Prazosin for Alcohol Dependence and Posttraumatic Stress Disorder

Phase 2

Completed

Conditions: Posttraumatic Stress Disorder
Alcohol Abuse

Interventions: Drug: Placebo medication
Drug: Prazosin

Registration Number: NCT01518972

Lead Sponsor: Seattle Institute for Biomedical and Clinical Research

Brief Summary: 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).

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 30

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo medication	Placebo medication
Prazosin	Prazosin	Prazosin medication

Primary Outcome Measures

Name	Time	Method
Percent Heavy Drinking Days Per Week	6 weeks	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.
Total Drinks Per Week	6 weeks	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.
Percent Drinking Days Per Week	6 weeks	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.

Secondary Outcome Measures

Name	Time	Method
PTSD Symptom Assessments	6 weeks	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.