*The most common reasons for screening failures included a clinically
significant medical condition, active hepatitis (aspartate transaminase [AST]
or alanine transaminase [ALT] >3 times the upper limit of normal), failure
to meet an average of 2 episodes of heavy drinking per week for the 30 days
before randomization, and clinically significant psychiatric disease. †Enrollment
failures due to investigator judgment were from seizure; an ongoing unresolved,
unstable medical condition; and planned surgery to include opiate analgesia.
Intention-to-treat analysis shows the cumulative mean event rate of
heavy drinking during the study by treatment group. The participant retention
rates are shown at 4-week intervals through 24 weeks, which was the intended
duration of the treatment.
In addition to injections of study treatment, all patients received
standardized, low-intensity psychosocial support. This represents an intention-to-treat
analysis with the last observation carried forward. The bars represent interquartile
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Garbutt JC, Kranzler HR, O’Malley SS, Gastfriend DR, Pettinati HM, Silverman BL, Loewy JW, Ehrich EW, Vivitrex Study Group FT. Efficacy and Tolerability of Long-Acting Injectable Naltrexone for Alcohol DependenceA Randomized Controlled Trial. JAMA. 2005;293(13):1617–1625. doi:10.1001/jama.293.13.1617
Context Alcohol dependence is a common disorder associated with significant
morbidity and mortality. Naltrexone, an opioid antagonist, has been shown
to be effective for treatment of alcohol dependence. However, adherence to
daily oral pharmacotherapy can be problematic, and clinical acceptance and
utility of oral naltrexone have been limited.
Objective To determine efficacy and tolerability of a long-acting intramuscular
formulation of naltrexone for treatment of alcohol-dependent patients.
Design, Setting, and Participants A 6-month, randomized, double-blind, placebo-controlled trial conducted
between February 2002 and September 2003 at 24 US public hospitals, private
and Veterans Administration clinics, and tertiary care medical centers. Of
the 899 individuals screened, 627 who were diagnosed as being actively drinking
alcohol-dependent adults were randomized to receive treatment and 624 received
at least 1 injection.
Intervention An intramuscular injection of 380 mg of long-acting naltrexone (n = 205)
or 190 mg of long-acting naltrexone (n = 210) or a matching volume
of placebo (n = 209) each administered monthly and combined with
12 sessions of low-intensity psychosocial intervention.
Main Outcome Measure The event rate of heavy drinking days in the intent-to-treat population.
Results Compared with placebo, 380 mg of long-acting naltrexone resulted in
a 25% decrease in the event rate of heavy drinking days (P = .03) and 190 mg of naltrexone resulted in a 17% decrease
(P = .07). Sex and pretreatment abstinence
each showed significant interaction with the medication group on treatment
outcome, with men and those with lead-in abstinence both exhibiting greater
treatment effects. Discontinuation due to adverse events occurred in 14.1%
in the 380-mg and 6.7% in the 190-mg group and 6.7% in the placebo group.
Overall, rate and time to treatment discontinuation were similar among treatment
Conclusions Long-acting naltrexone was well tolerated and resulted in reductions
in heavy drinking among treatment-seeking alcohol-dependent patients during
6 months of therapy. These data indicate that long-acting naltrexone can be
of benefit in the treatment of alcohol dependence.
Alcohol dependence is a major public health problem, which worldwide
is the fourth leading cause of disability.1 Alcohol
dependence is present in approximately 4% of the US adult population,2 is common among primary care patients,3,4 and
may contribute to more than 100 000 preventable deaths per year.5 Addiction counseling, behavioral treatments, and self-help
groups (eg, Alcoholics Anonymous) are the primary interventions used to treat
alcohol dependence in the United States. Although these treatments are often
effective, a substantial number of patients fail to complete them or relapse.6
Similar to diabetes, hypertension, and asthma, alcohol dependence is
increasingly recognized as a chronic disease in which genetic vulnerability
and social and environmental factors are involved in the etiology and course
of the disease.7 As with other chronic diseases,
long-term comprehensive management strategies are necessary to achieve and
sustain the benefits of alcohol dependence treatment. Pharmacotherapy represents
an emerging treatment option that could be used by primary care practitioners
and addiction specialists.8
In 1994, naltrexone was approved by the US Food and Drug Administration
to treat alcohol dependence after the medication was shown to reduce drinking
frequency and the likelihood of relapse to heavy drinking.9,10 Naltrexone,
an opioid antagonist, is thought to reduce the reinforcing subjective or behavioral
response to alcohol.11,12 In about
3200 alcohol-dependent patients in at least 19 published controlled studies,
oral naltrexone, compared with placebo, has shown efficacy in the treatment
of alcohol dependence although some studies have reported no or minimal effectiveness.13- 18 Despite
substantial evidence of efficacy, clinical use of naltrexone has been limited,
in part because of the heterogeneity in treatment response.19
One documented reason for the heterogeneity of response across naltrexone
trials has been poor adherence to the daily medication regimen.20- 23 Adherence
to a daily oral medication regimen is a general problem in medicine.7 Additional challenges to adherence in the context
of substance abuse include variable patient motivation toward treatment; impaired
cognitive function, particularly executive function; and denial.24 As
a prototypical addictive disorder, alcohol dependence is thought to involve
dysfunction of the brain’s reward system with attendant impaired control
over drives and motivation.25 Moreover, treatment
may directly conflict with the behaviors and rewards associated with the abused
Since the 1970s, several efforts have been made to develop a parenteral
extended-release naltrexone,27- 29 and
1 formulation has reported an effect on abstinence.29 Recently,
a new polylactide-co-glycolide (PLG)–based, long-acting naltrexone formulation
that releases naltrexone for 1 month following a single injection was developed.30 We conducted a 6-month, multicenter, randomized,
double-blind, placebo-controlled study of the efficacy and safety of 2 dosing
levels of this long-acting injectable formulation of naltrexone in combination
with a low-intensity psychosocial intervention for treatment of alcohol dependence.
This study was conducted at 24 US public hospitals, private and Veterans
Administration clinics, and tertiary care medical centers. Of 899 individuals
who were screened, 627 were determined eligible and were randomly assigned
to receive treatment during the period of February 2002 to September 2003
(Figure 1). All patients provided written,
informed consent, which, along with the protocol, was approved by each center’s
institutional review board.
Participants were male or nonpregnant nonlactating female outpatients
aged 18 years or older with a current diagnosis of alcohol dependence defined
by the Diagnostic and Statistical Manual of Mental Disorders,Fourth Edition (DSM-IV).31 Patients also had a minimum of
2 episodes of heavy drinking (≥5 standard drinks/d for men and ≥4 standard
drinks/d for women) per week during the 30 days before screening. Race determination
was based on the participant’s response during the screening interview.
Although race was used to compare medication groups at baseline, there was
no a priori hypothesis about race and treatment effect.
Exclusion criteria included evidence of liver failure; alanine aminotransferase
(ALT) or aspartate aminotransferase (AST) levels greater than 3 times the
upper limit of normal; any clinically significant medical condition that in
the opinion of the investigator would adversely affect safety or study participation;
major depression with suicidal ideation, psychosis, or bipolar disorder (patients
with treated depression and stable pharmacotherapy for at least 8 weeks were
not excluded); dependence within the past year on benzodiazepines, opiates,
or cocaine; more than 7 days of inpatient treatment for substance abuse in
the month before screening; or use of opiates, oral naltrexone, or disulfiram
in the 2 weeks before screening. A negative urine test result for opiates
and methadone was required on the day of randomization. Detoxification prior
to randomization was performed only if medically indicated. Use of benzodiazepines
was prohibited during the week before the first dose of study medication.
Important selection features were that inclusion did not require intent to
abstain and ongoing active drinking was not a cause for exclusion. A subpopulation
of lead-in abstinent patients was defined as those who reported no drinking
during the 7 consecutive days preceding the first dose of study medication.
Patients were randomized to 1 of 3 treatment groups: long-acting injectable
naltrexone 380 mg (4 mL), long-acting injectable naltrexone 190 mg (2 mL),
or placebo (half of this group received 4-mL injections of microspheres without
naltrexone, and the other half received 2-mL injections). The study used a
dynamic randomization procedure based on the biased coin principle32 to optimally balance the allocation of participants
based on 4 characteristics: sex, patient-specified goal of total abstinence,
self-reported abstinence for the 7-day lead-in period prior, and study site.
Over 24 weeks, patients received at 4-week intervals intramuscular gluteal
injections of the study medication on alternating sides. Injections were prepared
in amber-colored syringes to mask a slight color difference between the active
and placebo microspheres. To preserve the blind, injections were administered
by individuals who were not involved in any of the safety or efficacy assessments
or psychosocial treatments. Treatment assignment was blinded to all other
All patients received standardized supportive therapy (12 sessions)
using the Biopsychosocial, Report, Empathy, Needs, Direct advice, and Assessment
(BRENDA) model,33 a 6-stage, low-intensity
intervention designed to facilitate direct feedback of addiction-related consequences.
During this trial, BRENDA sessions were administered by psychologists, nurses,
therapists, counselors, and physicians at the study sites. At each study visit,
patients were systematically asked whether any adverse events had occurred
and injection sites were inspected.
The number of standard drinks consumed per day was recorded using the
timeline follow back method, which uses calendars and recall of drinking patterns
to yield reliable and valid reports by patients.34 To
maximize the accuracy of self-report, such data were collected only when breath
alcohol levels were 0.02 g/dL or less. Patients who discontinued study drug
treatment prematurely were allowed to remain in the study, continue to follow
the established visit and procedure schedule, and receive BRENDA treatment.
At the end of the study or at early termination, participants were referred
for appropriate alcoholism treatment as determined by the site research team.
The naltrexone long-acting injection used in this study consisted of
microspheres (approximately 100-μm diameter) composed of naltrexone and
PLG polymeric matrix. PLG is a common biodegradable medical polymer with an
extensive history of human use in absorbable sutures and extended-release
pharmaceuticals. Following injection, naltrexone is released from the microspheres,
yielding peak concentrations within 3 days. Thereafter, by a combination of
diffusion and erosion, naltrexone is released for more than 30 days.30,35
The primary efficacy end point was the event rate, which combines the
frequency and pattern of heavy drinking days over the 24 weeks of treatment.
The definition of heavy drinking (≥5 drinks per day for men and ≥4 drinks
per day for women) is consistent with that used in previous trials of oral
the event rate of heavy drinking is the number of heavy drinking days divided
by the number of days at risk for heavy drinking. On each day, the treatment
group event rate was contrasted with the placebo group event rate by forming
the event rate ratio. The method of analysis estimates the average event rate
ratio over time taking into account patient discontinuation.
Secondary end points included the event rate of “risky”
drinking days (>2 drinks per day for men and >1 drink per day for women) adapted
from the National Institute on Alcohol Abuse and Alcoholism37 and
the event rate of any drinking days. Exploratory end points included changes
in serum γ-glutamyl transferase concentration over time and time to
study discontinuation. Adverse events were coded using the preferred terminology
of the Medical Dictionary for Regulatory Activities.38 Serious
adverse events (SAEs) were defined as any untoward medical occurrence that
at any dose results in death, is life-threatening, requires in-patient hospitalization
or prolongation of existing hospitalization, results in persistent or significant
disability or incapacity, or is a congenital anomaly or birth defect. Serious
adverse events could also be identified by the investigator if the events
would have jeopardized the patient or required intervention to prevent one
of the other outcomes listed previously.
The primary analysis for the primary and secondary end points was performed
on the intention-to-treat population. The primary objective was to determine
whether either dosage of long-acting naltrexone decreased the event rate of
heavy drinking days compared with placebo. Statistical methods to analyze
multiple drinking episodes in alcoholism treatment clinical trials have been
described by Wang et al.39
The primary analysis for the end point was performed using a stratified
Andersen-Gill recurrent-event Cox model with robust variance estimation.40,41 The model estimated the treatment
effects of naltrexone 190 mg vs placebo and naltrexone 380 mg vs placebo.
The analysis was performed on all heavy drinking events between the
first treatment and 30 days following the last dose. In the case of dropouts,
last-day drinking data were collected. Analyses of the primary end point were
performed for each of the predefined stratification variables (sex, goal of
abstinence, 7-day period of abstinence prior to treatment). No imputations
were performed for days in which drinking data were unavailable. Retention
rate comparability between treatment groups was evaluated by generating Kaplan-Meier
curves for the time-to-study discontinuation. A log-rank test was used to
examine treatment group differences. Furthermore, to adjust for the impact
of participant discontinuation during the study while measuring the treatment
effect on heavy drinking, a pattern mixture-model approach was implemented
in the generalized Andersen-Gill recurrent-event Cox model.42 We
used SAS version 8.2 statistical software (SAS Institute Inc, Cary, NC). We
considered P<.05 (2-tailed) to be statistically
Between February 2002 and September 2003, 627 patients were randomly
assigned to one of the treatment groups. Three patients did not receive their
first injection based on investigator decision, leaving 624 patients who received
treatment and constituted the intention-to-treat population for analyses (Figure 1). Four hundred twenty-three patients
(68%) were men and 521 (83%) were white. The mean age was 45 years (range,
19-74 years). The mean (SD) of heavy drinking days in the 30 days before randomization
was 20 (8) days. Overall, 53 (8.8%) of patients were abstinent in the 7 days
before receiving the first injection, and 270 (43%) of the patients had a
treatment goal of total abstinence. Pretreatment characteristics of the patients
in the 3 treatment groups were similar although women differed from men on
several measures, including being more likely to use antidepressant medication
and less likely to smoke (Table 1).
In 401 patients (64%), all 6 injections were administered, and 463 (74%)
received at least 4 injections. Time to discontinuation was similar among
groups. The median rate of therapy sessions completed was 92% (11 of 12 possible),
and 267 (43%) of patients attended all therapy sessions. The number of therapy
sessions and the percentage of patients attending all sessions were similar
among treatment groups.
Adverse events occurring in at least 10% of the patients during treatment
with long-acting injectable naltrexone are listed in Table 2. The most common adverse events were nausea, headache, and
fatigue. Nausea was mild or moderate in approximately 95% of cases; however,
the large majority of these episodes occurred only during the first month
of treatment. Nausea and decreased appetite occurred more frequently in patients
treated with long-acting naltrexone 380 mg.
The most common injection site reaction was tenderness, occurring after
15.9% of 380-mg and 13.6% of 190-mg naltrexone doses and after 17.6% of 4-mL
placebo and 9.2% of 2-mL placebo injections. Seven patients (about 1%) discontinued
injections due to site reactions: 4 in the 380-mg naltrexone and 2 in the
190-mg naltrexone groups and 1 in the 4-mL placebo group.
Study discontinuation secondary to adverse events occurred in 29 (14.1%)
in the 380-mg naltrexone, 14 (6.7%) in the 190-mg naltrexone and 14 (6.7%)
in the placebo groups (P = .01, 380 mg
vs 190 mg and placebo; the group difference being accounted for by a greater
number of adverse events of nausea, injection site reaction, and headache).
The percentage of patients who experienced SAEs during treatment was similar
among the treatment groups: 11 (5.4%) for 380-mg and 10 (4.8%) for 190-mg
naltrexone and 15 (7.2%) for placebo. The most common SAE was hospitalization
for alcohol detoxification. Two SAEs (eosinophilic pneumonia and interstitial
pneumonia) were judged by the investigator to be possibly related to study
medication. Both events occurred in patients treated with naltrexone 380 mg
and resolved with treatment. These complications have not been reported previously
with either naltrexone or the PLG microspheres.
Mean AST and ALT levels did not change significantly over the course
of treatment or with medication. Furthermore, there was no effect of medication
on the proportion of patients in the different groups who had AST or ALT elevations
higher than 3 times the upper limit of normal.
Analyses of primary and secondary efficacy variables measured during
the 6-month treatment period are listed in Table
3. Patients treated with long-acting naltrexone 380 mg experienced
approximately a 25% greater reduction in the rate of heavy drinking relative
to placebo-treated patients (P = .03; Figure 2 and Figure
3). Patients treated with naltrexone 190 mg reported a 17% greater
reduction in the rate of heavy drinking than placebo-treated patients (P = .07). Neither the rate of National Institute
on Alcohol Abuse and Alcoholism risky drinking nor the rate of any drinking
was significantly lower with either dose of long-acting naltrexone (Table 3). Consistent with observed reductions
in heavy drinking, there was a 15% reduction in γ-glutamyl transferase
observed during the study for the overall sample. The rate of nausea was not
related to the event rate of heavy drinking.
Treatment × factor interactions were examined for the 3 predefined
randomization factors: sex, lead-in abstinence, and treatment goal of abstinence.
Treatment × factor interactions with long-acting naltrexone demonstrated
significant effects for sex (P = .002)
and lead-in abstinence (P = .02). The treatment
goal of abstinence did not demonstrate a significant interaction with treatment.
To further explore the observed treatment × factor interactions, treatment
effects were calculated for the individual subgroups defined by the factors
(Table 3). The results indicate that
the treatment effect among men taking 380-mg naltrexone vs placebo was highly
significant (hazard ratio [HR], 0.56, P<.001),
whereas the treatment effect was not significant in women (HR, 1.23, P = .28). Significant treatment effects were
observed with long-acting naltrexone 380 mg vs placebo irrespective of whether
patients were abstinent during lead-in; however, treatment effects were greater
for patients with lead-in abstinence (HR, 0.20, P = .005)
compared with patients who drank during the lead-in period (HR, 0.79,P = .05). The subset of patients with lead-in
abstinence also showed a significant treatment effect with long-acting naltrexone
190 mg vs placebo (HR, 0.05, P<.001). However,
due to small numbers in certain of the individual subgroups, these and the
following analyses should be interpreted with caution.
To explore factors that could be influential alone and in combination
with treatment for heavy drinking outcomes in women, 9 factors were examined
including age, lead-in drinking, attendance at self-help group meetings, treatment
goal, employment status, body mass index, use of antidepressants, race, and
history of depression. Each factor was dichotomized, and efficacy analyses
for each subgroup of women were performed. These either showed no difference
between subgroup pairs or yielded subgroup sizes that were too small for meaningful
interpretation. In addition, the treatment effects of naltrexone 380 mg vs
placebo in women and in the overall sample were not influenced by adjusting
for smoking status.
Patients in all 3 treatment groups substantially reduced the number
of heavy drinking days compared with their pretreatment levels. Figure 3 shows the change from pretreatment in the median number
of heavy drinking days per month by treatment group and sex.
It was found that time to subject discontinuation was comparable for
all treatment groups (log-rank test, P = .92).
When the exposure times between treated and control groups are comparable,
bias of the estimated treatment effect (as a result of dropouts) may be of
The pattern mixture model analysis indicated that the treatment effect
of long-acting, injectable naltrexone 380 mg compared with placebo was significant
(P = .001). These results argue against
there being a bias toward an effect of long-acting naltrexone treatment as
a result of the pattern of participant discontinuation.
The patients enrolled in this study predominantly were actively drinking,
with only 8.3% abstinent for the 7-day lead-in period. The number of patients
who maintained complete abstinence during the trial was 14 (7%) in the 380-mg
naltrexone group, 13 (6%) in the 190-mg naltrexone group, and 11 (5%) in the
placebo group. Among patients with lead-in abstinence, the rate of total abstinence
was 41% in the 380-mg naltrexone group, 35% in the 190-mg naltrexone group,
and 17% in the placebo group. Group differences on these measures did not
Headache did not show a clear dose-response relationship with medication;
a relationship between drinking outcomes and headache was not a preplanned
This study demonstrated that a long-acting injectable formulation of
naltrexone in conjunction with psychosocial treatment significantly reduced
heavy drinking in a large geographically varied sample of treatment-seeking
patients with alcohol dependence. Treatment effects were influenced by sex
and prerandomization abstinence from alcohol. The efficacy of the 380-mg dose
was evident within the first month after the initial injection and was maintained
over the 24-week treatment period. Naltrexone injections were well tolerated,
few serious adverse events were reported, and there was no evidence of hepatotoxicity.
The primary outcome measure in this study—heavy drinking—is
the sine qua non of alcoholism and is both clinically meaningful and of public
health importance. Of the various measures of drinking behavior, heavy drinking
shows the highest correlation with negative life consequences such as impaired
driving, interpersonal problems, and injuries.43 Reductions
in heavy drinking, as observed in this study with long-acting naltrexone,
can be expected to lead to improvements in various areas of health and in
the quality of life in alcohol-dependent patients although direct evaluation
of these outcomes is needed. The 25% relative reduction in the heavy drinking
event rate with the 380-mg dose reflects the average reduction in drinking
events within the treatment group. However, the average reduction in events
is disproportionately weighted by participants who were drinking at the highest
levels during the study. These patients contributed a greater number of events
to the overall analysis and thus had a greater impact on the average. As can
be seen in Figure 3, the 48% reduction
in the median percentage of days of heavy drinking reflects the response by
the typical individual patient in the study. Analyses assessing the relationship
between alcohol consumption and disease risk indicate increased risk for a
variety of adverse health consequences that are detectable with each additional
alcoholic drink per day.44 In addition, since
no single treatment will reduce completely the risk of heavy drinking among
all alcohol-dependent patients, we believe that an important clinical benefit
of long-acting naltrexone is that it provides a firm basis for combination
with other treatments, including psychotherapy, other medications, or both.
In contrast to the majority of clinical investigations of oral naltrexone
use that have required patients to be abstinent prior to starting medication,
the current study did not impose such a requirement; rather, the majority
of patients enrolled were drinking heavily. Thus, the study demonstrates the
efficacy of directly initiating long-acting, injectable naltrexone treatment
in patients who are actively drinking but who are motivated to reduce their
drinking—circumstances that are commonly seen in general medical practice.
Although not required for efficacy, the results suggest that this medication
formulation is also compatible with an abstinence orientation. Patients who
entered treatment with a goal of abstinence had a greater degree of drinking
reduction than those who only intended to reduce their drinking, and both
groups derived the same added advantage from injectable naltrexone vs placebo.
However, patients who were abstinent when they began treatment benefited to
a greater degree from the active agent than those who were still drinking
at the time of the first injection.
Men comprised the majority (68%) of patients in this study, which is
consistent with the prevalence pattern of alcohol dependence in the United
States,2 and showed a substantial treatment
effect. Although it may be tempting to speculate that naltrexone may not work
for women, such a conclusion is not justified because the study was not designed
to answer this question, the women who participated may not be representative
of women with alcohol dependence in the general population, and the number
of women studied was small. Moreover, men and women in this study differed
on a number of important variables, including the prevalence of smoking and
antidepressant use, weight, and commitment to abstinence. Although these variables
did not explain the sex differences in naltrexone efficacy, the men and women
in this sample may have differed on other variables that may positively influence
naltrexone response but were not assessed in this study, such as family history
of alcoholism. In addition, alcohol-dependent women have been shown to respond
better than men to a variety of psychosocial interventions,45- 47 making
it difficult to demonstrate an added effect of medication. An important aim
of future studies should be to seek a better understanding of the response
by alcohol-dependent women to naltrexone.
The pharmacokinetic profile of long-acting injectable naltrexone differs
substantially from that of the oral formulation. The new preparation has no
daily naltrexone peaks and a reduced ratio of 6-β-naltrexol to the parent
compound.30,48 The implications,
if any, of these pharmacokinetic differences from oral naltrexone for efficacy
and tolerability in alcohol dependence need further study.
Our study has limitations. This trial was designed to study a broad
range of alcohol-dependent patients by including patients from both public
and private treatment settings and also from specialty and nonspecialty practices.
However, clinical trials may enroll patients with a greater degree of motivation
for change than is seen among patients who are treated in traditional outpatient
settings. Although treatment attendance was relatively high in this study,
dropouts reduce the extent to which the findings generalize to the population
of all alcoholics. Furthermore, drinking data for dropouts were not obtained
once they left the study, so it is not known how these drinking outcomes would
have affected the results. Factors that potentially mitigate the impact of
dropouts include the observations that dropout rates were equivalent across
the 3 treatment groups and that the effects of long-acting naltrexone were
noted before many participants dropped out. An important strength of the study
is, in fact, that the multiple time-to-event analysis allowed information
from early discontinuation to be captured in the overall efficacy analysis.
Additional research is needed to determine the optimal duration of treatment
with long-acting naltrexone, as well as indicators that treatment can be discontinued.
The utility of long-acting naltrexone in special populations (such as individuals
with alcohol dependence and a major mental disorder or those who are in the
criminal justice system) remains to be examined.
In summary, the results from this trial, with one of the largest samples
ever treated with a medication for alcohol dependence, indicate that long-acting
injectable naltrexone is well tolerated and is associated with a significant
reduction in heavy drinking in a population of actively drinking patients.
The long-acting formulation has the potential to improve intervention strategies
for alcohol dependence by providing a predictable pharmacological foundation
for treatment. In addition to their utility for alcohol dependence, long-acting
formulations may prove to be an important treatment strategy for a variety
of addictive disorders.
Corresponding Author: James C. Garbutt,
MD, CB No. 7160, University of North Carolina at Chapel Hill, Chapel Hill,
NC 27599-7160 (e-mail: email@example.com).
Author Contributions: Dr Garbutt had full access
to all of the data in the study and takes responsibility for the integrity
of the data and the accuracy of the data analysis.
Study concept and design: Kranzler, Silverman,
Loewy, O’Malley, Ehrich.
Acquisition of data: Garbutt, Kranzler, O’Malley,
Analysis and interpretation of data: Garbutt,
Kranzler, Gastfriend, Pettinati, Silverman, Loewy, O’Malley Silverman,
Drafting of the manuscript: Garbutt, Kranzler,
O’Malley, Gastfriend, Pettinati, Silverman, Loewy, Ehrich.
Critical revision of the manuscript for important
intellectual content: Garbutt, Kranzler, O’Malley, Gastfriend,
Pettinati, Silverman, Loewy, Ehrich.
Statistical analysis: Loewy, Ehrich.
Obtained funding: Silverman, Ehrich.
Administrative, technical, or material support:
Study supervision: Garbutt, Kranzler, O’Malley,
Financial Disclosures: Dr Garbutt has served
on the advisory board and received research support from Bristol-Meyers Squibb
and received research support from Alkermes and Oy ContrAl Pharma and has
served on the advisory board and speakers bureau for Forest Laboratories and
has been on the speakers bureau for Wyeth-Ayerst. Dr Kranzler has served as
a consultant for and has research support from Drug Abuse Sciences and Alkermes,
Forest Laboratories, Ortho-McNeil Pharmaceuticals, and Bristol-Myers Squibb.
Dr O’Malley has research support from Alkermes, Forest Laboratories,
Pfizer, Ortho-McNeil, DuPont, Lipha, and Bristol-Myers Squibb and has served
as a consultant for Alkermes, Forest Laboratories, Johnson & Johnson,
Pfizer, and Ortho-McNeil. Dr Gastfriend has served as a consultant for and
on the advisory board and has received research support from and is now employed
at Alkermes. Dr Pettinati has received research support from Alkermes, AstraZeneca,
Bristol-Myers Squibb, Oy ContrAl Pharma, Drug Abuse Sciences, Eli Lilly, Lipha-Merck-KGaA,
Ortho-McNeil, and Pfizer; has served as a consultant for Alkermes, AstraZeneca,
Axis-Shield, Oy ContrAl Pharma, and Titan; and has participated in CME speakers
programs for Forest Laboratories. Drs Silverman, Loewy, and Ehrich are employed
Funding/Support: The preparation of the manuscript
was supported in part by grants K24-AA13736 (Dr Kranzler) and K24-DA00427
(Dr Gastfriend) from the National Institutes of Health. The development of
Vivitrex was supported by a Small Business Innovation Research award, N43AA01002
from the National Institute on Alcohol Abuse and Alcoholism to Alkermes Inc.
This study was funded, conducted, and designed by Alkermes with suggestions
from the investigators.
Role of the Sponsor: Data were collected and
monitored by Alkermes and Pharmaceutical Product Development Inc, a contract
research organization. Data were managed and analyzed by Alkermes clinical
and regulatory personnel and were interpreted by authors on the study with
input from Alkermes clinical and statistical staff. The majority of the first
draft was prepared by the lead author. The draft was reviewed by all authors
over 2 meetings and at least 6 teleconferences, at which time the selection
of data and their interpretation were determined by consensus.
Independent Statistical Review: We thank L.
J. Wei, PhD, professor of biostatistics at Harvard School of Public Health,
for performing an independent review of the data analysis.
Vivitrex Study Group/Principal Investigators: Robert
Anthenelli, MD, Cincinnati, Ohio; Louise Beckett, MD, Oklahoma City, Okla;
Michael Bohn, MD, Middleton, Wis; Paul Casadonte, MD, New York, NY; Domenic
Ciraulo, MD, Boston, Mass; James Garbutt, MD, Chapel Hill, NC; David Gastfriend,
MD, Boston, Mass; Lawrence Ginsberg, MD, Houston, Tex; Hisham Hafez, MD, Nashua,
NH; Bankole Johnson, MD, San Antonio, Tex; Philip Kanof, MD, PhD, Tucson,
Ariz; Henry Kranzler, MD, Farmington, Conn; Sandra Lapham, MD, Albuquerque,
NM; Peter Martin, MD, Nashville, Tenn; Barbara Mason, PhD, Miami, Fla; Mary
McCaul, PhD, Baltimore, Md; Denis Mee-Lee, MD, Honolulu, Hawaii; Stephanie
O’Malley, PhD, New Haven, Conn; Helen Pettinati, PhD, Philadelphia,
Pa; Robert Riesenberg, Atlanta, Ga; Ihsan Salloum, MD, Pittsburgh, Pa; Jeffery
Wilkins, MD, Los Angeles, Calif; Mark Willenbring, MD, Minneapolis, Minn;
Allen Zweben, PhD, Milwaukee, Wis.
Acknowledgment: We thank the staff at Alkermes
for their work in the implementation and biostatistical analysis of this study,
especially: Chester Osborn, MD, Kathleen Ford, Anne Giovanoni, Ari Illeperuma,
Song Liou, and Erin Lake, PhD. Michael Fried, MD, and Patrick O’Connor,
MD, provided helpful comments on the manuscript.