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

Abstract

BACKGROUND Naltrexone (NTX) is under-utilized in clinical treatment settings because it’s efficacy is modest, it is not effective for all alcoholics and, when it is effective, a significant number of alcoholics fail to maintain initial treatment gains and subsequently relapse to heavy drinking. This has slowed acceptance of NTX by the treatment community and there is a clear need for additional treatments for alcoholism and alcohol use disorders. Given that NTX and prazosin can each reduce alcohol drinking in rats selectively bred for alcohol preference and high voluntary alcohol drinking (alcohol-preferring “P” rats), we tested whether a combination of NTX + prazosin is more effective in decreasing alcohol drinking than is either drug alone. METHODS P rats were given access to a 15% (v/v) alcohol solution for two hrs daily. Rats were fed NTX and prazosin, alone or in combination, prior to onset of the daily 2 hr alcohol access period for 4 weeks and the effect of drug treatment on alcohol and water intake was assessed. RESULTS During the first week of treatment neither a low dose of NTX, nor prazosin, was effective in decreasing alcohol intake when each drug was administered alone, but combining the two drugs in a single medication significantly reduced alcohol intake. The combination was as effective as was a higher dose of NTX. Using a low dose of NTX in combination with prazosin may reduce the potential for undesirable side effects early in treatment which, in turn, may improve patient compliance and result in a more successful outcome when NTX is used for treating alcoholism and alcohol use disorders. CONCLUSIONS Combining low dose NTX and prazosin in a single medication may be more useful than is either drug alone for treating both inpatient and outpatient alcoholics and heavy drinkers early in the treatment process.

Low-dose prazosin alone and in combination with propranolol or naltrexone: effects on ethanol and sucrose seeking and self-administration in the P rat

“…These two dose combinations of prazosin/naltrexone are the one example of the increased effectiveness of combination treatment on ethanol-reinforced responding that was not also observed with sucrose-reinforced responding. This is also in agreement with Froehlich and colleagues (2013a) in which 2.0 mg/kg prazosin in combination with 10 mg/kg naltrexone, administered via an oral gelatin, reduced ethanol consumption more effectively than either drug alone during one week of consecutive treatment in a free-access 2-hour, 2-bottle choice paradigm in P rats.…”

“…Recent evidence suggests that the noradrenergic system plays a key role in mediating ethanol-motivated behaviors in both alcohol-dependent and non-dependent humans and rats (Froehlich et al 2013a,b; Fox et al 2012; Gilpin and Koob 2010; Rasmussen et al 2009; Simpson et al 2009; Verplaetse et al 2011; Walker et al 2008). Prazosin, an α 1 -adrenergic antagonist, has been found to reduce ethanol drinking in home cage, limited access paradigms in P rats (Rasmussen et al 2009) and block operant responding for ethanol in dependent Wistar rats, with higher doses necessary to be effective in non-dependent animals in a fixed ratio (FR) paradigm (Walker et al 2008).…”

“…Similarly, drugs with different mechanisms of action can be used in combination and in a lower dose range to potentially minimize side effects associated with higher doses of either drug alone (Anton et al 2006; Mattson and Litten 2005). In fact, recent evidence suggests that prazosin in combination with propranolol suppresses ethanol drinking in P rats during ethanol withdrawal and after prolonged abstinence (Rasmussen et al 2014), and prazosin in combination with naltrexone decreases ethanol intake in a free-access two-hour, two-bottle choice procedure in P rats (Froehlich et al 2013a). …”

Prazosin Reduces Alcohol Intake in an Animal Model of Alcohol Relapse

“…Anxiolyic agents, such as prazosin, may substitute for the anxiolytic effects of alcohol and thereby reduce motivation to drink and reduce alcohol intake. In a series of preclinical studies we have found that prazosin decreased alcohol drinking/self-administration in many experimental conditions: in rats selectively bred for high voluntary alcohol drinking during both acute (Rasmussen et al, 2009) and prolonged (Froehlich et al, 2013a) treatment; when administered alone or in combination with naltrexone (Froehlich et al, 2013b); when administered during reaccess to alcohol following periods of alcohol deprivation (Rasmussen et al, 2009); and when administered during acute alcohol withdrawal (Walker et al, 2008). In humans, prazosin has been used to treat posttraumatic stress disorder (PTSD) where it reduces hyperarousal, overall PTSD severity (Raskind et al, 2003) and, parenthetically, alcohol drinking (Raskind et al, 2009).…”

The α2-adrenergic receptor agonist, clonidine, reduces alcohol drinking in alcohol-preferring (P) rats

“…Prazosin dose-dependently reduced withdrawal-induced operant self-administration of alcohol in alcohol-dependent Wistar rats (Walker, Rasmussen, Raskind, & Koob, 2008). Prazosin also suppressed voluntary alcohol drinking by rats selectively bred for alcohol preference (P line) when administered either acutely (Rasmussen, Alexander, Raskind, & Froehlich, 2009) or chronically (Froehlich, Hausauer, Federoff, Fischer, & Rasmussen, 2013; Froehlich, Hausauer, & Rasmussen, 2013). The ability of prazosin to reduce alcohol drinking has been confirmed in humans; Simpson and colleagues (2009) reported that prazosin decreased relapse alcohol drinking in treatment-seeking alcohol-dependent men.…”