Acamprosate to Reduce Symptoms of Alcohol Withdrawal
关键词
抽象
描述
Objective: Clinical as well as preclinical studies indicate that the process of developing alcohol dependence recruits a progressively aggravated hyperglutamatergic state, which in turn is a key signal for emotional dysregulations leading to craving and relapse, as well as neurotoxicity leading to cognitive impairment and loss of grey matter in alcoholic patients. Acamprosate has recently been approved for relapse prevention in sober alcoholics, an effect mediated through largely unknown mechanisms. Preclinical data indicate, however, that it might primarily be useful for targeting the hyperglutamatergic state that develops during recurring withdrawal episodes, halting the process described above. If so, acamprosate might be of value as a withdrawal treatment to prevent the progression of alcohol dependence. The aim of the present protocol is to evaluate, in a randomized controlled trial, the effects of acamprosate during withdrawal and the early post-withdrawal phase. The primary outcome variable will be central glutamate/glutamine concentration as determined by MR spectroscopy. A number of exploratory biological and clinical measures will in addition be obtained and used for secondary analyses as specified below.
Study Population: We will study patients age 21 - 65, without gross impairment of judgment or complicated psychiatric or other morbidity, going into withdrawal or with a high probability of doing so, will be admitted as inpatients to the NIAAA CC-unit. A group of healthy volunteers who do not receive study medication will be examined separately in order to confirm that a hyperglutamatergic state is present in the patients during withdrawal.
Design: All patients will receive standard care for alcohol detoxification. In addition, half of them will be randomized in a blinded fashion to oral acamprosate, two 333 mg tablets taken 3 times daily or corresponding placebo. Validated rating scales (CIWA-Ar, CPRS-SA) will be used to assess intensity of withdrawal and psychopathology. If severity of withdrawal exceeds a predefined criterion, standard diazepam treatment will be added to study medication. The accrual target is based on a primary analysis sample of patients who will not require diazepam medication, which is a potential confound. A secondary analysis will be carried out on the complete sample, analyzing the requirement for/amount of diazepam supplement as a secondary outcome variable.
Outcome Measures: A battery of tests will be obtained during the 1st and 3rd week of inpatient treatment. These will include NMR-spectroscopy to quantify central levels of excitatory and inhibitory amino acids (primary outcome variable: GluX concentration); lumbar puncture to obtain CSF for analysis of neurotransmitter/neurohormone metabolites and synaptic proteins. Repeated 4 x daily blood collection for analysis of serum cortisol and ACTH will be obtained to assess spontaneous activity and circadian variation of the HPA-axis, and the combined dexamethasone - CRH test will be carried out to dynamically probe this system, and gauge its sensitivity for feedback inhibition.
日期
最后验证: | 12/31/2011 |
首次提交: | 03/18/2005 |
提交的预估入学人数: | 03/18/2005 |
首次发布: | 03/20/2005 |
上次提交的更新: | 01/09/2012 |
最近更新发布: | 01/11/2012 |
首次提交结果的日期: | 11/29/2011 |
首次提交质量检查结果的日期: | 11/29/2011 |
首次发布结果的日期: | 01/04/2012 |
实际学习开始日期: | 02/28/2005 |
预计主要完成日期: | 06/30/2010 |
预计完成日期: | 06/30/2010 |
状况或疾病
干预/治疗
Procedure: NMR-spectroscopy
Drug: Acamprosate
相
手臂组
臂 | 干预/治疗 |
---|---|
Placebo Comparator: Placebo For subjects randomized to placebo control, placebo doses were given every 8 hours. | |
Experimental: Acamprosate For subjects randomized to active treatment, the first 3 acamprosate doses were 1332 mg every 8 hours in an attempt to more rapidly achieve active plasma concentrations, followed by 666 mg acamprosate every 8 hours for the remainder of the study. | Drug: Acamprosate For subjects randomized to active treatment, the first 3 acamprosate doses were 1332 mg every 8 hours in an attempt to more rapidly achieve active plasma concentrations, followed by 666 mg acamprosate every 8 hours for the remainder of the study. |
资格标准
有资格学习的年龄 | 21 Years 至 21 Years |
有资格学习的性别 | All |
接受健康志愿者 | 是 |
标准 | - INCLUSION CRITERIA - PATIENTS: 1. Alcohol dependence according to DSM-IV, based on the alcohol dependence module of the SCID I-interview, and alcohol withdrawal, based on either of: Clinically manifest significant alcohol withdrawal symptoms, with or without detectable blood alcohol concentrations. In absence of the above, current intoxication above 0.1 g/dl BAC, self-reported history of continuous alcohol use > 1 month, and self-reported previous episodes of significantly distressful alcohol withdrawal symptoms, whether treated or not. 2. Age 21 - 65; in younger subjects, maturation processes of the central nervous system are still ongoing; while in older subjects, degenerative changes may confound the measures studied. 3. Smoking status: this will be noted and evaluated using the Fagerstrom inventory, so that its potential contribution to group differences can be assessed. This variable will not otherwise affect inclusion / exclusion. INCLUSION CRITERIA - HEALTHY CONTROLS: Subjects will be eligible for inclusion if they are aged 21-65. They will be as closely as possible matched to the patient population with regard to gender and age. EXCLUSION CRITERIA - PATIENTS: 1. Current or prior history of any disease, including cardiovascular, respiratory, gastrointestinal, hepatic, renal, endocrine, or reproductive disorders, or a positive hepatitis or HIV test at screening. 2. Current Axis-I psychiatric illness. 3. Current or prior history of any alcohol or drug dependence, as well as non-drinkers (alcohol-naive individuals or current abstainers). 4. Positive result on urine screen for illicit drugs. 5. Nursing, pregnancy or intention to become pregnant for women. Female participants will undergo a urine beta-hCG test to ensure they are not pregnant. 6. Pregnancy (negative test required) or ongoing breastfeeding. 7. Use of prescription or OTC medications know to interact with alcohol within 2 weeks of the study. These include, but may not be limited to: isosorbide, nitroglycerine, benzodiazepines, warfarin, anti-depressants such as amitriptyline, clomipramine and nefazodone, anti-diabetes medications such as glyburide, metformin and tolbutamide, H2-antagonists for heartburn such as cimetidine and ranitidine, muscle relaxants, anti-epileptics including phenytoin and Phenobarbital codeine, and narcotics including darvocet, percocet and hydrocodone. Drugs known to inhibit or induce enzymes that metabolize alcohol should not be used for 4 weeks prior to the study. These include chlorzoxazone, isoniazid, metronidazole and disulfiram. Cough-and-cold preparations which contain anti-histamines, pain medicines and anti-inflammatories such as aspirin, ibuprofen, acetaminophen, celecoxib and naproxen, should be withheld for at least a 72 hours prior to each study session. 8. Self-reported history of flushing upon intake of alcohol. 9. Inability to undergo an MR scan, due to presence of ferromagnetic objects in their bodies which could cause adverse effects in the MRI scanner, pronounced anxiety provoked by enclosed spaces, or other reasons. EXCLUSION CRITERIA - HEALTHY CONTROLS: 1. History of any substance use disorder. 2. Average weekly consumption over last 4 weeks, assessed with Time-Line Follow-Back, exceeding 210g pure alcohol / week, or consumption of more than 60g pure alcohol on any single occasion within last 3 days 3. Any history of a psychotic disorder or a history of any other psychiatric diagnosis within the last 12 months 4. Any prescription medication within the last 2 months 5. Pregnant (negative pregnancy test required) or breastfeeding 6. Inability to undergo an MR scan, due to presence of ferromagnetic objects in their bodies which could cause adverse effects in the MRI scanner, pronounced anxiety provoked by enclosed spaces, or other reason |
结果
主要结果指标
1. Ratio of Glutamate to Creatine in the Anterior Cingulate of the Brain, Measured on Day 4 [Day 4]
2. Ratio of Glutamate to Creatine in the Anterior Cingulate of the Brain, Measured on Day 25 [Day 25]