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Prazosin for Harm Reduction in Alcohol Use Disorder?



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


Increasing doses of prazosin reduced heavy drinking, but adverse effects were common.

In some patients with post-traumatic stress disorder (PTSD), the alpha-1 noradrenergic blocker prazosin has been helpful for nightmares and, in open-label studies, has decreased stress reactivity, alcohol craving, and alcohol use. The alpha-1 noradrenergic blocker doxazosin has also been found to be useful for alcohol and other substance use disorders. These investigators conducted a randomized, placebo-controlled, double-blind, 12-week study of prazosin for alcohol use disorder in 92 outpatients without PTSD (mean age, 48; 79% men).

Participants averaged >67% heavy drinking days and 12 drinks per drinking day in the prior 90 days. After two 1-mg bedtime test doses, prazosin and placebo were up-titrated, depending on adverse effects, over 2 weeks; prazosin targets were 4 mg in the morning, 4 mg in the afternoon, and 8 mg at bedtime. Twelve patients dropped out during titration; of the 80 completers, 70 reached the target dose. The prazosin group took ≥1 dose on a mean of 65% of days and all 3 doses on 55% of days.

Prazosin was associated with self-reported fewer heavy drinking days and fewer drinks per week (–8 vs. –1.5 with placebo); differences in drinks per week accelerated after 8 weeks. Drinking days per week and craving showed no group differences. Mean systolic blood pressure decreased by 3.5 mm Hg with prazosin. Frequent adverse effects with prazosin were drowsiness (64% vs. 31% with placebo) and edema (20% vs. 4%). Symptomatic (1 patient in each group) and asymptomatic orthostatic hypotension did not differ between groups.



Evidence suggests that elevated brain noradrenergic activity
appears to be involved in the initiation and maintenance of
alcohol use disorder (1, 2). A clinically feasible approach to
reducing brain noradrenergic activity is to reduce activation
by norepinephrine at the postsynaptic a-1 adrenoceptor.
Prazosin is a clinically available lipid-soluble a-1 adrenoceptor
antagonist that reduces brain a-1 adrenoceptor–
mediated signaling when administered peripherally (3). In
rodents, prazosin has been shown to decrease withdrawalinduced
alcohol intake (4), alcohol drinking by alcoholpreferring
(P) rats (2), and stress-induced alcohol seeking
(5), and it has been shown to block yohimbine-induced reinstatement
of alcohol seeking (6). In human alcohol use disorder
studies, prazosin has been shown to reduce reactivity
to stress and to result in reduced craving (7), reduced drinks
per week (8, 9), and reduced drinking days per week (8). In
persons with DSM-IV alcohol dependence and comorbid
posttraumatic stress disorder (PTSD), one study found that
prazosin reduced drinking but not PTSD outcomes (10), and
another study found no prazosin effect on either outcome (11).
Doxazosin, another a-1 adrenoceptor antagonist, did
not outperform placebo on drinking outcomes in a study of alcohol treatment seekers, but among those with a high family
history density of alcohol problems, the active medication
was associated with improved drinking outcomes (12). Across
the entire sample, alcohol treatment seekers with higher
standing diastolic blood pressure receiving active medication
had better outcomes than those receiving placebo (13).
After obtaining positive results in a pilot study (8), we
conducted a 12-week randomized controlled trial comparing
prazosin and matched placebo in 92 participants who met
diagnostic criteria for alcohol use disorder but not PTSD.
Individuals with PTSD were excluded because there is evidence
that prazosin reduces symptoms of PTSD (14), and we
were interested in isolating the effects of prazosin on drinking
alone in light of evidence linking excessive drinking to
stress and the adrenergic system. Both treatment arms included
medical management (15), and daily symptoms were
monitored via a telephone-based interactive voice response
system to obtain close to real-time data regarding alcohol
consumption. Our primary hypotheses were that prazosin
would lead to a decreased likelihood over time of any drinking
and of heavy drinking (i.e., $4 drinks for women, $5 drinks
for men) as well as a decrease in number of drinks consumed.



These results indicate that prazosin has the potential to
reduce the likelihood of heavy drinking and number of
drinks per week over time but not the number of drinking
days per week. They suggest that prazosin may be most
useful in reducing heavy drinking associated with negative
consequences (29), which is consistent with a harm reduction
approach characterized by safer consumption rather
than full abstinence.

 In addition to reducing rodent self-administration of
alcohol (33), prazosin compared with vehicle has also been
shown to reduce self-administration of cocaine (34), heroin
(35), and nicotine (36). In humans, the previous positive pilot
studies of prazosin for alcohol use disorder (8, 10) and the
present study provide preliminary support for an effect of
prazosin on heavy drinking and number of drinks per week.
Another a-1 antagonist, doxazosin, has shown a signal for
reducing drinking in alcohol-dependent individuals who
have a positive family history of alcohol problems (12).
Doxazosin has also been found to reduce cocaine use in
cocaine-dependent individuals compared with placebo (37)





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