This study will determine whether naltrexone, a medicine used to treat alcoholism, can
lessen the craving for alcohol during alcohol withdrawal and examine how the drug affects
brain activity during alcohol infusion.
People between 21 and 50 years of age who are right-handed, alcohol-dependent, and have at
least one family member with a history of alcoholism, may be eligible for this study.
Participants are admitted to the NIH Clinical Center for 1 month for the following
- Medical history, alcohol-use history and family history of alcoholism
- Physical examination, psychological tests and blood tests
- Medicine to lessen alcohol withdrawal symptoms, if necessary
- Alcohol detoxification
- Medical and psychological evaluations
- Assignment to naltrexone or placebo group
Days 7 through 28
- Drug treatment: Take naltrexone or placebo capsule every morning
- Additional alcohol-dependence treatment: Cognitive and behavioral therapies and
participation in self-help groups, such as Alcoholics Anonymous
- Weekly questionnaires to measure mood and desire for alcohol
- Blood tests
- Alcohol craving stimulation test (day 7): Subjects handle and sniff water and then
their favorite alcoholic beverage. They then rate their urge to drink alcohol and their
level of anxiety and their heart rate is measured.
- Alcohol infusion test (day 9): Subjects have an MRI scan during infusion through a vein
of saline (salt water), followed by infusion of alcohol. For this test, a catheter
(plastic tube) is placed in a vein in each arm, one for administering the saline and
then alcohol; the other for drawing blood samples to measure blood alcohol level and
body chemistries. Before, during and after the infusion, subjects are asked to respond
to questions about their feelings, cravings and mood changes.
Subjects are asked to participate in a 3-month outpatient assessment program involving five
outpatient visits (at 1, 2, 4, 8 and 12 weeks after discharge). At each visit, they fill out
questionnaires and to take a breathalyzer test and blood and urine tests for drugs. They may
continue naltrexone therapy and weekly group therapy sessions during this time. Subjects who
do not participate in the assessment program are contacted at home by phone once a week for
1 month and then every other week for the next 2 months to monitor alcohol abstinence.
Alcoholism is a chronic, progressive, brain disorder with a profound impact on individuals'
lives and economic cost to society. The positive reinforcing effect of alcohol is a key
element in the transitional development from alcohol intake to alcohol addiction. Findings
from animal and human studies indicate that the rewarding properties of ethanol arise in
part from a complex interaction between alcohol, endogenous opioids, and dopamine (DA)
systems. Acute administration of ethanol increases the release of opioid peptides, which in
turn, increases the release of DA in the mesocorticolimbic system. Naltrexone (NTX), an
opioid receptor antagonist, has been studied widely in both preclinical and clinical
research for the treatment of alcoholism. Numerous clinical studies have shown that
short-term use of NTX on alcohol-dependent patients effectively prevents relapse and reduces
the level of craving. Genetic studies have suggested that individuals with mu-opioid
receptors (OPRMs) encoded by the 118G gain-of function variant allele experience a greater
therapeutic response to NTX. There are no data utilizing functional Magnetic Resonance
Imaging (fMRI) to study the effect of NTX on brain activity during an intravenous (IV)
infusion of ethanol.
To study the effect of NTX on the blood oxygen level dependent (BOLD) response in the
ventral striatum area of the brain in response to an ethanol infusion.
To study the effect of NTX on cue reactivity (CR) to alcohol-associated cues.
Alcohol-dependent patients between the ages of 21-50 years.
All participants will complete a screening telephone interview before coming to the NIAAA
Inpatient Unit. The interviewer will inform eligible participants about the requirements and
procedures associated with current protocols. Following admission to NIAAA Inpatient Unit,
all participants will be enrolled in the Assessment and Treatment of People with Alcohol
Drinking Problems protocol (#05-AA-0121). Protocol 05-AA-0121 will allow us to evaluate each
participant's general medical and psychiatric conditions and provide standard of care for
treatment seeking alcoholics.
Participants, who fulfill the specific requirements of the NTX protocol, will be thoroughly
informed about the nature of the study before obtaining an informed consent. Consented
participants will be randomized, using a double-blind design, to receive either 50 mg of NTX
per day or placebo. Medications will be administered at 8:00 AM on a daily basis by the
Prior to the challenge procedures (CR on Day 7 and fMRI/ethanol infusion on Day 9), a
clinical nurse specialist who is not involved with the protocol will re-consent each
participant when they are not in acute withdrawal. The re-consenting process will provide
reassurance that participants understand the requirements and implications associated with
participation in the CR and fMRI/ethanol infusion procedures. Individuals who elect not to
participate in the CR and fMRI/ethanol infusion sessions will be discharged from the
in-patient unit and encouraged to continue treatment in the NIAAA Outpatient Clinic for the
next three months.
Participants who elect to remain in the study will take part in the CR session on Day 7 and
fMRI/ethanol infusion session on Day 9 (procedures are described on Page 13 under study
procedures). Following the fMRI/ethanol infusion session, participants will remain in the
hospital for approximately three weeks to monitor their craving and take part in our
inpatient treatment program for alcoholism. During the post-challenge hospitalization, all
participants will be offered 50 mg of NTX once a day. Following discharge from the hospital,
participants will be encouraged to continue treatment in NIAAA Outpatient Clinic for three
BOLD response during the ethanol infusion challenge.
BOLD brain response to emotional facial stimuli.
Self-reported Alcohol Urge Questionnaires (AUQ), Penn Alcohol Craving Scale (PACS),
Obsessive Compulsive Drinking Scale (OCDS) and Profile of Mood Status (POMS).
Hormonal responses to the ethanol challenge: plasma ACTH, cortisol, and beta-endorphin.
Subjective responses to the ethanol challenge as rated by stimulation, sedation, high, and
Cue-induced craving during the CR session.
- INCLUSION CRITERIA:
All participants must:
- be right-handed
- between 21 and 50 years of age
- meet the DSM-IV diagnostic criteria for alcohol dependence (polysubstance abuse is
common in younger alcohol-dependent patients, and will not be exclusionary)
- have a positive family history of alcoholism (one or more first-degree relatives with
In addition, female participants:
- must have a negative urine pregnancy test (beta-hCG)
- of childbearing capability will be required to use a double contraceptive method
(such as oral contraceptives, condom with spermicide or intra-uterine device with
spermicide) from the start of the study until at least one month following the last
dose of NTX.
General exclusion criteria for the NIAAA Intramural treatment program:
- people who present with complicated medical problems requiring intensive medical or
diagnostic management, such as uncontrolled hypertension, gastro-intestinal (GI)
bleeding, major organ or body system dysfunction or thyroid disease
- people who are infected with human immunodeficiency virus (HIV)
- serious neuro-psychiatric conditions which impair judgment or cognitive function to
an extent that precludes them from providing informed consent or complying with study
procedures, such as psychotic illness, or severe dementia (individuals not competent
to give informed consent)
- people who are unlikely or unable to complete the study because they are likely to be
incarcerated while on the protocol
- people who are required to receive treatment by a court of law or who are
involuntarily committed to treatment
Specific exclusion criteria for this protocol include:
- clinically significant hepatobiliary disease
- a history of facial flushing in response to alcohol
- a history of seizures
- currently psychotic
- currently abusing opioids
- use of psychotropic medications (antidepressant, lithium, antipsychotic, anxiolytic,
antiepileptic) regularly within the last 4 weeks prior to admission
- having a positive pregnancy test, contemplating pregnancy in the next 3 months,
nursing, or not using an effective contraceptive method (if the participant is of
- a history of allergy or unusual reactions to NTX
- have received treatment with NTX in the six-month period prior to enrollment
- presence of ferromagnetic brain aneurysm clips, implanted pacemaker, hearing aid, or
any other metallic implant, such as pins, screws, plates, dentures, or non-removable
jewelry, in or on the body
- pronounced claustrophobia