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Appendix B. Review of Research Evidence Supporting Guideline Statements

Assessment and Determination of Treatment Goals

Statement 1: Assessment of Substance Use

APA recommends (1C) that the initial psychiatric evaluation of a patient with suspected alcohol use disorder include assessment of current and past use of tobacco and alcohol as well as any misuse of other substances, including prescribed or over-the-counter medications or supplements.

Evidence for this statement comes from general principles of assessment and clinical care in psychiatric practice. Expert opinion suggests that conducting such assessments as part of the initial psychiatric evaluation improves the identification and diagnosis of substance use disorders. See APA Practice Guidelines for the Psychiatric Evaluation of Adults (American Psychiatric Association 2016) for additional details. A detailed systematic review to support this statement was outside the scope of this guideline; however, less comprehensive searches of the literature did not yield any studies that related to this recommendation in the context of AUD treatment. Consequently, the strength of research evidence is rated as low. Indirect evidence from outpatient primary care settings suggests that screening for use of tobacco, alcohol, and other substances can be beneficial if coupled with a brief intervention. Screening and intervention for tobacco use has been recommended by the U.S. Preventive Services Task Force (2009). Screening for at-risk drinking or AUD has also been recommended by the USPSTF (Moyer and U.S. Preventive Services Task Force 2013) as well as by professional organizations such as the American College of Obstetricians and Gynecologists (2011). Although several outpatient randomized controlled trials (RCTs) have not found a significant benefit of screening and brief intervention for alcohol (Kaner et al. 2013) or substance use (Saitz et al. 2014), screening may increase the likelihood that these dis orders will be identified and documented in the clinical record (Mitchell et al. 2012; Williams et al. 2014), which would be expected to improve clinical decision making. Recognition of these disorders is particularly important given the high rates of comorbidity in individuals with AUD (S. P. Chou et al. 2016; Grant et al. 2016) and the frequent lack of treatment for these disorders (Centers for Disease Control and Prevention 2011; Hasin and Grant 2015).

Statement 2: Use of Quantitative Behavioral Measures

APA recommends (1C) that the initial psychiatric evaluation of a patient with suspected alcohol use disorder include a quantitative behavioral measure to detect the presence of alcohol misuse and assess its severity.

Evidence for this statement is indirect and comes from studies of screening for alcohol use disorder (AUD) and studies of the properties of commonly used alcohol-related quantitative measures (Jonas et al. 2012a, 2012b). The strength of research evidence for this statement is rated as low. Findings from the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) study suggest that in individuals receiving treatment for AUD, scores on the Alcohol Use Disorders Identification Test (AUDIT) reflect the severity of the disorder (Donovan et al. 2006). Severity of AUD is also reflected by AUDIT or AUDIT-C scores in other outpatient settings and community samples (Chavez et al. 2012; Dawson et al. 2012; Rubinsky et al. 2013; Williams et al. 2014). In primary care settings, the USPSTF (Moyer and U.S. Preventive Services Task Force 2013, p. 212) recommends screening for alcohol misuse and notes that “both the AUDIT and the abbreviated AUDIT-C have good sensitivity and specificity for detecting the full spectrum of alcohol misuse across multiple populations.” Other scales that have been used for screening purposes in routine care (Cherpitel 2002; Dhalla and Kopec 2007; Humeniuk et al. 2008) have been less well studied as an indicator of AUD severity.

The USPSTF notes that their recommendations do not apply to individuals seeking treatment for alcohol misuse, but the ability to implement screening with these measures in primary care settings suggests that it would be feasible to use them in outpatient alcohol treatment. In addition to use for screening in hospital and emergency department settings, quantitative measures have been used for screening purposes in outpatient psychiatric settings, again suggesting the feasibility of implementation in AUD treatment (Nehlin et al. 2012). This recommendation is also consistent with Guideline VII on Quantitative Assessment as part of the APA Practice Guidelines for the Psychiatric Evaluation of Adults (American Psychiatric Association 2016).

Statement 3: Use of Physiological Biomarkers

APA suggests (2C) that physiological biomarkers be used to identify persistently elevated levels of alcohol consumption as part of the initial evaluation of patients with alcohol use disorder or in the treatment of individuals who have an indication for ongoing monitoring of their alcohol use.

Evidence for this statement is indirect, and the strength of research evidence for this statement is rated as low. Evidence comes from information on the sensitivity and specificity of physiological biomarkers in detecting alcohol consumption (Alatalo et al. 2009; Bergström and Helander 2008a; Hietala et al. 2006; Hock et al. 2005; Lowe et al. 2015; Substance Abuse and Mental Health Services Administration 2012; Walther et al. 2015; Wurst et al. 2015). In addition, some (Harasymiw and Bean 2007; Wetterling et al. 2014) but not all (Bertholet et al. 2014; Liangpunsakul et al. 2010) studies suggest that physiological biomarkers can supplement patient self-report in identifying alcohol use in community samples, primary care, and other medical settings. Research also suggests that physiological biomarkers can be used to identify relapse to drinking (Mundle et al. 1999) and to promote abstinence (McDonell et al. 2017) or to demonstrate risk for alcohol-related behaviors such as driving while intoxicated (Maenhout et al. 2014; Marques et al. 2010) or health complications after liver transplant (Kollmann et al. 2016; Piano et al. 2014; Staufer et al. 2011). Additional information on the rationale for using physiological biomarkers in the management of individuals with AUD can be found in the advisory from the Substance Abuse and Mental Health Services Administration (2012).

Statement 4: Assessment of Co-occurring Conditions

APA recommends (1C) that patients be assessed for co-occurring conditions (including substance use disorders, other psychiatric disorders, and other medical disorders) that may influence the selection of pharmacotherapy for alcohol use disorder.

Evidence for this statement comes from general principles of assessment and clinical care in psychiatric practice. Expert opinion suggests that conducting such assessments as part of the initial psychiatric evaluation improves diagnostic accuracy, appropriateness of treatment selection, and treatment safety. For additional details, see Guideline I, “Review of Psychiatric Symptoms, Trauma History, and Psychiatric Treatment History,” and Guideline VI, “Assessment of Medical Health,” in the APA Practice Guidelines for the Psychiatric Evaluation of Adults (American Psychiatric Association 2016). A detailed systematic review to support this statement was outside the scope of this guideline; however, less comprehensive searches of the literature did not yield any studies that related to this recommendation in the context of AUD treatment. Consequently, the strength of research evidence is rated as low.

Statement 5: Determination of Initial Treatment Goals

APA suggests (2C) that the initial goals of treatment of alcohol use disorder (e.g., abstinence from alcohol use, reduction or moderation of alcohol use, other elements of harm reduction) be agreed on between the patient and clinician and that this agreement be documented in the medical record.

Evidence for this statement comes from general principles of assessment and clinical care in psychiatric practice. Also, in choosing pharmacotherapy for AUD and particularly before deciding to prescribe disulfiram, it is essential to know whether or not the patient has a goal of abstinence from alcohol use. More generally, expert opinion suggests that engaging patients in shared decision making improves the therapeutic alliance and adherence. For additional details, see Guideline VIII, “Involvement of the Patient in Treatment Decision Making,” in the APA Practice Guidelines for the Psychiatric Evaluation of Adults (American Psychiatric Association 2016). There has also been increasing attention to shared decision making in treatment of AUD (Bradley and Kivlahan 2014) as well as in other areas of medicine (Durand et al. 2014; Makoul and Clayman 2006).

A detailed systematic review to support this statement was outside the scope of this guideline; however, a less comprehensive search of the literature did not yield any studies that were directly related to this recommendation. Consequently, the strength of research evidence is rated as low. However, secondary analyses of clinical trial data show that patient-stated goals of abstinence at study initiation are associated with more days abstinent and greater reductions in alcohol consumption than patient-stated goals of reduced alcohol use (Adamson et al. 2010; Al-Otaiba et al. 2008; Berger et al. 2016; Bujarski et al. 2013; Chang et al. 2006; Dunn and Strain 2013; Gueorguieva et al. 2014; Meyer et al. 2014; Mowbray et al. 2013). In addition, patient goals sometimes changed in the course of treatment. Several smaller studies also related to determining patient goals at the start of treatment. One small study examined the number and types of goals set in the course of treatment by individuals with AUD who were chronically homeless (Collins et al. 2015). Drinking-related goals were most frequent and typically included reducing drinking and reducing alcohol-related consequences, rather than abstinence-based goals. Quality-of-life goals and health-related goals were also reported throughout the course of treatment. In addition, a small study of at-risk elderly drinkers who were treated in primary care compared enhanced referral with integrated care, which included treatment goal setting among multiple other components (Lee et al. 2009). Individuals receiving integrated care were more likely to access care and had fewer drinks in the past week and fewer binge-drinking episodes in the past 3 months than those assigned to receive enhanced referral.

Statement 6: Discussion of Legal Obligations

APA suggests (2C) that the initial goals of treatment of alcohol use disorder include discussion of the patient’s legal obligations (e.g., abstinence from alcohol use, monitoring of abstinence) and that this discussion be documented in the medical record.

Evidence for this statement comes from general principles of assessment and clinical care in psychiatric practice. A detailed systematic review to support this statement was outside the scope of this guideline; however, on the basis of prior searches related to psychiatric assessment and treatment planning, we would not anticipate finding any studies with a direct bearing on this recommendation.

Statement 7: Review of Risks to Self and Others

APA suggests (2C) that the initial goals of treatment of alcohol use disorder include discussion of risks to self (e.g., physical health, occupational functioning, legal involvement) and others (e.g., impaired driving) from continued use of alcohol and that this discussion be documented in the medical record.

Evidence for this statement comes from general principles of clinical care in psychiatric practice. A detailed systematic review to support this statement was outside the scope of this guideline; however, evidence does suggest that abstaining from or reducing alcohol consumption is associated with significant health benefits (Charlet and Heinz 2017). In addition, having the patient identify negative consequences of drinking for himself or herself is an element of motivational enhancement therapy (Miller and Rollnick 2013; Miller et al. 1994). Assessment of drinking consequences has been a part of many studies of treatment for AUD, including Matching Alcoholism Treatments to Client Heterogeneity (Project MATCH; Miller et al. 1995; Project MATCH Research Group 1997) and the COMBINE study (Anton et al. 2006), although the specific effect of this element on outcomes has not been separated from other elements of treatment.

Statement 8: Evidence-Based Treatment Planning

APA recommends (1C) that patients with alcohol use disorder have a documented comprehensive and person-centered treatment plan that includes evidence-based nonpharmacological and pharmacological treatments.

Evidence for this statement comes from general principles of assessment and clinical care in psychiatric practice. A detailed systematic review to support this statement was outside the scope of this guideline; however, less comprehensive searches of the literature did not yield any studies that directly related to this recommendation. Consequently, the strength of research evidence is rated as low.

Expert opinion suggests that when using pharmacotherapy to treat AUD, it is beneficial for a treatment plan to incorporate nonpharmacological treatments and have a patient-centered focus. Furthermore, major clinical trials of alcohol pharmacotherapy, such as the COMBINE study, include some form of nonpharmacological treatment in all treatment arms. For example, medication management included elements of education, encouragement, approaches to enhancing medication adherence, and supportive interactions to promote abstinence.

In terms of person-centered care, one meta-analysis (Barrio and Gual 2016) assessed the role of patient-centered care in individuals with AUD. Of the 40 included studies, 5 involved use of pharmacological agents on an “as needed” basis, and 35 involved motivational interviewing, with more than one session occurring in 15 of the studies. Despite significant heterogeneity in the studies, a benefit of “as needed” medication was described with positive alcohol-related outcomes in some of the multiple-session motivational interviewing studies.

In terms of treatment preferences related to AUD, a study of 399 primary care patients included 65 individuals (68% male) with a score of greater than 8 on the AUDIT (Lieberman et al. 2014). When asked about potential treatments, 68% reported interest in “getting help from my doctor,” 37% reported interest in an Internet program, and 23% reported interest in Alcoholics Anonymous (AA). In terms of pharmacotherapy, 55% reported interest in “taking a medication that would make it easier to avoid alcohol (but would not make me sick if I drank),” with 20% reporting interest in “taking a medication that would make me sick if I drank.” Alcohol-related treatment preferences were also assessed in a large (N = 9,005) population-based study in Sweden (Andréasson et al. 2013). Among respondents who reported the highest number of standard drinks per week (> 28 for men and > 18 for women), approximately 40% expressed a preference for AA or another support group, approximately 40% expressed a preference for psychotherapy, approximately 15% expressed a preference for pharmacotherapy, and approximately 5% expressed a preference for Internet-based intervention. Data from the COMBINE study demonstrate that patient views of treatment, including treatment cost-effectiveness, may differ from clinician views (Dunlap et al. 2010). In addition, the time that patients must invest in attending treatment sessions and traveling to treatment is often considerable (Dunlap et al. 2010).

Selection of a Pharmacotherapy

Statement 9: Naltrexone or Acamprosate

APA recommends (1B) that naltrexone or acamprosate be offered to patients with moderate to severe alcohol use disorder who

  • have a goal of reducing alcohol consumption or achieving abstinence,

  • prefer pharmacotherapy or have not responded to nonpharmacological treatments alone, and

  • have no contraindications to the use of these medications.

Evidence supporting the use of naltrexone and acamprosate comes from multiple double-blind RCTs. All trials described below were conducted in the outpatient setting, with subject recruitment typically occurring by print and other media advertising or by referrals (e.g., from inpatient detoxification programs or other outpatient clinicians). Most studies were conducted in Europe or the United States; the remaining studies were conducted in Asia, Australia, or South America. To be included in the systematic review of evidence, trials needed to be at least 12 weeks in length, with some extending to 26 weeks or more. Posttreatment follow-up was typically minimal, but some trials followed subjects up to a year after treatment discontinuation. The majority of the trials included psychotherapies or other psychosocial interventions (e.g., motivational therapies, cognitive-behavioral interventions, manual-based medication management approaches) for all treatment groups.

The vast majority of trials established eligibility for the trial on the basis of DSM-IV criteria or ICD-10 criteria for alcohol dependence as well as numerical descriptions of alcohol use (e.g., days of drinking in past week or month, threshold numbers for drinks per day or drinks per week), typically with lower thresholds for women than for men. In framing the guideline recommendation in terms of DSM-5 AUD, we relied on evidence that DSM-IV alcohol dependence corresponds to DSM-5 AUD of at least moderate severity (Compton et al. 2013; Hasin et al. 2013; Peer et al. 2013). In terms of exclusion criteria, other substance use disorders, besides nicotine and sometimes marijuana, typically precluded participation, as did use of psychotropic medications, and significant physical or psychiatric illnesses were also exclusion criteria for most trials. Other exclusion criteria related to ability to consent (e.g., language barriers, cognitive deficits) and to potential safety risks with the medication such as pregnancy or breastfeeding or need for opioid medication (with naltrexone). Study subjects were generally limited to adults, with a mean age of subjects in the mid-40s. The majority of trials had a preponderance of men. Other demographic characteristics were often unreported.

Most study outcomes were focused on abstinence-related outcomes such as any drinking, time to first drink, or time to relapse or alcohol consumption–related outcomes such as number of drinking days, number of heavy drinking days, drinks per drinking day, or drinks per week. Other important outcomes such as quality of life, accidents, injuries, and mortality were reported infrequently. In trials that included information about adverse events, the methods for identifying such events were frequently unclear. Numbers of serious events (including suicide or suicide attempts) were small, making it impossible to identify whether differences existed among treatment conditions. Some studies reported information only about adverse events that were statistically different from placebo, which could affect the meta-analyses on harms.

Benefits of Acamprosate

The AHRQ review (Jonas et al. 2014) found that acamprosate treatment at a dose of 666 mg and three times daily (range 1,000 mg to 3,000 mg per day in divided doses) was associated with a decreased likelihood of returning to alcohol use as compared with placebo (moderate strength of evidence; risk difference [RD] –0.09; 95% confidence interval [CI] –0.14 to –0.04; number needed to treat [NNT] = 12) (Table B–1). Number of drinking days was also reduced with acamprosate treatment relative to placebo (moderate strength of evidence; weighted mean difference [WMD] –8.8; 95% CI –12.8 to –4.8; 13 trials). However, for both outcomes, the benefits of acamprosate were seen primarily in studies done outside of the United States. Return to heavy drinking (moderate strength of evidence) and number of heavy drinking days (insufficient strength of evidence) showed no effect of acamprosate. The available evidence also did not permit any conclusions about the effect of acamprosate on outcomes such as quality of life, functioning, accidents, injuries, or mortality. In studies that assessed response rates by sex, men and women did not differ on any measure of efficacy.

Acamprosate compared with placebo

Outcome

Number of studies;

number of subjects

Risk of bias; design

Consistency

Directness

Precision

Summary effect size (95% CI)

NNTh

Strength of evidence grade

Return to any drinking

16;a 4,847

Medium;

RCTs

Consistentb

Direct

Precise

RD: –0.09 (–0.14 to –0.04)

12

Moderate

Return to heavy drinking

7; 2,496

Low; RCTs

Consistent

Direct

Precise

RD: –0.01 (–0.04 to 0.03)

NA

Moderatec

Drinking days

13;d 4,485

Medium;

RCTs

Consistent

Direct

Precise

WMD: –8.8 (–12.8 to –4.8)

NA

Moderate

Heavy drinking days

1; 100

Medium;

RCT

Unknown

Direct

Imprecise

WMD: –2.6 (–11.4 to 6.2)

NA

Insufficient

Drinks per drinking day

1;d 116

Low; RCT

Unknown

Direct

Imprecise

WMD: 0.40 (–1.81 to 2.61)

NA

Insufficient

Accidents

0;e 0

NA

NA

NA

NA

NA

NA

Insufficient

Injuries

0; 0

NA

NA

NA

NA

NA

NA

Insufficient

Quality of life or function

1; 612

Low; RCT

Unknown

Direct

Unknown

NSDf

NA

Insufficient

Mortality

8;g 2,677

Medium;

RCTs

Unknown

Direct

Imprecise

7 (ACA) vs. 6 (PBO)

NA

Insufficient

aTwo additional studies were rated high risk of bias; one additional study was rated as unclear risk of bias.

bAlthough there was considerable statistical heterogeneity, 14 of 15 studies reported point estimates that favored acamprosate; differences were in magnitude of benefit.

cThe relatively small number of studies reporting this outcome raises concern for potential reporting bias, hence the rating of moderate rather than high.

dOne additional study was rated high risk of bias.

eThe single study that reported this outcome was rated as unclear risk of bias. It reported that one patient in the placebo group died by “accident.” No other details on the cause or nature of the accident were provided.

fResults were not reported for each treatment group separately, but there were no clinically significant differences across treatment groups.

gOne additional study reported a death but did not specify in which treatment group it occurred.

hValues for NNT were added from Jonas et al. (2014), Table 37. For values marked NA, NNT was not calculated because either the risk difference (95% CI) was not statistically significant or the effect measure was not one that allows direct calculation of NNT (e.g., WMD).

Abbreviations: ACA=  acamprosate; CI = confidence interval; NA = not applicable; NNT = number needed to treat; NSD = no statistically significant difference; PBO = placebo; RCT = randomized controlled trial; RD = risk difference; WMD = weighted mean difference.

Source. Jonas et al. 2014, Table D–1.

Acamprosate compared with placebo

Enlarge table

In the studies with long-term use of acamprosate (48–52 weeks), there was an 11% absolute reduction in return to any drinking (RD, –0.11; 95% CI, –0.16 to –0.06; 4 trials) and 12.2% fewer drinking days than for those treated with placebo over 48–52 weeks (WMD, –12.2; 95% CI, –16.4 to –8.0; I2 0%).

A number of relevant studies that are not included in the AHRQ meta-analysis or in Table B–1 have shown mixed results for acamprosate. In a pragmatic trial in France, 422 patients treated by 149 practitioners were randomly assigned to standard care (typically outpatient detoxification followed by psychotherapy) or to acamprosate plus standard care (Kiritzé-Topor et al. 2004). The trial reported better outcomes for the acamprosate group on a number of alcohol-related measures, with an NNT of about 7. A 24-week study (total N = 327) with low risk of bias that was conducted in Japan (Higuchi and Japanese Acamprosate Study Group 2015) showed greater rates of abstinence with acamprosate than placebo at 24 weeks (47.2% for acamprosate vs. 36.0% for placebo; p = 0.039), but there was no significant effect of treatment on secondary endpoints (i.e., cumulative days of abstinence during 24 weeks of treatment, time to first relapse, and time to 3 or more days of consecutive drinking). Furthermore, the generalizability of this study to the United States may be limited because patients were enrolled on discharge from 2 months of inpatient detoxification/rehabilitation.

In two additional RCTs, effects of acamprosate did not differ from placebo. The German PREDICT study (Mann et al. 2013), modeled after the COMBINE study, recruited subjects (total N = 426) at time of discharge from medical detoxification (average length of stay 18 days). The time to first heavy drinking (primary outcome) did not differ among the treatment groups. Relapse-free survival at 90 days was 48.3% for acamprosate versus 51.8% for placebo. Another study (total N = 100) with low risk of bias in a primary care setting (Berger et al. 2013) found no effect of acamprosate on percent days abstinent (primary outcome), percent heavy drinking days, or change in gamma-glutamyl transferase (GGT) levels. Nevertheless, both acamprosate and placebo groups showed improvement during the 12-week trial, particularly among individuals with a treatment goal of abstinence.

Grading of the Overall Supporting Body of Research Evidence for Efficacy of Acamprosate

  • Magnitude of effect: Weak. When present, the magnitude of the effect is small.

  • Risk of bias: Medium. Studies are RCTs of low to medium bias based on their described randomization and blinding procedures and descriptions of study dropouts.

  • Applicability: The included trials all involve individuals with AUD, by either prior diagnostic criteria or other evidence of harmful levels of drinking. The studies include subjects from around the world, including North America. However, studies from the United States, including the COMBINE study, showed minimal or no response to acamprosate, whereas benefits of acamprosate were found in studies from Europe, where acamprosate was typically started in the hospital during a period of abstinence. The doses of acamprosate and characteristics of subjects in the studies appear to be representative of outpatient clinical practice.

  • Directness: Direct. Studies measured abstinence and alcohol consumption.

  • Consistency: Inconsistent. There was considerable heterogeneity, as evidenced by I2 values of 70%–80% on return to any drinking and on percent drinking days.

  • Precision: Imprecise. Confidence intervals for studies cross the threshold for clinically significant benefit of the intervention.

  • Dose-response relationship: Present. Although not analyzed as part of the AHRQ meta-analysis, all three trials that examined several doses of acamprosate found at least a trend for improved response at higher doses.

  • Confounding factors (including likely direction of effect): Absent. No known confounding factors are present that would be likely to reduce the effect of the intervention.

  • Publication bias: Not identified. No publication bias was noted by the AHRQ review; however, they note that they were unable to assess for publication bias for early clinical trials (prior to the advent of https://clinicaltrials.gov).

  • Overall strength of research evidence: Moderate. A large number of RCTs have been conducted, most of which have low to medium risk of bias. Many of the RCTs are funded by governmental agencies. Although the studies have good applicability and measure outcomes of interest directly, the imprecision and inconsistency of findings are limitations.

Harms of Acamprosate

The AHRQ review (Jonas et al. 2014) found statistically significant increases in diarrhea and vomiting as compared with placebo, although statistical heterogeneity was high, particularly for diarrhea (Table B–2). In studies published since the AHRQ report (Jonas et al. 2014) and not included in Table B–2, diarrhea was also common. In a study by Berger et al. (2013), diarrhea occurred in almost one-third of subjects, but there was no difference between acamprosate and placebo. In a study by Higuchi and Japanese Acamprosate Study Group (2015), diarrhea occurred more frequently with acamprosate than with placebo (12.9% vs. 4.9%, respectively). In a study by Mann et al. (2013), diarrhea was also noted to be greater with acamprosate than with placebo.

Acamprosate compared with placebo

Outcome

Number of studies; number of subjects

Risk of bias; design

Consistency

Directness

Precision

Summary effect size (95% CI)

Strength of evidence grade

Withdrawals due to AEs

13;a 4,653

Medium; RCTs

Consistent

Direct

Imprecise

RD 0.006 (–0.003 to 0.015)

Low

Anorexia

0; 0

NA

NA

NA

NA

NA

Insufficient

Anxiety

1;b 601

Medium; RCT

Unknown

Direct

Imprecise

RD 0.164 (0.095 to 0.234)

Insufficient

Cognitive dysfunction

0; 0

NA

NA

NA

NA

NA

Insufficient

Diarrhea

12; 3,299

Medium; RCTs

Consistent

Direct

Precise

RD 0.099 (0.030 to 0.168)

Moderate

Dizziness

2; 151

Low to medium; RCTs

Inconsistent

Direct

Imprecise

RD 0.08 (–0.22 to 0.38)

Low

Headache

6;b 1,074

Medium; RCTs

Inconsistent

Direct

Imprecise

RD 0.001 (–0.052 to 0.05)

Low

Insomnia

3;b 251

Medium; RCTs

Inconsistent

Direct

Imprecise

RD 0.019 (–0.10 to 0.138)

Low

Nausea

7;b 1,758

Low to medium; RCTs

Consistent

Direct

Imprecise

RD 0.006 (–0.012 to 0.023)

Moderate

Numbness/tingling/paresthesias

1;b 262

Medium; RCT

Unknown

Direct

Imprecise

RD 0.008 (–0.013 to 0.029)

Insufficient

Rash

1;b 35

Low; RCT

Unknown

Direct

Imprecise

RD 0.111 (–0.069 to 0.291)

Insufficient

Suicide attempts or suicidal ideation

1;c

581

Medium; RCT

Unknown

Direct

Imprecise

RD 0.007 (–0.005, 0.019)

Insufficient

Taste abnormalities

0; 0

NA

NA

NA

NA

NA

Insufficient

Vision changes

0; 0

NA

NA

NA

NA

NA

Insufficient

Vomiting

4;b 1,817

Medium; RCTs

Consistent

Direct

Precise

RD 0.024 (0.007 to 0.042)

Moderate

aThree additional studies were rated high or unclear risk of bias.

bOne additional study was rated high or unclear risk of bias.

cTwo additional studies were rated high or unclear risk of bias.

Abbreviations: AE = adverse effect; CI = confidence interval; RCT = randomized controlled trial; RD = risk difference.

Source.  Jonas et al. 2014, Table D–33.

Acamprosate compared with placebo

Enlarge table

Anxiety was also noted to be greater with acamprosate than with placebo in the AHRQ review, but this finding was based on one study, and other studies have noted no difference from placebo (Micromedex 2017a) or less anxiety (Mann et al. 2013) or even somnolence (Forest Pharmaceuticals 2005) with acamprosate. In studies published since the AHRQ report (Jonas et al. 2014), other side effects occurred in less than 10% of individuals treated with acamprosate or placebo (Berger et al. 2013; Higuchi and Japanese Acamprosate Study Group 2015), without differences in overall side effects (Higuchi and Japanese Acamprosate Study Group 2015) or study attrition due to adverse events (Mann et al. 2013) between the two groups.

In the package insert for acamprosate (Forest Pharmaceuticals 2005), adverse events of a suicidal nature were described as somewhat more common with acamprosate as compared with placebo (1.4% vs. 0.5% in studies of 6 months or less; 2.4% vs. 0.8% in year-long studies), with suicide in 3 of 2,272 (0.13%) patients in the pooled acamprosate group and 2 of 1,962 patients (0.10%) in the pooled placebo group. However, the AHRQ report notes that evidence was not sufficient to make a determination about the risk of suicide-related events (Jonas et al. 2014). The package insert also notes that acamprosate is contraindicated with severe renal impairment (creatinine clearance [CrCl] 30 mL/min or less) and requires dose adjustments for moderate renal impairment (CrCl of 30–50 mL/min). Other information on harms of acamprosate comes from nonrandomized trials and drug information databases and is noted in Statement 9, Implementation.

Grading of the Overall Supporting Body of Research Evidence for Harms of Acamprosate

  • Magnitude of effect: Weak. When present, the magnitude of effect is small.

  • Risk of bias: High. Studies are RCTs of low to medium bias based on their described randomization and blinding procedures and descriptions of study dropouts. However, methods for determining harms are not well specified, and there is potential for selective reporting of results.

  • Applicability: The included trials all involve individuals with AUD, by either prior diagnostic criteria or other evidence of harmful levels of drinking. The studies include subjects from around the world, including North America. The doses of acamprosate and characteristics of subjects in the studies appear to be representative of outpatient clinical practice.

  • Directness: Direct. Studies measured common side effects and dropouts due to adverse events.

  • Consistency: Inconsistent. There was considerable heterogeneity, particularly in reported rates of diarrhea.

  • Precision: Imprecise. Confidence intervals for studies are wide in many studies and cross the threshold for clinically significant harms of the intervention.

  • Dose-response relationship: Unknown. Dose-response information on side effects was not well described.

  • Confounding factors (including likely direction of effect): Absent. No known confounding factors are present that would be likely to modify adverse events of the intervention. Although abnormalities in renal function could affect blood levels of drugs, individuals with significant renal impairment were excluded from the clinical trials.

  • Publication bias: Not identified. No publication bias was noted by the AHRQ review; however, they note that they were unable to assess for publication bias for early clinical trials (prior to the advent of https://clinicaltrials.gov).

  • Overall strength of research evidence: Low. A large number of RCTs have been conducted, but few have assessed adverse events in a systematic and predefined fashion. Many of the RCTs are funded by governmental agencies. Although the studies have good applicability and measure outcomes of interest directly, imprecision and inconsistency of findings are a limitation.

Data Abstraction: Acamprosate

Studies related to acamprosate are listed in Table B–3.

Studies related to acamprosate

Author and year; trial name

Study characteristics

Treatment administered, including study arm, dose (mg/day), sample size (N), and co-intervention

Rx duration, weeks (follow-up)

Sample characteristics, including diagnostic inclusions and major exclusions

Outcome measures, main results, and overall percent attrition

Risk of bias

Anton and COMBINE Study Research Group 2003

Design: DBRCT

Setting: 11 academic outpatient sites

Country: United States

Funding: govt, meds

ACA 3,000 + CBI + MM (9); ACA 3,000 + MM (9); NTX 100 + CBI + MM (9); NTX 100 + MM (9); PBO + CBI + MM (9); PBO + MM (8)

Other Tx: as randomized

16

DSM-IV alcohol dependence

Mean age: 38–42 years

17%–22% Nonwhite

22%–33% Female

Other Dx: NR

Drinking outcomes were not reported for this pilot feasibility study.

ACA-NTX group adherence was equal to, or better than, adherence with PBO, ACA alone, or NTX alone.

Adverse events were comparable in all groups.

Attrition: 31%

Medium

Anton et al. 2006; Donovan et al. 2008; LoCastro et al. 2009; COMBINE

Design: DBRCT

Setting: 11 academic outpatient sites

Country: United States

Funding: govt, meds

ACA 3,000 + CBI + MM (151); ACA 3,000 + MM (152); NTX 100 + CBI + MM (155); NTX 100 + MM (154); PBO + CBI + MM (156); PBO + MM (153)

Other Tx: as randomized; community support group participation (e.g., AA) encouraged

16 (68)

DSM-IV alcohol dependence

Mean age: 44 years

23% Nonwhite

31% Female

Other Dx: NR

All groups showed substantial reductions in alcohol use, but ACA did not have a significant effect compared with PBO by itself or with any combination of NTX, CBI, or both.

Differences between ACA and PBO were percent drinking days: –0.1 (95% CI –4.21, 4.01), return to any drinking: –0.02 (95% CI –0.08, 0.04), and return to heavy drinking: –0.04 (95% CI –0.11, 0.04).

Mean treatment adherence for ACA was 84.2%, and 94% of those in the study provided drinking data for 16 weeks.

Diarrhea was more frequent with ACA (65% vs. 35% with PBO), but the proportion of serious adverse effects and withdrawals due to adverse effects did not differ.

Low

Baltieri and De Andrade 2004

Design: DBRCT

Setting: outpatient

Country: Brazil

Funding: NR

ACA 1,998 (40); PBO (35)

Other Tx: AA encouraged

12 (24)

ICD-10 alcohol dependence

Mean age: 18–60 years

% Nonwhite NR

0% Female

Other Dx: 0%

Differences between ACA and PBO for return to any drinking: –0.22 (95% CI –0.45, 0).

Kaplan-Meier survival curves (ITT analysis) showed lower relapse rates for ACA vs. PBO (p = 0.02).

Attrition: 23% at 12 weeks

Medium

Berger et al. 2013, 2016

Design: DBRCT

Setting: 2 outpatient primary care sites

Country: United States

Funding: Forest

ACA 1,998 (51); PBO (49)

Other Tx: brief structured behavioral intervention from primary care physician

12

DSM-IV alcohol dependence

Mean age: 48 years

9% Nonwhite

38% Female

Other Dx: tobacco use 44%

Differences between ACA and PBO were percent drinking days: 0.9 (95% CI –11.59, 13.39), percent heavy drinking days: –2.6 (95% CI –11.38, 6.18), and return to any drinking: 0.12 (95% CI 0, 0.25).

Both treatment groups improved with greater response in those with a goal of abstinence.

No deaths or serious adverse events

Attrition: 19%

Medium

Besson et al. 1998

Design: DBRCT

Setting: 3 outpatient psychiatric sites

Country: Switzerland

Funding: govt, Lipha

ACA 1,300–1,998 (55); PBO (55)

Other Tx: routine counseling 100%; voluntary disulfiram 22%–24%

52 (108)

DSM-III chronic or episodic alcohol dependence

Mean age: 42 years

% Nonwhite NR

20% Female

Other Dx: 0%

Differences between ACA and PBO were percent drinking days: –19 (95% CI –32.43, –5.57) and return to any drinking: –0.11 (95% CI –0.26, 0.04).

Diarrhea occurred more often with ACA.

Attrition: 65% at 360 days

Medium

Chick et al. 2000b

Design: DBRCT

Setting: 20 outpatient clinics

Country: United Kingdom

Funding: Lipha

ACA 1,998 (289); PBO (292)

Other Tx: usual psychosocial; outpatient treatment program

24

DSM-III alcohol dependence

Mean age: 43 years

% Nonwhite NR

16% Female

Other Dx: 0%

Differences between ACA and PBO were percent drinking days: 2 (95% CI –3.71, 7.71), return to any drinking: –0.01 (95% CI –0.06, 0.04), and return to heavy drinking: 0.02 (95% CI –0.04, 0.08).

Overall rate of abstinence was 12%.

Only 43% were taking 90% of tablets at 2 weeks, and adherence was 28% at 24 weeks.

Attrition: 64%

Medium

De Sousa and De Sousa 2005

Design: OLRCT

Setting: outpatient private psychiatric hospital

Country: India

Funding: NR

ACA 1,998 (50); DIS 250 (50)

Other Tx: weekly supportive group psychotherapy offered

35

DSM-IV alcohol dependence

Exclusions: previous disulfiram or acamprosate treatment

Mean age: 42–43 years

100% Nonwhite

0% Female

Other Dx: NR

DIS had a lower relapse rate than ACA (88% vs. 46%; p = 0.0001) and a longer mean time to first relapse (123 days vs. 71 days; p = 0.0001).

ACA had lower craving scores than DIS.

Attrition: 7%

High

Geerlings et al. 1997

Design: DBRCT

Setting: 22 outpatient substance use treatment centers

Country: Belgium, the Netherlands, and Luxembourg

Funding: Lipha

ACA 1,332–1,998 (128); PBO (134)

Other Tx: ACA: benzodiazepines 5%; PBO: benzodiazepines 6%

26 (52)

DSM-III alcohol dependence

Mean age: 40–42 years

% Nonwhite NR

24% Female

Other Dx: NR

Differences between ACA and PBO were percent drinking days: –10 (95% CI –18.66, –1.34) and return to any drinking: –0.12 (95% CI –0.21, –0.02).

Diarrhea was more frequent with ACA: 19.5% vs. PBO 11.5%.

Attrition: 64%

Medium

Greenfield et al. 2010; Fucito et al. 2012; COMBINE

Design: secondary data analysis

Setting: 11 academic outpatient sites

Country: United States

Funding: govt, meds

ACA 3,000 + CBI + MM (151); ACA 3,000 + MM (152); NTX 100 + CBI + MM (155); NTX 100 + MM (154); PBO + CBI + MM (156); PBO + MM (153)

Other Tx: as randomized; community support group participation (e.g., AA) encouraged

68

DSM-IV alcohol dependence

Mean age: 44 years

23% Nonwhite

31% Female

Other Dx: 0%

There was a significant NTX by CBI interaction for women on two primary outcomes (percent days abstinent and time to first heavy drinking day) and also secondary outcome measures (good clinical response, percent heavy drinking days, and craving).

Only the NTX by CBI interaction was significant for percent days abstinent.

The NTX by CBI interaction was significant for time to first heavy drinking day in men (p = 0.048), with each treatment showing slower relapse times.

A nonsignificant trend was present in women.

NTX or CBI alone was superior to groups receiving neither in the percent of heavy drinking days.

Low

Gual and Lehert 2001

Design: DBRCT

Setting: outpatient, multicenter hospitals

Country: Spain

Funding: Lipha

ACA 1,998 (148); PBO (148)

Other Tx: NR

26

DSM-III-R alcohol dependence

Mean age: 41 years

% Nonwhite NR

20%–21% Female

Other Dx: NR

Differences between ACA and PBO were percent drinking days: –10.6 (95% CI –18.11, –3.09) and return to any drinking: –0.09 (95% CI –0.19, 0.02).

Rates of complete abstinence as estimated by survival analysis were 35% and 26% for ACA vs. PBO.

Overall adverse effects were comparable, but gastrointestinal effects were more frequent with ACA vs. PBO.

Attrition: 35%

Medium

Higuchi and Japanese Acamprosate Study Group 2015

Design: DBRCT

Setting: outpatient

Country: Japan

Funding: Nippon Shinyaku Company

ACA 1,998 (163); PBO (184)

24 (24)

ICD-10 alcohol dependence

Mean age: 52.4 years

% Nonwhite NR

12.5% Female

Other Dx: NR

Abstinence rates with ACA vs. PBO were 47.2% vs. 36.0% with 11.3% (95% CI 0.6%, 21.9%) difference (P = 0.039).

Overall adverse events and diarrhea were common and more frequent with ACA.

Attrition: 38%

Low

Kiefer et al. 2003, 2004, 2005

Design: DBRCT

Setting: 1 outpatient site

Country: Germany

Funding: univ; meds

ACA 1,998 (40); NTX 50 (40); PBO (40); ACA 1,998 + NTX 50 (40)

Other Tx: group therapy

12

DSM-IV alcohol dependence without any withdrawal symptoms

Exclusions: homelessness

Mean age: 46 years

% Nonwhite NR

26% Female

Other Dx: 0%

Differences between ACA and PBO were return to any drinking: –0.17 (95% CI –0.33, –0.02) and return to heavy drinking: –0.13 (95% CI –0.33, 0.08).

ACA was superior to PBO on time to first relapse by survival analysis.

At the end of active treatment, relapse rates with ACA + NTX did not differ from ACA alone.

Attrition: 66%

Low

Laaksonen et al. 2008

Design: OLRCT

Setting: 6 outpatient sites in 5 cities

Country: Finland

Funding: govt

ACA 1,998 or 1,333 (81); DIS 100–200 (81); NTX 50 (81)

Other Tx: manual-based CBT

Up to 52 (119)

ICD-10 alcohol dependence

Mean age: 43 years

0% Nonwhite

29% Female

Other Dx: NR

During the continuous medication period (1–12 weeks), the DIS group did significantly better than the NTX and ACA groups in time to first heavy drinking day (p = 0.001), days to first drinking (p = 0.002), abstinence days, and average weekly alcohol intake.

During the targeted medication period (13–52 weeks), there were no significant differences between the groups in time to first heavy drinking day and days to first drinking, whereas the DIS group reported significantly more frequent abstinence days than the ACA and NTX groups.

During the whole study period (1–52 weeks), the DIS group did significantly better in the time to the first drink compared with the other groups.

Attrition: 52%

High

Lhuintre et al. 1985

Design: DBRCT

Setting: outpatient methadone maintenance clinics

Country: France

Funding: meds

ACA 1,000–2,250 (42); PBO (43)

Other Tx: meprobamate 100% for first month

13

Alcohol dependence indicated by morning withdrawal, > 200 g/day daily alcohol intake, or at least two failed treatment attempts; GGT > 30 IU/L; and red blood cell volume > 96 fL

Mean age: 40–43 years

% Nonwhite NR

11% Female

Other Dx: NR

Difference between ACA and PBO for return to any drinking: –0.2 (95% CI –0.4, 0)

Abstinence rates for those who remained in the study: ACA 61% vs. PBO 32%

Attrition: 18%

High

Lhuintre et al. 1990

Design: DBRCT

Setting: outpatient substance use disorders clinic

Country: France

Funding: NR

ACA 1,332 (279); PBO (290)

Other Tx: psychotherapy allowed

12 (12)

At least one sign of alcohol dependence, GGT > 2× normal, or mean red blood cell corpuscular volume > 98 fL

Mean age: 42–43 years

% Nonwhite NR

18% Female

Other Dx: NR

Difference between ACA and PBO for return to any drinking: –0.1 (95% CI –0.16, –0.03)

GGT as a marker of alcohol use was significantly lower with ACA vs. PBO at 12 weeks.

Diarrhea was more common with ACA vs. PBO.

Attrition: 37%

High

Mann et al. 2013; PREDICT

Design: DBRCT

Setting: NR

Country: Germany

Funding: govt, meds

ACA 1,998 (172); NTX 50 (169); PBO (86)

Other Tx: MM

12

Alcohol dependence

Mean age: 45 years

% Nonwhite NR

23% Female

Other Dx: NR

Difference between ACA and PBO for return to heavy drinking: 0.04 (95% CI –0.09, 0.16)

Point estimates for heavy drinking relapse free survival from the Kaplan Meier curves were 48.3% for ACA, 49.1% for NTX, and 51.8% for PBO.

Diarrhea was greater in ACA-treated patients.

Attrition: 34%

Medium

Mason et al. 2006

Design: DBRCT

Setting: 21 outpatient clinics

Country: United States

Funding: Lipha

ACA 2,000 (258); ACA 3,000 (83); PBO (260)

Other Tx: brief abstinence-oriented protocol-specific counseling and self-help materials 100%

24 (32)

DSM-IV alcohol dependence

Mean age: 44–45 years

14%–15% Nonwhite

29%–36% Female

Other Dx: tobacco use 77%

Differences between ACA and PBO were percent drinking days: –5.9 (95% CI –11.51, –0.29), return to any drinking: 0.04 (95% CI 0, 0.08), and return to heavy drinking: –0.04 (95% CI –0.12, 0.04).

A linear effect of dose was present in ITT analysis and a subgroup of motivated subjects.

Attrition: 51%

Low

Morley et al. 2006, 2010

Design: DBRCT

Setting: 3 outpatient intensive substance use treatment sites

Country: Australia

Funding: govt

ACA 1,998 (55); NTX 50 (53); PBO (61)

Other Tx: all offered 4–6 sessions of manualized compliance therapy; uptake/attendance NR

12

DSM-IV alcohol dependence or abuse and with alcohol abstinence for 3–21 days

Mean age: 45 years

% Nonwhite NR

30% Female

Other Dx: substantial levels of emotional distress (anxiety, stress, and depression); 3% severe concurrent illness (psychiatric or other)

Differences between ACA and PBO were drinks per drinking days: 0.4 (95% CI –1.81, 2.61), return to any drinking: –0.02 (95% CI –0.16, 0.12), and return to heavy drinking: –0.02 (95% CI –0.14, 0.19).

No differences in side effects were noted, except headache was more frequent with PBO.

Attrition: 36%

Low

Narayana et al. 2008

Design: prospective cohort

Setting: military, outpatient

Country: India

Funding: NR

ACA 1,332–1,998 (28); NTX 50 (26); TOP 100–125 (38)

Other Tx: various psychotherapies were offered

52

ICD-10 alcohol dependence

Mean age: 38 years

100% Nonwhite

0% Female

Other Dx: NR

TOP (76.3%) was significantly more effective (p < 0.01) in sustaining abstinence, although 57.7% NTX and 60.7% ACA maintained complete abstinence.

7 TOP subjects (18.4%) reported decreased relapses compared with 8 NTX (30.8%) and 9 ACA (32.1%) subjects.

Attrition: 18%

High

Paille et al. 1995

Design: DBRCT

Setting: NR

Country: France

Funding: NR

ACA 1.3 g (188); ACA 2 g (173); PBO (177)

Other Tx: supportive psychotherapy 100%; hypnotics 6%–7%; anxiolytics 8%–12%; antidepressants 8%–9%

52 (78)

DSM-III-R alcohol dependence

Exclusions: three previous detoxification attempts

Mean age: 43 years

% Nonwhite NR

20% Female

Other Dx: NR

Differences between ACA and PBO were percent drinking days: –10.2 (95% CI –16.53, –3.87) and return to any drinking: –0.07 (95% CI –0.13, –0.01).

Mean days of continuous abstinence and cumulative abstinence were greater with the higher dose of ACA vs. PBO (p ≤ 0.005).

No overall difference in side effects among groups except for a dose-dependent increase in diarrhea with ACA

Attrition: 56%

Medium

Pelc et al. 1992, 1996

Design: DBRCT

Setting: outpatient, multicenter

Country: Belgium

Funding: NR

ACA 1,332–1,998 (55); PBO (47)

Other Tx: supportive psychotherapy 100%

26

DSM-III alcohol dependence and GGT values above normal

Mean age: 43 years

% Nonwhite NR

31% Female

Other Dx: NR

Difference between ACA and PBO for return to any drinking: –0.19 (95% CI –0.32, –0.07)

Survival analysis indicated rates of abstinence throughout the trial of 24% ACA vs. 4% PBO.

Attrition: 45% day 90; 65% day 180

High

Pelc et al. 1997

Design: DBRCT

Setting: outpatient, after inpatient detoxification

Country: Belgium, France

Funding: Lipha

ACA 1,332 (63); ACA 1,998 (63); PBO (62)

Other Tx: counseling, social support when needed 100%

13

DSM-III-R alcohol dependence

Mean age: NR

% Nonwhite NR

% Female NR

Other Dx: NR

Differences between ACA and PBO were percent drinking days: –22.2 (95% CI –35.7, –8.7) and return to any drinking: –0.27 (95% CI –0.39, –0.14).

Cumulative abstinence duration was greater in both ACA groups vs. PBO.

Of those taking ACA, 41% were abstinent through 13 weeks vs. 15% for PBO.

Attrition: 37%

Medium

Poldrugo 1997

Design: DBRCT

Setting: inpatient for 1–2 weeks, then outpatient; multicenter community-based alcohol rehabilitation program

Country: Italy

Funding: Lipha

ACA 1,332–1,998 (122); PBO (124)

Other Tx: community-based rehabilitation program with group sessions, alcohol education, community meetings 100%

26 (52)

DSM-III chronic or episodic alcohol dependence

Mean age: 43–45 years

% Nonwhite NR

23%–31% Female

Other Dx: 0%

Differences between ACA and PBO were percent drinking days: –16 (95% CI –30.3, –1.7) and return to any drinking: –0.16 (95% CI –0.28, –0.04).

Adverse effects did not differ between groups.

Attrition: 54%

Medium

Ralevski et al. 2011a, 2011b

Design: DBRCT

Setting: outpatient univ and VA health centers

Country: United States

Funding: govt, Forest

ACA 1,998 (12); PBO (11)

Other Tx: weekly skills training that incorporated cognitive-behavioral drug relapse prevention strategies 100%

12

DSM-IV alcohol dependence and DSM-IV schizophrenia, schizoaffective disorder, or psychotic disorder NOS

Mean age: 51 years

65% Nonwhite

17% Female

Other Dx: schizophrenia spectrum disorders 100%

Differences between ACA and PBO were drinks per drinking day: 1.8 (95% CI –3.53, 7.13), percent drinking days: 3.7 (95% CI –12.5, 19.9), and percent heavy drinking days: 1.9 (95% CI –6.86, 10.66).

Positive symptoms (via PANSS) decreased in both groups, but there was no effect of treatment.

Adverse effects did not differ for ACA vs. PBO.

Attrition: 35%

High

Sass et al. 1996

Design: DBRCT

Setting: psychiatric outpatient

Country: Germany

Funding: Lipha

ACA 1,332–1,998 (136); PBO (136)

Other Tx: counseling/psychotherapy 100%

48 (96)

At least 5 DSM-III-R alcohol dependence criteria

Mean age: 41–42 years

% Nonwhite NR

22% Female

Other Dx: NR

Differences between ACA and PBO were percent drinking days: –17.1 (95% CI –27.18, –7.02) and return to any drinking: –0.2 (95% CI –0.31, –0.09).

Median time to first relapse was 131 days for ACA vs. 45 days for PBO.

Of those completing treatment, 44.8% of ACA-treated subjects had continuous abstinence vs. 25.3% with PBO.

Attrition: 51%

Medium

Tempesta et al. 2000

Design: DBRCT

Setting: outpatient

Country: Italy

Funding: Lipha

ACA 1,998 (164); PBO (166)

Other Tx: medical and behavioral counseling

26 (39)

DSM-III-R alcohol dependence and GGT values > 2× normal or mean corpuscular volume > 95 fL

Mean age: 46 years

% Nonwhite NR

17% Female

Other Dx: 0%

Differences between ACA and PBO were percent drinking days: –11.7 (95% CI –21.17, –2.23) and return to any drinking: –0.16 (95% CI –0.27, –0.06).

Median time of abstinence was greater with ACA (135 days) vs. PBO (58 days).

Continuous abstinence for 26 weeks occurred in 48% of ACA subjects vs. 33% with PBO (p < 0.01).

Rates of adverse effects did not differ between groups.

Attrition: 25%

Medium

Whitworth et al. 1996

Design: DBRCT

Setting: outpatient specialty clinic

Country: Austria

Funding: Lipha

ACA 1,332 or 1,998 (224); PBO (224)

Other Tx: NR

52 (104)

DSM-III chronic or episodic alcohol dependence

Mean age: 42 years

% Nonwhite NR

21% Female

Other Dx: NR

Differences between ACA and PBO were percent drinking days: –10 (95% CI –17.76, –2.24) and return to any drinking: –0.11 (95% CI –0.17, –0.05).

At 48 weeks, 18.3% of ACA subjects were continuously abstinent vs. 7.1% with PBO.

Adverse effects did not differ between groups, except diarrhea was more frequent with ACA (20.1%) vs. PBO (12.1%).

Attrition: 60%

Medium

Wölwer et al. 2011

Design: DBRCT

Setting: outpatient; 4 univ hospitals, 1 nonacademic clinic

Country: Germany

Funding: govt, meds

ACA 1,998 + IBT (124); ACA 1,998 + TAU (122); PBO + IBT (125)

Other Tx: NR

24 (52)

DSM-IV alcohol dependence

Mean age: 46 years

% Nonwhite NR

29% Female

Other Dx: NR

Difference between ACA and PBO for return to heavy drinking: 0 (95% CI –0.12, 0.13).

Differences among all treatment groups were not significant at 24 weeks of active treatment or at 52 weeks.

Attrition: 55%

Medium

Note. Unless noted elsewhere, subjects were excluded if they had contraindications for specific medications; were pregnant, breastfeeding, or unreliable in using contraception; were receiving psychotropic medications; or had another substance use disorder (except nicotine dependence), other psychiatric conditions, suicidal or homicidal ideas, or significant physical illness (including renal or hepatic disease). Studies comparing ACA with PBO or ACA with comparators other than NTX are included here. Studies comparing ACA with NTX are in Table B–13. Industry-sponsored studies list the name of the pharmaceutical company.

Abbreviations: AA = Alcoholics Anonymous; ACA = acamprosate; CBI = combined behavioral intervention; CBT = cognitive-behavioral therapy; CI = confidence interval; DBRCT = double-blind, randomized controlled trial; DIS = disulfiram; Dx = diagnosis; fL = femtoliters; GGT = gamma-glutamyl transferase; govt = governmental; IBT = integrative behavior therapy; ITT = intention to treat; meds = medications supplied by pharmaceutical company; MM = medical management; NOS = not otherwise specified; NR = not reported; NTX = naltrexone; OLRCT = open-label, randomized controlled trial; PANSS = Positive and Negative Syndrome Scale; PBO = placebo; TAU = treatment as usual; TOP = topiramate; Tx = treatment; univ = university; VA = U.S. Department of Veterans Affairs.

Studies related to acamprosate

Enlarge table

Benefits of Naltrexone

In the AHRQ review (Jonas et al. 2014) (Table B–4), studies of oral naltrexone typically used a dose of 50 mg/day (Table B–5), but a few trials used doses of 100–150 mg/day (Table B–6); trials of long-acting injectable naltrexone used doses of 150–400 mg/month (Table B–7). With naltrexone treatment, 4% fewer subjects returned to any drinking than with placebo (RD, –0.04; 95% CI, –0.07 to –0.01; 21 trials of low or medium bias), and 7% fewer subjects returned to heavy drinking than with placebo (RD, –0.07; 95% CI, –0.11 to –0.03; 23 trials of low or medium bias). For oral naltrexone at a dose of 50 mg/day, the NNT was 20 to prevent one person from returning to any drinking, with a NNT of 12 to prevent one person from returning to heavy drinking. For doses of oral naltrexone of 100 mg/day and for injectable naltrexone, effects were similar to those for oral naltrexone at 50 mg/day but were not statistically significant. As compared with placebo, subjects who received naltrexone also had 4.6% fewer drinking days (WMD, –4.6; 95% CI, –6.6 to –2.5; 19 trials), 3.8% fewer heavy drinking days (WMD, –3.8; 95% CI, –5.8 to –1.8; 11 trials), and 0.5% fewer drinks per drinking day (WMD, –0.54; 95% CI, –1.01 to –0.07; 11 trials). The single study of injectable naltrexone found a large effect size (WMD, –8.6) for fewer drinking days relative to placebo.

Naltrexone (any dose and delivery) compared with placebo

Outcome

Number of studies; number of subjects

Risk of bias; design

Consistency

Directness

Precision

Summary effect size (95% CI)

NNTg

Strength of evidence grade

Return to any drinking

21;a 4,233

Medium; RCTs

Consistent

Direct

Precise

RD: –0.04 (–0.07 to –0.01)

NC

Moderate

Return to heavy drinking

23;a 4,347

Medium; RCTs

Consistent

Direct

Precise

RD: –0.07 (–0.11 to –0.03)

NC

Moderate

Drinking days

19;b 3,329

Medium; RCTs

Consistent

Direct

Precise

WMD: –4.57 (–6.61 to –2.53)

NC

Moderate

Heavy drinking days

11;c 2,034

Medium; RCTs

Consistent

Direct

Precise

WMD: –3.81 (–5.85 to –1.78)

NC

Moderate

Drinks per drinking day

11;d 1,422

Medium; RCTs

Consistent

Direct

Imprecise

WMD: –0.54 (–1.01 to –0.07)

NC

Low

Accidents

0; 0

NA

NA

NA

NA

NA

NC

Insufficient

Injuries

0; 0

NA

NA

NA

NA

NA

NA

Insufficient

Quality of life

4; 1,513

Medium; RCTs

Inconsistent

Direct

Imprecise

Unable to pool data; some conflicting resultse

NA

Insufficient

Mortality

6;f 1,738

Medium; RCTs

Unknown

Direct

Imprecise

1 (NTX) vs. 2 (PBO)

NA

Insufficient

aTwo additional studies were rated high risk of bias; two additional studies were rated as unclear risk of bias.

bThree additional studies were rated high risk of bias.

cTwo additional studies were rated high risk of bias.

dFive additional studies were rated high risk of bias.

eTwo studies found no significant difference between naltrexone- and placebo-treated subjects. One study reported that patients receiving injectable naltrexone 380 mg/month had greater improvement on the mental health summary score than those receiving placebo at 24 weeks (8.2 vs. 6.2, p = 0.044). One study measured alcohol-related consequences (with the DrInC) and reported that more subjects who received placebo (N = 34) had ≥ 1 alcohol-related consequence than those who received naltrexone (N = 34): 76% vs. 45%, P = 0.02.

fOne additional study reported a death but did not specify in which treatment group it occurred.

gValues for NNT were added from Jonas et al. (2014), Table 37. For values marked NA, NNT was not calculated either because the risk difference (95% CI) was not statistically significant or the effect measure was not one that allows direct calculation of NNT (e.g., WMD); NC indicates that the Agency for Healthcare Research and Quality review did not comment on a NNT for these outcomes.

Abbreviations: CI = confidence interval; NA = not applicable; DrInC = Drinker Inventory of Consequences; NNT = number needed to treat; NSD = no significant difference; NTX = naltrexone; PBO = placebo; RCT = randomized controlled trial; RD = risk difference; WMD = weighted mean difference.

Source. Jonas et al. 2014, Table D–3.

Naltrexone (any dose and delivery) compared with placebo

Enlarge table

Oral naltrexone (50 mg) compared with placebo

Outcome

Number of studies; number of subjects

Risk of bias; design

Consistency

Directness

Precision

Summary effect size (95% CI)

NNT

Strength of evidence grade

Return to any drinking

16; 2,347

Medium; RCTs

Consistent

Direct

Precise

RD: –0.05 (–0.10 to –0.00)

20

Moderate

Return to heavy drinking

19; 2,875

Medium; RCTs

Consistent

Direct

Precise

RD: –0.09 (–0.13 to –0.04)

12

Moderate

Drinking days

15; 1,992

Medium; RCTs

Consistent

Direct

Precise

WMD: –5.4 (–7.5 to –3.2)

NA

Moderate

Heavy drinking days

6; 521

Medium; RCTs

Consistent

Direct

Precise

WMD: –4.1 (–7.6 to –0.61)

NA

Moderate

Drinks per drinking day

9; 1,018

Medium; RCTs

Consistent

Direct

Imprecise

WMD: –0.49 (–0.92 to –0.06)

NA

Low

Abbreviations: CI = confidence interval; NA = not applicable; NNT = number needed to treat; NSD = no significant difference; NTX = naltrexone; PBO = placebo; RCT = randomized controlled trial; RD = risk difference; WMD = weighted mean difference.

Source. Jonas et al. 2014, Table D–4, with values for NNT added from Table 37.

Oral naltrexone (50 mg) compared with placebo

Enlarge table

Oral naltrexone (100 mg) compared with placebo

Outcome

Number of studies; number of subjects

Risk of bias; design

Consistency

Directness

Precision

Summary effect size (95% CI)

NNT

Strength of evidence grade

Return to any drinking

3; 946

Medium; RCTs

Consistent

Direct

Imprecise

RD: –0.03 (–0.08 to 0.02)

NA

Low

Return to heavy drinking

2; 858

Medium; RCTs

Consistent

Direct

Imprecise

RD: –0.05 (–0.11 to 0.01)

NA

Low

Drinking days

2; 858

Medium; RCTs

Consistent

Direct

Imprecise

WMD: –0.9 (–4.2 to 2.5)

NA

Low

Heavy drinking days

2; 423

Medium; RCTs

Consistent

Direct

Imprecise

WMD: –3.1 (–5.8 to –0.3)

NA

Low

Drinks per drinking day

1; 240

Medium; RCT

Unknown

Direct

Imprecise

WMD: 1.9 (–1.5 to 5.2)

NA

Insufficient

Abbreviations: CI = confidence interval; NA = not applicable; NNT = number needed to treat; RCT = randomized controlled trial; RD = risk difference; WMD = weighted mean difference.

Source. Jonas et al. 2014, Table D–5, with values for NNT added from Table 37.

Oral naltrexone (100 mg) compared with placebo

Enlarge table

Injectable naltrexone compared with placebo

Outcome

Number of studies; number of subjects

Risk of bias; design

Consistency

Directness

Precision

Summary effect size (95% CI)

NNT

Strength of evidence grade

Return to any drinking

2; 939

Medium; RCTs

Consistent

Direct

Imprecise

RD: –0.04 (–0.10 to 0.03)

NA

Low

Return to heavy drinking

2; 615

Medium; RCTs

Inconsistent

Direct

Imprecise

RD: –0.01 (–0.14 to 0.13)

NA

Low

Drinking days

1; 315

Medium; RCT

Unknown

Direct

Imprecise

WMD: –8.6 (–16.0 to –1.2)

NA

Insufficient

Heavy drinking days

2;a 926

Medium; RCTs

Consistent

Direct

Imprecise

WMD: –4.6 (–8.5 to –0.56)

NA

Low

Drinks per drinking day

0; 0

NA

NA

NA

NA

NA

NA

Insufficient

aContains data from personal communication (B. Silverman, November 14, 2013).

Abbreviations: CI = confidence interval; NA = not applicable; NNT = number needed to treat; RCT = randomized controlled trial; RD = risk difference; WMD = weighted mean difference.

Source. Jonas et al. 2014, Table D–6, with values for NNT added from Table 37.

Injectable naltrexone compared with placebo

Enlarge table

Only a limited number of studies assessed factors related to quality of life, and these studies used different measures, making comparison or meta-analysis impossible. In addition, quality of life measures were secondary outcomes, and studies were not adequately powered to assess these effects. One study found better overall mental health, but not physical health, with long-acting injectable naltrexone at 380 mg/month but no benefit on either measure at a dose of 190 mg/month. A placebo-controlled study of 50 mg/day of oral naltrexone found fewer alcohol-related consequences in the naltrexone group (76% vs. 45%, p = 0.02). The other two studies assessing quality of life measures showed no statistical difference with naltrexone as compared with placebo.

One trial did not meet inclusion criteria for the comparative effectiveness review but was described in some detail in the AHRQ report. In this study (O’Malley et al. 2003), individuals all received oral naltrexone with random assignment to 10 weeks of either primary care management (PCM) or cognitive-behavioral therapy (CBT). Responders in each group (84.1% for PCM vs. 86.5% for CBT) continued with their assigned psychosocial treatment and were randomly assigned to continue naltrexone or switch to placebo. In the CBT group, the rates of abstinence decreased in those assigned to placebo but did not reach statistical significance, whereas in the PCM group, the placebo group had a greater reduction in abstinence rates than those who remained on naltrexone (80.8% vs. 51.9%, p = 0.03).

Several studies of oral naltrexone published since the AHRQ review (not included in Tables B–4, B–5, or B–6) have shown minimal benefits. In the German PREDICT study (total N = 426), modeled after the COMBINE study, there was no difference among naltrexone, acamprosate, and placebo groups on the time to first heavy drinking (Mann et al. 2013). In a 12-week, low-risk-of-bias trial, subjects (N = 221) were randomly assigned to 50 mg/day oral naltrexone or placebo in blocks on the basis of their OPRM1 genotype (Oslin et al. 2015). There was no difference in the odds of heavy drinking with naltrexone as compared with placebo for either genotype, although significant reductions in heavy drinking occurred in all treatment groups. A four-arm study (N = 200, medium risk of bias) of men who had sex with men investigated oral naltrexone 100 mg/day versus placebo and brief behavioral compliance treatment with and without modified behavioral self-control therapy (MBSCT) (Morgenstern et al. 2012). MBSCT was associated with a 28% decrease in drinks per week and a 35% decrease in heavy drinking days per week, whereas treatment with naltrexone did not have a statistically significant effect. However, naltrexone did increase the likelihood (odds ratio = 3.3) of achieving nonhazardous levels of drinking, which was the stated goal of study subjects.

In the majority of studies of naltrexone, individuals met criteria for alcohol dependence by DSM-IV criteria; however, one controlled trial of 153 early problem drinkers randomly assigned subjects to naltrexone, targeted naltrexone before high-risk drinking situations, or placebo (Kranzler et al. 2003), and found a reduced likelihood of drinking in the naltrexone or targeted treatment groups over an 8-week period. Although these findings require replication, they are consistent with possible benefit of naltrexone treatment in individuals with less severe AUD.

Although most trials of naltrexone excluded individuals with co-occurring physical or psychiatric illness, one study of naltrexone for smoking cessation conducted a subgroup analysis for individuals who also reported heavy drinking (Fridberg et al. 2014). The total sample included 315 smokers who were randomly assigned to placebo or naltrexone 50 mg/day for 12 weeks. In the subgroup of 69 heavy drinkers (at least two heavy drinking episodes per month), weekly alcohol consumption was reduced with naltrexone treatment (incidence rate ratio [IRR] 0.71, 95% CI = 0.51–1.0, p = 0.049), as was smoking urge. Smoking quit rates with naltrexone as compared with placebo were also significantly better in the heavy drinking subgroup at the end of the study and at 12-month follow-up. Another medium-risk-of-bias study (Foa et al. 2013) was excluded from the AHRQ review because of its study design but is of relevance to clinical practice. Subjects met DSM-IV criteria for posttraumatic stress disorder (PTSD) and for alcohol dependence and were randomly assigned to receive naltrexone 100 mg/day plus prolonged exposure therapy (N = 40), placebo plus prolonged exposure therapy (N = 40), naltrexone 100 mg/day plus supportive therapy (N = 42), or placebo plus supportive therapy (N = 43). Although attrition was relatively high in all groups during the 24-week trial, alcohol craving and the percentage of days drinking alcohol were reduced in all groups, with a greater mean difference in groups that received naltrexone as compared with placebo groups (p = 0.008). PTSD severity was reduced in all groups, with no significant effect of prolonged exposure over supportive therapy; however, those in the prolonged exposure plus naltrexone group were more likely to achieve a low level of PTSD symptoms.

Results of included studies that assessed the association between μ opioid receptor gene polymorphisms and naltrexone response

Author and year

Reported a significant positive association?

AA genotype, N

AA genotype, return to any drinking

AA genotype, return to heavy drinking—relapse

AG/GG genotypes, N

AG/GG genotypes, return to any drinking

AG/GG genotypes, return to heavy drinking—relapse

Anton et al. 2008b

Yesa

115b

NR

52

31b

NR

4

Coller et al. 2011

No

NR

NR

NR

NR

NR

NR

Gelernter et al. 2007

No

98

NR

35

33

NR

12

Kim et al. 2009

Mixedc

16

8

6

16

9

3

Kranzler et al. 2013

Yes

59

NR

NR

22

NR

NR

O’Malley et al. 2008

Nod

25

16

16

3

2

2

Rubio et al. 2002

No

29

9

9

16

4

4

aStatistically significant difference between groups for return to heavy drinking.

bData are for those who received naltrexone and medical management and do not include those who received naltrexone + medical management + CBI. The study found no gene by medication by time interactions for the latter group for percentage of days abstinent or heavy drinking days and did not report specific numbers by genotype for the outcomes.

cYes for time to first relapse (p = 0.014); no for abstinent rate (p = 0.656) and relapse rate (p = 0.072).

dStudy authors restricted analyses to A-allele homozygotes because they had only 17 of 92 genotyped participants with at least one G allele. The results for the 75 A-allele homozygotes were similar to the results for the total sample, indicating that treatment efficacy was not dependent on the presence of the G allele.

Abbreviations: N = number; NR = not reported.

Source. Jonas et al. 2014, Table 36.

Results of included studies that assessed the association between μ opioid receptor gene polymorphisms and naltrexone response

Enlarge table

The AHRQ review (Jonas et al. 2014) also examined studies that assessed whether μ opioid receptor gene polymorphism status was associated with a more robust response to naltrexone (Table B–8). The main single-nucleotide polymorphism (SNP) that was tested was an asparagine to aspartate substitution in exon 1 of the μ opioid receptor. (Because of changes in the National Center for Biotechnology Information Human Genome Reference Assembly, this SNP has been referred to by a number of designations, including A118G, Asn40Asp, rs1799971, A355G, and Asn102Asp.) The review found no significant difference between A-allele homozygotes and those with at least one G allele in terms of the outcomes return to any drinking (RD, 0.01; 95% CI, –0.2 to 0.2) and return to heavy drinking (RD, 0.14; 95% CI, –0.03 to 0.3) when all available studies were considered together. However, in its conclusions, the AHRQ report also noted that for return to heavy drinking, “it is possible that patients with at least one G allele of A118G polymorphism of OPRM1 might be more likely to respond to naltrexone” (Jonas et al. 2014, p. 94). The reasons behind this interpretation are severalfold. Of the seven studies, three studies, including the COMBINE study (Anton et al. 2008b), reported positive associations between OPRM1 polymorphisms and naltrexone response. In the COMBINE study, individuals who received medical management (MM) without cognitive-behavioral intervention were more likely to have a good clinical outcome if they had at least one Asp40 allele and received naltrexone (87.1%), as compared with Asn40 homozygotes treated with naltrexone (54.8%). About half of those treated with placebo also had a good outcome, regardless of genotype. This difference in outcomes would be clinically significant. One additional study did not meet a priori inclusion criteria for the systematic review, but it also included information on naltrexone response and OPRM1 genotype (Oslin et al. 2003). This study also found that naltrexone-treated subjects with at least one Asp40 allele as compared with Asn40 homozygotes had significantly lower rates of relapse (p = 0.044) and a longer time to return to heavy drinking (p = 0.04). When the results of this study were added to the meta-analysis in a sensitivity analysis, a positive association between genotype and response emerged (RD, 0.16; 95% CI, 0.02 to 0.29).

Since the AHRQ review, additional studies have not found a relationship between genotype and naltrexone response. As described above, one study randomly assigned subjects (N = 221) to 50 mg/day oral naltrexone or to placebo with stratification on the basis of their OPRM1 genotype (Oslin et al. 2015). In this 12-week trial, there was no difference in the odds of heavy drinking with naltrexone as compared with placebo for either genotype. A secondary analysis of OPRM1 genotype has been conducted in a sample of veterans with alcohol dependence and other psychiatric conditions (Arias et al. 2014). Subjects in this 12-week, medium-risk-of-bias study were randomly assigned to placebo alone (N = 64), naltrexone 50 mg/day (N = 59), disulfiram 250 mg/day plus placebo (N = 66), or naltrexone 50 mg/day and disulfiram 250 mg/day (N = 65). OPRM1 genotyping was conducted for a subset of 107 European American subjects. No significant interactions were found between genotype and the response to naltrexone.

Taken together, the findings on OPRM1 genotype and naltrexone response did not seem to indicate a current role for OPRM1 genotype determination in clinical practice, and no guideline statement was made. However, use of genotype to identify predictors of response remains a promising avenue for research.

Grading of the Overall Supporting Body of Research Evidence for Efficacy of Naltrexone

  • Magnitude of effect: Weak. When present for specific outcomes, the magnitude of the effect is small.

  • Risk of bias: Medium. Studies are RCTs of low to medium bias based on their described randomization and blinding procedures and descriptions of study dropouts.

  • Applicability: The included trials all involve individuals with AUD, by either prior diagnostic criteria or other evidence of harmful levels of drinking. The studies include subjects from around the world, including North America. The doses of naltrexone appear to be representative of outpatient clinical practice, but in some studies, the proportion of females in the trial was small.

  • Directness: Direct. Studies measured abstinence and heavy drinking rates as well as measures of alcohol consumption.

  • Consistency: Inconsistent. There was considerable heterogeneity as evidenced by I2 values on drinking-related outcomes.

  • Precision: Imprecise. Confidence intervals for studies cross the threshold for clinically significant benefit of the intervention.

  • Dose-response relationship: Unclear. Studies typically used a single dose of naltrexone, and when comparisons were available, outcomes were at least as good and in some instances better for 50 mg/day of oral naltrexone as compared with 100 mg/day.

  • Confounding factors (including likely direction of effect): Unclear. Some studies suggest a possible effect of genetic polymorphisms on treatment response, which could confound study interpretation.

  • Publication bias: Not identified. No publication bias was noted by the AHRQ review; however, they note that they were unable to assess for publication bias for early clinical trials (prior to the release of https://clinicaltrials.gov).

  • Overall strength of research evidence: Moderate. A large number of RCTs have been conducted, most of which have low to medium risk of bias. Many of the RCTs are funded by governmental agencies. Although the studies have good applicability and measure outcomes of interest directly, the imprecision and inconsistency of findings are a limitation. Another limitation is that the majority of trials use oral formulations at a dose of 50 mg/day; the strength of research evidence is less robust for other formulations (e.g., long-acting injections) and doses.

Grading of the Overall Supporting Body of Research Evidence for Predicting Efficacy of Naltrexone Through OPRM1 Genetic Polymorphism Testing

  • Magnitude of effect: Unclear. However, if present, the magnitude of the effect is small.

  • Risk of bias: High. Studies are RCTs of low to medium bias based on their described randomization and blinding procedures and descriptions of study dropouts. However, with one exception, all of the genotyping studies are based on secondary analyses, often with a subset of the original sample.

  • Applicability: The included trials all involve individuals with AUD, by either prior diagnostic criteria or other evidence of harmful levels of drinking. The studies include subjects from around the world, including North America. The doses of naltrexone appear to be representative of outpatient clinical practice; however, many of the studies have few or no women. Some of the studies limit the analysis to white/European American subjects.

  • Directness: Direct. Studies measured abstinence, heavy drinking, and measures of alcohol consumption.

  • Consistency: Inconsistent. There was considerable heterogeneity as evidenced by I2 values in the meta-analysis.

  • Precision: Imprecise. Confidence intervals for studies cross the threshold for clinically significant benefit.

  • Dose-response relationship: Not assessed.

  • Confounding factors (including likely direction of effect): Likely. Given the known differences in genotype frequency among different races and ethnicities, the inclusion or exclusion of nonwhites could influence the study conclusions and the overall meta-analysis.

  • Publication bias: Not identified. No publication bias was noted by the AHRQ review; however, they note that they were unable to assess for publication bias for early clinical trials (prior to the release of https://clinicaltrials.gov).

  • Overall strength of research evidence: Low. Although a large number of secondary analyses have been conducted on the basis of government-funded RCTs, the applicability, inconsistency, lack of precision, and potential for confounding factors are limitations.

Harms of Naltrexone

The AHRQ review (Jonas et al. 2014) found a statistically significant increased risk of withdrawal due to adverse events, dizziness, nausea, and vomiting in individuals treated with naltrexone as compared with placebo (Table B–9). Of studies that reported on mortality, no studies found more than one death in any one treatment group (Jonas et al. 2014). Effects of naltrexone on hepatic enzymes were viewed as intermediate outcomes and were not included in the AHRQ meta-analysis (D. Jonas, personal communication, July 2016). None of the literature identified in the updated literature search provided additional information on harms of naltrexone. Other information on harms of naltrexone comes from nonrandomized trials and drug information databases and is noted in Statement 9, Implementation.

Naltrexone compared with placebo

Outcome

Number of studies; number of subjects

Risk of bias; design

Consistency

Directness

Precision

Summary effect size (95% CI)

Strength of evidence grade

Withdrawals due to AEs

17;a 2,743

Medium; RCTs

Consistent

Direct

Precise

RD 0.021 (0.009 to 0.034)

Moderate

Anorexia

1; 175

Medium; RCT

Unknown

Direct

Imprecise

RD 0.077 (0.014 to 0.140)

Insufficient

Anxiety

7;b 1,461

Medium; RCTs

Consistent

Direct

Imprecise

RD 0.007 (–0.022 to 0.036)

Low

Cognitive dysfunction

1; 123

Medium; RCT

Unknown

Direct

Imprecise

RD 0.190 (0.038 to 0.341)

Insufficient

Diarrhea

11;c 2,358

Medium; RCTs

Consistent

Direct

Imprecise

RD 0.013 (–0.011 to 0.038)

Moderate

Dizziness

13;d 2,675

Medium; RCTs

Consistent

Direct

Precise

RD 0.063 (0.036 to 0.089)

Moderate

Headache

17;e 3,347

Medium; RCTs

Inconsistent

Direct

Imprecise

RD 0.008 (–0.019 to 0.034)

Low

Insomnia

8;d 1,637

Medium; RCTs

Consistent

Direct

Imprecise

RD 0.027 (–0.002 to 0.057)

Low

Nausea

24;f 4,655

Medium; RCTs

Consistent

Direct

Precise

RD 0.112 (0.075 to 0.149)

Moderate

Numbness/tingling/paresthesias

1;b 123

Medium; RCT

Unknown

Direct

Imprecise

RD -0.008 (–0.185 to 0.168)

Insufficient

Rash

4;c 469

Medium; RCTs

Consistent

Direct

Imprecise

RD -0.010 (–0.060 to 0.040)

Low

Suicide

0; 0

NA

NA

NA

NA

NA

Insufficient

Taste abnormalities

1; 123

Medium; RCT

Unknown

Direct

Imprecise

RD –0.006 (–0.182 to 0.171)

Insufficient

Vision changes (blurred vision)

2; 133

Medium; RCTs

Inconsistent

Direct

Imprecise

RD 0.079 (–0.172 to 0.331)

Low

Vomiting

9;b 2,438

Medium; RCTs

Consistent

Direct

Precise

RD 0.043 (0.023 to 0.062)

Moderate

aThree additional studies were rated high or unclear risk of bias.

bTwo additional studies were rated high or unclear risk of bias.

cOne additional study was rated high or unclear risk of bias.

dFour additional studies were rated high or unclear risk of bias.

eFive additional studies were rated high or unclear risk of bias.

fSeven additional studies were rated as high or unclear risk of bias.

Abbreviations: AE = adverse effect; CI = confidence interval; RCT = randomized controlled trial; RD = risk difference.

Source. Jonas et al. 2014, Table D–34.

Naltrexone compared with placebo

Enlarge table

Grading of the Overall Supporting Body of Research Evidence for Harms of Naltrexone

  • Magnitude of effect: Small. When present, the magnitude of effect is small.

  • Risk of bias: High. Studies are RCTs of low to medium bias based on their described randomization and blinding procedures and descriptions of study dropouts. However, methods for determining harms are not well specified, and there is potential for selective reporting of results.

  • Applicability: The included trials all involve individuals with AUD, by either prior diagnostic criteria or other evidence of harmful levels of drinking. The studies include subjects from around the world, including North America. The doses of naltrexone appear to be representative of outpatient clinical practice.

  • Directness: Direct. Studies measured common side effects and dropouts due to adverse events.

  • Consistency: Consistent. For adverse events that showed a significant effect (e.g., withdrawal due to adverse events, dizziness, nausea, and vomiting), the findings were consistent across trials.

  • Precision: Imprecise. Confidence intervals for studies are wide in many studies and cross the threshold for clinically significant harms of the intervention.

  • Dose-response relationship: Unknown. Dose-response information on side effects was not well described.

  • Confounding factors (including likely direction of effect): Absent. No known confounding factors are present that would be likely to modify adverse events of the intervention.

  • Publication bias: Not identified. No publication bias was noted by the AHRQ review; however, they note that they were unable to assess for publication bias for early clinical trials (prior to the release of https://clinicaltrials.gov).

  • Overall strength of research evidence: Moderate. A large number of RCTs have been conducted, but few have assessed adverse events in a systematic and predefined fashion. Many of the RCTs are funded by governmental agencies. Although imprecision is a limitation, the studies have good applicability, measure outcomes of interest directly, and are relatively consistent in finding naltrexone to have greater frequencies of withdrawal due to adverse events, dizziness, nausea, and vomiting as compared with placebo.

Data Abstraction: Naltrexone

Studies related to naltrexone are listed in Table B–10.

Studies related to naltrexone

Author and year; trial name

Study characteristics

Treatment administered, including study arm, dose (mg/day), sample size (N), and co-intervention

Rx duration, weeks (follow-up)

Sample characteristics, including diagnostic inclusions and major exclusions

Outcome measures, main results, and overall percent attrition

Risk of bias

Ahmadi and Ahmadi 2002; Ahmadi et al. 2004

Design: DBRCT

Setting: outpatient

Country: Iran

Funding: NR

NTX 50 (58); PBO (58)

Other Tx: individual counseling 100%

12

DSM-IV alcohol dependence

Mean age: 43 years

% Nonwhite NR

0% Female

Other Dx: NR

Differences between NTX and PBO were return to heavy drinking: –0.36 (95% CI –0.53, –0.2) and return to any drinking: –0.19 (95% CI –0.36, –0.02).

NTX was associated with more nausea than PBO.

Attrition: 39%

High

Anton and COMBINE Study Research Group 2003

Design: DBRCT

Setting: 11 academic outpatient sites

Country: United States

Funding: govt, meds

ACA 3,000 + CBI + MM (9); ACA 3,000 + MM (9); NTX 100 +  CBI + MM (9); NTX 100 + MM (9); PBO + CBI + MM (9); PBO + MM (8)

Other Tx: as randomized

16

DSM-IV alcohol dependence

Mean age: 38–42 years

17%–22% Nonwhite

22%–33% Female

Other Dx: NR

ACA-NTX group adherence was equal to, or better than, adherence with PBO, ACA alone, or NTX alone.

Adverse events were comparable in all groups.

Attrition: 31%

Medium

Anton et al. 1999, 2001

Design: DBRCT

Setting: outpatient academic site

Country: United States

Funding: govt, meds

NTX 50 (68); PBO (63)

Other Tx: CBT 100%

12

DSM-III-R alcohol dependence, including loss of control over drinking

Mean age: 41–44 years

11%–18% Nonwhite

27%–31% Female

Other Dx: 0%

Differences between NTX and PBO were drinks per drinking day: –1.7 (95% CI –3.02, –0.38), percent drinking days: –8 (95% CI –15.22, –0.78), return to any drinking: –0.14 (95% CI –0.3, 0.03), and return to heavy drinking: –0.22 (95% CI –0.39, –0.05).

Kaplan-Meier survival analysis showed a longer time to first relapse with NTX vs. PBO (p < 0.02).

Adverse effects that were more frequent with NTX vs. PBO were nausea/vomiting, abdominal pain, daytime sleepiness, and nasal congestion.

Attrition: 17%

Medium

Anton et al. 2005

Design: DBRCT

Setting: outpatient

Country: United States

Funding: govt, meds

NTX 50 + CBT (39); NTX 50 + MET (41); PBO + CBT (41); PBO + MET (39)

Other Tx: CBT and MET as randomized

12

DSM-IV alcohol dependence, including loss of control over drinking

Exclusions: > 2 prior detoxification admissions requiring medication

Mean age: 43–45 years

8%–23% Nonwhite

21%–27% Female

Other Dx: NR

Differences between NTX and PBO were drinks per drinking day: –0.7 (95% CI –2.06, 0.66), percent drinking days: –6.8 (95% CI –15.12, 1.52), and return to heavy drinking: –0.17 (95% CI –0.32, –0.02).

Kaplan-Meier survival analysis showed a longer time to first relapse in the NTX groups.

The NTX + CBT group had fewer relapses than the other groups.

Attrition: 19%

Medium

Anton et al. 2006; Donovan et al. 2008; LoCastro et al. 2009; COMBINE

Design: DBRCT

Setting: 11 academic outpatient sites

Country: United States

Funding: govt, meds

ACA 3,000 + CBI + MM (151); ACA 3,000 +  MM (152); NTX 100 +  CBI + MM (155); NTX 100 + MM (154); PBO + CBI + MM (156); PBO + MM (153)

Other Tx: as randomized; community support group participation (e.g., AA) encouraged

16 (68)

DSM-IV alcohol dependence

Mean age: 44 years

23% Nonwhite

31% Female

Other Dx: NR

All groups had a substantial reduction in drinking.

Differences between NTX and PBO were percent drinking days: –1.1 (95% CI –5.2, 3), return to any drinking: –0.04 (95% CI –0.1, 0.02), and return to heavy drinking: –0.06 (95% CI –0.13, 0.01).

Nausea and somnolence were more common with NTX vs. PBO.

Complete within-treatment drinking data were provided by 94% of study subjects.

Low

Anton et al. 2008b

Design: DBRCT

Setting: 11 outpatient sites

Country: United States

Funding: govt, meds

NTX 100 (301); PBO (303)

Other Tx: MM 100%, CBI 49%, ACA % NR

16

DSM-IV alcohol dependence

Mean age: 45–46 years

0% Nonwhite

30% Female

Other Dx: NR

NTX was associated with fewer heavy drinking days and trend for more abstinent days over time in subjects with at least one copy of the Asp40 allele.

Medium

Anton et al. 2011

Design: DBRCT

Setting: outpatient

Country: United States

Funding: govt

NTX 50 (50); PBO (50); NTX 50 + 6 weeks gabapentin, with 1,200 maximum dose (50)

Other Tx: used COMBINE’s manual (CBT + MM + 12-step techniques) 100%

16

DSM-IV alcohol dependence

Exclusion: > 1 prior detoxification admission

Mean age: 43–47 years

13% Nonwhite

18% Female

Other Dx: NR

During the first 6 weeks, the NTX/gabapentin group took a longer time to relapse and had fewer heavy drinking days and fewer drinks per drinking day than the placebo and NTX alone groups.

Time to relapse did not differ at the end of study.

Complete within-treatment drinking data were provided by 82%–88% of subjects.

Medium

Balldin et al. 2003

Design: DBRCT

Setting: 10 outpatient sites

Country: Sweden

Funding: DuPont, Meda AB

NTX 50 + CBT (25); NTX 50 +ST (31); PBO + CBT (30); PBO + ST (32)

Other Tx: none

26

DSM-IV alcohol dependence

Mean age: 48–51 years

% Nonwhite NR

9%–23% Female

Other Dx: 0%

Differences between NTX and PBO were drinks per drinking day: 0.2 (95% CI –1.47, 1.87), percent drinking days: –9.9 (95% CI –20.54, 0.74), percent heavy drinking days: –11 (95% CI –20.95, –1.05), return to any drinking: 0.03 (95% CI –0.03, 0.09), and return to heavy drinking: 0.01 (95% CI –0.07, 0.1).

Decreased libido and abdominal pain were reported more often with NTX vs. PBO but did not require treatment cessation.

Attrition: 23%

Low

Baltieri et al. 2008, 2009

Design: DBRCT

Setting: outpatient

Country: Brazil

Funding: govt

TOP to 200–400 (52); NTX 50 (49); PBO (54)

Other Tx: psychosocial 100%; AA recommended

12

ICD-10 alcohol dependence

Mean age: 44–45 years

29% Nonwhite

0% Female

Other Dx: tobacco use 66%

Differences between NTX and PBO were percent heavy drinking days: –7.5 (95% CI –23.48, 8.48), percent drinking days: –8.3 (95% CI –23.93, 7.33), and return to any drinking: –0.01 (95% CI –0.18, 0.17).

Smokers relapsed more rapidly than nonsmokers.

Attrition: 45%

High

Brown et al. 2009

Design: DBRCT

Setting: outpatient univ health center

Country: United States

Funding: govt

NTX 50 (20); PBO (23)

Other Tx: CBT 100%

12

Alcohol dependence and bipolar I or II disorder, with current depressed or mixed mood state

Exclusions: severe mood symptoms

Mean age: 41 years

26% Nonwhite

49% Female

Other Dx: bipolar (current depressed or mixed mood) 100%; cannabis abuse 21%; cocaine abuse 12%; amphetamine abuse 7%

Differences between NTX and PBO were drinks per drinking day: –1.8 (95% CI –3.67, 0.07) and return to heavy drinking: –0.28 (95% CI –0.55, –0.01).

Rates of medication adherence and number of CBT sessions attended were comparable for the two groups, as were adverse effects.

Attrition: 48%

High

Carroll et al. 1993

Design: OLRCT

Setting: outpatient

Country: United States

Funding: govt

DIS 250 (9); NTX 50 (9)

Other Tx: weekly individual psychotherapy 100%

12

DSM-III-R alcohol abuse/dependence and cocaine dependence

Mean age: 32 years

39% Nonwhite

72% Female

Other Dx: cocaine dependence 100%

Subjects taking DIS showed lower percentage of alcohol use days compared with those taking NTX (4.0% vs. 26.3%, t = 3.73, p < 0.01).

Subjects taking DIS also reported fewer total days using alcohol (2.4. vs. 10.4 days, t = 3.00, p < 0.01), fewer total drinks (2.3 vs. 27.0, t =  –2.00, p = 0.06), and more total weeks of abstinence (mean 7.2 vs. 1.1 weeks, t = 4.72, p < 0.001) compared with those taking NTX.

Attrition: 67%

High

Chick et al. 2000a

Design: DBRCT

Setting: 6 outpatient sites—5 alcohol treatment units and 1 academic hepatology department

Country: United Kingdom

Funding: DuPont

NTX 50 (90); PBO (85)

Other Tx: usual psychosocial treatment program

12

DSM-III-R alcohol dependence or abuse

Mean age: 43 years

% Nonwhite NR

25% Female

Other Dx: 0%

Differences between NTX and PBO were return to any drinking: 0.01 (95% CI –0.11, 0.13) and return to heavy drinking: 0 (95% CI –0.14, 0.14)

In adherent subjects, greater reductions in craving noted with NTX vs. PBO (p < 0.05)

Attrition: 59% at 12 weeks, 19% lost to follow-up

Medium

Coller et al. 2011

Design: Open label

Setting: outpatient

Country: Australia

Funding: govt

NTX 50 (100)

Other Tx: CBI 100%

12

DSM-IV alcohol dependence

Exclusions: NTX use in last 6 months

Mean age: 43 years

% Nonwhite NR

43% Female

Other Dx: NR

Alcohol use decreased significantly, as did GGT and MCV values, with no differences among OPRM1 A118G genotype groups, A/A (65) or A/G and G/G (35)

Medium

De Sousa and De Sousa 2004

Design: OLRCT

Setting: outpatient

Country: India

Funding: NR

DIS 250 (50); NTX 50 (50)

Other Tx: supportive group psychotherapy 100%

52

DSM-IV alcohol dependence

Exclusions: previous NTX and/or DIS treatment

Mean age: 43–47 years

% Nonwhite NR

0% Female

Other Dx: NR

DIS was associated with greater reduction in relapse, greater survival time until the first relapse, and more days of abstinence than NTX: At study endpoint, relapse was 14% with DIS vs. 56% with NTX.

NTX group reported lower composite craving scores than DIS group.

Attrition: 3%

High

Flórez et al. 2008

Design: OLRCT

Setting: outpatient substance use disorders clinic

Country: Spain

Funding: NR

TOP to 200 (51); NTX 50 (51)

Other Tx: therapy based on relapse prevention model 100%

26

ICD-10 alcohol dependence

Mean age: 47 years

0% Nonwhite

15% Female

Other Dx: personality disorders 27%

TOP and NTX were both effective but did not differ in efficacy as measured by a composite alcohol use metric.

Adverse effects, particularly weight loss, were greater with TOP vs. NTX.

Attrition: 10%

High

Flórez et al. 2011

Design: OLRCT

Setting: outpatient substance use disorders clinic

Country: Spain

Funding: NR

TOP 200 (91); NTX 50 (91)

Other Tx: BRENDA 100%; at least monthly meeting with psychiatrist 100%

26

ICD-10 alcohol dependence

Mean age: 47–48 years

% Nonwhite NR

15% Female

Other Dx: personality disorders 23%

At 3 and 6 months, patients with TOP reported lower scores than those with NTX on craving and alcohol-related measures; those with TOP also scored less on disability-related measures at 6 months.

TOP was associated with fewer drinks per drinking day and fewer heavy drinking days at 3 and 6 months compared with NTX.

The percentage of days abstinent and total drinking days were comparable for TOP and NTX.

A greater proportion of TOP subjects reported adverse effects at 3 months but not 6 months.

Attrition: 10%

High

Foa and Williams 2010; Foa et al. 2013; McLean et al. 2014; Zandberg et al. 2016

Design: DBRCT

Setting: outpatient

Country: United States

Funding: govt

NTX 100 + PE (40); NTX 100 + SuppTx (42); PBO + PE (40); PBO + SuppTx (43)

Other Tx: single-blind randomization to prolonged exposure therapy (12 weekly 90-min sessions, then 6 biweekly sessions) vs. supportive therapy; BRENDA provided to all subjects

24 (52)

DSM-IV alcohol dependence and PTSD

Mean age: 42.7 years

70% Nonwhite

34.5% Female

Other Dx: PTSD 100%

Percentages of days drinking alcohol and craving were reduced in all groups, with largest effect in groups that received NTX (p = 0.008).

PTSD severity was reduced in all groups, with no significant effect of prolonged exposure versus supportive therapy.

Low PTSD symptoms were more likely with prolonged exposure plus NTX.

Attrition: 44%

Medium

Fogaça et al. 2011

Design: DBRCT

Setting: outpatient

Country: Brazil

Funding: govt

NTX 50 (20); PBO (20); NTX 50 + PUFA (20); PUFA (20)

Other Tx: none

12

DSM-IV alcohol dependence; male; age 30–50 years

Mean age: NR

% Non-white NR

0% Female

Other Dx: NR

All groups showed improvement at 3 months (p < 0.001) on drinking days, alcohol dependence severity, and craving scores, with no difference in treatment groups.

Attrition: 46%

High

Garbutt et al. 2010; Lucey et al. 2008; Pettinati et al. 2009

Design: DBRCT

Setting: inpatient and outpatient public hospitals, private and VA clinics, and tertiary care medical centers

Country: United States

Funding: Alkermes

NTX inj 380 every 4 weeks (208); NTX inj 190 every 4 weeks (210); PBO (209)

Other Tx: BRENDA standardized supportive therapy 100%

26

DSM-IV alcohol dependence with goal of reduced drinking or abstinence

Mean age: 45 years

17% Nonwhite

32% Female

Other Dx: NR

Differences between NTX and PBO were percent heavy drinking days: –5.14 (95% CI –10.04, –0.23) and return to any drinking: –0.01 (95% CI –0.05, 0.03)

Decreased appetite was greater with NTX vs. PBO and was related to dose; nausea, fatigue, and dizziness were also greater for NTX groups taken together vs. PBO.

Attrition: 39%

Medium

Gastpar et al. 2002

Design: DBRCT

Setting: 7 outpatient sites

Country: Germany

Funding: DuPont

NTX 50 (84); PBO (87)

Other Tx: psychosocial treatment

12

DSM-III-R alcohol dependence or abuse

Mean age: 43 years

0% Nonwhite

28% Female

Other Dx: 0%

Differences between NTX and PBO were return to any drinking: –0.03 (95% CI –0.18, 0.12) and return to heavy drinking: –0.01 (95% CI –0.16, 0.14)

Kaplan-Meier survival analysis showed no NTX vs. PBO difference in time to heavy drinking.

Adverse effects did not differ between groups.

Attrition: 36%

Medium

Gelernter et al. 2007

Design: DBRCT

Setting: multisite VAMCs

Country: United States

Funding: VA

NTX 50 (149); PBO (64)

Other Tx: NR

13

DSM-IV alcohol dependence

Mean age: 50 years

26% Nonwhite

0% Female

Other Dx: cannabis and cocaine 27%; major depression 13.9%; social phobia 7.7%; generalized anxiety disorder 5.1%; PTSD 13.6%; antisocial personality disorder 8.1%; tobacco use 71.8%

Treatment condition, age, and number of drinks per drinking day at baseline were significant (p < 0.05) predictors of relapse rate and time to relapse.

No significant interactions were found between individual SNP and NTX treatment response.

In the subsample of patients with genotype information for OPRM1Asn40Asp, OPRK1, or OPRD1 rs678849, NTX treatment significantly reduced the odds of relapse.

Subjects in the PBO group were about twice as likely to relapse as subjects in the NTX group.

Attrition: 65%

High

Greenfield et al. 2010; Fucito et al. 2012; COMBINE

Design: secondary data analysis

Setting: 11 academic outpatient sites

Country: United States

Funding: govt, meds

ACA 3,000 + CBI + MM (151); ACA 3,000 +  MM (152); NTX 100 + CBI + MM (155); NTX 100 + MM (154); PBO + CBI + MM (156); PBO + MM (153)

Other Tx: as randomized; community support group participation (e.g., AA) encouraged

68

DSM-IV alcohol dependence

Mean age: 44 years

23% Nonwhite

31% Female

Other Dx: 0%

There was a significant NTX by CBI interaction for women on two primary outcomes (percent days abstinent and time to first heavy drinking day) and also secondary outcome measures (good clinical response, percent heavy drinking days, and craving).

Only the NTX by CBI interaction was significant for percent days abstinent.

The NTX by CBI interaction was significant for time to first heavy drinking day in men (p = 0.048), with each treatment showing slower relapse times; a nonsignificant trend was present in women.

NTX or CBI alone was superior to groups receiving neither in the percent of heavy drinking days.

Complete within-treatment drinking data were provided by 94% of study subjects.

Low

Guardia et al. 2002

Design: DBRCT

Setting: 7 outpatient sites

Country: Spain

Funding: Pharmazam/Zambon

NTX 50 (101); PBO (101)

Other Tx: psychosocial

12

DSM-IV alcohol dependence

Mean age: NR

% Nonwhite NR

25% Female

Other Dx: NR

Differences between NTX and PBO were drinks per drinking day: –0.51 (95% CI –1.03, 0.01), percent drinking days: –2.3 (95% CI –9.31, 4.71), return to any drinking: –0.01 (95% CI –0.15, 0.13), and return to heavy drinking: –0.11 (95% CI –0.2, –0.02)

Kaplan-Meier survival analysis showed greater time to first relapse with NTX vs. PBO (p < 0.05).

Rates of nausea and headache were greater with NTX vs. PBO.

Attrition: 41%

Medium

Heinälä et al. 2001

Design: DBRCT

Setting: outpatient

Country: Finland

Funding: govt

NTX 50 daily for 12 weeks, then targeted + CS (34); PBO + CS (33); NTX 50 daily for 12 weeks, then targeted + ST (29); PBO + ST (25)

Other Tx: none

32

DSM-IV alcohol dependence

Mean age: 46 years

% Nonwhite NR

29% Female

Other Dx: 0%

There was a significant treatment effect on relapse rate to heavy drinking, and there was an interaction between the medication and the type of therapy, with best response for the coping/NTX group.

Among patients never relapsed to heavy drinking, NTX showed a significantly better response than PBO in the coping groups (p = 0.08).

Among patients who relapsed to heavy drinking, 19.1% of the coping/NTX group relapsed only once, compared with 3.2% of the coping/PBO group.

Coping/NTX had better outcomes on reported alcohol consumption (mean ± SD g/week) than the other three groups (231 ± 40 for coping/NTX, 354 ± 62 for coping/PBO, 357 ± 81 for supportive/NTX, and 326 ± 80 for supportive/PBO).

Attrition: 32%

High

Huang et al. 2005

Design: DBRCT

Setting: 1 week alcohol treatment inpatient unit, then outpatient site

Country: Taiwan

Funding: NR

NTX 50 (20); PBO (20)

Other Tx: weekly individual psychotherapy sessions 100%

14

Subjects admitted for alcohol detoxification and meeting DSM-III-R alcohol dependence

Mean age: 38–43 years

100% Nonwhite

0% Female

Other Dx: NR

Difference between NTX and PBO for return to heavy drinking: 0.05 (95% CI –0.18, 0.28).

Craving was less with NTX vs. PBO, although relapse rates did not differ.

Attrition: 40%

High

Johnson et al. 2004b

Design: DBRCT

Setting: 4 outpatient sites

Country: United States, France, the Netherlands

Funding: univ, meds

NTX inj 400 every 28 days (25); PBO inj (5)

Other Tx: psychosocial support 100%

17

DSM-IV alcohol dependence

Mean age: 43 years

37% Nonwhite

27% Female

Other Dx: NR

Differences between NTX and PBO were drinks per drinking day: –2.2 (95% CI –3.19, –1.21), percent heavy drinking days: –13 (95% CI –44.48, 18.48), and percent drinking days: –6.8 (95% CI –53.75, 40.15).

Injection site induration and angioedema led to NTX discontinuation in 2 of the 25 NTX subjects.

Attrition: 30%

High

Kiefer et al. 2003, 2004, 2005

Design: DBRCT

Setting: 1 outpatient site

Country: Germany

Funding: univ, meds

ACA 1,998 (40); NTX 50 (40); PBO (40); ACA 1,998 + NTX 50 (40)

Other Tx: group therapy

12

DSM-IV alcohol dependence without any withdrawal symptoms

Exclusions: homelessness

Mean age: 46 years

% Nonwhite NR

26% Female

Other Dx: 0%

Differences between NTX and PBO were return to any drinking: –0.28 (95% CI –0.44, –0.11) and return to heavy drinking: –0.25 (95% CI –0.45, –0.05)

Kaplan-Meier survival analysis showed significantly longer time to relapse and to first alcohol use for NTX or NTX + ACA vs. PBO.

At the end of active treatment, relapse rates with ACA + NTX did not differ from ACA alone. Adverse effects were minor, and differences between groups were not clinically significant.

Attrition: 53%

Low

Killeen et al. 2004

Design: DBRCT

Setting: outpatient community substance use treatment center

Country: United States

Funding: govt

NTX 50 + TAU (54); PBO + TAU(43); TAU alone (48)

Other Tx: several types and intensities

12

Current alcohol use disorder

Exclusions: > 10 days outpatient treatment past 3 months

Mean age: 37 years

24% Nonwhite

37% Female

Other Dx: comorbid psychiatric disorder 51%; other substance use disorder 35%

Differences between NTX and PBO were drinks per drinking day: 1.6 (95% CI –0.55, 3.75), percent drinking days: –1.2 (95% CI –9.31, 7.33), percent heavy drinking days: –2.9 (95% CI –9.94, 4.14), return to any drinking: 0 (95% CI –0.21, 0.22), and return to heavy drinking: 0.08 (95% CI –0.13, 0.28).

Daytime sleepiness, fatigue, and dizziness were more common with NTX vs. PBO.

Attrition: 28%

Medium

King et al. 2012; Fridberg et al. 2014

Design: DBRCT

Setting: outpatient

Country: United States

Funding: govt

NTX 50 (34); PBO (35)

Other Tx: behavioral therapy and open-label nicotine patch

12 (52)

Healthy smokers with heavy drinking

Mean age: 35.5 years

37% Nonwhite

38% Female

Other Dx: nicotine dependence 100%

Weekly alcohol consumption was reduced with NTX (IRR 0.71; 95% CI 0.51, 1.0; p = 0.049).

Smoking quit rates were 23% NTX vs. 15% PBO at 12-month follow-up.

Attrition: 25%

Medium

Kranzler et al. 2004

Design: DBRCT

Setting: outpatient

Country: United States

Funding: DrugAbuse Sciences

NTX inj once a month 150 (185); PBO inj (157)

Other Tx: MET 100%

12

DSM-IV alcohol dependence

Mean age: 44 years

17%–18% Nonwhite

33%–37% Female

Other Dx: NR

Differences between NTX and PBO were percent drinking days: –8.6 (95% CI –16.01, –1.19), percent heavy drinking days: –3.4 (95% CI –10.24, 3.44), return to any drinking: –0.08 (95% CI –0.15, 0), return to heavy drinking: –0.07 (95% CI –0.16, 0.02).

Difficulties giving the injection occurred in 21% of injections, with 4% withdrawing because of injection site reactions, but rates in NTX and PBO groups did not differ.

Adverse effects did not differ between the groups.

Attrition: 22%

Medium

Kranzler et al. 2009

Design: DBRCT

Setting: outpatient

Country: United States

Funding: govt

NTX 50 targeted (38); NTX 50 once daily (45); PBO targeted (39); PBO once daily (41)

Other Tx: brief coping skills training 100%

12

Average weekly alcohol consumption of ≥ 24 standard drinks for men and ≥ 18 standard drinks for women

Exclusions: recent unsuccessful attempt to reduce drinking or past/current significant alcohol withdrawal symptoms

Mean age: 49 years

3% Nonwhite

42%Female

Other Dx: substance use disorder < 1%; social phobia 3%; antisocial personality disorder 3%; dysthymic disorder < 1%; agoraphobia without panic disorder < 1%; OCD < 1%; GAD < 1%

The difference between the targeted NTX group and the mean of the other three groups was not significant (p = 0.038), but the targeted NTX group drank 16.5% less per day than the other groups.

Heavier drinkers reported greater decreases in drinks per day during the study period (b =  –0.004, SE = 0.002, p = 0.038).

Men in the targeted NTX group had fewer drinks per drinking day than the daily NTX group (p = 0.014).

The targeted NTX group drank 19% less on drinking days than the other groups.

Nausea and dizziness were more frequent with NTX vs. PBO.

Attrition: 15%

Medium

Krystal et al. 2001; VACS425

Design: DBRCT

Setting: multisite outpatient

Country: United States

Funding: VA, meds

NTX 50 for 12 months (209); NTX 50 for 3 months, then PBO (209); PBO (209)

Other Tx: 12-step facilitation

12 or 52

DSM-IV alcohol dependence

Exclusions: homelessness; alcohol-related disability pension

Mean age: 49 years

37% Nonwhite

3% Female

Other Dx: 0%

Differences between NTX and PBO were percent drinking days: –2.7 (95% CI –6.62, 1.22), return to any drinking: –0.06 (95% CI –0.14, 0.02), return to heavy drinking: –0.06 (95% CI –0.15, 0.02), and drinks per drinking day: 0.2 (95% CI –1.38, 1.78)

Median time to relapse was 135 days, with no differences by group.

Adverse effects did not differ among groups.

Attrition: 27%

Medium

Laaksonen et al. 2008

Design: OLRCT

Setting: 6 outpatient sites in 5 cities

Country: Finland

Funding: govt

ACA 1,998 or 1,333 (81); DIS 100–200 (81); NTX 50 (81)

Other Tx: manual-based CBT

Up to 52 (119)

ICD-10 alcohol dependence

Mean age: 43 years

0% Nonwhite

29% Female

Other Dx: NR

During the continuous medication period (1–12 weeks), the DIS group did significantly better than the NTX and ACA groups in time to first heavy drinking day (p = 0.001), days to first drinking (p = 0.002), abstinence days, and average weekly alcohol intake.

During the targeted medication period (13–52 weeks), there were no significant differences between the groups in time to first heavy drinking day and days to first drinking, whereas the DIS group reported significantly more frequent abstinence days than the ACA and NTX groups.

During the whole study period (1–52 weeks), the DIS group did significantly better in time to the first drink compared with the other groups.

Attrition: 52%

High

Latt et al. 2002

Design: DBRCT

Setting: 4 hospital-based outpatient sites

Country: Australia

Funding: govt

NTX 50 (56); PBO (51)

Other Tx: no extensive psychosocial interventions

12 (26)

DSM-IV alcohol dependence

Mean age: 45 years

% Nonwhite NR

30% Female

Other Dx: 0%

Differences between NTX and PBO were percent drinking days: –0.9 (95% CI –26.7, 24.9) and return to heavy drinking: –0.19 (95% CI –0.37, –0.01).

Kaplan-Meier survival analysis showed longer time to relapse for NTX (median 90 days) vs. PBO (median 42 days), with relapse in 33.9% with NTX vs. 52.9% with PBO.

Headache was more common with PBO vs. NTX; other adverse effects did not differ.

Attrition: 31%

Medium

Lee et al. 2001

Design: DBRCT

Setting: inpatient for 1 month, then outpatient

Country: Singapore

Funding: meds

NTX 50 (35); PBO (18)

Other Tx: intensive inpatient rehabilitation program; postdischarge therapy encouraged 100%

12

DSM-IV alcohol dependence

Mean age: 45 years

≥ 88% Nonwhite

0% Female

Other Dx: NR

Difference between NTX and PBO for return to any drinking: –0.07 (95% CI –0.35, 0.21)

Decrease in craving was more frequent with NTX vs. PBO.

Adverse effects were minor and did not differ with NTX vs. PBO.

Attrition: 66% at 12 weeks; 26% with missing data

High

Longabaugh et al. 2009

Design: DBRCT

Setting: outpatient

Country: United States

Funding: govt

NTX 50 for 24 weeks + BST (36); NTX 50 for 12 weeks, then PBO for 12 weeks + BST (35); NTX 50 for 24 weeks + MET (33); NTX 50 for 12 weeks, then PBO for 12 weeks + MET (38)

Other Tx: none

12–24 (72)

DSM-IV alcohol dependence

Mean age: 44–46 years

6%–14% Nonwhite

33%–43% Female

Other Dx: NR

With 12 additional weeks of NTX, the median time to first heavy drinking day was longer for those in the BST group than for those in the other three groups (61 days vs. between 11 and 20 days, Wilcoxon chi-square = 5.05, p < 0.03).

With 12 additional weeks of NTX, the median time to first drink was longer for those in the BST group than for the other three groups (27.5 days vs. between 2 and 10 days, Wilcoxon chi-square = 6.12, p < 0.02).

Neither percentage of abstinent days nor percentage of heavy drinking days was significantly greater for the BST/NTX condition than any other condition.

Attrition: 18%

Medium

Mann et al. 2013; PREDICT

Design: DBRCT

Setting: NR

Country: Germany

Funding: govt, meds

ACA 1,998 (172); NTX 50 (169); PBO (86)

Other Tx: MM

12

Alcohol dependence

Mean age: 45 years

% Nonwhite NR

23% Female

Other Dx: NR

Difference between NTX and PBO for return to heavy drinking: 0.03 (95% CI –0.1, 0.16)

Point estimates for heavy drinking relapse–free survival from the Kaplan-Meier curves were 48.3% for ACA, 49.1% for NTX, and 51.8% for PBO.

No adverse effects were greater with NTX than other groups.

Attrition: 34%

Medium

Monterosso et al. 2001

Design: DBRCT

Setting: outpatient

Country: United States

Funding: govt

NTX 100 (121); PBO (62)

Other Tx: BRENDA

12

DSM-III-R alcohol dependence

Mean age: 46 years

27% Nonwhite

27% Female

Other Dx: NR

Difference between NTX and PBO for percent heavy drinking days: –3.9 (95% CI –7.58, –0.22)

NTX was most efficacious in those with higher craving (p = 0.02).

Attrition: 18%

Medium

Monti et al. 2001; Rohsenow et al. 2000, 2007

Design: DBRCT

Setting: 2 weeks partial hospital (premedication), 52 weeks outpatient

Country: United States

Funding: govt

NTX 50 (64); PBO (64)

Other Tx: brief physician outpatient contacts (intensive therapy occurred prior to medication portion of trial)

12 (52)

DSM-IV alcohol abuse or dependence

Mean age: 39 years

3% Nonwhite

24% Female

Other Dx: cocaine use 23%; sedative use 8%; opiate use 4%

Differences between NTX and PBO were return to heavy drinking: –0.05 (95% CI –0.2, 0.11) and drinks per drinking day: –3.83 (95% CI –5.55, –2.11).

Survival analysis showed no difference in time to relapse between groups.

Data were available for 91% of the sample at 3 months and 87% at 12 months, with no difference between groups.

Medium

Morgenstern et al. 2012; Chen et al. 2014

Design: DBRCT

Setting: NR

Country: United States

Funding: govt

NTX 100 + MBSCT (51); NTX 100 (51); PBO + MBSCT (50); PBO (48)

Other Tx: brief behavioral medication compliance enhancement therapy 100%

12

Average weekly consumption of at least 24 standard drinks per week over the previous 90 days and being sexually active with other men; 90% with DSM-IV alcohol dependence

Mean age: 40 years

26% Nonwhite

0% Female

Other Dx: HIV 15%; any drug use 67%

Among those receiving usual care only, those receiving NTX were significantly more likely to have nonhazardous drinking during the treatment period than those receiving PBO (OR = 3.33, 95% CI  2.14,17.42).

Among those receiving MBSCT, NTX had no significant effect (OR = 0.53, 95% CI  0.26, 1.07).

Adverse effects did not differ between groups at study endpoint.

Attrition: 16%

Medium

Morley et al. 2006, 2010

Design: DBRCT

Setting: 3 outpatient intensive substance use treatment sites

Country: Australia

Funding: govt

ACA 1,998 (55); NTX 50 (53); PBO (61)

Other Tx: all offered 4–6 sessions of manualized compliance therapy; uptake/attendance NR

12

DSM-IV alcohol dependence or abuse and with alcohol abstinence for 3–21 days

Mean age: 45 years

% Nonwhite NR

30% Female

Other Dx: substantial levels of emotional distress (anxiety, stress, and depression); 3% severe concurrent illness (psychiatric or other)

Differences between NTX and PBO were drinks per drinking days: = –1.2 (95% CI –3.43, 1.03), percent drinking days: –1.3 (95% CI –14.56, 11.96), return to any drinking: –0.01 (95% CI –0.13, 0.15), and return to heavy drinking: 0.03 (95% CI –0.13, 0.20)

No significant adverse effects were noted.

Attrition: 35%

Low

Morris et al. 2001

Design: DBRCT

Setting: outpatient

Country: Australia

Funding: govt, meds

NTX 50 (55); PBO (56)

Other Tx: group psychoeducation and social support

12

DSM-III-R alcohol dependence

Mean age: 47 years

% Nonwhite NR

0% Female

Other Dx: PTSD 23%; GAD 32%; panic disorder 4%; MDD 6%; BPD 1%

Differences between NTX and PBO were percent drinking days: –11 (95% CI –26.34, 4.34), return to any drinking: –0.09 (95% CI –0.23, 0.05), and return to heavy drinking: –0.26 (95% CI –0.43, –0.09)

Survival analyses showed longer time to first relapse with NTX (6.7 weeks) vs. PBO (4.2 weeks) but no difference in time to first drink.

Attrition: 36%

Medium

Narayana et al. 2008

Design: prospective cohort

Setting: military, outpatient

Country: India

Funding: NR

ACA 1,332–1,998 (28); NTX 50 (26); TOP 100–125 (38)

Other Tx: various psychotherapies were offered

52

ICD-10 alcohol dependence

Mean age: 38 years

100% Nonwhite

0% Female

Other Dx: NR

TOP (76.3%) was significantly more effective (p < 0.01) in sustaining abstinence, although 57.7% NTX and 60.7% ACA maintained complete abstinence.

7 TOP subjects (18.4%) reported decreased relapses compared with 8 NTX (30.8%) and 9 ACA (32.1%) subjects.

Attrition: 22%

High

Nava et al. 2006

Design: OLRCT

Setting: outpatient

Country: Italy

Funding: govt

GHB 50 (28); NTX 50 (24); DIS 200 (28)

Other Tx: CBT

52

DSM-IV-TR alcohol dependence

Exclusions: any withdrawal syndrome, HIV antibodies, homelessness

Mean age: 38.5–42.7 years

% Nonwhite NR

15% Female

Other Dx: 0%

At the end of the study, no statistical difference was found among groups in terms of the number of withdrawn, abstinent, nonabstinent, and relapsed patients.

A significant reduction in alcohol intake, craving, and laboratory markers of alcohol abuse was found in all groups.

The GHB group showed greater decreases in alcohol craving and in laboratory markers of alcohol abuse compared with the NTX and DIS groups.

Attrition: 31%

High

O’Malley et al. 1992, 1996

Design: DBRCT

Setting: outpatient univ alcohol treatment unit

Country: United States

Funding: govt, meds

NTX 50 + CS (29); NTX 50 + ST (23); PBO + CS (25); PBO + ST (27)

12 (38)

DSM-III-R alcohol dependence

Mean age: 41 years

7% Nonwhite

26% Female

Other Dx: NR

Differences between NTX and PBO were drinks per drinking day: –1.75 (95% CI –4.07, 0.57), percent drinking days: –5.6 (95% CI –11.07, –0.13), return to any drinking: –0.2 (95% CI –0.38, –0.02), and return to heavy drinking: –0.19 (95% CI –0.38, –0.01).

Subjects treated with NTX were less likely to meet AUD criteria at treatment endpoint than with PBO treatment.

Benefits of treatment lasted through only 1 month of follow-up.

Attrition: 18%

Medium

O’Malley et al. 2007

Design: DBRCT stratified by eating disorder

Setting: univ mental health center

Country: United States

Funding: govt

NTX 50 (57); PBO (50)

Other Tx: cognitive-behavioral coping skills therapy 100%, based on manualized approach used in Project MATCH

12

DSM-IV alcohol dependence

Exclusions: > 30 days abstinence, obesity or significant underweight

Mean age: 40 years

11% Nonwhite

100% Female

Other Dx: eating disorder 28%

Differences between NTX and PBO were return to any drinking: 0.1 (95% CI –0.05, 0.25) and return to heavy drinking: 0.04 (95% CI –0.14, 0.22).

Survival analysis showed no difference between NTX and PBO for time to first day of drinking or time to first day of heavy drinking.

Decreased appetite, depression, dizziness, and overall reports of adverse effects were more common with NTX vs. PBO.

Attrition: 43%

Medium

O’Malley et al. 2008

Design: DBRCT

Setting: Alaskan outpatient site

Country: United States

Funding: govt, meds

NTX 50 (34); PBO (34); NTX 50 + SERT 100 (33)

Other Tx: MM 100%

16

DSM-IV alcohol dependence

Mean age: 40 years

70% Nonwhite

34% Female

Other Dx: NR

Differences between NTX and PBO were drinks per drinking day: –0.3 (95% CI –0.7, 0.1), percent drinking days: –9.1 (95% CI –10.55, –7.65), percent heavy drinking days: –7.5 (95% CI –8.91, –6.09), return to any drinking: –0.24 (95% CI –0.43, –0.04), and return to heavy drinking: –0.18 (95% CI –0.38, 0.03).

There was a statistically significant advantage of NTX over PBO but no additional benefit from the addition of SERT to NTX on total abstinence (NTX vs. PBO, p = 0.04; NTX vs. NTX + SERT, p = 0.56) or the percentage who reported a drinking-related problem during treatment (NTX vs. PBO, p = 0.04; NTX vs. NTX + SERT, p = 0.85).

Time to first heavy drinking day was longer but not significantly greater for the NTX-only group compared with PBO (NTX vs. PBO, p = 0.14; NTX vs. NTX + SERT, p = 0.84).

Treatment efficacy was not dependent on the presence of an Asn40 allele.

Nausea, sleepiness, and dizziness were greater with NTX vs. PBO, with even greater rates with NTX + SERT.

Attrition: 33%

Medium

Oslin et al. 1997

Design: DBRCT

Setting: outpatient substance use disorders clinic and VAMC

Country: United States

Funding: DuPont Merck

NTX 100 on Monday and Wednesday, 150 on Friday (21); PBO (23)

Other Tx: group therapy and case manager 100%

12

DSM-III-R alcohol dependence

Mean age: 58 years

64% Nonwhite

% Female NR

Other Dx: 0%

Differences between NTX and PBO were percent drinking days: –4.6 (95% CI –12.76, 3.56), return to any drinking: –0.06 (95% CI –0.34, 0.21), and return to heavy drinking: –0.2 (95% CI –0.45, 0.04).

Adverse effects did not differ for NTX vs. PBO.

Attrition: 39%

Medium

Oslin et al. 2008

Design: DBRCT

Setting: outpatient psychiatry clinic

Country: United States

Funding: govt

NTX 100 + CBT (40); NTX 100 + BRENDA (39); NTX 100 + doctor only (41); PBO + CBT (40); PBO + BRENDA (40); PBO + doctor only (40)

Other Tx: none

24

DSM-IV alcohol dependence

Mean age: 41 years

27% Nonwhite

27% Female

Other Dx: NR

Differences between NTX and PBO were drinks per drinking day: 1.86 (95% CI –1.47, 5.19), percent drinking days: –0.4 (95% CI –6.14, 5.34), percent heavy drinking days: –2 (95% CI –6.2, 2.2), return to any drinking: –0.01 (95% CI –0.11, 0.09), and return to heavy drinking: –0.03 (95% CI –0.15, 0.1).

There was no overall effect of NTX, but psychosocial treatment had a modest main effect favoring CBT.

Insomnia was more frequent with NTX vs. PBO, but other adverse effects did not differ.

Subjects attended 31.3% of psychosocial intervention sessions, and 50.4% of subjects adhered to medication.

Attrition: 23%

Medium

Oslin et al. 2015

Design: DBRCT, block randomized by Asn40 allele genotype

Setting: outpatient

Country: United States

Funding: govt

NTX 50 (111); PBO (110)

Other Tx: MM

12

DSM-IV alcohol dependence, European or Asian descent

Mean age: 48.5 years

1.8% Nonwhite

14.1% Female

Other Dx: NR

Time-dependent decrease in heavy drinking for all groups (GEE score test χ21 = 12.18, P = 0.001), with no significant group × time interactions.

No moderating effect of OPRM1 gene status was found.

Attrition: 31%

Low

Petrakis et al. 2004; Ralevski et al. 2006

Design: DBRCT

Setting: New England Mental Illness and Research Education Clinical Center outpatient sites

Country: United States

Funding: VA

NTX 50 (16); PBO (15)

Other Tx: CBT + psychiatric treatment as usual; neuroleptics 52%; benzodiazepines 16%; thymoleptics 39%

12

DSM-IV alcohol dependence or abuse and schizophrenia or schizoaffective disorder

Mean age: 46 years

19% Nonwhite

0% Female

Other Dx: schizophrenia or schizoaffective disorder 100%

Differences between NTX and PBO were drinks per drinking day: 2.98 (95% CI –4.63, 10.59), percent drinking days: –8.7 (95% CI –19.16, 1.76), and percent heavy drinking days: –1.5 (95% CI –4.49, 1.49).

Adverse effects were similar for NTX and PBO, and psychotic symptoms (via the PANSS) and AIMS scores did not differ between groups.

Attrition: 24%

Medium

Petrakis et al. 2005, 2006, 2007; Ralevski et al. 2007; VAMIRECC

Design: DBRCT

Setting: outpatient VA

Country: United States

Funding: govt

DIS 250 (66); NTX 50 (59); PBO (64); NTX 50 + DIS 250 (65)

Other Tx: psychiatric treatment as usual 100%

12

DSM-IV alcohol dependence and other Axis I disorder

Exclusions: psychosis

Mean age: 47 years

26% Nonwhite

3% Female

Other Dx: Axis I disorder 100%

Differences between NTX and PBO were percent drinking days: –1.9 (95% CI –6.46, 2.66), percent heavy drinking days: –2 (95% CI –6.25, 2.25), and return to any drinking: 0.01 (95% CI –0.16, 0.18).

Those in both NTX and DIS groups had significantly fewer drinking days per week (F1,246 = 5.71, p = 0.02) and more consecutive days of abstinence (F1,246 = 4.49, p = 0.04) than those assigned to PBO.

No significant differences were found between groups in terms of the percent days of abstinence, percent of heavy drinking days, and the number of subjects with total abstinence.

DIS showed greater reductions over time of GGT (F1,454 = 5.85, p < 0.02) compared with NTX.

DIS-treated subjects reported a significantly greater change over time in craving compared with the NTX-treated subjects (z = 3.98, p < 0.01).

Adverse effects were most frequent in subjects treated with NTX + DIS.

Attrition: 35%

High

Petrakis et al. 2012

Design: DBRCT

Setting: outpatient; multiple psychiatric centers, primarily VA

Country: United States

Funding: VA

DMI 200 + PBO (24); paroxetine 40 + PBO (20); DMI 200 + NTX 50 (22); paroxetine 40 + NTX 50 (22)

Other Tx: clinical management; compliance enhancement therapy 100%

12

DSM-IV alcohol dependence and PTSD

Exclusions: psychosis

Mean age: 47 years

25% Nonwhite

9% Female

Other Dx: PTSD 100%

Compared with paroxetine, DMI significantly reduced the percentage of heavy drinking days (F1.84 = 7.22, p = 0.009) and drinks per drinking days (F1.84 = 5.04, p = 0.027).

There was a significant interaction for time by DMI/paroxetine treatment on drinks per week (ATS6.82 = 2.46, p = 0.018): DMI subjects had a greater reduction in their drinking over time compared with paroxetine subjects.

NTX, compared with PBO, significantly decreased craving (F1582.0 = 6.39, p = 0.012); NTX = 19.88 (SD = 12.89) and PBO = 21.1 (SD = 12.89) at baseline vs. NTX = 6.7 (SD = 14.07) and PBO = 8.3 (SD = 13.38) at endpoint).

GGT declined more in the DMI-treated participants (F1229.5 = 5.08, p = 0.02; DMI baseline = 55.2, paroxetine baseline = 86.4; DMI week 4 = 48.7, paroxetine week 4 = 46.1; DMI week 8 = 41.7, paroxetine week 8 = 47.1; DMI week 12 = 37.5, paroxetine week 12 = 57.1).

Attrition: 44.3%

High

Pettinati et al. 2008b

Design: DBRCT

Setting: univ-affiliated outpatient substance use disorder treatment research facility

Country: United States

Funding: govt, meds

NTX 150 (82); PBO (82); subjects also randomly assigned to either CBT or BRENDA (2 × 2 design)

Other Tx: NR

12

DSM-IV alcohol dependence and cocaine dependence

Mean age: 39 years

76% Nonwhite

29% Female

Other Dx: cocaine dependence 100%

Differences between NTX and PBO were drinks per drinking day: –1.7 (95% CI –3.29, –0.11), percent drinking days: –2.3 (95% CI –6.85, 2.25), and percent heavy drinking days: –2.72 (95% CI –6.16, 0.72).

Type of psychosocial treatment did not affect outcomes.

Nausea was more frequent with NTX vs. PBO.

Attrition: 36%

Medium

Pettinati et al. 2010

Design: DBRCT

Setting: outpatient

Country: United States

Funding: govt, meds

SERT 200 (40); NTX 100 (49); PBO (39); SERT 200 + NTX 100 (42)

Other Tx: CBT 100%

14

DSM-IV alcohol dependence and major depression

Mean age: 43 years

35% Nonwhite

38% Female

Other Dx: depression 100%

Difference between NTX and PBO for return to any drinking: 0.03 (95% CI –0.15, 0.2)

SERT + NTX was associated with a higher rate of abstinence and longer time to heavy drinking relapse than PBO or either drug alone.

Rates of adverse effects were not significantly different among groups.

Attrition: 43%

Medium

Schmitz et al. 2004

Design: DBRCT

Setting: outpatient

Country: United States

Funding: govt

NTX 50 + RPT (20); NTX 50 + DC (20); PBO + RPT (20); PBO + DC (20)

Other Tx: RPT or DC as randomized

12

DSM-IV alcohol dependence and cocaine dependence

Mean age: 36 years

71% Nonwhite

16% Female

Other Dx: cocaine dependence 100%

Differences between NTX and PBO were drinks per drinking day: 2 (95% CI –1.14, 5.14) and percent drinking days: –0.4 (95% CI –6.91, 6.11).

Cocaine use was not affected by NTX vs. PBO.

Adverse effects did not differ among groups.

Attrition: 69%

High

Schmitz et al. 2009

Design: DBRCT

Setting: outpatient substance use disorders clinic

Country: United States

Funding: govt

NTX 100 + CBT (20); NTX 100 + CBT and CM (25); PBO + CBT (27); PBO + CBT and CM (14)

Other Tx: CBT 100%

12

DSM-IV alcohol dependence and cocaine dependence

Mean age: 34 years

84%–93% Nonwhite

13% Female

Other Dx: cocaine use disorder 100%

The probability of drinking days (any drinking) showed an effect for time, F1, 365 = 5.27, p ≤ 0.02: for each successive week in treatment, the odds of drinking decreased by a factor of 0.94 (95% CI 0.89, 0.99).

Mean percent drinking days: 40% for NTX with CBT, 33% for NTX with CBT + CM, 23% for PBO with CBT, and 33% for PBO with CBT + CM.

In the CBT group, the odds of heavy drinking decreased by a factor of 0.81 over time in treatment (95% CI 0.74, 0.88), whereas for participants in the CBT + CM group, the odds of heavy drinking remained stable over time (OR = 0.99; 95% CI 0.92, 1.06).

For participants receiving NTX, the odds of a heavy drinking day decreased over time by a factor of 0.83 (95% CI 0.78, 0.88).

For participants receiving PBO, the odds of heavy drinking did not change over time (OR = 0.96; 95% CI 0.87, 1.07).

Attrition: 76%

High

Silverman et al. 2011

Design: DBRCT

Setting: outpatient

Country: Germany, Austria

Funding: Alkermes

NTX inj 380 every 4 weeks (152); PBO (148)

Other Tx: NR

12

Dx NR

Mean age: 46 years

% Nonwhite NR

20% Female

Other Dx: NR

Difference between NTX and PBO for return to heavy drinking: 0.07 (95% CI –0.05, 0.18)

Attrition: 37%

Medium

Volpicelli et al. 1992, 1995

Design: DBRCT

Setting: substance use disorder treatment unit of a VAMC

Country: United States

Funding: govt, meds

NTX 50 (54); PBO (45)

Other Tx: outpatient treatment program and group therapy 100%

12

Score > 5 on the Michigan Alcohol Screening Test (MAST)

Mean age: NR

≥ 78% Nonwhite

0% Female

Other Dx: NR

Differences between NTX and PBO were return to heavy drinking: –0.19 (95% CI –0.37, –0.02) and return to any drinking: –0.08 (95% CI –0.27, 0.12).

Kaplan-Meier survival analysis found a longer time to relapse with NTX vs. PBO.

Rates of craving were less with NTX than PBO.

Adverse effects did not differ between groups.

Attrition: NR

Medium

Volpicelli et al. 1997

Design: DBRCT

Setting: outpatient substance use disorders clinic; univ/VA treatment research center

Country: United States

Funding: govt, meds

NTX 50 (48); PBO (49)

Other Tx: counseling 100%

12

DSM-III-R alcohol dependence and completed medical detoxification for alcohol withdrawal

Exclusions: alcohol abstinence > 21 days

Mean age: 38–39 years

60%–65% Nonwhite

18%–26% Female

Other Dx: NR

Differences between NTX and PBO were percent drinking days: –4.6 (95% CI –10.1, 0.9), return to any drinking: –0.09 (95% CI –0.28, 0.1), and return to heavy drinking: –0.18 (95% CI –0.37, 0.02).

Of those who completed treatment, fewer relapses were seen with NTX (26%) vs. PBO (53%), with even greater effects in those who were adherent to medication.

Adverse effects did not differ between groups.

Attrition: 27%

Medium

Note. Unless noted elsewhere, subjects were excluded if they had contraindications for specific medications; were pregnant, breastfeeding, or unreliable in using contraception; were receiving psychotropic medications; or had another substance use disorder (except nicotine dependence), other psychiatric conditions, suicidal or homicidal ideas, or significant physical illness (including renal or hepatic disease). Studies comparing NTX with PBO or NTX with comparators other than ACA are included here. Studies comparing NTX with ACA are in Table B–13. Industry-sponsored studies list the name of the pharmaceutical company.

Abbreviations: AA = alcoholics anonymous; ACA = acamprosate; AIMS = Abnormal Involuntary Movement Scale; ATS = ANOVA-type statistic; AUD = alcohol use disorder; BPD = borderline personality disorder; BRENDA = Biopsychosocial evaluation, Report of findings to patient, Empathetic understanding of patient’s situation, Needs to be addressed, Direct advice to patient on how to meet those needs, and Assessing reaction/behaviors of patient to advice and adjusting treatment plan as necessary for best care; BST = broad-spectrum treatment; CBI = combined behavioral intervention; CBT = cognitive-behavioral therapy; CI = confidence interval; CM = contingency management; COMBINE =  Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence; CS = coping skills; DBRCT = double-blind, randomized controlled trial; DC = drug counseling; DIS = disulfiram; DMI = desipramine; Dx = diagnosis; GAD = generalized anxiety disorder; GEE = generalized estimating equation; GGT = gamma-glutamyl transferase; GHB = gamma-hydroxybutyrate; govt = governmental; inj = injection; IRR = Incidence Rate Ratio; MATCH = Matching Alcoholism Treatments to Client Heterogeneity; MBSCT = modified behavioral self-control therapy; MCV = mean corpuscular volume; meds = medications supplied by pharmaceutical company; MET = motivational enhancement therapy; MM = medical management; NOS = not otherwise specified; NR = not reported; NTX = naltrexone; OCD = obsessive-compulsive disorder; OLRCT = open label, randomized controlled trial; OR = odds ratio; PANSS = Positive and Negative Syndrome Scale; PBO = placebo; PE = prolonged exposure therapy; PTSD = posttraumatic stress disorder; PUFA = polyunsaturated fatty acids; RPT = relapse prevention therapy; SD = standard deviation; SE = significant effect; SERT = sertraline; SNP = single nucleotide polymorphism; ST = supportive therapy; SuppTx = supportive counseling; TAU = treatment as usual; TOP = topiramate; Tx = treatment; univ = university; VA = U.S. Department of Veterans Affairs; VAMC = U.S. Veterans Affairs Medical Center; VAMIRECC = Veterans Affairs Mental Illness Research Education Clinical Centers.

Studies related to naltrexone

Enlarge table

Benefits of Acamprosate Compared With Naltrexone

The AHRQ meta-analysis (Jonas et al. 2014) found no statistically significant difference between naltrexone and acamprosate on return to any drinking (RD, 0.02; 95% CI, –0.03 to 0.08; three trials), return to heavy drinking (RD, 0.01; 95% CI, –0.05 to 0.06; four trials), or drinking days (WMD, –2.98; 95% CI, –13.4 to 7.5) (Table B–11). Patient characteristics did not appear to be associated with a preferential response to either medication.

Acamprosate compared with naltrexone

Outcome

Number of studies; number of subjects

Risk of bias; design

Consistency

Directness

Precision

Summary effect size (95% CI)

Strength of evidence grade

Return to any drinking

3; 800

Low; RCTs

Consistent

Direct

Imprecise

RD 0.02 (–0.03 to 0.08)a

Moderate

Return to heavy drinking

4; 1,141

Low; RCTs

Consistent

Direct

Imprecise

RD 0.01 (–0.05 to 0.06)a

Moderate

Drinking days

2; 720

Low; RCTs

Inconsistent

Direct

Imprecise

WMD –2.98 (–13.42 to 7.45)a

Low

Heavy drinking days

1; 612

Low; RCT

Unknown

Direct

Unknown

Significant NTX by CBI interaction, P = 0.006

Insufficient

Drinks per drinking day

2; 720

Low; RCTs

Inconsistent

Direct

Unknown

Unable to pool datab

Insufficient

Accidents

0; 0

NA

NA

NA

NA

NA

Insufficient

Injuries

0; 0

NA

NA

NA

NA

NA

Insufficient

Quality of life or function

1;c 612

Low; RCT

Unknown

Direct

Imprecise

NSD for all measures except SF-12v2® physical health, which favored NTX + CBI

Insufficient

Mortality

0;d 0

NA

NA

NA

NA

NA

Insufficient

aPositive value indicates that naltrexone is favored.

bTwo trials reported some information about drinks per drinking day, but there were not enough data for us to conduct a quantitative synthesis. One trial conducted in Australia reported no statistically significant difference between ACA and NTX (mean, SD: 7.5, 6.1 vs. 5.9, 6.1; P not reported)., The COMBINE study reported that analyses of alternative summary measures of drinking, including drinks per drinking day (P = 0.03), were consistent with those for the co-primary endpoints (percent days abstinent from alcohol and time to first heavy drinking day), all showing a significant naltrexone by CBI interaction.

cOne additional study was rated high risk of bias. It found that quality of life improved for both groups over the 52-week follow-up compared with baseline but found no difference between the ACA and NTX groups.

dOne study that reported this outcome was rated high risk of bias; another reported one death but did not specify in which treatment group it occurred.

Abbreviations: ACA = acamprosate; CBI = combined behavioral intervention; CI = confidence interval; COMBINE =  Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence; NA = not applicable; NTX = naltrexone; NSD = no significant difference; RCT = randomized controlled trial; RD = risk difference; SD = standard deviation; WMD = weighted mean difference.

Source.  Jonas et al. 2014, Table D–8.

Acamprosate compared with naltrexone

Enlarge table

The COMBINE study (Anton et al. 2006, p. 2003) found that “patients receiving medical management with naltrexone, CBI, or both fared better on drinking outcomes than those who received placebo, but acamprosate showed no evidence of efficacy, with or without CBI.” Analyses of alternative summary measures of drinking, including drinks per drinking day (p = 0.03) and heavy drinking days per month (p = 0.006), were consistent with those for the co-primary end points (percentage of days abstinent from alcohol and time to first heavy drinking day) in showing a significant naltrexone by CBI interaction. Although the CBI and naltrexone treatment combination showed a statistically significant difference in quality of life measures, the AHRQ review noted that this was unlikely to be clinically significant (Jonas et al. 2014). In a subsequent analysis that examined predictors of abstinence from heavy drinking, assignment to a specific treatment was not a major contributor to outcome, but individuals with more consecutive days of abstinence, with a drinking goal of abstinence, or with a lesser frequency of alcohol use prior to treatment were more likely to achieve abstinence from heavy drinking (Gueorguieva et al. 2011, 2014). By 3 years, median but not mean costs (treatment cost plus social costs of AUD such as health care, arrests, and motor vehicle accidents) were diminished in the COMBINE study by a number of treatment combinations that included pharmacotherapy (Zarkin et al. 2010). Treatment arms that were cost-effective, from a policy (Dunlap et al. 2010) and patient-centered (Zarkin et al. 2008) standpoint, were MM with placebo, MM plus naltrexone therapy, and MM plus combined naltrexone and acamprosate therapy.

The medium-risk-of-bias German PREDICT study (total N = 426) is the only study identified in the updated literature search that included a head-to-head comparison of acamprosate and naltrexone (Mann et al. 2013) and is not included in Table B–11. This trial was modeled after the COMBINE study and found no difference among naltrexone, acamprosate, and placebo groups on the time to first heavy drinking. Point estimates for heavy drinking relapse free survival from the Kaplan-Meier curves were 48.3% for acamprosate, 49.1% for naltrexone, and 51.8% for placebo. A secondary analysis of adherent patients also showed no significant differences among the treatment groups.

Grading of the Overall Supporting Body of Research Evidence for Head-to-Head Comparison of Acamprosate and Naltrexone Benefits

  • Magnitude of effect: None.

  • Risk of bias: Low. Studies are RCTs that are generally of low bias based on their described randomization and blinding procedures and descriptions of study dropouts.

  • Applicability: The included trials all involve individuals with AUD, by either prior diagnostic criteria or other evidence of harmful levels of drinking. The studies include subjects from around the world, including North America. The doses of acamprosate and naltrexone appear to be representative of outpatient clinical practice.

  • Directness: Direct. Studies measured abstinence and heavy drinking rates as well as measures of alcohol consumption.

  • Consistency: Consistent. There was some heterogeneity as evidenced by increased I2 values on one drinking-related outcome, but confidence intervals are overlapping.

  • Precision: Imprecise. Confidence intervals for studies cross the threshold for clinically significant benefit of the intervention.

  • Dose-response relationship: Unclear. Studies used a single dose of naltrexone and acamprosate.

  • Confounding factors (including likely direction of effect): Unclear. Some studies suggest a possible effect of genetic polymorphisms on treatment response, which could confound study interpretation.

  • Publication bias: Not identified. No publication bias was noted by the AHRQ review; however, they note that they were unable to assess for publication bias for early clinical trials (prior to the release of https://clinicaltrials.gov).

  • Overall strength of research evidence: Moderate. A number of RCTs have been conducted, most of which are governmentally funded and have a low risk of bias. Although the studies have good applicability, imprecision is a limitation. Another limitation is that the trials use oral formulations of naltrexone without considering the long-acting injectable formulation.

Harms of Acamprosate Compared With Naltrexone

In terms of adverse events, the risks of headache, nausea, and vomiting were noted to be slightly higher for individuals treated with naltrexone as compared with acamprosate in the AHRQ review (Jonas et al. 2014) (Table B–12). The number of deaths in head-to-head studies of naltrexone and acamprosate was extremely small, and no statistical comparison was possible (Jonas et al. 2014). In the PREDICT trial (not included in Table B–12), diarrhea was significantly greater with acamprosate, and nervousness/anxiety was greater in placebo subjects. Serious adverse events (9.9% of patients during active treatment and 17.4% during follow-up) and related dropouts (6.3%) did not differ among the treatment groups.

Acamprosate compared with naltrexone

Outcome

Number of studies; number of subjects

Risk of bias; design

Consistency

Directness

Precision

Summary effect size (95% CI)a

Strength of evidence grade

Withdrawals due to AEs

2;b 953

Medium; RCTs

Consistent

Direct

Imprecise

RD 0.015 (–0.04 to 0.07)

Low

Anorexia

0; 0

NA

NA

NA

NA

NA

Insufficient

Anxiety

0; 0

NA

NA

NA

NA

NA

Insufficient

Cognitive dysfunction

0; 0

NA

NA

NA

NA

NA

Insufficient

Diarrhea

4;b 836

Low to medium; RCTs

Consistent

Direct

Imprecise

RD 0.18 (–0.02 to 0.37)

Moderate

Dizziness

2;b 144

Low to medium; RCTs

Inconsistent

Direct

Imprecise

RD 0.08 (–0.23 to 0.39)

Low

Headache

3;b 301

Medium; RCTs

Inconsistent

Direct

Imprecise

RD –0.056 (–0.120 to 0.008)

Lowd

Insomnia

2; 144

Low to medium; RCTs

Inconsistent

Direct

Imprecise

RD 0.07 (–0.20 to 0.34)

Low

Nausea

4;c 836

Low to medium; RCTs

Consistent

Direct

Imprecise

RD –0.08 (–0.18 to 0.02)

Lowe

Numbness/tingling/paresthesias

0; 0

NA

NA

NA

NA

NA

Insufficient

Rash

0; 0

NA

NA

NA

NA

NA

Insufficient

Suicide

0; 0

NA

NA

NA

NA

NA

Insufficient

Taste abnormalities

0; 0

NA

NA

NA

NA

NA

Insufficient

Vision changes

0; 0

NA

NA

NA

NA

NA

Insufficient

Vomiting

2; 648

Low; RCTs

Consistent

Direct

Precise

RD –0.06 (–0.11 to –0.01)

Moderate

aIn this column, a positive value favors naltrexone.

bOne additional study was rated high or unclear risk of bias.

cTwo additional studies were rated high risk of bias.

dThe additional study rated as high risk of bias found similar results as the medium-risk-of-bias studies. Meta-analysis including all three found a higher risk of headache with naltrexone than with acamprosate: RD –0.087 (–0.159 to –0.015).

eMeta-analysis including the two additional studies rated as high or unclear risk of bias found a higher risk of nausea with naltrexone than with acamprosate: RD –0.096 (–0.178 to –0.015).

Abbreviations: AE = adverse effect; CI = confidence interval; RCT = randomized controlled trial; RD = risk difference.

Source. Jonas et al. 2014, Table D–35.

Acamprosate compared with naltrexone

Enlarge table

Grading of the Overall Supporting Body of Research Evidence for Head-to-Head Comparison of Acamprosate and Naltrexone Harms

  • Magnitude of effect: Very small. When present, the magnitude of effect is very small.

  • Risk of bias: Medium. Studies are RCTs of low bias based on their described randomization and blinding procedures and descriptions of study dropouts. However, methods for determining harms are not always well specified, and there is potential for selective reporting of results.

  • Applicability: The included trials all involve individuals with AUD, by either prior diagnostic criteria or other evidence of harmful levels of drinking. The studies include subjects from around the world, including North America. The doses of acamprosate and naltrexone appear to be representative of outpatient clinical practice.

  • Directness: Direct. Studies measured common side effects and dropouts due to adverse events.

  • Consistency: Inconsistent. As indicated by the high values of I2, there was substantial heterogeneity in the reported adverse events among the trials.

  • Precision: Imprecise. Confidence intervals for studies are wide in many studies and cross the threshold for clinically significant harms of the intervention.

  • Dose-response relationship: Unknown. Studies used a single dose of acamprosate and naltrexone.

  • Confounding factors (including likely direction of effect): Absent. No known confounding factors are present that would be likely to modify adverse events of the intervention.

  • Publication bias: Not identified. No publication bias was noted by the AHRQ review; however, they note that they were unable to assess for publication bias for early clinical trials (prior to the release of https://clinicaltrials.gov).

  • Overall strength of research evidence: Low. Several RCTs have been conducted, some of which have assessed adverse events in a systematic and predefined fashion. Many of the RCTs are funded by governmental agencies. However, findings are imprecise and inconsistent, making it difficult to draw conclusions about differences in side effects between the two medications.

Data Abstraction: Acamprosate Versus Naltrexone

Studies comparing acamprosate and naltrexone are listed in Table B–13.

Studies related to acamprosate versus naltrexone head-to-head comparison

Author and year; trial name

Study characteristics

Treatment administered, including study arm, dose (mg/day), sample size (N), and co-intervention

Rx duration, weeks (follow-up)

Sample characteristics, including diagnostic inclusions and major exclusions

Outcome measures, main results, and overall percent attrition

Risk of bias

Anton et al. 2006; Donovan et al. 2008; LoCastro et al. 2009; COMBINE

Design: DBRCT

Setting: 11 academic outpatient sites

Country: United States

Funding: govt, meds

ACA 3,000 + CBI + MM (151); ACA 3,000 + MM (152); NTX 100 + CBI + MM (155); NTX 100 + MM (154); PBO + CBI + MM (156); PBO + MM (153)

Other Tx: as randomized; community support group participation (e.g., AA) encouraged

16 (68)

DSM-IV alcohol dependence

Mean age: 44 years

23% Nonwhite

31% Female

Other Dx: NR

Differences between ACA and NTX were percent drinking days: 1 (95% CI –3.12, 5.12), return to any drinking: 0.03 (95% CI –0.04, 0.09), and return to heavy drinking: 0.03 (95% CI –0.05, 0.1).

ACA showed no effect; NTX, CBI, or both had the best outcomes.

Complete within-treatment drinking data were provided by 94% of study subjects.

Low

Anton and COMBINE Study Research Group 2003

Design: DBRCT

Setting: 11 academic outpatient sites

Country: United States

Funding: govt, meds

ACA 3,000 + CBI + MM (9); ACA 3,000 + MM (9); NTX 100 + CBI + MM (9); NTX 100 + MM (9); PBO + CBI + MM (9); PBO + MM (8)

Other Tx: as randomized

16

DSM-IV alcohol dependence

Mean age: 38–42 years

17%–22% Nonwhite

22%–33% Female

Other Dx: NR

ACA-NTX group adherence was equal to, or better than, adherence with PBO, ACA alone, or NTX alone.

Adverse events were comparable in all groups.

Attrition: 31%

Medium

Greenfield et al. 2010; Fucito et al. 2012; COMBINE

Design: secondary data analysis

Setting: 11 academic outpatient sites

Country: United States

Funding: govt, meds

ACA 3,000 + CBI + MM (151); ACA 3,000 + MM (152); NTX 100 + CBI + MM (155); NTX 100 + MM (154); PBO + CBI + MM (156); PBO + MM (153)

Other Tx: as randomized; community support group participation (e.g., AA) encouraged

68

DSM-IV alcohol dependence

Mean age: 44 years

23% Nonwhite

31% Female

Other Dx: 0%

There was a significant NTX by CBI interaction for women on two primary outcomes (percent days abstinent and time to first heavy drinking day) and also secondary outcome measures (good clinical response, percent heavy drinking days, and craving).

Only the NTX by CBI interaction was significant for percent days abstinent.

The NTX by CBI interaction was significant for time to first heavy drinking day in men (p = 0.048), with each treatment showing slower relapse times; a nonsignificant trend was present in women.

NTX or CBI alone was superior to groups receiving neither in the percent of heavy drinking days.

Complete within-treatment drinking data were provided by 94% of study subjects.

Low

Kiefer et al. 2003, 2004, 2005

Design: DBRCT

Setting: 1 outpatient site

Country: Germany

Funding: univ, meds

ACA 1,998 (40); NTX 50 (40); PBO (40); ACA 1,998 + NTX 50 (40)

Other Tx: group therapy

12

DSM-IV alcohol dependence without any withdrawal symptoms

Exclusions: homelessness

Mean age: 46 years

% Nonwhite NR

26% Female

Other Dx: 0%

Time to relapse or time to first drink did not differ between ACA- and NTX-treated groups by survival analysis, although the combination of the drugs was associated with better outcomes than PBO (p < 0.01) or than ACA alone (p = 0.04).

Attrition: 53%

Low

Laaksonen et al. 2008

Design: OLRCT

Setting: 6 outpatient sites in 5 cities

Country: Finland

Funding: govt

ACA 1,998 or 1,333 (81); DIS 100 to 200 (81); NTX 50 (81)

Other Tx: manual-based CBT

Up to 52 (119)

ICD-10 alcohol dependence

Mean age: 43 years

0% Nonwhite

29% Female

Other Dx: NR

During the continuous medication period (1–12 weeks), the DIS group did significantly better than the NTX and ACA groups in time to first heavy drinking day (p = 0.001), days to first drinking (p = 0.002), abstinence days, and average weekly alcohol intake.

During the targeted medication period (13–52 weeks), there were no significant differences between the groups in time to first heavy drinking day and days to first drinking, whereas the DIS group reported significantly more frequent abstinence days than the ACA and NTX groups.

During the whole study period (1–52 weeks), the DIS group did significantly better in the time to the first drink compared with the other groups.

Attrition: 52%

High

Mann et al. 2013; PREDICT

Design: DBRCT

Setting: NR

Country: Germany

Funding: govt, meds

ACA 1,998 (172); NTX 50 (169); PBO (86)

Other Tx: MM

12

Alcohol dependence

Mean age: 45 years

% Nonwhite NR

23% Female

Other Dx: NR

Difference between ACA and NTX for return to heavy drinking: 0.01 (95% CI –0.1, 0.11)

Point estimates for heavy drinking relapse-free survival from the Kaplan-Meier curves were 48.3% for ACA, 49.1% for NTX, and 51.8% for PBO.

Attrition: 34%

Medium

Morley et al. 2006, 2010

Design: DBRCT

Setting: 3 outpatient intensive substance use treatment sites

Country: Australia

Funding: govt

ACA 1,998 (55); NTX 50 (53); PBO (61)

Other Tx: all offered 4–6 sessions of manualized compliance therapy; uptake/attendance NR

12

DSM-IV alcohol dependence or abuse and with alcohol abstinence for 3–21 days

Mean age: 45 years

% Nonwhite NR

30% Female

Other Dx: substantial levels of emotional distress (anxiety, stress, and depression); 3% severe concurrent illness (psychiatric or other)

There was no significant difference between treatments with respect to the number of days to first relapse (Breslow test: t2 = 0.4, P = 0.81) or the number of days to first relapse (Breslow test: t2 = 2.9, P = 0.23) by survival analysis.

Regardless of medication group, significant effects for time were found for drinks per drinking day (F1,159 = 6.8, P < 0.01) and dependence severity (F1,103 = 12.81, P < 0.001) but not for craving (F1,103 = 2.0, P = 0.16).

Attrition: 35%

Low

Narayana et al. 2008

Design: prospective cohort

Setting: military, outpatient

Country: India

Funding: NR

ACA 1,332 to 1,998 (28); NTX 50 (26); TOP 100 to 125 (38)

Other Tx: various psychotherapies were offered

52

ICD-10 alcohol dependence

Mean age: 38 years 100% Nonwhite

0% Female

Other Dx: NR

TOP (76.3%) was significantly more effective (p < 0.01) in sustaining abstinence, although 57.7% NTX and 60.7% ACA maintained complete abstinence.

7 TOP subjects (18.4%) reported decreased relapses compared with 8 NTX (30.8%) and 9 ACA (32.1%) subjects.

Attrition: 18%

High

Rubio et al. 2001

Design: SBRCT

Setting: outpatient

Country: Spain

Funding: govt

ACA 1,665–1,998 (80); NTX 50 (77)

Other Tx: supportive group therapy weekly, weekly visits with a psychiatrist for 3 months, then biweekly until end of study

52

DSM-III-R alcohol dependence

Exclusions: previous NTX or ACA treatment

Mean age: 44 years

% Nonwhite NR

0% Female

Other Dx: 0%

At the end of 1 year, 41% receiving NTX and 17% receiving ACA had not relapsed (P = 0.0009), and the accumulated abstinence was greater for NTX compared with ACA (mean number of days: 243 vs. 180).

NTX had longer survival until first relapse than ACA (63 days vs. 42 days, p = 0.02).

Relapse to some alcohol use occurred on average 12 days later in the NTX group (SD = 16) vs. after 6 days in the ACA group (SD = 8).

Survival analysis of time to first alcohol consumption showed no significant differences between the two groups (the mean number of days: 44 for the NTX group and 39 for the ACA group; p = 0.34).

Attrition: 17%

High

Note. Unless noted elsewhere, subjects were excluded if they had contraindications for specific medications; were pregnant, breastfeeding, or unreliable in using contraception; were receiving psychotropic medications; or had another substance use disorder (except nicotine dependence), other psychiatric conditions, suicidal or homicidal ideas, or significant physical illness (including renal or hepatic disease). Industry-sponsored studies list the name of the pharmaceutical company.

Abbreviations: AA = Alcoholics Anonymous; ACA = acamprosate; CBI = combined behavioral intervention; CI = confidence interval; COMBINE =  Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence; DBRCT = double-blind, randomized controlled trial; DIS = disulfiram; Dx = diagnosis; govt = governmental; meds = medications supplied by pharmaceutical company; MM = medical management; NOS = not otherwise specified; NR = not reported; NTX = naltrexone; OLRCT = open-label, randomized controlled trial; PBO = placebo; TOP = topiramate; SBRCT = single-blind, randomized controlled trial; SD = standard deviation; Tx = treatment; univ = university.

Studies related to acamprosate versus naltrexone head-to-head comparison

Enlarge table

Statement 10: Disulfiram

APA suggests (2C) that disulfiram be offered to patients with moderate to severe alcohol use disorder who

  • have a goal of achieving abstinence,

  • prefer disulfiram or are intolerant to or have not responded to naltrexone and acamprosate,

  • are capable of understanding the risks of alcohol consumption while taking disulfiram, and

  • have no contraindications to the use of this medication.

Benefits of Disulfiram

Evidence for the benefits of disulfiram comes from randomized controlled double-blind and open-label trials as well as expert opinion. The AHRQ review (Jonas et al. 2014) included four studies conducted at Veterans Health Administration Medical Centers and found no statistically significant difference between disulfiram 250 mg/day and sham comparators (i.e., placebo, disulfiram 1 mg/day, riboflavin). In the two trials included in the AHRQ review that assessed percentage of drinking days, one reported no significant difference among treatment groups. The other trial limited its reporting to a subset of subjects (those who drank during the trial and who also completed all assessments) and found that disulfiram was associated with fewer drinking days (p = 0.05) than for those who received a comparator (49% with disulfiram 250 mg/day vs. 75.4% with disulfiram 1 mg/day and 86.5% with riboflavin). In the two RCTs included in the AHRQ analysis that had a medium risk of bias (Fuller and Roth 1979, 1986), treatment adherence was associated with abstinence, regardless of whether the subject was assigned to active disulfiram or control treatment. Some shorter RCTs of disulfiram have also been associated with benefits on drinking-related outcomes (Jørgensen et al. 2011).

In a medium-risk-of-bias trial conducted in Japan (Yoshimura et al. 2014), subjects (total N = 109) were randomly assigned according to a 2 × 2 design with disulfiram 200 mg/day vs. placebo and receipt of educational material on drinking harms and craving management vs. no such education. At 26 weeks, there were no differences among groups in the percent of individuals who remained abstinent. However, this study may have limited generalizability because individuals were randomly assigned to disulfiram after a 2- to 3-month inpatient stay.

A single study in the AHRQ review (Petrakis et al. 2005) compared disulfiram, naltrexone, placebo, and the combination of disulfiram plus naltrexone for 12 weeks in Veterans Health Administration outpatient settings (Table B–14). Naltrexone was given in a double-blind fashion, but disulfiram was administered as an open-label medication. The trial found no statistically significant difference between disulfiram and naltrexone for number of subjects achieving total abstinence (51 vs. 38, p = 0.11), percentage of days abstinent (96.6 vs. 95.4, p = 0.55), or percentage of heavy drinking days (3.2 vs. 4, p = 0.65).

A meta-analysis (Skinner et al. 2014) differed from the AHRQ analysis in including RCTs that were open-label as well as randomized controlled double-blind trials. Skinner and colleagues (2014) hypothesized that in a double-blind trial, subjects in both disulfiram and placebo groups would avoid drinking because of having been warned of the potential for adverse events regardless of actual treatment assignment. They included 22 studies (2,414 subjects) and found a significant overall effect but no difference between disulfiram and control groups in the double-blind RCTs. When only open-label trials were considered, disulfiram was significantly better than controls on alcohol-related outcomes (Hedges’ g = 0.70; 95% CI = 0.46–0.93), for which control conditions included acamprosate, naltrexone, and no disulfiram. Individual comparisons for each of these control conditions were also statistically significant. In studies where medication adherence was assured through supervised administration, the effect of disulfiram was large. As with the double-blind RCTs, however, only a small proportion of women were included in the open-label trials, which limits generalizability.

Disulfiram compared with control

Outcome

Number of studies; number of subjects

Risk of bias; design

Consistency

Directness

Precision

Summary effect size (95% CI)

NNTd

Strength of evidence grade

Return to any drinking

2;a 492

Medium; RCTs

Consistentb

Direct

Imprecise

RD 0.04 (–0.11 to 0.03)

NA

Low

Return to heavy drinking

0; 0

NA

NA

NA

NA

NA

NA

Insufficient

Drinking days

2; 290

Medium; RCTs

Inconsistent

Indirectc

Imprecise

1 study reported similar percentages and no significant difference; the other reported that DIS was favored among the subset of subjects who drank and had a complete set of assessment interviews (N = 162/605 subjects), p = 0.05

NA

Insufficient

Heavy drinking days

0; 0

NA

NA

NA

NA

NA

NA

Insufficient

Drinks per drinking day

0; 0

NA

NA

NA

NA

NA

NA

Insufficient

Accidents

0; 0

NA

NA

NA

NA

NA

NA

Insufficient

Injuries

0; 0

NA

NA

NA

NA

NA

NA

Insufficient

Quality of life or function

0; 0

NA

NA

NA

NA

NA

NA

Insufficient

Mortality

0; 0

NA

NA

NA

NA

NA

NA

Insufficient

aOne additional study was rated high risk of bias.

bInclusion of the study rated high risk of bias would have made this inconsistent, although it would not have changed the conclusion (the meta-analysis still found no statistically significant difference between groups).

cWe considered this indirect because the larger study did not report the outcome for the randomized sample; it reported this outcome only for the subset (162/605) who drank and who had a complete set of assessment interviews.

dNA entry for NNT indicates that the risk difference (95% CI) was not statistically significant, so we did not calculate a NNT, or that the effect measure was not one that allows direct calculation of NNT (e.g., WMD).

Abbreviations: CI = confidence interval; DIS = disulfiram; NA = not applicable; NNT = number needed to treat; RCT = randomized controlled trial; RD = risk difference; WMD = weighted mean difference.

Source. Jonas et al. 2014, Table D–2.

Disulfiram compared with control

Enlarge table

Grading of the Overall Supporting Body of Research Evidence for Efficacy of Disulfiram

  • Magnitude of effect: No effect in double-blind studies, moderate effect in open-label studies.

  • Risk of bias: High. Studies are RCTs and a meta-analysis that includes open-label trials. RCTs are of medium to high risk of bias, and open-label studies have not been formally rated but are likely to be of high risk of bias.

  • Applicability: The included trials all involve individuals with AUD, by either prior diagnostic criteria or other evidence of harmful levels of drinking. The double-blind studies primarily included subjects from the U.S. Veterans Health Administration Medical Centers that are overrepresented among study locations, and the vast majority of subjects are men. The doses of disulfiram used in the studies appear to be representative of outpatient clinical practice.

  • Directness: Direct. Studies measured abstinence and alcohol consumption.

  • Consistency: Inconsistent. There was considerable heterogeneity in the trial findings in both the AHRQ meta-analysis and the meta-analysis by Skinner et al. (2014), which included open-label trials.

  • Precision: Imprecise. Confidence intervals for studies cross the threshold for clinically significant benefit of the intervention.

  • Dose-response relationship: No data available to assess.

  • Confounding factors (including likely direction of effect): Present. As noted above, the subjects’ knowledge of treatment assignment may be important in the desire to maintain abstinence to avoid an aversive experience when drinking.

  • Publication bias: Possible. The meta-analysis of Skinner et al. (2014), which included open-label trials, noted funnel plot asymmetry, suggesting a potential for publication bias. Virtually all of the disulfiram trials were conducted prior to the advent of https://clinicaltrials.gov.

  • Overall strength of research evidence: Low. A small number of RCTs have been conducted, most of which have medium to high risk of bias; open-label studies also are likely to have a high risk of bias. The available evidence is limited in its generalizability because of the location of the trials and the small proportion of women in the studies. The imprecision and inconsistency of findings are additional limitations.

Harms of Disulfiram

The data on harms from the studies included in the AHRQ report were insufficient to conduct meta-analyses. One study showed a greater rate of drowsiness in patients receiving versus not receiving disulfiram (8% vs. 2%, p = 0.03). Several patients discontinued disulfiram because of increased levels of hepatic enzymes. A four-arm study (2 × 2, disulfiram vs. placebo, naltrexone vs. placebo) showed greater rates of specific side effects in patients taking any study medication but no differences between groups. In this study, patients taking disulfiram and placebo experienced 6 of 14 serious adverse events. In the study of Yoshimura and colleagues (2014), 1/53 disulfiram treated subjects had a dermatological problem, 2/53 had liver enzyme elevations, and 1/53 had renal dysfunction, whereas no adverse events were noted in placebo-treated subjects. In the study of Petrakis and colleagues (2005), which compared disulfiram, naltrexone, placebo, and the combination of disulfiram plus naltrexone, fever was more common in the disulfiram group than in the naltrexone group (p = 0.03), whereas nervousness (p = 0.005) and restlessness (p = 0.03) were more common in the naltrexone group than in the disulfiram group.

In the meta-analysis of Skinner et al. (2014), data from randomized, controlled, open-label trials showed considerable heterogeneity but showed a significantly greater number of adverse events with disulfiram as compared with control conditions.

Additional information on potential harms of disulfiram comes from the product labelling (Rising Pharmaceuticals 2016), which notes that disulfiram should not be given to individuals who have recently received metronidazole, paraldehyde, alcohol (within 12 hours), or alcohol-containing preparations. It is also noted to be contraindicated in the presence of severe myocardial disease or coronary occlusion. When alcohol is taken within 14 days of disulfiram ingestion, it can produce the following:

flushing, throbbing in head and neck, throbbing headache, respiratory difficulty, nausea, copious vomiting, sweating, thirst, chest pain, palpitation, dyspnea, hyperventilation, tachycardia, hypotension, syncope, marked uneasiness, weakness, vertigo, blurred vision, and confusion. In severe reactions, there may be respiratory depression, cardiovascular collapse, arrhythmias, myocardial infarction, acute congestive heart failure, unconsciousness, convulsions, and death.

Disulfiram is noted to be contraindicated in the presence of psychosis or in individuals with hypersensitivity to disulfiram or thiuram derivatives used in pesticides and rubber production. Hepatic toxicity is also reported to have occurred in individuals receiving disulfiram.

Grading of the Overall Supporting Body of Research Evidence for Harms of Disulfiram

  • Magnitude of effect: Small. When instructions for avoiding disulfiram-alcohol reactions are followed, the proportion of individuals who experience adverse events is small.

  • Risk of bias: High. Studies do not prespecify harm outcomes and do not report them consistently.

  • Applicability: The included trials all involved individuals with AUD by prior diagnostic criteria. The vast majority of study subjects are men, which limits the generalizability of the findings. The doses of disulfiram used in the trials appear to be representative of outpatient clinical practice.

  • Directness: Indirect. Studies generally measured adverse events as a general category or assessed the numbers of individuals who required intervention because of an adverse effect.

  • Consistency: Inconsistent. There was considerable heterogeneity in the findings of the meta-analysis by Skinner et al. (2014), which included open-label trials.

  • Precision: Imprecise. Confidence intervals for studies cross the threshold for clinically significant benefit of the intervention.

  • Dose-response relationship: No data are available to assess.

  • Confounding factors (including likely direction of effect): Not identified.

  • Publication bias: Possible. The meta-analysis of Skinner et al. (2014), which included open-label trials, noted funnel plot asymmetry, suggesting a potential for publication bias. Virtually all of the disulfiram trials were conducted prior to the advent of https://clinicaltrials.gov.

  • Overall strength of research evidence: Low. A small number of double-blind RCTs have been conducted, but measures of adverse events were minimal and not systematically defined. With data from open-label trials, the imprecision and inconsistency of findings are limitations, in addition to the high risk of bias associated with an open-label study design.

Data Abstraction: Disulfiram

Studies related to disulfiram are listed in Table B–15.

Studies related to disulfiram

Author and year; trial name

Study characteristics

Treatment administered, including study arm, dose (mg/day), sample size (N), and co-intervention

Rx duration, weeks (follow-up)

Sample characteristics, including diagnostic inclusions and major exclusions

Outcome measures, main results, and overall percent attrition

Risk of bias

Carroll et al. 1993

Design: OLRCT

Setting: outpatient

Country: United States

Funding: govt

DIS 250 (9); NTX 50 (9)

Other Tx: weekly individual psychotherapy 100%

12

DSM-III-R alcohol abuse/dependence and cocaine dependence

Mean age: 32 years

39% Nonwhite

72% Female

Other Dx: cocaine dependence 100%

Subjects taking DIS reported lower percentage of alcohol use days compared with those taking NTX (4.0% vs. 26.3%, t = 3.73, p < 0.01).

Subjects taking DIS also reported fewer total days using alcohol (2.4 vs. 10.4 days, t = 3.00, p < 0.01), fewer total drinks (2.3 vs. 27.0, t = –2.00, p = 0.06), and more total weeks of abstinence (mean 7.2 vs. 1.1 weeks, t = 4.72, p < 0.001) compared with those taking NTX.

Attrition: 67%

High

De Sousa and De Sousa 2004

Design: OLRCT

Setting: outpatient

Country: India

Funding: NR

DIS 250 (50); NTX 50 (50)

Other Tx: supportive group psychotherapy

52

DSM-IV alcohol dependence

Exclusions: previous NTX and/or DIS treatment

Mean age: 43–47 years

% Nonwhite NR

0% Female

Other Dx: NR

DIS was associated with greater reduction in relapse, greater survival time until the first relapse, and more days of abstinence than NTX. At study endpoint, relapse was 14% with DIS vs. 56% with NTX.

NTX reported lower composite craving scores than DIS.

Attrition: 3%

High

De Sousa and De Sousa 2005

Design: OLRCT

Setting: outpatient; private psychiatric hospital

Country: India

Funding: NR

ACA 1,998 (50); DIS 250 (50)

Other Tx: weekly supportive group psychotherapy offered

35

DSM-IV alcohol dependence

Exclusions: previous DIS or ACA treatment

Mean age: 42–43 years

100% Nonwhite

0% Female

Other Dx: NR

DIS had a lower relapse rate than ACA (88% vs. 46%, p = 0.0001) and a longer mean time to first relapse (123 days vs. 71 days, p = 0.0001).

ACA had lower craving scores than DIS.

Attrition: 7%

High

De Sousa et al. 2008

Design: OLRCT

Setting: inpatient and outpatient alcohol treatment center

Country: India

Funding: NR

TOP 150 (50); DIS 250 (50)

Other Tx: weekly supporting group psychotherapy offered

39

DSM-IV alcohol dependence

Exclusions: previous TOP or DIS treatment

Mean age: 43 years

100% Nonwhite

0% Female

Other Dx: NR

DIS had greater mean time to first relapse than TOP (133 days vs. 79 days, p = 0.0001) and a lower relapse rate at study endpoint (10% vs. 44%; p = 0.0001).

TOP had less craving than DIS.

Attrition: 8%

High

Fuller and Roth 1979

Design: DBRCT

Setting: outpatient; VA

Country: United States

Funding: VA

DIS 250 (43); DIS 1 (43); RIB 50 (42)

Other Tx: counseling (unspecified) 100%

52

Admitted for alcohol-related illness or requesting treatment for alcoholism

Mean age: 43 years

61% Nonwhite

0% Female

Other Dx: NR

Complete abstinence rates did not differ between regular dose (23%) and no DIS (12%).

Median percentages of drinking days among the DIS 500/250 mg, DIS 1 mg, and no DIS groups were 31%, 32%, and 37%, respectively.

Attrition: NR

Medium

Fuller et al. 1986

Design: DBRCT

Setting: outpatient; 9 VA medical centers

Country: United States

Funding: VA

DIS 250 (202); DIS 1 (204); RIB 50 (199)

Other Tx: counseling (loosely defined) % NR

52

Requesting alcohol treatment and meeting National Council on Alcoholism criteria

Mean age: 41–42 years

47% Nonwhite

0% Female

Other Dx: NR

No significant differences were found among the groups with respect to percentages of those remaining abstinent for the full year: 18.8%, 22.5%, and 16.1% (p = 0.25) and in the time to first drinking day (p = 0.26).

Of those who reported drinking and provided all scheduled interviews, subjects taking 250 mg of DIS had significantly fewer total drinking days (49 ± 8 days) compared with those taking either 1 mg of DIS (75 ± 12 days) or no DIS (86.5 ± 14 days).

Of those who reported drinking and provided six or fewer interviews, the differences among the groups in total drinking days were not statistically significant.

Attrition: 5%

Medium

Laaksonen et al. 2008

Design: OLRCT

Setting: 6 outpatient sites in 5 cities

Country: Finland

Funding: govt

ACA 1,998 or 1,333 (81); DIS 100 to 200 (81); NTX 50 (81)

Other Tx: manual-based CBT

Up to 52 (119)

ICD-10 alcohol dependence

Mean age: 43 years

0% Nonwhite

29% Female

Other Dx: NR

During the continuous medication period (1–12 weeks), the DIS group did significantly better than the NTX and ACA groups in time to first heavy drinking day (p = 0.001), days to first drinking (p = 0.002), abstinence days, and average weekly alcohol intake.

During the targeted medication period (13–52 weeks), there were no significant differences between the groups in time to first heavy drinking day and days to first drinking, whereas the DIS group reported significantly more frequent abstinence days than the ACA and NTX groups.

During the whole study period (1–52 weeks), the DIS group did significantly better in time to the first drink compared with the other groups.

Attrition: 52%

High

Ling et al. 1983

Design: DBRCT

Setting: outpatient; VA

Country: United States

Funding: VA

DIS 250 + methadone (41); PBO + methadone (41)

Other Tx: methadone 100% as randomized

37

Two of four consecutive > 0.05% alcohol readings in subjects on methadone maintenance or at risk of clinic discharge for problem behavior

Mean age: 39 years

% Nonwhite NR

% Female NR

Other Dx: heroin use 80%, marijuana use 36%, other drug use 67%, depression 83%, moderate to high depression 50%

Both groups reported fewer episodes of morning drinking, alcoholic blackouts, fights, binge drinking, hospitalizations, and alcohol-related arrests.

Attrition: 57% at 12 weeks; 55% lost to follow-up

High

Nava et al. 2006

Design: OLRCT

Setting: outpatient

Country: Italy

Funding: govt

GHB 50 (28); NTX 50 (24); DIS 200 (28)

Other Tx: CBT

52

DSM-IV-TR alcohol dependence

Exclusions: any withdrawal syndrome, HIV antibodies, homelessness

Mean age: 38.5–42.7 years

% Nonwhite NR

15%% Female

Other Dx: 0%

At the end of the study, no statistical difference was found among groups in terms of the number of withdrawn, abstinent, nonabstinent, and relapsed patients.

Significant reduction in alcohol intake, craving, and laboratory markers of alcohol abuse was found in all groups.

The GHB group showed greater decreases in alcohol craving and in laboratory markers of alcohol abuse compared with the NTX and DIS groups.

Attrition: 31%

High

Petrakis et al. 2005, 2006, 2007; Ralevski et al. 2007; VAMIRECC

Design: DBRCT

Setting: outpatient VA

Country: United States

Funding: govt

DIS 250 (66); NTX 50 (59); PBO (64); NTX 50 + DIS 250 (65)

Other Tx: psychiatric treatment as usual 100%

12

DSM-IV alcohol dependence and other Axis I disorder

Exclusions: psychosis

Mean age: 47 years

26% Nonwhite

3% Female

Other Dx: Axis I disorder 100%

Difference between DIS and PBO for return to any drinking: –0.12 (95% CI –0.27, 0.04)

High rates of abstinence were present in all groups, but there were no differences by group.

Fever was more likely in those taking DIS vs. NTX.

DIS + NTX had the highest rates of adverse effects as compared with other groups.

Attrition: 35%

High

Yoshimura et al. 2014

Design: DBRCT

Setting: outpatient

Country: Japan

Funding: govt

DIS 200 + letter (28); DIS 200 no letter (26); PBO + letter (29); PBO no letter (26)

Other Tx: proportion of subjects received letter discussing harms of alcohol use and approaches to manage craving

26

ICD-10 alcohol dependence

Mean age: 52.1 years

% Nonwhite NR

0% Female

Other Dx: NP

No difference in the proportion achieving abstinence at 26 weeks

Attrition: 25%

Medium

Note. Unless noted elsewhere, subjects were excluded if they had contraindications for specific medications; were pregnant, breastfeeding, or unreliable in using contraception; were receiving psychotropic medications; or had another substance use disorder (except nicotine dependence), other psychiatric conditions, suicidal or homicidal ideas, or significant physical illness (including renal or hepatic disease). Industry-sponsored studies list the name of the pharmaceutical company.

Abbreviations: ACA = acamprosate; CBT = cognitive-behavioral therapy; CI = confidence interval; DBRCT = double blind, randomized controlled trial; DIS = disulfiram; Dx = diagnosis; GHB = gamma-hydroxybutyrate; govt = governmental; NR = not reported; NTX = naltrexone; OLRCT = open label, randomized controlled trial; PBO = placebo; RIB = riboflavin; TOP = topiramate; Tx = treatment; VA = U.S. Department of Veterans Affairs; VAMIRECC = Veterans Affairs Mental Illness Research Education Clinical Centers.

Studies related to disulfiram

Enlarge table

Statement 11: Topiramate or Gababentin

APA suggests (2C) that topiramate or gabapentin be offered to patients with moderate to severe alcohol use disorder who

  • have a goal of reducing alcohol consumption or achieving abstinence,

  • prefer topiramate or gabapentin or are intolerant to or have not responded to naltrexone and acamprosate, and

  • have no contraindications to the use of these medications.

Benefits of Topiramate

Evidence for topiramate comes from multiple randomized controlled trials, some of which included subjects with co-occurring conditions. The AHRQ review (Jonas et al. 2014) included three studies of topiramate versus placebo and one study of topiramate versus naltrexone versus placebo. The latter study (Baltieri et al. 2008, 2009) was rated as having a high risk of bias and showed no significant differences in the two treatments on drinking outcomes. The two placebo-controlled trials (total N = 521) that had a low or medium risk of bias were included in the AHRQ meta-analysis (Johnson et al. 2003, 2007). These trials had a duration of 12–14 weeks and were both conducted in the United States. On the basis of this meta-analysis, the AHRQ review concluded that there was a moderate strength of evidence for topiramate efficacy on drinks per drinking days (WMD: –1.10, 95% CI –1.75 to –0.45), percentage of heavy drinking days (WMD: –11.53, 95% CI –18.29 to –4.77), and percentage of drinking days. For the latter outcome, it was not possible to combine the results of the two trials, but each showed a comparable mean difference (WMD: –8.5, 95%, CI –15.9 to –1.1; mean difference –11.6, 95% CI –3.98 to –19.3). Findings from sensitivity analyses were similar when high-risk-of-bias studies were included.

A number of subsequent randomized controlled trials (not included in Table B–16) have also examined effects of topiramate. In a low-risk-of-bias U.S. government–funded trial, topiramate in doses of up to 200 mg/day (N = 67) was compared with placebo (N = 71) and was associated with a larger (p = 0.001) and more rapid (p = 0.0001) reduction in heavy drinking and a larger (p = 0.03) and more rapid (p = 0.01) increase in the number of days abstinent (Kranzler et al. 2014a). Topiramate subjects were more likely to have had no heavy drinking days in the last 4 weeks of treatment (35.8% vs. 16.9% with placebo, OR = 2.75, 95% CI 1.24–6.10) and to have abstained from alcohol use at the end of treatment (OR = 2.57, 95% CI  1.13–5.84). The odds of a heavy drinking day were greater in the placebo group than the topiramate group (OR = 5.33, 95% CI  1.68–7.28) by the last week of treatment. These benefits of topiramate appeared to be limited to individuals who were homozygous for the rs2832407 C-allele of GRIK1 (which encodes the kainate GluK1 receptor subunit). However, at 3- and 6-month follow-up, the beneficial effects of topiramate on percent heavy drinking days and percent days abstinent were no longer significant (Kranzler et al. 2014c). Topiramate (300 mg/day; N = 21) was also one of the treatment arms in a 14-week medium-risk-of-bias, double-blind, randomized controlled trial of several other anticonvulsant agents that included levetiracetam (N = 21), zonisamide 400 mg/day (N = 19), and placebo (N = 24) (Knapp et al. 2015). For topiramate as compared with placebo, significant treatment effects were seen for weekly percent days drinking (P < 0.0001), percent days heavy drinking (P < 0.0001), and drinks consumed per day (P = 0.0007). A 12-week, medium-risk-of-bias, double-blind, randomized placebo-controlled trial of topiramate (260 mg/day average dose) conducted in Thailand (total N = 106) was limited by 50% attrition rates but showed no significant difference between the treatments in heavy drinking days, time to first heavy drinking day, or secondary drinking outcomes (Likhitsathian et al. 2013).

Several smaller studies of topiramate have been conducted in individuals with a co-occurring psychiatric disorder. A small (total N = 30) double-blind, randomized placebo-controlled trial of flexibly dosed topiramate (up to 300 mg/day) was conducted at a Veterans Affairs Medical Center in individuals with co-occurring PTSD (Batki et al. 2014) (Table B–16). This low-risk-of-bias study showed a 51% decrease in drinking days with topiramate as compared with placebo as well as reductions in standard drinks per week but no effect on the percent of heavy drinking days. Another U.S. government–funded, low-risk-of-bias, double-blind, randomized placebo-controlled trial of topiramate (300 mg/day) enrolled individuals with co-occurring cocaine dependence (Kampman et al. 2013). During the 13-week trial, 41/87 (47%) of placebo-treated subjects were lost to follow-up versus 29/83 (35%) with topiramate. However, on primary outcome measures of weekly differences in percent days drinking, percent days heavy drinking, and mean drinks per drinking day, there was no difference between the placebo and topiramate-treated groups. An additional study in individuals with co-occurring bipolar disorder reported the results of 12 randomly assigned participants but had difficulty recruiting subjects because of problems with topiramate tolerability (Sylvia et al. 2016).

Topiramate compared with placebo

Outcome

Number of studies; number of subjects

Risk of bias; design

Consistency

Directness

Precision

Summary effect size (95% CI)

Strength of evidence grade

Return to any drinking

0;a 0

NA

NA

NA

NA

NA

Insufficient

Return to heavy drinking

0; 0

NA

NA

NA

NA

NA

Insufficient

Drinking days

2;b 521

Low; RCTs

Consistent

Direct

Imprecise

Trial 1: WMD: –8.5 (–15.9 to –1.1)b

Trial 2: mean difference –11.6 (–3.98 to –19.3)

Moderateb

Heavy drinking days

2;b 521

Low; RCTs

Consistent

Direct

Imprecise

WMD: –11.53 (–18.29 to –4.77)

Moderateb

Drinks per drinking day

2;b 521

Low; RCTs

Consistent

Direct

Imprecise

WMD: –1.10 (–1.75 to –0.45)

Moderateb

Accidents

0; 0

NA

NA

NA

NA

NA

Insufficient

Injuries

1; 371

Low; RCT

Unknown

Direct

Imprecise

4.4% (TOP) vs. 11.7% (PBO); p = 0.01

Insufficient

Quality of life or function

0; 0

NA

NA

NA

NA

NA

Insufficient

Mortality

1; 371

Low; RCT

Unknown

Direct

Imprecise

0 (TOP) vs. 1 (PBO)

Insufficient

aOne study conducted in Brazil, rated as high risk of bias, reported this outcome. It reported that more patients treated with TOP returned to any drinking than with PBO (24/52 vs. 15/54).

bOne additional study reporting this outcome was rated as high risk of bias. Our meta-analysis found a lower percentage of drinking days for patients treated with TOP than for those who received PBO both without and with including the trial rated as high risk of bias (WMD –9.7; 95% CI –16.4 to –3.1). Our meta-analysis found a lower percentage of heavy drinking days for patients treated with topiramate than for those who received placebo both without and with including the trial rated as high risk of bias (WMD –11.4; 95% CI –20.4 to –2.4). Our meta-analysis found no statistically significant difference between TOP and PBO when only including the trial rated as low risk of bias but found a statistically significant reduction of 1.2 drinks per drinking day when including the trial rated as high risk of bias (WMD –1.2; 95% CI –2.2 to –0.2). We were unable to include “trial 2” (N = 150), rated as medium risk of bias, in our meta-analyses because of differences in the type of data reported, but its findings are shown in the SOE table and were generally consistent with those of the low risk of bias trial (“trial 1,” N = 371).

Abbreviations: CI = confidence interval; NA = not applicable; PBO = placebo; RCT = randomized controlled trial; SOE =  strength of evidence; TOP = topiramate; WMD = weighted mean difference.

Source. Jonas et al. 2014, Table D–26.

Topiramate compared with placebo

Enlarge table

Grading of the Overall Supporting Body of Research Evidence for Efficacy of Topiramate

  • Magnitude of effect: Moderate. When present for specific outcomes, the magnitude of the effect is moderate.

  • Risk of bias: Medium. Studies are RCTs of low to high bias based on their described randomization and blinding procedures and descriptions of study dropouts, with the largest trials having low to medium risk of bias.

  • Applicability: The included trials all involve individuals with AUD, by either prior diagnostic criteria or other evidence of harmful levels of drinking. The studies include subjects from around the world, including North America. The doses of topiramate appear to be representative of outpatient clinical practice.

  • Directness: Direct. Studies measured abstinence and heavy drinking rates as well as measures of alcohol consumption.

  • Consistency: Inconsistent. There was considerable heterogeneity in the study findings, with a proportion of trials showing no effect of topiramate.

  • Precision: Imprecise. Confidence intervals for studies cross the threshold for clinically significant benefit of the intervention.

  • Dose-response relationship: Unclear. No dose-response relationship studies were done.

  • Confounding factors (including likely direction of effect): Unclear. One study suggests a possible effect of genetic polymorphisms on treatment response, which could confound study interpretation.

  • Publication bias: Not identified. No publication bias was noted by the AHRQ review; however, they note that they were unable to assess for publication bias for early clinical trials (prior to the advent of https://clinicaltrials.gov).

  • Overall strength of research evidence: Moderate. A number of RCTs have been conducted, with low to high risk of bias. Several of the RCTs are funded by governmental agencies. Other studies show inconsistent findings or had high rates of attrition.

Harms of Topiramate

Studies of topiramate in other disorders have reported a number of treatment-related side effects. In the studies of topiramate for AUD that were included in the AHRQ report (Jonas et al. 2014), the most notable side effects of topiramate as compared with placebo were cognitive dysfunction and numbness/tingling/paresthesias (Table B–17). In the study of Likhitsathian et al. (2013), paresthesias were more common in the topiramate group as compared with placebo (45.3% vs. 17%). Kampman et al. (2013) also found a greater frequency of paresthesias in topiramate-treated subjects as compared with placebo-treated subjects (20% vs. 3%). Knapp et al. (2015) also noted paresthesias in 19% of topiramate subjects and erectile dysfunction in 14% of topiramate subjects. In addition, Knapp et al. (2015) found a significant effect of topiramate on the mental slowing subscale of the A-B Neurotoxicity Scales relative to placebo (P = 0.008). Batki et al. (2014) found no significant differences in side effects between topiramate- and placebo-treated subjects.

Results of meta-analyses and risk difference calculations for adverse events: topiramate compared with placebo

Outcome

N trials

N subjects

RD

95% CI

I2

Strength of evidence grade

Withdrawal due to adverse events

2

521

0.06

–0.12 to 0.25

93.4%

Low

Withdrawal due to adverse events—SA

3

599

0.06

–0.06 to 0.18

86.9%

Anorexia

1

371

0.13

0.06 to 0.20

NA

Insufficient

Cognitive dysfunction

2

521

0.08

0.01 to 0.16

38.5%

Moderate

Diarrhea

1

371

0.04

–0.03 to 0.10

NA

Insufficient

Diarrhea—SA

2

477

0.00

–0.07 to 0.08

61 .1%

Insufficient

Dizziness

2

521

0.10

–0.01 to 0.22

65 .0%

Low

Dizziness—SA

3

627

0.08

0.01 to 0.14

51.5%

Low

Headache

1

371

-0.08

–0.17 to 0.01

NA

Insufficient

Insomnia

1

371

0.03

–0.05 to 0.11

NA

Insufficient

Insomnia—SA

2

477

0.03

–0.03 to 0.10

0.0%

Insufficient

Nausea

1

371

–0.06

–0.13 to 0.01

NA

Insufficient

Nausea—SA

2

477

–0.02

–0.11 to 0.06

62.0%

Insufficient

Numbness/tingling/paresthesias

2

521

0.40

0.32 to 0.47

0.0%

Moderate

Numbness/tingling/paresthesias—SA

3

627

0.29

0.05 to 0.52

93.1%

Moderate

Taste abnormalities

1

371

0.18

0.11 to 0.25

NA

Insufficient

Note. Positive risk differences favor placebo. Sensitivity analyses include studies rated as high risk of bias.

Abbreviations: CI = confidence interval; N = number of trials or subjects contributing data; NA = not applicable; RD = risk difference; SA = sensitivity analysis.

Source. Jonas et al. 2014, Table 31; values for strength of evidence are from Table D–37.

Results of meta-analyses and risk difference calculations for adverse events: topiramate compared with placebo

Enlarge table

Grading of the Overall Supporting Body of Research Evidence for Harms of Topiramate

  • Magnitude of effect: Moderate. When present, the magnitude of effect is moderate for cognitive dysfunction and for numbness/tingling/paresthesias.

  • Risk of bias: High. Studies are RCTs of low to high bias based on their described randomization and blinding procedures and descriptions of study dropouts. However, methods for determining harms are not well specified, and there is potential for selective reporting of results.

  • Applicability: The included trials all involve individuals with AUD, by either prior diagnostic criteria or other evidence of harmful levels of drinking. The studies include subjects from around the world, including North America. The doses of topiramate appear to be representative of outpatient clinical practice.

  • Directness: Direct. Studies measured common side effects and dropouts due to adverse events.

  • Consistency: Consistent. For adverse events that showed a significant effect (cognitive dysfunction and numbness/tingling/paresthesias), the findings were consistent across trials.

  • Precision: Precise. Confidence intervals for cognitive dysfunction and for numbness/tingling/paresthesias are relatively narrow.

  • Dose-response relationship: Unknown. Dose response information on side effects was not well described.

  • Confounding factors (including likely direction of effect): Possible and may reduce reported side effects. Given the high rates of attrition in some of the studies and the lack of systematic assessment of side effects, it is possible that attrition occurred because of unrecognized adverse events.

  • Publication bias: Not identified. No publication bias was noted by the AHRQ review; however, they note that they were unable to assess for publication bias for early clinical trials (prior to the advent of https://clinicaltrials.gov).

  • Overall strength of research evidence: Moderate. A number of RCTs have been conducted, but few have assessed adverse events in a systematic and predefined fashion. Many of the RCTs are funded by governmental agencies. Nevertheless, the studies are relatively consistent in reporting increased likelihood of cognitive dysfunction and numbness/tingling/paresthesias with topiramate, which is consistent with reported side effects in clinical trials for other indications.

Data Abstraction: Topiramate

Studies related to topiramate are listed in Table B–18.

Studies related to topiramate

Author and year

Study characteristics

Treatment administered, including study arm, dose (mg/day), sample size (N), and co-intervention

Rx duration, weeks

Sample characteristics, including diagnostic inclusions and major exclusions

Outcome measures, main results, and overall percent attrition

Risk of bias

Baltieri et al. 2008, 2009

Design: DBRCT

Setting: outpatient

Country: Brazil

Funding: govt

TOP to 200–400 (52); NTX 50 (49); PBO (54)

Other Tx: psychosocial 100%; AA recommended

12

ICD-10 alcohol dependence

Mean age: 44–45 years

29% Nonwhite

0% Female

Other Dx: tobacco use 66%

Time to first relapse was greater with TOP than PBO (7.8 weeks vs. 5.0 weeks).

NTX was not significantly different from either of the other groups (5.7 weeks).

Cumulative abstinence duration was also greater with TOP (8.2 weeks vs. NTX 6.6 weeks vs. PBO 5.6 weeks), as was the mean number of weeks with heavy drinking, but the rate of complete abstinence at study endpoint was comparable in the 3 groups.

Smokers relapsed more rapidly than nonsmokers.

Attrition: 45%

High

Batki et al. 2014

Design: DBRCT

Setting: outpatient

Country: United States

Funding: govt

TOP to 300 (14); PBO (16)

Other Tx: MM

12

DSM-IV alcohol dependence and PTSD

Mean age: NR

47% Nonwhite

7% Female

Other Dx: PTSD 100%; SUD 33%

TOP was associated with 51% fewer drinking days but showed no effect on heavy drinking days.

No difference in adverse events between groups or cognition at end of trial.

PTSD severity was reduced in TOP group.

Attrition: 10%

Low

De Sousa et al. 2008

Design: OLRCT

Setting: inpatient and outpatient alcohol treatment center

Country: India

Funding: NR

TOP 150 (50); DIS 250 (50)

Other Tx: weekly supporting group psychotherapy offered

39

DSM-IV alcohol dependence

Exclusions: previous TOP or DIS treatment

Mean age: 43 years

100% Nonwhite

0% Female

Other Dx: NR

DIS had greater mean time to first relapse than TOP (133 days vs. 79 days, p = 0.0001) and a lower relapse rate at study endpoint (10% vs. 44%; p = 0.0001).

TOP had less craving than DIS.

Attrition: 8%

High

Flórez et al. 2008

Design: OLRCT

Setting: outpatient substance use disorders clinic

Country: Spain

Funding: NR

TOP up to 200 (51); NTX 50 (51)

Other Tx: therapy based on relapse prevention model 100%

26

ICD-10 alcohol dependence

Mean age: 47 years

0% Nonwhite

15% Female

Other Dx: personality disorders 27%

TOP and NTX were both effective but did not differ in efficacy as measured by a composite alcohol use metric.

Adverse effects, particularly weight loss, were greater with TOP vs. NTX.

Attrition: 10%

High

Flórez et al. 2011

Design: OLRCT

Setting: outpatient substance use disorders clinic

Country: Spain

Funding: NR

TOP 200 (91); NTX 50 (91)

Other Tx: BRENDA 100%; at least monthly meeting with psychiatrist 100%

26

ICD-10 alcohol dependence

Mean age: 47–48 years

% Nonwhite NR

15% Female

Other Dx: personality disorders 23%

At 3 and 6 months, patients with TOP reported lower scores than those with NTX on craving and alcohol-related measures; those with TOP also scored less on disability related measures at 6 months.

TOP was also associated with fewer drinks per drinking day and fewer heavy drinking days at 3 and 6 months compared with NTX.

The percentage of days abstinent and total drinking days were comparable for TOP and NTX.

A greater proportion of TOP subjects reported adverse effects at 3 months but not 6 months.

Attrition: 10%

High

Johnson et al. 2003, 2004a; Ma et al. 2006

Design: DBRCT

Setting: 1 outpatient site

Country: United States

Funding: Ortho-McNeil

TOP 25–300 (75); PBO (75)

Other Tx: brief behavioral compliance enhancement therapy

12

DSM-IV alcohol dependence

Mean age: 41.5 years

36% Nonwhite

29% Female

Other Dx: 0%

Differences between TOP and PBO were drinks per drinking day: –1.2 (95% CI –2.023, –0.3777) and percent heavy drinking days: –14.9 (95% CI –22.556, –7.244).

TOP had significant improvements on all drinking outcomes, including 27% fewer heavy drinking days compared with PBO (p < 0.001) as well as improvements on reported abstinence and not seeking alcohol (OR = 2.63; 95% CI 1.52, 4.53; p = 0.001).

Craving was significantly less with TOP vs. PBO. TOP also improved the odds of overall well-being (OR = 2.17; 95% CI 1.16, 2.60; p = 0.01) and overall life satisfaction (OR = 2.28; 95% CI 1.21, 4.29; p = 0.01) and reduced harmful drinking consequences (OR =  –0.07; 95% CI –0.12, –0.02; p = 0.01) relative to PBO.

TOP had more frequent adverse events compared with PBO: dizziness (28.0% vs. 10.7%; p = 0.01), paresthesia (57.3% vs. 18.7%; p < 0.001), psychomotor slowing (26.7% vs. 12.0%; p = 0.02), memory or concentration impairment (18.7% vs. 5.3%; p = 0.01), and weight loss (54.7% vs. 26.7%; p= 0.001).

Attrition: 35%

Medium

Johnson et al. 2007, 2008

Design: DBRCT

Setting: 17 academic outpatient sites

Country: United States

Funding: Ortho-McNeil

TOP 50–300, mean 171 (183); PBO (188)

Other Tx: brief behavioral medication compliance enhancement therapy 100%

14

DSM-IV alcohol dependence

Exclusions: > 4 unsuccessful inpatient treatment attempts

Mean age: 47–48 years

15% Nonwhite

26%–28% Female

Other Dx: NR

Differences between TOP and PBO were drinks per drinking day: –0.93 (95% CI –1.986, 0.126), percent drinking days: –8.5 (95% CI –15.88, –1.12), and percent heavy drinking days: –8 (95% CI –15.919, –0.081).

Paresthesia, taste abnormalities, loss of appetite, and problems with concentration were more frequent with TOP vs PBO.

Attrition: 31%; 6% lost to follow-up

Low

Kampman et al. 2013

Design: DBRCT

Setting: outpatient

Country: United States

Funding: govt

TOP to 300 (83); PBO (87)

Other Tx: individual cognitive-behavioral coping skills (Project MATCH)

13

In 30-day period in past 90 days had at least 48/60 drinks (women/men), with 2 or more heavy drinking days; DSM-IV cocaine dependence

Mean age: 44 years

83% Nonwhite

21% Female

Other Dx: cocaine dependence 100%

No differences were found in weekly percent days drinking, weekly percent days heavy drinking, and mean drinks per drinking day.

Paresthesias occurred in 20% of TOP-treated subjects and 3% of PBO subjects.

Attrition: 59%

Low

Knapp et al. 2015

Design: DBRCT

Setting: outpatient

Country: United States

Funding: govt

TOP 300 (21); levetiracetam 2,000 (21); zonisamide 400 (19); PBO (24)

Other Tx: brief behavioral compliance enhancement treatment

14

DSM-IV alcohol dependence

Mean age: 47 years

9% Nonwhite

43.5% Female

Other Dx: NR

Significant treatment effects were seen for weekly percent days drinking (P < 0.0001), percent days heavy drinking (P < 0.0001), and drinks consumed per day (P = 0.0007) for TOP as compared with PBO.

Significant effect of TOP was seen on the mental slowing subscale of A-B Neurotoxicity Scales (p = 0.008).

Paresthesias (19%) and erectile dysfunction (14%) were more common with TOP.

Attrition: 24%

Medium

Kranzler et al. 2014a

Design: DBRCT

Setting: outpatient

Country: United States

Funding: VA

TOP to 200 (67); PBO (71)

Other Tx: MM

12

Average weekly use of standard drinks > 23 for men and > 17 for women; goal of reducing but not abstaining from alcohol; majority with DSM-IV alcohol dependence

Mean age: 51.1 years

12% Nonwhite

38% Female

Other Dx: lifetime MDD 19%

TOP was associated with a larger and more rapid decrease in heavy drinking and days with drinking.

At the end of treatment, TOP group was more likely to have abstained from alcohol use (OR = 2.57; 95% CI  1.13, 5.84) and had no heavy drinking days (35.8% vs. 16.9% with PBO, OR = 2.75; 95% CI  1.24, 6.10).

TOP subjects reported significantly higher rates of adverse events, specifically numbness/tingling, change in taste, loss of appetite, weight loss, difficulty concentrating, and difficulty with memory.

Attrition: 15%

Low

Likhitsathian et al. 2013

Design: DBRCT

Setting: outpatient

Country: Thailand

Funding: govt

TOP up to mean dose 260 (53); PBO (53)

Other Tx: MET and MM

12

At least 1 of 4 weeks prior to admission with more than 34 standard drinks per week

Mean age: 41.5 years

% Nonwhite NR

0% Female

Other Dx: NR

Both groups had reduced drinking, but there was no difference in heavy drinking days or time to first heavy drinking day between groups.

Paresthesias were more common with TOP (45.3% vs. 17%).

Attrition: 50%

Medium

Narayana et al. 2008

Design: prospective cohort

Setting: military, outpatient

Country: India

Funding: NR

ACA 1,332–1,998 (28); NTX 50 (26); TOP 100–125 (38)

Other Tx: various psychotherapies offered

52

ICD-10 alcohol dependence

Mean age: 38 years

100% Nonwhite

0% Female

Other Dx: NR

TOP (76.3%) was significantly more effective (p < 0.01) in sustaining abstinence, although 57.7% NTX and 60.7% ACA maintained complete abstinence.

7 TOP subjects (18.4%) reported decreased relapses compared with 8 NTX (30.8%) and 9 ACA (32.1%) subjects.

Attrition: 22%

High

Rubio et al. 2009

Design: DBRCT

Setting: outpatient

Country: Spain

Funding: govt

TOP 250 (31); PBO (32)

Other Tx: supportive group therapy offered

12

DSM-IV alcohol dependence

Mean age: 42 years

% Nonwhite NR

0% Female

Other Dx: NR

Differences between TOP and PBO were drinks per drinking day: –2.3 (95% CI –4.715, 0.115), percent drinking days: –14.9 (95% CI –30.07, 0.27), and percent heavy drinking days: –17.6 (95% CI –30.565, –4.635).

Attrition: 5%

High

Note. Unless noted elsewhere, subjects were excluded if they had contraindications for specific medications; were pregnant, breastfeeding, or unreliable in using contraception; were receiving psychotropic medications; or had another substance use disorder (except nicotine dependence), other psychiatric conditions, suicidal or homicidal ideas, or significant physical illness (including renal or hepatic disease). Industry-sponsored studies list the name of the pharmaceutical company.

Abbreviations: AA = Alcoholics Anonymous; ACA = acamprosate; BRENDA = Biopsychosocial evaluation, Report of findings to patient, Empathetic understanding of patient’s situation, Needs to be addressed, Direct advice to patient on how to meet those needs, and Assessing reaction/behaviors of patient to advice and adjusting treatment plan as necessary for best care; CI = confidence interval; DBRCT = double blind, randomized controlled trial; DIS = disulfiram; Dx = diagnosis; govt = governmental; MDD = major depressive disorder; MET = motivational enhancement therapy; MM = medical management; NR = not reported; NTX = naltrexone; OLRCT = open-label, randomized controlled trial; OR = odds ratio; PBO = placebo; PTSD = posttraumatic stress disorder; SUD = substance use disorder; TOP = topiramate; Tx = treatment; VA = U.S. Department of Veterans Affairs.

Studies related to topiramate

Enlarge table

Benefits of Gabapentin

The AHRQ review (Jonas et al. 2014) did not include any studies with a primary focus on gabapentin. In one included study (Anton et al. 2011), gabapentin was added in one treatment arm as an adjunct to naltrexone during the initial 6 weeks of the trial and was associated with improved outcomes at 6 weeks but not at the end of the trial. Several small randomized trials of shorter duration also showed benefit of gabapentin on alcohol-related outcomes (Anton et al. 2009; Furieri and Nakamura-Palacios 2007).

A government-funded low-risk-of-bias, double-blind, randomized controlled dose-ranging trial (Mason et al. 2014) compared gabapentin at 900 mg/day (N = 54) and 1,800 mg/day (N = 47) with placebo (N = 49). The primary study outcomes, which were rate of complete abstinence (chi square = 4.19; P = .04) and rate of no heavy drinking (chi square = 5.39; P = .02), increased linearly with the dose of gabapentin. Sustained 12-week abstinence was 4.1% (95% CI 1.1%–13.7%) with placebo, 11.1% (95% CI 5.2%–22.2%) with 900 mg/day of gabapentin, and 17.0% (95% CI 8.9% –30.1%; NNT = 8) with 1,800 mg/day gabapentin with a NNT of 8 for increased rate of abstinence at a dose of 1,800 mg daily. Corresponding rates of no heavy drinking were 22.5% (95% CI 13.6%–37.2%), 29.6% (95% CI 19.1%–42.8%), and 44.7% (95% CI 31.4%–58.8%; NNT = 5), respectively, with a NNT of 5 for reduction in heavy drinking days at a dose of 1,800 mg daily. Significant dose-dependent reductions were also noted in the prespecified secondary outcomes: levels of GGT, alcohol craving, sleep, and depression. For subjects who completed the trial, rates of complete abstinence, drinks per week, and number of heavy drinking days per week were sustained at 24-week follow-up. The most frequent adverse events were fatigue (23%), insomnia (18%), and headache (14%), but rates of these side effects did not differ among the three study arms. In addition, there were no differences in the number, severity, or type of reported adverse effects (Mason et al. 2014). Insufficient information was available on side effects of gabapentin to grade the overall supporting body of research evidence for harms.

Grading of the Overall Supporting Body of Research Evidence for Efficacy of Gabapentin

  • Magnitude of effect: Moderate. When present for specific outcomes, the magnitude of the effect is moderate.

  • Risk of bias: Low. One large RCT accounts for the preponderance of findings and has a low risk of bias based on the described randomization and blinding procedures and descriptions of study dropouts.

  • Applicability: The included trials all involve individuals with AUD, by either prior diagnostic criteria or other evidence of harmful levels of drinking. The studies include subjects from North America. The doses of gabapentin are representative of outpatient clinical practice.

  • Directness: Direct. Studies measured abstinence and heavy drinking rates as well as measures of alcohol consumption.

  • Consistency: Not applicable. Data are predominantly from a single study.

  • Precision: Imprecise. Confidence intervals for some outcomes cross the threshold for clinically significant benefit of the intervention.

  • Dose-response relationship: Present. Linear increases in efficacy are noted with increases in gabapentin dose for multiple outcomes.

  • Confounding factors (including likely direction of effect): Not identified.

  • Publication bias: Not identified.

  • Overall strength of research evidence: Low. Findings are predominantly from a single study with a low risk of bias, a large sample size, and a significant dose-response relationship. Other support for gabapentin is from trials of short duration or combination treatments, rather than gabapentin alone.

Data Abstraction: Gabapentin

Studies related to gabapentin are listed in Table B–19.

Studies related to gabapentin

Author and year

Study characteristics

Treatment administered, including study arm, dose (mg/day), sample size (N), and co-intervention

Rx duration, weeks

Sample characteristics, including diagnostic inclusions and major exclusions

Outcome measures, main results, and overall percent attrition

Risk of bias

Mason et al. 2014

Design: DBRCT

Setting: outpatient

Country: United States

Funding: govt, meds

Gabapentin 900 (54); gabapentin 1,800 (47); PBO (49)

Other Tx: manual guided weekly counseling

12

DSM IV alcohol dependence

Mean age: 44.5 years

19% Nonwhite

43% Female

Other Dx: 0%

Gabapentin dose showed linear increases with rate of complete abstinence (P = 0.04), rate of no heavy drinking (P = 0.02), sustained 12-week abstinence (17.0% with NNT = 8 for 1,800 mg/day), and rates of no heavy drinking with PBO (44.7% NNT = 5 for 1,800 mg/day).

Adverse events did not differ among groups, with the predominant side effects of fatigue (23%), insomnia (18%), and headache (14%).

Attrition: 43%

Low

Note. Unless noted elsewhere, subjects were excluded if they had contraindications for specific medications; were pregnant, breastfeeding, or unreliable in using contraception; were receiving psychotropic medications; or had another substance use disorder (except nicotine dependence), other psychiatric conditions, suicidal or homicidal ideas, or significant physical illness (including renal or hepatic disease).

Abbreviations: DBRCT = double-blind, randomized controlled trial; Dx = diagnosis; govt = governmental; meds = medications supplied by pharmaceutical company; NNT = number needed to treat; NR = not reported; PBO = placebo; Tx = treatment.

Studies related to gabapentin

Enlarge table

Recommendations Against Use of Specific Medications

Statement 12: Antidepressants

APA recommends (1B) that antidepressant medications not be used for treatment of alcohol use disorder unless there is evidence of a co-occurring disorder for which an antidepressant is an indicated treatment.

Benefits of Antidepressants

Evidence for this recommendation comes from a number of studies of serotonin reuptake inhibitors and tricyclic antidepressants that assessed alcohol-related outcomes in individuals with alcohol dependence and a depressive or anxiety disorder (Jonas et al. 2014). On the basis of a substantial number of trials that directly assess the efficacy of antidepressant medications in treating AUD, the strength of research evidence is rated as moderate.

The AHRQ review (Jonas et al. 2014) included seven trials comparing placebo with sertraline in doses of 50–200 mg/day and treatment durations of 12–26 weeks. Of the seven studies, five were done in the United States, three included only individuals with major depressive disorder and alcohol dependence, and one included individuals with PTSD and alcohol dependence. Meta-analysis did not show a benefit of sertraline on the alcohol-related outcomes, and for the outcome of percent of heavy drinking days the comparison favored placebo (low strength of research evidence; WMD: 1.85 [0.70 to 3.0]). An additional study (total N = 170) compared placebo with naltrexone alone, sertraline alone, or the combination of naltrexone and sertraline and reported no difference between sertraline and placebo conditions on abstinence rates (Pettinati et al. 2010). The combination of naltrexone plus sertraline showed greater abstinence rates than either treatment alone (p = 0.001) as well as a longer time to relapse to heavy drinking. A subsequent double-blind RCT of sertraline 200 mg/day (N = 32) versus placebo (N = 37) was conducted in individuals with co-occurring PTSD and alcohol dependence (Hien et al. 2015). Treatment in this low-risk-of-bias trial also included 12 sessions of a “Seeking Safety” intervention. At the end of treatment, at 6-month follow-up, and at 12-month follow-up, both sertraline and placebo subjects showed a decreased number of drinks per drinking day, a decrease in heavy drinking days, and an increase in 7-day abstinence rate. PTSD symptoms showed greater improvement with sertraline than placebo, but there was no specific effect of sertraline treatment as compared with placebo on alcohol-related outcomes.

The AHRQ review included two trials (Naranjo et al. 1995; Tiihonen et al. 1996) of 12–13 weeks duration that compared citalopram 40 mg/day with placebo. Both trials were rated as having a high risk of bias, and neither trial showed an effect of citalopram on drinking-related outcomes. A subsequent medium-risk-of-bias 12-week trial of citalopram 40 mg/day (N = 138) versus placebo (N = 127) found worse outcomes with citalopram than placebo in terms of the percentage decrease in the frequency of alcohol consumption (p = 0.016), the percentage decrease in the quantity of alcohol consumed per drinking day (p = 0.025), the average number of heavy drinking days (p = 0.007), drinks per drinking day (p = 0.03), and money spent on alcohol (p = 0.041) (Charney et al. 2015). When individuals with depression were compared with those without depression, the findings in both subgroups were consistent with findings for the overall sample. In another 12-week study in which all subjects (total N = 138) received naltrexone (up to 100 mg/day), there was no significant difference on alcohol use or depression-related outcomes between subjects who were randomly assigned to citalopram (up to 60 mg/day) and those assigned to placebo (Adamson et al. 2015).

The AHRQ review (Jonas et al. 2014) included three U.S. trials lasting 12–15 weeks and comparing placebo with fluoxetine in doses from 20 mg to 60 mg per day (Cornelius et al. 1995; Kabel and Petty 1996; Kranzler et al. 1995). In one of the trials, in which all subjects (N = 51) had major depressive disorder, subjects treated with fluoxetine had fewer drinking days (WMD –11.6; 95% CI –22.7 to –0.5) and fewer heavy drinking days (4.8 versus 16, p = 0.04) than those who received placebo (Cornelius et al. 1995). When the two medium-risk-of-bias trials were combined (Cornelius et al. 1995; Kranzler et al. 1995), meta-analysis found no difference between fluoxetine and placebo in drinking days (WMD –3.2; 95% CI –18.2 to 11.9) or heavy drinking days (WMD –1.2; 95% CI –4.6 to 2.2).

In a single European trial of fluvoxamine 100–300 mg/day as compared with placebo, there was no difference at 12 weeks of treatment or at 52 weeks of follow-up in the percent of subjects who had returned to drinking or the percent who returned to heavy drinking (Chick et al. 2004). At 12 weeks, fluvoxamine-treated patients had more drinking days in the prior month than placebo-treated patients, but the groups did not differ on this outcome at 52 weeks of follow-up.

One randomized trial compared paroxetine (10–60 mg/day, mean dose 45 mg/day) with placebo in individuals with social anxiety disorder, of whom 79% of 42 subjects also had a co-occurring diagnosis of alcohol dependence (Book et al. 2008; Thomas et al. 2008). After 16 weeks (12 weeks at final paroxetine dose), there was no difference in the mean number of drinks per drinking day or the proportion of drinking days or heavy drinking days for paroxetine-treated patients as compared with placebo-treated patients. In an additional high-risk-of-bias trial (Petrakis et al. 2012), paroxetine with and without naltrexone was compared with desipramine with and without naltrexone in subjects with co-occurring alcohol dependence and PTSD. Individuals who received paroxetine had more heavy drinking days (p = 0.009) and drinks per drinking day (p = 0.027) than those who received desipramine. Although all groups showed reductions in PTSD symptoms, combination treatment with naltrexone and an antidepressant was associated with reduced craving as compared with groups treated with antidepressant plus placebo (Petrakis et al. 2012).

Another U.S. study with a medium-risk-of-bias compared desipramine (median dose = 200 mg/day) with placebo. In this trial, 39% also had a diagnosis of depression (Mason et al. 1996). Although 12% of desipramine-treated patients returned to heavy drinking as compared with 32% of placebo-treated patients, this difference was not statistically significant. A medium-risk-of-bias-study of imipramine 50–300 mg/day (mean dose = 262 mg/day) as compared with placebo in individuals with depression and alcohol dependence found no significant difference between imipramine and placebo groups on percent return to any drinking, percent heavy drinking, or number of drinks per drinking day (McGrath et al. 1996).

Grading of the Supporting Body of Research Evidence for Efficacy of Antidepressants

  • Magnitude of effect: None. When differences were present for specific outcomes, the magnitude of the effect is small and the effect favored placebo.

  • Risk of bias: Medium. Studies are RCTs of medium to high bias based on their described randomization and blinding procedures and descriptions of study dropouts.

  • Applicability: The included trials all have a substantial proportion of subjects with AUD, by either prior diagnostic criteria or other evidence of harmful levels of drinking. In most of the studies, subjects also had a co-occurring diagnosis of depression or an anxiety disorder. The studies include subjects from around the world, including North America. The doses of antidepressant medications appear to be representative of outpatient clinical practice.

  • Directness: Direct. Studies measured abstinence and heavy drinking rates as well as measures of alcohol consumption. Most studies also included measures related to symptoms of co-occurring disorders.

  • Consistency: Consistent. Although meta-analysis was not conducted across all studies of antidepressant medications, the main findings of the studies were consistent.

  • Precision: Not able to assess because confidence intervals were not calculated for the majority of the studies.

  • Dose-response relationship: Unclear. Studies typically adjusted medication doses on the basis of clinical response.

  • Confounding factors (including likely direction of effect): Not identified.

  • Publication bias: Not identified.

  • Overall strength of research evidence: Moderate. A number of RCTs have been conducted, most of which had medium to high risk of bias and moderate sample sizes. Many of the RCTs were funded by governmental agencies. Despite the inclusion of different antidepressants of different classes and subjects with different co-occurring conditions, the studies are consistent in showing minimal effect or a slightly detrimental effect of antidepressant medication on alcohol-related outcomes.

Data Abstraction: Antidepressants

Studies related to antidepressants are listed in Table B–20.

Studies related to antidepressants (listed alphabetically by medication name)

Author and year; trial name

Study characteristics

Treatment administered, including study arm, dose (mg/day), sample size (N), and co-intervention

Rx duration, weeks (follow-up)

Sample characteristics, including diagnostic inclusions and major exclusions

Outcome measures, main results, and overall percent attrition

Risk of bias

Charney et al. 2015

Design: DBRCT

Setting: outpatient

Country: Canada

Funding: govt

Citalopram 40 (138); PBO (127)

Other Tx: weekly individual and group psychotherapy

12

DSM-IV alcohol abuse or dependence

Mean age: 45.4 years

% Nonwhite NR

30% Female

Other Dx: depression only 22%; anxiety only 27%; mixed anxiety and depression 38%; personality disorder 42%

Citalopram was associated with worse outcomes than PBO on frequency of alcohol consumption (p = 0.016), quantity of alcohol consumed per drinking day (p = 0.025), average number of heavy drinking days (p = 0.007), drinks per drinking day (p = 0.03), and money spent on alcohol (p = 0.041).

Median survival time to first relapse was not significantly different with treatment in depressed or nondepressed subjects.

Attrition: 47%

Medium

Naranjo et al. 1995

Design: DBRCT

Setting: outpatient research center

Country: Canada

Funding: govt, Lundbeck A/S

Citalopram 40 (53); PBO (46)

Other Tx: brief psychosocial intervention 100%

12 (20)

Mild to moderate alcohol dependence with at least 28 drinks per week

Mean age: 45 years

% Nonwhite NR

44% Female

Other Dx: NR

Both treatment groups showed a significant decrease in alcohol intake (p < 0.001) (35.1% citalopram vs. 38.8% PBO).

Citalopram had a significant initial effect; reduced alcohol intake during the first week of the treatment period by 47.9% from baseline compared with 26.1% (p < 0.01) decrease in the PBO group.

During weeks 2–12, the effects of citalopram and PBO were similar; reductions in alcohol intake were 33.4% and 40.5%, respectively.

Percentage of abstinent days in the citalopram group increased from baseline to 27.3% ± 3.6 (p <  0.001).

The PBO group increased their abstinent days from 7.1% ± 2.3 at baseline to 23.5% ± 3.1 (p <  0.001); drinks per drinking day decreased from baseline for citalopram (from 7.6 ± 0.6 to 5.4 ± 0.4, p < 0.001) and PBO (from 6.4 ± 0.4 to 4.7 ± 0.4, p < 0.001).

Attrition: 37%

High

Tiihonen et al. 1996

Design: DBRCT

Setting: outpatient; community-based alcohol rehabilitation center

Country: Finland

Funding: Lundbeck

Citalopram 40 (31); PBO (31)

Other Tx: supportive psychotherapy intervention 100%

13 (17)

DSM-III-R alcohol dependence

Mean age: 45–47 years

% Nonwhite NR

0% Female

Other Dx: 0%

The citalopram group reported better outcomes than PBO in dropout rates, GGT changes, and the reports of patients and relatives: significant differences in dropout rates (32% vs. 58%, p < 0.05) and in relatives’ reports (26% vs. 7%, p < 0.05).

Attrition: 45%

High

Mason et al. 1996

Design: DBRCT

Setting: psychiatry outpatient departments at 2 urban medical centers

Country: United States

Funding: govt

DMI median 200 (37); PBO (34)

Other Tx: AA and other psychosocial treatments encouraged

26

DSM-III-R alcohol dependence

Mean age: 40 years

38% Nonwhite

17% Female

Other Dx: depression 39%

Kaplan-Meier survival curves showed a significant difference between PBO and DMI in time to relapse (P = 0.03).

There were more relapses on PBO than on DMI among depressed patients (40% vs. 8.3%) and among nondepressed patients (26.6% vs. 14.3%), but the differences were not statistically significant.

Patients who relapsed had more severe alcohol dependence than those who did not (mean ± SD: 24.46 ± 8.8 and 18.7 ± 6.9, respectively)

Attrition: 52%

High

Petrakis et al. 2012

Design: DBRCT

Setting: outpatient; multiple psychiatric centers, primarily VA

Country: United States

Funding: VA

DMI 200 + PBO (24); paroxetine 40 + PBO (20); DMI 200 + NTX 50 (22); paroxetine 40 + NTX 50 (22)

Other Tx: clinical management; compliance enhancement therapy 100%

12

DSM-IV alcohol dependence and PTSD

Exclusions: psychosis

Mean age: 47 years

25% Nonwhite

9% Female

Other Dx: PTSD 100%

Compared with paroxetine, DMI significantly reduced the percentage of heavy drinking days (F1.84 = 7.22, p = 0.009) and drinks per drinking days (F1.84 = 5.04, p = 0.027).

There was a significant interaction for time by DMI/paroxetine treatment on drinks per week (ATS6.82 = 2.46, p = 0.018): DMI subjects had a greater reduction in their drinking over time compared with paroxetine subjects.

NTX, compared with PBO, significantly decreased craving (F1582.0 = 6.39, p = 0.012; NTX = 19.88 [SD = 12.89] and PBO = 21.1 [SD = 12.89] at baseline vs. NTX = 6.7 [SD = 14.07] and PBO = 8.3 [SD = 13.38] at endpoint).

GGT declined more in the DMI-treated participants (F1229.5 = 5.08, p = 0.02; DMI baseline = 55.2, paroxetine baseline = 86.4; DMI week 4 = 48.7, paroxetine week 4 = 46.1; DMI week 8 = 41.7, paroxetine week 8 = 47.1; DMI week 12 = 37.5, paroxetine week 12 = 57.1).

Attrition: 44.3%

High

Cornelius et al. 1995, 1997

Design: DBRCT

Setting: inpatient psychiatric institute

Country: United States

Funding: govt

Fluoxetine 20–40 (25); PBO (26)

Other Tx: usual care: psychotherapy 100%

12

DSM-III-R alcohol dependence and major depression

Mean age: 35 years

53% Nonwhite

49% Female

Other Dx: MDD 100%

Differences between fluoxetine and PBO were drinks per drinking day: –3 (95% CI –5.4, –0.6), percent drinking days: –11.6 (95% CI –22.71, –0.49), and return to any drinking: –0.13 (95% CI –0.35, 0.1).

Fluoxetine produced more improvement in depressive symptoms on the Ham-D but not on the BDI.

Attrition: 10%

Medium

Kabel and Petty 1996

Design: DBRCT

Setting: inpatient substance abuse treatment

Country: United States

Funding: govt

Fluoxetine 20–60 (15); PBO (13)

Other Tx: NR

15

Alcohol dependence

Mean age: 47 years

46% Nonwhite

0% Female

Other Dx: cocaine use 14%; an average of 4 DSM-III-R personality disorders

Difference between fluoxetine and PBO for return to any drinking: 0.16 (95% CI –0.2, 0.51)

Abstinence was maintained at 12 weeks in 53% of fluoxetine subjects and 69% of PBO subjects (p = NSD).

Craving was significantly reduced with fluoxetine vs. PBO.

Attrition: 42%

High

Kranzler et al. 1995

Design: DBRCT

Setting: outpatient

Country: United States

Funding: govt

Fluoxetine 20–60, mean 47 (51); PBO (50)

Other Tx: group psychotherapy 79%; individual psychotherapy 21%

12 (38)

DSM-III-R alcohol dependence

Mean age: 40 years

5% Nonwhite

20% Female

Other Dx: major depression 14%

Difference between fluoxetine and PBO for drinks per drinking day: 0.5 (95% CI –1.61, 2.61), percent drinking days: 3.8 (95% CI –2.08, 9.68).

Survival analysis showed no difference between groups on proportion remaining abstinent.

There were no significant differences in adverse effects except more reports of reduced sexual interest with fluoxetine vs. PBO.

Attrition: 16%

Medium

Chick et al. 2004

Design: DBRCT

Setting: 10 outpatient sites

Country: United Kingdom, Ireland, Austria, Switzerland

Funding: Solvay-Duphar

Fluvoxamine 100–300 (261); PBO (260)

Other Tx: psychosocial treatment

52

DSM-III-R alcohol dependence

Exclusions: not wishing to aim for total abstinence

Mean age: 42 (19–72) years

% Nonwhite NR

35% Female

Other Dx: NR

There was no difference in abstinence at week 52 (fluvoxamine: n = 75, 55% vs. PBO: n = 117, 63%; p = 0.24 by LOCF analysis).

At week 12, the percentage of days not drinking since the last assessment was 69% for fluvoxamine and 77% for PBO (p = 0.009).

The mean dependence severity was more favorable for the PBO group (p = 0.029).

Attrition: 64% noncompleters; 21% lost to follow-up

Medium

McGrath et al. 1996

Design: DBRCT

Setting: university-based depression research clinic

Country: United States

Funding: govt

IMI 50–300; mean 262 (36); PBO (33)

Other Tx: weekly relapse prevention psychotherapy

12

DSM-III-R alcohol dependence or abuse and with major depression, dysthymia, or depressive disorder NOS

Exclusions: history of mania

Mean age: IMI 37 years, PBO 11 yearsa

17%–22% Nonwhite

49%–53% Female

Other Dx: MDD 71%–72%, bipolar 11%– 12%, atypical depression 70%–72%, other substance abuse 16%

CGI response to IMI (52%; 95% CI, 33%–70%) was significantly better than response to PBO (21%; 95% CI, 9%–38%).

Patients receiving IMI were significantly less depressed than patients taking PBO by the Ham-D.

IMI and PBO did not differ in rates of alcohol abstinence in either the last week (44% vs. 22%) or the last 4 weeks (31% vs. 21%) and did not differ in percent of days drinking, percent days of heavy drinking, or standard drinks per drinking day.

Attrition: 23%

Medium

Book et al. 2008; Thomas et al. 2008

Design: DBRCT

Setting: outpatient

Country: United States

Funding: govt, meds

Paroxetine titration over 4 weeks 10–60; average 45 (20); PBO (22)

Other Tx: MM 100%; optional one individual therapy session 67%

16

DSM-IV alcohol use disorder (abuse: 21% and dependence: 79%) and social anxiety disorder, generalized type

Mean age: 28–30 years

0%–18% Nonwhite

45%–50% Female

Other Dx: social anxiety disorder 100%, MDD ~ 10%

Drinking outcomes did not change with paroxetine or PBO.

Liebowitz Social Anxiety Scale scores were improved with paroxetine vs. PBO by week 7 through week 16.

Attrition: 37%

Medium

Brady et al. 2005

Design: DBRCT

Setting: outpatient

Country: United States

Funding: meds

SERT 150 (49); PBO (45)

Other Tx: CBT 100%

12

DSM-IV alcohol dependence and current PTSD in response to civilian trauma

Mean age: 37 years

% Nonwhite NR

43%–49% Female

Other Dx: PTSD 100%, depressive disorder 51%, anxiety disorder 38%

Differences between SERT and PBO were percent heavy drinking days: 1.8 (95% CI 0.65, 2.95) and drinks per drinking day: 0.5 (95% CI –2.42, 3.42).

No side-effect differences were reported between groups.

Attrition: 34%

Medium

Coskunol et al. 2002

Design: DBRCT

Setting: inpatient (mean 1 month) followed by 6 months outpatient; substance abuse treatment unit

Country: Turkey

Funding: Pfizer

SERT 100 (30); PBO (29)

Other Tx: thiamine 500 mg/day 100%; pyridoxine 500 mg/day 100%; AA during inpatient 100%

26

DSM-III-R alcohol dependence

Mean age: 44 years

% Nonwhite NR

0% Female

Other Dx: 0%

Difference between SERT and PBO for return to heavy drinking: –0.19 (95% CI –0.44, 0.06).

Relapse rates at 6 months were 50% SERT and 69% PBO.

Attrition: 5%

Medium

Gual et al. 2003

Design: DBRCT

Setting: 1 outpatient site

Country: Spain

Funding: NR

SERT 50–150 (44); PBO (39)

Other Tx: NR

24

DSM-IV and ICD-10 criteria for alcohol dependence and for major depression or dysthymia or both

Mean age: 47 years

% Nonwhite NR

47% Female

Other Dx: depression/dysthymia 100%

Differences between SERT and PBO were percent drinking days: 0.6 (95% CI –46.17, 47.37) and return to heavy drinking: 0.09 (95% CI –0.1, 0.28).

Rates of adverse effects did not differ between the groups.

Attrition: 45%

Medium

Hien et al. 2015

Design: DBRCT

Setting: outpatient

Country: United States

Funding: govt

SERT 200 (32); PBO (37)

Other Tx: “Seeking Safety” 12 sessions

12 (12)

DSM-IV-TR alcohol dependence or alcohol abuse with 2 heavy drinking days in past 90 days; additional inclusion criteria based on consumption patterns

Co-occurring DSM-IV-TR PTSD

Mean age: 42.2 years

59% Nonwhite

81% Female

Other Dx: PTSD or subthreshold PTSD 100%; other SUD 55%

Decreased number of drinks per drinking day, a decrease in heavy drinking days, and an increase in 7-day abstinence rate in both groups; no effect of SERT

Seeking safety plus SERT led to greater reduction in PTSD symptoms than seeking safety plus PBO (79% vs. 48%).

Attrition: 42%

Low

Kranzler et al. 2011, 2012b

Design: DBRCT

Setting: outpatient; university health center

Country: United States

Funding: govt, meds

SERT 50–200 (63); PBO (71)

Other Tx: coping skills training 100%

12 (26)

DSM-IV alcohol dependence

Mean age: 48 years

8% Nonwhite

19% Female

Other Dx: cannabis use disorder 17%; cocaine use disorder 19%; past MDD 21%

Differences between SERT and PBO were percent heavy drinking days: 6.6 (95% CI –4.63, 17.83) and percent drinking days: 3.8 (95% CI –7.95, 15.55).

Attrition: 38%

Medium

Moak et al. 2003

Design: DBRCT

Setting: 1 outpatient site

Country: United States

Funding: govt, meds

SERT 50–200 (38); PBO (44)

Other Tx: CBT

12

Mild to moderate alcohol dependence or alcohol abuse and DSM-III-R major depressive episode or dysthymic disorder

Exclusions: bipolar affective or psychotic disorder; treatment-resistant depression

Mean age: 41 years

1% Nonwhite

39% Female

Other Dx: depression/dysthymia 100%

Differences between SERT and PBO were percent drinking days: 0 (95% CI –11.39, 11.39) and drinks per drinking day: –1.2 (95% CI –2.56, 0.16).

Kaplan-Meier survival analysis showed no difference in time to first heavy drinking day.

Attrition: 41%

Medium

O’Malley et al. 2008

Design: DBRCT

Setting: Alaskan outpatient site

Country: United States

Funding: govt, meds

NTX 50 (34); PBO (34); NTX 50 + SERT 100 (33)

Other Tx: MM 100%

16

DSM-IV alcohol dependence

Mean age: 40 years

70% Nonwhite

34% Female

Other Dx: NR

There was a statistically significant advantage of NTX over PBO but no additional benefit from the addition of SERT to NTX on total abstinence (NTX vs. PBO, p = 0.04; NTX vs. NTX+ SERT, p = 0.56) or the percentage who reported a drinking-related problem during treatment (NTX vs. PBO, p = 0.04; NTX vs. NTX+ SERT, p = 0.85).

Time to first heavy drinking day was longer but not significantly greater for NTX compared with PBO (NTX vs. PBO, p = 0.14; NTX vs. NTX+ SERT, p = 0.84).

Treatment efficacy was not dependent on the presence of an Asn40 allele.

Attrition: 33%

Medium

Pettinati et al. 2001

Design: DBRCT

Setting: outpatient

Country: United States

Funding: govt, meds

SERT 200 (50); PBO (50)

Other Tx: 12-step facilitation

14

DSM-III-R alcohol dependence

Mean age: 44 years

80% Nonwhite

48% Female

Other Dx: depression 47%

Difference between SERT and PBO for percent drinking days: –1.27 (95% CI –11.59, 9.05).

Sexual disturbance, headache, and fatigue were more common with SERT vs. PBO.

Survival analysis showed time to relapse was longer with SERT vs. PBO and was more prominent in those without a history of MDD.

Attrition: 42%

Medium

Pettinati et al. 2010

Design: DBRCT

Setting: outpatient

Country: United States

Funding: govt, meds

SERT 200 (40); NTX 100 (49); PBO (39); SERT 200 + NTX 100 (42)

Other Tx: CBT 100%

14

DSM-IV alcohol dependence and major depression

Mean age: 43 years

35% Nonwhite

38% Female

Other Dx: depression 100%

SERT vs. PBO total abstinence: 27.5% abstinent vs. 23.1%.

Time (days) to relapse to heavy drinking: median 23 vs. 26; mean 39.9 vs. 41.7.

SERT+ NTX was associated with a higher rate of abstinence and longer time to heavy drinking relapse than PBO or either drug alone.

Rates of adverse effects were not significantly different among groups.

Attrition: 43%

Medium

Note.  Unless noted elsewhere, subjects were excluded if they had contraindications for specific medications; were pregnant, breastfeeding, or unreliable in using contraception; were receiving psychotropic medications; or had another substance use disorder (except nicotine dependence), other psychiatric conditions, suicidal or homicidal ideas, or significant physical illness (including renal or hepatic disease). Industry-sponsored studies list the name of the pharmaceutical company.

aThe study reported 11 years, but it was clearly a reporting error; likely 31 or 41 years.

Abbreviations: AA = Alcoholics Anonymous; ATS = ANOVA-type statistic; BDI = Beck Depression Inventory; CBT = cognitive-behavioral therapy; CGI = Clinical Global Impression Scale; DBRCT = double-blind, randomized controlled trial; DMI = desipramine; Dx = diagnosis; GGT =  gamma-glutamyl transferase; govt = governmental; Ham-D = Hamilton Rating Scale for Depression; IMI = imipramine; LOCF = last observation carried forward; MDD = major depressive disorder; meds = medications supplied by pharmaceutical company; MM = medical management; NOS = not otherwise specified; NR = not reported; NSD = no significant difference; NTX = naltrexone; PBO = placebo; PTSD = posttraumatic stress disorder; SD = standard deviation; SERT = sertraline; Tx = treatment; VA = U.S. Department of Veterans Affairs

Studies related to antidepressants (listed alphabetically by medication name)

Enlarge table

Statement 13: Benzodiazepines

APA recommends (1C) that in individuals with alcohol use disorder, benzodiazepines not be used unless treating acute alcohol withdrawal or unless a co-occurring disorder exists for which a benzodiazepine is an indicated treatment.

Evidence for this recommendation is indirect and is based primarily on expert opinion. Consequently, the strength of research evidence is rated as low. The systematic review of the literature did not yield any references that dealt directly with the use of a benzodiazepine to treat AUD, except in the context of alcohol withdrawal or alcohol detoxification. A Cochrane review of pharmacotherapy for co-occurring AUD and anxiety disorders also did not find any randomized trials of benzodiazepines for anxiety disorders in this population, although studies of naltrexone, acamprosate, and disulfiram were excluded from the review (Ipser et al. 2015). One small open-label study (Bogenschutz et al. 2016) assessed use of lorazepam in combination with disulfiram and manual-based MM in individuals with DSM-IV alcohol dependence and symptoms of anxiety. Subjects had reductions in anxiety, depression, and craving and had no signs of misuse or dose escalations for lorazepam, but two-thirds of the 41 subjects were no longer adherent to treatment at 16 weeks.

Statement 14: Pharmacotherapy in Pregnant or Breastfeeding Women

APA recommends (1C) that for pregnant or breastfeeding women with alcohol use disorder, pharmacological treatments not be used unless treating acute alcohol withdrawal with benzodiazepines or unless a co-occurring disorder exists that warrants pharmacological treatment.

Evidence for this recommendation is indirect and is based on data from case reports, registries, case control studies of birth outcomes, and, in some instances, animal studies of teratogenicity and neurodevelopmental effects of medication exposure during pregnancy. Consequently, the strength of research evidence is rated as low. Additional evidence that was considered in making this recommendation was the relatively small effect sizes of these medications for treatment of AUD as discussed with Statements 9, 10, and 11.

Data in pregnant animals suggest a moderate risk for use of naltrexone, high risk for use of acamprosate, and possible risks for use of gabapentin and topiramate (Briggs and Freeman 2015). For disulfiram, Briggs and colleagues (Briggs and Freeman 2015) noted that there are no animal data available. Data for the use of these medications in pregnant women is limited (Briggs and Freeman 2015); however, an increased risk of malformation does appear to be associated with use of topiramate (Alsaad et al. 2015; Briggs and Freeman 2015; Tennis et al. 2015; Weston et al. 2016) but not gabapentin (Weston et al. 2016). No clustering of birth defects has been seen when disulfiram is taken by pregnant women, but samples have been small (Briggs and Freeman 2015).

Little data are available on the use of these medications in breastfeeding women, but there may be potential for toxicity with disulfiram and naltrexone (Briggs and Freeman 2015; Sachs and Committee on Drugs 2013) as well as topiramate (Briggs and Freeman 2015), whereas acamprosate and gabapentin are noted to be “probably compatible” (Briggs and Freeman 2015) with breastfeeding.

Statement 15: Acamprosate in Severe Renal Impairment

APA recommends (1C) that acamprosate not be used by patients who have severe renal impairment.

Evidence for this statement comes from a pharmacokinetic study (Sennesael 1992), which shows increases in terminal elimination half-life and peak plasma concentration with decreases in renal clearance of drug from plasma after a single dose of 666 mg of acamprosate. Individuals with moderate (CrCl of 1.8–3.6 L/h/1.73 m2) or severe (CrCl of 0.3–1.74 L/h/1.73 m2) renal impairment had a mean terminal elimination half-life of 33.4 hours and 46.6 hours, respectively, as compared with 18.2 hours for healthy volunteers (with CrCl of > 4.5 L/h/1.73 m2). Peak plasma concentrations were 198 mcg/L for healthy volunteers, as compared with 398 mcg/L and 813 mcg/L for individuals with moderate or severe renal impairment, respectively. On the basis of the significant curvilinear relationship between renal impairment and pharmacokinetic properties, the overall strength of research evidence was viewed as low.

Statement 16: Acamprosate in Mild to Moderate Renal Impairment

APA recommends (1C) that for individuals with mild to moderate renal impairment, acamprosate not be used as a first-line treatment and, if used, the dose of acamprosate be reduced compared with recommended doses in individuals with normal renal function.

Evidence for this statement also comes from a pharmacokinetic study (Sennesael 1992), as described in Statement 15 above. Evidence for reducing the dose of acamprosate, if it is used, comes from basic principles of pharmacokinetics.

Statement 17: Naltrexone in Acute Hepatitis or Hepatic Failure

APA recommends (1C) that naltrexone not be used by patients who have acute hepatitis or hepatic failure.

Evidence for this recommendation is indirect. Direct data are not available for the conditions specified in this recommendation (i.e., acute hepatitis, hepatic failure) because individuals with these conditions were excluded from clinical trials. Consequently, the strength of research evidence is rated as low. In early studies of other conditions (e.g., obesity, dementia), some patients had severalfold elevations in hepatic transaminase levels with naltrexone treatment (Knopman and Hartman 1986; Malcolm et al. 1985; Mitchell et al. 1987; Pfohl et al. 1986; Verebey and Mulé 1986). The FDA initially included a black box warning on the package labeling discussing potential hepatotoxicity and recommending that naltrexone not be used in individuals with acute hepatitis or hepatic failure. However, subsequent studies suggested that elevations of hepatic enzymes in individuals treated with naltrexone occurred at about the same frequency as in individuals treated with placebo (Brewer and Wong 2004; Lucey et al. 2008; Vagenas et al. 2014; Yen et al. 2006). In addition, a small study suggested that hepatic enzymes did not change and that reducing the dose of naltrexone was not needed in individuals with mild to moderate hepatic impairment (Turncliff et al. 2005). Consequently, the FDA removed the black box warning (Stoddard and Zummo 2015), although the potential for adverse hepatic effects continues to be noted in the package labeling for naltrexone.

Statement 18: Naltrexone With Concomitant Opioid Use

APA recommends (1C) that naltrexone not be used as a treatment for alcohol use disorder by individuals who use opioids or who have an anticipated need for opioids.

Evidence for this recommendation is indirect, and consequently, the strength of research evidence is rated as low. Multiple studies have used opioid antagonists to hasten opioid discontinuation in individuals with opioid use disorder (Gowing et al. 2009, 2010). Although opioid antagonist administration was reliable in producing opioid withdrawal, the extent of any benefit was unclear, and potential for complications was noted (Gowing et al. 2009, 2010). These findings suggest that naltrexone not be given to individuals who are currently using opioids unless there is a clinically appropriate period of opioid abstinence before naltrexone initiation. Expert opinion is consistent with this recommendation. Clinical experience also suggests a need for adjustment to typical regimens for pain management in individuals who are receiving naltrexone (R. Chou et al. 2016; Vickers and Jolly 2006) because of the effects of naltrexone in blocking opioid receptors.

Treatment of Alcohol Use Disorder and Co-occurring Opioid Use Disorder

Statement 19: Naltrexone for Co-occurring Opioid Use Disorder

APA recommends (1C) that in patients with alcohol use disorder and co-occurring opioid use disorder, naltrexone be prescribed to individuals who

  • wish to abstain from opioid use and either abstain from or reduce alcohol use and

  • are able to abstain from opioid use for a clinically appropriate time prior to naltrexone initiation.

Evidence for this statement is primarily indirect from research findings of naltrexone efficacy in AUD (see Statement 9) and separate studies of naltrexone in individuals with opioid use disorder. Consequently, the strength of research evidence is rated as low. Efficacy has been reported in several studies of long-acting injectable or implanted naltrexone (Krupitsky et al. 2011, 2012, 2013; Larney et al. 2014; Sullivan et al. 2015; Syed and Keating 2013; Timko et al. 2016), with minimal responses to oral naltrexone (Minozzi et al. 2011), likely related to high percentages of attrition.

One double-blind, placebo-controlled trial (Mannelli et al. 2011) randomly assigned individuals with opioid dependence who were undergoing a methadone taper to very low dose naltrexone (0.125 or 0.250 mg/day). Of the subjects, 79 of 174 also had problem drinking, and this group had reduced withdrawal symptoms, less treatment discontinuation, and less resumption of alcohol use after treatment as compared with those who received placebo. However, the relevance of this study to the guideline statement is limited by the use of low-dose naltrexone and the short duration of the trial in the context of methadone tapering.

In a nonblinded trial, persons infected with HIV with AUD and/or opioid use disorder were randomly assigned to treatment as usual or to extended-release naltrexone (Korthuis et al. 2017). Of 35 subjects with AUD, 8 also had opioid use disorder. Only two-thirds of those assigned to extended-release naltrexone initiated treatment, but of those who did initiate treatment, the medication was well tolerated, and rates of treatment retention were greater than in subjects who received treatment as usual. Given the fact that the study had a small sample and was limited to individuals infected with HIV, the relevance to other individuals with co-occurring AUD and opioid use disorder is unclear.