Rev Bras Psiquiatr 2004;26(Supl):43-46

The pharmacologic treatment of the alcohol

dependence
Luís André Castroa e Danilo Antonio Baltierib
aUnidade de Pesquisa Clínica da Uniad (Unidade de Pesquisa em Álcool e Drogas) e
Departamento de Psiquiatria EPM-UNIFESP
bGREA (Grupo Interdisciplinar de Estudos de Álcool e Drogas), Instituto de Psiquiatria
do Hospital das Clínicas e Faculdade de Medicina da Universidade de São Paulo

Abstract
The pharmacological intervention can play a crucial role in the reduction of craving and drinking and the maintenance of abstinence. This article
reviews pharmacotherapy for alcohol dependence with an emphasis on the naltrexone, dissulfiram and acamprosate. The opioid antagonist nal-
trexone lowers relapse rate, reduces drinking days and prolongs periods of abstinence. Acamprosate restores the normal activity of glutamate
and GABA systems. Disulfiram has been shown to be most effective for patients who believe in its efficacy and remain compliant with the treatment.
Ondansetron, has shown promise in the early-onset alcohol dependence but needs more extensive study. Topiramate (up to 300 mg per day) was
more efficacious than placebo in the treatment of alcohol dependence.

Keywords: Alcoholism. Alcoholism. Naltrexone. Disulfiram.

Introduction syndrome as important adjuvant interventions for psychosocial treat-

Inadequate use of alcohol represents a serious worldwide public ment. More recently, ondansetrom and topiramate have appeared as
health problem, what has stimulated innumerable investigations see- promising therapeutical strategies, being in the approval phase.1 2 This
king a better understanding of ethanol-related problems and their review of the literature will deal with currently-available PI for the
modes of treatment. Knowing that half of the patients with alcohol treatment of alcohol dependence, focusing on clinically-relevant issues
dependence syndrome relapse after a short detoxification period and for professionals who deal with these patients.
that studies in neurosciences are implying new neurotransmission
systems, such as those involved in mesocorticolimbic structures, in Disulfiram
their pathophysiology, the development of new pharmacological treat- Disulfiram (DSF) was the first pharmacological intervention approved
ment models has become an area of increasing worldwide interest. by the FDA for the treatment of alcohol dependence. For the success of
treatment with DSF all patients should be engaged in some treatment
Pharmacological Interventions. program. Supervised oral DSF is efficient, when incorporated to a
During several years, the pharmacological interventions (PI) were treatment which includes a community reinforcement approach, i.e.,
restricted to treatment of alcohol withdrawal syndrome (AWS) and to interventions developed in order to create new social skills, by means
the use of aversive drugs. In the last 10 years, naltrexone and acam- of counseling, besides resocialization (e.g., social clubs) and recre-
prosate have been proposed for the treatment of alcohol dependence ational activities which stimulate abstinence.3 4 It is important the
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Rev Bras Psiquiatr 2004;26(Supl):43-46 Pharmacologic treatment / Castro LA & Baltieri DA

adoption of strategies to increase the compliance with treatment such tion of this clinical condition may be performed, inclu- ding their
as: contingent social contracts - consisting of therapeutical agree- mildest forms, by means of hepatic function tests. It is recommended
ments between patients and the people involved in their treatment, to monitor the hepatic function every three months in the maintenance
aiming that any of the family members supervise the administration of phase. In the first month of treatment, these lab exams may be per-
the medication behavioral monitoring of abstinence, besides some formed every two weeks.5
form of positive reinforcement for abstinence. Treatment effectiveness 4. Clinical orientations
increases with these interventions. The habitual dose is 250 mg/day in a sole daily dose, after at least a 12-
1. Mechanism of action hour abstinence interval. Patients may also benefit from 500 mg daily
DSF is an irreversible and nonspecific enzyme-inhibitory agent which doses. The recommended duration of treatment is one year. Other
decomposes alcohol into the stage of acetaldehyde. When inhibiting the alternative modes of administration include: use of low maintenance
enzyme acetaldehyde-dehydrogenase (ALDH), an accumulation of doses during years or intermittent use on high-risk situations. The inhi-
acetaldehyde in the body will occur, leading to the ethanol-dissulfiram bition of the enzyme ALDH may last for up to two weeks, after the sus-
reaction (figure1). pension of DSF.6 Patients should be oriented to avoid all alcohol
2. Contraindications sources (e.g., vinegar).
Among the contraindications, hepatic cirrhosis with portal hyperten-
sion may evolve with vomiting-induced visceral hemorrhage, during Naltrexone
the ethanol-disulfiram reaction. In pregnancy there is the risk of con- Naltrexone is an opiate antagonist, used as an adjuvant of psychosocial
genital anomalies. DSF may be used on patients with history of convul- interventions in outpatient treatment of alcoholism. In 1995, the FDA
sions associated with alcohol withdrawal syndrome, provided it be approved naltrexone for the treatment of alcoholism. It is the first me-
ruled out the presence of epilepsy. Other contraindication is organic dication to be approved, since the introduction of DSF. According to
mental syndrome, due to the impairment of the patientsí capability of Srisurapanont and Jarusuraisin,7 pre-clinical studies suggest that o-
understanding the risk of the ethanol-dissulfiram reaction. Patients pioid antagonists attenuate the pleasant effects of alcohol consump-
should be explained the toxic effects of DSF before its use, as to not tion. Based on these animal studies, the efficacy and effectiveness of
using it without their previous consent. Therefore, patients should naltrexone have been investigated in the treatment of alcohol depen-
abstain completely from alcohol and have a full understanding of the dence.
risks and principles of the treatment. 1. Mechanism of action
Alcohol would stimulate indirectly the endogen opioid activity, by pro-
moting the release of endogen peptides (encephalins and endorphins),
in the synaptic cleft. The pleasant sensations of alcohol would be medi-
ated by the release of dopamine if the synaptic clefts of the nucleus
accumbens. Other mechanism proposed is the inhibitory acti- vity of
endogen peptides over the gabaergic inter-neurons situated in the ven-
tral tegmental area, which exert inhibitory effects on area A10
dopaminergic neurons. Naltrexone acts as a competitive antagonist on
opioid receptors. Therefore, the administration of opioid antagonists
would reduce the consumption of alcohol by means of the post-synap-
tic blocking of the and opioid receptors in the mesolimbic pathways.
2. Contraindications
The main contraindications to the use of naltrexone are acute and
chronic hepatic diseases. Among opioid users it is advisable to per-
form a test with naloxone to discard recent heroine use. The use of o-
pioid antagonists in heroine-dependent patients may trigger withdra-
wal syndrome symptoms, which start 5 minutes after the administra-
tion of the medication, lasting for approximately 48 hours. In these
patients a minimum period of seven days of abstinence is needed
before prescribing naltrexone chlorhiydrate. Among those treated with
methadone, a longer abstinence period is recommended: 10 to 14 days.
3. Adverse effects
The main adverse effect of naltrexone is nausea, which generally is
coincident with the plasmatic levels reached in a period of up to 90
minutes after the ingestion of the medication. Hepatotoxicity based on
the increase of hepatic transaminases (3 to 19 times the normal va-
lues) was observed on patients treated with high doses of naltrexone
(above 300 mg daily). In doses below 200 mg/day, no increase in hepa-
tic enzymes was found. However, it is important the monthly monito-
ring of bilirrubine values (total and fractions ) and of serum transam-
inases in the first three months, and afterwards every three months.
More frequent monitoring is indicated, when transaminases are high.
Naltrexone should be withdrawn when the rising of transaminases per-
sist, except if they are mild and attributed to alcohol consumption.
3. Adverse Effects 4. Clinical orientations
DSF is well-tolerated. Hepatitis is a rare adverse effect, which occurs The recommended dose of naltrexone in the treatment of alcoholism is
mainly after 2 months of treatment with this medication. Early detec- 50 mg/day. The therapeutic scheme consists of the prescription of 25
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 Pharmacologic treatment / Castro LA & Baltieri DA Rev Bras Psiquiatr 2004;26(Supl):43-46

mg/daily in the first week of treatment, aiming to decrease the inci- 4. Orientations
dence and severity of the adverse effects. After this period, the dose Acamprosate should be administered in alcohol-dependent patients
may be raised to 50 mg/daily. The clinical trials with naltrexone pro- with more than 60 Kg, in three daily doses, being two capsules with 333
pose a 12-week treatment. According to O’Malley et al.,8 naltrexone mg in the three periods of the day, always before meals. For patients
keep the reduced relapse rates up to the fifth month after its discon- with less than 60 Kg, most of the studies suggest the administration of
tinuation. Anton et al.9 have evidenced similar relapse rates among the lower doses, i.e., a capsule with 333 mg in the three periods of the day.
treatment groups, four months after discontinuation of naltrexone Maintenance time of the medication is variable. The clinical trials per-
chlorhydrate and placebo. Latt et al.10 found that the therapeutic formed used the drug for 6 to 12 months.20
effects on relapse rates are stronger in the first 42 days of treatment.
Future Perspectives
Acamprosate Currently, two medications, topiramate and ondansetrom, have shown
Acamprosate (calcium acetyl-homotaurinate) has been prescribed for promising in the treatment of alcohol-dependence.
more than one decade in several countries and has proven efficient in Topiramate is an antagonist of the Glutamate AMPA receptor, which
the treatment of alcohol dependence.11 Despite its approval for use in reduces the propriety of positive reinforcement related to the con-
the treatment of patients with Alcohol dependence syndrome in seve- sumption of ethanol. Johnson et al. (2003) have demonstrated, in one
ral European and Latin-American countries, up to now it has not been double-blind, placebo-controlled study, the efficacy of topiramate in
approved by the FDA for this indication. alcohol-dependent patients, in terms of abstinence rates, reduction of
1. Mechanisms of action craving and decrease in the serum levels of serum gama-glutamil
This medication inhibits the glutamatergic excitatory activity, acting, transpeptidase (GGT).
probably, on a subclass of Glutamate (NMDA) receptors, especially Ondansetron, a 5-HT3 antagonist, is a drug which has been proposed
when there is hyperactivity of these receptors. Acamprosate has been for the treatment of subjects with early-onset alcohol dependence.
considered a partial coagonist of the NMDA receptor.12 There is evi- These patients present significant family history for alcohol depen-
dence that this medication reduces glutamate-induced calcium reup- dence and anti-social behavior. It is supposed that the neurochemical
take on neurons, suppresses the conditioned responses to ethanol in substrate of these clinical characteristics is abnormalities of the sero-
dependent animals, even on those with protracted abstinence, reduces toninergic system. Johnson et al. (2000) have evidenced decrease of
the aversive effects of alcohol withdrawal, inhibits the brain hyperex- alcohol consumption among patients receiving 4g/kg of ondansetron
citability of glutamate and inhibits the c-fos gene expression.13 The along the 11 weeks of treatment.21
activity on the gabaergic system has been described, mainly involving
subcortical pathways. In an experimental study, Daoust et al.14 have Conclusions
described that acamprosate improves the reuptake of GABA in the tha- Acamprosate and naltrexone are important pharmacological
lamus and hypothalamus of inebriated rats. Stromberg et al.15 claim resources in the treatment of alcohol dependence syndrome. Under
that there are NMDA-type receptors in the nucleus accumbens which certain paired conditions, disulfiram is also an efficient intevervention.
receive stimuli from the amygdale, hippocampus, pre-frontal cortex We highlighted promising results with topiramate and ondansetron
and ventral tegmental area. These receptors, thus, seem to modulate which should be replicated by further clinical trials. The pharmacolo-
the dopaminergic activity of the nucleus accumbens, reducing the gical research in this area remains always guided by the neurobiolo-
ethanol-related positive reinforcement. gical alterations triggered by the intense consumption of ethanol,
2. Contraindications revealing new and promising breakthroughs. The pharmacological
Acamprosate has a good oral absorption, which is, however, impaired treatment of chemical dependences as a whole should not be the main
by the concomitant ingestion of food. It is not metabolized, being com- therapeutical strategy, as innumerable other factors, besides the bio-
pletely eliminated by the kidneys. Besides, it has no protein link. All logical, compose these diseases, but should be thought as an impor-
these characteristics suggest that this medication has no preoccu- tant medical tool for better approaching patients.
pying interactions with other drugs. Patients with hepatic insufficiency
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Correspondence
Rua Tenente Gomes Ribeiro, 30,
apto. 103 Vila Clementino
04038-040 São Paulo, SP, Brasil
E-mail: [email protected]
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