeking treatment for alcohol problems in UKATT (n = 742; 74.1% male). Interventions Naltrexone, acamprosate or placebo, and combined behavioral intervention or medication management in COMBINE. Social behavior network therapy or motivational enhancement therapy in UKATT. MEASUREMENTS: WHO risk-level reductions were assessed via the calendar method. Alcohol dependence was measured by the Alcohol Dependence Scale, the Leeds Dependence Questionnaire and the Diagnostic and Statistical Manual of Mental Disorders. Measures of functioning included alcohol-related consequences (Drinker Inventory of Consequences and Alcohol Problems Questionnaire), mental health (Short Form Health Survey) and liver enzyme tests. FINDINGS: One- and two-level reductions in WHO risk levels in the last month of treatment were maintained at the 1-year follow-up [adjusted odds ratio (OR), 95% confidence interval (CI) = one-level reduction in COMBINE: 3.51 (2.73, 4.29) and UKATT: 2.65 (2.32, 2.98)] and associated with fewer alcohol-related consequences [e.g. B, 95% CI = one-level reduction COMBINE: -26.22 (-30.62, -21.82)], better mental health [e.g. B, 95% CI = one-level reduction UKATT: 9.53 (7.36, 11.73)] and improvements in γ-glutamyltransferase [e.g. B, 95% CI = one-level reduction UKATT: -89.77 (-122.50, -57.04)] at the end of treatment, even among patients with severe alcohol dependence. Results were similar when abstainers were excluded. Conclusions Reductions in World Health Organization risk levels for alcohol consumption appear to be achievable, associated with better functioning and maintained over time in both the United States and the United Kingdom.
Assuntos
Consumo de Bebidas Alcoólicas/epidemiologia , Transtornos Relacionados ao Uso de Álcool/epidemiologia , Acamprosato/uso terapêutico , Adulto , Dissuasores de Álcool/uso terapêutico , Consumo de Bebidas Alcoólicas/terapia , Transtornos Relacionados ao Uso de Álcool/terapia , Alcoolismo/epidemiologia , Alcoolismo/terapia , Terapia Comportamental , Feminino , Inquéritos Epidemiológicos , Humanos , Masculino , Saúde Mental , Pessoa de Meia-Idade , Entrevista Motivacional , Naltrexona/uso terapêutico , Risco , Resultado do Tratamento , Reino Unido/epidemiologia , Estados Unidos/epidemiologia , Organização Mundial da SaúdeRESUMO
BACKGROUND AND AIMS: There is wide inter-individual variability in response to the treatment of alcohol use disorder (AUD) with the opioid receptor antagonist naltrexone. To identify patients who may be most responsive to naltrexone treatment, studies have examined the moderating effect of rs1799971, a single nucleotide polymorphism (SNP) that encodes a non-synonymous substitution (Asn40Asp) in the mu-opioid receptor gene, OPRM1. The aims of this study were to: (1) conduct a systematic review of randomized clinical trials (RCTs); (2) assess the bias of the available studies and gauge publication bias; and (3) meta-analyze the interaction effect of the Asn40Asp SNP on the response to naltrexone treatment. METHODS: We searched for placebo-controlled RCTs that examined the effect of Asn40Asp on the response to naltrexone treatment of heavy drinking or AUD. We tested the hypothesis that the minor (Asp40) allele was associated with a greater reduction in five alcohol consumption measures (relapse to heavy drinking, abstinence, percentage of heavy drinking days, percentage of days abstinent and drinks per day) in naltrexone-treated participants by meta-analyzing the interaction effects using a random effects model. RESULTS: Seven RCTs met the study criteria. Overall, risk of bias was low and we observed no evidence of publication bias. Of the five alcohol consumption outcomes considered, there was a nominally significant moderating effect of the Asn40Asp SNP only on drinks per day (d = -0.18, P = 0.02). However, the effect was not significant when multiple comparisons were taken into account. CONCLUSIONS: From the evidence to date, it remains unclear whether rs1799971, the OPRM1 Asn40Asp single nucleotide polymorphism, predicts naltrexone treatment response in individuals with alcohol use disorder or heavy drinking.