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1.
Nihon Yakurigaku Zasshi ; 155(2): 113-119, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32115477

RESUMO

Nalmefene (Selincro®), an opioid receptor modulator, is approved in Japan, the European Union, and other countries for reducing alcohol consumption in patients with alcohol dependence. This article reviews the efficacy and safety of as-needed use of nalmefene in the treatment of alcohol dependence, as well as summarizing its pharmacological properties. Ethanol increases the release of endogenous opioids, such as ß-endorphin, a µ-opioid receptor agonist; and dynorphin, a κ-opioid receptor agonist. Preclinical data suggest that nalmefene acts as an antagonist at the µ-opioid receptor and a partial agonist at the κ-opioid receptor, and reduces ethanol self-administration in ethanol-dependent and ethanol-non-dependent rats. Nalmefene counters alcohol-induced dysregulation of the ß-endorphin/µ-opioid receptor and the dynorphin/κ-opioid receptor systems. In a multicenter, randomized, double-blind, phase 3 study of as-needed use of nalmefene combined with psychosocial support in alcohol-dependent Japanese patients with at least high drinking risk level, compared with placebo, nalmefene 10 mg and 20 mg significantly reduced the number of heavy drinking days and total alcohol consumption at week 12. In the 24-week treatment period, treatment-emergent adverse events occurred in ≥5% of patients in either the nalmefene 10 mg or 20 mg group and at least twice as often as in the placebo group were nausea, dizziness, somnolence, vomiting, insomnia, decreased appetite, constipation, malaise, and palpitations. Most adverse events were mild or moderate in severity. In conclusion, as-needed use of nalmefene provides a new concept for the treatment of alcohol dependence: namely, "reduction of alcohol intake".


Assuntos
Consumo de Bebidas Alcoólicas/prevenção & controle , Alcoolismo/tratamento farmacológico , Naltrexona/análogos & derivados , Animais , Ensaios Clínicos Fase III como Assunto , Humanos , Japão , Estudos Multicêntricos como Assunto , Naltrexona/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Ratos , Receptores Opioides kappa/agonistas , Receptores Opioides mu/antagonistas & inibidores
2.
Expert Opin Pharmacother ; 21(3): 297-306, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31899990

RESUMO

Introduction: Insomnia has been implicated in the development, maintenance, worsening, and relapse of alcohol use disorder (AUD).Areas covered: The authors review the possible pharmacological and non-pharmacological treatment options of insomnia for patients with alcohol-use disorder and provide their expert opinion.Expert opinion: Abstinence, or at least a decrease in alcohol use, may improve insomnia symptoms. Second, sleep education is a cornerstone intervention that should be completed by more structured behavioral therapies or Cognitive Behavioral Therapy for Insomnia (CBT-I). CBT-I is the recommended first-line treatment of combined insomnia and AUD (high level of evidence). Third, in case of insufficient response or non-availability of CBT-I, pharmacological treatments might be added. In addition, CBT-I may take several weeks to be effective, and these medications could be proposed to patients with severe symptoms or psychiatric comorbidities. Mirtazapine, gabapentin immediate release, and quetiapine exhibit a moderate level of evidence. Melatonin, topimarate, trazodone, and acamprosate, have a low level of evidence. Benzodiazepines and other GABA-A agonists should be avoided. A particular attention should be provided to patients who use alcohol to help fall asleep as a higher risk of relapse exists after stopping treatment.


Assuntos
Alcoolismo/tratamento farmacológico , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Sono/efeitos dos fármacos , Comorbidade , Humanos , Resultado do Tratamento
3.
Expert Opin Drug Saf ; 19(2): 159-166, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31876433

RESUMO

Introduction: Sodium oxybate (SMO) has been approved in Italy and in Austria for the treatment of alcohol use disorder (AUD). This study describes the cumulative postmarketing and clinical safety experience with SMO in AUD.Areas covered: Safety data for SMO at approved posology in AUD were identified from: (i) the clinical trial registries of the US National Institutes of Health (NIH) and the European Medicines Agency (EMA), (ii) reports from the biomedical literature and (iii) available pharmacovigilance safety information from the EMA.Expert opinion: Safety data from 3 recent large randomized clinical studies (520 participants) and 43 earlier clinical studies (2547 participants) showed that SMO has a good safety profile in AUD patients. The safety profile was confirmed by pharmacovigilance data resulting from 299 013 patients exposed to SMO in Austria and Italy. Main adverse events were transitory dizziness and vertigo. Serious adverse events were rare. No death attributable to SMO has been reported. Risks of abuse or dependence are low in patients without psychiatric comorbidities or poly-drug use. The adverse events of SMO are transitory and do not require discontinuation of treatment. SMO abuse or dependence are extremely rare in patients without psychiatric comorbidities or poly-drug use.


Assuntos
Alcoolismo/tratamento farmacológico , Oxibato de Sódio/administração & dosagem , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Oxibato de Sódio/efeitos adversos
4.
Expert Opin Drug Saf ; 19(1): 9-17, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31868031

RESUMO

Introduction: Reduced drinking has been debated as a treatment goal for heavy drinking alcohol-dependent patients, in whom treatment based on abstinence is not always an option. Nalmefene was the first drug approved by the European Medicines Agency (2013) with the indication of reduced drinking in high drinking risk level alcohol-dependent patients. Six years after its introduction in Europe, data from clinical experience can be compared with those from preclinical studies and pivotal registration studies to evaluate what nalmefene has added to the treatment of AUD.Areas covered: Systematic review of efficacy and safety data of nalmefene use in humans from preclinical, phase III and phase IV studies, including systematic reviews, meta-analyses, cost-effectiveness analyses, and other secondary analyses.Expert opinion: Nalmefene introduces a paradigm change in the treatment of AUD that makes it appealing to patients that are reluctant to embrace abstinence, and facilitate patient-centered care in heavy users. However, information regarding safety data in special populations (e.g., patients with alcohol-related diseases, pregnancy, psychiatric disease), and direct comparisons with other potential drugs for alcohol reduction are further needed. Despite the promising role of nalmefene, there are still some factors that limit its wide prescription further than in specialized settings.


Assuntos
Alcoolismo/tratamento farmacológico , Naltrexona/análogos & derivados , Antagonistas de Entorpecentes/administração & dosagem , Consumo de Bebidas Alcoólicas/prevenção & controle , Transtornos Relacionados ao Uso de Álcool/tratamento farmacológico , Aprovação de Drogas , Humanos , Naltrexona/administração & dosagem , Naltrexona/efeitos adversos , Antagonistas de Entorpecentes/efeitos adversos
5.
Cochrane Database Syst Rev ; 2019(11)2019 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-31689723

RESUMO

BACKGROUND: Alcohol withdrawal syndrome (AWS) is a distressing and life-threatening condition that usually affects people who are alcohol dependent when they discontinue or decrease their alcohol consumption. Baclofen shows potential for rapidly reducing symptoms of severe AWS in people with alcoholism. Treatment with baclofen is easy to manage and rarely produces euphoria or other pleasant effects, or craving for the drug. This is an updated version of the original Cochrane Review first published in 2011 and last updated in 2017. OBJECTIVES: To assess the efficacy and safety of baclofen for people with AWS. SEARCH METHODS: We updated our searches of the following databases to June 2019: the Cochrane Drugs and Alcohol Group Specialised Register, CENTRAL, PubMed, Embase, and CINAHL. We also searched registers of ongoing trials. We handsearched the references quoted in the identified trials, and sought information from researchers, pharmaceutical companies, and relevant trial authors about unpublished or uncompleted trials. We placed no restrictions on language. SELECTION CRITERIA: We included all randomised controlled clinical trials (RCTs) evaluating baclofen versus placebo or any other treatment for people with AWS. We excluded uncontrolled, non-randomised, or quasi-randomised trials. We included both parallel group and cross-over studies. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included four RCTs with 189 randomised participants (one RCT new for this update). None of the included studies reported the primary outcomes of alcohol withdrawal seizures, alcohol withdrawal delirium, or craving. For the comparison of baclofen and placebo (1 study, 31 participants), there was no evidence of a difference in Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar) scores in eight-hour periods from days one to five (very low-quality evidence). For the comparison of baclofen and diazepam (2 studies, 85 participants), there was no evidence of a difference in change from baseline to days 10 to 15 on CIWA-Ar scores (very low-quality evidence, meta-analysis was not performed due to insufficient data). In one study (37 participants), there was no evidence of a difference in participants with at least one adverse event (risk difference (RD) 0.00, 95% confidence interval (CI) -0.10 to 0.10; very low-quality evidence), dropouts (RD 0.00, 95% CI -0.10 to 0.10; very low-quality evidence), and dropouts due to adverse events (RD 0.00, 95% CI -0.10 to 0.10; very low-quality evidence). For the comparison of baclofen and chlordiazepoxide (1 study, 60 participants), there was no evidence of a difference in difference from baseline to nine-day decremental fixed-dose intervention: CIWA-Ar scores (mean difference (MD) 1.00, 95% CI 0.70 to 1.30; very low-quality evidence), global improvement (MD 0.10, 95% CI -0.03 to 0.23; very low-quality evidence), 14/60 participants with adverse events (RD 2.50, 95% CI 0.88 to 7.10; very low-quality of evidence), dropouts (RD 0.00, 95% CI -0.06 to 0.06; very low-quality evidence), and dropouts due to adverse events (RD 0.00, 95% CI -0.06 to 0.06; very low-quality evidence). None of the RCTs provided information on random sequence generation or allocation concealment, therefore, we assessed them at unclear risk of bias. Two RCTs were not of double-blind design and had a high risk of bias in blinding (Addolorato 2006; Girish 2016). One RCT had more than 5% dropouts with high risk of attrition bias (Lyon 2011). We could not assess reporting bias as none of the prepublished protocols were available. AUTHORS' CONCLUSIONS: No conclusions can be drawn about the efficacy and safety of baclofen for the management of alcohol withdrawal because we found insufficient and very low-quality evidence.


Assuntos
Baclofeno/uso terapêutico , Agonistas GABAérgicos/uso terapêutico , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Alcoolismo/tratamento farmacológico , Fissura , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
7.
Alcohol Alcohol ; 54(5): 497-502, 2019 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31535696

RESUMO

AIMS: The development of novel and more effective medications for alcohol use disorder (AUD) is an important unmet medical need. Drug repositioning or repurposing is an appealing strategy to bring new therapies to the clinic because it greatly reduces the overall costs of drug development and expedites the availability of treatments to those who need them. Probenecid, p-(di-n-propylsulfamyl)-benzoic acid, is a drug used clinically to treat hyperuricemia and gout due to its activity as an inhibitor of the kidneys' organic anion transporter that reclaims uric acid from urine. Probenecid also inhibits pannexin1 channels that are involved in purinergic neurotransmission and inflammation, which have been implicated in alcohol's effects and motivation for alcohol. Therefore, we tested the effects of probenecid on alcohol intake in rodents. METHODS: We tested the effects of probenecid on operant oral alcohol self-administration in alcohol-dependent rats during acute withdrawal as well as in nondependent rats and in the drinking-in-the-dark (DID) paradigm of binge-like drinking in mice. RESULTS: Probenecid reduced alcohol intake in both dependent and nondependent rats and in the DID paradigm in mice without affecting water or saccharin intake, indicating that probenecid's effect was selective for alcohol and not the result of a general reduction in reward. CONCLUSIONS: These results raise the possibility that pannexin1 is a novel therapeutic target for the treatment of AUD. The clinical use of probenecid has been found to be generally safe, suggesting that it can be a candidate for drug repositioning for the treatment of AUD.


Assuntos
Consumo de Bebidas Alcoólicas/tratamento farmacológico , Alcoolismo/tratamento farmacológico , Conexinas/antagonistas & inibidores , Sistemas de Liberação de Medicamentos/métodos , Etanol/administração & dosagem , Proteínas do Tecido Nervoso/antagonistas & inibidores , Probenecid/uso terapêutico , Adjuvantes Farmacêuticos/farmacologia , Adjuvantes Farmacêuticos/uso terapêutico , Consumo de Bebidas Alcoólicas/metabolismo , Consumo de Bebidas Alcoólicas/psicologia , Alcoolismo/metabolismo , Alcoolismo/psicologia , Animais , Conexinas/metabolismo , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/metabolismo , Probenecid/farmacologia , Ratos , Ratos Wistar , Autoadministração
8.
Tijdschr Psychiatr ; 61(8): 544-553, 2019.
Artigo em Holandês | MEDLINE | ID: mdl-31512738

RESUMO

BACKGROUND: In the past years numerous studies have investigated the efficacy of baclofen for alcohol dependence. After publication of several reviews a number of new randomized controlled trials have been published. Two recent meta-analyses, based on largely the same studies, reported contrary results. One meta-analysis showed a positive effect on time to relapse and abstinence at endpoint. The other meta-analysis did not show an effect on the primary outcome measures.
AIM: To clarify the clinical relevance of the effect of baclofen on alcohol use in patients with a disorder in the use of alcohol, in the light of the positive and the negative meta-analysis.
METHOD: A systematic literature search using Medline, Embase and PsycINFO (Prisma guideline).
RESULTS: We found 16 randomized controlled trials in which the effect of baclofen was studied. Seven of them showed a significant positive effect of baclofen on (one or more of the) primary outcome measures.


Assuntos
Alcoolismo/tratamento farmacológico , Baclofeno/uso terapêutico , Agonistas dos Receptores de GABA-B/uso terapêutico , Humanos , Resultado do Tratamento
9.
BMC Med ; 17(1): 174, 2019 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-31526369

RESUMO

BACKGROUND: Different methodological choices such as inclusion/exclusion criteria and analytical models can yield different results and inferences when meta-analyses are performed. We explored the range of such differences, using several methodological choices for indirect comparison meta-analyses to compare nalmefene and naltrexone in the reduction of alcohol consumption as a case study. METHODS: All double-blind randomized controlled trials (RCTs) comparing nalmefene to naltrexone or one of these compounds to a placebo in the treatment of alcohol dependence or alcohol use disorders were considered. Two reviewers searched for published and unpublished studies in MEDLINE (August 2017), the Cochrane Library, Embase, and ClinicalTrials.gov and contacted pharmaceutical companies, the European Medicines Agency, and the Food and Drug Administration. The indirect comparison meta-analyses were performed according to different inclusion/exclusion criteria (based on medical condition, abstinence of patients before inclusion, gender, somatic and psychiatric comorbidity, psychological support, treatment administered and dose, treatment duration, outcome reported, publication status, and risk of bias) and different analytical models (fixed and random effects). The primary outcome was the vibration of effects (VoE), i.e. the range of different results of the indirect comparison between nalmefene and naltrexone. The presence of a "Janus effect" was investigated, i.e. whether the 1st and 99th percentiles in the distribution of effect sizes were in opposite directions. RESULTS: Nine nalmefene and 51 naltrexone RCTs were included. No study provided a direct comparison between the drugs. We performed 9216 meta-analyses for the indirect comparison with a median of 16 RCTs (interquartile range = 12-21) included in each meta-analysis. The standardized effect size was negative at the 1st percentile (- 0.29, favouring nalmefene) and positive at the 99th percentile (0.29, favouring naltrexone). A total of 7.1% (425/5961) of the meta-analyses with a negative effect size and 18.9% (616/3255) of those with a positive effect size were statistically significant (p < 0.05). CONCLUSIONS: The choice of inclusion/exclusion criteria and analytical models for meta-analysis can result in entirely opposite results. VoE evaluations could be performed when overlapping meta-analyses on the same topic yield contradictory result. TRIAL REGISTRATION: This study was registered on October 19, 2016, in the Open Science Framework (OSF, protocol available at https://osf.io/7bq4y/ ).


Assuntos
Metanálise como Assunto , Projetos de Pesquisa , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Alcoolismo/tratamento farmacológico , Humanos , Naltrexona/análogos & derivados , Naltrexona/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico
10.
Eur J Clin Microbiol Infect Dis ; 38(11): 2171-2176, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31392446

RESUMO

The aim of the study was to determine the effect of chronic alcohol abuse on the course and outcome of bacterial meningitis (BM). We analyzed records of patients with BM who were hospitalized between January 2010 and December 2017 in the largest neuroinfection center in Poland. Out of 340 analyzed patients, 45 (13.2%) were alcoholics. Compared with non-alcoholics, alcoholics were more likely to present with seizures (p < 0.001), scored higher on the Sequential Organ Failure Assessment (SOFA) (p = 0.002) and lower on the Glasgow Coma Scale (GCS) (p < 0.001), and had worse outcome as measured by the Glasgow Outcome Score (GOS) (p < 0.001). Furthermore, alcoholics were less likely to complain of headache (p < 0.001) and nausea/vomiting (p = 0.005) and had lower concentration of glucose in cerebrospinal fluid (CSF) (p = 0.025). In the multiple logistic regression analysis, alcoholism was associated with lower GCS (p = 0.036), presence of seizures (p = 0.041), male gender (p = 0.042), and absence of nausea/vomiting (p = 0.040). Furthermore, alcoholism (p = 0.031), lower GCS score (p = 0.001), and higher blood urea concentration (p = 0.018) were independently associated with worse outcome measured by GOS. Compared with non-alcoholics, chronic alcohol abusers are more likely to present with seizures, altered mental status, and higher SOFA score and have an increased risk of unfavorable outcome. In multivariate analysis, seizures and low GCS were independently associated with alcoholism, while alcoholism was independently associated with worse outcome.


Assuntos
Alcoolismo/epidemiologia , Meningites Bacterianas/epidemiologia , Adulto , Idoso , Alcoolismo/tratamento farmacológico , Alcoolismo/patologia , Alcoolismo/fisiopatologia , Infecções Comunitárias Adquiridas/epidemiologia , Infecções Comunitárias Adquiridas/patologia , Infecções Comunitárias Adquiridas/fisiopatologia , Feminino , Escala de Coma de Glasgow , Humanos , Masculino , Meningites Bacterianas/tratamento farmacológico , Meningites Bacterianas/patologia , Meningites Bacterianas/fisiopatologia , Pessoa de Meia-Idade , Escores de Disfunção Orgânica , Polônia/epidemiologia , Prognóstico , Risco
11.
J Christ Nurs ; 36(3): 148-156, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31180959

RESUMO

Largely underutilized in North America, the use of medications to treat alcohol dependence is frequently a successful method of reducing alcohol craving and promoting abstinence. Recovery from alcohol addiction can be a complicated process, requiring nutritional, social, psychological, spiritual, and physical aspects of healing and self-directed behavioral change. Nurses can intervene in alcohol use disorder via screening, referrals, support of medical and behavioral treatments, and spiritual care that emphasizes hope, forgiveness, and relief from shame and guilt.


Assuntos
Alcoolismo/reabilitação , Dissuasores de Álcool/uso terapêutico , Alcoolismo/tratamento farmacológico , Alcoolismo/enfermagem , Fissura , Humanos , Naltrexona/uso terapêutico , Enfermagem na Comunidade de Fé
12.
J Clin Psychopharmacol ; 39(4): 398-402, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31188242

RESUMO

PURPOSE/BACKGROUND: Varenicline has proven its efficacy in the treatment of nicotine dependence, and there is also evidence that it could be helpful in the treatment of alcohol dependence. In our pilot study, we investigated the feasibility and acceptability of varenicline for the treatment of a population of patients with severe alcohol dependence and multiple somatic comorbidities after alcohol detoxification. METHODS/PROCEDURES: We conducted a phase II, double-blind, placebo-controlled randomized trial of daily oral varenicline versus a placebo in alcohol-dependent men and women after alcohol detoxification (n = 28). Following our study protocol, somatic conditions and adverse events were thoroughly monitored and several study end points were investigated (percentage of abstinent days for both alcohol and nicotine, number of standardized drinks and cigarettes per day, days of heavy drinking). FINDINGS/RESULTS: Compared with the placebo, varenicline did not have more side effects and did not provoke more adverse events. Patients in the varenicline group did not show a significantly higher percentage of alcohol abstinent days or fewer heavy drinking days. A trend significance was found for a reduced number of standard drinks per day (P = 0.06) in the varenicline group. IMPLICATIONS/CONCLUSIONS: In this pilot trial, varenicline was shown to be well tolerated by our study population of severely alcohol-dependent patients with somatic conditions. Varenicline did not sustain alcohol abstinence or reduce the number of heavy drinking days, but it did reduce the daily amount of alcohol consumed.


Assuntos
Alcoolismo/tratamento farmacológico , Agonistas Nicotínicos/uso terapêutico , Vareniclina/uso terapêutico , Adulto , Idoso , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Adulto Jovem
13.
Alcohol Alcohol ; 54(4): 428-434, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31185085

RESUMO

AIMS: The objective of this study is to address equivocation in estimates of selective serotonin reuptake inhibitor initiation (SSRI) effect on all-cause and alcohol-related ER visits, and medical or psychiatric admissions within 2 years of initial Post-Traumatic Stress Disorder (PTSD) diagnosis in patients with PTSD and Alcohol Use Disorder (AUD). METHODS: This study is a quasi-experimental, new-user-design cohort study of 3235 patients seen at the VA North Texas Healthcare System between January 1, 2000 and December 31, 2016. High dimensional propensity score (HDPS) techniques were used to estimate likelihood of SSRI initiation within 30 days of first PTSD diagnosis. Propensity scores were used to calculate weights for likelihood of SSRI initiation which were used to control for baseline covariates in estimations of SSRI medication effect on odds of each outcome occurring. RESULTS: Compared to those who did not receive SSRIs, patients prescribed an SSRI within 30 days showed significantly lower odds of alcohol-related ER visits (OR=0.668, 95%CI = 0.476 to 0.938, P = 0.02) and alcohol-related medical admissions (OR=0.583, 95%CI = 0.399 to 0.851, P = 0.005). LIMITATIONS: Inconsistent assessment of PTSD severity necessitated the use of HDPS models to control for baseline confounding. Our study design mimicked intent-to-treat trial design and therefore could not control for SSRI initiations after the 30-day grace period following initial PTSD diagnosis. CONCLUSIONS: SSRI initiation in patients with AUD and PTSD is associated with significantly reduced odds of alcohol-related medical hospitalization and alcohol-related ER visits within 2 years of first PTSD diagnosis. Additional studies are needed to verify these results.


Assuntos
Alcoolismo/tratamento farmacológico , Alcoolismo/psicologia , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Inibidores de Captação de Serotonina/uso terapêutico , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Transtornos de Estresse Pós-Traumáticos/psicologia , Adulto , Alcoolismo/epidemiologia , Estudos de Coortes , Serviço Hospitalar de Emergência/tendências , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Resultado do Tratamento
14.
Drug Alcohol Depend ; 200: 181-190, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31160146

RESUMO

BACKGROUND: Despite known genetic variation across races, studies examining pharmacogenetics of a single nucleotide polymorphism (SNP) of the mu-opioid receptor gene (OPRM1) on clinical response to naltrexone have been conducted in predominantly Caucasian samples. Evidence is mixed for pharmacogenetic OPRM1 and naltrexone effects on neural responses to alcohol cues. The current study tests the pharmacogenetic effects of naltrexone and OPRM1 on neural responses to alcohol taste cues in heavy drinkers of East Asian descent. METHODS: Participants (N = 41) completed two double-blinded and counterbalanced functional magnetic resonance imaging (fMRI) sessions: one after taking naltrexone (50 mg/day) for four days and one after taking placebo for four days. Following titration, participants completed an fMRI alcohol taste-cues task. Analyses tested effects of naltrexone, OPRM1, and their interaction in whole-brain and region of interest (ROI) analyses of functional activation and functional connectivity in response to alcohol versus water taste cues. RESULTS: We found no effects of naltrexone orOPRM1 on neural activation in whole-brain and ROI analyses, which included left and right ventral striatum (VS), anterior cingulate cortex (ACC), and orbitofrontal cortex (OFC). Naltrexone increased functional connectivity between left VS and clusters in medial prefrontal cortex, posterior cingulate gyrus, as well as right VS and occipital cortex, compared to placebo. CONCLUSIONS: Naltrexone treatment enhanced functional connectivity in a key reinforcement-related pathway during alcohol versus water taste cues, corroborating neuroimaging work with other substances. Null medication and pharmacogenetics effects on functional activation add to a mixed naltrexone literature and may underscore the modest size of these effects in East Asians.


Assuntos
Alcoolismo/diagnóstico por imagem , Alcoolismo/tratamento farmacológico , Grupo com Ancestrais do Continente Asiático , Naltrexona/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Neuroimagem/métodos , Adulto , Alcoolismo/epidemiologia , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Método Duplo-Cego , Extremo Oriente/epidemiologia , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Adulto Jovem
15.
Eur Addict Res ; 25(5): 224-228, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31216535

RESUMO

IMPORTANCE: According to recent studies, only a small proportion of alcoholics in the system for addiction treatment receive expedited treatment [Rehm et al.: Sucht 2014;60:93-105] and that those who are untreated are at risk of harmful and dependent alcohol consumption. This is associated with significantly negative effects on morbidity, mortality, and quality of life [Kraus et al.: Sucht 2010;56:337-347]. As a result, not only individuals and their environment suffer but there is also a health economic impact. OBJECTIVE: How often do patients with a primary or secondary diagnosis of alcohol dependence who have been discharged from inpatient treatment receive anticraving medication in the follow-up period of 6 months? DESIGN, SETTING, AND PARTICIPANTS: Based on data from a statutory health insurance in Germany, 12,958 patients were investigated regarding alcohol dependence, rates for readmission to hospital, and prescription of anticraving drugs. In addition, outpatient and inpatient treatment costs were calculated. Main Outcomes and Measures: There will be an examination of how often anticraving medications are prescribed and what the economic consequences are. RESULTS: Two hundred and eighty-eight (2.22%) patients received anticraving medication, 98 (0.76%) in the first 6 months after inpatient treatment. Fifty-nine of the 288 patients were monitored with a pre- and postcomparison over a 90-day period. Inpatient treatment fell from 0.83 times (±1.10) during the 3 months afterward to 0.79 (±1.01). On average, the duration of an inpatient stay before anticraving treatment (n = 29) was 17.34 days (±14.37), with an average cost of EUR 4,142.70 (±2,721.28). Among the anticraving treatment group, this fell to 14.03 days (±9.96) with an average cost of EUR 3,685.43 (±2,307.67). Overall, the average outpatient and inpatient treatment costs dropped from EUR 1,533.88 before treatment to EUR 1,462.76 after treatment. If this is extrapolated to the whole group, it leads to between EUR 921,500 and EUR 6.6 million saving for a health insurance company. CONCLUSION: Anticraving medications are hardly ever prescribed. Their routine use could reduce hospital readmission rates and save on health-care costs.


Assuntos
Dissuasores de Álcool/uso terapêutico , Alcoolismo , Redução de Custos/economia , Naltrexona/uso terapêutico , Padrões de Prática Médica , Alcoolismo/tratamento farmacológico , Alcoolismo/economia , Feminino , Alemanha , Hospitalização , Humanos , Pacientes Internados , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Readmissão do Paciente/estatística & dados numéricos
16.
Expert Opin Drug Metab Toxicol ; 15(7): 553-564, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31162983

RESUMO

Introduction: Alcohol use disorder (AUD) is highly prevalent; costly economically, socially, and interpersonally; and grossly undertreated. The low rate of utilization of medications with demonstrated (albeit modest) efficacy is particularly noteworthy. One approach to increasing the utility and safety of available medications is to use a precision medicine approach, which seeks to identify patients for whom specific medications are likely to be most efficacious and have the fewest adverse effects. Areas Covered: We review the literature on the pharmacogenetics of AUD treatment using both approved and off-label medications. We cover both laboratory studies and clinical trials, highlighting valuable mechanistic insights and underscoring the potential value of precision-based care for AUD. Expert Opinion: Pharmacotherapy can be a useful component of AUD treatment. Currently, the evidence regarding genetic predictors of medication efficacy is very limited. Thus, a precision medicine approach is not yet ready for widespread clinical implementation. Further research is needed to identify candidate genetic variants that moderate the response to both established and novel medications. The growing availability of large-scale, longitudinal datasets that enable the synthesis of genetic and electronic health record data provides important opportunities to develop this area of research.


Assuntos
Alcoolismo/tratamento farmacológico , Farmacogenética , Medicina de Precisão/métodos , Dissuasores de Álcool/administração & dosagem , Dissuasores de Álcool/efeitos adversos , Alcoolismo/genética , Alcoolismo/fisiopatologia , Humanos , Uso Off-Label
18.
Alcohol Alcohol ; 54(3): 287-294, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31087085

RESUMO

AIM: This preliminary investigation evaluated the link between alcohol craving and insomnia in actively drinking patients with alcohol dependence (AD). METHODS: We conducted a secondary analysis of data from a clinical trial of treatment-seeking patients with AD who drank heavily (N = 61). The Penn Alcohol Craving Scale (PACS) evaluated alcohol craving, and the Short Sleep Index (SSI) assessed insomnia symptoms. We used linear regression models for baseline cross-sectional assessments. Linear mixed effects regression models evaluated craving scores longitudinally across insomnia groups (+/-), and insomnia scores longitudinally across craving groups(high/low). These longitudinal analyses were conducted separately in those treated with placebo (N = 32) and quetiapine (N = 29). RESULTS: The mean (standard deviation) for PACS total score was 15.9 (8.5) and for SSI was 2.1 (2.3). Alcohol craving was associated with the insomnia symptom of difficulty falling asleep (P = 0.03; effect size = -0.7) and with the SSI total score (P = 0.04, effect size = -0.7). In the longitudinal analysis, insomnia+ subjects had consistently higher PACS total scores, relative to the insomnia- group. The PACS score demonstrated significant group × time interactions in both treatment groups. Insomnia+ individuals demonstrated a relatively steeper rate of decline in the craving with quetiapine treatment (P = 0.03). Insomnia- individuals in the placebo group demonstrated a transient reduction in craving until week 8, followed by an increase in scores(P = 0.004). The SSI score did not demonstrate any interactive effect over time across the craving groups in either treatment arm. CONCLUSION: Insomnia was associated with higher alcohol craving and quetiapine differentially reduced craving in those with insomnia.


Assuntos
Alcoolismo/tratamento farmacológico , Fissura/efeitos dos fármacos , Fumarato de Quetiapina/uso terapêutico , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Adolescente , Adulto , Idoso , Alcoolismo/complicações , Alcoolismo/psicologia , Antidepressivos/uso terapêutico , Estudos Transversais , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Distúrbios do Início e da Manutenção do Sono/complicações , Adulto Jovem
19.
eNeuro ; 6(2)2019.
Artigo em Inglês | MEDLINE | ID: mdl-31058214

RESUMO

Dependence on opioids and the number of opioid overdose deaths are serious and escalating public health problems, but medication-assisted treatments for opioid addiction remain inadequate for many patients. Glucagon-like pepide-1 (GLP-1) is a gut hormone and neuropeptide with actions in peripheral tissues and in the brain, including regulation of blood glucose and food intake. GLP-1 analogs, which are approved diabetes medications, can reduce the reinforcing and rewarding effects of alcohol, cocaine, amphetamine, and nicotine in rodents. Investigations on effects of GLP-1 analogs on opioid reward and reinforcement have not been reported. We assessed the effects of the GLP-1 receptor agonist Exendin-4 (Ex4) on opioid-related behaviors in male mice, i.e., morphine-conditioned place preference (CPP), intravenous self-administration (IVSA) of the short-acting synthetic opioid remifentanil, naltrexone-precipitated morphine withdrawal, morphine analgesia (male and female mice), and locomotor activity. Ex4 treatment had no effect on morphine-induced CPP, withdrawal, or hyperlocomotion. Ex4 failed to decrease remifentanil self-administration, if anything reinforcing effects of remifentanil appeared increased in Ex4-treated mice relative to saline. Ex4 did not significantly affect analgesia. In contrast, Ex4 dose dependently decreased oral alcohol self-administration, and suppressed spontaneous locomotor activity. Taken together, Ex4 did not attenuate the addiction-related behavioral effects of opioids, indicating that GLP-1 analogs would not be useful medications in the treatment of opioid addiction. This difference between opioids and other drug classes investigated to date may shed light on the mechanism of action of GLP-1 receptor treatment in the addictive effects of alcohol, central stimulants, and nicotine.


Assuntos
Comportamento Animal/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Exenatida/farmacologia , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hipoglicemiantes/farmacologia , Atividade Motora/efeitos dos fármacos , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Alcoolismo/tratamento farmacológico , Animais , Receptor do Peptídeo Semelhante ao Glucagon 1/análise , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
20.
Can J Physiol Pharmacol ; 97(8): 781-785, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31100205

RESUMO

The objective of the study was to investigate the effects of CYP2D6 activity on the efficacy and safety of mirtazapine in patients with depressive disorders and comorbid alcohol use disorder who received mirtazapine. The study included 109 Russian patients who received mirtazapine at a dose of 30.0 [15.0; 45.0] mg per day. Genotyping of CYP2D6*4 (1846G > A, rs3892097) was performed using real-time polymerase chain reaction with allele-specific hybridization. The activity of CYP2D6 was evaluated by determining the concentration of endogenous substrate of the enzyme and its urinary metabolite - pinoline to 6-hydroxy-1,2,3,4-tetrahydro-beta-carboline ratio, using high-performance liquid chromatography - mass spectrometry. The statistically significant differences between the scores on the Hamilton Depression Rating Scale (HAMD) in patients with different genotypes were revealed by day 16: (GG) 5.0 [3.0; 6.0], (GA) 1.5 [1.0; 3.2] (p < 0.001), and for the The UKU Side Effects Rating Scale (UKU): (GG) 6.0 [6.0; 7.0], (GA) 8.5 [8.0; 10.0] (p < 0.001). The calculation of correlation coefficients between the differences in scale scores and metabolic rate showed the presence of statistically significant weak inverse correlation with the efficacy indicator evaluated by HAMD (r = -0.278, p < 0.05), but not by UKU (r = 0.274, p > 0.05). This study demonstrated that an increased CYP2D6 activity reduces the efficacy of treatment with mirtazapine.


Assuntos
Alcoolismo/tratamento farmacológico , Citocromo P-450 CYP2D6/metabolismo , Transtorno Depressivo/tratamento farmacológico , Mirtazapina/efeitos adversos , Mirtazapina/farmacologia , Segurança , Adulto , Alcoolismo/enzimologia , Alcoolismo/epidemiologia , Alcoolismo/genética , Comorbidade , Citocromo P-450 CYP2D6/genética , Transtorno Depressivo/enzimologia , Transtorno Depressivo/epidemiologia , Transtorno Depressivo/genética , Feminino , Genótipo , Humanos , Masculino , Mirtazapina/uso terapêutico , Polimorfismo Genético
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