Prazosin and Naltrexone (PaN) Study for Veterans With Alcohol Use Disorders (PaN)

Effect of Prazosin and Naltrexone on Personalized Script-Induced Alcohol Craving in Individuals With Alcohol Use Disorders With and Without Comorbid PTSD

The purpose of this study is to evaluate whether the combination of prazosin and naltrexone will decrease alcohol cravings and drinking in individuals who have problems with alcohol and have used alcohol at risky levels compare to naltrexone and placebo (Nal/Pl), prazosin and placebo (Praz/Pl), and double-placebo (Pl/Pl). We hypothesize that those assigned to both prazosin and naltrexone would report significantly greater decreases in percent drinking days and heavy drinking days as well as significantly greater reduction in craving from pre to post-treatment than those assigned to either single medication or double-placebo.

Prazosin is a medication that is approved by the U.S. Food and Drug Administration (FDA) to treat people with high blood pressure. Some studies have shown that prazosin may also decrease nightmares and improve sleep in Veterans suffering from Posttraumatic Stress Disorder (PTSD). Animal studies have consistently found that prazosin is associated with decreased alcohol consumption and that the combination of prazosin and naltrexone outperforms either medication alone. The current study is evaluating an "off-label" use of prazosin to determine whether it is helpful in decreasing alcohol cravings and consumption among people with alcohol problems. "Off-label" means that the FDA has not approved the use of prazosin for alcohol problems.

Naltrexone is a medication that is FDA approved for treating alcohol problems.

This study is sponsored by the Department of Defense and the Congressionally Directed Medical Research Program (DoD/CDMRP). We expect approximately 120 participants in this study, which will run over approximately 4 years. Study participants will be involved in the study for 7 weeks, or until they complete the Final Assessment.

Study Overview

• Status: Completed
• Conditions: Alcohol Use Disorder; Posttraumatic Stress Disorder (PTSD)
• Intervention / Treatment: Drug: Prazosin; Drug: Naltrexone; Drug: Placebo (Naltrexone); Drug: Placebo (Prazosin)

Detailed Description

In this double-blind, double-dummy, placebo-controlled study of prazosin and naltrexone, we will evaluate the combination of naltrexone and the noradrenergic medication prazosin (Nal/Praz) relative to naltrexone and placebo (Nal/Pl), prazosin and placebo (Praz/Pl), and double-placebo (Pl/Pl). Participants will undergo two craving inductions, one oriented towards relief craving and the other towards reward craving. Daily IVR (Interactive Voice Recording System) data on craving and consumption and PTSD symptomatology will be collected during the 7 days immediately following the initial assessment visit to establish a pre-medication baseline. One hundred twenty individuals with adequate IVR compliance and whose screening lab tests indicate it is safe for them to take the study medications will enter the medication phase of the study within 14 days of the initial assessment initiating prazosin/placebo as well as 50mg naltrexone/placebo treatment. Randomization will be blocked by gender, PTSD status, and desire to abstain vs. desire to cut down. Prazosin will be titrated to three times daily dosing (9 am: 4mg; 3pm: 4 mg; 9pm: 8mg) at the end of two weeks. Naltrexone will be taken once daily 50 mg/day with no titration schedule. The stable dose of both medications will continue for four more weeks and medication compliance will be evaluated through pill counts, the IVR daily monitoring, and riboflavin trace in urine analysis. On approximately day 42 participants will come into the lab for the craving inductions (there will be a two week window after day 42 in which participants may still be seen if scheduling issues arise). The order of the craving inductions will be counterbalanced, and their administration will be separated in time by 30 minutes to minimize carry over between them. Subjective responses to the craving inductions will be obtained via relief oriented craving items and reward oriented craving items from the Desire for Alcohol Questionnaire. Participants will then be assisted in returning their craving levels to baseline prior to debriefing. They will all be offered treatment referrals within the Veterans Affairs (VA) or in the community. Both prazosin and naltrexone can be safely discontinued without tapering.

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98108
      • VA Puget Sound Healthcare System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Veteran of the U.S. military or National Guard Reserve.
2. Current AUD by DSM-5 criteria.
3. Heavy drinking (>14 drinks per week for females; > 21 drinks per week for males) for at least 2 weeks in the last 3 months and some drinking during the past two weeks OR binge drinking for at least 3 days in the last month (4+ drinks for females; 5+ drinks for males).
4. At least mild alcohol craving as assessed by the Pennsylvania Alcohol Craving Scale (PACS; score > 10) at baseline.
5. Age 18-80.
6. English fluency and literacy.
7. Trying or planning to try to cut down on or abstain from alcohol.
8. Good general medical health.
9. Capable of giving informed consent.

Exclusion Criteria:

1. Uncontrolled psychiatric disorder with psychotic symptoms or cognitive impairment.
2. If taking psychiatric medication, NOT on a stable dose for at least 30 days prior to randomization.
3. Any suicidal ideation in the past 7 days, plan or intent past 6 months, or any suicide attempt past year.
4. Homicidal ideation with plan and intent in the past 30 days.
5. Patient Health Questionnaire-9 (PHQ-9) endorsement of hopelessness or self-harm/SI and/or sum scale score ≥ 19.
6. Any use of prazosin or naltrexone past 30 days.
7. Currently taking disulfiram or acamprosate OR planning to take any of these medications (including prazosin or naltrexone) during the study.
8. Current moderate or severe substance use disorder (past 30 days) on any psychoactive substance other than alcohol, nicotine, or cannabis, OR use of any amphetamine or opioid-containing medications during the previous 30 days.
9. Significant acute or chronic medical illness
10. Preexisting hypotension (sys <100) or orthostatic hypotension (systolic drop of > 20 mmHg; after two minutes of standing, or any drop with dizziness).
11. Allergy or previous adverse reaction to naltrexone, prazosin, quinazolines, or other α-1 adrenergic blockers or use of other α -1 adrenergic blocker.
12. Women who are pregnant, breastfeeding, or of childbearing potential and not using a contraceptive method judged by the investigator to be effective.
13. Legal involvement that could interfere with study participation, including being court ordered for treatment.
14. Signs or symptoms of withdrawal at time of initial consent.
15. Any participation in an experimental drug study or any addiction study past 30 days.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Praz/Nal; Prazosin and Naltrexone. Prazosin will be taken following this titration schedule: Days 1-2: 1 mg @ 9PM Days 3-4: 1 mg @ 9AM, 3PM, 9PM Days 5-7: 2 mg @ 9AM, 3PM, 9PM Days 8-10: 2mg @ 9 AM, 3 PM; 8mg @ 9 PM Days 11-14: 4mg @ 9 AM, 3 PM; 8mg @ 9 PM Days 15-42: 4mg @ 9 AM, 3 PM; 8mg @ 9 PM Naltrexone will be taken from day 1 to day 42 at 9 PM. Dose: 50 mg.	Drug: Prazosin; Prazosin Dosing Days 1-2: 1 mg @ 9PM Days 3-4: 1 mg @ 9AM, 3PM, 9PM Days 5-7: 2 mg @ 9AM, 3PM, 9PM Days 8-10: 2mg @ 9 AM, 3 PM; 8mg @ 9 PM Days 11-14: 4mg @ 9 AM, 3 PM; 8mg @ 9 PM Days 15-42: 4mg @ 9 AM, 3 PM; 8mg @ 9 PM; Other Names: Minipress; Drug: Naltrexone; Naltrexone Dosing Days 1-42: 50mg @ 9PM
Active Comparator: Praz/Pl; Prazosin and Placebo (Naltrexone) Prazosin will be taken following this titration schedule: Days 1-2: 1 mg @ 9PM Days 3-4: 1 mg @ 9AM, 3PM, 9PM Days 5-7: 2 mg @ 9AM, 3PM, 9PM Days 8-10: 2mg @ 9 AM, 3 PM; 8mg @ 9 PM Days 11-14: 4mg @ 9 AM, 3 PM; 8mg @ 9 PM Days 15-42: 4mg @ 9 AM, 3 PM; 8mg @ 9 PM Naltrexone Placebo will be taken from day 1 to day 42 at 9 PM. Dose: 50 mg.	Drug: Prazosin; Prazosin Dosing Days 1-2: 1 mg @ 9PM Days 3-4: 1 mg @ 9AM, 3PM, 9PM Days 5-7: 2 mg @ 9AM, 3PM, 9PM Days 8-10: 2mg @ 9 AM, 3 PM; 8mg @ 9 PM Days 11-14: 4mg @ 9 AM, 3 PM; 8mg @ 9 PM Days 15-42: 4mg @ 9 AM, 3 PM; 8mg @ 9 PM; Other Names: Minipress; Drug: Placebo (Naltrexone); Placebo Dosing Days 1-42: 50mg @ 9PM; Other Names: Placebo
Active Comparator: Nal/Pl; Naltrexone and Placebo (Prazosin) Prazosin Placebo will be taken following this titration schedule: Days 1-2: 1 mg @ 9PM Days 3-4: 1 mg @ 9AM, 3PM, 9PM Days 5-7: 2 mg @ 9AM, 3PM, 9PM Days 8-10: 2mg @ 9 AM, 3 PM; 8mg @ 9 PM Days 11-14: 4mg @ 9 AM, 3 PM; 8mg @ 9 PM Days 15-42: 4mg @ 9 AM, 3 PM; 8mg @ 9 PM Naltrexone will be taken from day 1 to day 42 at 9 PM. Dose: 50 mg.	Drug: Naltrexone; Naltrexone Dosing Days 1-42: 50mg @ 9PM; Drug: Placebo (Prazosin); Placebo Dosing Days 1-2: 1 mg @ 9PM Days 3-4: 1 mg @ 9AM, 3PM, 9PM Days 5-7: 2 mg @ 9AM, 3PM, 9PM Days 8-10: 2mg @ 9 AM, 3 PM; 8mg @ 9 PM Days 11-14: 4mg @ 9 AM, 3 PM; 8mg @ 9 PM Days 15-42: 4mg @ 9 AM, 3 PM; 8mg @ 9 PM; Other Names: Placebo
Placebo Comparator: Pl/Pl; Placebo (Prazosin) and Placebo (Naltrexone) Prazosin Placebo will be taken following this titration schedule: Days 1-2: 1 mg @ 9PM Days 3-4: 1 mg @ 9AM, 3PM, 9PM Days 5-7: 2 mg @ 9AM, 3PM, 9PM Days 8-10: 2mg @ 9 AM, 3 PM; 8mg @ 9 PM Days 11-14: 4mg @ 9 AM, 3 PM; 8mg @ 9 PM Days 15-42: 4mg @ 9 AM, 3 PM; 8mg @ 9 PM Naltrexone Placebo will be taken from day 1 to day 42 at 9 PM. Dose: 50 mg.	Drug: Placebo (Naltrexone); Placebo Dosing Days 1-42: 50mg @ 9PM; Other Names: Placebo; Drug: Placebo (Prazosin); Placebo Dosing Days 1-2: 1 mg @ 9PM Days 3-4: 1 mg @ 9AM, 3PM, 9PM Days 5-7: 2 mg @ 9AM, 3PM, 9PM Days 8-10: 2mg @ 9 AM, 3 PM; 8mg @ 9 PM Days 11-14: 4mg @ 9 AM, 3 PM; 8mg @ 9 PM Days 15-42: 4mg @ 9 AM, 3 PM; 8mg @ 9 PM; Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Percent Drinking Days (PDD) (Visit 8 PDD - Visit 2 PDD)	PDD was calculated based on self-reported drinking history collected via Form-90. Drinking days were defined as days when participants consumed alcohol. Form-90 was completed by participants in visit 2 (baseline) and visit 8 (last visit). Form-90 collected in the baseline visit recorded participants' alcohol consumption from 90 days prior to their baseline visit until the day before their baseline visit. Form-90 collected in the last visit recorded participants' alcohol consumption from baseline until the day before their last visit. This outcome measures changes in PDD between visit 8 and visit 2. Per the protocol, visit 8 is scheduled to occur 42 days (± 7days) after visit 2. In reality, visit 8 occurred 35 to 76 days after visit 2 with the average of 45 days. The outliers were due to scheduling difficulties.	Visit 2 (baseline) and visit 8 (last visit). Per the protocol, visit 8 is scheduled to occur 42 days (± 7days) after visit 2. In reality, visit 8 occurred 35 to 76 days after visit 2 with the average of 45 days due to scheduling difficulties.
Change in Percent Heavy Drinking Days (PHDD) (Visit 8 PHDD - Visit 2 PHDD)	PHDD was calculated based on self-reported drinking history collected via Form-90. Heavy drinking days were defined as days when participants consumed 4 or more drinks for females and 5 or more drinks for males. Form-90 was completed by participants in the baseline and last visit. Form-90 collected in the baseline visit recorded participants' alcohol consumption 90 days prior to their baseline visit. Form-90 collected in the last visit recorded participants' alcohol consumption from baseline until the day before their last visit. This outcome measures changes in PHDD between visit 8 and visit 2. Per the protocol, visit 8 is scheduled to occur 42 days (± 7days) after visit 2. In reality, visit 8 occurred 35 to 76 days after visit 2 with the average of 45 days. The outliers were due to scheduling difficulties.	Visit 2 (baseline) and Visit 8 (last visit). Per the protocol, visit 8 is scheduled to occur 42 days (± 7days) after visit 2. In reality, visit 8 occurred 35 to 76 days after visit 2 with the average of 45 days due to scheduling difficulties.
Change in Alcohol Craving (Visit 8 PACS - Visit 2 PACS)	Alcohol craving was assessed in visit 2 (baseline) and the last visit (visit 8) using the Pennsylvania Alcohol Craving Scale (PACS). The PACS had 5 questions, where each question had six options presented in Likert Scales from 0 to 6, with 0 being the least and 6 being the highest possible option, thus the possible minimum and maximum values are 0 and 30, respectively. Higher scores mean higher craving. This outcome measures the change in PACS scores between visits 2 and 8 (visit 8 PACS score - visit 2 PACS score). Per the protocol, visit 8 is scheduled to occur 42 days (± 7days) after visit 2. In reality, visit 8 occurred 35 to 76 days after visit 2 with the average of 45 days. The outliers were due to scheduling difficulties.	Visit 2 (baseline) and visit 8 (last visit). Per the protocol, visit 8 is scheduled to occur 42 days (± 7days) after visit 2. In reality, visit 8 occurred 35 to 76 days after visit 2 with the average of 45 days due to scheduling difficulties.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Mean Drinks Per Day of Drinking (Visit 8 - Visit 2)	Average drinks per day of drinking was calculated based on self-reported drinking history collected via Form-90. Drinking days were defined as days when participants consumed alcohol. Form-90 was completed by participants in visit 2 (baseline) and visit 8 (last visit). Form-90 collected in the baseline visit recorded participants' alcohol consumption 90 days prior to their baseline visit. Form-90 collected in the last visit recorded participants' alcohol consumption from baseline until the day before their last visit. This outcome reports the change in the mean drinks between visit 8 and visit 2. Per the protocol, visit 8 is scheduled to occur 42 days (± 7days) after visit 2. In reality, visit 8 occurred 35 to 76 days after visit 2 with the average of 45 days. The outliers were due to scheduling difficulties.	Visit 2 (baseline) and visit 8 (last visit). Per the protocol, visit 8 is scheduled to occur 42 days (± 7days) after visit 2. In reality, visit 8 occurred 35 to 76 days after visit 2 with the average of 45 days due to scheduling difficulties.

Collaborators and Investigators

• Sponsor: Seattle Institute for Biomedical and Clinical Research
• Collaborators: United States Department of Defense; VA Puget Sound Health Care System
• Investigators: Principal Investigator: Tracy Simpson, Ph.D., VA Puget Sound Health Care System

Publications and helpful links

General Publications

• Simpson TL, Miller WR. Concomitance between childhood sexual and physical abuse and substance use problems. A review. Clin Psychol Rev. 2002 Feb;22(1):27-77. doi: 10.1016/s0272-7358(00)00088-x.
• Berk E, Black J, Locastro J, Wickis J, Simpson T, Penk W. Traumatogenicity: effects of self-reported noncombat trauma on MMPIs of male Vietnam combat and noncombat veterans treated for substance abuse. J Clin Psychol. 1989 Sep;45(5):704-8. doi: 10.1002/1097-4679(198909)45:53.0.co;2-6.
• Simpson TL, Westerberg VS, Little LM, Trujillo M. Screening for childhood physical and sexual abuse among outpatient substance abusers. J Subst Abuse Treat. 1994 Jul-Aug;11(4):347-58. doi: 10.1016/0740-5472(94)90045-0.
• McCann BS, Simpson TL, Ries R, Roy-Byrne P. Reliability and validity of screening instruments for drug and alcohol abuse in adults seeking evaluation for attention-deficit/hyperactivity disorder. Am J Addict. 2000 Winter;9(1):1-9. doi: 10.1080/10550490050172173.
• Simpson TL. Women's treatment utilization and its relationship to childhood sexual abuse history and lifetime PTSD. Subst Abus. 2002 Mar;23(1):17-30. doi: 10.1080/08897070209511472.
• Simpson TL. Childhood sexual abuse, PTSD, and the functional roles of alcohol use among women drinkers. Subst Use Misuse. 2003 Jan;38(2):249-70. doi: 10.1081/ja-120017248.
• Comtois KA, Tisdall WA, Holdcraft LC, Simpson T. Dual diagnosis: impact of family history. Am J Addict. 2005 May-Jun;14(3):291-9. doi: 10.1080/10550490590949479.
• Simpson TL, Kivlahan DR, Bush KR, McFall ME. Telephone self-monitoring among alcohol use disorder patients in early recovery: a randomized study of feasibility and measurement reactivity. Drug Alcohol Depend. 2005 Aug 1;79(2):241-50. doi: 10.1016/j.drugalcdep.2005.02.001. Epub 2005 Feb 25.
• Dobie DJ, Maynard C, Kivlahan DR, Johnson KM, Simpson T, David AC, Bradley K. Posttraumatic stress disorder screening status is associated with increased VA medical and surgical utilization in women. J Gen Intern Med. 2006 Mar;21 Suppl 3(Suppl 3):S58-64. doi: 10.1111/j.1525-1497.2006.00376.x.
• Bowen S, Witkiewitz K, Dillworth TM, Chawla N, Simpson TL, Ostafin BD, Larimer ME, Blume AW, Parks GA, Marlatt GA. Mindfulness meditation and substance use in an incarcerated population. Psychol Addict Behav. 2006 Sep;20(3):343-7. doi: 10.1037/0893-164X.20.3.343.
• Kaysen D, Simpson T, Dillworth T, Larimer ME, Gutner C, Resick PA. Alcohol problems and posttraumatic stress disorder in female crime victims. J Trauma Stress. 2006 Jun;19(3):399-403. doi: 10.1002/jts.20122.
• Simpson T, Jakupcak M, Luterek JA. Fear and avoidance of internal experiences among patients with substance use disorders and PTSD: the centrality of anxiety sensitivity. J Trauma Stress. 2006 Aug;19(4):481-91. doi: 10.1002/jts.20128.
• Simpson TL, Kaysen D, Bowen S, MacPherson LM, Chawla N, Blume A, Marlatt GA, Larimer M. PTSD symptoms, substance use, and vipassana meditation among incarcerated individuals. J Trauma Stress. 2007 Jun;20(3):239-49. doi: 10.1002/jts.20209.
• Kaysen D, Dillworth TM, Simpson T, Waldrop A, Larimer ME, Resick PA. Domestic violence and alcohol use: trauma-related symptoms and motives for drinking. Addict Behav. 2007 Jun;32(6):1272-83. doi: 10.1016/j.addbeh.2006.09.007. Epub 2006 Nov 13.

Study record dates

Study Major Dates

• Study Start (Actual): March 3, 2015
• Primary Completion (Actual): October 10, 2018
• Study Completion (Actual): October 10, 2018

Study Registration Dates

• First Submitted: December 17, 2014
• First Submitted That Met QC Criteria: December 17, 2014
• First Posted (Estimate): December 22, 2014

Study Record Updates

• Last Update Posted (Actual): December 29, 2020
• Last Update Submitted That Met QC Criteria: December 28, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Keywords: PTSD; Alcohol Dependence; Alcohol Drinking; Naltrexone; Addiction; Craving; Posttraumatic Stress Disorder; Substance Use Disorder; Substance Abuse; Alcohol Use Disorder; Alcohol Abuse; Prazosin; Substance Dependence; Alcohol Treatment; SUD; Adrenergic Antagonists; Drinking Behavior; Adrenergic Alpha-1 Receptor Antagonists; Adrenergic Alpha-Antagonists; mu-Opioid Receptor Antagonist; Opioid Antagonist; Pharmacology Treatment; AUD; Alcohol Addiction; Substance Addiction
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Pathologic Processes; Drinking Behavior; Alcohol-Related Disorders; Substance-Related Disorders; Trauma and Stressor Related Disorders; Alcohol Drinking; Alcoholism; Disease; Stress Disorders, Traumatic; Stress Disorders, Post-Traumatic; Physiological Effects of Drugs; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Peripheral Nervous System Agents; Sensory System Agents; Narcotic Antagonists; Alcohol Deterrents; Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Naltrexone; Prazosin
• Other Study ID Numbers: W81XWH-14-1-0025

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No