Protocol Number: 05-AA-0120

Title:

Acamprosate for Central Nervous System Hyperexcitability and Neuroadaptation in Alcohol Withdrawal

Number:

05-AA-0120

Summary:

This study will examine whether a new drug called acamprosate can be helpful for alcohol withdrawal, a result of drinking high amounts of alcohol for long periods of time. Alcohol withdrawal can cause various symptoms, including nausea or vomiting, anxiety or depression, tremor, high blood pressure, and others. During withdrawal, brain chemicals called neurotransmitters change, with some rising to abnormally high levels. These changes may contribute to alcohol craving, drinking relapse and impaired mental performance. This study will see if taking acamprosate for 4 weeks can lower the levels of neurotransmitters, such as glutamate, lessen withdrawal symptoms and decrease alcohol craving and brain damage associated with withdrawal.

Healthy normal volunteers and alcohol-dependent patients between 21 and 65 years of age may be eligible for this study.

Participants are admitted to the hospital for 28 days. They receive standard inpatient care for alcohol detoxification, including a medical history and physical examination, neurological evaluation, laboratory tests, nursing, nutrition, discharge planning and referrals for treatment of concomitant conditions, if needed. In addition, they are randomly assigned to take either two acamprosate or two placebo pills three times a day for 28 days and undergo the following tests and procedures:

-Days 1-28: Drug treatment. Patients take acamprosate or placebo daily. Patients with severe withdrawal symptoms may also receive diazepam (Valium). Throughout their hospitalization, patients fill out questionnaires about their emotional state and personality and are interviewed by staff about their mental health, use of alcohol, cigarettes, and illicit drugs, employment, support systems and family and social relationships, and their legal status.

-Days 2 and 3: Blood tests. Blood is tested for levels of the stress hormones cortisol and ACTH, which are released to excess during alcohol withdrawal. For this test, a heparin lock (thin, flexible plastic tube with a rubber stopper on the end) is placed in an arm vein for blood collections each day at 6 AM, 12 noon, 6 PM and 12 midnight. Patients rest in bed for 30 minutes before each collection.

-Day 4: Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). These procedures are done at the same time. They use a strong magnetic field and radio waves to show structural and chemical changes in the brain. The patient lies on a table in a space enclosed by a metal cylinder (the scanner) for about 20 to 30 minutes during the test.

-Day 5: Lumbar puncture (spinal tap). A local anesthetic is given to numb the area for the procedure. Then, a needle is inserted in the space between the bones in the lower back where the cerebrospinal fluid circulates below the spinal cord. A small amount of fluid is collected through the needle.

-Days 5 and 6: Dexamethasone-corticotropin releasing factor (CRF) test. This test measures the effect of alcohol withdrawal on ACTH and cortisol. The patient takes a standard dose of the steroid dexamethasone at 11 PM on day 5. At noon the next day, they are given lunch and then stay in bed and rest. A plastic tube is put in an arm vein. A salt water solution is slowly infused through the catheter and a blood sample is withdrawn through it. At 3 p.m., the patient is given 100 micrograms of the hormone CRF. Repeated blood samples are obtained to measure ACTH and cortisol.

-Days 23-27: All of the tests done on days 2-6 are repeated, except the MRI. MRS is repeated to measure neurotransmitters.

Sponsoring Institute:

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

Eligibility Criteria:

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-na ve 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 leasta 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

Special Instructions:

Currently Not Provided

Keywords:

Alcoholism

Acamprosate

Withdrawal

Glutamate

Magnetic Resonance Spectroscopy

Recruitment Keyword(s):

Alcohol Dependence

Alcoholism

Healthy Volunteer

HV

Condition(s):

Alcohol-Related Disorders

Alcohol Dependence

Alcoholism

Healthy Volunteer

HV

Investigational Drug(s):

None

Investigational Device(s):

None

Intervention(s):

Procedure/Surgery: NMR-spectroscopy

Drug: Oral acamprosate

Supporting Site:

National Institute on Alcohol Abuse and Alcoholism

Contact(s):

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citation(s):

Daeppen JB, Gache P, Landry U, Sekera E, Schweizer V, Gloor S, Yersin B. Symptom-triggered vs fixed-schedule doses of benzodiazepine for alcohol withdrawal: a randomized treatment trial. Arch Intern Med. 2002 May 27;162(10):1117-21.

Liskow BI, Goodwin DW. Pharmacological treatment of alcohol intoxication, withdrawal and dependence: a critical review. J Stud Alcohol. 1987 Jul;48(4):356-70. Review.

Mayo-Smith MF. Pharmacological management of alcohol withdrawal. A meta-analysis and evidence-based practice guideline. American Society of Addiction Medicine Working Group on Pharmacological Management of Alcohol Withdrawal. JAMA. 1997 Jul 9;278(2):144-51.

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