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.
When our group studied AUDs, we focused on the similarities between alcohol and other drugs of abuse on dopaminergic pathways. Like all drugs of abuse, alcohol releases dopamine, and we think that is the basis for much of alcohol's reinforcing effects. More recent evidence shows that alcohol also has endorphin or endogenous opioid stimulating effects and directly stimulates the hypothalamic-pituitary-adrenal (HPA) axis. Alcohol has a direct impact on glucocorticoid receptors in extrahypothalamic, limbic forebrain, and medial Prefrontal Cortex (PFC) circuits, which contribute to the development of AUDs and relapse.[xv]
Chronic alcohol use changes stress system controls and autonomic arousal contributing to acute alcohol withdrawal symptoms, stress-induced craving, and alcohol relapse risk. The hypothalamic-pituitary system (HPA) and prefrontal cortex become dysfunctional in AUD, activate, and continue to misfire during AUDwithdrawal. New studies suggest HPA axis dysfunction follow binge/heavy drinking. Alcohol-associated alterations in HPA axis responses to stress and alcohol regulates desire to drink alcohol. Resiliency, adjustment to novelty and threats, coping, and recovery from early alcohol abstinence can be undermined by stress system dysfunction. Researchers have thought that treatment that normalizes HPA axis functioning may prevent AUD relapse. Preclinical evidence reported by many labs and researchers has shown that noradrenergic disruption may contribute to these alcohol-related stress arousal changes and that alpha-1 adrenergic antagonists, such as Prazosin, may normalize these stress system adaptations and reduce alcohol intake. Soi, it follows that Prazosin would reduce stress-induced craving and improve neuroendocrine and autonomic response to stress and alcohol cue exposure during early abstinence
Prazosin Works in AUD
In the most recent study[xvi] , Prazosin 16 mg/d, TID. Attenuated stress cue-induced alcohol craving and anxiety during early abstinence while improving adrenergic and stress system function, effects which are independent of a history of lifetime anxiety disorders. Those with the most AUD withdrawal symptoms respond the best to prazosin treatment. The findings indicate that alcohol withdrawal symptoms are a significant moderator of prazosin treatment response for alcohol use outcomes and associated symptoms of alcohol craving, anxiety, and mood symptoms. These data support further evaluation of alcohol withdrawal symptoms as a prognostic indicator of Prazosin's efficacy in treating AUD[xvii].
This major double-blind study of 100 people entering outpatient treatment after being diagnosed with alcohol use disorder was just reported in November 2020. Yale researchers gave the drug to all patients who had experienced withdrawal symptoms before entering treatment. According to the Yale alcohol and stress experts, research subjects with more shakes heightened cravings and anxiety, and difficulty sleeping who receive Prazosin significantly had less heavy drinking episodes. Days they drank compared to those who received a placebo. The drug had little effect on those with few or no withdrawal symptoms. "There has been no treatment readily available for people who experience severe withdrawal symptoms, and these are the people at highest risk of relapse and are most likely to end up in hospital emergency rooms," said Dr. Rajita Sinha, director of the Yale Stress Center[xviii].
Who Has an AUD?
Problem drinking described as severe is given the medical diagnosis of "alcohol use disorder" or AUD. An estimated 15 million people in the United States have AUD. 14.4 million adults in the United States ages 18 and older have an AUD, including 9.2 million men and 5.3 million women. An estimated 401,000 adolescents ages 12–17 had AUD. AUD is a chronic relapsing addiction previously called alcoholism. AUD is characterized by an impaired ability to stop or control alcohol use despite adverse social, occupational, or health consequences[xix].
To be diagnosed with AUD, individuals must meet specific Diagnostic and Statistical Manual of Mental Disorders (DSM criteria). Using the DSM–5, anyone meeting any two of the 11 criteria during the same 12-month period receives an AUD diagnosis. The severity of AUD—mild, moderate, or severe—is based on the number of criteria met.
To assess whether you or a loved one may have AUD, here are some questions the NIAAA suggests to ask[xx]. In the past year, have you:
1. Had times when you ended up drinking more or longer than you intended?
2. More than once wanted to cut down or stop drinking, or tried to, but couldn't?
3. Spent a lot of time drinking? Or being sick or getting over the aftereffects?
4. Experienced craving — a strong need, or urge, to drink?
5. Found that drinking — or being sick from drinking — often interfered with taking care of your home or family? Or caused job troubles? Or school problems?
6. Continued to drink even though it was causing trouble with your family or friends?
7. Given up or cut back on activities that were important or interesting to you, or gave you pleasure, in order to drink?
8. More than once gotten into situations while or after drinking that increased your chances of getting hurt (such as driving, swimming, using machinery, walking in a dangerous area, or having unsafe sex)?
9. Continued to drink even though it made you feel depressed or anxious or adding to another health problem? Or after having had a memory blackout?
10. Had to drink much more than you once did to get the effect you want? Or found that your usual number of drinks had much less effect than before?
11. Found that when the effects of alcohol were wearing off, you had withdrawal symptoms, such as trouble sleeping, shakiness, irritability, anxiety, depression, restlessness, nausea, or sweating? Or sensed things that were not there?
AUDs and other addictions are chronic, lifelong and relapsing. Untreated , addictions are progressive and often-fatal diseases. Like others, we have remained positive about the improvements in treatment and outcomes that have followed NIDA, NIAAA and other research. With both with changes in public policy and with advancements in translating research and science into the practice of addiction medicine . [xxi] After evaluating 35 studies, involving the work of 145 scientists and the outcomes of 10,080 participants Alcoholics Anonymous, Stanford University expert Dr. Keith Humphreys[xxii] and colleagues concluded that AA, is the most cost-effective path to abstinence. While AA was nearly always found to be more effective than psychotherapy in achieving abstinence and lowering health care costs. AA plus a medication to reduce craving, relapse, and return to heavy drinking may be the best way to treat patients with AUDs. Fortunately, we have a number of medications approved for AUDs.
Based on the data, the FDA decides which treatments are safe and effective…and for which disease. Medications are utilized to treat patients with AUDs that reduce withdrawal distress, prevent seizures during withdrawal, or delirium tremens. Drugs are also used to reduce harm, alcohol intake, binges, and relapse. Three oral medications (Naltrexone, acamprosate, and disulfiram) and one injectable medication (extended-release injectable Naltrexone) are currently approved for treating alcohol use disorders. All of these AUD medications have been shown to help patients drink less alcohol, avoid relapse to heavy drinking, achieve and maintain abstinence. Prazosin may have something new to add to AUD MATs. Prazosin is the first alpha-1 medication to be proposed and tried in AUDs. Prazosin was invented and used in primary care to treat high blood pressure. Prazosin is safe and has been approved by the FDA for other uses. It has been tested for over a decade in many studies by investigators around the world. Previous studies conducted at Yale have shown Prazosin has essential effects on the brain, bolstering compromised stress centers in the brain. Prazosin can also help to curb alcohol abstinence related anxiety and craving. Sinha's lab has shown that the brain's stress centers are severely disrupted early in AUD recovery. Patients with withdrawal symptoms and high cravings may benefit from Prazosin. MATs for AUD, like Prazosin, could help bridge that gap by reducing alcohol cravings and withdrawal symptoms and increasing the chances that patients refrain from drinking.
 Dr. Mark Gold- Washinton University School of Medicine, Department of Psychiatry
 Dr. Lantie Jorandby- firstname.lastname@example.org-Chief Medical Officer Lakeview Health System, Jacksonville, Florida
[iv] Pollard MS, Tucker JS, Green HD. Changes in Adult Alcohol Use and Consequences During the COVID-19 Pandemic in the US. JAMA Netw Open. 2020;3(9):e2022942. doi:10.1001/jamanetworkopen.2020.22942
[v] Pettinati HM, O'Brien CP, Rabinowitz AR, Wortman SP, Oslin DW, Kampman KM, Dackis CA. The status of naltrexone in the treatment of alcohol dependence: specific effects on heavy drinking. J Clin Psychopharmacol. 2006 Dec;26(6):610-25. doi: 10.1097/01.jcp.0000245566.52401.20. PMID: 17110818.
[vi] Sinha R, Wemm S, Fogelman N, Milivojevic V, Morgan PM, Angarita GA, Hermes G, Fox HC. Moderation of Prazosin's Efficacy by Alcohol Withdrawal Symptoms. Am J Psychiatry. 2020 Nov 19:appiajp202020050609. doi: 10.1176/appi.ajp.2020.20050609. Epub ahead of print. PMID: 33207935.
[ix] Simpson TL, Saxon AJ, Meredith CW, Malte CA, McBride B, Ferguson LC, Gross CA, Hart KL, Raskind M. A pilot trial of the alpha-1 adrenergic antagonist, prazosin, for alcohol dependence. Alcohol Clin Exp Res. 2009 Feb;33(2):255-63. doi: 10.1111/j.1530-0277.2008.00807.x. Epub 2008 Oct 21. PMID: 18945226.
[x] Srivastava AB, Gold MS. Naltrexone: A History and Future Directions. Cerebrum. 2018 Sep 1;2018:cer-13-18. PMID: 30746025; PMCID: PMC6353110.
[xi] Simpson TL, Saxon AJ, Stappenbeck C, Malte CA, Lyons R, Tell D, Millard SP, Raskind M. Double-Blind Randomized Clinical Trial of Prazosin for Alcohol Use Disorder. Am J Psychiatry. 2018 Dec 1;175(12):1216-1224. doi: 10.1176/appi.ajp.2018.17080913. Epub 2018 Aug 29. PMID: 30153753; PMCID: PMC6395537.
[xii] Milivojevic V, Angarita GA, Hermes G, Sinha R, Fox HC. Effects of Prazosin on Provoked Alcohol Craving and Autonomic and Neuroendocrine Response to Stress in Alcohol Use Disorder. Alcohol Clin Exp Res. 2020 Jul;44(7):1488-1496. doi: 10.1111/acer.14378. Epub 2020 Jun 12. PMID: 32449942; PMCID: PMC7572699.
[xiii] Sinha R. The role of stress in addiction relapse. Curr Psychiatry Rep. 2007 Oct;9(5):388-95. doi: 10.1007/s11920-007-0050-6. PMID: 17915078.
[xiv] Fox HC, Anderson GM, Tuit K, Hansen J, Kimmerling A, Siedlarz KM, Morgan PT, Sinha R. Prazosin effects on stress- and cue-induced craving and stress response in alcohol-dependent individuals: preliminary findings. Alcohol Clin Exp Res. 2012 Feb;36(2):351-60. doi: 10.1111/j.1530-0277.2011.01628.x. Epub 2011 Sep 15. PMID: 21919922; PMCID: PMC3243763.
[xv] Blaine SK, Sinha R. Alcohol, stress, and glucocorticoids: From risk to dependence and relapse in alcohol use disorders. Neuropharmacology. 2017 Aug 1;122:136-147. doi: 10.1016/j.neuropharm.2017.01.037. Epub 2017 Feb 1. PMID: 28159647; PMCID: PMC5479733.
[xvi] Milivojevic V, Angarita GA, Hermes G, Sinha R, Fox HC. Effects of Prazosin on Provoked Alcohol Craving and Autonomic and Neuroendocrine Response to Stress in Alcohol Use Disorder. Alcohol Clin Exp Res. 2020 Jul;44(7):1488-1496. doi: 10.1111/acer.14378. Epub 2020 Jun 12. PMID: 32449942; PMCID: PMC7572699.
[xvii] Sinha R, Wemm S, Fogelman N, Milivojevic V, Morgan PM, Angarita GA, Hermes G, Fox HC. Moderation of Prazosin's Efficacy by Alcohol Withdrawal Symptoms. Am J Psychiatry. 2020 Nov 19:appiajp202020050609. doi: 10.1176/appi.ajp.2020.20050609. Epub ahead of print. PMID: 33207935.
Dr. Mark S. Gold is a teacher of the year, translational researcher, author, mentor and inventor best known for his work on the brain systems underlying the effects of opiate drugs, cocaine and food. Read more by Dr. Gold here.