ADDICTION TREATMENT

Forum
 

N A LT R E XO N E C L I N I C A L U PD AT E 
 

Evidence for the Efficacy of Naltrexone
 

in the Treatment of
 

Alcohol Dependence (Alcoholism)
 

Stewart B. Leavitt, PhD, Editor 

ABSTRACT 

Each year, more than 1.5 million Americans seek treatment for quantity of alcohol consumption in those who do drink, and alcoalcohol-related problems. In 1994, naltrexone became only the hol craving. 

second drug approved to date for treating alcoholism by the U.S. In brief, naltrexone is significantly beneficial in helping those 

FDA. Naltrexone blocks opioid receptors in the brain, stemming patients who cannot remain abstinent to reduce their drinking 

the endorphin-mediated reinforcing effects of drinking alcohol. behaviors, breaking the vicious, self-destructive cycle in alcoholics 

Recognizing that healthcare providers need credible scientific whereby one drink leads to another, and allowing more quality time 

information for decision-making purposes when considering phar- for psychosocial therapy to be productive. Naltrexone has demonmacotherapies for alcoholism, such as naltrexone, this report strated effectiveness in a variety of alcohol-treatment settings 

focuses on the highest level of clinical evidence – randomized con- using adjunctive psychosocial therapies that provide motivation to 

trolled trials (RCTs). Through year 2001 there were 14 RCTs stay in treatment, avoid relapses, and take medications. 

assessing the effectiveness of naltrexone compared with placebo Individualized, flexible naltrexone dosing can be of benefit. 

for treating alcoholism, enrolling 2127 subjects, in five countries. Longer-term naltrexone therapy extending beyond three months 

An analysis of these trials, consistent with prior systematic may be most effective, and naltrexone might be used on an asreviews and meta-analyses, concludes: A) RCTs of naltrexone in needed, “targeted,” basis indefinitely. It is expected that the inforthe treatment of alcoholism are recent, extensive, and of good mation in this report will help healthcare providers to better use this 

quality, B) There is strong evidence that naltrexone significantly effective medication. 

reduces alcohol relapses to heavy drinking, the frequency and 

From Snake Pits to Science 

About 14 million American adults meet diagnostic criteria for 

alcohol abuse or alcohol dependence (alcoholism). And, every year, 

more than 1.5 million seek treatment for their alcohol-related problems (Highlights... 2000; Kurtzweil 1996). 

Throughout history, attempts to treat alcoholics have been illconceived and gave disappointing results. A first treatment for chronic drunkenness may have been devised by ancient Romans, who 

lowered habitual drunkards into snake-filled pits, thinking the terror 

would shock them into abandoning their wayward practices (Sournia 

1990). 

By the close of the 19th Century, Merck’s Manual of the 

Materia Medica (1899) was recommending such nostrums for alcoholism as arsenic, bromides, cocaine, chloral hydrate, opium, and 

strychnine. Roughly 50 years later, in 1948, disulfiram became the 

first U.S. Food and Drug Administration (FDA) approved drug for 

alcoholism treatment (Kurtzweil 1996). It induces nausea, vomiting, 

and other aversive reactions in those who drink alcohol while taking 

the medication. 

After nearly another half-century passed, in late 1994, naltrexone became only the second drug approved to date for alcoholism by 

the FDA (Kurtzweil 1996).This new indication was authorized in 

part because of naltrexone’s accumulated record of safety during 

extensive prior use for opioid detoxification and in the treatment of 

heroin addiction (Naltrexone... 1997; Miller 1997, p75). 

A deciding factor, however, was results from two pivotal studies demonstrating naltrexone’s usefulness as part of a clinical program for treating alcoholism (O’Malley et al. 1992; Volpicelli et al. 

1992). In its approval, the FDA recommended that naltrexone also be 

used with adjunctive psychosocial therapies for alcoholism. 

1 
Naltrexone’s pharmacologic actions are 

fairly straightforward. Alcohol is a complex 

substance, affecting a number of chemical systems in the brain. Among other effects, it is 

suspected that, when an alcoholic imbibes, the 

brain’s opioid system releases endorphins 

triggering reinforcement that entices the 

person to drink more (Goldstein 1997; 

Naltrexone...1997; O’Brien 1997; O’Malley 

1998, Swift 1995). 

Unlike earlier drugs used to treat alcoholism, naltrexone is not addictive and does 

not react aversively with alcohol. It blocks opioid receptors in the 

brain (it is an antagonist), and this has been proposed as stemming 

the endorphin-mediated reinforcing effects of drinking alcohol. The 

validity of this concept has been supported by observations that 

alcoholics experience increased opioid system activity in response to 

alcohol (Herz 1997; Miller 1997). 

Some controversy has surrounded the use of naltrexone for 

alcoholism (Freed and York, 1997). First, healthcare providers, and 

patients themselves, sometimes question the value of using any drug 

to treat drug or alcohol addiction. Second, research on the effectiveness of naltrexone and how best to use it in treating alcoholism has 

evolved rapidly during just the past decade and cumulative findings 

are not widely known or appreciated. 

In this era of managed care and increasing pressures of accountability, healthcare providers need credible scientific information for 

decision-making purposes in recommending medications such as naltrexone. They need to respond authoritatively to questions such as: 

•	 Where did you learn that naltrexone is effective in treating 

alcoholism? 

• How do you know the information is reliable and valid? 

• What results do you expect from using naltrexone? 

These questions serve as the foundation of this clinical update 

report. The goal is to provide healthcare providers with useful, evidence-based answers. 

Treatment Expectations 

It has been stressed that both alcoholics and alcohol abusers 

need treatment, although the goals may differ. According to the FDA, 

“In most cases of alcohol abuse, the goal is to limit drinking, while 

for alcoholism, it is to stop drinking altogether” (Kurtzweil 1996). 

The immediate goal of most recovery programs is alcohol abstinence, yet that is often too strict a standard. According to some studies, about half of patients experience a relapse to heavy drinking 

within 12 weeks of beginning treatment, and up to 90% will relapse 

at least once during four years following treatment. (Kurtzweil 1996; 

Nathan 1986; Volpicelli et al. 1992). 

When sustained abstinence cannot be achieved, other goals, 

such as reducing the number, frequency, or severity of relapses could 

be of significant clinical value. A great potential benefit of naltrexone, in combination with appropriate psychosocial therapy, would be 

providing the patient relief from the self-destructive cycle of intoxication to enhance engagement in treatment and achieve long-term 

recovery objectives (Miller 1997, p59). 

Volpicelli et al. (1992) have suggested that the ideal pharmacological agent for use in alcoholism treatment would, first, decrease 

alcohol craving and reduce the initial motivation to drink. Second, if 

drinking does occur, the agent should block the reinforcing or desirNaltrexone 

is not addictive 

and does not react 

aversively with 

alcohol. 

able qualities of alcohol to decrease further 

drinking behavior, so a “lapse” does not 

progress to a relapse. Naltrexone’s ability to 

fulfill those requirements is examined in the 

research evidence. 

Evidence Selection 

The various types of research study 

designs may be ranked according to a “hierarchy of evidence,” based on their relative 

strengths for providing results that are likely to 

be valid and free of bias. Randomized controlled clinical trials (RCTs) are considered by many as the “gold 

standard” when addressing questions of a drug’s therapeutic efficacy 

(Guyatt and Drummond 1993; Sackett et al. 1997), and are the focus 

of this report. 

Naltrexone Clinical RCTs 

Through year 2001 there were 14 clinical RCTs to assess the 

effectiveness of naltrexone for treating alcoholism, enrolling 2127 

subjects, and conducted in five countries. 

Table 1 presents summaries of those trials. For some of the earlier studies, multiple published articles have discussed data from the 

same treatment population and are grouped together. Unless noted 

otherwise, all of the RCTs reported in Table 1 had the following characteristics in common: 

•	 Subjects met criteria for alcohol dependence according to the 

Diagnostic and Statistical Manual of Mental Disorders 3rd or 

4th editions (DSM 1987, 1994), had a recent history of alcohol 

intoxication, and were between 18 and 65 years of age. 

•	 Subjects were excluded if they had significant liver disease, a 

psychiatric diagnosis beyond alcohol dependence that was being 

treated with psychotropic medication, or substance abuse (other 

than alcohol and excluding nicotine or occasional marijuana use). 

Pregnant women or those likely to become pregnant while on 

naltrexone also were excluded. 

•	 Subjects were withdrawn (detoxified) from alcohol and abstinent 

for a period of time prior to administration of study medication. 

An exception was the RCT by Heinala et al. (2001), in which 

prior alcohol abstinence was not required. 

•	 Subjects were randomly assigned to treatment groups and there 

were no significant demographic differences between groups at 

the start. 

•	 Naltrexone (NTX) was compared to an identical-appearing inert 

substance (placebo, PBO). The naltrexone dose was equivalent to 

50 mg/day, except in the study by Monterosso et al. (2001; 

100 mg/day). 

•	 Neither subjects nor investigators knew if NTX or PBO was 

being taken (double-blind). 

Outcome Measures 

Table 1 shows seven outcome measures used to compare the 

efficacy of naltrexone with placebo. The first two – abstinence and 

time to first drink – portray alcohol avoidance during the respective 

trial. 

The next four are alcohol consumption outcomes in those subjects who were not abstinent: number of drinking days, drinks per 

drinking day, relapse rate, and days of heavy drinking. In most stud2 
Table 1: R

Study* 

(Authors/Year 

Country, Sites) 

N 

CTs

Study 

Duration 

(Rand

Type of 

Psychosocial 

Therapy 

omized, 

NTX Efficacy Outcomes 

Abstinence

Time to 1st Drink

Drinking Days

Days Heavy

Drinking

Craving Score 

Drinks per

Drinking Day

Relapse 

Controlled Clinical Trials) – Naltre

Notes 

xone (NTX) vs Placebo (PBO) 

O’Malley et al. 1992, 

1996a, 1996b; Jaffe 

et al. 1996. 

USA-single site. 

97 12 wk CST vs ST NS ++ + ++ + CST had the significant effects on all outcomes, and 

results were better in trial completers. During a 24 wk 

off-tx followup, NTX group had fewer heavy drinking days 

and fewer redeveloped the full syndrome of alcoholism. 

Volpicelli et al. 1992, 

1995b. 

USA-single site. 

70 12 wk TAU NS + ++ ++ NTX had greatest effect in decreasing subsequent drinking once drinking occurred. Besides reducing relapse 

rate, NTX significantly increased the time to relapse. 

Volpicelli et al.1995a, 

O’Brien et al. 1996. 

USA-single site. 

99 12 wk TAU NS + + ++ NTX reduced the risk of excessive drinking in the event 

of a slip. (Some subjects in this study overlap with those 

in the earlier report by Volpicelli et al. 1992.) 

Balldin et al. 1997; 

Bergland 1997, 

Mansson et al. 1999. 

Sweden-multisite. 

120 24 wk CST vs ST NS NS + + + Effects seen only in the NTX/CST group, and persisted 

during 24 wk off-treatment follow-up period. ST was 

described as Treatment As Usual by the authors and 

was abstinence-oriented. 

Oslin et al. 1997. 

USA-single site. 

44 12 wk ST NS NS + NS NS Studied older men (mean age 58 years). Relapse was 20% 

less in NTX group, but was NS. NTX significantly reduced 

relapse progression in subjects sampling any alcohol. 

Volpicelli et al. 1997. 

USA-single site. 

97 12 wk CST NS + + NS Outcomes are expressed for study completers; ITT 

analyses demonstrated weaker effects of NTX. Subjective 

“high” associated with drinking was reduced by NTX. 

Anton et al. 1999, 

2001. 

USA-single site. 

131 12 wk CST NS NS + ++ + NS For those who drank, NTX significantly increased number 

of days between episodes. By the end of a 14-wk off-tx 

followup period, significant benefits of NTX had faded. 

Chick et al. 2000. 

UK-multisite. 

175 12 wk TAU NS NS NS + ++ Outcomes are expressed for completing & compliant 

subjects. Only craving remained significant in ITT analysis. 

Kranzler et al. 2000. 

USA-single site. 

124 12 wk CST NS NS NS NS NS NTX-compliant patients had better outcomes, but these 

were NS compared with PBO. Only study in which retention and compliance were significantly lower in NTX group. 

Heinala et al. 2001. 

Finland-single site. 

121 12 wk CST vs ST NS NS ++ NTX/CST had the primary effect. There was a 20 wk 

followup using NTX on a “targeted” basis, during which 

reduced relapse rates persisted in NTX/CST group. 

Monterosso et al. 

2001. 

USA-single site. 

183 12 wk TAU + + NTX dose was 100 mg/day (50 mg BID). NTX was 

associated with significantly less clinical deterioration. 

Positive NTX effects were associated with higher initial 

craving and a greater family history of alcoholism. 

Monti et al. 2001. 

USA-single site. 

128 12 wk CST vs ST NS + NS + + More significant effects seen in patients compliant with 

medication and in the CST group. Compliant patients 

also had fewer relapses, but was NS. Beneficial NTX 

effects faded during off-tx followup at 6 and 12 months. 

Morris et al. 2001. 

Australia-single site. 

111 12 wk CST NS NS ++ ++ Outcomes are for study completers. ITT analysis for relapse was NS, but time to relapse was highly significant. 

Krystal et al. 2001. 

USA-multisite. 

627 13 wk & 

52 wk 

ST NS NS NS NTX tx was either 13 wk or 52 wk vs PBO 52 wks. ITT 

analyses shown; however, in all groups, more compliant subjects and those attending more therapy or AA 

sessions had better outcomes. 

*Multiple analyses of the same patient population are grouped together as one study. NTX dose = 50 mg/day, except Monterosso et al. 2001. 

Psychosocial Therapy: CST = Coping Skills (relapse prevention) Therapy; ST = Supportive (abstinence-oriented) Therapy; TAU = Treatment As Usual or “standard therapy.” 

Outcomes: Favoring NTX: + - p< 0.05; ++ - p< 0.01. NS = No Significant Difference (equivalent). Blank means the outcome was not reported in the study. 

Abbreviations: NTX = naltrexone; PBO = placebo; wk = week; ITT = intention-to-treat (includes dropouts & noncompliers); tx = treatment. 

3 
Abstinence

Time to 1st Drink 

# Drinking Days 

Drinks / Drink Day 

Relapse 

Heavy Drinking 

Craving 

ies, relapse was defined as having 5 or more drinks on any single 

occasion for men and 4 or more drinks for women, or drinking 5 or 

more days within one week, or attending a treatment session intoxicated. “Heavy” drinking was commonly defined as more than five 

drinks, which would make this measure equivalent to a relapse day. 

Finally, nine studies evaluated craving, although this was variously defined by investigators using different assessment instruments 

to arrive at a patient-determined score. Often, craving at the beginning 

of treatment was compared with craving at end of treatment to note 

differences. 

Unfortunately, there is no standard set of efficacy outcome measures used in all studies. Blank boxes in Table 1 indicate those measures not mentioned in the respective published RCT reports. 

Adjunctive Psychosocial Therapy 

Researchers have paired naltrexone and placebo with different 

psychosocial therapies to compare the combined efficacy. Table 1 

indicates three general types that have been variously described and 

used: 

Supportive Therapy (ST) – focuses on abstinence from alcohol, without teaching specific coping skills to avoid relapse. ST 

may be 12-step oriented and include encouragement to attend 

Alcoholics Anonymous meetings. 

Coping Skills Therapy (CST) – also called relapse prevention 

therapy or cognitive behavioral therapy (CBT) – teaches 

patients ways of dealing with situations and feelings that provoke a return to drinking, and how to keep a drink (“slip”) from 

leading to a relapse. 

Therapy As Usual (TAU) – is the “Standard Therapy” at the 

particular study center and may mix components of CST and/or 

ST modalities. If it could be determined that TAU seemed slanted toward either supportive or coping skills therapy, the psychosocial therapy was respectively coded ST or CST in Table 1. 

Research teams appeared to modify psychosocial approaches 

based on their clinical experience, so there may have been some differences in how the same type of therapy was structured in various 

RCTs. For the two multisite RCTs, there also is the question of 

whether the same therapy was delivered consistently at various locations by different therapists. 

Summary of RCT Results 

Drinking Outcomes 

Outcome values in Table 1 are denoted in terms of the statistical 

significance of data comparing naltrexone with placebo (see sidebox 

on “Significance”). Thus, on each particular measure, the effects of 

naltrexone were either comparable to placebo (NS or nonsignificant), 

of significant advantage (+), or very significantly beneficial (++). In 

no case was naltrexone of less benefit than placebo. 

Figure 1 graphically summarizes the advantages of naltrexone 

relative to placebo. It represents for each outcome an averaging of 

results across all RCTs that reported the measure. 

Naltrexone does not appear to exert an influence compared with 

placebo on maintaining abstinence or in postponing the first drink in 

those patients who cannot avoid alcohol. However, there is clear and 

consistent evidence that naltrexone is significantly beneficial in helping those patients who cannot remain abstinent to reduce their drinking behaviors. They drink less often and in lower quantities, avoiding full-blown relapse. 

Volpicelli et al. (1992) reported that naltrexone appeared to be 

most effective in decreasing drinking in subjects who had at least one 

1.2 NTX Outcome Measures 

1 

0.8 

0.6 

0.4 

0.2
 

0
 

Figure 1: NTX score measures the strength of evidence favoring naltrexone, represented by averaging efficacy scores for all RCTs in Table 1 that measured the 

particular outcome. Points were assigned as: 0 (NS), 1 (+), and 2 (++). Score of 1 

or above represents statistically significant advantage of NTX over PBO. 

alcohol-sampling episode or “slip.” Whereas, almost all (95%) 

placebo-treated subjects who slipped proceeded to relapse, those taking naltrexone typically drank less during a slip and only half of them 

actually relapsed to heavy drinking. 

Volpicelli and colleagues (1995a, 1995b) also observed that naltrexone-treated subjects reported that the subjective “high” or eupho- NTX Evidence Score 

The Significance of “Significance” 

The RCTs evaluated for this report compared naltrexone with placebo 

on each particular outcome measure studied to determine superiority of 

one over the other. Statistical analyses were used by the researchers to 

evaluate and quantify the significance of any differences, with a standard cut-off point for significance of p < 0.05 (designated ‘+’ in Table 1). 

Probability- or p-values are considered in this report as a relative indicator of effect size and strength. In a broad sense, a p < 0.05 means that 

the observed benefit for naltrexone on the particular outcome measure 

is large enough to be considered a true and “significant” advantage; that 

there is less than a 5% probability that the effect occurred merely due 

to chance. Put another way, with a p-value of 0.05 or less there is at 

least a 95% certainty that the observed effect is “real” and valid, rather 

than being merely a coincidence. 

Probability-values less than 0.01 (designated ‘++’ in Table 1) suggest the 

effect favoring naltrexone is even stronger. There is 99% certainty the 

effect is not due to chance. 

Conversely, any p-value greater than the 5% cut-off point (e.g., p = 

0.06), suggests that differences between groups may be due merely to 

chance and are not statistically significant (designated NS in Table 1). In 

essence, the effect of naltrexone, although possibly appearing to be 

favorable in terms of absolute value, must be considered as no better 

than placebo on the particular measure. 

Hypothetically, it is possible to have negative effects; that is, naltrexone 

producing worse results than those observed in the placebo group.

However, this was not observed in any of the clinical RCTs to date. 

Also, it is important to note that an outcome may not be statistically significant but still have clinical significance. For example, due to study limitations or variability in results, an overall 20% reduction in relapse rate 

associated with naltrexone may not reach statistical significance (as in 

the study by Oslin et al. 1997). However, this still can be clinically valuable by preventing full-blown relapse in one additional patient for every 

five treated with naltrexone. 

4 
Number of Weeks Receiving Medication 

Cumulative Proportion

Without Relapse

Naltrexone-treated group 

Placebo-treated group 

Figure 2: Progressive proportions of patients without relapse – “survival 

analysis” – for NTX vs PBO groups, significantly favoring NTX (data from 

Volpicelli et al. 1995a). 

ria produced by alcohol was significantly less than usual. This is consistent with naltrexone’s action in blocking opioid receptors and 

diminishing pleasurable effects associated with alcohol drinking. 

Besides reducing overall relapse rates, naltrexone also appears 

to significantly prolong the relapse-free time in those who eventually do relapse. Figure 2 depicts the typical relationship plotted over 

time, called a “survival curve,” comparing naltrexone with placebo 

(Morris et al. 2001, Volpielli et al. 1995a). 

Furthermore, Anton et al. (1999) found that naltrexone effectively doubled the time between a first relapse (or heavy drinking 

day) and a second such episode. Taken together, naltrexone’s effects 

in stemming relapse to heavy drinking allow more quality time for 

psychosocial therapy to be productive. 

Alcohol Craving 

Alcohol craving was measured and reported in 9 of 14 RCTs. As 

Figure 1 indicates, naltrexone therapy quite significantly reduced 

craving. 

Various researchers have noted that patients with higher initial 

craving appear to derive greatest benefit from naltrexone (Jaffe et al. 

1996; O’Malley et al. 1992; Monterosso et al. 2001). Volipicelli 

(2001) recently observed that naltrexone seems to have an immediate effect of reducing the urge to drink and this can be very useful in 

helping patients focus on other issues besides alcohol craving, especially during early stages of recovery. 

There is the question of why this reduced craving effect did not 

enhance abstinence in the RCTs. First, craving may be but one drive 

motivating drinking. Second, heavy drinking may itself induce craving and, since naltrexone-group patients drank less often and in 

lower quantities, this helps explain their lower craving scores but 

only equivalent abstinence compared with placebo-treated subjects 

(Chick et al. 2000). 

Impact of Psychosocial Therapy 

RCT results suggest that the efficacy of naltrexone can be 

dependent on the type of psychosocial therapy with which it is 

paired. As Table 1 demonstrates, supportive, abstinence-oriented, 

therapy (ST) was largely ineffective in conjunction with naltrexone 

on any outcome measures, with the single exception of the trial by 

Oslin et al. (1997) in older patients. 

Oslin and colleagues found naltrexone significantly effective in 

reducing the extent of drinking and progression to relapse in subjects 

sampling alcohol. This was unlikely related to the supportive psychosocial therapy, since its goal was to avoid any drinking at all. 

In general, coping skills therapy (CST), emphasizing relapseprevention strategies, proved much more effective than supportive 

therapy in achieving positive outcomes associated with naltrexone. 

“Treatment as usual” (TAU) therapies also were effective, and 

observed primarily in three investigations at University of 

Pennsylvania treatment centers (Volpicelli et al. 1992, 1995a; 

Monterosso et al. 2001). The approach here emphasized support of 

abstinence, including participation in group therapy stressing motivational enhancement, relapse prevention skills, and compliance 

with the medication regimen. Therapy was customized to patient 

needs and seemed to benefit from a synergism of the best that supportive and coping skills therapy might offer individually. 

Contrary Evidence 

Only 2 of 14 RCTs to date have failed to demonstrate significantly favorable effects of naltrexone: Kranzler et al. 2000 and, most 

recently, Krystal et al. 2001. 

Krystal and colleagues raised doubts about the utility of naltrexone in older patients with chronic, severe alcohol dependence. 

They studied a population of men averaging 49 years of age and 20 

years of heavy drinking. However, their findings conflict with other 

RCTs, involving almost identical populations of older males with 

long drinking histories, which reported significantly favorable 

results for naltrexone in terms of relapse, frequency of drinking, and 

quantity of alcohol consumed (Morris et al. 2001; Oslin et al. 1997). 

A critical factor in the RCT by Krystal et al. was the adjunctive 

use of strictly abstinence-based therapy focusing on 12-step facilitation counseling. In prior research, this was not found to be effective 

in combination with naltrexone. Still, these researchers did observe 

that naltrexone treatment extended the time to relapse by nearly 70% 

and this might have been a significant benefit clinically. A survival 

analysis of the sort shown in Figure 2 was not reported. 

Finally, the Krystal et al. trial was conducted at 15 Veterans 

Affairs medical centers, so the quantity, quality, and consistency of 

psychosocial therapy across treatment centers is questionable. This 

intersite variability combined with relatively small numbers of 

patients at each center might have led to reduced effect sizes. 

This phenomenon also was evident in a multisite RCT by Chick 

et al. (2000) in which psychosocial therapy reportedly varied widely 

by center and naltrexone benefits were most significant for those 

patients staying in treatment and taking medication. In their trial, 

Krystal et al. did not report on the subgroup of completing and compliant patients. 

The earlier Kranzler et al. (2001) trial, was the only RCT to date 

in which naltrexone-treated patients exhibited significantly less medication compliance and more study withdrawals than the placebo 

group. In all other trials reporting the measures, naltrexone treatment 

was associated with greater or equivalent compliance and retention 

compared with placebo. 

Also in contrast to other RCTs, Kranzler and colleagues reported significantly more side effects with naltrexone, primarily gastrointestinal-related (eg, nausea, vomiting, diarrhea). They observed 

that subjects with more GI complaints pretreatment were more susceptible to subsequent GI symptoms when treated with naltrexone, 

resulting in less medication compliance and, eventually, early withdrawal from the study. Patients who were able to tolerate naltrexone 

had better outcomes, but the trends were not statistically significant. 

Although standard inclusion/exclusion criteria were used for 

subject selection by Kranzler et al., they reported enrolling 183 of 

5 
194 persons recruited (94%). 

This is an unusually high acceptance rate and it is possible that 

the study population was biased 

in some way, resulting in a 

greater proportion of subjects 

with predispositions to adverse 

reactions when taking psychoactive medications. For example, a 

separate arm of this trial investigated possible benefits of nefazodone, an antidepressant, and 

also observed significant increases in side effects in that group. 

On the basis of these two 

trials, any deficiencies of naltrexone’s efficacy in particular 

patient populations cannot be 

concluded. 

Interacting Factors 

The efficacy of naltrexone in 

treating alcoholism has been 

demonstrated across a range of 

treatment programs, internationally, using differing psychosocial therapies, and in diverse patient 

populations. Table 2 summarizes demographic data for all RCT 

participants. 

It should be noted, that RCTs to date have focused on males 

between 39 and 58 years of age, on average. Other factors also may 

interact to influence efficacy outcomes. 

Importance of Retention/Compliance 

Naltrexone appears to be especially effective for patients who 

stay in treatment and comply with medication regimens (Chick et al. 

2000; Monti et al. 2001; O’Brien et al. 1996; O’Malley et al. 1992; 

Volpicelli et al. 1997). As Table 2 shows, naltrexone was associated 

with slightly greater retention and compliance than placebo, 

although this trend was not statistically significant and there was a 

wide range across studies. 

Most RCTs reported “intention-to-treat” (ITT) analyses that 

included data from all patients, whether or not they remained in the 

study or took their medication. This tends to understate medication 

efficacy and might have occurred, for example, in the Oslin et al. 

(1997) trial. There was very low treatment compliance (less than a 

third of patients in either group) and consequently few significant 

benefits of naltrexone were reported in the ITT analysis. (Oslin and 

colleagues also used an unusual dosing schedule: every other day – 

100, 100, 150 mg – considered equivalent to 50 mg/day). 

Four of the naltrexone RCTs – Chick et al. 2000; Morris et al. 

2001; O’Malley et al. 1992; Volpicelli et al. 1997 – reported analyses 

focusing on patients who completed the trials and were compliant 

with medication regimens. These analyses, known as “per protocol,” 

demonstrated significant effects of naltrexone and are reflected in 

Table 1. 

This apparently did not slant the summarization of outcomes in 

this report, since a recent meta-analysis by Streeton and Whelan 

(2001) using only ITT data reached the same conclusions as presented above in figure 1. That is, naltrexone significantly improves outcomes in terms of alcohol consumption, relapse to heavy drinking, 

and alcohol craving. 

It should be noted that 

advantages of naltrexone are 

also based on its specific nature, 

rather than simply study retention and/or medication compliance. As Litten and Allen (1998) 

have observed, in most RCTs, 

patients do better with naltrexone than placebo-treated subjects who are equally retained 

and compliant. 

Long-Term Efficacy 

Six of 14 RCTs examined 

long-term effects of naltrexone 

during followup periods ranging 

from 14 to 40 weeks after the 

end of drug treatment (ie, offtreatment). Results suggest that 

naltrexone is effective as long as 

it is taken, but benefits begin 

fading once the medication is 

terminated (see Table 1 “Notes” 

– Anton et al. 1999; Heinala 

2001; Krystal et al. 2001; Monti et al. 2001; O’Malley et al. 1996a; 

Mansson et al. 1999). 

Some researchers have recommended a minimum of six months 

treatment with naltrexone (Naltrexone...1997; Volpicelli 2001). It 

also has been proposed that, following a course of daily treatment, 

naltrexone can be useful on an as-needed or short-term basis; using 

the drug during high-risk periods or after a resumption of drinking 

following successful abstinence (O’Malley 1998; Volpicelli 2001). 

In their RCT, Heinala et al. (2001) included a 20-week “targeted” naltrexone period following daily dosing. Subjects were instructed to take naltrexone only when craving alcohol and/or drinking was 

likely. This intervention was of significant benefit in warding off 

relapse. Others have reported using this targeted-naltrexone 

approach effectively in reducing all measures of alcohol consumption (Kranzler et al. 1997). 

Naltrexone Dose 

Most research on naltrexone for alcoholism has used a 50 

mg/day dosing schedule. This is comparable to daily naltrexone 

doses used for opioid-abstinence therapy, and is believed to be optimal for opiate-receptor blockade (Saitz and O’Malley 1997). 

Individualized dosing regimens have been investigated and recommended for selected patients, ranging from 12.5 mg/day to 150 

mg/day (Croop et al. 1997, O’Malley 1998; Saitz and O’Malley 

1997). Lower doses are sometimes initiated to minimize potential 

side effects and then gradually increased. 

In the RCT by Monti et al. (2001), patients were started at 25 

mg/day for the first two days and then given 25 mg twice daily. 

Although the authors did not report on adverse events, minimization 

of side effects with this dosing schedule might have contributed to an 

unusually high naltrexone-group retention rate (91%) in this trial. 

Current thinking is that doses of 100 mg/day up to 150 mg/day 

can be safely and effectively used in many patients (Volpicelli 2001). 

Monterosso et al. (2001) administered 100 mg/day (50 mg BID) in 

their RCT, and retention/compliance rates were well above average. 

Table 2: Summary of Demographic Data 

Total: 14 RCTs; 2127 Subjects 

Measure No.* Mean** Range 

Males 14 84% 71% - 100% 

Age (years) 13 44.5 39 - 58 

Married 12 42% 16% - 73% 

Employed 9 62% 27% - 84% 

Years Drinking 7 21 15 - 30 

Drinks Per Day Prior 7 12 10 - 13.5 

Study Retention 12 

Naltrexone 72% 41% - 91% 

Placebo 70% 42% - 91% 

Medication Compliance*** 10 

Naltrexone 66% 32% - 98% 

Placebo 64% 31% - 98% 

*Number of studies reporting the measure. **Based on averages across 

studies. ***Compliance is variously defined across studies. 

6 
Naltrexone in Dual-Diagnosed 

Patients 

RCTs reviewed in this report primarily 

included subjects without substantial psychiatric comorbidity, yet such disorders are common in alcoholics (Bowden 1997; Khantzian 

1997). An exception was the trial by Morris et 

al. (2001), in which more than half of subjects 

had psychiatric diagnoses concurrent with 

alcoholism. These researchers observed that 

significant benefits of naltrexone were independent of such coexisting disorders. 

In an observational study (non-RCT), 

Salloum (1998) evaluated naltrexone in 

depressed alcoholics who had failed to abstain 

from alcohol despite treatment with antidepressants. There were significant decreases in alcohol use and in cravings 

with naltrexone, plus improvements in depressive symptoms and 

overall functioning. Similarly, in a study of mentally ill alcoholic 

patients taking multiple psychiatric medications, Maxwell and 

Shinderman (2000) found that naltrexone produced a 75% reduction 

in alcohol consumption in more than 80% of patients. 

Pretreatment Abstinence 

Almost all RCTs required alcohol abstinence prior to beginning 

naltrexone therapy – ranging from a few days to several weeks. This 

may have affected some results, especially time to first drink, retention, and medication compliance (Streeton and Whelan 2001). 

However, Heinala et al. (2001), in Finland, enrolled nonabstinent 

subjects. Naltrexone was well-tolerated and significantly reduced 

relapse rates, while also achieving above average study-retention 

(84%). Further RCTs investigating this approach seem warranted. 

Safety Profile 

At usual doses, there have not been any reported serious adverse 

events directly attributed to naltrexone in the treatment of alcoholism 

(Highlights... 2000). Overall, RCTs to date have demonstrated that 

the incidence of subjects reporting side effects or discontinuing from 

naltrexone treatment due to such effects was roughly equivalent to 

placebo (Streeton and Whelan 2001). 

Naltrexone has been associated with increased nausea and vomiting. Less common side effects include headache, dizziness, fatigue, 

or insomnia. These effects are usually mild, often single occurrences, 

and resolve soon after dose stabilization (Lynch et al. 1998; 

Naltrexone... 1997; O’Malley et al. 1992; Salloum et al. 1998; 

Volpicelli et al. 1992). 

Naltrexone undergoes first-pass metabolism in the liver, 

although it does not interact with the P450 enzyme system 

(Naltrexone... 1997). Product literature specifies that naltrexone is 

contraindicated in patients with acute hepatitis or liver failure 

(DEPADE® 2000; ReVia® 1997), and liver function monitoring is 

recommended in some cases (O’Malley 1998). 

However, in the absence of preexisting hepatic dysfunction, naltrexone at doses up to 200 mg/day has not been associated with liver 

damage (Croop et al. 1997; Marrazzi et al. 1997). In some studies, 

naltrexone-treated patients experienced an improvement in liver 

enzyme values (Volpicelli et al. 1992; Volpicelli 2001), most likely 

associated with abstinence or reduced alcohol consumption. 

Naltrexone 

appears to break 

the vicious, 

self-destructive 

cycle in alcoholics 

whereby one drink 

leads to another. 

Practice Implications 

Consistent with a prior systematic review 

of naltrexone trials by the Agency for Health 

Care Policy and Research (Garbutt et al. 

1999), this present report concludes: 

• Randomized controlled trials of naltrexone 

in the treatment of alcoholism are recent, 

extensive, and of good quality. 

• There is good evidence that naltrexone 

significantly reduces alcohol relapses, the frequency and quantity of alcohol consumption 

in those who do drink, and alcohol craving. 

In brief, naltrexone appears to break the 

vicious, self-destructive cycle in alcoholics 

whereby one drink leads to another. 

Harm Reduction Strategy 

Just as with the medication management of other serious chronic illness, a more pragmatic strategy, using naltrexone, seeks to 

induce remissions when possible, limit relapses, slow deterioration, 

and support patients in improving their quality of life (Olson and 

Willenbring 1999). 

This approach is known as “clinical harm reduction,” to distinguish it from the “abstinence-or-fail” outlooks of other alcoholism 

treatments (Freed and York 1997). According to the evidence 

reviewed in this report, naltrexone can be an important adjunct in 

fostering harm-reduction as a component of alcoholism-recovery 

goals, including eventual sustained abstinence. 

Clinical Action Steps 

Treatment plans using naltrexone ideally respond to individual 

patient needs. In that regard, practitioners may want to consider the 

following evidence-based conclusions: 

1.	 Naltrexone is effective in a variety of alcoholism-treatment settings where motivation to stay in treatment, avoid relapses to 

heavy drinking, and take medications is supported by appropriate psychosocial therapy. 

2.	 Naltrexone may be especially useful in repeat alcohol relapsers, 

by reducing the frequency and scope of drinking episodes to 

allow continued progress toward recovery goals. 

3.	 Individualized naltrexone dosing regimens can be of benefit, 

possibly starting at lower doses and titrating upward. 

4.	 Alcohol abstinence prior to initiating naltrexone therapy may 

not be necessary in all cases. 

5.	 Extended daily use of naltrexone may be helpful: longer-term 

therapy (6 to 9 months) can be more effective than short-term (3 

months). 

6.	 Following daily therapy, naltrexone might be used on an asneeded, “targeted,” basis indefinitely. 

Research results require careful consideration. Statistical significance of outcomes is important but can be misleading, for even 

small improvements can be clinically and socially significant when 

each percentage point may represent thousands of lives benefitted. 

As Enoch Gordis, MD, former Director of the National Institute on 

Alcohol Abuse and Alcoholism (NIAAA), once observed, “While 

not a ‘magic bullet,’ naltrexone promises to help many patients 

in their struggle against chronic relapsing disease” 

(Naltrexone...1995). 

7 
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DEPADE® is a registered trademark of Mallinckrodt Inc. ReVia® is a Registered U.S. 

Trademark of The DuPont Merck Pharmaceutical Company. 

AT Forum thanks the following reviewers for their comments and suggestions: David Sinclair, PhD, National Public Health Institute (KLT), Helsinki,

Finland; Robert Swift, MD, PhD, Brown University, Providence, RI; 

Joseph Volpicelli, MD, PhD, University of Pennsylvania, Philadelphia, PA. 

ADDICTION TREATMENT 

Forum
 

is published by: Addiction Treatment Forum 

P.O. Box 685 

Mundelein, IL 60060 

Editor: 

Art Director: 

Stewart B. Leavitt, Ph.D. 

Julia Kim 

©2002 Clinco Communications, Inc. 

Addiction Treatment Forum is made possible by an educational grant from Mallinckrodt Inc., a 

distributor of naltrexone (DEPADE®). 

March 2002 

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