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. Author manuscript; available in PMC: 2011 May 16.
Published in final edited form as: Int J Neuropsychopharmacol. 2008 Sep 17;12(5):589–597. doi: 10.1017/S146114570800936X

Dose Dependent Reduction of Hazardous Alcohol Use in a Placebo-Controlled Trial of Naltrexone for Smoking Cessation

Stephanie S O’Malley a, Suchitra Krishnan-Sarin a, Sherry A McKee a, Robert F Leeman a, Ned L Cooney a, Boris Meandzija a, Ran Wu a, Robert W Makuch b
PMCID: PMC3094855  NIHMSID: NIHMS133352  PMID: 18796184

Abstract

The opiate antagonist naltrexone has demonstrated efficacy in the treatment of alcohol dependence and as a component of treatment to reduce heavy drinking. At present, there are no published dose-ranging clinical trials of the oral preparation for treatment of problem drinking. The present study evaluated the effects of naltrexone on alcohol use among the subset of hazardous drinkers (N = 102) who participated in a placebo-controlled, dose-ranging trial of oral naltrexone (25 mg, 50 mg and 100 mg doses) combined with open-label transdermal nicotine patch for enhancing smoking cessation. On the primary outcome—no hazardous drinking (drinking that exceeded weekly or daily limits) during treatment—25 mg and 50 mg naltrexone were superior to placebo (each p < 0.05). These findings remained after controlling for baseline predictors or smoking abstinence during treatment. Time to remission of hazardous drinking was examined as a secondary outcome with definitions of hazardous drinking based on weekly limits, daily limits and the combination of weekly and daily limits and the results were consistent with the primary findings. In conclusion, the findings suggest that naltrexone can reduce the risk of hazardous drinking in smokers who are not seeking or receiving alcohol treatment, providing strong evidence for the pharmacological effects of naltrexone on drinking. This effect appears to favor lower doses that may be better tolerated and less expensive than the higher 100 mg dose. Given its efficacy and favorable side effect profile, the 25 mg dose should be considered for future studies of combination therapy.

Keywords: smoking cessation, heavy drinking, drinking reduction, naltrexone, measurement sensitivity

Introduction

Naltrexone is an opioid antagonist that was FDA-approved for the treatment of alcohol dependence in 1994 based in part on two efficacy studies of 50 mg daily (O’Malley et al., 1992; Volpicelli et al., 1992). The majority of subsequent clinical trial findings support naltrexone’s efficacy. A recent meta-analysis including 27 randomized controlled trials, mostly involving the approved oral dose of 50 mg, showed that naltrexone treatment in conjunction with psychosocial therapy decreased the likelihood of relapse to heavy drinking in the short-term (Srisurapanont and Jarusuraisin, 2005). Since this meta-analysis was completed, reports from two large, multi-site trials have been published: one examined two doses of long acting extended release naltrexone (XR-NTX) in combination with brief counseling (Garbutt et al., 2005; O’Malley et al., 2007); the other tested 100 mg oral naltrexone along with brief medically oriented counseling or coupled with a more intensive form of psychosocial therapy (The COMBINE Study, Anton et al., 2006). Both provided evidence of naltrexone’s efficacy in reducing heavy drinking in conjunction with some form of psychosocial therapy. In the study of extended release naltrexone, the 380 mg dose of XR-NTX, in contrast to the 190 mg dose, was the most efficacious compared to placebo.

The majority of clinical trials of naltrexone have enrolled alcohol dependent patients presenting for alcohol treatment who had some level of motivation to quit drinking. However, it is known that some drinkers, primarily those without severe alcohol dependence, are capable of reaching goals of moderate drinking (Miller and Wilbourne, 2003). Recent work has explored the use of naltrexone for this indication. Kranzler et al. (2003) conducted a placebo-controlled study of 50 mg naltrexone taken either daily or on a targeted basis (i.e., as needed in anticipation of drinking situations) in a sample of 150 early problem drinkers, of whom the majority (83%) had a goal of reduced drinking. In this 8-week trial, naltrexone, especially daily dosing, reduced the frequency of heavy drinking compared with placebo. While the findings of Kranzler’s trial argue that naltrexone can be efficacious for heavy drinkers not interested in stopping drinking, it is important to note that participants in this study were nonetheless motivated to change their drinking behavior and psychosocial therapy aimed at drinking reduction was provided along with naltrexone.

Another test of the pharmacological effects of naltrexone on reducing drinking would be to evaluate it among individuals who are not counseled to modify their drinking. A recent investigation by Tidey and colleagues (2008) found that 50 mg naltrexone reduced the frequency of drinking in a two-week double blind placebo controlled treatment period in heavy drinkers who were not advised to change their drinking; 63% of these subjects met criteria for current alcohol dependence. Similarly, using a cross over design in which 25 heavy drinking participants received either naltrexone 50 mg daily or placebo for one week and were not instructed to change their drinking, Mitchell et al. (2007) found a significant decrease in the number of drinks consumed while on naltrexone. In addition, laboratory studies have shown that naltrexone can decrease the amount of alcohol consumed during a drinking episode by nontreatment seeking heavy drinkers or alcohol dependent subjects (Anton et al., 2004; Krishnan-Sarin et al., 2007; O’Malley et al., 2002).

Surprisingly, there are no published placebo controlled clinical trials of multiple doses of oral naltrexone and only a handful of alcohol administration laboratory studies that have systematically examined different naltrexone doses (Doty and deWit 1995; Doty et al., 1997; Krishnan-Sarin et al., 2007; McCaul et al., 2000a; McCaul et al., 2000b; McCaul et al., 2001). Of these laboratory studies, only the report by Krishnan-Sarin and colleagues (2007) examined naltrexone effects on drinking behavior.

The present report provides information about the effects of different doses of oral naltrexone on alcohol drinking by conducting analyses of drinking data obtained in a naltrexone clinical trial designed to test the primary hypothesis involving smoking cessation (O’Malley et al., 2006). In this study, 400 smokers received 6-weeks of treatment with a transdermal nicotine replacement (21 mg/day) along with either placebo or one of three doses of oral naltrexone: 25, 50 or 100 mg daily. Prior to randomization, a substantial proportion of the participants met the National Institute on Alcohol Abuse and Alcoholism’s (2005) criteria for hazardous drinking, which is determined by exceeding daily or weekly drinking limits. This category of drinkers has public health relevance because hazardous drinking is four times more prevalent than alcohol dependence (Reid et al., 1999; Wilk et al., 1997), and these drinkers consume sufficient quantities of alcohol to be at risk for alcohol-related consequences (e.g., impaired driving, liver disease, hypertension). It is known that hazardous drinkers represent 80% of all individuals who experience alcohol problems (Institute of Medicine, 1990). As a result, data from this subsample provided a unique opportunity to examine the dose dependent effects of naltrexone on drinking behavior among individuals not motivated to reduce their drinking and in the absence of alcohol counseling. In making these comparisons, we explored the utility of several distinct definitions of reduced drinking to determine their ability to distinguish among different drug doses in terms of efficacy. We examined whether weekly limits, daily limits or the combination of daily and weekly limits was most sensitive to the effects of naltrexone. The final goal of this effort was to identify a group of independent and important baseline predictors of outcome. Such information could prove useful in the design and analysis of future studies.

Methods

Participants

Participants included in this analysis were a subgroup of those enrolled in the O’Malley et al. trial (2006) who met criteria for hazardous drinking at baseline and who provided any drinking data during treatment. The methods of the original trial, including a CONSORT flow diagram, were described in detail in O’Malley et al. (2006). Briefly, participants were recruited primarily through advertisements. In order to enroll, smokers had to be 18 years or older, be able to speak English, weigh at least 45 kg (≥ 100 lb), smoke 20 or more cigarettes daily for at least the past year, give an expired carbon monoxide (CO) level > 10ppm and report at least one prior quit attempt. Only one individual per household was allowed to enroll. Women were not allowed to enroll if pregnant, nursing or not using a reliable form of birth control. Other exclusion criteria included unstable cardiac disease, use of psychotropic medications, opiate use, elevated liver function tests (i.e., aspartate amino transferase (AST) or amino alanine transferase (ALT) >3 times normal or elevated bilirubin) and current alcohol dependence.

Those exceeding the gender-specific recommendations for maximum weekly or daily drinking delineated by the NIAAA (DHHS, 2005) during the six weeks prior to randomization were considered to be heavy drinkers and were included in the present report; specifically, male heavy drinkers consuming more than 14 drinks/week or greater than 4 drinks on at least one occasion and female drinkers consuming more than 7 drinks/week or greater than 3 drinks on at least one occasion. A drink was defined as a beverage containing 0.5 oz. (14.12 gms) of ethanol.

Procedures

Participants were enrolled at two sites: the Connecticut Mental Health Center in New Haven and the Veterans Affairs (VA) Connecticut Healthcare System, Newington. The trial was approved by the following institutional review boards: the VA Connecticut Healthcare System, Yale University School of Medicine in New Haven and the University of Connecticut Health Center in Farmington. Eligible participants were randomized using a block randomization procedure, stratified by sex for the final 250 individuals. All participants received open label 21-mg transdermal nicotine patches (Nicoderm CQ, GlaxoSmithKline, Research Triangle Park, NC), brief weekly smoking cessation counseling with handouts and one of four doses of medication: placebo, 25 mg, 50 mg or 100 mg oral naltrexone (Mallinckrodt Pharmaceuticals, Hazelwood, MO) to be taken daily for a period of six weeks. Naltrexone was titrated up to the target dose over the first week (i.e., 12.5 mg for one day, 25 mg for one day, 50 mg for two days, 100 mg thereafter). Medication compliance was monitored with the use of eDEM caps, which record the time of bottle openings (APREX [AARDEX USA], Union City, CA) and plasma levels of naltrexone and 6-beta naltrexol. Participants and study staff members interacting with participants were blind to naltrexone dose assignment.

No formal alcohol-related counseling was provided. The only information about alcohol use was limited to written advice to avoid alcohol, as well as other beverages associated with smoking. Smoking cessation counseling was provided and assessments were conducted on a weekly basis during the six weeks of treatment. At each appointment, self-reported tobacco and alcohol use were assessed using a Timeline Followback Interview (TLFB). Other baseline assessments reported in this paper include the Alcohol Use Disorders Identification Test (Babor et al., 1992), the Fagerström Test for Nicotine Dependence (Heatherton et al., 1991) and the Center for Epidemiologic Studies Depression Scale (CES-D) (Radloff, 1977). Tobacco use was biochemically verified using CO levels at weekly appointments. Individuals were considered continuously abstinent from smoking if they abstained from smoking “not even a puff” for the six weeks and had a CO level ≤ 10ppm.

Statistical Analyses

Our primary outcome used the definition of hazardous drinking above to classify patients in a binary fashion as either a ‘success’ or ‘failure’ at the completion of their treatment based on whether they continued to meet heavy drinking criteria during the six-week treatment period. This categorical outcome was analyzed with logistic regression in which each active dose was contrasted to placebo.

Several additional distinct definitions of reduction-in-drinking ‘success’ were also examined using ‘survival’ or time-to-event analyses. NIAAA Guidelines define hazardous drinking as exceeding either weekly limits or daily limits. We examined three definitions of success based on either the composite of weekly and daily limits, weekly limits alone, or daily limits alone and modeled success defined by time to the first week when hazardous drinking stopped and nonhazardous drinking was maintained for the remainder of the treatment period. The first (DEFINITION 1 – Composite Outcome) defined hazardous drinking as exceeding either the NIAAA weekly or daily limits and involved the time to the first week without hazardous drinking and with continued adherence to drinking under the composite drinking limit for the remainder of the treatment period, where continued adherence required that drinking was less than both daily and weekly limits defined above. The second (DEFINITION 2 – Weekly Limits) definition of reduction-in-drinking ‘success' involved examination of only one category of hazardous drinking, ie, more than 14 drinks during a week among males and more than 7 drinks during a week among females. For this single-category definition, we measured the time to the first week without hazardous weekly drinking and with continued adherence to this criterion for the remainder of the study period. A third definition (DEFINITION 3 – Daily Limits) involved measuring the time to the first week without hazardous drinking defined by daily limits (greater than 4 drinks/day for males and greater than 3 drinks/day for females) and with continued adherence to this criterion for the remainder of the study period. Finally, we repeated the analysis of the primary outcome of success or failure based on whether or not the person met criteria for the composite definition of hazardous drinking at any point during the six-week treatment period, this time controlling for baseline patient characteristics using logistic regression in which each active dose was contrasted to placebo. The baseline characteristics reported in Table 1 were included in these analyses. The backward selection method was used in this process to eliminate any nonsignificant factors (α =.05). Medication groups were forced into every model. Logistic regression analyses were also used to compare the medication groups to placebo on continuous abstinence from smoking following randomization to first examine whether naltrexone promoted smoking abstinence in this subsample and then to examine the effects of naltrexone on the primary outcome of hazardous drinking controlling for smoking abstinence, which could potentially influence drinking behavior. Time-to-event analyses were performed using the Kaplan-Meier method to display the curves, and using the log-rank test to compare the curves. SAS (Version 9.1) was used for all statistical analyses. All p-values in this report are of the 2-sided type.

Table 1.

Baseline characteristics for the entire sample and by dose group

Group
Overall
(N = 102)		 Placebo
(n = 26)		 25 mg
(n = 23)		 50mg
(n = 25)		 100mg
(n = 28) 		p value
Overall
Age (yr) 42.37±11.91 41.19±11.57 40.87±13.92 40.68±13.67 46.21±7.84 0.259
Female sex (%) 45.1 42.31 52.17 52 35.71 0.568
White race (%) 87.25 88.46 82.61 92 85.71 0.79
Body Mass Index 28.00±4.70 28.75±5.48 27.41±4.20 27.08±4.28 28.62±4.70 0.487
Education (%) 0.149
    High-school graduate or less 30.53 33.33 18.18 26.09 42.31
    Some education after high school 43.16 54.17 50 30.43 38.46
    College graduate or more 26.32 12.5 31.82 43.48 19.23
Married or cohabitating (%) 49.5 61.54 30.43 50 53.57 0.169
Full-time employment (%) 75.76 84 65.22 73.91 78.57 0.479
No. of cigarettes smoked per day 25.87±7.73 26.59±7.83 23.58±5.00 25.37±5.93 27.55±10.35 0.303
Years of smoking cigarettes 25.59±11.47 24.88±11.81 24.82±11.99 24.00±13.13 28.30±9.05 0.546
Fagerstrom score 5.12±1.65 4.81±1.67 5.13±1.55 5.04±1.54 5.50±1.82 0.504
Other smokers in household (%) 37 42.31 27.27 44 33.33 0.596
Family history of alcoholism (%) 45.92 52 36.36 40 53.85 0.534
CES-D score 13.03±4.87 12.85±5.61 13.57±4.51 12.96±5.15 12.81±4.32 0.947
AUDIT score 4.37±3.17 4.96±2.88 3.18±2.04 3.96±3.66 5.15±3.50 0.108
Baseline drinks per occasion 4.15±3.02 3.68±2.03 3.56±1.60 4.14±2.64 5.08±4.54 0.247
Baseline percent days abstinent 58.52±35.23 53.15±34.18 66.33±32.28 57.81±39.17 57.74±35.60 0.631
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Results

Demographic and baseline characteristics

One hundred-two participants met hazardous drinking criteria at baseline. Of these, 16 exceeded weekly limits only, 37 exceeded daily limits only, and 49 exceeded both daily and weekly limits. The demographic and clinical characteristics of the 102 hazardous drinkers are presented in Table 1 for the naltrexone and placebo groups. The medication groups are similar with respect to race, body mass index, number of cigarettes smoked per day, and CES-D score. Several factors differed to varying degrees among the treatment groups, however. These differences were noted in the 100 mg group only which had an older average age, a higher percentage of males, fewer college graduates, a higher average Fagerstrom Nicotine Dependence score (Heatherton et al., 1991) and higher AUDIT scores and amount of alcohol consumed per occasion at baseline. Although none of these differences was statistically significant, analyses were performed to examine their influence on the end of treatment primary outcome variable of continued hazardous drinking.

Treatment Compliance and Adverse Events

There were no differences between the groups on the number of weeks in treatment (mean = 5.25, S.D. = 1.58, p = 0.96), the percentage of naltrexone doses taken (mean = 76.83, S.D. = 27.53, p = 0.99), or the number of weeks that nicotine patch was used (mean = 5.18, S.D. = 1.66; p = 0.98). The groups did not differ in the percentage of participants for whom naltrexone was either discontinued or the dose was reduced (p = 0.17). However, dose changes occurred in 8% of the 50 mg group and 10.7% of the 100 mg group with no changes made in the placebo and 25 mg groups. The percentage reporting any moderate-severe adverse event did not differ significantly by dose (p = 0.36). As would be expected, serum naltrexone and 6-b-naltexol concentrations were approximately dose proportional (data not shown).

Primary Outcome Results

On the primary outcome measure, incidence of any hazardous drinking during treatment, there was a statistically significant overall difference among the four groups (p = 0.024), with the placebo group being most likely to continue meeting hazardous drinking criteria (22/26, 85%) vs. 43% (10/23), 56% (14/25), and 64% (18/28) for the 25 mg, 50 mg, and 100 mg groups, respectively. Pairwise treatment comparisons indicate that placebo was worse than the 25 mg group [relative risk (RR) = .14 (2-sided 95% confidence interval = (0.04, 0.54)); p = .004] and worse than the 50 mg group [RR = 0.23 (2-sided 95% confidence interval = (0.06, 0.87)); p = 0.031]. There was a trend for the placebo group to be worse than the 100 mg group [RR=.33 (2-sided 95% confidence interval = (0.09, 1.22)); p = 0.096].

Secondary Definitions of Success

Figure 1 shows the time to remission of hazardous drinking defined by weekly and daily limits (i.e., Definition 1). There was a statistically significant difference overall (log rank test, p = 0.028), with all three treatment groups having a shorter time compared to placebo. The 25 mg group had a statistically significantly shorter time to termination of hazardous drinking compared to placebo (log rank test, p = 0.002), with a RR = 2.48 indicating that one was 2.48 times more likely to stop hazardous drinking earlier if randomized to receive 25 mg naltrexone. The estimated median time to continued remission of hazardous drinking was 1 week for the 25 mg naltrexone group versus 6 weeks for the placebo group. There were non-significant trends for improvement seen in the other two naltrexone groups as well, with a RR = 1.64 for the 50 mg group (log rank test, p = 0.14) and a RR =1.68 for the 100 mg group (log rank test, p = 0.09). Compared to the estimated median time to remission of hazardous drinking of 6 weeks for the placebo group, the 50 mg and 100 mg naltrexone groups had median times to remission of 2 and 3 weeks, respectively.

Figure 1.

Figure 1

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Time to Termination of Hazardous Drinking Defined by Weekly or Daily Limits.

Figure 2 shows the time to the first week of remission of hazardous drinking with hazardous drinking defined as exceeding weekly limits (i.e., Definition 2: drinking > 14 drinks/week for men and > 7 drinks/week for females). Unlike the previous analysis in which naltrexone was significantly superior to placebo when remission meant that both weekly and daily nonhazardous drinking criteria were met and maintained, the analysis of a remission outcome based on only weekly drinking limits only showed a trend overall favoring the naltrexone groups when all four groups are included in the analysis (overall log rank test, p = 0.14). There was a statistically significantly shorter time to remission in the 25 mg versus placebo (log rank test, p = 0.028), which was not seen in the 50 mg versus placebo comparison (log rank test, p = 0.67) or the 100 mg versus placebo comparison (log rank test, p = 0.16). The estimated median time to remission from hazardous drinking based on weekly drinking limits was 3.5, 1.0, 1.0, and 1.0 weeks for the placebo, 25 mg, 50 mg, and 100 mg groups, respectively. Thus, compared to the dual criteria hazardous drinking outcome in Figure 1, the definitional change of remission in Figure 2 to a single weekly drinking limit reduced the median time to remission for the placebo group from 6 weeks to 3.5 weeks, while the active treatment median estimates changed less. Between-treatment sensitivity seems to be substantially enhanced when hazardous drinking is defined using both daily and weekly limits. When the analysis of remission based on weekly limits was restricted to the smaller subsample of 65 participants who exceeded weekly limits at baseline, the results were not statistically significant.

Figure 2.

Figure 2

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Time to Termination of Hazardous Drinking Defined by Weekly Limits.

When we compared the time to remission of hazardous drinking with hazardous drinking defined as exceeding daily limits (i.e., Definition 3), we found there was a highly statistically significant difference among the four groups (p < 0.001 overall), with significantly more rapid remission seen in the 25 mg and 50 mg dose naltrexone groups when compared to placebo (p = 0.006 and 0.007, respectively). This is presented graphically in Figure 3. Only a trend in time to remission was seen in the high dose naltrexone comparison versus placebo (p = 0.08). The estimated median time to remission from hazardous drinking defined by daily limits was 6, 1.0, 1.0, and 3 weeks for the placebo, 25 mg, 50 mg, and 100 mg groups, respectively. The statistically significant difference between the four groups remained when the analysis was restricted to the 86 participants who exceeded daily limits at baseline. In this subgroup, the placebo group had the poorest outcome, the 25 mg dose was most effective, and the 50mg and 100mg doses were similar and intermediate.

Figure 3.

Figure 3

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Time to Termination of Hazardous Drinking Defined by Daily Limits.

Analyses Controlling for Baseline Predictors and Smoking Cessation Success

After controlling for baseline predictors of the primary composite outcome of any hazardous drinking during treatment, our findings were similar to that in which the simple model without covariates was used. Subjects in 25mg (OR: 0.132; CI: 0.027, 0.657) and 50mg (OR: 0.178; CI: 0.038–0.833) dose groups were less likely than the placebo group to report any hazardous drinking activity during treatment in the final model controlling for significant baseline predictors. The significant baseline predictors of drinking outcome were age, Fagerström scores, years of daily smoking and percent days abstinent from alcohol. Specifically, continued hazardous drinking was associated with younger age (OR: 0.816; CI: 0.682, 0.976), lower Fagerström scores (OR: 0.665; CI: 0.461, 0.961), longer duration of daily smoking (OR: 1.198; CI: 1.005, 1.428) and fewer days of abstinence in the six weeks prior to treatment (OR: 0.960; CI: 0.938, 0.984).

In this subsample of hazardous drinkers, naltrexone did not increase smoking abstinence rates significantly at any dose compared to placebo. The number and percentage who achieved continuous smoking abstinence from the quit date was 12 (47.2%), 11 (47.8%), 8 (32%) and 14 (50%) for the placebo, 25 mg, 50 mg and 100 mg conditions respectively. The dose dependent effects of naltrexone on the primary composite outcome of no hazardous drinking were unchanged when continuous abstinence from smoking was entered as a covariate into a logistic regression analysis. Continuous abstinence from smoking was not significantly associated with reduced risk of hazardous drinking during treatment (Χ2 = 2.22, 1df, p = .14, OR: 1.938; CI: 0.811, 4.631).

DISCUSSION

This placebo controlled 6-week study presents new findings about the effect of different doses of oral naltrexone on alcohol drinking in a hazardous drinking sample that was not seeking treatment to reduce hazardous drinking and in the absence of specific counseling to reduce or abstain from alcohol. Most prior investigations have recruited alcohol dependent patients and have made use of the FDA-approved oral dose of 50 mg, although the COMBINE Study, the largest study to date, used 100 mg daily (Anton et al., 2006). Our data suggest that among individuals who are smokers and are not currently alcohol dependent, 25 mg and 50 mg daily are optimally effective for reducing hazardous drinking, with somewhat less efficacy found for 100 mg daily. These findings persisted even in analyses that controlled for potential baseline predictors of outcome. The results of the baseline predictors, however, suggest that those who are younger, have smoked longer, have lower Fagerström scores and have fewer days of abstinence are less likely to reduce their hazardous drinking during a smoking cessation effort that does not include counseling to help them reduce their drinking. In contrast to some but not all prior studies (e.g. Krishnan-Sarin et al., 2007, Garbutt et al., 2005), gender and family history of alcoholism did not alter these findings; these differential effects could be related to the non-dependent nature of the population examined in our study.

A further strength of this investigation is that it provided an unbiased endpoint determination of drinking, since the primary purpose of this trial involved the comparative evaluation of smoking cessation outcomes. Even in trials involving high proportions of patients interested in moderate drinking rather than abstinence (e.g., Kranzler et al., 2003), these individuals were still seeking treatment for their alcohol use, and alcohol consumption was the primary focus of prior studies in nontreatment seeking subjects (e.g., Tidey et al.; Mitchell et al., 2007). The finding that naltrexone reduced risky drinking adds to the growing literature on the benefits of naltrexone on heavy alcohol consumption (Anton et al., 2006; Garbutt et al., 2005; Kranzler et al., 2003, for a review see Pettinati et al., 2006), and extends this to a sample of individuals who were not seeking or receiving counseling for their drinking. This provides strong evidence for a pharmacological effect of naltrexone, and is consistent with the results of laboratory studies demonstrating reductions in drinking among nontreatment seeking hazardous and alcohol dependent drinkers (Anton et al., 2004; Krishnan-Sarin et al., 2007; O’Malley et al., 2002) and two short-term outpatient studies in in nontreatment seeking heavy alcohol drinkers (Tidey et al., 2008; Mitchell et al., 2007). One clinical implication of the current study is that naltrexone may be helpful in reducing hazardous drinking among individuals who are lacking in motivation for alcohol treatment.

The efficacy of the 25 mg dose is particularly promising and warrants replication given that 25 mg was associated with somewhat better compliance and fewer side effects than the 100 mg dose in the larger parent study (O’Malley et al., 2006) and did not require dose reductions in the subsample of hazardous drinkers. The observed dose dependent effects of naltrexone could reflect differences in opioid receptor specificity with different doses of naltrexone and changes in receptor levels produced by chronic naltrexone. Naltrexone is more specific for mu opioid receptors at lower doses with greater activity at delta and kappa opioid receptors at higher doses. Recent evidence suggests that a 50 mg dose of naltrexone results in complete occupancy of the mu-opioid receptors (Bencherif et al., 2007), indicating that the reduction in drinking observed with a 25 mg dose in our study is probably related to mu-receptor occupancy. Additionally, chronic treatment with higher doses of naltrexone may result in greater upregulation of mu opiate receptors (Brady, 1992).

In this paper, we chose to examine three different definitions for remission from hazardous drinking during the course of this six-week smoking intervention trial. The first remission definition being the joint requirement of termination of both weekly and daily excessive drinking, the remaining two definitions of remission being based on termination of drinking that exceeded either weekly or daily drinking limits. We also presented data in terms of ‘time to event’ analysis in order to develop a good ‘sensitivity’ assay in terms of time to remission and the ability to discriminate between active treatment groups, and between active treatment groups versus placebo. With regard to these definitions, the findings suggest that in order to discern treatment effects, it is best if both daily and weekly criteria for drinking ‘success’ be met and maintained and that these outcomes can show between-treatment differences that are highly statistically significant (certainly less than 0.01). However, when the components making up this composite were examined separately, the effects of naltrexone were most apparent on drinking that exceeded daily limits rather than weekly limits. In designing future studies, the data suggest that there may be an advantage in using a composite measure of success, in which several components of drinking reduction (e.g., weekly success and daily success) are combined and that this composite endpoint be maintained over the entire treatment course as well. Of note, in the COMBINE Study, the strongest effect of naltrexone was found for a composite index of good clinical outcome that incorporated information on drinks per week, days of heavy drinking and drinking related problems over the last eight weeks of the 16 week trial (Anton et al., 2006). Composite outcomes seem to be most relevant and attractive from a practical viewpoint, since it is the total drinking experience of an individual that is probably important.

Several limitations may impact the generality of the results. First, this was a secondary analysis using a subset of hazardous drinkers participating in a larger dose ranging study of naltrexone for smoking cessation and randomization was not stratified on the basis of hazardous drinking status. While there were nonsignificant differences between the groups at baseline, accounting for baseline characteristics did not change the findings. The sample was comprised exclusively of smokers who did not meet current criteria for alcohol dependence. Thus, the findings may not generalize to nonsmokers, to those meeting current criteria for alcohol dependence, and to conditions in which participants are seeking to change their drinking with more intensive counseling. Related to this last point, the COMBINE Study found that naltrexone was beneficial when provided in conjunction with Medical Management, but not in combination with a more intensive behavioral treatment and Medical Management (Anton et al., 2006). Additionally, all participants received open-label 21 mg transdermal nicotine patch combined with naltrexone. Prior research has demonstrated that nicotine patch can attenuate drinking behavior (Acheson et al., 2006; McKee et al., 2008), and it is possible that transdermal nicotine limited differences observed between placebo and active naltrexone groups. Another important limitation is that drinking was only examined during six weeks of treatment. We do not know how drinking would be affected by a longer duration of treatment. Despite these qualifiers, this study provides important information about oral naltrexone dosing and on measures of treatment success that are most sensitive to naltrexone.

In conclusion, the results of this study suggest that naltrexone can reduce the risk of hazardous drinking in smokers who are not seeking or receiving counseling to reduce their drinking. This effect appears to favor lower doses of naltrexone that may be better tolerated and less expensive than the higher 100 mg dose. Given the favorable side effect profile and efficacy of the 25 mg dose, this dose should be considered for future studies of combination therapy. Based on the present results, naltrexone in combination with nicotine replacement may provide an effective strategy for reducing hazardous alcohol consumption in the context of a smoking cessation intervention.

Acknowledgements

This study was supported by the following NIH grants P50-DA-13334, P50-AA-15632, K02-AA00171, and R01-AA11197; grant 039787 from the Robert Wood Johnson Foundation, Princeton, NJ; and by the Department of Veterans Affairs, Newington, Conn. GlaxoSmithKline generously donated nicotine patches. Naltrexone and matching placebo were purchased from Mallinckrodt Pharmaceuticals. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, or the National Institutes of Health.

Footnotes

CLINICAL TRIAL REGISTRATION INFORMATION: NCT00218153

STATEMENT OF INTERESTS: Drs. O’Malley, Krishnan-Sarin and Meandzija are inventors on unlicensed patents held by Yale University for the use of naltrexone for smoking cessation. Dr. O’Malley has received research support (medication supplies or contracts) from Alkermes, Inc, Dupont, GlaxoSmithKline Inc, Forest Laboratories, Lipha Pharmaceuticals, Ortho-McNeil Inc, Bristol-Myers Squibb, Pfizer Inc, Sanofi-Aventis, and Mallinckrodt Pharmaceuticals; served as a consultant Alkermes Inc, Forest Laboratories, GlaxoSmithKline Inc, Ortho-McNeil/Johnson & Johnson, and Eli Lilly; received travel reimbursement from Alkermes; and gave a talk for the Medical Education Speakers Network. Dr. McKee received nicotine patches from GlaxoSmithKline and worked on contracts to Yale University from Pfizer Pharmaceuticals. Dr. Meadzija worked on clinical trial contracts to Yale University from Alkermes Inc, Bristol-Myers Squibb, and Ortho-McNeil, Inc. Dr. Krishnan-Sarin received research support from Pfizer Inc. Dr. Cooney’s spouse is on the speaker’s bureau of Pfizer Pharmaceuticals.

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