Combining Naltrexone and Prazosin in a Single Oral Medication Decreases Alcohol Drinking More Effectively Than Does Either Drug Alone

Alcoholism is the most prevalent and widespread of all addictive diseases and development of effective treatments is a high priority. Only three drugs have been approved by the FDA for the treatment of alcohol dependence in the United States: disulfiram (antabuse), acamprosate, and naltrexone (tradename Trexan or Revia). Although naltrexone (NTX) is more effective than is acamprosate (Anton et al., 2006), and compliance is far greater with NTX than with disulfiram (Anton et al., 2006; Fuller et al., 1986), NTX is under-utilized because its efficacy is modest (Froehlich et al., 2003; O’Malley and Froehlich, 2003), it is not effective for all alcoholics (Kranzler and Van Kirk, 2001; Oncken et al., 2001) and, when it is effective, a significant number of alcoholics fail to maintain initial treatment gains and subsequently relapse to heavy drinking (Anton et al., 2006; Garbutt et al., 2005; Krystal et al., 2001). These facts have slowed acceptance of NTX by the treatment community (O’Malley and Froehlich, 2003) and illustrate the importance of finding additional medications for the treatment of alcoholism and alcohol abuse. One of the strongest positively reinforcing effects of alcohol is induction of euphoria (“high”) and feelings of well being (Gilman et al., 2008). Naltrexone, the prototypical opioid receptor antagonist, reduces the reinforcing or euphoriant effects of alcohol by blocking opioid receptors in the brain (Froehlich et al., 2003; Froehlich and Li, 1994; Mitchell et al., 2012; O’Malley and Froehlich, 2003; O’Malley et al., 1996; Volpicelli et al., 1995). One of the strongest negatively reinforcing effects of alcohol is anxiety reduction. More than 50% of patients with anxiety, or major depression, abuse alcohol in an effort to self-medicate since alcohol has both anxiolytic and sympatho-suppressive properties (Kushner et al., 2000; Spanagel et al., 1995). Activation of the noradrenergic system accompanies anxiety and hyperexcitability (Aston-Jones and Cohen, 2005) and agents that reduce central noradrenergic signaling (anxiolytic agents) may substitute for the anxiolytic effects of alcohol and thereby reduce motivation to drink and alcohol intake. We recently began a research program to determine which agents that decrease central noradrenergic signaling are effective in decreasing alcohol drinking in a rodent model of alcoholism. One especially promising agent is prazosin, an α1-adrenergic receptor antagonist. In preclinical studies prazosin decreased alcohol drinking/self-administration in a variety of experimental conditions: a) in rats selectively bred for high voluntary alcohol drinking (alcohol preferring or “P” rats) during both acute (Rasmussen et al., 2009a,b) and prolonged (Froehlich et al., 2013) treatment, b) in P rats when access to alcohol was reintroduced following periods of alcohol deprivation (Rasmussen et al., 2009a) and c) in alcohol-dependent Wistar rats during acute alcohol withdrawal (Walker et al., 2008). In humans, prazosin has been used to treat post traumatic stress disorder (PTSD) where it reduces hyperarousal, overall PTSD severity (Raskind et al., 2003) and, parenthetically, alcohol drinking (Raskind et al., 2009). Recently, prazosin was found to decrease relapse drinking in alcohol-dependent men without PTSD (Simpson et al., 2009) and a preliminary study reports that prazosin decreases stress- and cue-induced alcohol craving in alcohol-dependent individuals (Fox et al., 2011). Both NTX and prazosin, when given alone, can decrease alcohol drinking in rodents and humans and both are safe, orally active, well-characterized, inexpensive, FDA-approved for human use and well-tolerated when administered in clinically relevant doses. Therefore, combining these two classes of drugs may be beneficial in treating alcoholism and alcohol use disorders. Using an animal model of alcoholism, we assessed whether combining NTX and prazosin in a single medication was more effective in decreasing alcohol drinking than was either drug alone. NTX and prazosin were administered orally for a month in order to determine their efficacy, alone or in combination, over the course of prolonged treatment. We hypothesized that combining NTX + prazosin in a single medication will represent a new clinically useful option for treating alcoholism and alcohol use disorders.