Acamprosate to Reduce Symptoms of Alcohol Withdrawal
Condition: Alcohol-Related Disorders; Alcohol Dependence; Alcoholism; Healthy Volunteer
MeSH terms: Alcoholism; Alcohol-Related Disorders
Study type: Interventional
Phase: Phase 2

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.
    

Detailed description: 
      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.
    

Intervention name(s): NMR-spectroscopy; Oral acamprosate
Intervention type(s): Procedure; Drug
Intervention description(s): 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.
Other intervention name(s): Magnetic Resonance Spectroscopy; MRS; Campral
Intervention MeSH terms: Acamprosate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Keywords: Alcoholism; Acamprosate; Withdrawal; Glutamate; Magnetic Resonance Spectroscopy; Alcohol Dependence; Healthy Volunteer; HV