Doxazosin an a1 Antagonist for Alcohol Dependence

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 designed 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.

Study Overview

• Status: Completed
• Conditions: Alcohol Dependence; Anxiety
• Intervention / Treatment: Drug: Doxazosin; Drug: Placebo

Detailed Description

Pre-clinical and clinical evidence has clearly demonstrated that the noradrenergic (NE) system is involved in the neurobiology of AD, thus representing an interesting new pharmacotherapy target and the theoretical rationale for this proposal. Consistent with the concept that the NE system may represent a new pharmacological target for AD, recent studies have shown that the prototype alpha-1 NE receptor antagonist prazosin reduces alcohol drinking in different animal models. Furthermore, clinical evidence has also confirmed that prazosin appears to be efficacious in reducing alcohol consumption in alcohol-dependent individuals. While prazosin has a significant side effect profile and must be taken three times a day, no other α1-blockers have been investigated in alcohol research. Prazosin is a short-acting α1-blocker approved to treat hypertension (HTN) and benign prostatic hyperplasia (BPH). After the approval of prazosin in the 70's, other selective α1-blockers have been developed to treat HTN and/or BPH. Among them, doxazosin has shown a more manageable and safer profile than prazosin. In fact, doxazosin is a long-acting α1-blocker, thus it is taken only once/day. Doxazosin is also less likely to give hypotensive side-effects. Thus, doxazosin is more commonly used in clinical practice to treat HTN and/or BPH, than short-acting α1-blockers, such as prazosin. Poor adherence to medications and/or side-effects represent important factors limiting the effectiveness of pharmacotherapies for patients with AD. If effective for AD, doxazosin may represent a simple, manageable and safe medication, which might be more easily transferable to clinical practice. However, doxazosin has never been tested in AD. This project is a 10-week, double-blind, placebo-controlled, between-subject randomized clinical trial with doxazosin (16mg once/day) in alcohol dependent (AD) individuals. This study attempts to address whether doxazosin is an effective and safe pharmacotherapy for AD.

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Brown University Center for Alcohol and Addiction Studies
    • Providence, Rhode Island, United States, 02912
      • Brown University Center for Alcohol and Addiction Studies

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• age ≥18
• females must be post-menopausal for ≥1 year, surgically sterile, or practicing a birth control before entry and throughout the study; have a negative urine pregnancy test at screening and before randomization
• good health (confirmed by medical history, physical, ECG, blood/urine labs)
• DSM-IV diagnosis of AD
• average of ≥4 drinks/d for women and ≥5 drinks/d for men during 30 days within the 90 days prior to screening
• desire to reduce or quit drinking.

Exclusion Criteria:

• females who are of child bearing potential and not practicing effective birth control
• lifetime DSM-IV diagnosis of schizophrenia, bipolar disorder, or other psychosis
• recent (past 6 months) DSM-IV diagnosis of any anxiety disorder or major depression
• in the investigators' opinion, risk of suicide (e.g. active plan, or recent attempt in last year)
• DSM-IV diagnosis of dependence on any psychoactive substance other than alcohol and nicotine
• positive urine screen for any illegal substance other than marijuana
• history of hospitalization for alcohol intoxication delirium, seizure or alcohol withdrawal delirium
• Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) score ≥10, at any assessment
• treatment with naltrexone, acamprosate, topiramate, disulfiram within 1 month prior to Wk 00
• current use of psychotropic medications or drugs that interfere with doxazosin's metabolism
• use of PDE5 inhibitor erectile dysfunction drugs (e.g. sildenafil)
• treatment with any antihypertensive drug and/or any α-blocker for BPH or sleep problems (e.g. trazodone)
• baseline hypotension
• history of allergy to any α-blocker
• contraindications to take doxazosin (history of fainting and/or syncopal attacks, heart failure, significant liver diseases)
• serious illnesses, e.g. kidney failure, epilepsy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Doxazosin; Doxazosin Capsule 16mg/day 10 weeks.	Drug: Doxazosin; Doxazosin were prepared as opaque capsules by a compounding pharmacy and inserted into blister packs. Consistent with the recommended titration, doxazosin was titrated up to 16 mg daily (or maximum tolerable dose) during the first 4 weeks. A 1-week downward titration for safety reasons was also planned. Study medication adherence was assessed by self-report and pill count. Additionally, capsules contained 25mg riboflavin as a marker of adherence through urine sample.; Other Names: Cardura
Placebo Comparator: Placebo; Placebo (lactose capsules designed to be the same as experimental drug given the same exact way over 10 weeks.	Drug: Placebo; Matched placebo were prepared as opaque capsules by a compounding pharmacy and inserted into blister packs. Consistent with the recommended titration, doxazosin or matched placebo was titrated up to 16 mg daily (or maximum tolerable dose) during the first 4 weeks. A 1-week downward titration for safety reasons was also planned. Study medication adherence was assessed by self-report and pill count. Additionally, capsules contained 25mg riboflavin as a marker of adherence through urine sample.; Other Names: Lactose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
drinking days per week (DDW)	whether doxazosin, as compared to placebo, decreases the number of drinking days per week (DDW), as measured by the timeline follow-back (TLFB). A drink is defined as a Standard Drinking Unit (SDU).	16 weeks
drinks per week (DPW)	whether doxazosin, as compared to placebo, decreases the number of drinks per week (DPW), measured by the TLFB	16 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
alcohol craving	whether doxazosin, as compared to placebo, results in diminished alcohol craving, as measured by the Obsessive Compulsive Drinking Scale (OCDS)	16 weeks
anxiety	whether doxazosin, as compared to placebo, results in diminished anxiety scores, measured by the Hamilton Anxiety Scale (HAMA).	16 weeks
Adverse Events	whether doxazosin, as compared to placebo, increases the frequency and intensity of Adverse Events (AE).	16 weeks

Collaborators and Investigators

• Sponsor: Brown University
• Collaborators: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
• Investigators: Principal Investigator: GEORGE A KENNA, PhD RPh, Brown University

Publications and helpful links

General Publications

• Kenna GA, Haass-Koffler CL, Zywiak WH, Edwards SM, Brickley MB, Swift RM, Leggio L. Role of the alpha1 blocker doxazosin in alcoholism: a proof-of-concept randomized controlled trial. Addict Biol. 2016 Jul;21(4):904-14. doi: 10.1111/adb.12275. Epub 2015 Jun 2.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2011
• Primary Completion (Actual): August 1, 2013
• Study Completion (Actual): March 1, 2015

Study Registration Dates

• First Submitted: September 19, 2011
• First Submitted That Met QC Criteria: September 19, 2011
• First Posted (Estimated): September 20, 2011

Study Record Updates

• Last Update Posted (Actual): August 18, 2025
• Last Update Submitted That Met QC Criteria: August 14, 2025
• Last Verified: February 1, 2016

More Information

Terms related to this study

• Keywords: Alcohol drinking; Alcohol craving
• Additional Relevant MeSH Terms: Mental Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Alcohol-Related Disorders; Alcoholism; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Agents; Adrenergic Agents; Antihypertensive Agents; Adrenergic Antagonists; Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Doxazosin
• Other Study ID Numbers: 1101000328; 1R21AA019994-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: email the PI to make arrangements for sharing the available database.

Drug and device information, study documents

• product manufactured in and exported from the U.S.: No