What is the data on the use of naltrexone (Vivitrol) in alcohol use disorder? What is the safety profile, ideal population, and efficacy?

Comment by InpharmD Researcher

Extended-release intramuscular naltrexone injection has been found to be safe and effective, as an adjunct to psychosocial interventions, for treating alcohol use disorder. Additional sources also support injectable naltrexone to reduce drinking days and increasing abstinence rate. A subgroup analysis of a randomized controlled trial suggests extended-release naltrexone injection is more effective in patients who were abstinent for at least 4 days prior to treatment initiation (Table 5). Common side effects may include somnolence, nausea, vomiting, decreased appetite, abdominal pain, insomnia, and dizziness.

Background

A 2022 meta-analysis sought to gauge the impact of extended-release injectable naltrexone, in comparison to a placebo, on alcohol consumption among patients dealing with alcohol use disorder (AUD). The analysis incorporated seven trials involving 1,500 adults with AUD who received monthly injections of either placebo or extended-release naltrexone at doses ranging from 150 to 400 mg for 2 to 6 months. These trials were conducted in outpatient clinic settings in the United States or Europe, including specialized alcohol/substance use clinics and HIV clinics. Generally, participants were treatment-seeking adult males or non-pregnant, non-lactating females with moderate to severe alcohol use, assessed through validated tools, and a minimum of one weekly episode of heavy drinking. The analysis measured the pooled weighted mean difference (WMD) in drinking days per month and heavy drinking days per month. [1]

The WMD favored extended-release naltrexone, showing -2.0 (95% confidence interval [CI] -3.4 to -0.6; p = 0.03) for drinking days per month and -1.2 (95% CI -0.2 to -2.1; p = 0.02) for heavy drinking days per month, reflecting that treatment resulted in two fewer drinking days per month and 1.2 fewer heavy drinking days per month compared to the placebo. Trials not mandating lead-in abstinence and those lasting over 3 months reported larger reductions in heavy drinking days per month, with WMDs of -2.0 (95% CI -3.52 to -0.48; p = 0.01) and -1.9 (95% CI -3.2 to -0.5; p = 0.01), respectively. [1]

Two trials comparing the clinical and cost-effectiveness of oral and injectable naltrexone were identified. Due to limited available data, a meta-analysis could not be performed. Nevertheless, these studies reported 3 to 6 monthly heavy drinking days with no significant differences between groups, suggesting equal efficacy between the two formulations. [1]

The findings suggest that adding extended-release naltrexone to common psycho-social interventions intended for treating AUD leads to a substantial improvement in heavy drinking compared to the placebo, with more pronounced effects observed over longer treatment periods. Further research is warranted to explore the efficacy of extended-release naltrexone in actively drinking versus recently abstinent patients with AUD. It's important to note that none of the included studies lasted longer than 6 months, making the results applicable only to treatment durations under 6 months. [1]

The fourth Society for Academic Emergency Medicine (SAEM) published 2024 Guidelines for Reasonable and Appropriate Care in the Emergency Department (GRACE-4) regarding alcohol use disorder. Naltrexone is conditionally recommended in adult emergency department (ED) patients who are not taking opioids to prevent and reduce return to heavy drinking. Oral and intramuscular naltrexone has been shown to increase abstinence from alcohol and reduce binge drinking, including multiple reviews and meta-analyses. Naltrexone is considered to be well-tolerated with minimal side effects with common events including somnolence, nausea, vomiting, decreased appetite, abdominal pain, insomnia, and dizziness. [2]

A 2023 systematic review and meta-analysis evaluated the efficacy and comparative efficacy of pharmacotherapies for alcohol use disorder. This analysis included data from 118 randomized clinical trials encompassing 20,976 participants. The paper assessed nine therapies, including oral and IV naltrexone. The numbers needed to treat to prevent one return to any drinking was 18 (95% CI, 4 to 32) for oral naltrexone. However, naltrexone was associated with higher rates of nausea (risk ratio, 1.73; 95% CI, 1.51 to 1.98) and vomiting (risk ratio, 1.53; 95% CI, 1.23 to 1.91) compared to placebo. Injectable naltrexone also reported fewer drinking days over 30 days, but was not associated with lower rates of return to any drinking. The analysis concluded with moderate strength of evidence for the benefit of oral naltrexone at reducing return to any drinking, return to heavy drinking, and percentage of drinking days. [3]

A 2023 systematic review examined the efficacy of extended-release injectable naltrexone in treating alcohol use disorder (AUD). The 11 included studies focused on AUD treatment with injectable naltrexone and consisted of human participants in peer-reviewed English-language journals. The review assessed outcomes such as time to first drinking day, number of heavy drinking days, abstinence rates, and alcohol cravings, often observing statistically significant improvements in these metrics with the use of injectable naltrexone, particularly over 3- to 6-month follow-up periods. Most studies demonstrated that injectable naltrexone was effective in reducing the time to first drink and the number of heavy drinking days, while also increasing abstinence rates. However, in all studies, less than half of the participants achieved complete abstinence, highlighting the challenges in treating AUD. The review also noted variations in adherence to the naltrexone regimen and psychosocial therapy, which were integral components of the treatment protocols. Despite limitations such as varying study designs and small sample sizes, the results suggest injectable naltrexone, particularly when combined with psychosocial interventions. [4]

References:

[1] Murphy CE 4th, Wang RC, Montoy JC, Whittaker E, Raven M. Effect of extended-release naltrexone on alcohol consumption: a systematic review and meta-analysis. Addiction. 2022;117(2):271-281. doi:10.1111/add.15572
[2] Borgundvaag B, Bellolio F, Miles I, et al. Guidelines for Reasonable and Appropriate Care in the Emergency Department (GRACE-4): Alcohol use disorder and cannabinoid hyperemesis syndrome management in the emergency department. Acad Emerg Med. 2024;31(5):425-455. doi:10.1111/acem.14911
[3] McPheeters M, O'Connor EA, Riley S, et al. Pharmacotherapy for Alcohol Use Disorder: A Systematic Review and Meta-Analysis. JAMA. 2023;330(17):1653-1665. doi:10.1001/jama.2023.19761
[4] Kedia SK, Ahuja N, Dillon PJ, Jones A, Kumar S, Satapathy S. Efficacy of Extended-Release Injectable Naltrexone on Alcohol Use Disorder Treatment: A Systematic Review. J Psychoactive Drugs. 2023;55(2):233-245. doi:10.1080/02791072.2022.2073300
Literature Review

A search of the published medical literature revealed 5 studies investigating the researchable question:

What is the data on the use of naltrexone (Vivitrol) in alcohol use disorder? What is the safety profile, ideal population, and efficacy?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-5 for your response.

 

Efficacy and Tolerability of Long-Acting Injectable Naltrexone for Alcohol Dependence

Design

Multicenter, randomized, double-blind, placebo-controlled trial

N= 624

Objective

To determine efficacy and tolerability of a long-acting intramuscular formulation of naltrexone for treatment of alcohol-dependent patients

Study Groups

380 mg of long-acting naltrexone (n= 205)

190 mg of long-acting naltrexone (n= 210)

Placebo (n= 209)

Inclusion Criteria

Male or non-pregnant, non-lactating female outpatients aged 18 years or older with a current diagnosis of alcohol dependence; minimum of 2 episodes of heavy drinking (≥ 5 standard drinks/day for men and ≥ 4 standard drinks/day for women) per week during the 30 days before screening

Exclusion Criteria

Evidence of liver failure; alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels greater than 3 times the upper limit of normal; 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

Methods

Eligible patients were randomly assigned to one of three treatment groups. Over a span of 24 weeks, patients received intramuscular gluteal injections of the study medication at 4-week intervals, alternating sides. Additionally, all patients underwent standardized supportive therapy consisting of 12 sessions. This therapy followed the Biopsychosocial, Report, Empathy, Needs, Direct advice, and Assessment (BRENDA) model, a 6-stage, low-intensity intervention aimed at facilitating direct feedback on addiction-related consequences. Throughout the trial, psychologists, nurses, therapists, counselors, and physicians at the study sites conducted the BRENDA sessions.

To assess the patients' alcohol consumption, the timeline follow-back method was employed. This method utilizes calendars and relies on patients' recall of drinking patterns to generate reliable and valid reports.

Duration

February 2002 to September 2003

Outcome Measures

Primary: frequency and pattern of heavy drinking days over the 24 weeks of treatment

Secondary: event rate of “risky” drinking days (>2 drinks per day for men and >1 drink per day for women)

Baseline Characteristics

  

380 mg of long-acting naltrexone

(n= 205)

190 mg of long-acting naltrexone

(n= 210)

Placebo

(n= 209) 

  

Age, years

 45.0 44.6 44.7  

Female

32.7% 32.4%  31.6%  

White

 83.9% 80.5% 86.1%   

Other drug use

Current smoker

Antidepressants

 

48.3%

30.2%

 

50.5%

26.3%

 

42.1%

29.2%

  

Liver enzyme levels, U/L

AST

ALT

GGT

 

30.0

31.9

58.6

 

32.7

32.9

73.5 

 

31.9

34.0

75.6

  

Drinking behavior

Abstinence goal

Abstinence for 7 d before randomization

Self-help group attendance

Heavy drinking in 30 d before randomization

 

43.9%

8.3%

11.7%

25.9%

 

42.9%

8.1%

10.5%

26.4% 

 

43.1%

9.1%

11.0%

24.8% 

  

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyltransferase

Results

Endpoint

Naltrexone 380 mg vs placebo

Naltrexone 190 mg vs placebo
Hazard ratio (95% CI)  p-value Hazard ratio (95% CI)  p-value

Heavy drinking (n= 624)

 0.75 (0.60-0.94  0.03 0.83 (0.68-1.02) 0.07 

Sex

Men (n= 423)

Women (n= 201)

 

0.56 (0.41-0.77)

1.23 (0.85-1.78)

 

< 0.001

0.28

 

0.83 (0.64-1.07)

1.07 (0.73-1.58)

 

0.16

0.72

Goal of total abstinence

Yes (n= 270)

No (n= 354)

 

0.72 (0.48-1.08)

0.79 (0.59-1.05

 

0.11

0.10

 

0.88 (0.61-1.28)

0.91 (0.70-18)

 

0.50

0.48

Lead-in drinking

Yes (n= 571)

No (n= 53)

 

0.79 (0.62-1.00)

0.20 (0.07-0.62)

 

0.05

0.005

 

0.93 (0.75-1.15)

0.05 (0.02-0.15)

 

0.48

<0.001

Risky drinking (n= 624)

 0.90 (0.76-1.07) 0.23 0.95 (0.81-1.13) 0.58

Nonabstinent days (n= 624)

 0.96 (0.83-1.11) 0.58 0.98 (0.85-1.14) 0.80

Safety

  

Adverse event type

 Naltrexone 380 mg (n= 205) Naltrexone 190 mg (n= 210) Placebo (n= 209)  

Nausea

 33%† 25% 11%  

Headache

 22% 16% 16%  

Fatigue

 20%† 16% 11%  

Insomnia

 14% 13% 12%  

Vomiting

 14% 11% 6%  

Decreased appetite

 13%† 6%‡ 1%  

Diarrhea

 13% 11% 9%  

Dizziness

 13%† 11% 4%  

Injection site pain

 12%† 9% 9%  

Nasopharyngitis

 11% 15% 12%  

Upper respiratory tract infection

 10% 7% 9%  

Discontinuation due to adverse events occurred in 14.1% in the 380 mg, 6.7% in the 190 mg group, and 6.7% in the placebo group.

†p-Value < 0.05 when compared to placebo

‡p-Value < 0.05 when compared to 380 mg naltrexone dose

Adverse Events

 See Results

Study Author Conclusions

Long-acting naltrexone was well tolerated and resulted in reductions in heavy drinking among treatment-seeking alcohol-dependent patients during 6months of therapy. These data indicate that long-acting naltrexone can be of benefit in the treatment of alcohol dependence.

InpharmD Researcher Critique

The study's broad inclusion of alcohol-dependent patients from various treatment settings is a strength, but it introduces limitations. Clinical trials may attract individuals with higher motivation for change, impacting the generalizability of findings to the broader alcoholic population. The dropout rate, though equivalent across treatment groups, poses a challenge, as dropouts reduce the study's applicability to all alcoholics. The lack of post-dropout drinking data further hinders result interpretation. Despite strengths like high treatment attendance and early detection of long-acting naltrexone effects, these limitations underscore the need for cautious interpretation, emphasizing the specific study population and circumstances. 



References:

Garbutt JC, Kranzler HR, O'Malley SS, et al. Efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence: a randomized controlled trial [published correction appears in JAMA. 2005 Apr 27;293(16):1978] [published correction appears in JAMA. 2005 Jun 15:293(23):2864]. JAMA. 2005;293(13):1617-1625. doi:10.1001/jama.293.13.1617

 

Treatment outcomes of long-acting injectable naltrexone versus oral naltrexone in alcohol use disorder in veterans

Design

Retrospective chart review

N= 32

Objective

To compare the effectiveness, defined by time to relapse, of long-acting injectable (LAI) naltrexone versus oral naltrexone

Study Groups

Oral Naltrexone (n =16)

Long-Acting Injectable Naltrexone (n = 16)

Inclusion Criteria

Subjects prescribed either oral or LAI naltrexone, greater than 21 years of age, had a diagnosis of alcohol use disorder (AUD) or alcohol dependence, received treatment in the Substance Use Disorder Recovery Program (SUDRP) at the Veterans Affairs Medical Center (VAMC) main campus, and were abstaining from alcohol use at medication initiation

Exclusion Criteria

Prescribed naltrexone for any indication other than AUD, pregnant, initiated on either dosage form during hospital admission, discontinued LAI naltrexone after 1 dose, or relapse was not documented

Methods

Those prescribed oral naltrexone were randomized to match LAI naltrexone subjects at a 1:1 ratio. 

For oral naltrexone, medication possession ratio (MPR) was defined as number of tablets dispensed during a time period divided by days in that time period. For LAI naltrexone, MPR was defined as number of injections given multiplied by 28 days divided by the number of days in the time period.

Duration

August 1, 2016 to July 31, 2018 

Outcome Measures

Primary: time to relapse defined as patient, family, or friend volunteered report; hospitalization for alcohol intoxication; positive ethyl glucuronide; or elevated blood alcohol concentration

Secondary: MPR, comorbid mental health diagnosis, substance use, past pharmacological treatment, liver and kidney function, and enrollment in addiction-focused psychosocial therapy

 

Baseline Characteristics

  

Oral Naltrexone (n =16)

Long-Acting Injectable Naltrexone (n = 16)

  

Age, years

 49.25 ± 13.12 56.81 ± 12.93  

Female

12.5%  18.7%   

White

 68.8% 56.3%   

Co-occurring mental health diagnosis

Depressive

Psychotic

Mood

 

62.5%

0

12.5% 

 

56.3%

6.3%

18.7% 

  

Posttraumatic stress disorder

Other

None

 

12.5%

25%

 

18.7%

18.7%

  

Results

Endpoint

Oral Naltrexone (n = 16)

Long-Acting Injectable Naltrexone (n = 16)

p-value

Time to relapse, days

 50.5 ± 78.8  150.5 ± 108.9 0.009

Medication possession ratio

81.0%  76.2%  0.478

Other substance use

 13 (81.3%) 14 (87.5%) 0.626
Past pharmacological treatment

4 (25.0%)

 3 (18.7%) 0.669
Engagement in alcoholics anonymous

3 (18.7%)

 1 (6.2%) 0.285

Adverse Events

No statistically significant differences were found in safety parameters between the 2 groups, including serum creatinine, aspartate transaminase, or alanine transaminase greater than 3 times the upper limit of normal.

Study Author Conclusions

In conclusion, based on the results of this study, LAI naltrexone is associated with increased time to relapse compared to oral naltrexone at this VAMC. This study showed no difference in patient adherence or safety outcomes. Moving forward, LAI naltrexone should be considered as a first-line agent for veterans diagnosed with alcohol use disorder.

InpharmD Researcher Critique

The study's retrospective nature, small sample size, and restriction to a single practice center pose limitations, affecting the generalizability of findings. The 7-year age difference between groups introduces a confounding variable, potentially influencing treatment outcomes. Reliance on volunteered reports for assessing relapse and the recorded date may introduce subjectivity and inaccuracies. Exclusion of patients not enrolled in the studied treatment program introduces selection bias. While patient self-reporting increases variability, its consistency between oral and LAI naltrexone groups is a positive aspect, though it warrants consideration of the potential impact on study reliability. 



References:

Leighty AE, Ansara ED. Treatment outcomes of long-acting injectable naltrexone versus oral naltrexone in alcohol use disorder in veterans. Ment Health Clin. 2019;9(6):392-396. Published 2019 Nov 27. doi:10.9740/mhc.2019.11.392

 

Efficacy of long-acting, injectable versus oral naltrexone for preventing admissions for alcohol use disorder

Design

Retrospective cohort study

N= 79

Objective

To compare clinical outcomes in veterans treated with long-acting, injectable naltrexone (LAI NTX) or oral naltrexone

Study Groups

Oral naltrexone (n= 65)

LAI naltrexone (n= 14)

Inclusion Criteria

First-time receipt (either an outpatient prescription or inpatient medication order) of oral NTX or LAI NTX; use of NTX for alcohol use disorder (AUD)

Exclusion Criteria

Concurrent use of acamprosate or disulfiram and use of NTX for any diagnoses other than AUD

Methods

Electronic medical record system within the VA was retrospectively reviewed to identify eligible veterans and categorized into oral and LAI NTX groups. Prior to LAI therapy, patients could receive up to 30 days of oral NTX. History and physical note was generally utilized to identify clinical encounters of interest, such as alcohol-related hospital admissions and outpatient clinic visits. Dispensing information outside of the VA pharmacy would not be used. 

Duration

First-time receipt: between January 1, 2015 and December 31, 2015

Outcome Measures

Primary: 90-day alcohol-related hospital admissions per patient (ARA90)

Secondary: 90-day outpatient clinic and emergency department (ED) visits, 30-day alcohol-related admissions (ARA30), and medication adherence

Baseline Characteristics

   Oral naltrexone (n= 65)

LAI naltrexone (n= 14)

  

Age, years

 46.9 47.9  

Male

 93.8% 85.7%  

Additional mental health diagnoses 

Depressive disorder

Psychotic disorder 

Anxiety disorder 

Mood disorder 

Other substance disorder 

Posttraumatic stress disorder 

 

58.5%

3.1%

26.2%

10.8%

72.3%

53.8%

 

42.9%

0

42.9%

7.1%

78.6%

42.9%

  

Baseline health care utilization in the 12 months prior to naltrexone initiation

Alcohol-related admissions, per patient 

Alcohol-related ED visits, per patient

Mental health clinic visits, per patient 

 

1.18

1.11

2.8

 

1.57

1.36

1.64

  

Include relevant baseline characteristics that will provide a general (big picture) view of the patients in the study.

Results

Endpoint (healthcare utilization after naltrexone initiation, per patient)

 Oral naltrexone (n= 65)

LAI naltrexone (n= 14)

p-value

ARA90

 0.17 0.64 0.06

ED visit, 90 d

 0.23  0.71  0.03 

Clinic visit, 90 d

 0.91 1.86 < 0.01

ARA 30

 0.05 0.36 < 0.01

6-month data 

ARA 

ED visits 

Mental health clinic visits 

 

0.32

0.32

1.92

 

1.14

1.14

3.64

 

< 0.01

< 0.01

< 0.01

Medication adherence as measured by average medication possession ratio (MPR) based on medication refill dates, as well as medication administration chart notes, was 65.14% for oral naltrexone and 67% for LAI naltrexone. 

Adverse Events

 N/A

Study Author Conclusions

Oral NTX was associated with lower healthcare utilization compared to LAI NTX in this veteran population. This indicates that LAI NTX may not provide additional benefits justifying the cost. This study had several limitations. Randomized trials comparing efficacy between oral NTX and LAI NTX are needed.

InpharmD Researcher Critique

 The study is limited to its retrospective nature, as clinical outcomes documented in chart notes may be subject to errors. Additionally, the patient population is limited to the veteran, further limiting the generalizability to a broader patient population. Other factors,  such as medical comorbidities and homelessness, were not accounted for in outcome measurements. 



References:

Beatty A, Stock C. Efficacy of long-acting, injectable versus oral naltrexone for preventing admissions for alcohol use disorder. Ment Health Clin. 2018;7(3):106-110. Published 2018 Mar 23. doi:10.9740/mhc.2017.05.106

 

Extended-release naltrexone reduces alcohol consumption among released prisoners with HIV disease as they transition to the community

Design

Randomized, double-blind, placebo-controlled trial

N= 100

Objective

To determine if extended-release naltrexone (XR-NTX) improved alcohol consumption parameters among incarcerated persons living with HIV (PLH) as compared to placebo upon release to the community 

Study Groups

XR-NTX (n= 67)

Placebo (n= 33)

Inclusion Criteria

Age ≥ 18 years with documented HIV-infection; transitioning to greater New Haven or Hartford metropolitan areas in Connecticut; met criteria for alcohol abuse or dependence using the Mini International Neuropsychiatric Interview (MINI) or hazardous drinking using AUDIT (score ≥ 4 for women and ≥ 8 for men)

Exclusion Criteria

Concurrent prescription of opioid pain medications or expressing a medical indication for them; having grade 3 or higher aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevations (> 5x upper limit of normal); evidence of Child’s Pugh Class C cirrhosis

Methods

Participants were randomized 2:1 to receive 6 monthly injections of XR-NTX or placebo, starting one week prior to release from prison. XR-NTX (Vivitrol) was administered in 380 mg doses intramuscularly every 28 days for 6 months. The parent study was designed to investigated proportion of patients achieving HIV-1 RNA viral suppression, the current analysis focused on alcohol consumption before and after incarceration. 

Duration

Intervention: 6 months

Outcome Measures

Time to first heavy drinking day post-incarceration, total number of drinks per drinking day; the percent of heavy drinking days; comparison of pre- and post-incarceration change in average drinks per drinking day; total number of drinking days

Baseline Characteristics

  

XR-NTX (n= 67)

Placebo (n= 33)

  

Age, years

 44.91  45.21   

Female

23.9% 15.2%  

Ethnicity

Black

Hispanic

White

 

68.7%

16.4%

14.9%

 

57.6%

24.2%

18.2%

  

Alcohol Use Severity (AUDIT criteria)

Abstinent or low-risk drinking

Hazardous drinking

Harmful drinking

Dependence

 

3%

7.5%

0

89.6% 

 

0

6%

12.1%

81.8% 

  

Heavy drinking (≥ 5 drinks/day for men, ≥ 4 drinks/day for women)

 98.5% 100%  

Alcohol craving (0 to 10 scale)

 4.08 3.44  

Cumulative injections received

6

5

4

3

2

1

 

14.9%

28.4%

40.3%

56.7%

73.1%

91.0%

 

18.2%

24.2%

42.4%

45.5%

51.2%

72.7%

  

Results

Endpoint

XR-NTX (n= 67)

Placebo (n= 33)

p-Value

Time to first heavy drinking day post-incarceration, days

 80.4 73.5 0.77

No significant differences were observed between groups for average drinks per drinking day, percent of heavy drinking days, total number of drinking days, or craving for alcohol. However, a composite alcohol improvement score was calculated, based on measured variables, finding that participants who received ≥ 4 injections of XR-NTX were significantly more likely to have a higher alcohol consumption improvement score (p< 0.005) compared to those who received ≥ 4 injections of placebo. 

Adverse Events

 Injection-site infections, immediate sensitivity reactions, nausea, diarrhea, headache, fatigue or increased anxiety were reported, but were within previously reported frequencies; no significant differences between groups were reported for any adverse events. 

Study Author Conclusions

Extended-release naltrexone is acceptable, safe, and effective in lengthening the time to heavy drinking among those who are younger living with HIV and being released from a criminal justice system setting, and higher treatment intensity is associated with greater overall global alcohol consumption improvement score. Integration of naltrexone-based pharmacotherapies to prevent relapse to alcohol use in this vulnerable population should be explored further.

InpharmD Researcher Critique

Since this was an analysis of a study initially designed to detect a different treatment outcome (HIV viral load), the calculated power analysis may not have been appropriate to detect differences in alcohol-related outcome variables. 



References:

Springer SA, Di Paola A, Azar MM, Barbour R, Krishnan A, Altice FL. Extended-release naltrexone reduces alcohol consumption among released prisoners with HIV disease as they transition to the community. Drug Alcohol Depend. 2017;174:158-170. doi:10.1016/j.drugalcdep.2017.01.026

 

Efficacy and Tolerability of Long-Acting Injectable Naltrexone for Alcohol Dependence

Design

Subgroup analysis of a multicenter, randomized, double-blind, placebo-controlled trial (Garbutt et al.; 2005)

N= 682

Objective

To determine efficacy and tolerability of a long-acting intramuscular formulation of naltrexone for treatment of alcohol-dependent patients who had 4 or more days of voluntary abstinence prior to treatment initiation

Study Groups

380 mg of long-acting naltrexone (n= 28)

190 mg of long-acting naltrexone (n= 26)

Placebo (n= 28)

Inclusion Criteria

Male or non-pregnant, non-lactating female outpatients aged 18 years or older with a current diagnosis of alcohol dependence; minimum of 2 episodes of heavy drinking (≥ 5 standard drinks/day for men and ≥ 4 standard drinks/day for women) per week during the 30 days before screening; had 4 or more days of voluntary abstinence prior to treatment initiation

Exclusion Criteria

Evidence of liver failure; alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels greater than 3 times the upper limit of normal; 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

Methods

Eligible patients who were voluntarily abstinent for 4 or more days were randomly assigned to one of three treatment groups. Over 24 weeks, patients received intramuscular gluteal injections of the study medication at 4-week intervals, alternating sides. Additionally, all patients underwent standardized supportive therapy consisting of 12 sessions. This therapy followed the Biopsychosocial, Report, Empathy, Needs, Direct advice, and Assessment (BRENDA) model, a 6-stage, low-intensity intervention aimed at facilitating direct feedback on addiction-related consequences. Throughout the trial, psychologists, nurses, therapists, counselors, and physicians at the study sites conducted the BRENDA sessions.

To assess the patients' alcohol consumption, the timeline follow-back method was employed. This method utilizes calendars and relies on patients' recall of drinking patterns to generate reliable and valid reports.

Duration

February 2002 to September 2003

Outcome Measures

Primary: frequency and pattern of heavy drinking days over the 24 weeks of treatment

Secondary: event rate of “risky” drinking days (>2 drinks per day for men and >1 drink per day for women)

Baseline Characteristics

  

380 mg of long-acting naltrexone

(n= 28)

190 mg of long-acting naltrexone

(n= 26)

Placebo

(n= 28)

  

Age, years

 45.5 43.0 43.5  

Male

 78.6% 69.2% 82.1%  

White

 89.3% 80.8% 78.6%   

Other drug use

Current smoker

Antidepressants

 

50%

25%

 

46.2%

11.5%

 

53.6%

35.7%

  

Drinking behavior

Abstinence goal

Detoxified before entry

 

64.3%

25%

 

57.7%

30.8%

 

75%

28.6%

  

Results

Endpoint

380 mg of long-acting naltrexone

(n= 28)

190 mg of long-acting naltrexone

(n= 26)

Placebo

(n= 28)

p-value

(380 mg vs placebo)

Total abstinence

 32% 23% 11% 0.02

Drinking days per month

 0.7 1.2 7.2 0.004

Heavy drinking days per month

 0.2 0.2 2.9 0.007

Satisfactory response to treatment

 70% 65% 30% 0.006

Adverse Events

 Not discussed

Study Author Conclusions

Long-acting naltrexone 380 mg prolonged abstinence, beyond that found with psychosocial support, in a subset of patients who had stopped drinking for at least 4 days before treatment initiation. Furthermore, long-acting naltrexone 380 mg reduced the number of heavy drinking days and drinking days in a similar comparison. Thus, a long duration of abstinence is not required to achieve positive outcomes with long-acting naltrexone 380 mg.

InpharmD Researcher Critique

The study's broad inclusion of alcohol-dependent patients from various treatment settings is a strength, but it introduces limitations. Clinical trials may attract individuals with higher motivation for change, impacting the generalizability of findings to the broader alcoholic population. The dropout rate, though equivalent across treatment groups, poses a challenge, as dropouts reduce the study's applicability to all alcoholics. The lack of post-dropout drinking data further hinders result interpretation. Despite strengths like high treatment attendance and early detection of long-acting naltrexone effects, these limitations underscore the need for cautious interpretation, emphasizing the specific study population and circumstances. 

Notably, this was a post-hoc subgroup analysis of a previous trial, which may be subject to retrospective biases.

 

References:

O'Malley SS, Garbutt JC, Gastfriend DR, Dong Q, Kranzler HR. Efficacy of extended-release naltrexone in alcohol-dependent patients who are abstinent before treatment. J Clin Psychopharmacol. 2007;27(5):507-512. doi:10.1097/jcp.0b013e31814ce50d