Moderation of Prazosin’s Efficacy by Alcohol Withdrawal Symptoms

Sinha, Rajita; Wemm, Stephanie; Fogelman, Nia; Milivojevic, Verica; Morgan, Peter M; Angarita, Gustavo A.; Hermes, Gretchen; Fox, Helen

doi:10.1176/appi.ajp.2020.20050609

Cited by 49 publications

(55 citation statements)

References 35 publications

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“…For example, a recent meta-regression analysis of randomized controlled trials (RCTs) for alcohol dependence (AD) revealed that baseline drinking risk levels and pretreatment abstinence duration profoundly influence alcohol-related responses to placebo (Scherrer et al, 2021), resulting in increased variability in the control group and decreased statistical power to detect an effect of the experimental drug. Other findings supporting the power of stratifying subjects in AUD research come from recent randomized clinical trials, in which the efficacies of prazosin (Sinha et al, 2021) and gabapentin (Anton et al, 2020) to treat AUD symptoms were significantly moderated by AWS severity (i.e., low vs high). Thus, in this study we show that a score computed from the combined outcomes of various behavioral tests can be used to define strata and determine the severity of the withdrawal "syndrome" in mice chronically exposed to alcohol.…”

Section: The Presence Of Subpopulations Suggests Different Sensitivit...mentioning

confidence: 97%

Behavioral characterization of withdrawal following chronic voluntary ethanol consumption via intermittent two‐bottle choice points to different susceptibility categories

Cardé

Biasi

2022

Alcoholism Clin & Exp Res

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Background Alcohol is among the most commonly abused drugs worldwide. Cessation of chronic alcohol consumption can result in the appearance of withdrawal symptoms that commonly promote relapse in individuals with alcohol use disorder (AUD). Thus, preclinical models of voluntary alcohol consumption, in which animals manifest spontaneous signs of withdrawal after alcohol cessation, can be useful for studying AUD and its treatment. The intermittent two‐bottle choice paradigm (I2BC) has been used extensively to examine alcohol intake in rodents. However, previous studies have reported conflicting observations regarding its potential to result in the spontaneous manifestation of withdrawal upon alcohol cessation. Methods We employed a battery of behavioral tests to examine the emergence of affective and physical signs of withdrawal in female and male mice exposed to alcohol in the I2BC for 10 weeks. Specifically, mice of both sexes undergoing 24‐h withdrawal from the I2BC were tested for physical signs of withdrawal, anxiety‐like behavior in the open field arena (OFA) and elevated plus maze (EPM), and anxiety/compulsive‐like behavior in the marble burying test (MBT). The main outcomes from these tests were combined into a behavioral severity score to describe the overall behavioral phenotype. Results Both female and male mice undergoing withdrawal from the I2BC displayed elevated physical signs of withdrawal and anxiety‐associated behavior in the EPM and MBT. Analysis of the overall behavioral severity score revealed more severe phenotypes in female and male mice undergoing withdrawal from the I2BC than controls. Additionally, stratification of the mice based on severity scores demonstrated a differential distribution of severities between the exposure groups. Conclusions We confirmed that a significant fraction of mice chronically exposed to alcohol in the I2BC display spontaneous withdrawal. In addition, we showed that computing a severity score from a combination of behavioral metrics can be useful in preclinical research to model evaluation tools used in patients with AUD.

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Section: The Presence Of Subpopulations Suggests Different Sensitivit...mentioning

confidence: 97%

Behavioral characterization of withdrawal following chronic voluntary ethanol consumption via intermittent two‐bottle choice points to different susceptibility categories

Cardé

Biasi

2022

Alcoholism Clin & Exp Res

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“…However, further examination of clinical moderators revealed that doxazosin significantly reduced drinks per week and heavy-drinking days among individuals with higher family history of AUD and higher standing diastolic blood pressure [209]. Similarly, moderator analyses from a 12-week RCT of prazosin (N = 100) found that one's degree of alcohol withdrawal symptoms predicted clinical response, such that participants with high levels of withdrawal symptoms benefited the most from treatment (e.g., reduced craving and heavy-drinking days; improved mood symptoms) [210]. A small meta-analysis of 6 studies with a total of 319 participants tested the effectiveness of drugs acting on adrenergic receptors for AUD and found a significant treatment effect of prazosin and doxazosin on alcohol consumption but not abstinence [211].…”

Section: Prazosin and Doxazosinmentioning

confidence: 99%

Novel Agents for the Pharmacological Treatment of Alcohol Use Disorder

Burnette

Nieto

Grodin

et al. 2022

Drugs

103

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Alcohol use disorder (AUD) is a highly prevalent but severely under-treated disorder, with only three widely-approved pharmacotherapies. Given that AUD is a very heterogeneous disorder, it is unlikely that one single medication will be effective for all individuals with an AUD. As such, there is a need to develop new, more effective, and diverse pharmacological treatment options for AUD with the hopes of increasing utilization and improving care. In this qualitative literature review, we discuss the efficacy, mechanism of action, and tolerability of approved, repurposed, and novel pharmacotherapies for the treatment of AUD with a clinical perspective. Pharmacotherapies discussed include: disulfiram, acamprosate, naltrexone, nalmefene, topiramate, gabapentin, varenicline, baclofen, sodium oxybate, aripiprazole, ondansetron, mifepristone, ibudilast, suvorexant, prazosin, doxazosin, N-acetylcysteine, GET73, ASP8062, ABT-436, PF-5190457, and cannabidiol. Overall, many repurposed and novel agents discussed in this review demonstrate clinical effectiveness and promise for the future of AUD treatment. Importantly, these medications also offer potential improvements towards the advancement of precision medicine and personalized treatment for the heterogeneous AUD population. However, there remains a great need to improve access to treatment, increase the menu of approved pharmacological treatments, and de-stigmatize and increase treatment-seeking for AUD.

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“…This rise in use shows patterns of racial disparity in overdose deaths and is exaggerated in people also using heroin and LSD. 1,2 Behavioral interventions other than contingency management have demonstrated poor efficacy in treating methamphetamine use disorder, 3 while barriers are considerable: limited Medicaid support, public stigma, and low motivation to seek treatment. 4 There are currently no FDA-approved treatments for stimulant use disorders.…”

Section: Symposium IImentioning

confidence: 99%

Symposia, Case Conference, and Medical Update

2021

American J Addict

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Moderation of Prazosin’s Efficacy by Alcohol Withdrawal Symptoms

Cited by 49 publications

References 35 publications

Behavioral characterization of withdrawal following chronic voluntary ethanol consumption via intermittent two‐bottle choice points to different susceptibility categories

Behavioral characterization of withdrawal following chronic voluntary ethanol consumption via intermittent two‐bottle choice points to different susceptibility categories

Novel Agents for the Pharmacological Treatment of Alcohol Use Disorder

Symposia, Case Conference, and Medical Update

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