Reference: Anton RF, Moak DH, Latham P, Waid LR, Myrick H, Voronin K, et al. Naltrexone combined with either cognitive behavioral or motivational enhancement therapy for alcohol dependence. Journal of Clinical Psychopharmacology. 2005;25(4):349–357. [PubMed: 16012278]

Purpose: Compare the effectiveness of naltrexone and placebo when specifically combined with either cognitive-behavioral therapy (CBT) or motivational enhancement therapy (MET) in outpatients with alcoholism.

Conclusions: Naltrexone was superior to placebo in reducing relapse and craving, especially when combined with CBT.

Methodology: Outpatients who had maintained abstinence before study enrollment and met the study inclusion/exclusion criteria were given a baseline assessment over a 5–10-day period. Study participants were randomly assigned to one of four study groups: CBT plus placebo, CBT plus naltrexone, MET plus placebo, and MET plus naltrexone. Participants in the CBT groups had therapy weekly for 12 weeks, whereas those in the MET groups met 4 times in 12 weeks.

Summary of Results: A total of 160 outpatients were randomized into 1 of 4 study groups. Compliance, study retention, and characteristics of study participants were similar across the study groups. Fewer patients relapsed (38 percent) in the CBT/naltrexone group than in the other groups (p < 0.05). The percentage of days abstinent was highest in the CBT/naltrexone group (91 percent vs. 79 percent in the CBT-only group [p < 0.05]). Naltrexone, independent of therapy group, slowed the time to the first relapse (p = 0.05), and the time to successive relapses was significantly prolonged for the CBT/naltrexone group (p = 0.02 for third relapse and p = 0.01 for fourth relapse). The obsession factor decreased more in subjects treated with naltrexone (F_1,146 = 3.95, p = 0.049). Gamma glutamyl transpeptidase decreased significantly more in subjects treated with naltrexone (F_2,149 = 10.41, p < 0.0001).

Reference: Anton RF, O’Malley SS, Ciraulo DA, Cisler RA, Couper D, Donovan DM, et al. COMBINE Study Research Group. Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence: The COMBINE study, A randomized controlled trial. JAMA. 2006;295(17):2003–2017. [PubMed: 16670409]

Purpose: Study whether medications for alcohol are effective without specialist intervention and whether combining different medications improves efficacy.

Conclusions: Patients receiving medical management had better outcomes with either combined behavioral intervention (CBI) or naltrexone. Acamprosate was ineffective with or without CBI. The combined use of naltrexone and acamprosate was not more effective than naltrexone or CBI alone.

Methodology: Random assignment of 1,383 study participants into 9 study groups for 16 weeks of outpatient treatment occurred after a baseline assessment and abstinence for at least 4 days. Eight study groups received medical management and, of these, four received CBI and four did not. Within each grouping of four, one received placebo, one naltrexone, one acamprosate, and one naltrexone and acamprosate combined. The ninth study group received CBI alone without pills or medical management.

Summary of Results: Adverse events such as nausea (p < 0.001), vomiting (p < 0.001), diarrhea (p < 0.001), decreased appetite (p = 0.002), and somnolence (p = 0.003) differed significantly, with higher percentages in the combined medication groups. Internal study validity was high, and all groups showed substantial reduction in drinking. For percentage of days abstinent through end of treatment, none of the main effects of acamprosate, naltrexone, and CBI were significant; however, the two-factor interaction was significant (naltrexone/no CBI [80.6] vs. placebo/no CBI [75.1] [p = 0.009]). For percentage of participants with 1 or more heavy drinking days during treatment, only the main effect of naltrexone versus placebo was significant (68.2 percent vs. 71.4 percent, p = 0.02).

Reference: Anton RF, Swift RM. Current pharmacotherapies of alcoholism: A U.S. perspective. American Journal on Addictions. 2003;12(Suppl 1):S53–S68. [PubMed: 14972780]

Purpose: Review current knowledge about the newest medications being used to reduce alcohol consumption and craving and prevent relapse in patients in the United States.

Conclusions: Medications should be used as part of a comprehensive treatment plan that addresses the psychological, social, and spiritual needs of the patient.

Methodology: Eleven naltrexone studies were reviewed. Several studies were reviewed for all other medications.

Summary of Results: Craving is likely to have a neuroanatomical basis; the effects of medications on craving are varied. Disulfiram has limited acceptance and may be most effective among older, motivated individuals who receive supervised medication administration. Naltrexone has been shown to reduce relapse and heavy drinking and modestly increase abstinence; it may work best with relapse prevention therapy. Enhancing adherence is key to the use of medications. A naltrexone monthly injection has been developed to increase adherence. Acamprosate is well tolerated and has been shown to reduce relapse and increase days of abstinence. Patients taking selective serotonin reuptake inhibitors report a decreased desire and liking for alcohol. People with Type A alcoholism (later onset and less severe dependence) appeared to benefit from fluoxetine compared with placebo. Low doses of ondansetron moderately reduced alcohol consumption in males who are alcohol dependent. Lithium has not been shown to reduce drinking. Carbamazine has been reported to reduce alcohol withdrawal and may reduce rebound drinking. Multiple medications administered together or in sequence may be required to obtain optimal treatment effectiveness. Medications must be cost effective to be used in alcoholism treatment programs.

Reference: Boothby LA, Doering PL. Acamprosate for the treatment of alcohol dependence. Clinical Therapeutics: International Peer-Reviewed Journal of Drug Therapy. 2005;27(6):695–714. [PubMed: 16117977]

Purpose: Review the existing data on the pharmacokinetics and efficacy of acamprosate.

Conclusions: Evidence shows moderate efficacy of acamprosate. The combination of acamprosate, naltrexone, and psychosocial treatment has superior efficacy.

Methodology: The study reviewed articles from 1966 to 2005 in MEDLINE, International Pharmaceutical Abstracts, Current Contents, Cumulative Index to Nursing, and Allied Health Literature.

Summary of Results: Thirty-two articles were reviewed. According to the evidence, acamprosate is an analog of taurine and gamma-aminobutyric acid (GABA); it acts on GABA and glutaminergic receptors in the nucleus accumbens; and it suppresses the excitatory neurochemical process that occurs with chronic alcohol use. The percentage of treatment subjects who achieved abstinence ranged from 18 to 61.

Reference: Bouza C, Magro A, Muñoz A, Amate JM. Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: A systematic review. Addiction. 2004;99:811–828. [PubMed: 15200577]

Purpose: Determine the efficacy and safety of naltrexone and acamprosate in treating alcohol dependence.

Conclusions: Acamprosate appears to fit well within a classic therapeutic framework with a goal of abstinence, whereas naltrexone seems more useful when the goal is controlled consumption. Both drugs appear to be safe.

Methodology: This study was a literature review of 33 studies that measured relapse and abstinence rates. All studies were published, randomized, controlled clinical trials, comparing naltrexone or acamprosate with a placebo or control group. All studies were on adults who were alcohol dependent. The review included studies in which the analysis and data presented were comparable with one another.

Summary of Results: The acamprosate-versus-placebo trials included 4,000 subjects who were alcohol dependent who had undergone detoxification. As shown on the seven studies that supplied data, acamprosate doubled the cumulative days of abstinence. Naltrexone studies included 3,205 participants. These studies showed a favorable effect on time to relapse, percentage of drinking days, number of drinks per drinking day, days of abstinence, and total consumption of alcohol during treatment.

Reference: Brewer C, Meyers RJ, Johnsen J. Does disulfiram help to prevent relapse in alcohol abuse? CNS Drugs. 2000;14(5):329–341.

Purpose: Review published clinical studies in which disulfiram administration was supervised to assess whether disulfiram successfully prevents relapse to alcohol abuse.

Conclusions: All but one of the controlled studies reviewed demonstrated positive outcomes from supervised disulfiram administration to prevent relapse to alcohol abuse. Patients who benefit the most from supervised disulfiram therapy are those who have a history of repeated nonpharmacological treatment failure, who have numerous drinking triggers, and who face serious consequences if they relapse.

Methodology: MEDLINE was searched for all studies between 1966 and 1999 in which disulfiram administration was directly supervised at least weekly. Thirteen controlled and five uncontrolled studies were reviewed and summarized.

Summary of Results: Supervised disulfiram use is more effective in preventing relapse to alcohol abuse than unsupervised use. In several studies, the supervised group experienced reduced drinking, prolonged remissions, reduced absenteeism at work, improved treatment retention, and improved compliance with other therapy. A few studies compared supervised disulfiram with acamprosate or naltrexone. The effectiveness of acamprosate was increased in one study by combining it with supervised disulfiram. In another study, the disulfiram group did significantly better on all measures of both cocaine and alcohol use than did the naltrexone group. Disulfiram has a deterrent effect because of the disulfiram–alcohol reaction; patients surrender control over their urge to drink by taking the medication. Administration can be monitored by a spouse, family member, employer, partner, landlord, health professional, therapist, or probation officer. Failure of compliance is detected by the monitor and reported quickly to a health professional who can intervene before the patient resumes drinking. Supervised disulfiram therapy should continue for at least 6 months.

Reference: Buonopane A, Petrakis IL. Pharmacotherapy of alcohol use disorders. Substance Use & Misuse. 2005;40:2001–2020. [PubMed: 16282090]

Purpose: Provide an overview of the literature on the epidemiology, gender, and psychiatric comorbidity of alcohol use disorders; issues in neurobiology; and future treatment directions for alcohol pharmacotherapy.

Conclusions: Alcohol pharmacotherapy research has resulted in new pharmacological interventions; however, barriers still exist to their use. More research and clinical guidelines are needed to identify subgroups of patients who may benefit from the use of specific medications or combinations of different treatments acting on different neurotransmitters.

Methodology: Medications used clinically for the treatment of alcoholism are reviewed in detail. These include disulfiram, naltrexone, acamprosate, and serotonergic agents.

Summary of Results: The epidemiology of alcoholism in the United States reveals that almost 14 percent of Americans have alcohol use-related problems in their lifetimes. Women have higher rates of alcohol-related morbidity and mortality despite ingesting smaller daily amounts of alcohol. All patients, but especially women with alcohol use disorders, have high rates of comorbid psychiatric or mood disorders. An overview is given of the effect of alcohol on a variety of neurotransmitters such as dopamine, glutamate, gamma-aminobutyric acid, β-endorphin, serotonin, cannabinoids, and neuropeptides. Medications that interact with these neurotransmitters are reviewed. Of these medications, naltrexone, acamprosate, and serotonergic agents are reviewed in detail. Future directions for treating alcohol dependence include the use of anticonvulsants and the opioid antagonist nalmefene, which is less hepatotoxic than naltrexone. Future research may indicate that the use of combinations of medications rather than the use of a single medication may achieve better results with alcoholism treatment.

Reference: Chick J. Safety issues concerning the use of disulfiram in treating alcohol dependence. Drug Safety. 1999;20(5):427–435. [PubMed: 10348093]

Purpose: Review the literature on the safety of disulfiram when used to treat alcohol dependence.

Conclusions: Although disulfiram may cause hepatotoxicity, fatal hepatitis is a rare consequence of disulfiram use. Occasional, dose-related cases of psychosis and confusional states, peripheral neuropathy, and optic neuritis have been reported. Medical supervision of patients taking disulfiram should be at least monthly for the first 6 months and continue throughout the course of drug therapy.

Methodology: The literature on the safety of disulfiram was reviewed by searching MEDLINE and the Adis International database from 1966 to 1998. A manual search was conducted of the Quarterly Journal of Studies on Alcohol, British Medical Journal, and Journal of the American Medical Association from 1950 to 1966. All studies were included, although many reported on individual cases.

Summary of Results: Disulfiram may cause hepatotoxicity at the recommended dosage level of 250 mg/day and may rarely cause fatal hepatitis. The risk of fatal hepatitis caused by disulfiram has been estimated at 1 in 30,000 patients per year and may be more likely when disulfiram is continued after jaundice develops. Because the onset of hepatitis is rapid, frequent monitoring of liver function tests may not detect it. An occasional confusional state (beginning with fatigue and forgetfulness) or psychosis was reported particularly with the use of high doses (500 mg/day or more) of disulfiram. Neuropathy is a rare and reversible event, peaking 1 year after starting treatment. Common but less serious adverse effects include tiredness, headache, sleepiness, and an unpleasant “garlic-like” breath odor. Patients and their families should be advised of possible adverse effects of disulfiram.

Reference: Chick J, Gough K, Falkowski W, Kershaw P, Hore B, Mehta B, et al. Disulfiram treatment of alcoholism. British Journal of Psychiatry. 1992;161:84–89. [PubMed: 1638335]

Purpose: Assess the efficacy of disulfiram in outpatient treatment of alcohol dependence.

Conclusions: Disulfiram improves treatment outcomes for people with alcohol dependence in outpatient treatment.

Methodology: This randomized, partially blind clinical trial enrolled 126 patients who had relapsed after previous treatment and were attending treatment at an outpatient alcoholism clinic. Exclusion criteria were pregnancy; cardiac disease; psychosis; habitual drug abuse; and high levels of serum bilirubin, aspartate aminotransferase, or alanine aminotransferase. Subjects were randomized to either a 200 mg tablet of disulfiram or 100 mg of vitamin C for 6 months. Outcome measures were blood tests, medical and psychiatric history, compliance (monitored by self-report, the clinician, and an informant), alcohol consumption, alcohol dependence (using the Severity of Alcohol Dependence Questionnaire), and alcohol-related health and social problems.

Summary of Results: Subjects were mostly unemployed males. The mean age was 43. Change in weekly consumption before and after treatment was significant, according to patient (M = 44, 95 percent CI = 14−79, P < 0.01) and assessor (M = 31, 95 percent CI = 6−63, P ≤ 0.05) measures. Change in amount consumed in the past 6 months was also significant, comparing pretreatment and posttreatment, according to patient (M = −1702, 95 percent CI = −2016 to −290, P < 0.01), informant (M = −1636, 95 percent CI = −2052 to −238, P 0.05), and assessor (M = −1124, 95 percent CI = −1620 to −84, P≤0.05) measures. There were no treatment differences at month 5 in amount of days since last drink (7.77 days for disulfiram vs. 3.65 days for vitamin C). Alcohol dependence scores fell from pretreatment to posttreatment for patients in both groups (disulfiram mean change with treatment: −8.3, SD = 15.8 vs. vitamin C mean change with treatment: −10.8, SD = 16.9). Alcohol-related problems were not significantly different between the treatment and control groups (P = 0.06).

Reference: Chick J, Lehert P, Landron F. Plinius Maior Society. Does acamprosate improve reduction of drinking as well as aiding abstinence? Journal of Psychopharmacology. 2003;17(4):397–402. [PubMed: 14870951]

Purpose: Determine the impact of acamprosate on patients in abstinence-oriented treatment who relapse.

Conclusions: Acamprosate helps control the drinking of patients in abstinence-oriented treatment who relapse.

Methodology: Secondary data were analyzed from 15 placebo-controlled clinical trials on acamprosate for patients in abstinence-oriented treatment. Outcomes were median drinks per drinking day (quantity) and per week (frequency). Total consumption was calculated using the values for quantity and frequency.

Summary of Results: Patients using acamprosate had lower quantities, lower frequencies, and less consumption than patients receiving placebo. This was true for four different treatment periods: 30 days (P = 0.006, 0.101, < 0.001), 90 days (P = 0.005, 0.027, 0.001), 180 days (P = 0.004, 0.005, < 0.001), and 360 days (0.074, 0.245, < 0.001).

Reference: De Sousa A, De Sousa A. A one-year pragmatic trial of naltrexone vs. disulfiram in the treatment of alcohol dependence. Alcohol & Alcoholism. 2004;39(6):528–531. [PubMed: 15525790]

Purpose: Compare effectiveness of naltrexone and disulfiram in treating alcohol dependence.

Conclusions: Disulfiram appears to control drinking more effectively.

Methodology: The study included 100 men who were alcohol dependent (per DSM-IV) from stable family environments. Family members agreed to support and monitor compliance. Subjects with other substance dependence (other than nicotine) or comorbid psychiatric disorder were excluded. Subjects were told that relapse or noncompliance would result in exclusion from the trial. Subjects received a daily dose of either naltrexone or disulfiram. Subjects knew which group they were in and were told what to expect from their treatment. They were seen weekly for 3 months, then every other week until the end of 1 year. Cumulative days of abstinence, days to first relapse, drinks per week, drinks per occasion, craving measures, and serum gamma glutamyl transpeptidase (GGT) were measured regularly. Chi-squared test and t-test were used in statistical analysis.

Summary of Results: Time to first relapse was greater for disulfiram than for naltrexone: relapse occurred at a mean of 119 days with disulfiram and 63 with naltrexone (p = 0.02). Fourteen percent of the disulfiram group relapsed, compared with 56 percent of the naltrexone group (p = 0.0009). Twice as many disulfiram patients remained abstinent as naltrexone patients. Naltrexone patients had lower craving levels. Mean serum GGT was 117 U/I with naltrexone and 85 U/I with disulfiram (p = 0.038).

Reference: De Witte P, Littleton J, Parot P, Koob G. Neuroprotective and abstinence-promoting effects of acamprosate. CNS Drugs. 2005;19(6):517–537. [PubMed: 15963001]

Purpose: Evaluate multiple lines of recent (since 2000) evidence on the effects of acamprosate on the glutamatergic system, revealing the underlying biology of alcohol dependence and the abstinence-promoting benefit of acamprosate.

Conclusions: There is strong evidence that acamprosate has a normalizing effect on glutamatergic hyperactivity.

Methodology: An extensive literature review was conducted on excitatory amino acid receptors; excitatory amino acids in alcohol withdrawal; excitatory amino acids in alcohol dependence; excitatory amino acids and the neurotoxicity of ethanol; and excitatory amino acid, ethanol, and acamprosate in humans. References list 121 sources.

Summary of Results: Extrapolating from review findings on the role of the glutamatergic system in alcohol dependence and the effect of acamprosate on the glutamatergic system, the authors conclude that acamprosate should reduce craving and reduce the quantity and severity of relapses caused by dysphoria. Cues for alcohol consumption that contribute to alcohol dependence may be extinguished or prevented by acamprosate. Acamprosate’s action of inhibiting glutamatergic transmission is likely to ease the severity of withdrawal syndrome. Finally, acamprosate is likely to protect against neuronal loss during withdrawal and rehabilitation.

Reference: Dunbar JL, Turncliff RZ, Dong Q, Silverman BL, Ehrich EW, Lasseter KC. Single- and multiple-dose pharmacokinetics of long-acting injectable naltrexone. Alcoholism: Clinical and Experimental Research. 2006;30(3):480–490. [PubMed: 16499489]

Purpose: Evaluate the pharmacokinetics and tolerability of long-acting naltrexone in a sample of healthy people.

Conclusions: Long-acting naltrexone, in single and multiple doses, had adequate pharmacokinetics and was well tolerated among healthy subjects.

Methodology: This single-center, randomized, double-blind, parallel-group study (two panels) enrolled healthy, nonsmoking men and women ages 18–50. Exclusion criteria included a history of alcohol or opioid dependence or both, potential for use of narcotic analgesia during the study, and women who tested positive for pregnancy. One group received a 50 mg dose of oral naltrexone and, after a 7-day intermission, a 190 mg (n = 12) or 380 mg (n = 12) injection of long-acting naltrexone or placebo (n = 4). A second group received a daily 50 mg dose of oral naltrexone for 5 days and, after a 7-day intermission, one 380 mg (n = 12) injection of long-acting naltrexone or placebo (n = 2) per week for 4 weeks. Blood samples were obtained and analyzed for naltrexone and the metabolite 6-β-naltrexol. Outcomes for pharmacokinetics were dose proportionality, time dependency, accumulation, and achievement of a steady state. Outcomes for tolerability were reported to the investigator, who evaluated their intensity.

Summary of Results: Twenty-one subjects, with equal distributions of males and females, ranging in age from 20 to 49 years (μ = 36.9, SD = 7.9) completed the trial. Pharmacokinetics of single and multiple doses of long-acting naltrexone were adequate and consistent (naltrexone: AUC∞ = 1.975, 90 percent CI = 1.756−2.222; C_max = 1.455, 90 percent CI = 0.991−2.135; AUC = 1.124, 90 percent CI = 0.982−1.287; t_1/2 = 0.951, 90 percent CI = 0.772−1.172; accumulation = 1.134, 90 percent CI = 0.048−1.226. 6-β-naltrexol: AUC∞ = 1.843, 90 percent CI = 1.590−2.137; C_max = 1.565, 90 percent CI = 1.075−2.279; AUC = 0.896, 90 percent CI = 0.754−1.065; t_1/2 = 0.908, 90 percent CI = 0.755−1.092; accumulation = 1.114, 90 percent CI = 1.043−1.191). Naltrexone was well tolerated by participants. Mild events reported by participants were nausea (n = 5), somnolence (n = 4), and dizziness (n = 2).

Reference: Fuller RK, Branchey L, Brightwell DR, Derman RM, Emrick CD, Iber FL, et al. Disulfiram treatment of alcoholism: A Veterans Administration cooperative study. JAMA. 1986;256(11):1449–1455. [PubMed: 3528541]

Purpose: Identify the effectiveness of disulfiram for treatment of alcohol dependence among men seeking treatment.

Conclusions: Disulfiram is useful in reducing drinking days among men who are unable to achieve total abstinence.

Methodology: This controlled, blinded, multicenter study recruited men seeking treatment at nine Veterans Administration medical centers, who met National Council on Alcoholism criteria for alcoholism. Exclusion criteria were living alone, presence of a medical condition that contraindicated treatment with disulfiram, history of destructive behavior, uncooperativeness, psychoactive drug abuse, abstinent for more than 1 month, and place of residence more than 80 km from the hospital. Subjects were randomized to one of three conditions: 250 mg of disulfiram, 1 mg of disulfiram (a control for the threat of the disulfiram–alcohol reaction), and no disulfiram (a control for the counseling that all received). The first two conditions were double blind, and the third was single blind. All groups received counseling. The treatment period was 1 year. The outcome measures were abstinence, time to first drink, and number of drinking days.

Summary of Results: There were no differences among study groups on abstinence (P = 0.25) and time to first drink (P = 0.26). Subjects who reported drinking and completed all assessments in the 250 mg disulfiram group reported significantly fewer drinking days (49 ±8 days, P = 0.05) compared with subjects in the other treatment conditions. Subjects who were compliant, regardless of treatment condition, were more likely to be abstinent than those who were not compliant (43 percent vs. 8 percent, P < 0.001).

Reference: Fuller RK, Gordis E. Does disulfiram have a role in alcoholism treatment today? Addiction. 2004;99:21–24. [PubMed: 14678055]

Purpose: Review the efficacy and safety of disulfiram over the past 55 years.

Conclusions: Disulfiram has a role in alcoholism treatment for the patient who is struggling to achieve sobriety and where medication administration can be supervised. Side effects are usually minor, and serious adverse reactions are uncommon, although monitoring for hepatotoxicity should be done.

Methodology: A review of research studies and clinical experience with disulfiram over the past 55 years was organized to include the efficacy of disulfiram, dosage, side effects and adverse reactions, acamprosate and naltrexone combined with disulfiram, antidepressants and disulfiram, and patients who may benefit from disulfiram.

Summary of Results: Effectiveness of disulfiram is limited unless the medication administration is supervised. The dose needs to be sufficient to cause a disulfiram–alcohol reaction after alcohol ingestion, but not too high to risk toxicity. It is suggested to begin with the 250 mg daily dose for all patients. The most common side effect, of short duration, is drowsiness, which can be managed by having the patient take the dose in the evening. There can also be a rare but potentially fatal hepatotoxicity at a rate of 1 per 25,000 patients. Liver function tests are recommended at baseline, 2-week intervals for 2 months, and 3–6-month intervals after that. When administered in clinical trials in combination with acamprosate and naltrexone, all medications were well tolerated and effective. Further research is needed on the effectiveness of disulfiram in combination with other pharmacotherapies. Disulfiram in combination with monoamine oxidase inhibitors is not safe, and it should not be used with tricyclic antidepressants. Supervised disulfiram is useful in the treatment of patients who have difficulty with treatment but are motivated to remain in treatment.

Reference: Garbutt JC, Kranzler HR, O’Malley SS, Gastfriend DR, Pettinati HM, Silverman BL, et al. for the Vivitrex Study Group. Efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence: A randomized controlled trial. JAMA. 2005;293(13):1617–1625. [PubMed: 15811981]

Purpose: Identify the efficacy of long-acting naltrexone.

Conclusions: Long-acting naltrexone treatment is an effective and safe treatment for adults with alcohol dependence.

Methodology: Subjects were outpatient adults with an alcohol dependence diagnosis who also reported a minimum of two weekly episodes of heavy drinking during the month before screening. Exclusion criteria were clinically significant medical conditions; major depression with suicidal ideation; psychosis; bipolar disorder; past-year dependence on benzodiazepines, opioids, or cocaine; inpatient substance abuse treatment for more than 7 days during the month before screening; use of opioids, oral naltrexone, or disulfiram during the 2 weeks before screening; and use of benzodiazepines the week before the first administration of study naltrexone. Subjects were randomized to 380 mg of naltrexone, 190 mg of naltrexone, or placebo. All subjects received 12 therapy sessions of the Biopsychosocial, Report, Empathy, Needs, Direct Advice, and Assessment model. Treatment was administered monthly, during a 24-week period. The event rate, defined as the frequency and pattern of heavy drinking (≥ 5 standard drinks for men and ≥ 4 for women) during treatment, was the primary outcome of interest. The event rate of risky drinking (> 2 drinks for men and > 1 for women) was a secondary outcome.

Summary of Results: Naltrexone was more effective than placebo in reducing the rate of heavy drinking. The subjects who took 380 mg of naltrexone experienced a reduction in heavy drinking that was 25 percent (P = 0.03) greater than the reduction among placebo subjects, and subjects taking 190 mg experienced a 17 percent (P = 0.07) greater reduction. Differences in risky drinking among the three groups were not significant (380 mg vs. placebo: hazard ratio = 0.90, 95 percent CI = 0.76−1.07, P = 0.23; 190 mg vs. placebo: hazard ratio = 0.95, 95 percent CI = 0.81−1.13, P = 0.58). The most common minor adverse events reported by subjects were nausea (380 mg = 33 percent, 190 mg = 25 percent, placebo = 11 percent), headache (380 mg = 22 percent, 190 mg = 16 percent, placebo = 16 percent), and fatigue (380 mg = 20 percent, 190 mg = 16 percent, placebo = 11 percent).

Reference: Garbutt JC, West SL, Carey TS, Lohr KN, Crews FT. Pharmacological treatment of alcohol dependence: A review of the evidence. JAMA. 1999;281(14):1318–1325. [PubMed: 10208148]

Purpose: Assess the efficacy of five categories of drugs used to treat alcohol dependence: disulfiram, opioid antagonists naltrexone and nalmefene, acamprosate, various selective serotonin reuptake inhibitors (SSRIs), and lithium.

Conclusions: Efficacy trials examine how a health intervention works in an ideal treatment setting, whereas effectiveness studies focus on the effect of an intervention in everyday settings. Disulfiram shows limited efficacy and is not used frequently, although it may still have some value. Newer medications such as naltrexone and acamprosate are more likely to be used at increasing rates but will require more study to determine effectiveness. At this time, use of the SSRIs fluoxetine, citalopram, buspirone, and ondansetron or lithium for patients with primary alcohol dependence does not appear to be supported by efficacy data.

Methodology: The article reviews and analyzes data from 41 studies and 11 followup or subgroup evaluations, including 11 disulfiram studies, with 1 subgroup publication; 1 nalmefene article; 3 naltrexone studies, with 5 subgroup publications; 9 acamprosate articles; 9 serotonergic studies not restricted to comorbid populations, with 1 subgroup study; and 3 serotonergic agent studies restricted to persons with co-occurring depression or anxiety, with 1 subgroup analysis. One article discussed both fluoxetine and acamprosate. Inclusion criteria included males and females older than 18 who were alcohol dependent, excluding pregnant women; location of study (United States, Canada, Europe, Latin America, Asia, Australia/New Zealand); double- or single-blind randomized control trial; prospective and retrospective controlled studies; sample size of more than 10; and inpatient and outpatient settings from 1966 to December 1997. Additional criteria required inclusion only of studies that provided standard alcohol outcomes: drinking days, return to drinking, time to first drink, episodes of heavy drinking, craving, and relapse.

Summary of Results: Oral disulfiram outcome measures and results vary, providing modest evidence that the drug reduces drinking frequencies without significantly enhancing abstinence rates. Naltrexone had a positive effect on abstinence only when combined with psychosocial therapies. In two trials, relapse rates at the end of the trials were higher for the placebo groups (54 percent and approximately 80 percent) than for the naltrexone groups. In another trial, end-of-study relapse rates for all subjects were 53 percent and 35 percent for placebo and naltrexone patients, respectively; however, for compliant patients, the figures were 52 percent and 14 percent, respectively. The most reliable finding in the acamprosate trials has been its effect on drinking frequency; nondrinking days were typically increased by 30 to 50 percent. Several studies also found that acamprosate approximately doubled abstinent rates, although the majority of patients returned to drinking while taking acamprosate. Subjects followed up for almost a year after trial completion who were taking acamprosate showed a greater number of cumulative nondrinking days and a higher abstinence rate than did those receiving placebo. Acamprosate continued to exert a positive effect on abstinence rates but not on the number of nondrinking days. The literature did not allow the authors to evaluate the important question of efficacy of pharmacotherapy when combined with varying types and intensities of psychosocial therapies.

Reference: Johnson BA, Ait-Daoud N, Aubin HJ, van den Brink W, Guzzetta R, Loewy J, et al. A pilot evaluation of the safety and tolerability of repeat dose administration of long-acting injectable naltrexone (Vivitrex) in patients with alcohol dependence. Alcoholism: Clinical and Experimental Research. 2004;28(9):1356–1361. [PubMed: 15365306]

Purpose: Obtain descriptive data to support the safety and tolerability of long-acting injectable naltrexone.

Conclusions: Long-acting naltrexone was well tolerated and safe.

Methodology: This double-blind, placebo-controlled, randomized trial was conducted at two U.S. and two European sites. Subjects were men and women, older than age 18, who met criteria for alcohol dependence according to the DSM-IV. Exclusion criteria were medical conditions requiring immediate treatment, other Axis I diagnoses, treatment with naltrexone 10 days before the study, intolerance to naltrexone, opioid use 2 weeks before screening, and other medical treatments for alcohol dependence. Subjects were randomized to receive 400 mg of naltrexone or placebo once a month for 4 months. Both groups received psychosocial support. Outcome measures for safety were adverse events, site assessments, laboratory tests, and physical examination. Outcomes for pharmacokinetics were plasma levels of naltrexone and 6-β-naltrexol and alcohol consumption.

Summary of Results: Thirty subjects (22 male and 8 female), mainly White non-Hispanic (63.3 percent), and ranging in age from 26 to 58 (μ = 42.6, SD = 9.2), completed the trial. Among treatment condition subjects, days of abstinence (39.2 percent vs. 69.4 percent), drinks per drinking day (7.4 percent vs. 3.8 percent), and number of heavy drinking days (45.3 percent vs. 15.4 percent) improved from preintervention to postintervention. Treatment-condition subjects improved on all measures compared with subjects receiving placebo: days of abstinence (69.4 percent vs. 62.6 percent), drinks per drinking day (3.8 percent vs. 6 percent), and number of heavy drinking days (15.4 percent vs. 23.4 percent). Plasma levels of naltrexone (average μ = 1.33ng/ml, SD = 1.74 ng/ml) and 6-β-naltrexol were relatively constant (μ = 3.03g/ml, SD = 3.29 ng/ml). No major adverse events were reported. Minor events occurring in as much as 10 percent of subjects were headaches, dizziness, somnolence, nausea, abdominal pain, dry mouth, vomiting, injection site pain, fatigue, and decreased appetite.

Reference: Kiefer F, Helwig H, Tarnaske T, Otte C, Jahn H, Weidemann K. Pharmacological relapse prevention of alcoholism: Clinical predictors of outcome. European Addiction Research. 2005;11:83–91. [PubMed: 15785069]

Purpose: Determine whether somatic distress, depression, anxiety, craving, or typological differentiation (early-or late-onset dependence) helps predict relapse with use of acamprosate or naltrexone.

Conclusions: Different subgroups respond differently to naltrexone and acamprosate. Psychopathology and typological differentiation might be useful in determining appropriate pharmacotheraputic treatments.

Methodology: One hundred sixty adult patients meeting the DSM-IV criteria for alcohol dependence, who had been abstinent for 12–15 days, participated in a 3-month double-blind study. Patients kept a daily drinking diary, corroborated by breath alcohol tests and physician evaluation. Patients received acamprosate, naltrexone, acamprosate and naltrexone, or placebo. Researchers applied a median split for the Symptom Checklist-90 sum score, the subscores of somatic distress, depression, and anxiety and for craving followed by t tests for unpaired samples with the abstinence duration as the independent variable.

Summary of Results: A total of 46.9 percent (75) of patients were abstinent throughout the treatment period; 42.5 percent (68) relapsed; and 10.6 percent (17) dropped out. Mean numbers of days elapsed before the first drink were placebo, 23.3 ± 26.9; acamprosate, 34.9 ± 32.0; naltrexone, 45.4 ± 32.7; and combined treatment, 54.8 ± 34.4. Mean numbers of days before relapse were placebo, 35.6 ± 33.8; acamprosate, 43.7 ± 32.0; naltrexone, 50.4 ± 34.4; and combined treatment, 58.5 ± 33.8. Naltrexone was more effective for people with addictions who had high depression scores and high somatic symptoms than for those with low depression or somatic symptoms. Acamprosate was more effective on those with low scores of somatic distress than on those with high scores. Relapse prevention was most effective in patients of type II (early-onset) alcohol addiction. Neither treatment enhanced abstinence for people with late-onset alcoholism.

Reference: Keifer F, Weidemann K. Combined therapy: What does acamprosate and naltrexone combination tell us? Alcohol & Alcoholism. 2004;39(6):542–547. [PubMed: 15456690]

Purpose: Evaluate safety and effectiveness of combined therapy.

Conclusions: Combination treatment is well tolerated and more effective than monotherapy.

Methodology: A literature review of three preclinical and four clinical studies was conducted.

Summary of Results: The preclinical studies used mice and rats. All found combination therapy to be effective, but with differing results that may have been caused by procedural differences. The human studies found that the combination therapy is safe, although side effects of both drugs were present. One of the clinical reviews examined data from a study in progress: Data were available for 108 of a planned 1,374 subjects. In this study, it was found that the amount of time before the first relapse was longer in the group on combined therapy than for those on acamprosate alone. The proportion of patients who had relapsed by the end of the study period and the amount of time until the first drink were also better for the combination group. This study also found that the incidence of diarrhea and nausea was greater among the combination group. The authors of this review give three hypotheses regarding the greater efficacy of combination therapy: first, that different subgroups may respond better to one drug or the other; second, that a synergistic effect produces a stronger anticraving effect; and third, that a pharmacokinetic interaction enhances bioavailability of one or both drugs.

Reference: Killeen TK, Brady KT, Gold PB, Simpson KN, Faldowski RA, Tyson C, et al. Effectiveness of naltrexone in a community treatment program. Alcoholism, Clinical and Experimental Research. 2004;28(11):1710–1717. [PubMed: 15547458]

Purpose: Determine the efficacy of naltrexone among people diagnosed with alcohol dependence seeking treatment at a community program.

Conclusions: Naltrexone might have some benefits for people diagnosed with alcohol dependence who continue to drink until right before beginning treatment.

Methodology: This randomized trial recruited patients entering community treatment for a DSM-IV alcohol disorder. Patients were randomized to one of three groups over 12 weeks: 50 mg of naltrexone and treatment as usual, placebo and treatment as usual, or treatment as usual. Outcome measures included the Time Line Follow-Back for self-reported drinking, the Addiction Severity Index for psychosocial functioning, the Obsessive Compulsive Drinking Scale for alcohol craving, the Alcohol Dependence Scale for alcohol severity, and a symptom checklist for adverse effects and liver enzymes.

Summary of Results: There were no significant differences between the treatment groups on any outcome. Posthoc analyses showed differences among patients who drank during the 2 weeks after signing the consent form and before starting the medication. Those receiving naltrexone had significantly fewer abstinent days (p = 0.01) compared with those who received treatment as usual. There were no significant differences between those in the naltrexone treatment and those receiving placebo.

Reference: King AC, Schluger J, Gunduz M, Borg L, Perret G, Ho A, et al. Hypothalamic-pituitary-adrenocortical (HPA) axis response and biotransformation of oral naltrexone: Preliminary examination of relationship to family history of alcoholism. Neuropsychopharmacology. 2002;26(6):778–788. [PubMed: 12007748]

Purpose: Learn (1) the acute neuroendocrine and mood response to naltrexone in healthy subjects, (2) the mood response to naltrexone related to family history of alcoholism, and (3) the association of serum naltrexone and 6-β-naltrexol levels with HPA axis and subjective response after taking naltrexone.

Conclusions: This study provides evidence that cortisol and adrenocorticotropic hormone (ACTH) elevations from oral naltrexone result from opioid antagonist disinhibition in the central nervous system.

Methodology: Subjects were 17 healthy, social drinkers ages 23 to 47. Exclusion criteria included any current or history of substance dependence, psychiatric or medical disorders, and uncertainty about biological family history of alcohol dependence. The testing was a 2day inpatient trial, during which subjects stayed in a low-stress environment and were provided regular meals. Baseline blood samples were followed immediately by a 50 mg dose of naltrexone. Subjects completed several different questionnaires as a baseline, then at 90 and 240 minutes after naltrexone administration, focusing on mood, side effects, and alcohol urges. The study was double blind—neither the study nurse nor the subject was aware of the capsule contents. However, to measure biotransformation, all subjects received naltrexone on day 1 and placebo on day 2. Samples were analyzed for cortisol, ACTH, naltrexone, and 6-β-naltrexol levels.

Summary of Results: Baseline ACTH and cortisol levels were similar between naltrexone and placebo sessions. Naltrexone increased levels of ACTH (p < 0 .05) and cortisol (p < 0.05). Mood changes after naltrexone administration compared with placebo were few. Naltrexone decreased vigor ratings at both 90- and 240-minute intervals (p < 0.05). For side effects, there was no difference between naltrexone and placebo. Groups with family history of alcoholism (FH+) responded differently from those without (FH−) in terms of ACTH (p < 0.05) and cortisol (p < 0.05). The FH+ group had increases in these neuroendocrine parameters many hours after taking medication, whereas the FH− group did not show neuroendocrine changes over time. The FH+ group did not show the normal decline in cortisol or ACTH in the naltrexone session. The FH+ group had more sensitivity to mood effects after the naltrexone dose. There was an inverse relationship (p = 0.08) between naltrexone and 6-β-naltrexol levels.

Reference: Kranzler HR, Armeli S, Tennen H, Blomquist O, Onken C, Petry N, et al. Targeted naltrexone for early problem drinkers. Journal of Clinical Psychopharmacology. 2003;23(3):294–304. [PubMed: 12826991]

Purpose: Evaluate efficacy of naltrexone treatment for early problem drinkers.

Conclusions: Naltrexone was better than placebo in reducing the frequency of heavy drinking during the treatment period.

Methodology: A total of 153 subjects ages 18 to 60 participated in an 8-week trial. Patients were excluded, for among other reasons, if they had a current DSM-IV diagnosis of moderate or higher severity alcohol dependence. Half were given placebo. The placebo group and naltrexone group were each divided into two groups, one on a daily schedule and the other on a targeted schedule. The daily group members received doses enough for each day and were told to take one a day; the targeted group members were given seven doses for the first week, but doses were decreased so that during the last week, patients received zero pills. The targeted group members were instructed to take a pill if they anticipated a high-risk situation. Patients could choose a goal of abstinence or nonhazardous drinking. Biweekly counseling sessions emphasized problemsolving, interpersonal skills, and ways of coping with cravings. Patients underwent a battery of assessments. Among them was the Drinker Inventory of Consequences, which was used as a pretreatment and end-oftreatment evaluation. Subjects kept nightly diaries of alcohol and medication intake.

Summary of Results: Analyses were completed on 150 subjects. The majority (84 percent) of patients were lifetime alcohol dependent as defined by DSM-IV. Eighty-six percent of subjects completed the 8-week treatment. Compliance was 86 percent. Eleven patients discontinued pills because of various adverse effects. The overall likelihood of drinking on any given day during the study was 0.62 compared with 0.86 during the 3 months before treatment. Subjects with fewer drinking days in the pretreatment period (p = 0.001), a treatment goal of abstinence (p < 0.001), or greater lifetime alcohol dependence (p = 0.035) had fewer drinking days during treatment. In the targeted schedule group, the effect of tablet taking had a significant (p < 0 = 0.001) influence: subjects tended not to drink heavily on days they took a tablet (naltrexone or placebo). Other characteristics of patients who were less likely to drink heavily were being women (p < 0.001), fewer heavy drinking days in pretreatment period (p < 0.001), a treatment goal of abstinence (p = 0.001), greater lifetime alcohol dependence symptoms (p = 0.05), and lower overall study compliance (p < 0.001). The decreased risk of heavy drinking among patients in the targeted schedule group declined as the number of available tablets declined to fewer than three per week.

Reference: Latt NC, Jurd S, Houseman J, Wutzke SE. Naltrexone in alcohol dependence: A randomised controlled trial of effectiveness in a standard clinical setting. Medical Journal of Australia. 2002;176:530–534. [PubMed: 12064984]

Purpose: Study whether naltrexone given in a standard medical clinical setting, with or without psychosocial interventions, is effective in treating alcoholism.

Conclusions: Naltrexone was significantly more effective than placebo in preventing relapse in a standard medical outpatient clinic for 3 months. The effect was most marked during the first 6 weeks, suggesting a rapid onset. Ongoing monitoring of depression among patients who are alcohol dependent is advised.

Methodology: Patients with alcohol dependence were recruited at four hospitals in Australia. Exclusion criteria included pregnant women or women not protected by contraception, use of opioids, significant liver disease, any concomitant major medical or psychiatric illness, untreated major depression, or a recent suicide attempt. Of the 164 patients assessed, 107 were enrolled in the study and randomly assigned, 56 to the naltrexone (50 mg/day) group and 51 to the placebo group. Study participants received a full history and clinical examination at baseline and were followed up by a physician at 1, 2, 3, 4, 6, 8, and 12 weeks. Optional counseling was offered to all study participants. Compliance with treatment was assessed by attendance at followup, pill counts, and random breath tests. Relapse rates were defined as drinking to previous heavy levels.

Summary of Results: There were no significant differences in patient characteristics between the study groups. The Kaplan-Meier survival curve showed that the relapse rate was significantly lower in the naltrexone group compared with the placebo group (log-rank test, χ² = 4.15, p = 0.042). There were no significant differences between the naltrexone and the placebo groups in the number of drinking days per week, attendance at the followup clinic or Alcoholics Anonymous meetings, mean alcohol consumption, or mean craving scores. Beck Depression Inventory scores above 20 were more prevalent in the naltrexone group (22 percent) at 3 months compared with the placebo group (3 percent, p = 0.023). There was no significant difference in side effects between the two groups, except for an increase in headaches in the placebo group (p = 0.03).

Reference: Mann K, Lehert P, Morgan M. The efficacy of acamprosate in the maintenance of abstinence in alcohol-dependent individuals: Results of a meta-analysis. Alcoholism: Clinical and Experimental Research. 2004;281(1):51–63. [PubMed: 14745302]

Purpose: Assess the efficacy of treatment with acamprosate using meta-analytical techniques.

Conclusions: Acamprosate significantly improves abstinence rates in subjects who are alcohol dependent.

Methodology: Researchers conducted a search of 10 databases, using a number of keywords, and made a manual search of journals, symposia, and conference proceedings. The identified studies were assessed and culled based on design, sample size, randomization methods, blinding, selection and exclusion criteria, outcome criteria, and statistical analysis. Researchers combined the data from these studies with clinical trial data provided by the manufacturer of acamprosate and additional data from some of the studies’ authors to undertake a meta-analysis assessing the efficacy of acamprosate in achieving patients’ continuous abstinence over 6 months. Researchers undertook numerous sensitivity analyses and adjusted for sample size, DSM-III-R/DSM-IV classification, age, gender, and attrition rates. The 17 studies included in the analysis were placebo-controlled, double-blind trials involving 4,087 patients. Results of studies of less than 6 months in duration were extrapolated using last observation carried forward methodology.

Summary of Results: The following table compares the percentage of subjects abstinent after different periods on acamprosate with those on placebo.

The benefit of treatment was not affected by age, severity of dependence, or attrition rates. The studies overall had a high attrition rate, averaging 51 percent.

Reference: Mark TL, Kranzler HR, Song X, Bransberger P, Poole VH, Crosse S. Physicians’ opinions about medications to treat alcoholism. Addiction. 2003;98:617–626. [PubMed: 12751979]

Purpose: Survey physicians who treat substance abuse to learn about their knowledge of, attitudes toward, and use of naltrexone, disulfiram, and acamprosate to treat alcoholism and their opinions about barriers to its treatment with medication.

Conclusions: The identification and testing of new medications to treat alcoholism must be accompanied by increased efforts to inform physicians and the public about their value.

Methodology: A questionnaire was developed from focus group interviews of physicians and patients that assessed knowledge and use of medications, factors affecting decisions to prescribe, opinions about medications, and opinions about medication attributes. The questionnaire was sent to members of the American Society of Addiction Medicine and the American Academy of Addiction Psychiatry. Incentives to complete the questionnaire were a cover letter, a $50 honorarium check, and a postage-paid, return envelope. Nonrespondents were contacted after 3 weeks and again after 2 months. Questionnaires were received from 1,388 respondents resulting in a response rate of 65 percent.

Summary of Results: Most physicians were confident or somewhat confident in their knowledge of naltrexone (86 percent) and disulfiram (92 percent) but not acamprosate (20 percent). Physicians’ rating of the effect size of naltrexone was consistent with the clinical literature (14.6 percent vs. 12 percent effect size for promoting abstinence and 18.4 percent vs. 16 percent effect size for reducing heavy drinking). The three top factors influencing physicians to prescribe naltrexone were the patient was willing to comply with the regimen (83 percent), the patient was experiencing craving (79 percent), and the patient was requesting naltrexone (77 percent). To increase the use of medications to treat alcohol dependence, physicians advocated more research to develop new medications (33 percent), more education of physicians about existing medications (17 percent), and increased involvement of physicians in alcoholism treatment (17 percent).

Reference: Mason BJ. Treatment of alcohol-dependent outpatients with acamprosate: A clinical review. Journal of Clinical Psychiatry. 2001;62(Suppl 20):42–48. [PubMed: 11584875]

Purpose: Review all published, double-blind, placebo-controlled clinical trials of acamprosate among outpatients who are alcohol dependent.

Conclusions: Acamprosate can be used for a broad range of patients who are alcohol dependent and being treated with other drugs and with behavioral therapy. Patients treated with acamprosate had a significantly higher rate of treatment completion, longer time to first drink, higher abstinence rate, and/or longer cumulative abstinence duration than patients treated with placebo.

Methodology: Of the 16 clinical trials of acamprosate in 11 European countries, 15 have been published and were reviewed. These 15 studies were grouped according to duration of treatment: 4 short-term studies with less than 6 months of treatment, 6 studies with 6 months of treatment, and 5 long-term studies with a year or more of treatment. All 15 studies were double-blind, placebo-controlled clinical trials involving more than 4,500 outpatients with alcohol dependence.

Summary of Results: The results of 13 studies found that acamprosate prolongs abstinence and reduces the rate of relapse. Differences in abstinence rates between the acamprosate and placebo groups emerged within the first 30 to 90 days of treatment, were sustained for up to 1 year after treatment, and were maintained for as long as 12 months after treatment. In two studies, there was no significant difference between the acamprosate and placebo groups. Acamprosate is a relapse-prevention drug; it did not reduce craving compared with the placebo. It has minimal pharmacologic effects, does not interact with ethanol or other drugs used to treat alcoholism, can be administered to patients with liver dysfunction, and does not cause acute opioid withdrawal symptoms in patients using opioids. It can be used in a variety of settings with a range of psychosocial interventions. It appears to be safe and well tolerated with mild diarrhea or loose stool as the only consistent adverse event.

Reference: Mason BJ. Rationale for combining acamprosate and naltrexone for treating alcohol dependence. Journal of Studies on Alcohol. 2005;(Suppl 15):148–156. [PubMed: 16223066]

Purpose: Review the similarities and differences between acamprosate and naltrexone and their interaction and effectiveness when used in combination.

Conclusions: Although differing in mechanism of action, acamprosate and naltrexone have good tolerability profiles and may have enhanced efficacy when given in combination.

Methodology: The published clinical trials of acamprosate and naltrexone were reviewed for effectiveness. Two published pharmacokinetic and pharmacodynamic drug interaction studies of these drugs were reviewed as was the one single-site clinical trial of acamprosate and naltrexone in combination.

Summary of Results: Both drugs have good safety profiles and are acceptable to patients, and neither modifies the properties of alcohol. However, they differ in their mechanism of action. Whereas naltrexone is an opioid receptor antagonist and is contraindicated for patients maintained on methadone, acamprosate is a taurine analog that acts by normalizing the dysregulation of N-methyl-D-aspartic acid-mediated glutamatergic neurotransmission. Although naltrexone has a rapid onset, it does not have any long-term efficacy once discontinued. Acamprosate has a slow onset of action (1 week), but its effect may persist for up to 1 year after discontinuation. Naltrexone has a dose-dependent hepatotoxicity, whereas acamprosate has none. The efficacy of acamprosate, based on published placebo-controlled studies, supports abstinence over a broad range of patients in association with a variety of different psychosocial interventions. The effect of naltrexone may be to reduce consumption by a person who drinks, and its effect on relapse may be dependent on associated psychotherapy (i.e., cognitive-behavioral therapy), especially in patients who are not abstinent. Poor compliance of naltrexone, because of adverse events such as nausea and headache, may cause a decrease in effectiveness. When acamprosate and naltrexone are used in combination, the rate and extent of absorption of acamprosate is increased by an average of 33 percent. Preliminary support for enhanced efficacy of combination treatment relative to acamprosate alone was seen in the single combination clinical trial.

Reference: Maxwell S, Shinderman MS. Use of naltrexone in the treatment of alcohol use disorders in patients with concomitant major mental illness. Journal of Addictive Diseases. 2000;19(3):61–96. [PubMed: 11076120]

Purpose: Report on the efficacy of naltrexone therapy in patients with co-occurring alcohol dependence and Axis I disorders.

Conclusions: Patients with co-occurring disorders had a very positive response to naltrexone therapy.

Methodology: The authors reviewed the case records of 72 patients with an alcohol use disorder and at least one Axis I psychiatric disorder, including major depression, schizophrenia, bipolar disorder, schizoaffective disorder, and gender identity disorder. Data collected included diagnoses, medications, and the duration and side effects of and response to naltrexone treatments. During naltrexone therapy, patients continued with any treatment and drugs prescribed for their other disorder. Response to naltrexone was estimated for the first 8 weeks of treatment, based on practitioner notes, patient self-reports, and clinician assessments, as corroborated by case manager reports, urine toxicologies and Breathalyzer^™, and family reports. Responses were categorized as follows: excellent, more than 90-percent reduction in alcohol consumption; very good, 75–90 percent; good, 50–75 percent; fair, 25–50 percent; and poor, less than 25-percent reduction in drinking.

Summary of Results: Of the initial 72 patients, 59 completed at least 8 weeks of naltrexone therapy; 97 percent (n = 70) drank alcohol during treatment; 70.8 percent (n = 51) had an excellent response; 11 percent (n = 8) had very good reductions in drinking; 6.9 percent (n = 5) had a good response; 1.4 percent (n = 1) had a fair response; and 2.8 percent (n = 2) had a poor response.

Reference: McCaul ME, Petry NM. The role of psychosocial treatments in pharmacotherapy for alcoholism. American Journal on Addictions. 2003;12:S41–S52. [PubMed: 14972779]

Purpose: Review seven psychotherapies and their use in combination with pharmacotherapy (naltrexone and acamprosate).

Conclusions: Psychotherapy may enhance and extend the effect of pharmacotherapy.

Methodology: The seven major types of psychotherapy are reviewed by describing the theoretical basis for each psychotherapy, the evidence supporting the efficacy of each, and when combined with medication the resulting efficacy or interaction of psychotherapy and the medication.

Summary of Results: Brief therapeutic interventions in general medical settings have been shown to be effective in reducing alcohol use in those who drink heavily but are not alcohol dependent, especially when combined with naltrexone. Motivation enhancement therapy (MET) has been effective as a four-session manual-guided intervention especially with angry subjects. When MET was used with acamprosate in general healthcare settings, study subjects motivated to abstain had good medication efficacy. Cognitive-behavioral therapy (CBT), effective with patients who abuse substances, has been shown to produce delayed, positive effects after treatment completion. When CBT was used in conjunction with naltrexone, patients were successfully engaged in treatment and medication compliance. Cue exposure therapy (CET) has been shown to reduce the urge to drink and increase the use of coping strategies. When CET was combined with naltrexone, each independently reduced the urge to drink, heavy drinking days, and drinks per drinking day. Behavioral treatments have enhanced compliance with treatment by providing vouchers or cash contingent on naltrexone consumption, thereby increasing treatment retention. Behaviorally based couples therapy when used in conjunction with naltrexone for opioid dependence increased treatment retention and drug-free urine toxicology screens. Twelve- Step therapies, although thought to discourage the use of medication, may be adapted to use with pharmacotherapy and have achieved high rates of alcohol abstinence and low proportions of drinking days.

Reference: McCaul ME, Wand GS, Rohde C, Lee SM. Serum 6-βnaltrexol levels are related to alcohol responses in heavy drinkers. Alcoholism: Clinical and Experimental Research. 2000;24(9):1385–1391. [PubMed: 11003204]

Purpose: Examine the relationship between serum levels of 6-β-naltrexol and the effects of alcohol.

Conclusions: Concentrations of 6-β-naltrexol may help predict patients’ response to naltrexone.

Methodology: The study was conducted over a 6-week period with 23 subjects, ages 25 to 60, who reported moderate to heavy alcohol use. The 6 weeks alternated between inpatient stays and outpatient washout periods (time for medication to leave the person’s system). All subjects were on inpatient stay for 3 weeks, in each of which they were subject, at random, to a different dosage of naltrexone: 0, 50, or 100 mg/day. Three alcohol dosages (none, moderate, high) were administered in random order during each week. Alcohol content of drinks and naltrexone doses were concealed to nurses, study assistants, and subjects. Subjects took naltrexone, then had serum drawn 16 hours later to test their levels of 6-β-naltrexol, the biologically active metabolite of naltrexone. Within half an hour of the serum draw, subjects ingested an alcohol placebo or a moderate or high dose of alcohol. Subjects took a computerized self-assessment, measuring relative levels of sedation, sickness/unpleasantness, and intoxication before and after ingesting the alcohol dose.

Summary of Results: At the 100 mg dosage, 6-β-naltrexol levels varied within and across subjects. There was a positive relationship between subjects’ feelings of sedation before drinking and their 6-β-naltrexol levels (p = 0.002). The 6-β-naltrexol levels appear to affect other baseline measures. Levels of 6-β-naltrexol were related to subjects’ reporting of the pleasant effects of alcohol: when levels were higher, subjects were less likely to report feelings of pleasure and of liking the effects of the beverage/capsule combination.

Reference: McKay JR. Is there a case for extended interventions for alcohol and drug use disorders? Addiction. 2005;100:1594–1610. [PubMed: 16277622]

Purpose: Review the evidence for the feasibility and effectiveness of extended interventions for alcohol and drug use disorders.

Conclusions: Patients who have failed prior treatments are the best candidates for extended interventions. Most published studies support the effectiveness of using extended interventions.

Methodology: Published studies were reviewed if they contained an extended intervention. An extended intervention was defined as a therapeutic protocol that has a planned duration of longer than 6 months. The theoretical rationale for extended intervention is the continued vulnerability to relapse, a function of poor compliance with treatment and continuing care, stress, craving, low motivation, poor self-efficacy, lack of social support, and biological factors such as genetic vulnerability, negative mood states, disturbed sleep, and cognitive impairments. New developments in the design and evaluation of treatments such as adaptive protocols and changing interventions were proposed as well as recommendations for a disease management approach to addictions treatment.

Summary of Results: Extended interventions are most appropriate for patients who have not achieved sustained reductions in alcohol or drug use on their own or following brief interventions. Results of studies with long-term behavioral treatments suggest that the 1year versions of treatment had improved outcomes. Continuing care interventions using home visits, workplace counseling, and behavioral marital therapy sessions were effective in preventing relapse. Extended pharmacotherapy interventions using acamprosate and outpatient therapy were effective; however, a long-term intervention using naltrexone was not. Regular monitoring, such as followup assessments and assessments plus referral to treatment via telephone monitoring and brief counseling, has been studied and found to be effective. Although there is not a lot of evidence, all except two of the behavioral and pharmacological extended interventions reviewed yielded positive effects. The extended intervention needs to be low intensity so that patients participate for long periods.

Reference: Monterosso JR, Flannery BA, Pettinati HM, Oslin DW, Rukstalis M, O’Brien MD, et al. Predicting treatment response to naltrexone: The influence of craving and family history. American Journal on Addictions. 2001;10:258–268. [PubMed: 11579624]

Purpose: Determine the influence of craving levels and family history of alcoholism on efficacy of naltrexone.

Conclusions: Naltrexone may be more effective with patients with a strong family history of alcoholism and those with high levels of craving.

Methodology: The 183 subjects met the DSM-III-R criteria for alcohol dependence, successfully detoxified for 3 days, in addition to a week placebo lead-in. Exclusion criteria were major psychiatric illness, history of unstable medical condition, use of opioids in the preceding 30 days, significant hepatocellular injury, current disulfiram treatment, comorbid dependence other than nicotine or cannabis, and abstinence from alcohol for more than 28 days. One-third of patients received placebo in this double-blind study. Two-thirds took 50 mg of naltrexone twice daily, except those who suffered nausea, who were directed to take it once daily. All patients received weekly sessions using the BRENDA approach (Biopsychosocial evaluation, Report, Empathy, Needs of patient, Direct advice, Assessment). Assessment instruments included a semistructured interview, a structured interview, and a questionnaire. Variables that differed between treatment groups at a level of p < 0.05 were included in analyses as covariates.

Summary of Results: The study was completed by 82.1 percent of patients. Excluding retention failures, 78.3 percent of patients were at least 90-percent compliant with the medication regimen. Drinking during the placebo lead-in week was positively associated with clinical deterioration (p < 0.001), as was severity of familial alcoholism (p = 0.003). Medication was more effective with patients with higher levels of craving (p = 0.02). Patients with high familial alcohol problems derived the most benefit from naltrexone therapy.

Reference: O’Malley SS, Krishnan-Sarin S, Farren C, O’Connor PG. Naltrexone-induced nausea in patients treated for alcohol dependence: Clinical predictors and evidence for opioid-mediated effects. Journal of Clinical Psychopharmacology. 2000;201:69–76. [PubMed: 10653211]

Purpose: Identify risk factors for naltrexone-precipitated nausea.

Conclusions: The risk of nausea associated with naltrexone is significantly predicted by age, gender, intensity of drinking, and duration of abstinence. Moderate to severe nausea is linked to poor compliance with the medication regimen.

Methodology: The 120 subjects were men and women from ages 18 to 65 who were alcohol dependent (as defined by DSM-III) with differing intensities of drinking habits. After a period of abstinence of 5 to 30 days, subjects got an initial dose of 25 mg of naltrexone; afterward, they took a daily 50 mg dose for 10 weeks. Subjects were excluded if they experienced one of the following:

• Currently abused or were dependent on substances other than alcohol and nicotine or had an acute major psychiatric illness, a psychotic illness, or cirrhosis
• Had serum glutamic-oxaloacetic transaminase or serum glutamic-pyruvic transaminase more than three times normal levels
• Had elevated bilirubin levels or an unstable medical condition
• Had previously undergone more than five treatments for alcohol dependence
• Were currently using disulfiram
• For women, were pregnant, were nursing, or refused to use a reliable form of birth control.

After initial testing using several variables, researchers removed those that were found not to affect levels of nausea. The remaining variables were alcohol consumption multiplied by abstinence, alcohol consumption, abstinence, age, and gender.

Summary of Results: Of the 120 subjects, 18 had moderate to severe nausea, 10 reported mild nausea, and the remaining 92 experienced nothing unusual. Of the 18 subjects with moderate to severe nausea, 8 discontinued naltrexone because of nausea and other side effects. For those who remained on naltrexone, the nausea subsided within a week for five subjects, subsided within 2 weeks for four, and continued intermittently for one subject. The patients who did not experience moderate to severe nausea were significantly more compliant in taking the daily dose than those who did (p < 0.05). Another factor affecting nausea levels was the quantity of alcohol regularly consumed before the abstinence period. Subjects with less nausea had consumed an average of 2.86 drinks per occasion, whereas those with moderate to severe nausea had consumed an average of 5.17.

Reference: O’Malley SS, Rounsaville BJ, Farren C, Namkoong K, Wu R, Robinson J, et al. Initial and maintenance naltrexone treatment for alcohol dependence using primary care vs. specialty care. Archives of Internal Medicine. 2003;163:1695–1704. [PubMed: 12885685]

Purpose: Study the effectiveness of a primary care approach to the management of alcohol dependence with naltrexone therapy.

Conclusions: Naltrexone therapy can be used effectively with a primary care model of counseling to treat patients dependent on alcohol.

Methodology: The study compared the effectiveness of a primary care model of counseling and naltrexone therapy with cognitive-behavioral therapy (CBT) and naltrexone therapy for 10 weeks, followed by a random assignment to the same therapy but with or without naltrexone for 6 months. The resulting nested sequence of 3 randomized clinical trials started with 197 patients dependent on alcohol, and 113 “responders” were randomized to the 6-month maintenance phase. Of the 425 eligible patients, 107 were excluded and 121 either declined to participate or dropped out before randomization.

Summary of Results: There was no difference between the two groups based on no more than 2 days of heavy drinking during the last 28 days; however, patients in the CBT and naltrexone group were more likely to be abstinent during the last 28 days (p = 0.02). Of the patients in the primary care group randomized to receive either naltrexone or a placebo for 6 months of maintenance treatment, the naltrexone group maintained fewer days of heavy drinking and more abstinence than the placebo group (81 percent vs. 52 percent, p = 0.03), and the placebo group had a decreased percentage of days abstinent (90 percent vs. 78 percent, p = 0.02). There was no difference in study outcomes for the patients in the CBT group randomized to receive either naltrexone or a placebo for 6 months of maintenance treatment.

Reference: Ooteman W, Verheul R, Naassila M, Daoust M, Schippers GM, Koeter MWJ, et al. Patient-treatment matching with anti-craving medications in alcohol-dependent patients: A review on phenotypic, endophenotypic and genetic indicators. Journal of Substance Use. 2005;10(2–3):75–96.

Purpose: Review the literature on predictors and matching variables of the effectiveness of pharmacological interventions (acamprosate, naltrexone, selective serotonin reuptake inhibitors [SSRIs]) in patients with alcohol dependence to decrease craving and prevent relapse.

Conclusions: To better match patients with the optimum pharmacotherapy more research is needed using genetic or endophenotypic variables.

Methodology: A search of PubMed, EMBASE, PsychINFO, the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, and the Database of Abstracts of Reviews of Effects was conducted in 2004. References were checked to identify trials, reviews, and meta-analyses. Studies were included if they reported data on at least one of the three types of possible anticraving medications (acamprosate, naltrexone, or SSRIs). Studies were reviewed for results that matched specific patients to specific treatment outcomes. The three-pathway (reward, relief, and obsessive) model of craving in patients with alcoholism was used as a theoretical framework.

Summary of Results: Limited support was found for the matching hypothesis of the three-pathway model (i.e., naltrexone for reward, acamprosate for relief, and SSRIs for obsessive pathways). Baseline craving and/or familial alcoholism could predict a match between patients with these characteristics and naltrexone. The best match for SSRI treatment could be patients with comorbid mood or anxiety disorders. Patients with early-onset or Cloninger Type II alcoholism may have a poor outcome with SSRI therapy. Promising findings suggest that genotypes may predict the best patient–treatment match. One study found a genetic indicator for naltrexone effectiveness, OPRM1 genotyping, which predicted which patients would have the best response. Combining therapies, such as naltrexone and acamprosate, seems to decrease craving more, perhaps by affecting both the reward and relief pathways at the same time.

Reference: Oslin DW, Berrettini W, Kranzler HR, Pettinati H, Gelernter J, Volpicelli JR, et al. A functional polymorphism of the μ-opiate receptor gene is associated with naltrexone response in alcohol-dependent patients. Neuropsychopharmacology. 2003;28(8):1546–1552. [PubMed: 12813472]

Purpose: Determine the relationship between two polymorphisms of the μ-opiate receptor and treatment outcomes among people with alcohol dependence taking naltrexone or placebo.

Conclusions: The study provides evidence of a relationship between the μ-opiate receptor gene and positive treatment outcomes for naltrexone.

Methodology: This study reported on three randomized clinical trials of naltrexone and placebo, both with adjunct psychosocial intervention. Subjects were mainly non-Hispanic White and African-American males. Study one randomized subjects to (1) 9 months of 100 mg naltrexone per day, (2) 12 weeks of 100 mg of daily naltrexone and 6 months of placebo, or (3) 9 months of placebo. Study two treatment conditions were 24 weeks of 100 mg of daily naltrexone and one of three psychosocial interventions. Study three treatment conditions were 50 mg daily of naltrexone, nefazodone, or placebo and cognitive-behavioral therapy. Outcome measures were the Addiction Severity Index for severity of alcohol-related problems, the Time Line Follow-Back for alcohol consumption, and relapse to heavy drinking as the main outcome. Blood samples were genotyped using the polymerase chain reaction-restriction fragment length polymorphism method.

Summary of Results: Naltrexone subjects with the Asp 40 variant of the μ-opiate receptor gene were less likely to relapse than naltrexone subjects who were homozygous for the Asn 40 allele (Wald = 4.05, 1df, OR = 3.52 [95 percent CI = 1.03–11.96] p = 0.044). Time to first relapse was also longer among naltrexone subjects with the Asp 40 variant (Wald = 4.22, 1df, OR = 2.79 [1.05, 7.41] p = 0.040). Rates of abstinence between these two groups did not differ (Wald = 0.259, 1df, OR = 0.76 [95 percent CI = 0.27–2.16] p = 0.611). There were no significant differences among the placebo subjects.

Reference: Petrakis IL, Nich C, Ralevski E. Psychotic spectrum disorders and alcohol abuse: A review of pharmacotherapeutic strategies and a report on the effectiveness of naltrexone and disulfiram. Schizophrenia Bulletin. 2006;32(4):644–654. [PMC free article: PMC2632271] [PubMed: 16887890]

Purpose: Assess efficacy of naltrexone and disulfiram in patients with co-occurring disorders.

Conclusions: Naltrexone and disulfiram can be used to effectively treat individuals with alcohol dependence and comorbid psychotic spectrum disorders.

Methodology: A short review of literature was followed by a clinical trial. Data were gathered on 251 subjects, all of whom were diagnosed as alcohol dependent as well as having a major Axis I disorder. Primary outcomes were measures of alcohol use. Detailed self-reports were collected weekly in interviews administered by research personnel. In addition, craving, psychiatric symptoms, and side effects were evaluated. Outcome variables included consecutive days of abstinence, total days abstinent, and the number of heavy (≥ 5 drinks) drinking days.

Summary of Results: In the entire sample, subjects significantly decreased alcohol use in all outcome measures. Subjects assigned to either drug had significantly fewer drinking days per week (p = 0.02) and more consecutive days of abstinence (p = 0.04) than the placebo group. In measures of heavy drinking days and number of days abstinent, there were no significant differences between the treatment groups. Subjects without psychotic spectrum disorders had better results than those with such disorders in terms of consecutive abstinence days, total days of abstinence, and heavy drinking days. There were no measurable effects on psychotic symptoms, and side effects were consistent with other studies and groups.

Reference: Pettinati HM, O’Brien CP, Rabinowitz AR, Wortman SM, Oslin DW, Kampman KM, et al. The status of naltrexone in the treatment of alcohol dependence: Specific effects on heavy drinking. Journal of Clinical Psychopharmacology. 2006;26(6):610–625. [PubMed: 17110818]

Purpose: Reevalute the literature on controlled naltrexone trials focusing on outcomes to reduce heavy drinking versus outcomes to increase abstinence.

Conclusions: The majority of clinical trials in the literature favor prescribing naltrexone to reduce heavy drinking, consistent with naltrexone’s mechanism of action.

Methodology: A search of MEDLINE between 1990 and 2006 was conducted to identify published studies evaluating the use of an opioid antagonist (naltrexone or nalmefene) for the treatment of alcohol dependence. Inclusion criteria were a double-blind, placebo-controlled study design, a sample of at least 20, and outcomes of both abstinence and excessive or heavy drinking. Of the 95 studies identified involving human subjects and randomized controlled trials, 27 met the inclusion criteria.

Summary of Results: Naltrexone blocks the ability of ethanol to increase dopamine release in the dopamine reward pathways, thus reducing the pleasurable effects of alcohol and excessive drinking. Nausea and vomiting are the most common side effects (< 15 percent of patients), and potential hepatotoxicity occurred at higher doses (350 mg/d) than the recommended daily dosage of 50 mg. The review of 27 studies revealed that 70 percent (19) favored naltrexone over placebo in reducing heavy or excessive drinking. Only 36 percent (9/25) favored naltrexone over placebo in increasing abstinence. Because naltrexone is specific for opiate receptors, if a patient with alcoholism does not have an endogenous opioid system sensitive to alcohol, naltrexone may not have an effect. Patients who may respond better to naltrexone have a family history of alcoholism, an intense craving for alcohol, an enhanced opioidergic activity in response to alcohol intake, and/or a genetic polymorphism.

Reference: Pettinati HM, Volpicelli JR, Pierce JD, O’Brien CP. Improving naltrexone response: An intervention for medical practitioners to enhance medication compliance in alcohol dependent patients. Journal of Addictive Diseases. 2000;19(1):71–83. [PubMed: 10772604]

Purpose: Conduct a reanalysis of existing data focusing on patient compliance and relapse rates. Conduct a preliminary analysis of the BRENDA (a focused clinician–patient monitoring of pill taking, patient education, and problemsolving related to daily pill taking and missed doses) intervention designed to improve treatment compliance for clinic patients who are alcohol dependent.

Conclusions: Compliance with treatment and medication will improve relapse rates and can be enhanced through a clinician–patient intervention.

Methodology: For the first study, two groups of patients dependent on alcohol and/or nicotine completed studies (12-week, double-blind, placebo-controlled studies of naltrexone [50 mg/day] and a mix of group and individual counseling sessions) were grouped together to assess the effect of treatment compliance on relapse rates. Treatment compliance was defined as at least 80-percent attendance at clinic visits and a self-report statement that naltrexone was taken as prescribed. Relapse was defined as drinking at least five drinks during one drinking occasion or a documented breath alcohol level greater than 100 mg/dL. For the second study, the BRENDA intervention was assessed. Treatment completion rates and pill compliance rates, as measured by pill counts, were compared between two groups of outpatients in a 12-week, double-blind, placebo-controlled naltrexone trial; one group received the BRENDA intervention.

Summary of Results: For the first study, of 104 compliant patients, only 10 percent of the patients in the naltrexone group relapsed versus 39 percent in the placebo group (χ² = 12.1, df = 1, p < 0.001). Of the 92 noncompliant patients, there was no significant difference in the relapse rates between the two groups. For the second study, of the 100 patients receiving the BRENDA intervention, 83 percent completed treatment compared with 56 percent in the other group (χ² = 17.4, df = 1, p < 0.001) and 77 percent were compliant in taking their medication, compared with 61 percent in the other group (χ² = 6.03, df = 1, p < 0.01).

Reference: Ramoz N, Schumann G, Gorwood P. Genetic and pharmacogenetic aspects of alcohol-dependence. Current Pharmacogenomics. 2006;4:19–32.

Purpose: Review the genetic and pharmacogenetic basis of alcohol dependence and discuss results from the field of pharmacogenetics of alcoholism to improve therapeutic response based on genotype.

Conclusions: The current knowledge of genes involved in the neurobiology of alcohol dependence allows for the selection of a sufficient number of candidate genes for pharmacogenetic studies.

Methodology: Published studies were reviewed that addressed glutamatergic and opioidergic genes and genes pertaining to pathways known to interact with these neurotransmitter systems. The review is organized into genome-wide scans, candidate genes in the metabolism of alcohol, candidate genes from reward circuits and neurotransmitter systems involved in alcohol, and expression profiles of genes and proteins.

Summary of Results: The heterogeneity of alcohol dependence is evident at both the clinical phenotypic and the neurobiological/genetic levels. One strategy to improve treatment results is the identification of more homogeneous subgroups of patients to receive specific treatments. The heritability rate of alcoholism is estimated at 50–60 percent. Genome scans implicate the involvement of loci on chromosomes 1, 2, 4, 5, 6, 7, 12, 14, 15, 16, and 17. In the metabolism of alcohol, the Lys487 allele, found in 50 percent of Asians, causes a dramatically reduced ability to catabolize the toxic acetaldehyde substrate, resulting in the Flushing Syndrome. In the reward circuits, characterized by dopaminergic activity, genes that may have pharmacogenetic relevancy are the GABRA6 gene (role of benzodiazepine in alcohol withdrawal), SLC6A4 gene (serotonin reuptake inhibitors may reduce alcohol intake in subgroups of patients), CB1 gene (the CB1 agonists modify alcohol consumption in rodents), and the OPRM1 gene (the 118G allele being associated with increased chances of naltrexone efficacy).

Reference: Rohsenow DJ. What place does naltrexone have in the treatment of alcoholism? CNS Drugs. 2004;18(9):547–560. [PubMed: 15222772]

Purpose: Review 17 studies of naltrexone to investigate its effectiveness and the characteristics of patients who would benefit from it.

Conclusions: Because naltrexone has been shown to be effective in most clinical trials, it has a place in therapy, combined with a good behavioral or counseling program. If treatment programs are tailored to individual needs and compliance is maximized, the likelihood of success when using naltrexone is improved.

Methodology: A review of 17 studies was completed to investigate the effectiveness of naltrexone and the characteristics of patients who would benefit from using it.

Summary of Results: Although a recent multicenter clinical trial of naltrexone did not find any significant differences between groups, other trials have consistently found that naltrexone, in combination with a behavioral treatment or counseling for alcoholism, results in a modest effect size resulting in significantly less severe drinking outcomes. The most beneficial results for naltrexone across studies are the reduction in heavy drinking and the number of drinking days. Naltrexone makes drinking less pleasurable so that patients who have a lapse are less likely to progress to heavy drinking. Naltrexone is best used in patients who are both able and willing to take it. Patients may not take naltrexone if they have a variety of medical conditions, poor liver function or history of liver disease, or any recent opioid use and, for women, if they are pregnant or are not using adequate birth control. Naltrexone may be most effective when combined with a comprehensive treatment program. Benefits of naltrexone include a reduced urge to drink or sense of craving; however, the benefits wear off soon after the drug is discontinued. Future research should focus on an increased drug dosage, increased length of treatment, improved compliance, and matching individuals with the most optimum treatment package.

Reference: Rubio G, Ponce G, Rodriguez-Jimenez R, Jimenez-Arriero MA, Hoenicka J, Palomo T. Clinical predictors of response to naltrexone in alcoholic patients: Who benefits most from treatment with naltrexone? Alcohol & Alcoholism. 2005;40(3):227–233. [PubMed: 15797885]

Purpose: Determine whether family history of alcoholism is a clinical marker for outcome of patients treated with naltrexone.

Conclusions: Naltrexone might help some men with alcohol abuse improve treatment outcomes.

Methodology: This randomized, open-controlled trial compared naltrexone (50 mg/day) plus psychotherapy with psychotherapy alone. Both treatments were administered for 6 months. Male patients were recruited after detoxification (mean days of abstinence = 14.5 days, SD = 7.2) at a hospital in Madrid, Spain. Exclusion criteria were use of opioids in the year before the trial, a DSM-IV psychiatric disorder (other than alcohol dependence), and a medical condition that would be exacerbated by naltrexone. Predictive variables were alcohol dependence based on DSM-IV criteria, the Severity of Alcohol Dependence Scale, and the Addiction Severity Index; frequency, duration, and intensity of craving; self-report alcohol intake and consumption pattern; biological measurements of alcohol use (aspartate aminotransferase, alanine transaminase, gamma glutamyl transpeptidase, and carbohydrate-deficient transferin); and family history of alcoholism based on interviews with first-degree relatives and, when necessary, the Research-Diagnostic Criteria-Family History. Outcome variables were number of drinking days, number of heavy drinking days (> 5 drinks or 40 g/day), abandonment of treatment, days of continued abstinence, and final abstinence (continued abstinence during the last 28 days of followup).

Summary of Results: Patients in the naltrexone group had more days of abstinence in the last 28 days of followup (71 percent vs. 59 percent, P = 0.030), fewer drinking days (2 percent vs. 14 percent, P = 0.007), and fewer heavy drinking days (6 percent vs. 28 percent, P = 0.015). The treatment groups did not differ on abstinence, days of consumption, continuous days in abstinence before first consumption, total consumption, and days of consumption. Treatment with naltrexone was associated with alcohol abuse before age 25 (χ² = 4.836, P < 0.028; OR = 2.004, P = 0.014), co-occurring drug use (χ² = 12.835, P < 0.001; OR = 6.348, P < 0.001), and/or a family history of alcoholism (χ² = 5.714, P < 0.017; OR = 2.084, P = 0.010).

Reference: Scott LJ, Figgitt DP, Keam SJ, Waugh J. Acamprosate: A review of its use in the maintenance of abstinence in patients with alcohol dependence. CNS Drugs. 2005;19(5):445–464. [PubMed: 15907154]

Purpose: Review relevant pharmacological data on acamprosate and highlight clinical evidence for its use in the management of abstinent adult patients with alcohol dependence.

Conclusions: In several clinical trials of up to 12 months, acamprosate effectively maintained abstinence in patients who were alcohol dependent and had been detoxified, irrespective of disease severity or the type of psychosocial support.

Methodology: This review covers the pharmacology of acamprosate, its therapeutic efficacy, and its tolerability, based on published literature.

Summary of Results: Acamprosate is thought to modulate the glutamatergic and GABAergic neurotransmitter systems in the central nervous system to restore the normal balance between these two systems. Acamprosate is indicated for the maintenance of abstinence in adult patients with alcohol dependence who are abstinent at treatment initiation. The recommended dosage of acamprosate is two 333 mg tablets three times daily, which may be taken without food. Acamprosate treatment should be accompanied by a comprehensive management program including psychosocial support and should be maintained if the patient relapses. If administered to lactating rats, acamprosate has been found in their milk and has been shown to cross the placental barrier. Acamprosate does not appear to be metabolized, with 99 percent of the drug eliminated unchanged in the urine. As a result, a 50-percent dosage reduction is recommended in patients with moderate renal impairment (creatinine clearance 1.8–3 L/h), and the drug is contraindicated in patients with severe renal impairment. Because acamprosate is not metabolized in the liver, there have been no clinically relevant effects of mild to moderate hepatic impairment on pharmacokinetic values of acamprosate. The most frequently reported adverse event is diarrhea, but it is generally well tolerated in this patient population. Limited data indicate that acamprosate has similar efficacy to naltrexone and that combination therapy with these two drugs provides better efficacy than acamprosate alone.

Reference: Soyka M, Chick J. Use of acamprosate and opioid antagonists in the treatment of alcohol dependence: A European perspective. American Journal on Addictions. 2003;(12):S69–S80. [PubMed: 14972781]

Purpose: Present the findings of placebo-controlled trials of acamprosate and naltrexone medications that took place in Europe and reflect that perspective and experience.

Conclusions: Rates of total abstinence for those using acamprosate were statistically and significantly better compared with those of the placebo groups in the studies reviewed. Rates are measured by time-to-first-drink data compiled in 13 studies (2 studies with fewer than 100 patients were eliminated). For the studies that also measured cumulative abstinence duration (CAD), a beneficial effect was seen in acamprosate use over placebo. It is recommended to begin acamprosate as soon as a patient is near successful detoxification to achieve the best effect. If a patient manages to abstain, the drug should be continued for 1 year. Studies in Germany and Austria followed up on patients after 1 year’s treatment and found greater improvement in the acamprosate-treated group. Improvement persisted into the second year of treatment without any indication for sudden relapse on cessation of the drug. Acamprosate appears to have a slight effect in reducing drinking during relapse and should not be stopped if the patient lapses. Results from studies on methadone have been less consistent than those reported for acamprosate; several European studies have been negative or partly negative. The Swedish and Finnish studies did not find naltrexone superior to placebo in their treatment-as-usual groups and groups with supportive therapy. There is evidence from the Swedish study that naltrexone is effective in settings offering coping skills training, that is, an approach that includes training in how to terminate drinking if it starts, rather than focusing on complete abstinence. There has been a trend to offer naltrexone to patients aiming for harm-free drinking rather than abstinence, provided favorable predictors exist for a nonabstinent goal such as low level of dependence and social support. For the Finnish 32-week study, the dropout rate was 16.5 percent in the initial 12‐week period and twice that by the end of the study. In the coping skills groups, naltrexone was superior to placebo in terms of percentage of patients never relapsing to heavy drinking (26 percent vs. 3 percent, p = 0.008), but in groups receiving supportive therapy, there was no significant difference (8 percent vs. 12 percent). The naltrexone Health Technology Board of Scotland (HTBS) study found an NNT (number needed to treat) of 12.4 for preventing relapse (defined as drinking more than 5 drinks in a day). The study comparing acamprosate with naltrexone (the Hamburg study) found the group with the fewest heavy drinking days was the combined naltrexone and acamprosate, followed by naltrexone on its own, then acamprosate on its own. All were associated with better outcomes than placebo. A Spanish study comparing acamprosate and naltrexone found no significant difference between them in terms of days to first drink. However, with relapse defined as five or more drinks, the time to the first relapse was longer for naltrexone than for acamprosate.

Methodology: The clinical studies of acamprosate met the following criteria for review: comparison with placebo, adequate measures of randomization, standard attempts to keep patients and assessors blind to treatment groups, and predefined primary outcome criteria (number of days to the first drink and secondary CAD). Followup rate was not an inclusion criterion. Fifteen studies (n = 3,979) were selected for analysis and review with two studies eliminated. For naltrexone, European studies that met Cochrane criteria for methodological quality are discussed as well as several reviews and meta-analyses. Swedish and Finnish studies compared the efficacy of naltrexone associated with different psychological treatments. A 32-week Finnish study tested groups of cognitive coping skills or supportive group therapy combined with either naltrexone or placebo but stopped medication at week 13 for all subjects with instructions to take the medication only when there was a risk of sampling alcohol or when craving threatened to overwhelm. The most extensive meta‐analysis was conducted by the HTBS. The HTBS review included 12 positive studies and 5 negative studies (n = 2,113) including a negative Veterans Administration study. In a single center study (Hamburg), the author randomly allocated 160 patients who were detoxified one 50 mg naltrexone daily, two 333 mg acamprosate three times per day, both, or a placebo.

Summary of Results: The use of acamprosate is believed to vary within and between countries of Europe. In a survey in Scotland, all National Health Service units specializing in alcohol treatment prescribe it. Although many centers routinely offer a trial of acamprosate to patients who are newly detoxified and aiming for abstinence, naltrexone usage varies. Naltrexone is suggested for patients aiming for abstinence and for patients for whom continued drinking is a therapeutic possibility or an inevitability.

Reference: Streeton C, Whelan G. Naltrexone, a relapse prevention maintenance treatment of alcohol dependence: A meta-analysis of randomized controlled trials. Alcohol & Alcoholism. 2001;36:544–552. [PubMed: 11704620]

Purpose: Review the existing evidence for the efficacy of naltrexone for the treatment of alcohol dependence.

Conclusions: Naltrexone is superior to placebo for the treatment of alcohol dependence.

Methodology: A literature review of randomized controlled trials published between 1976 and 2001 was indexed in MEDLINE, EMBASE, PsychLIT, and the Cochrane Controlled Trials Registry. Studies were selected according to the following characteristics: enrollment of adult subjects with alcohol dependence in outpatient or inpatient treatment; comparison of a 50 mg dose of naltrexone with placebo or another drug licensed in Australia; collection of data at least on relapse, abstinence, and discontinuation because of adverse events; provision of treatment for at least 3 months; and complete databases. Outcome measures were rates of relapse and abstinence; mean drinking days and number of drinks per drinking day, as measures of efficacy; reports of adverse events; and number of subjects who discontinued treatment because of an adverse event, as measures of safety.

Summary of Results: Seven trials were reviewed. All outcomes favored the naltrexone subjects over those receiving placebo: the average relapse rate was 14 percent lower; the average days of drinking was 3 percent lower; and the average abstinence rate was 10 percent greater. There were no differences in the incidence of reporting at least one adverse event or the incidence of discontinuation because of adverse events between the naltrexone and placebo subject groups.

Reference: Suh JJ, Pettinati HM, Kampman KM, O’Brien CP. The status of disulfiram: A half of a century later. Journal of Clinical Psychopharmacology. 2006;26(3):290–302. [PubMed: 16702894]

Purpose: Review the history, current status of treatment, and future developments of disulfiram for the treatment of alcohol and cocaine dependence.

Conclusions: Supervised disulfiram can be an effective treatment for alcohol use.

Methodology: A MEDLINE literature review (1937–2005) on the treatment of disulfiram for alcohol and cocaine dependence was conducted.

Summary of Results: Supervised disulfiram can be an effective treatment for alcohol use. Two studies presented conflicting evidence about the efficacy of disulfiram, compared with naltrexone. One study found similar efficacy when comparing disulfiram and acamprosate for treatment of alcohol use. Future efforts should focus on assessing the effectiveness of disulfiram combined with other pharmacotherapies, especially newer ones.

Reference: Thomas CP, Wallack SS, Lee S, McCarty D, Swift R. Research to practice: Adoption of naltrexone in alcoholism treatment. Journal of Substance Abuse Treatment. 2003;24:1–11. [PubMed: 12646325]

Purpose: Study factors associated with acceptance of naltrexone and other alcoholism treatment medications by clinicians and attitudes toward the role of medication in therapy.

Conclusions: Lack of information about naltrexone, its high cost, and organizational affiliation were important reasons for or against its acceptance.

Methodology: A survey was developed, based on a literature review and interviews with clinicians, and disseminated in 1999 in Massachusetts, Tennessee, and Washington State. The survey was based on a conceptual framework and measured clinician characteristics, clinic and patient characteristics, prescribing practices for medications used in alcoholism treatment, and reasons for or against prescribing these medications. The survey was mailed to practicing members of the American Society of Addiction Medicine and/or the American Academy of Addiction Psychiatrists with followup by mail and telephone.

Summary of Results: A total of 63 percent of physicians (n = 129) and 65 percent of nonphysician clinicians (n = 1,062) responded. Eighty percent of physicians had some experience prescribing naltrexone; however, only 15 percent prescribed it often. Among nonphysicians, 45 percent had some experience with it, and only 5 percent prescribed it often. Factors associated with prescribing naltrexone among physicians were being in an organization that actively recommends naltrexone (p < 0.001) and spending time in research (p < 0.05). Having an additional degree or being in recovery (p < 0.01) negatively predicted adoption of naltrexone. Among nonphysicians, factors associated with prescribing naltrexone were working in an organization that recommended it (p < 0.001), having received marketing information about it (p < 0.001), having a high proportion of Medicaid patients (p < 0.001), and working in Washington State (p < 0.05). Factors associated with not prescribing naltrexone were having a high proportion of self-pay patients (p < 0.05) or having a high proportion of State Block Grant patients (p < 0.05).

Reference: Verheul R, Lehert P, Geerlings PJ, Koeter MW, van den Brink W. Predictors of acamprosate efficacy: Results from a pooled analysis of seven European trials including 1,485 alcohol-dependent patients. Psychopharmacology. 2005;178(2–3):167–173. [PubMed: 15322728]

Purpose: Identify the patient characteristics that predict successful treatment with acamprosate for alcohol dependence.

Conclusions: Acamprosate is effective for all patients with alcohol dependence.

Methodology: The study analyzed data pooled from seven European randomized trials of acamprosate. Independent variables were severity of withdrawal symptoms, family history of alcoholism, age of onset, duration of alcohol dependence, anxiety (using the Hamilton Depression Scale), severity of craving, physiological dependence, and gender. Dependent variables were cumulative abstinence duration (CAD) and continuous abstinence (CA).

Summary of Results: Trials initiated treatment approximately 1–4 weeks after the initiation of a detoxification period, for a total time ranging from 3 to 12 months (median = 6 months). A total of 983 subjects were included in the multifactorial analysis. No significant interactions were found between the independent variables demonstrating main effects and the outcome variables: CAD (craving P = 0.347 and anxiety P = 0.829) and CA (values not reported).

Reference: Weiss RD. Adherence to pharmacotherapy in patients with alcohol and opioid dependence. Addiction. 2004;99:1382–1392. [PubMed: 15500591]

Purpose: Review the issues common to medication adherence including reliability of measurement, the complex reasons for nonadherence among patients, and strategies to increase adherence. Address the importance of medication adherence with disulfiram and naltrexone.

Conclusions: Nonadherence to medication regimens is a common problem in the treatment of chronic disorders, including substance use disorders. Nonadherence is associated with poor outcomes and increased costs. Improving patient adherence begins with paying close attention to it and using strategies to monitor it closely. The review presents a range of possible reasons for patient nonadherence and discusses in detail interventions the clinician can use in sessions with patients, including psyhosocial strategies and medication prescribing and dosing strategies that enhance adherence. For the treatment of alcohol dependence, ongoing development of long-acting preparations of naltrexone may hold promise for improved treatment results by addressing the limitation of oral naltrexone linked to nonadherence and gastrointestinal side effects.

Methodology: A review of the literature of English-language publications was performed that related to medication adherence among patients with alcohol and opioid dependence.

Summary of Results: Adherence is a complex issue. A major goal for practitioners should be improving adherence, and more research is needed to identify effective approaches. The authors suggest that treatments that are more efficacious, reduce dose complexity, and diminish side effects should be developed.