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Naltrexone and the Treatment of Alcohol Dependence

Naltrexone and the Treatment of Alcohol Dependence Naltrexone and the Treatment of Alcohol Dependence JO S E P H R . V O L P I C E L L I , M. D. , P H.D. ; K A R E N L . C L AY, B. A . ; NAT H A N T. WAT S O N , B. A. ; A N D LA U R A A . V O L P I C E L L I , B. A . There currently is a great demand for effective medications to reduce the high relapse rates that occur in the early stages of treatment for alcohol dependence. Recent clinical trials of the opiate antagonist naltrexone have shown that this medication significantly decreases excessive alcohol drinking. (Pro z a c ) (s ee th e art ic le by An t o n , pp. 26 5 – lt h o u g h cu r re nt tr e a t m e n ts fo r gi v e n th e dr u g na l t r e x o n e . Fi n a l l y , th e 2 7 1 ) . H o w e v e r , n o n e o f t h e s e c o m p o u n d s al c o ho l de p e n d en c e ca n sa f e l y ar t i c l e de s c r i b e s ho w na l t r e x o n e ma y wo r k h a v e b e e n s h o w n i n s t u d i e s t o w o r k b e t t e r an d ef f ec t iv e l y he l p pa t i e n t s st o p to re d u c e ex c e s s i v e dr i n k i n g . t h a n p l a c e b o i n a c l i n i c a l p o p u l a t i o n . Ad ri n ki ng al c o h o l , th e y are onl y A pr o m i s i n g ne w ap p r o a c h to th e mo d e s t l y su c c e s s f ul in re d u c i n g pa ti e n ts ’ pr o b l e m of re l a p s e is th e us e of op i a t e te n d e n c i e s to rel a ps e , or re t u r n to ex c es s i ve EXPERIMENTAL BACKGROUND an t a g o n i s t s . Th e s e su b s t a n c e s bl o c k sp e c i f ­ al c o ho l co n sum p ti o n . Ab o u t on e h ­ a lf of al l F o r o n e ­q u a r t e r o f a c e n t u r y , r e s e a r c h e r s ic po r t i o n s of ne u r o n s in th e br a i n — o p i a t e pa t i e n t s wh o com p le t e an in p at i e n t or re s i ­ h a v e s h o w n t h a t a l c o h o l c o n s u m p t i o n c a n re c e p t o r s — t h a t ar e st i m u l a t e d by op i o i d s , de n t i a l ps y c h o s o c i a l tr e a t m e n t pro g r a m a l t e r t h e a c t i v i t y o f o p i a t e r e c e p t o r s re l a p s e wi t h i n th e fi r s t 3 mon t h s of tr e a t ­ su c h as mo r p h i n e . Op i a t e re c e p t o r s al s o ( C o h e n a n d C o l l i n s 1 9 7 0 ; D a v i s a n d ar e ta r g e t s fo r al c o h o l ’ s ac t i v i t y in th e me nt , ca u sin g th i s per io d of re c o v e ry to be W a l s h 1 9 7 0 ) . T h e s e r e c e p t o r s e x i s t i n br a i n . Bl o c k i n g th e re c e p t o r s se e m s to cr i t ic a l fo r ma i n t a i n i n g ab s t i n en c e (M i l l er t h e b r a i n a n d n o r m a l l y a r e s t i m u l a t e d b y an d He s t e r 198 6 ; Na t h a n 19 8 6) . Be c a us e of pr e v e n t ma n y of th e po s i t i v e co n s e q u e n c e s n a t u r a l l y o c c u r r i n g s u b s t a n c e s ( e n d o g e ­ th e hi g h re l a p s e ra t e s th a t oc c u r ea r l y in of dr i n k i n g al c o h o l , su c h as th e al c o h o l n o u s o p i o i d s ) t h a t a r e r e l e a s e d b y n e u r o n s “h i g h , ” th e r e b y de c r e a s i n g th e li k e l i h o o d re c o v e r y , co n s i d e r a b l e in t e r e s t ha s de v e l ­ i n r e s p o n s e t o p h y s i c a l a n d e m o t i o n a l op e d in fi n d i n g me d i c a t i o n s th a t he l p pr e ­ of ex c e s s i v e al c o h o l co n s u m p t i o n . p a i n . D r u g s , s u c h a s m o r p h i n e , t h a t m i m i c ve n t a qu i c k re t u r n to al c o h o l ab u s e . A On e op i a t e an t a g o n i s t , na l t r e x o n e , t h e e f f e c t s o f e n d o g e n o u s o p i o i d s a l s o lo n g e r pe r i o d of ab s t i n e n c e is co n s i d e r e d to ap p e a r s to be a sa f e an d ef f e c t i v e ad j u n c t m a y s t i m u l a t e o p i a t e r e c e p t o r s . O t h e r in c r e a s e ev e n t u a l tr e a t m e n t su c c e s s . Th e fo r th e ea r l y tr e a t m e n t of al c o h o l de p e n d ­ mo s t co m m o n l y us e d an d re s e a r c h e d ph a r ­ en c e . Th i s ar t i c l e re v i e w s re s e a r c h su g g e s t ­ ma c o l o g i c a l ag e n t s in c l u d e di s u l f i r a m ; in g th a t op i a t e an t a g o n i s t s re d u c e ex c e s s i v e JO S E P H R . V O L P I C E L L I , M. D. , P H.D. , i s a n li t h i u m ; an d th o s e th a t in c r e a s e ac t i v i t y of a s s i s t a n t p r o f e s s o r a t t h e U n i v e r s i t y o f al c o h o l co n s u m p t i o n in an i m a l mo d e l s an d P e n n s y l v a n i a M e d i c a l C e n t e r , P h i l a d e l ­ th e se r o t o n i n sy s t e m (i . e . , th e sy s t e m th a t pr e s e n t s su p p o r t i n g da t a fr o m tw o cl i n i c a l p h i a , P e n n s y l v a n i a . a f f e c t s m o o d s t a t e s ) , s u c h a s f l u o x e t i n e sa m p l e s of al c o h o l d ­ ep e n d e n t pa t i e n t s KA R E N L . C L A Y , B. A . , N A T H A N T. W A T S O N , 1 2 T e r m s s u c h a s “ a l c o h o l a b u s e ” a n d “ a l c o h o l d e p e n d ­ T h e t e r m “ o p i o i d ” i s a g e n e r a l c a t e g o r y o f c o m ­ B. A . , A N D LA U R A A . V O L P I C E L L I , B. A . , a r e p o u n d s e n c o m p a s s i n g o p i a t e s , d e r i v e d d i r e c t l y f r o m e n c e ” a r e d e f i n e d i n t h i s a r t i c l e u s i n g c r i t e r i a f r o m r e s e a r c h a s s i s t a n t s a t t h e U n i v e r s i t y o f th e op i u m pl a n t , su c h as mo r p h i n e an d he r o i n , as we l l t h e A m e r i c a n P s y c h i a t r i c A s s o c i a t i o n ’ s D i a g n o s t i c as ot h e r co m p o u n d s th a t oc c u r na t u r a l l y in th e bo d y Pennsylvania Medical Ce nter, Phi lad el­ a n d S t a t i s t i c a l M a n u a l o f M e n t a l D i s o r d e r s , F o u r t h an d ac t li k e op i a t e s , su c h as en d o g e n o u s op i o i d s . E d i t i o n ( 1 9 9 4 ) . ph ia, Pen nsy lvan ia. 272 ALCOHOL HEALTH & RESEARCH WORLD Naltrexone for the Treatment of Alcoholism drugs, such as alcohol, may enhance opiate receptor activity indirectly, perhaps by stimulating the release of endogenous opioids. In support of this theory, animal studies have demonstrated important interactions between alcohol consumption and increases in opiate receptor activity. Specifically, alcohol consumption stimu­ lates opiate receptor activity; is influenced by the use of opiates, such as morphine; and is reduced by opiate antagonists, such as naltrexone (figure 1). Each of these findings is described below. Alcohol’s Effects on Opiate Receptor Activity Several mechanisms by which alcohol may indirectly affect opiate receptor activity have been suggested, but the one presented here appears most important in under­ standing alcohol dependence. Accumulating evidence, including studies in humans, shows that alcohol stimulates the release of endogenous opioids, such as beta­ endorphin, normally used by the body to mitigate pain, and other endorphins that produce pleasurable effects (see reviews by Gianoulakis 1993; Volpicelli et al. 1994). This release of endorphins may ex­ plain why some strains of rats and some people drink excessive amounts of alco­ hol. For example, rats bred to have a high 30 milligrams per kilogram (mg/kg) mor­ opiate withdrawal causes an increase in preference for alcohol show enhanced phine injection (a high dose) decreased alcohol consumption. beta­endorphin release when they con­ their alcohol but not their water consump­ An important exception to this rela­ sume alcohol compared with rats bred tion, demonstrating that morphine’s effect tionship comes from the research con­ for a low preference for alcohol (deWaele was restricted to alcohol (Sinclair 1974). ducted by Reid and associates (1991), in et al. 1992). Similarly, in a study conduct­ Ho and colleagues (1976) also found that which small doses of morphine were ed by Gianoulakis and colleagues (1990), rats decreased their alcohol consumption in found to increase alcohol drinking tran­ male social drinkers who were at increased inverse proportion to their morphine dose. siently in rats given limited access to risk for alcohol abuse, because they had In this study, rats given an incremental alcohol or water. For example, rats with alcohol­dependent parents, experienced dose regimen (i.e., 10, 30, 60 mg/kg) of 2­hour access to alcohol or water that a 170­percent increase in peripheral morphine showed a corresponding de­ received a low dose of morphine (general­ beta­endorphin levels after consuming a crease in alcohol consumption. ly less than 2.5 mg/kg) typically drank moderate dose of alcohol. In contrast, Although opiate use can reduce prefer­ more of an alcohol solution than did rats male social drinkers without alcohol­ ence for alcohol, preference dramatically injected with saline. dependent parents did not show any in­ increases during opiate withdrawal. For The effect of small doses of opioids to crease in beta­endorphin levels after example, Volpicelli and colleagues (1991) increase alcohol drinking is similar to drinking the same amount of alcohol. found that rats with free access to both receiving an appetizer before dinner. A Thus, enhanced release of endorphins alcohol and water decreased their alcohol small amount of a pleasurable substance induced even by small amounts of alcohol consumption, compared with control rats, can increase the motivation to consume may increase the risk for alcohol abuse, when injected with morphine. The day more of that substance. This appetizer, or and the more a person drinks, the more after receiving the injections, however, priming, effect has been observed across endorphins appear to be released. the morphine­injected rats drank approxi­ a variety of addictive drugs. For example, mately twice as much alcohol as the rats that have stopped signaling (by press­ control rats (figure 2). These results fur­ Opiate Effects on Alcohol ing a bar) to obtain cocaine will respond ther support an inverse relationship be­ Consumption again after receiving a small dose of co­ tween opiate receptor activity and alcohol Many studies show that the administration caine (Stewart 1983). Similarly, human consumption. An increase in activity at cocained ­ ependent patients often report that of opiates affects alcohol consumption (see opiate receptors causes a decrease in table 1). For example, rats given a single alcohol consumption, whereas subsequent sampling cocaine enhances the motivation VOL. 18, NO. 4, 1994 273 receptor activity primes, or enhances, the Table 1 Alcohol produces some of its effects by interacting with opiate receptors in the motivation to drink more alcohol. Thus a brain, which normally are activated in response to pain by naturally occurring vicious cycle could be established for substances called opioids. Substances that mimic opioid function, such as people at risk for developing alcohol morphine, are studied to elucidate alcoholʼs interaction with this system. These abuse. These people (such as the high­risk studies offer evidence of the contradictory effects of high and low doses of subjects mentioned above in the study by opioids on alcohol consumption in rats as well as the effects of opiate Gianoulakis and colleagues [1990]) may antagonists, substances that block opiate receptors, on alcohol consumption. find that one drink increases the motiva­ In general, higher doses of opioids decreased alcohol consumption by the tion and craving for the next drink, and rats, whereas low doses increased consumption. Doses of opioid antagonists, this may explain why some alcohol­ in contrast, decreased alcohol consumption regardless of the dose amount. dependent people find it difficult to con­ trol their alcohol consumption once they Effects of Opioids and Opioid Antagonists on Alcohol Drinking in Animals have begun to drink. This mechanism also suggests that the use of an opiate receptor 1 2 Study Drug/Amount Results blocker, such as naltrexone, could break the vicious cycle and thus reduce exces­ Moderate to High Doses sive alcohol consumption. (Table 1 sum­ of Opioids marizes studies that further demonstrate Beaman et al. (1984) Morphine 10 mg/kg Decreased alcohol intake the contradictory effects of opioids on Ho et al. (1976) Morphine 10, 30, 60 mg/kg Decreased alcohol alcohol consumption in animals.) consumption Reid et al. (1987) Morphine 7.5, 20.0 mg/kg Decreased alcohol intake Opiate Antagonist Effects on Ross et al. (1976) Morphine sulfate 7.5 mg/kg Decreased alcohol intake Alcohol Consumption Sinclair et al. (1974) Morphine 30 mg/kg Decreased alcohol intake Volpicelli et al. (1991) Morphine 10.0 mg/kg Decreased alcohol intake An extensive body of literature shows that compounds blocking opiate receptors— Low Doses of Opioids opiate antagonists—reduce alcohol drink­ Beaman et al. (1984) Morphine 2.5 mg/kg Increased alcohol intake ing in animals (table 1). Many of these Chol et al. (1990) Morphine 0.6 mg/kg Increased alcohol intake studies have been performed using nalox­ Czirr et al. (1987) Fentanyl 5, 10, 20, 40 µg/kg Dose-related increase in one, a short­acting, injected opiate antag­ alcohol intake onist. For example, Marfaing­Jallat and Hubbell et al. (1986) Morphine 2.5 mg/kg Increased alcohol intake colleagues (1983) found that naloxone Hubbell et al. (1988) Morphine 0.01, 0.1, 0.3, Increased alcohol intake reduces alcohol preference in rats given a 0.41, 0.56 1.0 mg/kg (doses > 0.41 mg/kg) choice between water and alcohol. Numer­ Reid et al. (1991) Morphine 2.0 mg/kg Increased alcohol intake ous researchers have replicated these results in a variety of studies (e.g., Samson Doses of Opiate and Doyle 1985; Froehlich et al. 1990). Antagonists Several animal studies also have used Altshuler et al. (1980) Naltrexone 1, 3, 5 g/kg Decreased responding to the opiate antagonist naltrexone to reduce receive alcohol alcohol consumption. Naltrexone is a Beaman et al. (1984) Naloxone 3 mg/kg Decreased total fluid intake longer acting compound developed from DeWitte (1984) Naloxone 1 mg/kg Reduced alcohol drinking naloxone that is used as a treatment for Froehlich et al. (1991) Naloxone 0.5–3.0 mg/kg Reduced alcohol preference opiate addiction. For example, Altshuler and colleagues (1980) found that naltrexone IC174864 0.5–3.0 mg/kg Reduced alcohol preference decreased alcohol intake among rhesus Froehlich et al. (1990) Naloxone 0.05–18.0 mg/kg Reduced alcohol intake monkeys trained to press levers to obtain Hubbell et al. (1988) Naloxone 3.0 mg/kg Reduced alcohol intake doses of intravenous alcohol. Similarly, in a LY117413 0.01, 0.1, 1.0, Reduced alcohol intake rat model of stressi ­ nduced excessive alco­ 3.0, 10.0 mg/kg hol consumption, researchers found that Marfaing-Jallat et al. (1983) Naloxone 1 mg/kg Reduced alcohol consumption naltrexone injections completely blocked Samson and Doyle (1985) Naloxone 5, 10, 20 mg/kg 20 mg dose decreased the animals’ stressi ­ nduced increases in alcohol intake; at alcohol consumption (Volpicelli et al. 1986). 5–20 mg, no change Volpicelli et al. (1986) Naltrexone 10 mg/kg Blocked alcohol intake Full citations of studies presented here are available from the author. ­ NALTREXONE STUDIES IN All terms in this column reflect how the drug given altered the animalsʼ alcohol intake. The specific terminology is ALCOHOL­D EPENDENT PEOPLE used in each case as it was in the study. Animals in this study were trained to perform a task, or to respond, to receive an intravenous dose of alcohol. The preclinical research studies discussed above have served as the impetus to test to use more cocaine, creating a vicious excessively. Like the injection of a small naltrexone in the treatment of alcohol­ addictive cycle (Jaffe et al. 1989). dose of morphine, alcohol consumption dependent patients. Overall, animal stud­ A similar addictive cycle may occur in may lead to modest increases in opiate ies suggest that alcohol produces impor­ animals or humans who drink alcohol receptor activity. This heightened opiate tant pharmacological effects that enhance 274 ALCOHOL HEALTH & RESEARCH WORLD Naltrexone for the Treatment of Alcoholism opiate receptor activity, that opiate recep­ times as many days as the naltrexone­ criterion was based on data suggesting that tor activity can influence the desire to treated subjects (14.0 percent of the study alcohol binges of five or more drinks for drink alcohol, and that opiate antagonists days versus 3.6 percent of the study days). males and four or more drinks for females can block alcohol’s rewarding effects. To support the results obtained from are associated with biopsychosocial prob­ the subjects’ self­reports of drinking, lems (i.e., any type of alcoholr ­ elated excessive alcohol consumption was as­ problems; Knupfer 1984). Volpicelli and The Volpicelli Study sessed by monitoring elevations in liver colleagues’ clinical data (1992) further To determine naltrexone’s efficacy in enzymes that signify liver damage. Al­ suggest that subjects who met the relapse reducing rates of relapse in alcohol­ though the naltrexone and placebo groups criteria were likely to meet other criteria dependent people, Volpicelli and col­ did not differ significantly from each for alcohol dependence, such as elevated leagues (1992) performed a 12w ­ eek, other, many naltrexone subjects had liver enzymes; a feeling of loss of control doubleb ­ lind clinical trial in which neither lower liver enzyme values. over alcohol use; interpersonal problems; the investigators nor the subjects knew if and, in the subjects who worked, occupa­ naltrexone or placebo was being adminis­ Effects on Relapse. An important meas­ tional problems. In contrast, none of the tered. The researchers administered either ure of naltrexone’s beneficial effects can subjects who drank alcohol but who did 50 mg of naltrexone or placebo daily on an be seen when looking at the loss of control not meet relapse criteria had any biopsy­ outpatient basis to 70 alcohol­dependent over alcohol drinking, or alcohol relapse, chosocial problems associated with their male veterans, predominantly African­ in these patients. For research purposes, alcohol use. Using this definition of re­ American and unemployed, who had been Volpicelli and colleagues defined alcohol lapse, about oneh ­ alf of the placebot ­ reated drinking heavily for an average of 20 relapse in the subjects as follows: consum­ subjects relapsed during the 12 weeks of years. In addition to their medication, all ing five or more drinks on a particular the study, whereas fewer than onef ­ ourth subjects received psychosocial therapy in drinking occasion, presenting for treatment of the naltrexonet ­ reated subjects relapsed the hospital that included supportive with a blood alcohol concentration greater (figure 4). alcoholism counseling, relapse prevention than 100 mg percent (legal intoxication), therapy, and referral to Alcoholics or consuming alcohol five or more times Side Effects. The study’s psychiatrist Anonymous meetings. Primary outcome during the previous week. assessed treatment side effects noticed measures included self­reports of alcohol The fived ­ rinksp ­ erd ­ rinkingo ­ ccasion by the subjects every 4 weeks. Of the 70 drinking and craving (i.e., the desire to criterion was the most sensitive measure of subjects enrolled, only 2 subjects with­ drink as assessed on a 10­point scale) and relapse, because virtually every subject drew from the study because they were liver damage as determined by increased who met the other relapse criteria also met unable to tolerate the side effects. Both liver enzyme levels. Alcohol relapse also the fived ­ rink criterion. The fived ­ rink subjects were taking naltrexone and was assessed as a measure different from sampling alcohol, or “slipping.” Craving. The naltrexone­treated subjects experienced a gradual decline in alcohol craving during the 12 weeks of the study. The placebo­treated subjects, however, had higher overall levels of craving throughout the study and experienced no reduction in craving (figure 3). Effects on Drinking. Possibly as a conse­ quence of their reduced desire to drink, naltrexone­treated subjects reported less alcohol consumption than the placebo­ treated subjects. Although the percentage of naltrexone­treated patients who drank any alcohol during the study was equal to the percentage of placebo­treated patients who drank, the naltrexone­treated patients who slipped consumed alcohol on fewer days than did placebo­treated patients. Of the subjects who slipped, the placebo­ treated group drank alcohol on nearly four No systematic validity checks were conducted to determine if subjects could determine whether they were taking active medication or placebo. Data collected using normal volunteers, however, indicate that subjects cannot differentiate between naltrexone or placebo; there are no discriminating variables until a subject begins drinking. VOL. 18, NO. 4, 1994 275 complained of nausea. This finding was not significant. Except for nausea, all other side effects were mild in nature and did not differ between groups. The O’Malley Study Another trial of naltrexone in a distinct outpatient population incorporated two different psychosocial therapies and further demonstrated the medication’s effectiveness at reducing slips and pre­ venting alcohol relapse among people in alcoholism treatment. In this study, O’Malley and colleagues (1992) adminis­ tered 50 mg of naltrexone or placebo for 12 weeks to 97 subjects (72 men and 25 women), predominately white and em­ ployed full time. Overall, O’Malley and colleagues found that naltrexone treatment reduced alcohol consumption and lowered relapse rates. In addition, the researchers investi­ gated the interaction of naltrexone with two types of psychosocial therapy. One type of therapy, coping skills therapy, taught patients strategies to cope with alcohol craving and to identify and cope with lifestyle factors that may lead to alcohol relapse (e.g., learning to manage anger or to communicate in close relation­ ships). The other type of therapy, support­ ive therapy, involved patients meeting with a nondirective therapist (i.e., one who encouraged abstinence without teaching specific coping skills) to discuss issues relating to abstinence and treatment. Similar to the Volpicelli study (1992), O’Malley defined relapse as drinking five or more drinks on an occasion for male subjects and four or more drinks on an occasion for females. Using these defini­ tions, O’Malley and colleagues found that naltrexone reduced overall relapse rates among subjects by approximately oneh ­ alf. Also, subjects taking naltrexone reported drinking on only 4.3 percent of the study days, whereas placebo subjects consumed alcohol on 9.9 percent of the study days. An interaction also appeared to occur between the use of medication and the type of psychotherapy group attended. Subjects taking naltrexone and receiving supportive therapy were less likely to sample a drink for the first time after beginning treatment than were subjects in the other treatment groups. Subjects taking naltrexone and receiving coping skills therapy, however, slipped as often as the placebo subjects but were less likely to relapse than any other group once a slip occurred. 276 ALCOHOL HEALTH & RESEARCH WORLD Naltrexone for the Treatment of Alcoholism The study by O’Malley and colleagues to recovering alcoholics raises ethical Why Might Naltrexone Work? concerns; therefore, the effects of naltrex­ suggests that a program combining nal­ Naltrexone may reduce alcohol craving one on reducing drinking pleasure are trexone treatment with coping strategies that alcohol­dependent people often feel. best studied using nondependent social seems particularly effective in reducing Alcohol dependence is characterized by drinkers. In one such study, Swift and alcohol relapse, alcohol craving, and loss a loss of control over drinking, expressed colleagues (in press) found that after a of control over alcohol drinking. by recovering alcoholics as feeling that standard dose of alcohol (e.g., a 5­ounce “1 drink is too many and 100 is not glass of wine), social drinkers who took enough.” Many alcohol­dependent pa­ naltrexone experienced less euphoria than EVIDENCE FOR NALTREXONE’S tients report that the more alcohol they the subjects who took the placebo. MECHANISM OF ACTION drink, the greater their craving becomes, Naltrexone not only reduced the plea­ and they are unable to stop drinking once surable effects associated with drinking, Both clinical trials of naltrexone demon­ they begin. As discussed earlier, this but it also increased the less desirable strated a significant reduction of alcohol vicious cycle may be initiated by alcohol­ sedative effects of alcohol relative to the relapse in those subjects taking naltrexone induced increases in opiate receptor activi­ effects felt by the placebo group. Thus, compared with subjects taking placebo. ty, leading to an increased motivation to although the naltrexone­treated subjects For example, nearly all the subjects taking drink alcohol. Naltrexone, by blocking experienced the negative effects of alco­ placebo who slipped during the study opiate receptors, should disrupt this cycle hol consumption, they did not experience went on to meet relapse criteria. In com­ by obstructing the enhanced opiate receptor the positive effect of euphoria that is a parison, only one­half of the subjects activity induced by alcohol consumption. motivation for drinking alcohol. taking naltrexone who slipped during the Naltrexone also may mitigate the Alternately, naltrexone may interact study relapsed (Volpicelli et al. 1992). pleasure people experience when they with alcohol consumption to produce an Although naltrexone may not reduce the drink. The animal data reviewed here aversive reaction, similar to the presumed risk of slipping, it appears to stop a slip suggest that alcohol is rewarding in part mechanism for disulfiram. For example, because of its effect on opiate receptor from becoming a relapse. Furthermore, some subjects taking naltrexone reported naltrexone seems to prevent the loss of activity. In some people, alcohol may that following alcohol consumption they produce a morphinelike high. If this is control over alcohol consumption and the felt “hungover” or nauseous a few hours true, it would be likely that these people after drinking. Consequently, they did return to alcohol abuse and dependence would not experience an alcohol high not enjoy the alcohol. In social drinkers, typical of many alcohol­dependent pa­ while taking naltrexone. Swift and colleagues (in press) have tients in treatment. It may do so by dimin­ To determine if naltrexone reduces the reported similar results: some subjects ishing alcohol’s pleasurable effects. pleasurable effects associated with drink­ taking naltrexone and drinking alcohol In Volpicelli and colleagues’ (1992) ing, studies must be conducted in which vomited. Taking naltrexone alone or clinical trial, subjects who experienced a the amount of alcohol consumed is con­ consuming alcohol alone was not associ­ slip during the trial were asked to report sistent across all groups. Giving alcohol ated with vomiting. the subjective effects of alcohol and to rate the “high,” or euphoria, from alcohol during their slip on a three­point scale (from ­1 to +1; see figure 5). The average rating was 0 ­ .58, implying that naltrexone­ treated patients experienced a decrease in 0.25 0.06 their high obtained from drinking alcohol. The placebo­treated patients, however, reported no change in alcohol euphoria -0.25 (mean rating, +0.06) (Volpicelli et al. +1 = Increased high 1992). This suggests that the decrease in -0.5 0 = Unchanged high alcohol consumption in the naltrexone -0.58 -1 = Decreased high -0.75 group was attributable to the reduction in the high normally caused by alcohol -1 consumption. However, in this study with Naltrexone Placebo alcohol­dependent subjects, the amount of Figure 5 Naltrexone’s effects on the alcohol “high” felt by patients who slipped alcohol consumed during a slip was not (tasted alcohol during the study) are shown. Patients compared the high control­led. Because naltrexone­treated they experienced at this time with the high they felt from alcohol before subjects also drank less alcohol than they entered treatment. Each bar represents the average score for all placebo­treated subjects did during their patients in each group. On a scale from negative 1 to positive 1, patients slips, the diminished high may instead given naltrexone who slipped during the study rated their alcohol high as have been a consequence of their reduced an average of -0.58. Patients on the placebo rated the high as an average alcohol intake. The studies with nonde­ of 0.06. pendent social drinkers reviewed below SOURCE: Volpicelli et al. 1992. (Swift et al. in press) support naltrexone’s ability to reduce alcohol’s high. VOL. 18, NO. 4, 1994 277 Mean Score (-1 to +1) DEWAELE, J.P.; PAPACHRISTOU, D.N.; AND GIANOULAKIS, dependence: A controlled study. Archives of General CONCLUSIONS C. The alcohol­preferring C57BL/6 mice present an Psychiatry 49(11):881–887, 1992. enhanced sensitivity of the hypothalamic B­endorphin Naltrexone has been shown in two inde­ system to ethanol than the alcohol­avoiding DBA/2 pendent, double­blind clinical trials to REID, L.D.; DELCONTE, J.D.; NICHOLS, M.L.; BILSKY, mice. Journal of Pharmacology and Experimental reduce alcohol consumption effectively in E.J.; AND HUBBARD, C.L. Tests of opioid deficiency Therapeutics 261:788–794, 1992. alcohol­dependent patients when used in hypotheses of alcoholism. Alcohol 8(4):247–257, 1991. conjunction with psychosocial therapy. FROEHLICH, J.C.; HARTS, J.; LUMENG, L.; AND LI, T.K. Alcohol­dependent patients who take Naloxone attenuates voluntary ethanol intake in rats SAMSON, H.H., AND DOYLE, T.F. Oral ethanol self­ naltrexone show significantly reduced selectively bred for high ethanol preference. Pharma­ administration in the rat: Effect of naloxone. 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Endorphins in certain medication) so that the appropriate self­administration behavior in the rat by intracerebral individuals with high and low risk for development of pharmacological interventions for each application of morphine in the ventral tegmental area. alcoholism. In: Reid, L.D., ed. Opioids, Bulimia, and group can be given. Additional research Alcohol Abuse and Alcoholism. New York: Springer­ Pharmacology, Biochemistry, and Behavior 20: on the most effective dose of naltrexone Verlag, 1990. pp. 229–246. 917–923, 1983. in the treatment of alcohol dependence and the most effective treatment duration HO, A.K.S.; CHEN, R.C.A.; AND MORRISON, J.M. SWIFT, R.M.; WHELIHAN, W.; KUZNETSOV, O.; also should be performed before naltrex­ Interactions of narcotics, narcotic antagonists, and BUONGIORNO, G.; AND HSUING, H. Naltrexone­induced one can be widely used in clinical set­ ethanol during acute, chronic, and withdrawal states. alterations in human ethanol intoxication. American tings. Even if naltrexone is found to be Annals of the New York Academy of Sciences 281: 297–310, 1976. Journal of Psychiatry, in press. pharmacologically effective, a patient’s motivation to refrain from drinking must JAFFE, J.H.; CASCELLA, N.G.; KUMOR, K.M.; AND be reinforced, or it is likely that poor VOLPICELLI, J.R.; DAVIS, M.A.; AND OLGIN, J.E. SHERER, M.A. Cocaine­induced cocaine craving. compliance will limit naltrexone’s clinical Naltrexone blocks the post­shock increase of ethanol Psychopharmacology 97(1):59–64, 1989. utility. The clinical studies reported here consumption. Life Sciences 38:841–847, 1986. included subjects who were actively KNUPFER, G. The risks of drunkenness (or, ebrietas engaged in psychotherapy. Thus, naltrex­ resurrecta): A comparison of frequent intoxication VOLPICELLI, J.R.; ULM, R.R.; AND HOPSON, N. 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FELD, R.S.; MEYER, R.E.; AND ROUNSAVILLE, B. Science 167:1005–1007, 1970. Naltrexone and coping skills therapy for alcohol Verlag, 1994. 278 ALCOHOL HEALTH & RESEARCH WORLD http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Alcohol Health and Research World Pubmed Central

Naltrexone and the Treatment of Alcohol Dependence

Volpicelli, Joseph R.; Clay, Karen L.; Watson, Nathan T.; Volpicelli, Laura A.
Alcohol Health and Research World , Volume 18 (4) – Feb 1, 167
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Naltrexone and the Treatment of Alcohol Dependence JO S E P H R . V O L P I C E L L I , M. D. , P H.D. ; K A R E N L . C L AY, B. A . ; NAT H A N T. WAT S O N , B. A. ; A N D LA U R A A . V O L P I C E L L I , B. A . There currently is a great demand for effective medications to reduce the high relapse rates that occur in the early stages of treatment for alcohol dependence. Recent clinical trials of the opiate antagonist naltrexone have shown that this medication significantly decreases excessive alcohol drinking. (Pro z a c ) (s ee th e art ic le by An t o n , pp. 26 5 – lt h o u g h cu r re nt tr e a t m e n ts fo r gi v e n th e dr u g na l t r e x o n e . Fi n a l l y , th e 2 7 1 ) . H o w e v e r , n o n e o f t h e s e c o m p o u n d s al c o ho l de p e n d en c e ca n sa f e l y ar t i c l e de s c r i b e s ho w na l t r e x o n e ma y wo r k h a v e b e e n s h o w n i n s t u d i e s t o w o r k b e t t e r an d ef f ec t iv e l y he l p pa t i e n t s st o p to re d u c e ex c e s s i v e dr i n k i n g . t h a n p l a c e b o i n a c l i n i c a l p o p u l a t i o n . Ad ri n ki ng al c o h o l , th e y are onl y A pr o m i s i n g ne w ap p r o a c h to th e mo d e s t l y su c c e s s f ul in re d u c i n g pa ti e n ts ’ pr o b l e m of re l a p s e is th e us e of op i a t e te n d e n c i e s to rel a ps e , or re t u r n to ex c es s i ve EXPERIMENTAL BACKGROUND an t a g o n i s t s . Th e s e su b s t a n c e s bl o c k sp e c i f ­ al c o ho l co n sum p ti o n . Ab o u t on e h ­ a lf of al l F o r o n e ­q u a r t e r o f a c e n t u r y , r e s e a r c h e r s ic po r t i o n s of ne u r o n s in th e br a i n — o p i a t e pa t i e n t s wh o com p le t e an in p at i e n t or re s i ­ h a v e s h o w n t h a t a l c o h o l c o n s u m p t i o n c a n re c e p t o r s — t h a t ar e st i m u l a t e d by op i o i d s , de n t i a l ps y c h o s o c i a l tr e a t m e n t pro g r a m a l t e r t h e a c t i v i t y o f o p i a t e r e c e p t o r s re l a p s e wi t h i n th e fi r s t 3 mon t h s of tr e a t ­ su c h as mo r p h i n e . Op i a t e re c e p t o r s al s o ( C o h e n a n d C o l l i n s 1 9 7 0 ; D a v i s a n d ar e ta r g e t s fo r al c o h o l ’ s ac t i v i t y in th e me nt , ca u sin g th i s per io d of re c o v e ry to be W a l s h 1 9 7 0 ) . T h e s e r e c e p t o r s e x i s t i n br a i n . Bl o c k i n g th e re c e p t o r s se e m s to cr i t ic a l fo r ma i n t a i n i n g ab s t i n en c e (M i l l er t h e b r a i n a n d n o r m a l l y a r e s t i m u l a t e d b y an d He s t e r 198 6 ; Na t h a n 19 8 6) . Be c a us e of pr e v e n t ma n y of th e po s i t i v e co n s e q u e n c e s n a t u r a l l y o c c u r r i n g s u b s t a n c e s ( e n d o g e ­ th e hi g h re l a p s e ra t e s th a t oc c u r ea r l y in of dr i n k i n g al c o h o l , su c h as th e al c o h o l n o u s o p i o i d s ) t h a t a r e r e l e a s e d b y n e u r o n s “h i g h , ” th e r e b y de c r e a s i n g th e li k e l i h o o d re c o v e r y , co n s i d e r a b l e in t e r e s t ha s de v e l ­ i n r e s p o n s e t o p h y s i c a l a n d e m o t i o n a l op e d in fi n d i n g me d i c a t i o n s th a t he l p pr e ­ of ex c e s s i v e al c o h o l co n s u m p t i o n . p a i n . D r u g s , s u c h a s m o r p h i n e , t h a t m i m i c ve n t a qu i c k re t u r n to al c o h o l ab u s e . A On e op i a t e an t a g o n i s t , na l t r e x o n e , t h e e f f e c t s o f e n d o g e n o u s o p i o i d s a l s o lo n g e r pe r i o d of ab s t i n e n c e is co n s i d e r e d to ap p e a r s to be a sa f e an d ef f e c t i v e ad j u n c t m a y s t i m u l a t e o p i a t e r e c e p t o r s . O t h e r in c r e a s e ev e n t u a l tr e a t m e n t su c c e s s . Th e fo r th e ea r l y tr e a t m e n t of al c o h o l de p e n d ­ mo s t co m m o n l y us e d an d re s e a r c h e d ph a r ­ en c e . Th i s ar t i c l e re v i e w s re s e a r c h su g g e s t ­ ma c o l o g i c a l ag e n t s in c l u d e di s u l f i r a m ; in g th a t op i a t e an t a g o n i s t s re d u c e ex c e s s i v e JO S E P H R . V O L P I C E L L I , M. D. , P H.D. , i s a n li t h i u m ; an d th o s e th a t in c r e a s e ac t i v i t y of a s s i s t a n t p r o f e s s o r a t t h e U n i v e r s i t y o f al c o h o l co n s u m p t i o n in an i m a l mo d e l s an d P e n n s y l v a n i a M e d i c a l C e n t e r , P h i l a d e l ­ th e se r o t o n i n sy s t e m (i . e . , th e sy s t e m th a t pr e s e n t s su p p o r t i n g da t a fr o m tw o cl i n i c a l p h i a , P e n n s y l v a n i a . a f f e c t s m o o d s t a t e s ) , s u c h a s f l u o x e t i n e sa m p l e s of al c o h o l d ­ ep e n d e n t pa t i e n t s KA R E N L . C L A Y , B. A . , N A T H A N T. W A T S O N , 1 2 T e r m s s u c h a s “ a l c o h o l a b u s e ” a n d “ a l c o h o l d e p e n d ­ T h e t e r m “ o p i o i d ” i s a g e n e r a l c a t e g o r y o f c o m ­ B. A . , A N D LA U R A A . V O L P I C E L L I , B. A . , a r e p o u n d s e n c o m p a s s i n g o p i a t e s , d e r i v e d d i r e c t l y f r o m e n c e ” a r e d e f i n e d i n t h i s a r t i c l e u s i n g c r i t e r i a f r o m r e s e a r c h a s s i s t a n t s a t t h e U n i v e r s i t y o f th e op i u m pl a n t , su c h as mo r p h i n e an d he r o i n , as we l l t h e A m e r i c a n P s y c h i a t r i c A s s o c i a t i o n ’ s D i a g n o s t i c as ot h e r co m p o u n d s th a t oc c u r na t u r a l l y in th e bo d y Pennsylvania Medical Ce nter, Phi lad el­ a n d S t a t i s t i c a l M a n u a l o f M e n t a l D i s o r d e r s , F o u r t h an d ac t li k e op i a t e s , su c h as en d o g e n o u s op i o i d s . E d i t i o n ( 1 9 9 4 ) . ph ia, Pen nsy lvan ia. 272 ALCOHOL HEALTH & RESEARCH WORLD Naltrexone for the Treatment of Alcoholism drugs, such as alcohol, may enhance opiate receptor activity indirectly, perhaps by stimulating the release of endogenous opioids. In support of this theory, animal studies have demonstrated important interactions between alcohol consumption and increases in opiate receptor activity. Specifically, alcohol consumption stimu­ lates opiate receptor activity; is influenced by the use of opiates, such as morphine; and is reduced by opiate antagonists, such as naltrexone (figure 1). Each of these findings is described below. Alcohol’s Effects on Opiate Receptor Activity Several mechanisms by which alcohol may indirectly affect opiate receptor activity have been suggested, but the one presented here appears most important in under­ standing alcohol dependence. Accumulating evidence, including studies in humans, shows that alcohol stimulates the release of endogenous opioids, such as beta­ endorphin, normally used by the body to mitigate pain, and other endorphins that produce pleasurable effects (see reviews by Gianoulakis 1993; Volpicelli et al. 1994). This release of endorphins may ex­ plain why some strains of rats and some people drink excessive amounts of alco­ hol. For example, rats bred to have a high 30 milligrams per kilogram (mg/kg) mor­ opiate withdrawal causes an increase in preference for alcohol show enhanced phine injection (a high dose) decreased alcohol consumption. beta­endorphin release when they con­ their alcohol but not their water consump­ An important exception to this rela­ sume alcohol compared with rats bred tion, demonstrating that morphine’s effect tionship comes from the research con­ for a low preference for alcohol (deWaele was restricted to alcohol (Sinclair 1974). ducted by Reid and associates (1991), in et al. 1992). Similarly, in a study conduct­ Ho and colleagues (1976) also found that which small doses of morphine were ed by Gianoulakis and colleagues (1990), rats decreased their alcohol consumption in found to increase alcohol drinking tran­ male social drinkers who were at increased inverse proportion to their morphine dose. siently in rats given limited access to risk for alcohol abuse, because they had In this study, rats given an incremental alcohol or water. For example, rats with alcohol­dependent parents, experienced dose regimen (i.e., 10, 30, 60 mg/kg) of 2­hour access to alcohol or water that a 170­percent increase in peripheral morphine showed a corresponding de­ received a low dose of morphine (general­ beta­endorphin levels after consuming a crease in alcohol consumption. ly less than 2.5 mg/kg) typically drank moderate dose of alcohol. In contrast, Although opiate use can reduce prefer­ more of an alcohol solution than did rats male social drinkers without alcohol­ ence for alcohol, preference dramatically injected with saline. dependent parents did not show any in­ increases during opiate withdrawal. For The effect of small doses of opioids to crease in beta­endorphin levels after example, Volpicelli and colleagues (1991) increase alcohol drinking is similar to drinking the same amount of alcohol. found that rats with free access to both receiving an appetizer before dinner. A Thus, enhanced release of endorphins alcohol and water decreased their alcohol small amount of a pleasurable substance induced even by small amounts of alcohol consumption, compared with control rats, can increase the motivation to consume may increase the risk for alcohol abuse, when injected with morphine. The day more of that substance. This appetizer, or and the more a person drinks, the more after receiving the injections, however, priming, effect has been observed across endorphins appear to be released. the morphine­injected rats drank approxi­ a variety of addictive drugs. For example, mately twice as much alcohol as the rats that have stopped signaling (by press­ control rats (figure 2). These results fur­ Opiate Effects on Alcohol ing a bar) to obtain cocaine will respond ther support an inverse relationship be­ Consumption again after receiving a small dose of co­ tween opiate receptor activity and alcohol Many studies show that the administration caine (Stewart 1983). Similarly, human consumption. An increase in activity at cocained ­ ependent patients often report that of opiates affects alcohol consumption (see opiate receptors causes a decrease in table 1). For example, rats given a single alcohol consumption, whereas subsequent sampling cocaine enhances the motivation VOL. 18, NO. 4, 1994 273 receptor activity primes, or enhances, the Table 1 Alcohol produces some of its effects by interacting with opiate receptors in the motivation to drink more alcohol. Thus a brain, which normally are activated in response to pain by naturally occurring vicious cycle could be established for substances called opioids. Substances that mimic opioid function, such as people at risk for developing alcohol morphine, are studied to elucidate alcoholʼs interaction with this system. These abuse. These people (such as the high­risk studies offer evidence of the contradictory effects of high and low doses of subjects mentioned above in the study by opioids on alcohol consumption in rats as well as the effects of opiate Gianoulakis and colleagues [1990]) may antagonists, substances that block opiate receptors, on alcohol consumption. find that one drink increases the motiva­ In general, higher doses of opioids decreased alcohol consumption by the tion and craving for the next drink, and rats, whereas low doses increased consumption. Doses of opioid antagonists, this may explain why some alcohol­ in contrast, decreased alcohol consumption regardless of the dose amount. dependent people find it difficult to con­ trol their alcohol consumption once they Effects of Opioids and Opioid Antagonists on Alcohol Drinking in Animals have begun to drink. This mechanism also suggests that the use of an opiate receptor 1 2 Study Drug/Amount Results blocker, such as naltrexone, could break the vicious cycle and thus reduce exces­ Moderate to High Doses sive alcohol consumption. (Table 1 sum­ of Opioids marizes studies that further demonstrate Beaman et al. (1984) Morphine 10 mg/kg Decreased alcohol intake the contradictory effects of opioids on Ho et al. (1976) Morphine 10, 30, 60 mg/kg Decreased alcohol alcohol consumption in animals.) consumption Reid et al. (1987) Morphine 7.5, 20.0 mg/kg Decreased alcohol intake Opiate Antagonist Effects on Ross et al. (1976) Morphine sulfate 7.5 mg/kg Decreased alcohol intake Alcohol Consumption Sinclair et al. (1974) Morphine 30 mg/kg Decreased alcohol intake Volpicelli et al. (1991) Morphine 10.0 mg/kg Decreased alcohol intake An extensive body of literature shows that compounds blocking opiate receptors— Low Doses of Opioids opiate antagonists—reduce alcohol drink­ Beaman et al. (1984) Morphine 2.5 mg/kg Increased alcohol intake ing in animals (table 1). Many of these Chol et al. (1990) Morphine 0.6 mg/kg Increased alcohol intake studies have been performed using nalox­ Czirr et al. (1987) Fentanyl 5, 10, 20, 40 µg/kg Dose-related increase in one, a short­acting, injected opiate antag­ alcohol intake onist. For example, Marfaing­Jallat and Hubbell et al. (1986) Morphine 2.5 mg/kg Increased alcohol intake colleagues (1983) found that naloxone Hubbell et al. (1988) Morphine 0.01, 0.1, 0.3, Increased alcohol intake reduces alcohol preference in rats given a 0.41, 0.56 1.0 mg/kg (doses > 0.41 mg/kg) choice between water and alcohol. Numer­ Reid et al. (1991) Morphine 2.0 mg/kg Increased alcohol intake ous researchers have replicated these results in a variety of studies (e.g., Samson Doses of Opiate and Doyle 1985; Froehlich et al. 1990). Antagonists Several animal studies also have used Altshuler et al. (1980) Naltrexone 1, 3, 5 g/kg Decreased responding to the opiate antagonist naltrexone to reduce receive alcohol alcohol consumption. Naltrexone is a Beaman et al. (1984) Naloxone 3 mg/kg Decreased total fluid intake longer acting compound developed from DeWitte (1984) Naloxone 1 mg/kg Reduced alcohol drinking naloxone that is used as a treatment for Froehlich et al. (1991) Naloxone 0.5–3.0 mg/kg Reduced alcohol preference opiate addiction. For example, Altshuler and colleagues (1980) found that naltrexone IC174864 0.5–3.0 mg/kg Reduced alcohol preference decreased alcohol intake among rhesus Froehlich et al. (1990) Naloxone 0.05–18.0 mg/kg Reduced alcohol intake monkeys trained to press levers to obtain Hubbell et al. (1988) Naloxone 3.0 mg/kg Reduced alcohol intake doses of intravenous alcohol. Similarly, in a LY117413 0.01, 0.1, 1.0, Reduced alcohol intake rat model of stressi ­ nduced excessive alco­ 3.0, 10.0 mg/kg hol consumption, researchers found that Marfaing-Jallat et al. (1983) Naloxone 1 mg/kg Reduced alcohol consumption naltrexone injections completely blocked Samson and Doyle (1985) Naloxone 5, 10, 20 mg/kg 20 mg dose decreased the animals’ stressi ­ nduced increases in alcohol intake; at alcohol consumption (Volpicelli et al. 1986). 5–20 mg, no change Volpicelli et al. (1986) Naltrexone 10 mg/kg Blocked alcohol intake Full citations of studies presented here are available from the author. ­ NALTREXONE STUDIES IN All terms in this column reflect how the drug given altered the animalsʼ alcohol intake. The specific terminology is ALCOHOL­D EPENDENT PEOPLE used in each case as it was in the study. Animals in this study were trained to perform a task, or to respond, to receive an intravenous dose of alcohol. The preclinical research studies discussed above have served as the impetus to test to use more cocaine, creating a vicious excessively. Like the injection of a small naltrexone in the treatment of alcohol­ addictive cycle (Jaffe et al. 1989). dose of morphine, alcohol consumption dependent patients. Overall, animal stud­ A similar addictive cycle may occur in may lead to modest increases in opiate ies suggest that alcohol produces impor­ animals or humans who drink alcohol receptor activity. This heightened opiate tant pharmacological effects that enhance 274 ALCOHOL HEALTH & RESEARCH WORLD Naltrexone for the Treatment of Alcoholism opiate receptor activity, that opiate recep­ times as many days as the naltrexone­ criterion was based on data suggesting that tor activity can influence the desire to treated subjects (14.0 percent of the study alcohol binges of five or more drinks for drink alcohol, and that opiate antagonists days versus 3.6 percent of the study days). males and four or more drinks for females can block alcohol’s rewarding effects. To support the results obtained from are associated with biopsychosocial prob­ the subjects’ self­reports of drinking, lems (i.e., any type of alcoholr ­ elated excessive alcohol consumption was as­ problems; Knupfer 1984). Volpicelli and The Volpicelli Study sessed by monitoring elevations in liver colleagues’ clinical data (1992) further To determine naltrexone’s efficacy in enzymes that signify liver damage. Al­ suggest that subjects who met the relapse reducing rates of relapse in alcohol­ though the naltrexone and placebo groups criteria were likely to meet other criteria dependent people, Volpicelli and col­ did not differ significantly from each for alcohol dependence, such as elevated leagues (1992) performed a 12w ­ eek, other, many naltrexone subjects had liver enzymes; a feeling of loss of control doubleb ­ lind clinical trial in which neither lower liver enzyme values. over alcohol use; interpersonal problems; the investigators nor the subjects knew if and, in the subjects who worked, occupa­ naltrexone or placebo was being adminis­ Effects on Relapse. An important meas­ tional problems. In contrast, none of the tered. The researchers administered either ure of naltrexone’s beneficial effects can subjects who drank alcohol but who did 50 mg of naltrexone or placebo daily on an be seen when looking at the loss of control not meet relapse criteria had any biopsy­ outpatient basis to 70 alcohol­dependent over alcohol drinking, or alcohol relapse, chosocial problems associated with their male veterans, predominantly African­ in these patients. For research purposes, alcohol use. Using this definition of re­ American and unemployed, who had been Volpicelli and colleagues defined alcohol lapse, about oneh ­ alf of the placebot ­ reated drinking heavily for an average of 20 relapse in the subjects as follows: consum­ subjects relapsed during the 12 weeks of years. In addition to their medication, all ing five or more drinks on a particular the study, whereas fewer than onef ­ ourth subjects received psychosocial therapy in drinking occasion, presenting for treatment of the naltrexonet ­ reated subjects relapsed the hospital that included supportive with a blood alcohol concentration greater (figure 4). alcoholism counseling, relapse prevention than 100 mg percent (legal intoxication), therapy, and referral to Alcoholics or consuming alcohol five or more times Side Effects. The study’s psychiatrist Anonymous meetings. Primary outcome during the previous week. assessed treatment side effects noticed measures included self­reports of alcohol The fived ­ rinksp ­ erd ­ rinkingo ­ ccasion by the subjects every 4 weeks. Of the 70 drinking and craving (i.e., the desire to criterion was the most sensitive measure of subjects enrolled, only 2 subjects with­ drink as assessed on a 10­point scale) and relapse, because virtually every subject drew from the study because they were liver damage as determined by increased who met the other relapse criteria also met unable to tolerate the side effects. Both liver enzyme levels. Alcohol relapse also the fived ­ rink criterion. The fived ­ rink subjects were taking naltrexone and was assessed as a measure different from sampling alcohol, or “slipping.” Craving. The naltrexone­treated subjects experienced a gradual decline in alcohol craving during the 12 weeks of the study. The placebo­treated subjects, however, had higher overall levels of craving throughout the study and experienced no reduction in craving (figure 3). Effects on Drinking. Possibly as a conse­ quence of their reduced desire to drink, naltrexone­treated subjects reported less alcohol consumption than the placebo­ treated subjects. Although the percentage of naltrexone­treated patients who drank any alcohol during the study was equal to the percentage of placebo­treated patients who drank, the naltrexone­treated patients who slipped consumed alcohol on fewer days than did placebo­treated patients. Of the subjects who slipped, the placebo­ treated group drank alcohol on nearly four No systematic validity checks were conducted to determine if subjects could determine whether they were taking active medication or placebo. Data collected using normal volunteers, however, indicate that subjects cannot differentiate between naltrexone or placebo; there are no discriminating variables until a subject begins drinking. VOL. 18, NO. 4, 1994 275 complained of nausea. This finding was not significant. Except for nausea, all other side effects were mild in nature and did not differ between groups. The O’Malley Study Another trial of naltrexone in a distinct outpatient population incorporated two different psychosocial therapies and further demonstrated the medication’s effectiveness at reducing slips and pre­ venting alcohol relapse among people in alcoholism treatment. In this study, O’Malley and colleagues (1992) adminis­ tered 50 mg of naltrexone or placebo for 12 weeks to 97 subjects (72 men and 25 women), predominately white and em­ ployed full time. Overall, O’Malley and colleagues found that naltrexone treatment reduced alcohol consumption and lowered relapse rates. In addition, the researchers investi­ gated the interaction of naltrexone with two types of psychosocial therapy. One type of therapy, coping skills therapy, taught patients strategies to cope with alcohol craving and to identify and cope with lifestyle factors that may lead to alcohol relapse (e.g., learning to manage anger or to communicate in close relation­ ships). The other type of therapy, support­ ive therapy, involved patients meeting with a nondirective therapist (i.e., one who encouraged abstinence without teaching specific coping skills) to discuss issues relating to abstinence and treatment. Similar to the Volpicelli study (1992), O’Malley defined relapse as drinking five or more drinks on an occasion for male subjects and four or more drinks on an occasion for females. Using these defini­ tions, O’Malley and colleagues found that naltrexone reduced overall relapse rates among subjects by approximately oneh ­ alf. Also, subjects taking naltrexone reported drinking on only 4.3 percent of the study days, whereas placebo subjects consumed alcohol on 9.9 percent of the study days. An interaction also appeared to occur between the use of medication and the type of psychotherapy group attended. Subjects taking naltrexone and receiving supportive therapy were less likely to sample a drink for the first time after beginning treatment than were subjects in the other treatment groups. Subjects taking naltrexone and receiving coping skills therapy, however, slipped as often as the placebo subjects but were less likely to relapse than any other group once a slip occurred. 276 ALCOHOL HEALTH & RESEARCH WORLD Naltrexone for the Treatment of Alcoholism The study by O’Malley and colleagues to recovering alcoholics raises ethical Why Might Naltrexone Work? concerns; therefore, the effects of naltrex­ suggests that a program combining nal­ Naltrexone may reduce alcohol craving one on reducing drinking pleasure are trexone treatment with coping strategies that alcohol­dependent people often feel. best studied using nondependent social seems particularly effective in reducing Alcohol dependence is characterized by drinkers. In one such study, Swift and alcohol relapse, alcohol craving, and loss a loss of control over drinking, expressed colleagues (in press) found that after a of control over alcohol drinking. by recovering alcoholics as feeling that standard dose of alcohol (e.g., a 5­ounce “1 drink is too many and 100 is not glass of wine), social drinkers who took enough.” Many alcohol­dependent pa­ naltrexone experienced less euphoria than EVIDENCE FOR NALTREXONE’S tients report that the more alcohol they the subjects who took the placebo. MECHANISM OF ACTION drink, the greater their craving becomes, Naltrexone not only reduced the plea­ and they are unable to stop drinking once surable effects associated with drinking, Both clinical trials of naltrexone demon­ they begin. As discussed earlier, this but it also increased the less desirable strated a significant reduction of alcohol vicious cycle may be initiated by alcohol­ sedative effects of alcohol relative to the relapse in those subjects taking naltrexone induced increases in opiate receptor activi­ effects felt by the placebo group. Thus, compared with subjects taking placebo. ty, leading to an increased motivation to although the naltrexone­treated subjects For example, nearly all the subjects taking drink alcohol. Naltrexone, by blocking experienced the negative effects of alco­ placebo who slipped during the study opiate receptors, should disrupt this cycle hol consumption, they did not experience went on to meet relapse criteria. In com­ by obstructing the enhanced opiate receptor the positive effect of euphoria that is a parison, only one­half of the subjects activity induced by alcohol consumption. motivation for drinking alcohol. taking naltrexone who slipped during the Naltrexone also may mitigate the Alternately, naltrexone may interact study relapsed (Volpicelli et al. 1992). pleasure people experience when they with alcohol consumption to produce an Although naltrexone may not reduce the drink. The animal data reviewed here aversive reaction, similar to the presumed risk of slipping, it appears to stop a slip suggest that alcohol is rewarding in part mechanism for disulfiram. For example, because of its effect on opiate receptor from becoming a relapse. Furthermore, some subjects taking naltrexone reported naltrexone seems to prevent the loss of activity. In some people, alcohol may that following alcohol consumption they produce a morphinelike high. If this is control over alcohol consumption and the felt “hungover” or nauseous a few hours true, it would be likely that these people after drinking. Consequently, they did return to alcohol abuse and dependence would not experience an alcohol high not enjoy the alcohol. In social drinkers, typical of many alcohol­dependent pa­ while taking naltrexone. Swift and colleagues (in press) have tients in treatment. It may do so by dimin­ To determine if naltrexone reduces the reported similar results: some subjects ishing alcohol’s pleasurable effects. pleasurable effects associated with drink­ taking naltrexone and drinking alcohol In Volpicelli and colleagues’ (1992) ing, studies must be conducted in which vomited. Taking naltrexone alone or clinical trial, subjects who experienced a the amount of alcohol consumed is con­ consuming alcohol alone was not associ­ slip during the trial were asked to report sistent across all groups. Giving alcohol ated with vomiting. the subjective effects of alcohol and to rate the “high,” or euphoria, from alcohol during their slip on a three­point scale (from ­1 to +1; see figure 5). The average rating was 0 ­ .58, implying that naltrexone­ treated patients experienced a decrease in 0.25 0.06 their high obtained from drinking alcohol. The placebo­treated patients, however, reported no change in alcohol euphoria -0.25 (mean rating, +0.06) (Volpicelli et al. +1 = Increased high 1992). This suggests that the decrease in -0.5 0 = Unchanged high alcohol consumption in the naltrexone -0.58 -1 = Decreased high -0.75 group was attributable to the reduction in the high normally caused by alcohol -1 consumption. However, in this study with Naltrexone Placebo alcohol­dependent subjects, the amount of Figure 5 Naltrexone’s effects on the alcohol “high” felt by patients who slipped alcohol consumed during a slip was not (tasted alcohol during the study) are shown. Patients compared the high control­led. Because naltrexone­treated they experienced at this time with the high they felt from alcohol before subjects also drank less alcohol than they entered treatment. Each bar represents the average score for all placebo­treated subjects did during their patients in each group. On a scale from negative 1 to positive 1, patients slips, the diminished high may instead given naltrexone who slipped during the study rated their alcohol high as have been a consequence of their reduced an average of -0.58. Patients on the placebo rated the high as an average alcohol intake. The studies with nonde­ of 0.06. pendent social drinkers reviewed below SOURCE: Volpicelli et al. 1992. (Swift et al. in press) support naltrexone’s ability to reduce alcohol’s high. VOL. 18, NO. 4, 1994 277 Mean Score (-1 to +1) DEWAELE, J.P.; PAPACHRISTOU, D.N.; AND GIANOULAKIS, dependence: A controlled study. Archives of General CONCLUSIONS C. 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Published: Feb 1, 167

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