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Role of the ?1 blocker doxazosin in alcoholism: a proof-of-concept randomized controlled trial.

ABSTRACT: Evidence suggests that the norepinephrine system represents an important treatment target for alcohol dependence (AD) and the ?1 -blocker prazosin may reduce alcohol drinking in rodents and alcoholic patients. The ?1 -blocker doxazosin demonstrates a more favorable pharmacokinetic profile than prazosin, but has never been studied for AD. A double-blind placebo-controlled randomized clinical trial was conducted in AD individuals seeking outpatient treatment. Doxazosin or matched placebo was titrated to 16?mg/day (or maximum tolerable dose). Drinks per week (DPW) and heavy drinking days (HDD) per week were the primary outcomes. Family history density of alcoholism (FHDA), severity of AD and gender were a priori moderators. Forty-one AD individuals were randomized, 30 (doxazosin?=?15) completed the treatment phase and 28 (doxazosin?=?14) also completed the follow-up. There were no significant differences between groups on DPW and HDD per week. With FHDA as a moderator, there were significant FHDA?×?medication interactions for both DPW (pcorrected ?=?0.001, d?=?1.18) and HDD (pcorrected ?=?0.00009, d?=?1.30). Post hoc analyses revealed that doxazosin significantly reduced alcohol drinking in AD patients with high?FHDA and by contrast increased drinking in those with low?FHDA. Doxazosin may be effective selectively in AD patients with high?FHDA. This study provides preliminary evidence for personalized medicine using ?1 -blockade to treat AD. However, confirmatory studies are required.

SUBMITTER: Kenna GA

PROVIDER: S-EPMC4668239 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Role of the α1 blocker doxazosin in alcoholism: a proof-of-concept randomized controlled trial.

Kenna George A GA Haass-Koffler Carolina L CL Zywiak William H WH Edwards Steven M SM Brickley Michael B MB Swift Robert M RM Leggio Lorenzo L

Addiction biology 20150602 4

Evidence suggests that the norepinephrine system represents an important treatment target for alcohol dependence (AD) and the α1 -blocker prazosin may reduce alcohol drinking in rodents and alcoholic patients. The α1 -blocker doxazosin demonstrates a more favorable pharmacokinetic profile than prazosin, but has never been studied for AD. A double-blind placebo-controlled randomized clinical trial was conducted in AD individuals seeking outpatient treatment. Doxazosin or matched placebo was titra ...[more]

PMID: 26037245

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Project description:BackgroundEndocannabinoid dysfunction in animal models of autism spectrum disorder (ASD) and accumulating, albeit anecdotal, evidence for efficacy in humans motivated this placebo-controlled double-blind comparison of two oral cannabinoid solutions in 150 participants (age 5-21 years) with ASD.MethodsWe tested (1) BOL-DP-O-01-W, a whole-plant cannabis extract containing cannabidiol and ?9-tetrahydrocannabinol at a 20:1 ratio and (2) BOL-DP-O-01, purified cannabidiol and ?9-tetrahydrocannabinol at the same ratio. Participants (N?=?150) received either placebo or cannabinoids for 12-weeks (testing efficacy) followed by a 4-week washout and predetermined cross-over for another 12 weeks to further assess tolerability. Registered primary efficacy outcome measures were improvement in behavioral problems (differences between whole-plant extract and placebo) on the Home Situation Questionnaire-ASD (HSQ-ASD) and the Clinical Global Impression-Improvement scale with disruptive behavior anchor points (CGI-I). Secondary measures were Social Responsiveness Scale (SRS-2) and Autism Parenting Stress Index (APSI).ResultsChanges in Total Scores of HSQ-ASD (primary-outcome) and APSI (secondary-outcome) did not differ among groups. Disruptive behavior on the CGI-I (co-primary outcome) was either much or very much improved in 49% on whole-plant extract (n?=?45) versus 21% on placebo (n?=?47; p?=?0.005). Median SRS Total Score (secondary-outcome) improved by 14.9 on whole-plant extract (n?=?34) versus 3.6 points after placebo (n?=?36); p?=?0.009). There were no treatment-related serious adverse events. Common adverse events included somnolence and decreased appetite, reported for 28% and 25% on whole-plant extract, respectively (n?=?95); 23% and 21% on pure-cannabinoids (n?=?93), and 8% and 15% on placebo (n?=?94). Limitations Lack of pharmacokinetic data and a wide range of ages and functional levels among participants warrant caution when interpreting the results.ConclusionsThis interventional study provides evidence that BOL-DP-O-01-W and BOL-DP-O-01, administrated for 3 months, are well tolerated. Evidence for efficacy of these interventions are mixed and insufficient. Further testing of cannabinoids in ASD is recommended. Trial registration ClinicalTrials.gov: NCT02956226. Registered 06 November 2016, https://clinicaltrials.gov/ct2/show/NCT02956226.

Dataset Information

Role of the ?1 blocker doxazosin in alcoholism: a proof-of-concept randomized controlled trial.

Publications

Role of the α1 blocker doxazosin in alcoholism: a proof-of-concept randomized controlled trial.

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