Effects of Naltrexone and Nalmefene on Subjective Response to Alcohol Among Non-Treatment-Seeking Alcoholics and Social Drinkers

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0145-6008/04/2809-1362$03.00/0 Vol. 28, No. 9 ALCOHOLISM:CLINICAL AND EXPERIMENTAL RESEARCH September 2004 Effects of Naltrexone and Nalmefene on Subjective Response to Alcohol Among Non-Treatment-Seeking Alcoholics and Social Drinkers

David J. Drobes, Raymond F. Anton, Suzanne E. Thomas, and Konstantin Voronin

Background: Despite the relative success of opiate antagonist medication within controlled clinical trials for alcoholism, laboratory studies have not fully examined potential mechanisms for their efficacy in alcohol-dependent persons. The present study evaluated the impact of naltrexone and nalmefene on craving and subjective effects after a moderate alcohol dose among non-treatment-seeking alcoholics (n ϭ 125) and social drinkers (n ϭ 90). Methods: Participants were randomly assigned to receive placebo, naltrexone (titrated to 50 mg/day), or nalmefene (titrated to 40 mg/day) for seven days before an alcohol challenge clinical laboratory session. During the clinical laboratory session, a drink of alcohol (0.4 mg/kg for men, 0.34 mg/kg for women) was provided in a bar-like setting. The effects of the alcohol dose on subjective craving, stimulation, and sedation were measured before having free access to alcohol. Results: Alcoholics reported higher levels of craving than social drinkers before and after the drink as well as higher levels of alcohol-induced stimulation. Both opiate antagonist medications suppressed initial increases in craving and stimulation. Conclusions: These findings demonstrate that both naltrexone and nalmefene are associated with reduced alcohol-induced craving and stimulation among alcoholics who are not actively attempting to reduce drinking. These data provide insights into potential mechanisms that may underlie opiate antagonists’ effects in the context of treatment. Key Words: Naltrexone, Nalmefene, Alcohol, Craving, Stimulation.

NUMBER OF RANDOMIZED clinical trials have understand the mechanisms that may mediate the effects of A demonstrated the efficacy of opiate antagonist medi- medications on alcohol-related behavior. cations in the context of treatment outcome research for Clinical laboratory paradigms have been used increas- alcoholics. The majority of these studies have used naltrex- ingly to evaluate medication effects in a time- and cost- one (e.g., Anton et al., 1999; Anton and Swift, 2003; Kiefer efficient manner. For instance, a number of recent et al., 2003; O’Malley et al., 1992, 1995; Volpicelli et al., laboratory-based studies have examined effects of naltrex- 1992, 1997). Nalmefene also seems to be associated with one on alcohol consumption and alcohol response (e.g., beneficial clinical outcomes (Mason et al., 1994, 1999). Davidson et al., 1996, 1999; de Wit et al., 1999; King et al., Despite promising results, findings with these and other 1997a; McCaul et al., 2000; O’Malley et al., 2002; Palfai et pharmacological agents in the treatment of alcoholism have al., 1999; Swift et al., 1994). Unfortunately, the majority of been highly variable (Gastpar et al., 2002; Krystal et al., these studies have been conducted in nonalcoholic subjects, 2001). There is clearly a need to determine more effective thereby limiting the extent to which findings from these formulations and to develop more efficient means to eval- studies are generalizable to alcoholics—those who are most uate potentially useful medications. There is also a need to likely to receive opiate antagonist treatment. Indeed, recent findings suggest that previously observed naltrexone- induced reductions in the stimulatory effects of alcohol From the Charleston Alcohol Research Center, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, (e.g., Swift et al., 1994) may only be evident in persons at South Carolina. high risk for alcohol dependence (King et al., 1997a) or Received for publication May 29, 2003; accepted May 20, 2004. those with high positive alcohol outcome expectancies (Pal- Supported by NIH Grant P50 AA10761. fai et al., 1999). Therefore, it is critical to determine the Reprint requests: David J. Drobes, PhD, Tobacco Research and Interven- comparability of laboratory effects in alcoholics and non- tion Program, H. Lee Moffitt Cancer Center & Research Institute, University of South Florida, 4115 E. Fowler Ave., Tampa, FL 33617; Fax: 813-632- alcoholics. Another limitation of prior studies is that many 1755; E-mail: [email protected]. have used a single-dose strategy. This is far removed from Copyright © 2004 by the Research Society on Alcoholism. the daily dosing regimen and titration schedule used in DOI: 10.1097/01.ALC.0000139704.88862.01 clinical settings, and it is possible that study findings were 1362 Alcohol Clin Exp Res, Vol 28, No 9, 2004: pp 1362–1370 OPIATE ANTAGONISTS AND SUBJECTIVE RESPONSE TO ALCOHOL 1363 disproportionately influenced by initial side effects that are holism (1988), and all study procedures were approved by the Medical often observed with opiate antagonists (i.e., those that University of South Carolina’s Institutional Review Board. quickly dissipate). O’Malley and her colleagues recently conducted a labo- Participants ratory study that overcame several limitations of prior stud- One-hundred twenty-five non-treatment-seeking alcoholics and 90 so- ies (O’Malley et al., 2002). These researchers examined cial drinkers were recruited through newspaper and community ads. All participants were between the ages of 21 and 65, and none had current naltrexone effects among non-treatment-seeking alcohol- major psychiatric disturbance, current drug dependence (except nicotine), ics. After 6 days of naltrexone or placebo, participants psychoactive drug use (except marijuana) in the past 30 days, past opiate receiving naltrexone reported reduced craving and con- abuse or dependence, current suicidal or homicidal ideation, past history Ն sumed less alcohol in the laboratory. Furthermore, in- of alcohol-related medical illness, liver enzymes 2.5 times normal, or creased craving was associated with decreased activation of significant health problems. All alcoholic participants met DSM-IV criteria for alcohol dependence (American Psychiatric Association, 1994), the hypothalamic-pituitary-adrenal (HPA) axis (e.g., corti- including criteria depicting loss of control drinking or an inability to cut sol), which suggests a potential mechanism that may un- down or quit. Social drinkers had no history of alcohol abuse or depen- derlie naltrexone effects in alcoholism treatment. A recent dence and reported drinking no more than 14 standard drinks per week report from our laboratory (Drobes et al., 2003), using a and no more than 5 drinks per occasion. Furthermore, social drinkers similar paradigm as O’Malley et al. (2002), compared the were required to have consumed two or more drinks on at least one occasion during the previous 30 days, so that the amount that would be effects of naltrexone and nalmefene on alcohol consump- ingested during the laboratory session would not exceed what they had tion among nontreated alcoholics and social drinkers. We consumed in the recent past. observed that alcoholics taking either opiate antagonist medication consumed less alcohol during a 5 day natural- Initial Assessment istic observation period, relative to placebo-treated sub- When each participant arrived for an initial evaluation, the study was jects. Those receiving active medication also showed re- described in detail to the participant and informed consent was obtained. duced alcohol consumption within a laboratory self- During the remainder of this session, and during a second session that was administration paradigm. We deemed these findings to be scheduled to occur within 1 week of the first session, several interview, questionnaire, and medical screening procedures were administered to consistent with previous basic and clinical studies by dem- evaluate inclusion/exclusion criteria and to facilitate sample description. onstrating an effect of opiate antagonism on alcohol con- Interviews included a demographic form, the Structured Clinical Interview sumption. These results also suggested that, despite subtle for the DSM-IV (First et al., 1994), a timeline follow-back interview to differences in basic opiate receptor pharmacology, the two quantify drinking during the preceding 90 days (Sobell and Sobell, 1992), opiate antagonists were equally effective in reducing drink- and a structured Family History Research Diagnostic Interview (An- dreasen et al., 1977) to obtain information on alcohol and other substance ing. Importantly, medication effects were most clearly ob- use problems among first- and second-degree relatives. Self-report mea- served in alcoholics. sures included the Obsessive-Compulsive Drinking Scale (Anton et al., The purpose of the current article is to further examine 1995), the Self-Administered Alcohol Screening Test (Davis et al., 1987), the effect of naltrexone and nalmefene in our previous the Alcohol Dependence Scale (Skinner and Allen, 1982), the Alcohol sample of non-treatment-seeking alcoholics and social Craving Questionnaire (Singleton et al., 1999), the Beck Depression In- ventory (Beck, 1967), and the Beck Anxiety Inventory (Beck et al., 1988). drinkers. Whereas the prior report focused on alcohol con- Finally, a physical exam was conducted, a urine specimen was collected to sumption measures, the present article describes subjective screen for abused drugs, and a blood sample was collected for liver responses after a moderate dose of alcohol. We predicted function and general health screening. that naltrexone and nalmefene would each reduce craving after alcohol administration and that both medications Medication Regimen and Prelaboratory Procedures might reduce subjective stimulatory effects of alcohol. Fur- Participants who passed all screening and eligibility criteria were ran- thermore, we expected that medication effects would be domized to one of three medication conditions (naltrexone, nalmefene, or most evident in alcoholic subjects and might be most pro- placebo), using an urn randomization procedure (e.g., Stout et al., 1994) to balance groups according to gender, smoking status, family history of nounced shortly after alcohol was consumed. We also alcohol problems, and preferred alcoholic beverage (beer, wine, or li- wished to explore any differences between the medications. quor). Among social drinkers, 30 were assigned to receive placebo, 29 to naltrexone, and 31 to nalmefene. Among the alcoholics, 50 were assigned to receive placebo, 39 to naltrexone, and 36 to nalmefene. Dosing param- eters for each medication were determined by existing clinical guidelines. METHODS As such, 50 mg of naltrexone was used because that was the dose found effective in many clinical trials, including our own (Anton et al. 1999). Overview Mason et al. (1994, 1999) reported that 40 mg of nalmefene was also Participants, initial assessments, medication regimens, and standard- effective in clinical trials. It was our intent to evaluate the doses of these ized alcohol administration procedures that have previously been reported drugs that were reported to have clinical efficacy and to be well-tolerated (Drobes et al., 2003) were used for the present research. The previous in alcoholics. An 8 day medication regimen for naltrexone consisted of 2 report focused on medication effects on alcohol consumption in alcoholics days at 25 mg/day, followed by 50 mg/day for each remaining day. The and social drinkers, whereas the present article focuses on subjective initial nalmefene regimen was similar, with 20 mg/day for 2 days and 40 effects after alcohol administration during the same laboratory session. All mg/day for each remaining day. However, after several of the first partic- alcohol administration procedures were conducted in accordance with ipants assigned to receive nalmefene exhibited intolerable side effects guidelines of the National Advisory Council on Alcohol Abuse and Alco- (e.g., dysphoria, temperature dysregulation, cognitive disturbances, illu- 1364 DROBES ET AL. sions, sleep difficulties), the nalmefene titration was slowed for the re- tion was initiated. The BAES was not administered at baseline, because mainder of the study as follows: 5, 10, 20, 40, 40, 40, 40, 40 mg/day. All we used the original version of the scale that explicitly asks participants to medications, including inactive placebo, were administered in standard report effects after receiving alcohol. gelcaps with 100 mg of riboflavin added to assess for compliance via At 3:00 PM (50 min after completion of the standard alcohol drink), a fluorescence assay (see Sullivan et al., 1989a). 90 min alcohol choice self-administration period commenced. These data Participants were given no explicit instructions regarding use of alcohol have been reported elsewhere (Drobes et al., 2003). After the alcohol or modification of their drinking behavior for the first 5 days taking self-administration period, the participant was required to remain in the medication in their naturalistic environment. However, they were required laboratory until 6:30 PM or until a breathalyzer reading was below 20 to abstain completely from drinking on days 6 and 7. Participants were mg/100 ml (whichever time was later). Before dismissal, the participant clinically evaluated for alcohol withdrawal in person on each of these two was given dinner and permitted to listen to music, watch videos, or read days using the Clinical Institute Withdrawal Assessment for Alcohol- magazines. Alcoholic participants were also given educational and self- Revised (Sullivan et al., 1989b), and a urine sample was collected to help materials regarding alcohol effects and changing drinking behavior. ascertain medication compliance on day 6. Participants were also famil- Participants were driven home by a friend or family member, or a taxi was iarized with the bar-lab room in which the laboratory session would be provided. On the day after the laboratory session, alcoholic participants conducted on day 8. Analysis of urine riboflavin data in 78% of the social attended an individual feedback and debriefing session designed to in- drinkers and 82% of the alcoholics yielded estimated compliance rates crease motivation to reduce drinking or seek treatment. All participants (Ͼ1500 ng/ml) in each group as follows: social drinkers (placebo, 91%; were paid $300 if they were fully participatory. naltrexone, 91%; nalmefene, 88%); alcoholics (placebo, 89%; naltrexone, 85%; nalmefene, 87%). Thus, overall compliance was quite good and did Data Analysis not differ as a function of drinking group or medication condition. In addition, medication ingestion was witnessed on days 1, 6, 7, and 8. Three-way mixed-design analyses of covariance (ANCOVA) were per- formed on the craving total score as well as the stimulation and sedation subscales of the BAES. Between-subject factors in each analysis were Laboratory Session Group (alcoholics versus social drinkers) and Medication (naltrexone versus nalmefene vs. placebo), and the repeated measures factor was Time On day 8 (following a 1 week medication regimen), participants at- (with four levels). Greenhouse-Geisser corrections were used for all ef- tended a clinical laboratory session in the bar-lab setting. Participants fects involving the repeated measure. We previously reported that alco- arrived at 11:00 AM and were provided with a standard caloric lunch holics achieved higher average peak blood alcohol levels than social (weight and gender adjusted). At 12:00, an indwelling catheter was in- drinkers in this paradigm (62 vs. 51 mg/100 ml; Drobes et al., 2003). serted to facilitate upcoming blood alcohol assessments. At 12:30 PM, the Therefore, to control for variability that could be due to blood alcohol participant received the final witnessed dose of study medication. At 2:00 differences across groups, peak blood alcohol level was used as a covariate PM, a curtain was pulled back to reveal a range of bar-like cues (perma- in the present analyses. Because we were particularly interested in evalu- nent bar, barstools, coasters, glass shelving with alcohol bottles, beer and ating medication effects in alcoholics, separate sets of analyses restricted liquor signs, etc.). Participants were then provided with a weight- and to alcoholic subjects were planned, a priori, so that any variability of gender-adjusted alcohol dose (0.4 g/kg for men, 0.34 g/kg for women) of medication effects in social drinkers would not obscure important obser- their preferred type of alcoholic beverage (beer, wine, spirits). The dose vations in alcoholics (who might be more sensitive to the medication was calculated to achieve a peak blood alcohol concentration (BAC) in the effects). We also planned contrasts between medication conditions at 50–60 mg/100 ml range. Participants were required to consume the bev- specific time points to evaluate the hypothesis that medication effects erage over a 10 min period, with the dose split into two equal halves (5 min would be most apparent at the immediate post-alcohol-consumption each). To make the consumption as naturalistic as possible, the beverage assessment. was prepared in the fashion that participants described as their preferred mode (e.g., on the rocks), and brand preferences were accommodated as much as possible. Immediately after the alcohol consumption period, RESULTS self-report measures related to alcohol craving and alcohol’s intoxicating effects were administered and blood samples were drawn, according to a Sample Characteristics predetermined schedule. Measures were selected to generally characterize Alcoholics and social drinkers did not differ with respect differences between alcoholics and social drinkers in acute alcohol response and to evaluate potential effects of opiate antagonist medications to age, gender, or racial composition, nor were there dif- on these responses. Two self-report measures served as the focus of the ferences in these variables across the three medication present study. First, we adapted five items from the Alcohol Craving conditions in each group. On average, participants were Questionnaire-Now (Singleton et al., 1999): (1) I would like to drink approximately 31 years old and the sample was predomi- alcohol, (2) I intend to drink alcohol in the near future, (3) Alcohol will nantly male (80%) and mostly Caucasian (93.5% white, make me feel good, (4) My craving for alcohol is. . ., and (5) Alcohol will get rid of any discomfort I am feeling. Each item is scored on a 100 mm 5.1% black, 0.9% Hispanic, and 0.5% Asian). Alcoholics graded visual analog scale, with anchor labels at opposite ends of the scale had significantly higher scores than social drinkers on all of “not at all” and “maximum possible.” Thus, the total craving score measures related to alcohol consumption, as well as higher ranged from 0 to 500 (five items with maximum score of 100 on each item). baseline levels of ␥-glutamyltransferase. Furthermore, al- Second, we administered the Biphasic Alcohol Effects Scale (BAES; coholics were more likely than social drinkers to have a Martin et al., 1993), a 14-item checklist designed to assess both the stimulating and sedating effects of alcohol. Items on the Stimulation first-degree relative with a history of significant alcohol subscale are elated, energized, excited, stimulated, talkative, up, and vigorous. problems, they were more likely to be smokers, and they Items on the Sedation subscale are difficulty concentrating, down, heavy exhibited higher (yet not clinically significant) levels of head, inactive, sedated, slow thoughts, and sluggish. Each item is scored on current anxiety and depression. The randomization proce- a 0 to 10 scale with anchors of not at all and extremely at opposite ends of dures were effective in equating medication conditions on the scale, and subscale scores can range from 0 to 70. The Craving form was administered at baseline (20 min before the alcohol administration) each of these measures within the alcoholic and social and at 20, 40, and 60 min after alcohol consumption was initiated. The drinker groups. Sample characteristics are provided in Ta- BAES was administered at 10, 20, 40, and 60 min after alcohol consump- ble 1. OPIATE ANTAGONISTS AND SUBJECTIVE RESPONSE TO ALCOHOL 1365

Table 1. Sample Description Group Social drinkers Alcoholics (n ϭ 90) (n ϭ 125) General characteristics Age 32.0 (10.9) 30.3 (11.2) Gender % male 77 82 Race % Caucasian 96 92 Preferred beverage % beer 58 70 % wine 18 9 % liquor 24 21 % Smokers** 6 36 % Family Alcohol Problems** 12 42 BDI** 1.4 (2.0) 5.4 (5.6) BAI** 1.3 (1.7) 5.2 (6.2) Drinking characteristics ADS** 1.3 (1.6) 12.3 (5.4) SAAST** 1.4 (2.0) 3.4 (1.9) OCDS** 2.1 (1.2) 12.2 (4.9) ACQ** 58.6 (13.1) 109.7 (45.8) TLFB** % drinking days 22 (17) 75 (20) drinks/drinking day 2.7 (1.2) 8.3 (3.1) GGT* 29.3 (24.2) 55.9 (84.5)

Standard deviations appear in parentheses. BDI, Beck Depression Inventory; BAI, Beck Anxiety Inventory; ADS, Alcohol Dependence Scale; SAAST, Self- Administered Alcohol Screening Test; OCDS, Obsessive-Compulsive Drinking Scale; ACQ, Alcohol Craving Questionnaire; TLFB, 90-Day Timeline Follow-Back; Fig. 1. Average craving ratings (ϮSEM) at each pre- and postdrinking time GGT, ␥-glutamyltransferase. point for alcoholics and social drinkers as a function of medication status. * p Ͻ 0.001. Significant overall effects were found for Group (alcoholics Ͼ social drinkers; p Ͻ ** p Ͻ 0.0001. 0.0001), Medication (naltrexone and nalmefene Ͻ placebo; p Ͻ 0.01), and Group ϫ Time (p Ͻ 0.05). For alcoholics, there was a significant effect for Medication Craving (p Ͻ 0.05), in which nalmefene reduced craving relative to placebo at each postalcohol time point and naltrexone reduced craving relative to placebo at the Figure 1 shows the unadjusted mean craving ratings at first postalcohol assessment. each time period for each of the six groups. The overall analysis revealed a significant main effect for Group, with alcoholics reporting higher craving than social drinkers analysis revealed a significant main effect for Group, with [F(1,178) ϭ 125.82, p Ͻ 0.0001]. There was also a signifi- alcoholics reporting greater stimulation than social drink- ϭ Ͻ ers [F(1,179) ϭ 29.77, p Ͻ 0.0001]. There was also a sig- cant main effect for Medication [F(2,178) 4.72, p 0.01], ϫ ϭ Ͻ with participants who were receiving active opiate antago- nificant Group Time interaction [F(3,537) 5.39, p nist medications reporting lower craving ratings than those 0.005], with stimulation decreasing over time for the alco- receiving placebo. Finally, there was a significant Group ϫ holics yet remaining stable for social drinkers. As with Time interaction [F(3,534) ϭ 3.56, p Ͻ 0.05]. Craving craving, there were no differences in self-reported stimula- tended to decrease slightly over time for social drinkers, tion after receiving alcohol in a direct comparison between whereas it remained relatively flat (active medication) or naltrexone and nalmefene participants. However, there was a significant Medication ϫ Time interaction in the increased (placebo) at the first assessment after alcohol ϭ Ͻ consumption among alcoholics. alcoholics-only analysis [F(3,315) 3.14, p 0.05]. The analyses restricted to alcoholics revealed a signifi- Planned contrasts indicated a trend in which participants ϭ ϭ receiving either active medication showed reduced stimu- cant effect of Medication condition [F(2,103) 3.06, p Ͻ 0.05]. Planned contrasts indicated that there were no med- lation at the immediate postalcohol assessment (p 0.09) ication effects on craving at the baseline assessment, yet but not at the later time points. nalmefene-treated subjects had significantly lower cravings Because the opiate antagonists seemed to be most effec- than placebo-treated subjects at each postalcohol assessment, tive at reducing stimulation in alcoholics soon after alcohol and naltrexone-treated subjects had significantly lower craving consumption (i.e., during rising BACs), we examined ratings than placebo-treated subjects at the first postalcohol whether there would be an interaction between medication assessment. In a direct comparison, there were no differences and peak BAC on stimulation; that is, would opiate antag- between naltrexone and nalmefene participants. onists be more effective in reducing stimulation among subjects who achieved a relatively lower BAC? For this analysis, alcoholics were divided into low and high BAC Biphasic Alcohol Effects Scale—Stimulation groups based on a median split of peak BAC levels (median Figure 2 shows average BAES-Stimulation scores at each ϭ 63 mg/100 ml). As depicted in Fig. 3, there was a signif- measurement period for each of the six groups. The overall icant interaction between peak BAC and medication on 1366 DROBES ET AL.

Fig. 3. Average BAES-Stimulation ratings (ϮSEM) for alcoholics on active medication (naltrexone and nalmefene combined) and placebo based on peak blood alcohol concentration median split (median ϭ 63 mg/100 ml ). There was a Fig. 2. Average BAES-Stimulation ratings (ϮSEM) at each postdrinking time significant BAC Group ϫ Medication interaction effect (p Ͻ 0.05), in which active point for alcoholics and social drinkers as a function of medication status. medication reduced stimulation in the low BAC group, but not in the high BAC Significant overall effects were found for Group (alcoholics Ͼ social drinkers; p Ͻ group. 0.0001) and Group ϫ Time (p Ͻ 0.005). Among alcoholics, there was a significant Medication ϫ Time effect (p Ͻ 0.05), in which both active medications reduced stimulation relative to placebo at the first postalcohol time point. treatment-seeking alcoholics taking either of these medications displayed significant reductions in subjective craving subjective stimulation after receiving alcohol [F(1,111) ϭ and stimulation, and to a lesser degree sedation, relative to 3.98, p Ͻ 0.05]. Post hoc tests confirmed that those on placebo-treated subjects. It is becomingly increasingly clear active medication reported less stimulation than those on that alcoholics taking opiate antagonist medications expe- placebo in the low blood alcohol group, whereas there was rience attenuated subjective reactions to alcohol. Craving no such medication effect in the higher blood alcohol and stimulation, in particular, are putatively related to the group. motivation to consume alcohol. Therefore, a reduction in these reactions after consuming alcohol would have obvi- ous benefits to those attempting to curtail or cease their Biphasic Alcohol Effects Scale—Sedation drinking. Together with recent findings that opiate antag- There were no significant main effects or interactions in onist medications such as naltrexone and nalmefene reduce the overall ANCOVA on the BAES-Sedation scores. Sim- alcohol consumption in natural and controlled environ- ilarly, there were no significant effects in the alcoholics- ments (Drobes et al., 2003; O’Malley et al., 2002), the only ANCOVA. However, there was a trend in which al- present data shed further light on the mechanisms by which coholics receiving opiate antagonists reported lower opiate antagonist medications may lead to reduced sedation at the immediate postalcohol assessment relative drinking. to those receiving placebo (p Ͻ 0.08). Finally, to parallel Marked differences in craving and other subjective re- our analysis of stimulation ratings, we examined sedation as ports were observed between alcoholics and social drinkers a function of peak BAC and medication status among in the present study. It is not surprising that alcoholics alcoholics. This analysis revealed no main effects for med- would report stronger cravings overall than social drinkers ication or peak BAC and no interaction between peak BAC as well as increases in craving after receiving a moderate and medication group. dose of alcohol (at least as shown in placebo-treated alcoholics), as craving is a core feature of addiction. Indeed, differences in craving were apparent even at baseline (be- DISCUSSION fore alcohol consumption), which further attests to the The present findings showed that each of two common differences between these two groups of subjects. It was opiate antagonist medications, naltrexone and nalmefene, somewhat less expected that alcoholics would report were associated with attenuated subjective effects from a greater stimulatory effects of alcohol than social drinkers, moderate dose of alcohol. Most importantly, non- given the potential that alcohol tolerance would be more OPIATE ANTAGONISTS AND SUBJECTIVE RESPONSE TO ALCOHOL 1367 salient among the alcoholics. This pattern of findings sug- be another salient factor that mediates opiate antagonist gests that early-stage alcoholics might display a sensitized effects. It would be interesting to test these hypotheses by reaction to alcohol (e.g., Robinson and Berridge, 1993). We examining medication effects on subjective effects of vary- recently reported that this pattern of stimulatory response ing alcohol doses among individuals who differ in blood was observed in comparing nonmedicated alcoholics and alcohol levels (or BAC curve characteristics) obtained from social drinkers (Thomas et al., 2004), so it does not seem a standard dose. that these group differences are specific to the active med- O’Malley and colleagues (O’Malley et al., 2002) found ication groups in the present study. However, given that we that naltrexone was associated with increased activation of did not obtain prealcohol ratings of stimulation or expected the HPA axis. That study also demonstrated an inverse effects of alcohol on stimulation, we cannot rule out the relationship between craving and HPA activation as well as possibility that these group differences are related to pre- lower overall craving and alcohol consumption after a low alcohol individual differences, rather than a pharmacolog- priming dose among those taking naltrexone. These find- ical effect of alcohol, per se. Another possibility is that ings may suggest that naltrexone obviates the need for differences in alcohol expectancies between alcoholics and greater alcohol consumption because naltrexone combined social drinkers (e.g., Goldman, 2002) could account for with small doses of alcohol achieves desired HPA effects differences in postalcohol stimulation ratings. In the ab- (e.g., stimulation). It is difficult to reconcile the present sence of an explicit measure of alcohol expectancies or a finding of reduced stimulation after alcohol, among alco- placebo alcohol experimental condition, it is difficult to holics taking opiate antagonists, with this interpretation of evaluate this possibility. Finally, although we attempted to the O’Malley et al. (2002) study. As suggested previously, statistically control for group differences in blood alcohol the relatively higher dose of alcohol used in the present levels, it is possible that the subjective effects were related study may interact differently with naltrexone. Further- to differences in blood alcohol levels between alcoholics more, the lack of HPA measurement or a baseline (preal- and social drinkers (see Drobes et al., 2003; Frezza et al., cohol) assessment of stimulation reduces the relevance of 1990; Lieber et al., 1994). This seems unlikely, though, as the present study for evaluating this interpretation. there were no zero-order correlations between peak blood Among alcoholics, medication effects on subjective reac- alcohol concentrations and stimulation ratings among ei- tions were most pronounced at the initial assessment after ther the alcoholics or the social drinkers in the present alcohol consumption. First, both naltrexone and nalmefene study. reduced craving at this time point, whereas nalmefene also We previously reported that naturalistic and laboratory reduced craving at each subsequent time point. In addition, alcohol consumption was reduced by opiate antagonist evidence of medication-attenuated stimulation and seda- medications in this sample and that these effects were tion was only observed at the initial time point. Of course, observed primarily among alcoholics (Drobes et al., 2003). sedation is not normally induced by alcohol within the first We suggested that this provided a rationale for evaluating few minutes, so it is possible that these differences reflected medication effects in subjects who closely resembled those general levels of sedation that were unrelated to direct who would likely use opiate antagonists in clinical settings alcohol effects. It is interesting to note that these early (i.e., alcoholics). The present findings promote a similar effects generally correspond to the time course of greatest message. For both craving and stimulation, medication ef- dopamine release in the nucleus accumbens (e.g., Yan, fects were mostly evident among the alcoholics. Conse- 1999) and behavioral activation (e.g., Moore et al., 1993) quently, the utility of including nonalcoholic drinkers in this during the ascending phase of the BAC curve in animal type of laboratory study may be limited to initial feasibility models. Opiate antagonists have been shown to reduce the studies or as procedural controls (to confirm that the alco- motoric stimulatory effects of alcohol in animals (Mid- holics are truly reacting differently to an alcohol challenge). daugh et al. 1978) and to block alcohol-induced dopamine An interesting finding in the present sample of alcoholics release in the nucleus accumbens (Benjamin et al. 1993). It was that opiate antagonist medications reduced stimulation is tempting to suggest that the blockade of dopamine by ratings only among subjects who achieved relatively lower naltrexone, and presumably nalmefene, was the biological peak blood alcohol levels. It may be that higher blood mechanism of the observed reduction in alcohol stimula- alcohol levels overwhelm the pharmacological impact of tion in this study. Together with our finding of larger opiate antagonist medications on reactions to alcohol. This medication effects among subjects who achieved a lower would be consistent with the relatively larger effect size for peak blood alcohol level, the overall pattern of findings naltrexone reducing alcohol consumption in the laboratory suggests that opiate antagonist effects on subjective re- study by O’Malley et al. (2002), in which a lower priming sponse to alcohol may be particularly pronounced soon BAC was obtained (approximately 30 mg/100 ml) than in after drinking, at lower levels, or during rising levels of the present study. An alternative possibility is that individ- blood alcohol. ual differences in peak BAC may be predictive of who Naltrexone and nalmefene were equally effective in re- would be most likely to benefit from opiate antagonist ducing initial increases in craving and stimulation after medications. Differences in the rate of BAC increase might alcohol consumption among alcoholics. However, the ef- 1368 DROBES ET AL. fects of nalmefene on craving were somewhat more pro- tions. It is clear, though, that the drinking patterns in this nounced and sustained over subsequent time periods, group were excessive (averaging eight drinks per drinking whereas the naltrexone effect dissipated after the initial day on 75% of days in the past month), diagnostically postalcohol assessment. Animal studies have indicated sub- relevant, and more closely aligned with treatment-seeking tle differences in the opiate receptor pharmacology of these samples than most prior laboratory studies that have fo- compounds, with nalmefene effecting ␦ and ␬ receptors cused on social drinkers. It may be feasible in the future to more than naltrexone (Culpepper-Morgan et al., 1995; De use similar paradigms with alcoholics exhibiting even more Haven-Hudkins et al., 1990; Emmerson et al., 1994; Mitch chronic and severe alcohol problems. Although we previ- et al., 1993). The present results suggest that differences in ously reported that many of these subjects reduce their opiate receptor binding between naltrexone and nalmefene alcohol consumption and may even seek treatment after may differentiate the length, and perhaps magnitude, of participating in this type of study (Drobes and Anton, clinical response. It is also possible that these differences 2000), more studies with nontreatment seekers should first may be related to the doses used in the present study; that be conducted to establish the validity and safety of the is, dosage equivalence is not ensured. However, the doses procedures. A third limitation concerns the use of a single were chosen based on their reported efficacy in double- alcohol dose. It is quite possible that different alcohol doses blind clinical trials. For the data observed here, it would would have revealed different effects on the range of de- seem that both medications would have similar efficacies in pendent measures. The selection of the moderate dose in clinical treatment. the present study was based partly on our expectation that We have recently discussed in some detail the side effect this dose would prime alcohol self-administration during a differences between the two opiate antagonist compounds subsequent study phase (see Drobes et al., 2003). Other (Drobes et al., 2003). It is important to note that, although researchers have observed effects with smaller doses there was a greater frequency of various central nervous (O’Malley et al., 2002). Indeed, it may be that medication system side effects with nalmefene, these effects were not effects on specific response systems (subjective, behavioral, severe and of little clinical significance. Furthermore, cen- neuroendocrine, etc.) differ according to the dose of alco- tral nervous system side effects with nalmefene were re- hol administered. duced substantially after a modification was made in the In summary, the present clinical laboratory paradigm titration schedule early in the study. Gastrointestinal side seems to provide a reliable procedure to evaluate medica- effects, also infrequent and mild in this study, were ob- tion effects on alcohol consumption in non-treatment- served equally with the two medications and were similar to seeking alcoholics. The finding that naltrexone and those reported in other clinical laboratory (King et al., nalmefene reduced alcohol craving and subjective effects of 1997a,b; Swift et al., 1994) and treatment studies (Anton et alcohol immediately after drinking a standard dose suggests al., 1999; Mason et al., 1994, 1999; O’Malley et al., 1992; that the paradigm may work well for testing other medica- Volpicelli et al., 1992). tions that could be clinically useful. With appropriate care, Several potential limitations suggest caution when inter- further alcohol administration studies may use alcoholics as preting the present findings. First, the observed medication subjects with confidence that the studies are ethical and effects on alcohol response during the present laboratory benign. assessment could potentially have been affected by medication effects on alcohol consumption and its effects during the week-long medication regimen in the naturalistic envi- ACKNOWLEDGEMENTS ronment. That is, we cannot rule out the possibility that We thank Catherine Kelly, Suzanne Wise, and Heather Brown medication-induced reductions in the amount of alcohol for their assistance in the conduct of this study and Wei Wang for consumed during the week preceding the laboratory ses- assistance with data management and analyses. We also thank sion (see Drobes et al., 2003), or potential differences in Dupont (naltrexone) and IVAX/Baker Norton (nalmefene) for donating medications and matching placebos. the experienced effects of alcohol during this week (which were not assessed), could have had an impact on subjective reactivity to alcohol in the laboratory. The present study REFERENCES was meant to evaluate medication effects within a paradigm American Psychiatric Association (1994). Diagnostic and Statistical Man- that had ecological validity for treatment-seeking alcohol- ual of Mental Disorders. 4th ed. American Psychiatric Association, ics. 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