barcelona . spain - European Association for the Study of the Liver

BARCELONA . SPAIN
82 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE 83
APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESS TM 2012
particular supportive and coping skills therapy. Naltrexone is also effective in decreasing alcohol desire
caused by images of alcoholic beverages. It also decreases alcohol intake in social drinkers, hazardous
drinkers and ‘problematic’ drinkers susceptible to risk situations. The efficacy of naltrexone in the treatment
of alcohol dependence or abuse in patients with complete participation in the treatment, including the
psychosocial management, was also shown in multicenter studies. However, two recent well-performed
placebo-controlled studies have shown low efficacy or no efficacy of naltrexone in treating patients with
alcohol problems. More recently, naltrexone was copared and combined with acamprosate. Naltrexone,
acamprosate and the combined medication were significantly more effective than placebo. Moreover,
naltrexone-treated patients showed a better outcome regarding time to first drink and time to relapse. The
combined medication was most effective with significantly lower relapse rates than placebo and acamprosate
but not lower than naltrexone. Finally, a recent comparative study between gammahydroxybutyric acid
(GHB) and naltrexone showed that GHB is more effective that naltrexone in treating alcohol addiction once
remission of the withdrawal syndrome has been achieved if the main outcome is to maintain abstinence;
on the other hand, the study confi rmed that naltrexone is useful in preventing alcohol relapse in heavy
drinking. In conclusion, naltrexone could be effective in treating patients with the need for reward as the
main component of alcohol craving, while GHB (see below) could be effective in treating patients with the
need for relief as the main component of alcohol craving. Side effects include nausea (10% and self limiting)
and, less frequently, headache, dizziness, insomnia, vomiting, anxiety and sleepiness. The incidence of
side effects increases if the patient does not abstain from alcohol. Naltrexone should not be administered
to patients with acute hepatitis or liver impairment.
Acamprosate
Even if the mechanism of action is not completely known, it seems that acamprosate affects calcium
channels with a subsequent decrease in the activity of the excitatory system in the central nervous system.
Acamprosate administration in alcohol-preferring rats causes a significant decrease in alcohol intake and an
increase in glutamate, taurin and GABA basal concentrations in the hypothalamus and nucleus accumbens.
Acamprosate may therefore provide a protective mechanism against neurotoxicity, in particular by reducing
the excitatory amino acid glutamate. Animal studies have also shown the anti-relapse properties and the
anti-craving action of the acamprosate. Double-blind clinical trials in alcoholic patients (1.3–3 g/day, orally
administered) have shown the efficacy of acamprosate in decreasing alcohol craving and maintaining
abstinence. Studies performed in a large number of alcohol-dependent patients showed that acamprosate
reduces the rate of episodes of ‘relapse’ and increases the number of alcohol-free days. However, in this
case a recent study showed a low efficacy of the drug in treating alcoholic patients. From this point of
view, it is important to consider the typology of the patient; in particular, recent evidence indicates that
acamprosate is effective in increasing sobriety times, but only in some typology of patients (i.e. Lesch
type I and II patients). Finally, a recent meta-analysis study showed that acamprosate has a significant
beneficial effect in enhancing abstinence in newly detoxified, alcohol-dependent patients. Acamprosate
could be effective in treating patients with relief craving.
Gamma-Hydroxybutyric Acid
GHB is an endogenous compound with neuromodulatory functions. It has an alcohol-mimetic effect on
the central nervous system. This substance interferes with some neurotransmitter systems, in particular
with the mesolimbic-cortical system, by inducing variations in dopamine, serotonin and GABA cerebral
concentrations. Both preclinical and clinical studies have shown that GHB is effective in the treatment
of alcohol dependence. Besides its effectiveness in the treatment of alcohol withdrawal syndrome with
efficacy equivalent to diazepam and clomethiazole, GHB (50 mg/kg body weight, divided into three daily
doses) decreases alcohol craving by reproducing rewarding effects and thus also reducing the number
of episodes of ‘relapse’. GHB is well tolerated; transient side effects, including dizziness, hyporeflexia
and somnolence, have been reported. Non therapeutic use of GHB can produce an anabolic side effect,
but the latter has not been reported in alcoholic patients at the therapeutic dose. Because of its alcoholmimicking
effect, cases of GHB craving and the consequent risk of GHB abuse and dependence have
been reported in the course of GHB treatment; however this phenomenon is relatively rare. Up to 30–40%
of alcohol-dependent patients do not respond to GHB treatment, the short half-life of the drug (about 2 h)
being considered a possible cause. Recent studies have shown that nonresponders to the conventional
fractioning into 3 daily doses of GHB seem to benefit from the subdivision into 6 daily doses at the same
total amount (50 mg/kg body weight/day). In these patients, the increased dose fractioning seems to be
able to cause a significant reduction in craving, increasing the therapeutic efficacy and decreasing the risk
of abuse. These results have also been confirmed in animal studies. GHB could be effective in treating
patients with reward and/or relief craving
Baclofen
Baclofen is a selective GABAB receptor agonist. Baclofen is well-absorbed after oral administration
and undergoes little liver metabolism (B15%), being primarily eliminated by renal excretion; about 85%
of a single oral dose is excreted unchanged in the urine. Preclinical pharmacological and behavioral
data indicate that baclofen effectively suppresses alcohol withdrawal symptoms (AWS), acquisition
and maintenance of alcohol drinking behaviour, relapse-like drinking, alcohol’s reinforcing, rewarding,
stimulating, and motivational properties in rats and mice. The first human open-label pilot study showed the
ability of baclofen (10 mg t.i.d. over 4 weeks) in reducing alcohol craving and intake in alcohol-dependent
individuals. These encouraging results led the same researchers to test baclofen in a randomized, doubleblind,
placebo-controlled design in which baclofen (10 mg t.i.d.) or placebo was administered for 4 weeks.
Results of this study showed baclofen’s efficacy, with respect to placebo, in reducing alcohol intake, craving
scores, and state anxiety, and in increasing cumulative abstinence duration. Subsequent open-label 12-
week pilot studies have further confirmed the role of baclofen in reducing alcohol intake and craving and
anxiety scores, and promoting alcohol abstinence. In both studies, baclofen was reasonably tolerated and
no serious adverse events were reported. The most common side effects were sleepiness, tiredness, and
vertigo, which tended to resolve within 1–2 weeks of drug treatment. Recently, these findings were extended
in a larger double blind placebo-controlled trial involving 84 alcohol-dependent patients affected by liver
cirrhosis (see next paragraph). Consistent with previous observations, this study showed a significant effect
of baclofen (10 mg t.i.d.), compared with placebo, in reducing alcohol craving and intake and in promoting
total alcohol abstinence.
All studies reported above tested baclofen at a dose of 10 mg t.i.d. However, the safety and the manageability
of baclofen led researchers to test baclofen at higher doses. The role of different doses of baclofen (10
mg or 20 mg t.i.d.) in alcohol dependence has been explored in a randomized double-blind placebocontrolled
12-week trial. The effect of baclofen 20 mg t.i.d. was significantly higher than that of baclofen
10 mg t.i.d., showing a dose–effect relationship. Both doses of baclofen were well tolerated. The role of
baclofen has also been reported in the management of AWS. A randomized study compared baclofen (10
mg t.id. for 10 consecutive days) with the ‘gold standard’ diazepam (0.5–0.75 mg/kg/day) in the treatment
of moderate to severe AWS, showing a comparable efficacy of the two drugs in reducing AWS symptoms.
Additional preliminary evidence further confirms these observations: a chart review showed that baclofen
prevented the development of AWS symptoms, and a placebo-controlled randomized study, where subjects
with AWS received baclofen 10 mg t.i.d. or placebo, showed that the need for benzodiazepines to control
symptoms of AWS was significantly lower in the baclofen group. In conclusion, considering its efficacy in
the management of AWS, in reducing alcohol craving, and in promoting alcohol abstinence, baclofen might
be considered a promising new drug for the treatment of alcohol dependence, particularly in alcoholic
patients with alcoholic liver disease. However, larger studies are needed to confirm the present findings and
to expand the information on the safety of higher doses of baclofen in the treatment of alcohol dependence.