By Dr. Mark Gold and Dr. Lantie Jorandby
Alcohol Use Today
At least 95,000 people (approximately 68,000 men and 27,000 women) die from alcohol-related causes annually. According to NIAAA, alcohol is a major cause of death, disease, and disability currently ranked as the third leading preventable cause of death in the United States[i] . According to the recent SAMSHA survey[ii] reported by NSDUH, 14.1 million adults ages 18 and older2 (5.6 percent of this age group) have Alcohol Use Disorder( AUD). Almost 1 in 4 adults have had a heavy drinking event in the past year (five or more drinks for men and four or more drinks for women). The NIH and CDC report increasing alcohol problems, deaths, and AUDs. The number of death certificates mentioning alcohol has doubled, and alcohol plays a role in approximately 3% of all deaths in the United States. Increases in alcohol-related deaths are consistent with reports of increased alcohol sales, consumption, alcohol-involved emergency department visits, and hospitalizations[iii]. The most recent alcohol data provide more evidence of increasing heavy alcohol use and associated consequences during the COVID-19 pandemic. Increased alcohol use may also worsen medical and mental health problems.[iv]
The FDA's current pharmacological treatments for alcohol use disorders include Antabuse, acamprosate, and Naltrexone. These medications are safe and effective but do not help everyone. Most double-blind clinical trials reported in the literature support prescribing Naltrexone for alcohol dependence to reduce heavy drinking[v]. This finding is consistent with our understanding of Naltrexone's anti-opioid mechanism of action and decreasing excessive drinking by reducing the reward associated with drinking alcohol. Naltrexone, in this regard, is a harm-reducing medication with primary endpoints of heavy or excessive drinking. Still, the current medications for alcohol use disorders AUD, show only modest efficacy. Addiction researchers and psychiatrists have used Prazosin for nearly a decade in patients with alcohol use. This medication for high blood pressure (Prazosin; Minipress) has been tested for over a decade, and new research shows that it can help patients with alcohol use disorders, alcoholics, who have alcohol withdrawal symptoms reduce or eliminate their drinking, Rajita Sinha and her Yale University research colleagues report in the American Journal of Psychiatry[vi].
American Psychiatric Association May 2018
Recognizing that relapse prevention and harm-reducing medications are safe and effective in AUDs, fewer than 10% of patients with AUD are given a MAT. The rates of AUD are increasing the APA recommended pharmacological treatment for patients with AUDs. The meeting of APA experts suggestions are summarized in an AUD practice guidelines[vii] , but in summary, they suggested the following for specific medication use:
1. [Recommendation] Naltrexone or acamprosate should be offered to those patients with moderate to severe AUD that have a goal of reducing consumption or achieving abstinence, prefer pharmacotherapy, or have not responded to nonpharmacologic therapies, and have no contraindications.
2. [Suggestion] Disulfiram should be offered to patients with moderate to severe AUD that seek to achieve abstinence, prefer the therapy, or have not responded (or are intolerant) to Naltrexone or acamprosate, and have no contraindications. Additionally, patients must understand the risks associated with consuming alcohol while on disulfiram.
3. [Suggestion] Topiramate or gabapentin should be offered to patients with moderate to severe AUD when they aim to reduce or achieve abstinence, prefer the 2 to other medications, or have not responded Naltrexone or acamprosate and have no contraindications.
4. Benzodiazepines use was discouraged except in patients with AUD who require treatment for acute alcohol withdrawal[viii].
Alpha 1 Medications in AUD
None of these medications listed above specifically target brain noradrenergic pathways. Theory and preclinical evidence suggest that noradrenergic circuits are essential in stress-anxiety, alcohol relief, anxiety, and relapse. These thoughts and ideas led to testing the alpha-1 adrenergic receptor antagonist, Prazosin, as a new approach to MAT pharmacotherapy for AUD[ix]. In one early study of 80 patients, there was a significant interaction between Prazosin and the number of drinks and heavy drinking days for patients with AUDs. Experts thought that just adding this medication might have harm reduction effects like suggested previously for Naltrexone. Naltrexone does not stop alcohol consumption but reduces alcohol drinking and binge drinking[x]. The drinking rate, the probability of heavy drinking decreased, and improvements in AUD [xi] were found for Prazosin treatment rather than for the placebo condition. Prazosin may work by effects on alcohol-stress system interactions. In a recent Yale study, Prazosin reduced stress cue-induced alcohol craving, stress- and alcohol cue-induced anxiety. It lowered stress hormones (basal cortisol and ACTH) and attenuated stress cue-induced rises in cortisol versus placebo. Prazosin directly reduces stress cue-induced alcohol craving and anxiety during early abstinence. Prazosin also improves overall adrenergic and stress system functionality, independent of a history of lifetime anxiety disorders[xii].
Alcohol and Anxiety-Stress Systems
Chronic alcohol use results in changes to stress biology, irritability, and autonomic arousal. Alterations in stress pathways may explain the importance of stress-related mechanisms on wanting a drink, alcohol craving, and relapse susceptibility. During acute alcohol withdrawal symptoms, the brain and hormonal responses produced anxiety and heightened arousal, which increases craving and the risk of alcohol relapse. Flight or fight response systems, anxiety, and stress are important factors known to increase alcohol and drug relapse risk. Empirical findings from basic science, human laboratory, and brain-imaging studies support the specific role of stress processes in alcohol-craving states. Noradrenergic disruption may underlie the alcohol-related stress arousal changes in the brain that compromise sobriety. Alpha-1 adrenergic antagonists, such as Prazosin, may normalize these stress system adaptations, reduce alcohol craving, and reduce overall alcohol intake.
Brain imaging studies have shown considerable overlap in brain systems involved in processing stress , drug cues , reinforcement and reward . More recent research efforts have begun to identify the relationships between brain imaging and activity during stress and drug cue exposure, and drug relapse . Overall, researchers have shown that medial prefrontal, anterior and posterior cingulate, striatal, and posterior insula regions are associated with outcomes[xiii]. Altered function in these brain regions can be induced during the development of AUDs and exposed during stress-induced and drug cue-induced craving states . These increase susceptibility to relapse. Stress, alcohol cues, and dysregulated stress responses increase alcohol craving and relapse susceptibility. The Yale group reported preliminary efficacy study of the alpha-1 receptor antagonist, Prazosin, in modulating these relapse-relevant factors in alcohol-dependent individuals in 2002[xiv] helped lead the way in looking for novel treatments for patients with AUDs, which supported an alcohol dysregulated stress-craving system. The anti-hypertensive Prazosin could reduce stress-induced craving and improve responses to stress during detoxification and early abstinence. Prazosin does work, and recent reports by Sinha and her Yale group show it effectively decreases stress- and cue-induced alcohol craving. Prazosin also normalizes the stress-anxiety dysregulation during early recovery from alcoholism.