Double-Blind Randomized Clinical Trial of Prazosin for Alcohol Use Disorder

Simpson, Tracy L.; Saxon, Andrew J.; Stappenbeck, Cynthia A.; Malte, Carol A.; Lyons, Robert; Tell, Dana; Millard, Steven P.; Raskind, Murray A.

doi:10.1176/appi.ajp.2018.17080913

Cited by 67 publications

(41 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…stress reactivity, measured via startle response and self-reported anxiety. These findings join with recent failures to replicate the treatment effects of prazosin for PTSD and AUD, suggesting the possibility that prazosin is a far less promising intervention for stress-related psychiatric disorders than originally believed (Petrakis et al 2016;Raskind et al 2018;Simpson et al 2018;Kleinman and Ostacher 2019). determination, and shock sensitivity assessment.…”

Section: Future Directions and Conclusionsupporting

confidence: 56%

Acute prazosin administration does not reduce stressor reactivity in healthy adults

Kaye¹,

Fronk²,

Zgierska³

et al. 2018

Preprint

View full text Add to dashboard Cite

Rationale: Norepinephrine plays a critical role in the stress response. Clarifying the psychopharmacological effects of norepinephrine manipulation on stress reactivity in humans has important implications for basic neuroscience and treatment of stress-related psychiatric disorders, such as posttraumatic stress disorder and alcohol use disorders. Preclinical research implicates the norepinephrine alpha-1 receptor in responses to stressors. The No Shock, Predictable Shock, Unpredictable Shock (NPU) task is a human laboratory paradigm that is well positioned to test crossspecies neurobiological stress mechanisms and advance experimental therapeutic approaches to clinical trials testing novel treatments for psychiatric disorders. Objectives:We hypothesized that acute administration of prazosin, a noradrenergic alpha-1 antagonist, would have a larger effect on reducing stress reactivity during unpredictable, compared to predictable, stressors in the NPU task. Methods:We conducted a double-blind, placebo-controlled, crossover randomized controlled trial in which sixty-four healthy adults (32 female) completed the NPU task at two visits (2mg prazosin vs. placebo). Results:A single acute dose of 2mg prazosin did not reduce stress reactivity in a healthy adult sample.Neither NPU startle potentiation nor self-reported anxiety was reduced by prazosin (vs. placebo) during unpredictable (vs. predictable) stressors. Conclusions:Further research is needed to determine whether this failure to translate preclinical neuroscience to human laboratory models is due to methodological factors (e.g., acute vs. chronic drug administration, brain penetration, study population) and/or suggests limited clinical utility of noradrenergic alpha-1 antagonists for treating stress-related psychiatric disorders.

show abstract

Section: Future Directions and Conclusionsupporting

confidence: 56%

Acute prazosin administration does not reduce stressor reactivity in healthy adults

Kaye¹,

Fronk²,

Zgierska³

et al. 2018

Preprint

View full text Add to dashboard Cite

show abstract

“…For example, Simpson et al . investigated the effect of prazosin, an α‐1 adrenergic receptor antagonist, on alcohol consumption in patients with alcohol use disorder by randomizing 92 study participants to receive either prazosin or placebo over a 12‐week period. Results from such RCTs are used to establish the standard of care for patients with substance use disorders and are cited as high‐quality supporting evidence for clinical practice guideline recommendations .…”

Section: Introductionmentioning

confidence: 99%

Evaluation of selective outcome reporting and trial registration practices among addiction clinical trials

et al. 2020

View full text Add to dashboard Cite

Background and Aims Selective outcome reporting occurs when trialists pre-specify primary and secondary outcomes during trial planning but alter the definitions in the published report. Here, we investigate selective outcome reporting in published addiction randomized controlled trials (RCTs) and evaluate whether particular funding sources are associated with an increased likelihood of selective outcome reporting. Design We conducted a cross-sectional study of published addiction clinical trials. A PubMed search was performed to identify RCTs in addiction journals from 2013 to 2017. Included studies used a randomized design to address one of the following topics: (1) drug, alcohol and tobacco addiction prevention, (2) stabilization following excessive use of a substance, (3) relapse prevention or (4) recovery maintenance.Setting Single-center, medical research institution. Participants Our sample included 162 RCTs that were prospectively registered with a clearly defined primary outcome. Measurement We extracted the following items from addiction RCTs: journal, funding source, trial registry number (if included), sample size, dates of subject enrollment, whether primary and secondary outcomes were denoted, all published outcomes, P-value for all outcomes and whether authors mentioned any deviations from the trial protocol as it related to RCT outcomes. Findings In total, 47 of 162 RCTs (29.0%) had at least one major discrepancy between the trial registry and published RCT. Overall, these 47 RCTs included 54 major discrepancies. The most common major discrepancy was demotion of a primary registered outcome (19/54, 35.2%). The majority of RCTs (132/162, 81.5%) were funded from public sources. Additionally, 166 RCTs were excluded from our sample because registration could not be confirmed. Conclusions There is evidence suggestive of selective outcome reporting in addiction randomized controlled trials (RCTs). The most common major discrepancies pertained to the primary outcome.

show abstract

“…However, a fourth small trial (N = 41) observed no effect of doxazosin on its primary clinical outcomes in patients with AUD (Kenna et al 2016). More importantly, two more recent studies of prazosin that used somewhat larger sample sizes (N = 92-96) observed no effects on similar primary clinical outcomes in patients with AUD (Petrakis et al 2016, Simpson et al 2018). These latter null findings somewhat temper optimism for this class of medications to treat stress-induced relapse in humans (Kaye et al 2019).…”

Section: Stress-relevant Pharmacologic Treatmentsmentioning

confidence: 97%

“…Research from animal models suggested that the NE system was another natural pharmacologic target to reduce stress-induced relapse in humans (Kaye et al 2017, Verplaetse et al 2015. However, the null findings from two recent clinical trials of prazosin (Petrakis et al 2016, Simpson et al 2018 have somewhat tempered optimism for this class of medications to treat stress-induced relapse in humans. Prazosin also may not reduce CNS allostasis in response to either unpredictable or predictable shock as might have been expected from animal models (Kaye et al 2019).…”

Section: State Of the Evidencementioning

confidence: 99%

Stress Allostasis in Substance Use Disorder: Promise, Progress, and Emerging Priorities

Fronk¹,

Sjk²,

Jt³

et al. 2020

Preprint

View full text Add to dashboard Cite

Clinicians and researchers alike have long believed that stressors play a pivotal etiologic role in risk, maintenance, and/or relapse of alcohol and other substance use disorders (SUDs). Numerous seminal and contemporary theories on SUD etiology posit that stressors may motivate drug use and that individuals who use drugs chronically may display altered responses to stressors. We use foundational basic stress biology research as a lens through which to evaluate critically the available evidence to support these key stress-SUD theses in humans. Additionally, we examine the field’s success to date in targeting stressors and stressor allostasis in treatments for SUDs. We conclude with our recommendations for how best to advance our understanding of the relationship between stressors and drug use, and we discuss clinical implications for treatment development.

show abstract

Double-Blind Randomized Clinical Trial of Prazosin for Alcohol Use Disorder

Abstract: Prazosin holds promise as a harm-reduction pharmacologic treatment for alcohol use disorder and deserves further evaluation by independent research groups.

Cited by 67 publications

References 39 publications

Acute prazosin administration does not reduce stressor reactivity in healthy adults

Acute prazosin administration does not reduce stressor reactivity in healthy adults

Evaluation of selective outcome reporting and trial registration practices among addiction clinical trials

Stress Allostasis in Substance Use Disorder: Promise, Progress, and Emerging Priorities

Contact Info

Product

Resources

About