Acamprosate to Reduce Symptoms of Alcohol Withdrawal
Condition: Alcohol-Related Disorders; Alcohol Dependence; Alcoholism; Healthy Volunteer
MeSH terms: Alcoholism; Alcohol-Related Disorders
Intervention: NMR-spectroscopy; Oral acamprosate
Intervention description: Scans were performed on a 3T scanner using the echo-time-averaged PRESS sequence previously published to detect glutamate's resonance line at 2.35 ppm and average out the interferences from glutamine, NAA and the macromolecules.; 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.
Intervention MeSH terms: Acamprosate
Phase: Phase 2
Study type: Interventional
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 56.0
Sex: All
Minimum age: 21 Years
Maximum age: 65 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Alcoholism; Acamprosate; Withdrawal; Glutamate; Magnetic Resonance Spectroscopy; Alcohol Dependence; Healthy Volunteer; HV

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.
    

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-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