Modulation of Pharmacologically Induced Alcohol Craving in Recently Detoxified Alcoholics

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Markus Heilig, National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT00605904
First received: January 30, 2008
Last updated: May 23, 2012
Last verified: May 2012
  Purpose

This study will determine if acamprosate, a drug approved to treat alcoholism, decreases alcohol cravings in alcohol-dependent subjects following infusions of yohimbine and mCPP. Yohimbine causes anxiety and may provoke a desire for alcohol; mCPP induces a feeling of having had a few drinks, which often creates a desire for more drinks. If acamprosate can prevent a craving following these stimuli, then the effectiveness of new experimental drugs for treating alcoholism can be tested for their ability to block yohimbine or mCPP-induced cravings. This type of investigation would be less expensive and less time-consuming than conducting clinical trials with alcohol-dependent people.

People between 21 and 65 years of age who are alcohol-dependent and have been drinking regularly for at least 1 month before entering the study may be eligible to participate.

Participants are admitted to the NIH Clinical Center for about 35 days, during which time they are asked to participate in an alcohol treatment program. They may request passes to leave the hospital during the day but must return overnight. Upon return to the hospital, subjects are required to take a breathalyzer test for alcohol and urine screen for drug use. Participants found to have used drugs or consumed alcohol while away from the hospital are terminated from the study.

Participants are randomly assigned to take acamprosate or placebo pills three times a day for about 2 weeks. They are then given three intravenous (through a vein) infusions, 5 to 7 days apart, each containing either yohimbine, mCPP or placebo. The drugs are infused for 20 minutes following a 1-hour infusion of saline (salt water). Subjects complete two questionnaires - an alcohol urge questionnaire to assess the desire for alcohol and a PASS rating scale to assess anxiety - several times during the study and during the infusions....


Condition Intervention Phase
Alcoholism
Drug: Acamprosate
Drug: Yohimbine
Drug: mCPP
Drug: Saline
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: Modulation of Pharmacologically Induced Alcohol Craving in Recently Detoxified Alcoholics

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Alcohol Craving Rating in Response to Saline Infusion [ Time Frame: 180 minutes after the start of the infusion ] [ Designated as safety issue: No ]
    Alcohol craving was measured using the Penn Alcohol Craving Scale (PACS). It is a 5-item self-administered instrument that measures frequency, intensity, and duration of thoughts about drinking, along with ability to resist drinking. There is a single outcome score than ranges from 0 to 30, with 30 being the maximum amount of alcohol craving.

  • Alcohol Craving Rating in Response to Meta-Chlorophenylpiperazine [ Time Frame: 180 minutes after the start of the infusion ] [ Designated as safety issue: No ]
    Alcohol craving was measured using the Penn Alcohol Craving Scale (PACS). It is a 5-item self-administered instrument that measures frequency, intensity, and duration of thoughts about drinking, along with ability to resist drinking. There is a single outcome score than ranges from 0 to 30, with 30 being the maximum amount of alcohol craving.

  • Alcohol Craving Rating in Response to Yohimbine Infusion [ Time Frame: 180 minutes after the start of the infusion ] [ Designated as safety issue: No ]
    Alcohol craving was measured using the Penn Alcohol Craving Scale (PACS). It is a 5-item self-administered instrument that measures frequency, intensity, and duration of thoughts about drinking, along with ability to resist drinking. There is a single outcome score than ranges from 0 to 30, with 30 being the maximum amount of alcohol craving.


Enrollment: 37
Study Start Date: January 2008
Study Completion Date: March 2011
Primary Completion Date: September 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Acamprosate
Subjects received 3 tablets of 333mg acamprosate orally, three times daily (total dose of 999 mg) for a minimum of 2 weeks.
Drug: Acamprosate
orally administered tablet, 333mg, three times daily for a minimum of 2 weeks (14 days)
Other Name: Campral
Drug: Yohimbine
Intravenous infusion of yohimbine (0.4 mg/kg) administered once over 10 minutes
Other Names:
  • Yohimbe
  • Yocon
  • Yohimex
  • Aphrodyne
Drug: mCPP
Intravenous infusion of mCPP (0.05 mg/kg) over 10 minutes, two times, for a total of 0.1 mg/kg
Other Names:
  • 3-CPP
  • CPP
Drug: Saline
Intravenous infusion of 0.9% sodium chloride solution over 10 minutes, three times during the study (2 times for the "Saline Infusion" milestone, and one time immediately following the "Yohimbine Infusion" milestone)
Other Names:
  • Normal Saline Flush
  • Sodium Chloride
Placebo Comparator: Placebo
Subjects received 3 tablets of placebo orally, three times daily, for a minimum of 2 weeks.
Drug: Yohimbine
Intravenous infusion of yohimbine (0.4 mg/kg) administered once over 10 minutes
Other Names:
  • Yohimbe
  • Yocon
  • Yohimex
  • Aphrodyne
Drug: mCPP
Intravenous infusion of mCPP (0.05 mg/kg) over 10 minutes, two times, for a total of 0.1 mg/kg
Other Names:
  • 3-CPP
  • CPP
Drug: Saline
Intravenous infusion of 0.9% sodium chloride solution over 10 minutes, three times during the study (2 times for the "Saline Infusion" milestone, and one time immediately following the "Yohimbine Infusion" milestone)
Other Names:
  • Normal Saline Flush
  • Sodium Chloride

Detailed Description:

Objective: The objective of the present study is to establish, in our laboratory, a published model of pharmacologically induced alcohol craving, and carry out an initial evaluation of its predictive validity for efficacy in treatment of alcoholism. Two pharmacological challenges are tested: 1. The alpha2-adrenergic antagonist yohimbine, which reliably induces reinstatement of alcohol seeking in experimental animals, but has produced less clear results in humans. 2. The serotonergic compound mCPP, which has been reported to robustly increase alcohol craving in human alcoholics, but for which animal data are less clear. Our objective study is to evaluate craving responses to infusion of yohimbine or mCPP using optimal assessment tools and subject population, and establish their sensitivity to the clinically effective alcoholism medication acamprosate.

Study Population: The study will be carried out in 60 subjects aged 21-65 years, with alcohol dependence as their primary complaint, and without other serious medical or psychiatric conditions. An additional inclusion criterion will be elevated trait anxiety as measured by the Spielberger Trait Anxiety Inventory. Subjects will be admitted to the NIAAA research inpatient unit at the NIH Clinical Research Center (CRC) through the platform training and natural history protocol (05-AA-0121 Assessment and Treatment of People with Alcohol Drinking Problems ), which provides basic assessments and standard withdrawal treatment if needed. Patients will enter into the present protocol once such treatment, if needed, is completed.

Design: Following inclusion, subjects will be randomized to acamprosate (n=25) or placebo (n=25), receiving either 3 tablets of 333mg acamprosate three times daily, or receiving identically looking placebo. Following a minimum of 2 weeks of treatment, subjects will undergo three challenge sessions, a minimum of 5 days apart, with yohimbine, m-CPP or placebo infusion, in counterbalanced order.

Outcome Measures: During the challenge sessions, subjective cravings for alcohol will be assessed using the Alcohol Urge Questionnaire. Neuroendocrine and cardiovascular measures will be collected for exploratory purposes.

  Eligibility

Ages Eligible for Study:   21 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

Subjects will be 60 recently detoxified alcoholics according to the following criteria:

  • DSM-IV diagnosis of alcohol dependence on SCID, alcohol problems as primary complaint among substance use disorder, and alcohol use within the last month.
  • Spielberger trait anxiety (21) score greater than 39
  • Age 21-65
  • Females of childbearing potential must agree to use a reliable method of birth control during the study. Reliable methods of birth control include oral contraceptives or Norplant(Registered Trademark); barrier methods such as diaphragms with contraceptive jelly, cervical caps with contraceptive jelly, condoms with contraceptive foam, or intrauterine devices; a partner with a vasectomy; or abstinence from intercourse.

EXCLUSION CRITERIA:

  • People who present with significant medical problems which in the assessment of the Lead Associate Investigator contraindicate administration of any of the study drugs. Examples are patients requiring intensive medical or diagnostic management, such as uncontrolled hypertension, serious GI bleeding, major organ or body system dysfunction such as decompensated liver disease, renal failure, myocardial ischemia, congestive heart failure or cerebrovascular disease, major endocrine problems such as uncontrolled diabetes, pancreatic or thyroid disease, or glaucoma.
  • People who are infected with the Human Immunodeficiency Virus (HIV).
  • People with the following specific neuro-psychiatric disorders: any psychotic disorder including schizophrenia; bipolar affective disorder; or panic disorder.
  • People with any other condition that impairs judgment or cognitive function to an extent that precludes them from providing informed consent or complying with treatment (incompetent individuals); or that requires management with pharmacotherapy that would make the subject ineligible for participation.
  • Contraindications for acamprosate (previously exhibited hypersensitivity to acamprosate calcium or any of its components; or severe renal impairment, manifested as creatinine clearance of 30 mL/min or less.
  • Contraindications for yohimbine or mCPP, such as liver or renal disease; chronic inflammation of the sexual organs or prostate gland; history of gastric and duodenal ulcers; glaucoma; hypersensitivity to yohimbine or mCPP
  • People who are unlikely or unable to complete the treatment program because they become, or 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.
  • Pregnancy or lactation (negative pregnancy test required)
  • Regular use of psychotropic medication, physician prescribed or purchased over the counter (e.g. antidepressant, lithium, antipsychotic, anxiolytic, antiepileptic, nasal decongestants in tablet form) or blood pressure medication (e.g. beta-blockers, calcium antagonists, ACE-inhibitors or AT1 antagonists) within the last 4 weeks, with the exception of benzodiazepines administered within the NIAAA program as part of alcohol withdrawal treatment. Specifically, no subject will be taken off psychoactive medications for the purpose of enrollment in this protocol.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00605904

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
  More Information

Publications:
Responsible Party: Markus Heilig, Clinical Director, NIAAA, National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier: NCT00605904     History of Changes
Other Study ID Numbers: 080058, 08-AA-0058
Study First Received: January 30, 2008
Results First Received: September 21, 2011
Last Updated: May 23, 2012
Health Authority: United States: Federal Government
United States: Food and Drug Administration

Keywords provided by National Institutes of Health Clinical Center (CC):
Chemical Stressor
Alcoholism
Yohimbine
Acamprosate
Craving

Additional relevant MeSH terms:
Alcoholism
Alcohol-Related Disorders
Substance-Related Disorders
Chemically-Induced Disorders
Mental Disorders
Yohimbine
Acamprosate
Mydriatics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions
Adrenergic alpha-2 Receptor Antagonists
Adrenergic alpha-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Urological Agents
Therapeutic Uses
Alcohol Deterrents
Central Nervous System Agents

ClinicalTrials.gov processed this record on October 19, 2014