Doxazosin an a1 Antagonist for Alcohol Dependence

Brown University

Status and phase

Completed

Early Phase 1

Conditions

Anxiety

Alcohol Dependence

Treatments

Drug: Doxazosin

Drug: Placebo

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT01437046

1R21AA019994-01A1 (U.S. NIH Grant/Contract)

1101000328

Details and patient eligibility

About

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.

Full 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.

Enrollment

41 patients

Sex

All

Ages

18 to 65 years old

Volunteers

No Healthy Volunteers

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.