Repurposing alpha1 Noradrenergic Antagonists for Alcoholism Treatment

Double-blind, placebo-controlled, cross-over design study examining the effects of a norepinephrine alpha1 receptor antagonist (prazosin) on stress reactivity in a laboratory stressor task.

Study Overview

• Status: Completed
• Conditions: Alcoholism
• Intervention / Treatment: Drug: Placebo; Drug: Prazosin

Detailed Description

OBJECTIVES

The first objective of the current study is to examine norepinephrine alpha1 (NE-alpha1) receptor involvement in reactivity to unpredictable stressors in humans, by using the NPU stress task in conjunction with an alpha1-blocker, prazosin. The second objective of the study is to provide preliminary evidence that prazosin is effective at reducing stress-reactivity in alcoholics in early abstinence.

PARTICIPANTS

Sixty-four healthy adult participants and sixty-four participants with an Alcohol Use Disorder in early abstinence.

STUDY OVERVIEW

Sixty-four healthy adult participants (32 males & 32 females) will be recruited to participate in a double-blind, placebo-controlled, cross-over design study examining the effects of a NE-alpha1 antagonist (prazosin) on the defensive (physiological and self-report affect) response to stressors using a well-validated animal-human translational stressor task. Participants will complete two overnight study visits where 2 mg prazosin and placebo are administered on separate visits separated by approximately 7 days. Drug order is randomly assigned and counterbalanced across participants (double-blind; study visits 1-2). On each of these two study visits, participants will complete the No Shock, Predictable Shock, Unpredictable Shock (NPU) task 90 minutes after drug administration. The NPU task is designed to examine stress reactivity to predictable and unpredictable stressors (i.e., electric shock). These two visits provide for a within-subject evaluation of the effect of acute antagonism of alpha1-NE receptors (via prazosin) to investigate the role of this NE mechanism in unpredictable (vs. predictable) stressor response.

After the full healthy adult/control sample has completed the study, the investigators will conduct preliminary data analysis to evaluate the first study hypothesis. These analyses are used to evaluate the sensitivity of the NPU task to NE-alpha1 mechanisms and its potential utility as an early surrogate endpoint for stress-related relapse mechanisms in alcoholism. The investigators will only recruit the sample of sixty-four alcoholic participants to complete the study if the first hypothesis is initially supported with healthy controls. These participants will meet Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) criteria for Alcohol Use Disorder (at least moderate severity) and be in early abstinence (1-8 weeks). All other study procedures will be identical for this sample.

OUTCOME MEASURES

The primary outcome is startle potentiation during the NPU task and the secondary outcome is self-reported retrospective fear/anxiety during the NPU task.

HYPOTHESES

1. Prazosin (2mg vs. placebo) will reduce stress reactivity to unpredictable (vs. predictable) stressors measured via startle potentiation and self-report.
2. Abstinent alcoholics (vs. controls) will display elevated stress reactivity to unpredictable (vs. predictable) stressors measured via startle potentiation and self-report.
3. The predicted effects of prazosin on reducing stress reactivity to unpredictable (vs. predictable) stressors (Hypothesis 1) measured via startle potentiation and self-report will be moderated by alcoholism, such that the effects of prazosin will be larger in abstinent alcoholics than control participants.

• Study Type: Interventional
• Enrollment (Actual): 70
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Wisconsin
    • Madison, Wisconsin, United States, 53706
      • University of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

INCLUSION CRITERIA: All Participants

• Can read and write in English.
• Ages of 18-50 years.

INCLUSION CRITERIA: Control Participants

• No current or lifetime history of Substance Use Disorder (except tobacco).

INCLUSION CRITERIA: Alcoholic Participants

• Current Alcohol Use Disorder with 1-8 weeks completely free from alcohol consumption.

Exclusion criteria are divided into three broad categories of Medical, Psychiatric/Behavioral, and Medications/Therapies.

EXCLUSION CRITERIA: Medical

• Colorblind
• Blood alcohol concentration (BAC) > 0.00
• Systolic BP <100 after five minutes seated.
• Systolic BP drop >20 mmHg after two minutes standing.
• Systolic BP drop >10 mgHg AND report dizziness, lightheadedness, unsteadiness or other problems (e.g, nausea, blurry vision) after two minutes standing.
• Heart rate >100 beats/ minute after two minutes seated.
• Heart rate <60 beats/ minute after two minutes seated.
• Scheduled for cataract surgery prior to study completion.
• Past or current coronary artery disease, cerebrovascular accident, congestive heart failure.
• Current renal insufficiency, liver insufficiency, pancreatitis, immunosuppressive therapy, or cancer with systemic effects or therapy.
• Benign positional vertigo, Meniere's disease or narcolepsy
• Current diabetes or polyneuropathy
• Previous allergic or adverse reaction to prazosin or other alpha1 norepinephrine antagonist.
• Other self-reported acute or unstable illness that, in the opinion of the study team, would preclude a safe and reliable study participation.

EXCLUSION CRITERIA: Female Participants Only

• Non-negative urine pregnancy test.
• Women of childbearing potential (see definition below) must agree to use one of the following forms of birth control until after study completion. Acceptable birth control is defined as the following methods of contraception: abstinence; hormonal contraceptives (e.g. combined oral contraceptives, patch, vaginal ring, injectables, and implants); intrauterine device (IUD) or intrauterine system (IUS); vasectomy of partner and tubal ligation; "single" barrier methods of contraception (e.g. male condom, female condom, cervical cap, diaphragm, contraceptive sponge) with use of spermicide; or "double barrier" method of contraception (e.g. male condom with diaphragm, male condom with cervical cap).
• Breastfeeding

NOTE: Women of childbearing potential are females who have experienced menarche and do not meet the criteria for women not of childbearing potential. Women not of childbearing potential are females who are permanently sterile (e.g., hysterectomy, bilateral oophorectomy) or postmenopausal. Postmenopausal is defined as 12 consecutive months with no menses without an alternative medical cause.

EXCLUSION CRITERIA: Psychological/Behavioral Exclusion

• Self-reported lifetime diagnosis of schizophrenia, schizoaffective disorder, psychotic disorder not otherwise specified (NOS), bipolar disorder, borderline personality disorder, or any neurocognitive disorder.

EXCLUSION CRITERIA: Medications/Therapies

• Currently prescribed or used within 72 hours: prazosin or other alpha1-NE antagonist (e.g., doxazosin, terazosin).
• Previous adequate trial of prazosin for alcohol use disorder or PTSD.
• Currently prescribed or used within 72 hours: Stimulants (e.g., d-amphetamine, methylphenidate) or alternative medications with stimulant properties (e.g., ephedra, pseudoephedrine).
• Currently prescribed or used within 72 hours: Sildenafil (Viagra), tadalafil (Cialis), or vardenafil (Levitra).
• Currently prescribed or used within 72 hours: beta-blockers (e.g., propranolol), alpha2 agonists (e.g., clonidine, guanfacine), or Serotonin-norepinephrine reuptake inhibitor (SNRI) anti-depressants (e.g., venlafaxine, duloxetine).
• Currently used daily or used within 72 hours: alpha1 agonists (e.g., midodrine, metaraminol, oxymetazoline, phenylephrine).
• Currently used daily or used within 72 hours: Benzodiazepines (e.g., diazepam, chlordiazepoxide, lorazepam, clonazepam, alprazolam), zolpidem (Ambien), zaleplon (Sonata), zopiclone (Imovane), eszopiclone (Lunesta), doxepin (Silenor).
• Currently prescribed and used daily or used within 72 hours: Trazodone (males only)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: SCREENING
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Prazosin 1st visit, Placebo 2nd visit; All participants receive 2mg prazosin and placebo in a cross-over design (e.g., one pill per visit). The order of prazosin vs placebo is counterbalanced between subjects (e.g., half participants receive prazosin at study visit 1 and half participants receive placebo at study visit 1).	Drug: Placebo; Placebo; Drug: Prazosin; 2mg Prazosin
EXPERIMENTAL: Placebo 1st visit, Prazosin 2nd visit; All participants receive 2mg prazosin and placebo in a cross-over design (e.g., one pill per visit). The order of prazosin vs placebo is counterbalanced between subjects (e.g., half participants receive prazosin at study visit 1 and half participants receive placebo at study visit 1).	Drug: Placebo; Placebo; Drug: Prazosin; 2mg Prazosin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Startle Potentiation During Stress Reactivity Task.	The unpredictable shock and predictable shock startle response potentiation (vs. no shock) during the administration of the NPU stressor task. Values represent point estimate of effect from unadjusted general linear model analyses with 95% confidence intervals	7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Self-reported Anxiety Potentiation During Stress Reactivity Task.	After the No-shock, Predictable-shock, Unpredictable-shock (NPU) task participants retrospectively reported their anxiety/fear during each condition on a 5-point likert scale (1 = 'Not at all anxious/ fearful', 5 = 'Very anxious/fearful'). The startle response is a defensive reflex that is elicited by an auditory stimuli (e.g., 50ms white noise) and measured via eyeblink electromyogram (EMG) activity over the obicularis oculi muscle. Startle potentiation is calculated as the increase in startle during unpredictable and predictable stressors relative to a no-stressor condition in the NPU task. Outcome is anxiety potentiation during unpredictable shock and predictable shock (vs. no-shock) conditions. This was assessed with a single question, total possible range was 1-5.	7 days

Collaborators and Investigators

• Sponsor: University of Wisconsin, Madison
• Collaborators: National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Publications and helpful links

Helpful Links

• Dr. John Curtin's Addiction Research Center

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 1, 2016
• Primary Completion (ACTUAL): March 12, 2018
• Study Completion (ACTUAL): March 12, 2018

Study Registration Dates

• First Submitted: November 15, 2016
• First Submitted That Met QC Criteria: November 16, 2016
• First Posted (ESTIMATE): November 17, 2016

Study Record Updates

• Last Update Posted (ACTUAL): May 28, 2019
• Last Update Submitted That Met QC Criteria: May 2, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Keywords: Anxiety; Stress; Alcoholism; Fear; Norepinephrine; Prazosin; Startle Potentiation
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Alcohol-Related Disorders; Substance-Related Disorders; Alcoholism; 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: 2014-0966 (Other Identifier: M D Anderson Cancer Center); F31AA022845-01 (NIH); Kaye2 (OTHER: Study Team)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The investigators will share on Open Science Framework de-identified and anonymous physiology (e.g., Electromyography (EMG) startle response) and self-report survey/questionnaire data collected from participants during the study.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No