Medications for treating alcohol dependence

Author: Steven H. Williams
Date: Nov 1, 2005

Medications for treating alcohol dependence primarily have been adjunctive interventions, and only three medications--disulfiram, naltrexone, and acamprosate--are approved for this indication by the U.S. Food and Drug Administration. Disulfiram, an aversive agent that has been used for more than 40 years, has significant adverse effects and compliance difficulties with no clear evidence that it increases abstinence rates, decreases relapse rates, or reduces cravings. In contrast, naltrexone, an anticraving agent, reduces relapse rates and cravings and increases abstinence rates. Acamprosate also reduces relapse rates and increases abstinence rates. Serotonergic and anticonvulsant agents promise to play more of a role in the treatment of alcohol dependence. Although not approved by the U.S. Food and Drug Administration for this indication, the anticonvulsant topiramate and several serotonergic agents (e.g., fluoxetine, ondansetron) have been shown in recent studies to increase abstinence rates and decrease drinking.

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Almost one third of Americans consume enough alcohol to be considered at risk for alcohol dependence, and alcohol abuse and dependence are associated with more than 100,000 deaths from alcohol-related diseases and injuries each year. The economic cost of alcohol abuse and dependence was estimated at more than $184 billion for 1998. (1) Use of screening tools and brief primary care interventions for alcohol problems significantly reduces drinking levels in "problem drinkers" who are not yet alcohol dependent. (2) Counseling and 12-step structured treatment programs have been the mainstays of alcohol dependence treatment, whereas pharmacologic treatments traditionally have played an adjunctive role.

To date, three medications--disulfiram (Antabuse), naltrexone (Trexan), and acamprosate (Campral)--have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of alcohol dependence, and only about 20 percent of eligible patients receive them. In the past decade, however, there has been a growing body of evidence supporting a more central role for medications in the treatment of alcohol dependence. These medications, the evidence supporting them, and recommended dosages are discussed in the following. Table 1 (3,4) provides a summary of the medications with prescribing information, adverse effects, contraindications, and costs.

Naltrexone

Naltrexone is an opioid-receptor antagonist approved for use in the treatment of alcohol dependence in conjunction with psychosocial interventions. It is believed that naltrexone works through its blockage of [micro]-opioid receptors, which reduces the reinforcing effects of alcohol leading to decreased feelings of intoxication and fewer cravings.

In a systematic review (5) of 11 double-blind, placebo-controlled trials, researchers found that naltrexone reduces short-term relapse rates in patients with alcohol dependence when combined with psychosocial treatments. Short-term outcomes in favor of naltrexone included fewer patients relapsing to alcohol dependence (38 versus 60 percent with placebo), fewer patients returning to drinking (61 versus 69 percent), reduced cravings for alcohol, and fewer drinking days. (5) The data showed one relapse was prevented for every five patients treated with naltrexone (i.e., number needed to treat [NNT] = 5).

More recent randomized controlled trials (RCTs) looking at longer-term outcomes report mixed results. In a systematic review (6) of three studies assessing medium-term outcomes (six to 12 months), researchers found no difference between naltrexone and placebo groups. In addition, a large trial (7) comparing outcomes of three therapy groups--12 months of naltrexone therapy, three months of naltrexone followed by nine months of placebo, and 12 months of placebo--found no significant differences among the groups in the number of days to relapse, number of drinking days, or number of drinks per drinking day. Although there is good evidence supporting short-term benefit with naltrexone, the evidence for longer-term use is less compelling.

The recommended dosage of naltrexone is 50 mg per day in a single dose. Long-term opioid therapy for chronic pain or heroin dependence is a contraindication for naltrexone because the drug could precipitate severe withdrawal syndrome. Naltrexone has been shown to have dose-related hepatotoxicity, although generally this occurs at doses higher than those recommended for treatment of alcohol dependence. The drug also is contraindicated in patients with hepatitis or liver failure, and all patients should have hepatic transaminase levels checked monthly for the first three months and every three months thereafter. (8)

Naltrexone generally is well tolerated; nausea is the most common adverse effect (reported by 10 percent of patients), followed by headache, anxiety, and sedation. (9)

Naltrexone is FDA pregnancy category C. Good compliance is considered essential for successful treatment.

Disulfiram

Disulfiram inhibits acetaldehyde dehydrogenase. Although it has been used to treat alcohol dependence for more than 40 years, the evidence for its effectiveness is weak. An evidence report from the Agency for Healthcare Research and Quality (6) concluded that studies using the disulfiram implant display serious methodologic weaknesses (most substantively, regarding the question of bioavailability), and that the four placebo-controlled RCTs using oral disulfiram produced mixed results. Although in two trials oral disulfiram was shown to reduce frequency of drinking days, it did not improve relapse rates compared with placebo. Two studies noted patient compliance with oral disulfiram and showed it to be low, and a third study had a 46 percent dropout rate. These methodologic limitations and mixed results make it difficult to state clearly how many patients benefit from disulfiram.

Disulfiram usually is given in a dosage of 250 mg per day with a maximum dosage of 500 mg per day. Consuming alcohol after taking disulfiram results in symptoms such as palpitations, flushing, nausea, vomiting, and headache. More severe reactions could include myocardial infarction, congestive heart failure, respiratory depression, and death. Because of the potential for a severe alcohol-disulfiram interaction, disulfiram is contraindicated in patients who are receiving or have recently received metronidazole or ingested alcohol, have psychosis, or have cardiovascular disease, and is not recommended for patients with severe pulmonary disease, chronic renal failure, or diabetes, or those older than 60 years. It also is not recommended in patients with peripheral neuropathy, seizures, or cirrhosis with portal hypertension. Hepatotoxicity is a rare but potentially fatal adverse effect. (8) Some experts recommend that baseline liver function tests should be obtained, with repeat testing at two weeks, three months, six months, and then every six months thereafter. Because of these significant restrictions and problems with compliance, disulfiram is not recommended for treating alcohol dependence, particularly in the primary care setting. (6) Disulfiram is FDA pregnancy category C.

Acamprosate

Acamprosate (calcium homotaurinate) is believed to block glutaminergic N-methyl-Daspartate receptors and activate [lambda]-aminobutyric acid type A receptors, and was recently approved by the FDA for the treatment of alcohol dependence. A systematic review (10) of 15 studies showed that acamprosate reduces short-term and long-term (more than six months) relapse rates in patients with alcohol dependence when combined with psychosocial treatments. Outcomes in favor of acamprosate included fewer patients returning to drinking (68 versus 80 percent, NNT = 8) and higher percentage of days of total abstinence (54 versus 38 percent, NNT = 7). (10)

Acamprosate is available in 333-mg enteric, coated tablets; dosing is by weight (Table 1 (3,4)). It is well tolerated with limited side effects, most commonly transient diarrhea (occurring in approximately 10 percent of patients). There are no interactions with concomitant use of alcohol, diazepam (Valium), disulfiram, or imipramine (Tofranil), so patients with alcohol dependence can continue to use acamprosate during a relapse. Patients with renal insufficiency or advanced cirrhosis should not take acamprosate, but it may be taken safely by patients with liver dysfunction. 11 Like naltrexone and disulfiram, acamprosate is FDA pregnancy category C (adverse effects on the fetus in animal studies but no human trials).

Serotonergic Agents

(20.) Brady KT, Myrick H, Henderson S, Coffey SF. The use of divalproex in alcohol relapse prevention: a pilot study. Drug Alcohol Depend 2002;67:323-30.

(21.) Mason BJ, Salvato FR, Williams LD, Ritvo EC, Cutler RB. A double-blind, placebo-controlled study of oral nalmefene for alcohol dependence. Arch Gen Psychiatry 1999;56:719-24.

STEVEN H. WILLIAMS, PH.D., is former director of behavioral medicine at the Harrisburg (Pa.) Family Practice Residency Program and currently is a clinical psychologist with the Psychology Service at the Veterans Affairs Medical Center in Lebanon, Pa. Dr. Williams received a doctoral degree in counseling psychology from the University of Florida, Gainesville, and a postdoctoral certification in psychopharmacology from Fairleigh Dickinson University, Teaneck, N.J.

Address correspondence to Steven H. Williams, Ph.D., VA Medical Center, 1700 S. Lincoln Ave., Lebanon, PA 17042. Reprints are not available from the author.

SORT: KEY RECOMMENDATIONS FOR PRACTICE EvidenceClinical recommendation rating ReferencesNaltrexone (Trexan) and acamprosate (Campral) A 5are recommended as FDA-approved options fortreatment of alcohol dependence inconjunction with behavior therapy.Disulfiram (Antabuse) does not increase B 6abstinence rates or decrease relapse ratesor cravings compared with placebo, and itis not recommended for routine use inprimary care.Fluoxetine (Prozac) and other SSRIs are B 13, 14recommended for patients with comorbiddepressive disorders.Topiramate (Topamax) and ondansetron (Zofran) B 3, 4are recommended to reduce drinking frequencyand increase abstinence.FDA = U.S. Food and Drug Administration; SSRI = selectiveserotonin reuptake inhibitor.A = consistent, good-quality patient-oriented evidence;B = inconsistent or limited-quality patient-orientedevidence; C = consensus, disease-oriented evidence,usual practice, expert opinion, or case series. Forinformation about the SORT evidence rating system,see page 1639 or http://www.aafp.org/afpsort.xml.Table 1Medications for Treatment of Alcohol Dependence FDAMedication approved? DosageAcamprosate Yes 333-mg enteric coated tablets(Campral) Adults [greater than or equal to] 132 lbs (60 kg): two tablets three times per day Adults < 132 lbs: two tablets with the morning meal, one with the midday meal, and one with the evening mealDisulfiram Yes Begin with 250 mg once per day;(Antabuse) increase to 500 mg once per day.Fluoxetine No Begin with 20 mg per day; may(Prozac) increase to 60 mg per day as needed.Nalmefene No Available only in an injectable form(Revex) (outside of research) to treat opiate overdose.Naltrexone Yes 50 mg once per day(Trexan)Ondansetron No 4 mcg per kg twice per day(Zofran)Topiramate No Begin with 25 mg morning dose and(Topamax) increase to a total of 300 mg given twice a day in divided doses.Medication Side effects Contraindications *Acamprosate Diarrhea, headache, Severe renal impairment(Campral) flatulence, nausea, (creatinine clearance vomiting, dyspepsia < 30 mL per minute [0.5 mL per second])Disulfiram Disulfiram-alcohol Alcohol, metronidazole(Antabuse) interaction: (Flagyl), or palpitations, paraldehyde flushing, nausea, use; psychosis; vomiting, headache cardiovascular diseaseFluoxetine Nausea, headache, Use of an MAOI,(Prozac) sedation, anxiety, mesoridazine sexual dysfunction (Serentil), or thioridazine (Mellaril)Nalmefene Nausea, tachycardia, None(Revex) vasodilation, dizziness, headache, chills, vomitingNaltrexone Nausea, headache, Narcotic use, acute(Trexan) anxiety, sedation opioid withdrawal, acute hepatitis, liver failureOndansetron Malaise, fatigue, None(Zofran) headache, dizziness, anxietyTopiramate Recent FDA warning None(Topamax) of metabolic acidosis, especially with renal or liver disease Dizziness, somnolence, ataxia, impaired concentration, confusion, fatigue, paresthesias, speech difficulties, diplopia, nauseaMedication Comments Cost ([dagger])Acamprosate To avoid adverse gastrointestinal $125(Campral) effects, initial dosing usually is at one half the given dosages with an increase of one tablet to the daily dosage each week.Disulfiram Initiate only after patient has 42(Antabuse) abstained from alcohol for at least 12 hours. Not generally recommended for treating alcohol dependence in the primary care setting Patient should carry an identification card describing the disulfiram- alcohol interaction. Monitor liver function tests for hepatotoxicity.Fluoxetine Recommended only in patients 127 (79 to(Prozac) with comorbid depression 89 generic)Nalmefene -- 62 (for 2 mL(Revex) [2 mg])Naltrexone Monitor liver function tests 205 (128 to(Trexan) for hepatotoxicity. 137 generic)Ondansetron -- 661 (for 4(Zofran) mg daily)Topiramate Consider interactions with 53(Topamax) other anticonvulsant drugs.FDA = U.S. Food and Drug Administration; MAOI = monoamineoxidase inhibitor.*--Other than hypersensitivity to the drug, which isa contraindication for all medications listed.([dagger])--Estimated cost to the pharmacist based on averagewholesale prices (rounded to the nearest dollar) in Red Book.Montvale, N.J.: Medical Economics Data, 2005. Cost to thepatient will be higher, depending on prescription filling fee.Information from references 3 and 4.

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