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