A Study on the Biobehavioral Mechanisms of Baclofen and Alcohol Drinking

• Sponsor: Brown University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01076283
• Collaborator: (none)
• Enrollment: 14
• Location: 1
• Arms: 2
• Duration (Months): 5
• Patients Per Site Per Month: 2.8

Study Details

Study Description

Brief Summary

This pilot trial has the goal to demonstrate the feasibility of a study to test the effects of baclofen in a laboratory experiment using cue-reactivity and alcohol-self administration paradigms in non-treatment seeking alcohol-dependent subjects.

Condition or Disease	Intervention/Treatment	Phase
Alcoholism	Drug: Baclofen; Drug: Cyproheptadine	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Pilot Study on the Biobehavioral Mechanisms of Baclofen and Alcohol Drinking
• Study Start Date: Dec 1, 2009
• Actual Primary Completion Date: Apr 1, 2010
• Actual Study Completion Date: May 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Baclofen Baclofen 10 mg three times a day (t.i.d.) for 8-10 days	Drug: Baclofen; Baclofen 10mg t.i.d.
Placebo Comparator: Cyproheptadine Cyproheptadine 2 mg t.i.d. for 8-10 days	Drug: Cyproheptadine; 'active' placebo

Outcome Measures

Primary Outcome Measures

1. Alcohol Urge [approximately 8 days after drug administration]

   Whether baclofen, as compared to active placebo, results in diminished cue-reactivity responses to alcohol cues in terms of urge to drink [as measured by the Alcohol Urge Questionnaire (AUQ)] during the Cue Reactivity. The Alcohol Urge Questionnaire (AUQ) consists of eight statements about the respondent's feelings and thoughts about drinking as they are completing the questionnaire (i.e., right now). The respondent is asked to respond to each statement about alcohol craving via a 7-item Likert scale ranging from "strongly disagree" to "strongly agree." Each item is scored on a 1 to 7 scale (Strongly Disagree = 1 and Strongly Agree = 7). Items 2 and 7 are reverse scored. A total score is computed by summing the item scores and ranges from 8 (lowest craving value) to 56 (highest craving value). Higher scores reflect greater craving (i.e. worse outcome).

2. Alcohol Drinking [approximately 8 days after drug administration]

   Whether baclofen, as compared to active placebo, results in lower quantity of alcohol consumed during the Alcohol Self-Administration (ASA). Consistent with O'Malley et al. 2002, the ASA paradigm allows to use a fixed-dose (the priming drink), followed by a 2-hour "free-choice" phase when subjects may choose to drink or not up to 8 mini-drinks. Participants receive a monetary compensation of $3 dollars per each mini-drink not consumed; therefore the amount of minidrinks consumed during the 2-hour sessions ranges 0-8, and the monetary compensation ranges $0-24. The quantity of alcohol consumed during the free-choice session is expressed as "standard drinking unit", where a standard drink unit contains about 14 grams of pure alcohol (about 0.6 fluid ounces or 1.2 tablespoons).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• must be male or female between 21 and 65 years old (inclusive).

• participants must meet criteria for current Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM-IV-TR) diagnosis of alcohol dependence, supported by the Structured Clinical Interview for DSM-IV-TR Axis I Disorders Patient Edition (SCID-I/P).

• participants must meet criteria for heavy drinking, defined as averaging ≥4 drinks/day for women and ≥5 drinks/day for men during a consecutive 30-day period within the 90 days prior to baseline evaluation (see: Anton et al, 2006). The gender-specific baseline was chosen as it represents heavy drinking that exceeds empirically based levels of moderate alcohol use that result in alcohol-related problems for women who consume ≥4 drinks/day, and men who consume ≥5 drinks/day (Sanchez-Craig et al, 1995).

• participants must be in good health as confirmed by medical history, physical examination, ECG, lab tests.

• females must be postmenopausal for at least one year, surgically sterile, or practicing an effective method of birth control before entry and throughout the study; have a negative urine pregnancy test at each visit.

• participants must be willing to take oral medication and adhere to the study procedures.

Exclusion criteria:

• individuals expressing interest in treatment for alcoholism.

• pregnancy or breast feeding women or not using an adequate form of birth control

• positive urine drug screen at baseline for any illegal substance (a urine drug screen may be repeated once during the screening period).

• individuals diagnosed with a current substance dependence diagnosis, other than alcohol or nicotine.

• meet DSM-IV Axis I criteria for a lifetime diagnosis of schizophrenia, bipolar disorder, or other psychoses.

• an active illness within the past 6 months of Visit 1 that meet the DSM-IV criteria for a diagnosis of Major Depressive Disorder (MDD) or Anxiety Disorder. Subjects with a history of suicide will be excluded.

• clinically significant medical abnormalities (i.e., unstable hypertension, ECG, bilirubin > 150% of the upper normal limit, ALT or AST elevations >300% the upper normal limit, creatinine clearance ≤ 60 dl/min).

• current use of psychotropic medications that cannot be discontinued that may have an effect on alcohol consumption or that may interact with baclofen or cyproheptadine.

• medical contraindications for use of baclofen or cyproheptadine.

• a history of adverse reaction or hypersensitivity to baclofen or cyproheptadine.

• individuals with a reasonable expectation of being institutionalized during the course of the trial.

• participants who have significant alcohol withdrawal symptoms, defined as a Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) >10.

• history of seizures (e.g. epilepsy).

• subjects who have participated in any behavioral and/or pharmacological study within the past 90 days.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Brown University Center for Alcohol and Addiction Studies	Providence	Rhode Island	United States	02903

Sponsors and Collaborators

• Brown University

Investigators

• Principal Investigator: Lorenzo Leggio, M.D., M.Sc., Brown University Center for Alcohol and Addiction Studies

Study Documents (Full-Text)

None provided.

More Information

Publications

• Addolorato G, Caputo F, Capristo E, Domenicali M, Bernardi M, Janiri L, Agabio R, Colombo G, Gessa GL, Gasbarrini G. Baclofen efficacy in reducing alcohol craving and intake: a preliminary double-blind randomized controlled study. Alcohol Alcohol. 2002 Sep-Oct;37(5):504-8.
• Addolorato G, Leggio L, Abenavoli L, Agabio R, Caputo F, Capristo E, Colombo G, Gessa GL, Gasbarrini G. Baclofen in the treatment of alcohol withdrawal syndrome: a comparative study vs diazepam. Am J Med. 2006 Mar;119(3):276.e13-8.
• Addolorato G, Leggio L, Abenavoli L, Caputo F, Gasbarrini G. Tolerance to baclofen's sedative effect in alcohol-addicted patients: no dissipation after a period of abstinence. Psychopharmacology (Berl). 2005 Mar;178(2-3):351-2. Epub 2004 Sep 30.
• Addolorato G, Leggio L, Abenavoli L, DeLorenzi G, Parente A, Caputo F, Janiri L, Capristo E, Rapaccini GL, Gasbarrini G. Suppression of alcohol delirium tremens by baclofen administration: a case report. Clin Neuropharmacol. 2003 Sep-Oct;26(5):258-62.
• Addolorato G, Leggio L, Ferrulli A, Cardone S, Vonghia L, Mirijello A, Abenavoli L, D'Angelo C, Caputo F, Zambon A, Haber PS, Gasbarrini G. Effectiveness and safety of baclofen for maintenance of alcohol abstinence in alcohol-dependent patients with liver cirrhosis: randomised, double-blind controlled study. Lancet. 2007 Dec 8;370(9603):1915-22.
• Colombo G, Addolorato G, Agabio R, Carai MA, Pibiri F, Serra S, Vacca G, Gessa GL. Role of GABA(B) receptor in alcohol dependence: reducing effect of baclofen on alcohol intake and alcohol motivational properties in rats and amelioration of alcohol withdrawal syndrome and alcohol craving in human alcoholics. Neurotox Res. 2004;6(5):403-14. Review.
• Evans SM, Bisaga A. Acute interaction of baclofen in combination with alcohol in heavy social drinkers. Alcohol Clin Exp Res. 2009 Jan;33(1):19-30. doi: 10.1111/j.1530-0277.2008.00805.x. Epub 2008 Oct 6.
• Leggio L, Garbutt JC, Addolorato G. Effectiveness and safety of baclofen in the treatment of alcohol dependent patients. CNS Neurol Disord Drug Targets. 2010 Mar;9(1):33-44. Review.

• Responsible Party: Lorenzo Leggio, Assistant Professor (Research), Brown University
• ClinicalTrials.gov Identifier: NCT01076283
• Other Study ID Numbers: 0906000002
• First Posted: Feb 26, 2010
• Last Update Posted: Oct 17, 2013
• Last Verified: Oct 1, 2013

• Keywords provided by Lorenzo Leggio, Assistant Professor (Research), Brown University: baclofen; alcoholism; urge; craving; alcohol drinking; biobehavioral mechanisms of baclofen in alcoholism
• Additional relevant MeSH terms: Alcoholism; Alcohol Drinking; Cyproheptadine; Baclofen

Study Results

Participant Flow

Recruitment Details	Potential participants came for an in-person screening (Visit 1) at the Brown University Center for Alcohol and Addiction Studies (CAAS). At Visit 2 (day 1), participants were randomized to either baclofen or active placebo by using a 3-urn variable procedure (Stout et al., 1994), i.e. gender, FH of alcoholism and baseline drinks per drinking day.
Pre-assignment Detail	19 participants signed the consent document; 5 of them did not satisfy the protocol-specific inclusion/exclusion criteria, therefore they were excluded from the trial. The remaining 14 subjects were assigned to the study groups.

Arm/Group Title	Baclofen	Cyproheptadine
Arm/Group Description	Baclofen 10 mg three times a day (t.i.d.) for 8-10 days	Cyproheptadine 2 mg t.i.d. for 8-10 days
Period Title: Overall Study
STARTED	7	7
COMPLETED	6	7
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Baclofen	Cyproheptadine	Total
Arm/Group Description	Baclofen 10 mg three times a day (t.i.d.) for 8-10 days	Cyproheptadine 2 mg t.i.d. for 8-10 days	Total of all reporting groups
Overall Participants	7	7	14
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	7 100%	7 100%	14 100%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	2 28.6%	2 28.6%	4 28.6%
Male	5 71.4%	5 71.4%	10 71.4%
Region of Enrollment (participants) [Number]
United States	7 100%	7 100%	14 100%

Outcome Measures

1. Primary Outcome

Title	Alcohol Urge
Description	Whether baclofen, as compared to active placebo, results in diminished cue-reactivity responses to alcohol cues in terms of urge to drink [as measured by the Alcohol Urge Questionnaire (AUQ)] during the Cue Reactivity. The Alcohol Urge Questionnaire (AUQ) consists of eight statements about the respondent's feelings and thoughts about drinking as they are completing the questionnaire (i.e., right now). The respondent is asked to respond to each statement about alcohol craving via a 7-item Likert scale ranging from "strongly disagree" to "strongly agree." Each item is scored on a 1 to 7 scale (Strongly Disagree = 1 and Strongly Agree = 7). Items 2 and 7 are reverse scored. A total score is computed by summing the item scores and ranges from 8 (lowest craving value) to 56 (highest craving value). Higher scores reflect greater craving (i.e. worse outcome).
Time Frame	approximately 8 days after drug administration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Baclofen	Cyproheptadine
Arm/Group Description	Baclofen 10 mg three times a day (t.i.d.) for 8-10 days	Cyproheptadine 2 mg t.i.d. for 8-10 days
Measure Participants	6	7
Mean (Standard Deviation) [units on a scale]	22.5 (11.4)	19.4 (19.6)

2. Primary Outcome

Title	Alcohol Drinking
Description	Whether baclofen, as compared to active placebo, results in lower quantity of alcohol consumed during the Alcohol Self-Administration (ASA). Consistent with O'Malley et al. 2002, the ASA paradigm allows to use a fixed-dose (the priming drink), followed by a 2-hour "free-choice" phase when subjects may choose to drink or not up to 8 mini-drinks. Participants receive a monetary compensation of $3 dollars per each mini-drink not consumed; therefore the amount of minidrinks consumed during the 2-hour sessions ranges 0-8, and the monetary compensation ranges $0-24. The quantity of alcohol consumed during the free-choice session is expressed as "standard drinking unit", where a standard drink unit contains about 14 grams of pure alcohol (about 0.6 fluid ounces or 1.2 tablespoons).
Time Frame	approximately 8 days after drug administration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Baclofen	Cyproheptadine
Arm/Group Description	Baclofen 10 mg three times a day (t.i.d.) for 8-10 days	Cyproheptadine 2 mg t.i.d. for 8-10 days
Measure Participants	6	7
Mean (Standard Deviation) [standard drinking units]	0.17 (0.41)	1.43 (2.30)

Adverse Events

Arm/Group Title	Baclofen		Cyproheptadine
Arm/Group Description	Baclofen 10 mg three times a day (t.i.d.) for 8-10 days		Cyproheptadine 2 mg t.i.d. for 8-10 days
All Cause Mortality
	Baclofen		Cyproheptadine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Baclofen		Cyproheptadine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/7 (0%)
Other (Not Including Serious) Adverse Events
	Baclofen		Cyproheptadine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/7 (85.7%)		3/7 (42.9%)
Gastrointestinal disorders
constipation	0/7 (0%)		1/7 (14.3%)
diarrhea	1/7 (14.3%)		0/7 (0%)
nausea	1/7 (14.3%)		0/7 (0%)
flatulence	1/7 (14.3%)		0/7 (0%)
stomachache	1/7 (14.3%)		0/7 (0%)
General disorders
dental pain	0/7 (0%)		1/7 (14.3%)
Musculoskeletal and connective tissue disorders
cramps	1/7 (14.3%)	2	0/7 (0%)	2
neck pain	1/7 (14.3%)		0/7 (0%)
Nervous system disorders
sleepness	2/7 (28.6%)		1/7 (14.3%)
sedation	3/7 (42.9%)		2/7 (28.6%)
insomnia	1/7 (14.3%)		0/7 (0%)
irritability	1/7 (14.3%)		0/7 (0%)
foggy	1/7 (14.3%)		0/7 (0%)
'high'	1/7 (14.3%)		0/7 (0%)
Renal and urinary disorders
increased urination	1/7 (14.3%)		0/7 (0%)
yellow urine	0/7 (0%)		1/7 (14.3%)
Reproductive system and breast disorders
loss of libido	1/7 (14.3%)		0/7 (0%)

Limitations/Caveats

Very small sample. This pilot trial was primarily aimed to determine a power analysis for future larger trials.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.