Alcohol Dependence
Conditions
Brief summary
To test the preliminary efficacy of 16.0 mg of Prazosin daily versus placebo in treatment seeking alcohol dependent individuals. This proposal is a laboratory and treatment outcome study to examine the effects of Prazosin on brief exposure to stress, drug cues and neutral situations on alcohol and drug craving, mood and neurobiological reactivity in a sample of cocaine and/or alcohol dependent individuals. Prazosin will be beneficial for reduction in stress and alcohol cue induced craving and related arousal. In a sample of treatment-seeking alcohol dependent men and women, we propose to examine (a) differences in measures of alcohol craving, emotion state, hypothalamic-pituitary-adrenal (HPA) activation, physiological arousal and plasma catecholamine response to stress imagery and to alcohol cue imagery as compared to neutral imagery; (b) reduction in alcohol abstinence symptoms; and (c) improvement in alcohol treatment outcomes as measured by reductions in heavy drinking days, any drinking days, secondarily on drinks/day, anxiety, mood and sleep.
Detailed description
This is a proof-of-concept (POC) experimental therapeutics study with 2 arms. The first is a double-blind placebo controlled laboratory study with 40 individuals meeting current alcohol dependence criteria (DSM-IVTR) who are admitted to the Clinical Neuroscience Research Unit and initiated on Prazosin vs Placebo (16mg/day) after admission and initial detoxification (if required). Experimental laboratory sessions are conducted after subjects achieved full dose after the 2-week titration, in week 3-4 of inpatient stay. The laboratory outcomes included alcohol craving, anxiety, negative affect and neuroendocrine and sympathetic arousal measures. Individuals who wished to remain on study medication for the outpatient (Arm 2) were maintained on study medication throughout the outpatient phase for a total period of 12 weeks. Arm 2 of the POC study is a 12-week randomized clinical trial (RCT) of Prazosin (16mg/day) versus Placebo in 100 treatment seeking alcohol dependent individuals, to assess whether high anxiety and distress, including alcohol craving, manifest as increased alcohol withdrawal symptoms at treatment entry moderates Prazosin effects on alcohol use outcomes. Primary alcohol use outcomes include heavy drinking days, any drinking days and secondarily drinks/day. Additional secondary outcomes include alcohol craving, anxiety and mood symptoms and sleep disturbances. Patients from Arm 1 who wished to continue on study medication for the outpatient phase were included in Arm 2. Arm 2 patients were initiated on study medication upon presenting with a negative breathalyzer without any minimum pre-treatment alcohol abstinence period prior to medication initiation.
Interventions
DRUGPrazosin Tablet
Target medication dosing was three times/day (t.i.d. dosing) with 5 mg in the morning, 5 mg in the afternoon and 6 mg at night reached at the end of the 2-week period, and maintained at this or their highest tolerated dose until week 11, followed by a 5-day taper in week 12, as in previous research.The titration schedule was as follows: 1 mg dose at bedtime for 2 nights, followed by a 1mg dose morning and night (8 AM/8 PM) on day 3, then 2 mg dose t.i.d., on days 4-6, 3 mg dose (2 pills each) morning and afternoon, and 4 mg dose (2 pills) at night for days 7-9, increased to 4 mg dosing t.i.d. on days 10-13, and from day 14 through week 11, 5 mg (1 pill) each in the morning and afternoon, and 6 mg for the night (2 pills) dose. This was followed by a 5-day taper in week 12. Patients were initiated on study medication upon presenting with a negative breathalyzer without any minimum pre-treatment alcohol abstinence period prior to medication initiation.
DRUGPlacebo Tablet
Placebo tablets identical in appearance and dosing schedule as the active study medication was utilized
Sponsors
National Institutes of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Yale University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Randomization into Prazosin/Placebo treatment was conducted by the Yale Stress Center biostatistician using an Urn randomization procedure that balanced groups on gender, age, nicotine smoking status, education years and lifetime history of DSM-IVTR anxiety disorders, including Post Traumatic Stress Disorder (PTSD). Random assignment of each patient was provided to the Yale Investigational Drug Service (IDS) Pharmacist, who formulated identical, matched tablets of Prazosin and Placebo, and provided dosing in weekly blister packs labeled by day and time of dosing for each subject to study staff for dispensing. All study personnel, including investigators, physicians, study staff and patients remained blind to medication group.
Intervention model description
Interaction effects of Alcohol withdrawal distress with Prazosin versus Placebo effects during the trial.
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Male or female individuals, ages 18-70 with alcohol dependence, treatment seeking with varying levels of alcohol withdrawal symptoms. * meet current DSM-IV criteria for alcohol dependence, * Subject has voluntarily given informed consent and signed the informed consent document. * Able to read English and complete study evaluations.
Exclusion criteria
* Meet current criteria for dependence on another psychoactive substance, excluding nicotine and caffeine; * Any current use of opiates; * Current use of any psychoactive drugs, including anxiolytics, antidepressants, naltrexone or disulfram, except for stabilized on SSRIs * Any psychotic disorder or current Axis I psychiatric symptoms requiring specific attention, including need for psychiatric medications for current major depression and anxiety disorders * Significant underlying medical conditions such as cerebral, renal, thyroid or cardiac pathology which in the opinion of study physician would preclude patient from fully cooperating or be of potential harm during the course of the study; * Hypotensive individuals with sitting blood pressure below 90/60 mmHG.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Heavy Drinking Days (HDD%) During the Full Dose Period From Weeks 3-12 | daily over 12 weeks | Percentage of heavy drinking days (HDD%) during the full dose period from weeks 3-12 where heavy drinking day (HDD) is defined as 5 or more for men and 4 or more for women in one sitting, measured as yes (1) or no(0), assessed via self reports by daily surveys and time-line follow back assessments |
| Percent of Drinkings Days During the Full Dose Period Between Weeks 3 and 12 | daily over 12 weeks | Percent of any drinkings days over the full dose period from weeks 3 to 12, defined as any alcoholic drink consumed each day measured as yes (1) or no(0), assessed via self reports by daily surveys and time-line follow back assessments |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| High Alcohol Withdrawal on Prazosin High AW (Clinical Institute of Withdrawal for Alcohol Revised (CIWA-Ar) scores at or above 3 randomized to Prazosin 16 mg/day (tid) for 12 weeks. | 21 |
| High Alcohol Withdrawal on PLA High AW (Clinical Institute of Withdrawal for Alcohol Revised (CIWA-Ar) scores at or above 3 randomized to matching Placebo tablets (tid) for 12 weeks. | 23 |
| Low Alcohol Withdrawal on Prazosin Low AW (Clinical Institute of Withdrawal for Alcohol Revised (CIWA-Ar) scores at or below 3 randomized to Prazosin 16 mg/day (tid) for 12 weeks. | 34 |
| Low Alcohol Withdrawal on PLA Low AW (Clinical Institute of Withdrawal for Alcohol Revised (CIWA-Ar) scores at or below 2 randomized to matching Placebo tablets (tid) for 12 weeks. | 22 |
| Total | 100 |
Baseline characteristics
| Characteristic | High Alcohol Withdrawal on Prazosin | High Alcohol Withdrawal on PLA | Low Alcohol Withdrawal on Prazosin | Low Alcohol Withdrawal on PLA | Total |
|---|---|---|---|---|---|
| Age, Continuous | 40.9 years STANDARD_DEVIATION 9.8 | 39.2 years STANDARD_DEVIATION 11.1 | 39.6 years STANDARD_DEVIATION 10.8 | 41.4 years STANDARD_DEVIATION 11.9 | 40.65 years STANDARD_DEVIATION 10.86 |
| Race/Ethnicity, Customized African American | 9 Participants | 13 Participants | 14 Participants | 12 Participants | 48 Participants |
| Race/Ethnicity, Customized Caucasian | 12 Participants | 10 Participants | 20 Participants | 9 Participants | 51 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Female | 8 Participants | 7 Participants | 13 Participants | 7 Participants | 35 Participants |
| Sex: Female, Male Male | 13 Participants | 16 Participants | 21 Participants | 15 Participants | 65 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 21 | 0 / 23 | 0 / 34 | 0 / 22 |
| other Total, other adverse events | 4 / 21 | 3 / 23 | 9 / 34 | 2 / 22 |
| serious Total, serious adverse events | 0 / 21 | 0 / 23 | 1 / 34 | 1 / 22 |
Outcome results
Primary
Percentage of Heavy Drinking Days (HDD%) During the Full Dose Period From Weeks 3-12
Percentage of heavy drinking days (HDD%) during the full dose period from weeks 3-12 where heavy drinking day (HDD) is defined as 5 or more for men and 4 or more for women in one sitting, measured as yes (1) or no(0), assessed via self reports by daily surveys and time-line follow back assessments
Time frame: daily over 12 weeks
Population: Mean percentage of heavy drinking days (HDD%) during the full dose period from weeks 3-12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| High Alcohol Withdrawal (AW) on Prazosin | Percentage of Heavy Drinking Days (HDD%) During the Full Dose Period From Weeks 3-12 | 8.2 percentage of heavy drinking days | Standard Error 4.09 |
| High Alcohol Withdrawal (AW) on PLA | Percentage of Heavy Drinking Days (HDD%) During the Full Dose Period From Weeks 3-12 | 27.11 percentage of heavy drinking days | Standard Error 7.97 |
| Low Alcohol Withdrawal (AW) on Prazosin | Percentage of Heavy Drinking Days (HDD%) During the Full Dose Period From Weeks 3-12 | 31.29 percentage of heavy drinking days | Standard Error 7.42 |
| Low Alcohol Withdrawal (AW) on PLA | Percentage of Heavy Drinking Days (HDD%) During the Full Dose Period From Weeks 3-12 | 7.32 percentage of heavy drinking days | Standard Error 3.54 |
Comparison: Intent-to-treat (ITT) analyses with baseline AW severity (mean-centered continuous CIWA-Ar scores) as a moderator of Time (Pre-Full Dose(FD): weeks 1-2; Post FD: weeks 3-12) were conducted with linear or generalized linear mixed effect (LME/GLME) piecewise growth models for continuous and binary outcomes. Control variables that were modeled in all analyses. As hypothesized, significant interactions were tested using AW median cut-offs for high and Low AW groups.p-value: 0.01695% CI: [0.1, 0.55]Mixed Models Analysis
Primary
Percent of Drinkings Days During the Full Dose Period Between Weeks 3 and 12
Percent of any drinkings days over the full dose period from weeks 3 to 12, defined as any alcoholic drink consumed each day measured as yes (1) or no(0), assessed via self reports by daily surveys and time-line follow back assessments
Time frame: daily over 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| High Alcohol Withdrawal (AW) on Prazosin | Percent of Drinkings Days During the Full Dose Period Between Weeks 3 and 12 | 26.89 Mean percent of any drinking days | Standard Error 7.45 |
| High Alcohol Withdrawal (AW) on PLA | Percent of Drinkings Days During the Full Dose Period Between Weeks 3 and 12 | 41.21 Mean percent of any drinking days | Standard Error 9.36 |
| Low Alcohol Withdrawal (AW) on Prazosin | Percent of Drinkings Days During the Full Dose Period Between Weeks 3 and 12 | 53.35 Mean percent of any drinking days | Standard Error 7.74 |
| Low Alcohol Withdrawal (AW) on PLA | Percent of Drinkings Days During the Full Dose Period Between Weeks 3 and 12 | 23.71 Mean percent of any drinking days | Standard Error 6.9 |
Comparison: Intent-to-treat (ITT) analyses with baseline AW severity (mean-centered continuous CIWA-Ar scores) as a moderator of Time (Pre-Full Dose(FD): weeks 1-2; Post FD: weeks 3-12) were conducted with linear or generalized linear mixed effect (LME/GLME) piecewise growth models for continuous and binary outcomes. Control variables that were modeled in all analyses. As hypothesized, significant interactions were tested using AW median cut-offs for high and Low AW groups.p-value: 0.00295% CI: [0.28, 0.92]Mixed Models Analysis