Prazosin for Alcohol Dependence and Posttraumatic Stress Disorder

A Placebo-Controlled Trial of Prazosin in Individuals With Co-occurring Alcohol Dependence and PTSD Seeking Abstinence

The purpose of this study is to determine whether the drug prazosin is effective for the treatment of alcohol dependency and symptoms of Posttraumatic Stress Disorder (PTSD).

Study Overview

• Status: Completed
• Conditions: Posttraumatic Stress Disorder; Alcohol Abuse
• Intervention / Treatment: Drug: Placebo medication; Drug: Prazosin

Detailed Description

Background: Alcohol dependence (AD) is a biologically, genetically based disease, yet the majority of clinically accepted treatments are behaviorally or psychosocially based. PTSD and alcohol use disorders (AUDs) commonly co-occur. This comorbidity is associated with more severe clinical impairment, shorter times to relapse, more treatment recidivism, overall greater use of treatment services, and greater treatment costs.

Neuropharmacology of alcohol and prazosin: Emerging pre-clinical evidence shows that noradrenergic systems are involved in brain processes relevant to AD, such as arousal, reinforcement, and stress responsivity. However, virtually no work to date has attempted to translate this knowledge into clinically effective biological interventions. The investigators have adopted the novel, promising strategy of reducing adrenergic activity by blocking noradrenaline binding to post-synaptic alpha-1 receptors via the non-selective, alpha-1 antagonist, prazosin. Preclinical studies have demonstrated that prazosin decreases reinstatement of alcohol consumption, and preliminary clinical data suggest that prazosin reduces alcohol use in humans with AD and reduces PTSD-related nightmares and other symptoms, though it has not been tested in individuals with comorbid AD and PTSD. Prazosin, FDA approved to treat hypertension, typically has few side effects, and is inexpensive.

Design: Randomized double-blind placebo-controlled clinical trial. Participants: 60 individuals with both AD and PTSD (25% women) with stated goal to abstain from alcohol use.

Intervention: Either prazosin titrated per study protocol or matched placebo for 6 weeks with Medical Management (MM) based on the COMBINE Study procedures and a final study visit two weeks after medication discontinuation.

Measures: The primary outcomes are alcohol use during the 12-week medication phase of the study and reports of craving during the same time period. Daily, prompted Interactive Voice Response (IVR) telephone monitoring will be done throughout the 8-week study to assess the primary outcomes and to provide information on affect and medication adherence. Such daily monitoring provides more accurate reports of alcohol use than standard retrospective outcome measures. Analyses: Hierarchical linear modeling to test for main effects of prazosin+MM versus placebo+MM on alcohol use and PTSD symptoms over time, and to evaluate whether reductions in PTSD mediate the effect of prazosin.

Findings to date: Participants randomized to prazosin had a greater reduction in percent days drinking per week and percent days heavy drinking per week between baseline and week 6 than did placebo participants. No significant differences were detected within or between groups in change from weeks 1 to 6 in total PTSD symptoms. Participants in the prazosin condition reported drowsiness on significantly more days than those in the placebo condition. Public health implications: There is a paucity of safe, tolerable, inexpensive, and efficacious drugs currently available for the treatment of AD and PTSD. Consistent with the extant research evaluating medications for comorbid PTSD/AD, the current evaluation of prazosin also found decreased alcohol consumption but no medication effect on PTSD symptomatology.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98108
      • VA Puget Sound Health Care System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Current primary DSM-IV diagnosis of alcohol dependence(AD)
• Current DSM-IV diagnosis of PTSD
• At least 14 (women) or 21 (men) drinks per week AND at least 2 days of heavy drinking during a consecutive 30 day period in the last 90 days
• Desire to abstain from drinking
• At least 18 years of age
• Good general medical health (see Exclusion Criteria below)
• Capacity to provide informed consent
• English fluency

Exclusion Criteria:

Psychiatric/behavioral:

• psychiatric disorder requiring any medication other than anti-depressants (individuals not on a stable dose of an anti-depressant for at least 30 days prior to randomization will be excluded from the study)
• currently taking disulfiram, acamprosate, or naltrexone in the last 30 days or planning to take any of these medications during the 12-week medication phase of the study
• acutely suicidal or homicidal
• current dependence on any other psychoactive substance other than nicotine or cannabis
• a current diagnosis of opioid abuse, use of any opioid- containing medications, methamphetamines, or benzodiazepines during the previous month, or UDA positive for opioids, methamphetamines, benzodiazepines, or sedative hypnotics

Medical:

• significant acute or chronic medical illness including unstable angina, recent myocardial infarction, history of congestive heart failure, preexisting hypotension (systolic <110) or orthostatic hypotension (defined as a systolic drop > 20mmHg after two minutes standing or any drop with dizziness); insulin-dependent diabetes mellitus; chronic renal or hepatic failure, pancreatitis, Meniere's disease, benign positional vertigo, narcolepsy
• for males only, concomitant use of trazodone (or use in the last 7 days), tadalafil, or vardenafil (or use in the last 3 days) due to increased risk of priapism
• history of prazosin-sensitivity; no prazosin for at least the past 30 days
• women who are pregnant, nursing infant(s), or of childbearing potential and not using a contraceptive method judged by the study physician or PA to be effective
• signs or symptoms of alcohol withdrawal at the time of initial consent
• legal involvement that could interfere with study treatment
• individuals court ordered for treatment will not be eligible to participate in this study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo medication	Drug: Placebo medication; Form: Placebo will be taken orally, in the form of pills. Dosing: 9 AM, 3 PM, 9 PM Days 1-2: 0 mg, 0 mg, 1 mg Days 3-4: 1 mg, 1 mg, 1 mg Days 5-7: 2 mg, 2 mg, 2 mg Day 8-10: 2 mg, 2 mg, 6 mg Day 11-14: 4 mg, 4 mg, 6 mg Day 15-84: 4 mg, 4 mg, 8 mg; Other Names: Placebo
Experimental: Prazosin; Prazosin medication	Drug: Prazosin; Form: Prazosin will be taken orally, in the form of pills. Dosing: 9 AM, 3 PM, 9 PM Days 1-2: 0 mg, 0 mg, 1 mg Days 3-4: 1 mg, 1 mg, 1 mg Days 5-7: 2 mg, 2 mg, 2 mg Day 8-10: 2 mg, 2 mg, 6 mg Day 11-14: 4 mg, 4 mg, 6 mg Day 15-84: 4 mg, 4 mg, 8 mg; Other Names: Minipress

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Drinking Days Per Week	Data for this measure came from the Form-42 and daily IVR (Interactive Voice Response) monitoring. The percentage of drinking days of each participant was calculated by summing the number of drinking days and comparing them with the number of total drinking days in the same week. The percentage of drinking days from each week was added and averaged to get the percentage of drinking days per week per participant. The percentage of drinking days of all participants in the Prazosin group was added and averaged to get the mean of the percentage of weekly drinking days of the Prazosin group. These steps were repeated for the Placebo group.	6 weeks
Percent Heavy Drinking Days Per Week	Data for this measure came from the Form-42 and daily IVR (Interactive Voice Response) monitoring. Heavy drinking was defined as 5 or more drinks per day for men and 4 or more drinks per day for women. The percentage of heavy drinking days of each participant was calculated by summing the number of heavy drinking days and comparing them with the total number of drinking days in the same week. The percentage of heavy drinking days from each week was added and averaged to get the percentage of heavy drinking days per week per participant. The percentage of heavy drinking days of all participants in the Prazosin group was added and averaged to get the mean of percentage of weekly heavy drinking days of the Prazosin group. These steps were repeated for the Placebo group.	6 weeks
Total Drinks Per Week	Data for this measure came from the Form-42 and daily IVR (Interactive Voice Response) monitoring. The weekly total drinks of each participant were calculated by adding the number of drinks by week. The total drinks from each week were added and averaged to get the weekly total drinks of each participant. The weekly total drinks of all participants in the Prazosin group were added and averaged to get the total drinks per week for the Prazosin group. These steps were repeated for the Placebo group.	6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PTSD Symptom Assessments	PTSD symptoms/changes in PTSD (Post-Traumatic Stress Disorder) symptomatology was calculated using data from the IVR (interactive Voice Response) monitoring. PTSD scores were derived by computing the daily average of the item totals for overall PTSD and the symptom clusters. The rating range was 0 (not at all) to 8 (extremely). The higher the score/rating, the more severe the PTSD symptoms. The lowest and highest possible average are 0 and 8, respectively.	6 weeks

Collaborators and Investigators

• Sponsor: Seattle Institute for Biomedical and Clinical Research
• Collaborators: National Institute on Alcohol Abuse and Alcoholism (NIAAA); VA Puget Sound Health Care System
• Investigators: Principal Investigator: Tracy L Simpson, PhD, VA Puget Sound Health Care System

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2009
• Primary Completion (Actual): June 1, 2012
• Study Completion (Actual): June 1, 2012

Study Registration Dates

• First Submitted: January 23, 2012
• First Submitted That Met QC Criteria: January 25, 2012
• First Posted (Estimate): January 26, 2012

Study Record Updates

• Last Update Posted (Actual): August 25, 2020
• Last Update Submitted That Met QC Criteria: August 13, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Keywords: PTSD; Treatment; Dependence; Alcohol; Alcoholism; Craving; Medical; Management; Alcoholic; Trauma; Placebo; Medication; Symptoms; Drug; Drinking; Prazosin; Disorder; Abuse; Study; Consumption; Binge; Post; Use; Medicine; Drink; Heavy; Posttraumatic
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Alcohol-Related Disorders; Substance-Related Disorders; Trauma and Stressor Related Disorders; Alcoholism; Stress Disorders, Traumatic; Stress Disorders, Post-Traumatic; Physiological Effects of Drugs; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Prazosin
• Other Study ID Numbers: P20AA017839 (U.S. NIH Grant/Contract); 1P20AA017839-01 (U.S. NIH Grant/Contract)