Prazosin for the Treatment of Alcohol Use Disorders

Alcohol use disorder is one of the top behavioral causes of global disease burden and is among the most pressing public health concerns in the United States (1). A major factor contributing to this burden is the chronic, relapsing nature of the illness, with compulsive alcohol seeking and the inability to successfully reduce alcohol intake during treatment (2). While naltrexone, disulfiram, and acamprosate have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of alcohol use disorder, the efficacy of these medications is modest, and clinical utilization is low, making further pharmacotherapy development for alcohol use disorder a national priority (1). Furthermore, while naltrexone targets chronic alcohol-related brain opioid dysregulation, significant evidence suggests that chronic alcohol-related brain noradrenergic system dysfunction affects regulation of stress, arousal, and cognition. In particular, alcohol-related noradrenergic disruption is associated with alcohol withdrawal and been shown to promote stress-provoked alcohol seeking and drinking in animals (3) and humans (2). Thus, α-1 adrenergic receptor targets such as prazosin have been found, in animal studies, to reduce withdrawal-induced operant compulsive alcohol intake (4) and to reduce stress-induced reinstatement of alcohol seeking (5). In humans, preliminary data have supported these early findings with evidence that prazosin at 16 mg/day decreases stress-induced craving in individuals with alcohol use disorder (6) and, in a pilot alcohol use disorder treatment study, that it facilitates abstinence (7).

In this issue, Simpson and colleagues (8) follow up on their previous pilot work with a larger sample of 92 treatment-seeking patients with alcohol use disorder and without posttraumatic stress disorder (PTSD). The study did not require that participants be abstinent before starting in the study, and being on a stable dosage of an antidepressant was not an exclusion criterion. The medication was titrated up to 16 mg/day of prazosin (or placebo) over the course of 2 weeks and continued in a 12-week double-blind placebo-controlled treatment study. The study medication was self-administered in thrice-daily dosing, at 4 mg in the morning, 4 mg in the afternoon, and 8 mg at bedtime. Data on alcohol consumption were obtained over the 12-week treatment period using an interactive voice recording method, in which patients reported daily on alcohol consumption, craving, and medication adherence for the previous 24-hour period. All patients were also offered weekly medical management to emphasize medication adherence and attendance at self-help meetings. The primary outcome measures were number of drinking days per week, number of heavy drinking days per week, and average number of drinks per week. In addition, daily craving ratings and standing systolic and diastolic blood pressure were assessed for change over the study period as secondary outcome measures.

Intent-to-treat analyses with the 80 patients who remained in the study past the titration period indicated that prazosin as compared with placebo reduced the probability of heavy drinking days and number of drinks per week, with greater decreases over time, but there was no effect on number of drinking days per week. Despite patients in the prazosin group reporting having taken all three daily medication doses on significantly fewer days (54.7%) than those in the placebo group (69.7%) during treatment, the findings indicated that heavy drinking days decreased more rapidly in the prazosin group than in the placebo group from week 3 to week 12. For the prazosin group, the odds of heavy drinking were 0.85 times the odds of heavy drinking the previous week, compared with 0.95 for the placebo group. The reduction in average number of drinks per week was lower by 6.5 drinks in the prazosin group compared with the placebo group. However, the groups did not differ on either primary outcome in week 12. No medication effects on weekly craving were observed, and modest significant reductions in systolic but not diastolic blood pressure were seen in the prazosin group compared with the placebo group over the study period. Sensitivity analyses with the sample of participants who completed 70% or more of all study visits and whose urine samples were positive for the medication adherence trace indicator (riboflavin) showed similar findings.

These significant results support previous positive translational and clinical findings on noradrenergic receptor targets such as prazosin in the treatment of alcohol use disorder, with a particular positive effect for the treatment goal of harm reduction. On the other hand, the medication effect of a 10% difference between groups in the odds of reduction in heavy drinking relative to the previous week is fairly modest, particularly as there was no significant effect on number of drinking days and alcohol craving. The efficacy of FDA-approved treatments for alcohol use disorder remains modest in no small part because of significant variation among treatment-seeking patients with alcohol use disorder in critical features and comorbidities that may influence treatment response, including specific gene polymorphisms, illness severity and chronicity, withdrawal symptoms and associated stress, history of early trauma and adversity, co-occurring drug use, and other psychiatric illnesses. Identifying which FDA-approved medications may be most effective for specific types of patients with alcohol use disorder is an important personalized-medicine goal and one that constitutes a public health priority.

In previous work, our group found (9) that individuals with alcohol use disorder who had a higher severity of compulsive alcohol intake and alcohol use disorder symptoms showed greater stress-induced alcohol craving, which in turn predicted earlier relapse after inpatient treatment. This is consistent with prazosin’s effects on reducing withdrawal-related alcohol intake and stress-induced alcohol seeking (5, 6). Simpson et al. did not assess withdrawal symptoms and thus were not able specifically to examine prazosin’s efficacy in patients with significant withdrawal symptoms. Given the withdrawal-related effect on drinking, Haass-Koffler et al. (10) focused on the blood pressure hyperactivity aspect of alcohol withdrawal and reported in a pilot study that higher pretreatment blood pressure predicted greater reduction in alcohol intake with doxazosin, another α-1 adrenergic antagonist with a longer half-life than prazosin. Secondary analyses by Simpson et al. in the present study, however, did not support a greater benefit with prazosin for participants with higher blood pressure. These mixed results suggest that adrenergic hyperactivity as measured by blood pressure is not a significant marker of withdrawal-related drinking, but perhaps withdrawal-related distress and motor and cognitive dysfunction are more sensitive moderators of withdrawal-related alcohol intake. Future studies may benefit from specifically assessing alcohol withdrawal symptoms to target withdrawal-related compulsive alcohol intake in alcohol use disorder with noradrenergic agents such as prazosin.

Given reports of prazosin’s beneficial effects in PTSD, the suggestion that this agent may be particularly helpful for patients with comorbid alcohol use disorder and PTSD has also been tested, by Petrakis et al. (11), in a U.S. veteran sample, but the study failed to show positive findings. Key differences between the Petrakis et al. and Simpson et al. studies are that in the former, more psychiatric medications were allowed and a minimum 2-day abstinence period was required. Thus, it is possible that prazosin’s efficacy in the Petrakis et al. study was hampered by permitting use of other psychiatric medications that may have had additional noradrenergic action and could have blocked prazosin’s specific efficacy on alcohol intake.

In summary, while previous work indicates noradrenergic involvement in the pathophysiology of alcohol use disorder and treatment with α-1 adrenergic agents such as prazosin shows significant promise for medication development in alcohol use disorder, given the moderate effect size and some mixed findings, it is critical that key moderators of the positive effect be identified and tested. It appears that individuals with alcohol use disorder who have withdrawal-related alcohol intake may be those likely to benefit the most from prazosin treatment. Further testing and development of this key moderator could enhance personalized-medicine approaches in the treatment of alcohol use disorders.