Alcoholism
Conditions
Keywords
Alcoholism, Prazosin, Startle Potentiation, Norepinephrine, Anxiety, Fear, Stress
Brief summary
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.
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.
Interventions
DRUGPrazosin
2mg Prazosin
DRUGPlacebo
Placebo
Sponsors
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
University of Wisconsin, Madison
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
SCREENING
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Startle Potentiation During Stress Reactivity Task. | 7 days | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Self-reported Anxiety Potentiation During Stress Reactivity Task. | 7 days | 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. |
Countries
United States
Participant flow
Pre-assignment details
In order to enroll 64 participants with valid data, 70 participants were randomized to account for 4 lost early in study flow (one data collection error, two startle non-responders, and one withdrawn after visit 1).
Participants by arm
| Arm | Count |
|---|---|
| All Participants Who Completed the Study 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).
Results are to be reported by treatment (placebo vs prazosin) each of which include results for all participants. Therefore we report baseline characteristics for the entire group. | 64 |
| Total | 64 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | data acquisition error | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | startle non-responder | 1 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | All Participants Who Completed the Study |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 64 Participants |
| Age, Continuous | 23 years STANDARD_DEVIATION 5.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 59 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 12 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 6 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 41 Participants |
| Region of Enrollment United States | 64 participants |
| Sex: Female, Male Female | 32 Participants |
| Sex: Female, Male Male | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 64 | 0 / 64 |
| other Total, other adverse events | 30 / 64 | 3 / 64 |
| serious Total, serious adverse events | 0 / 64 | 0 / 64 |
Outcome results
Primary
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
Time frame: 7 days
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Prazosin 2mg Trials | Startle Potentiation During Stress Reactivity Task. | Predictable Shock | 45.7 startle potentiation (μV) |
| Prazosin 2mg Trials | Startle Potentiation During Stress Reactivity Task. | Unpredictable Shock | 33.2 startle potentiation (μV) |
| Placebo Trials | Startle Potentiation During Stress Reactivity Task. | Predictable Shock | 40.1 startle potentiation (μV) |
| Placebo Trials | Startle Potentiation During Stress Reactivity Task. | Unpredictable Shock | 25.2 startle potentiation (μV) |
Secondary
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.
Time frame: 7 days
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Prazosin 2mg Trials | Self-reported Anxiety Potentiation During Stress Reactivity Task. | Predictable Shock | 2.0 units on a scale |
| Prazosin 2mg Trials | Self-reported Anxiety Potentiation During Stress Reactivity Task. | Unpredictable Shock | 2.3 units on a scale |
| Placebo Trials | Self-reported Anxiety Potentiation During Stress Reactivity Task. | Predictable Shock | 2.1 units on a scale |
| Placebo Trials | Self-reported Anxiety Potentiation During Stress Reactivity Task. | Unpredictable Shock | 2.4 units on a scale |