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

BARCELONA . SPAIN
84 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE 85
APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESS TM 2012
Topiramate
Topiramate, a sulfamate-substituted fructose-1,6-diphosphate analog with strong anticonvulsant properties,
increases GABAA-facilitated neuronal activity and also antagonizes AMPA and kainite glutamate with a
consequent reduction of dopamine release in the nucleus accumbens. Topiramate has an almost complete
oral absorption with high bioavailability (80%). The drug is not widely metabolized and is predominantly
eliminated (70%) unchanged in the urine (Shank et al, 2000). Several studies suggest a role for topiramate
in treating alcohol use disorders, although further studies are needed to confirm the present findings. The
first clinical trial with 150 alcohol-dependent patients showed topiramate’s efficacy in reducing alcohol
dependence and promoting abstinence. In this trial, topiramate was significantly more effective than placebo
in reducing drinking variables (drinks per day, drinks per drinking day, percentage of heavy drinking days,
plasma g-glutamyl transferase ratio), and in increasing the percentage of abstinent days. Topiramate was
effective in reducing some craving measurements (i.e. obsessive thoughts about alcohol, automaticity of
drinking, interference due to drinking). No serious adverse events were reported during the trial (Johnson et
al, 2003). These results were confirmed in a larger 14-week clinical trial with 371 alcohol-dependent patients
and performed across 17 US sites. In addition to confirming the efficacy of topiramate on alcohol drinking,
this trial also showed effects of topiramate on physical health, alcohol craving, and psychosocial wellbeing.
Outcome measures of physical health included liver function tests, hematological, and biochemical
measures (plasma cholesterol and bicarbonate and urine pH level), vital signs (blood pressure, pulse, and
temperature), and BMI. Topiramate was superior to placebo in improving physical health outcomes and
measures of psychosocial functioning. Altogether, these results suggest that topiramate has greater efficacy
than placebo to improve the quality of life, decrease the severity of alcohol dependence, and reduce the
detrimental consequences associated with heavy drinking. Future research may include the combination of
topiramate with other medications, as well as the identification of endophenotypes with different responses
to topiramate-induced side-effects.
Fluoxetine, Other Serotonin Reuptake Inhibitors and Ondansetron
Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), seems to act also through GABA-ergic action as
well as with serotoninergic mechanisms; it is administered at a dose of 20 mg/day for the fi rst 2 days with
a subsequent dose of 60 mg/day, taking care to note the possible occurrence of manic reactions . Recent
studies have shown the efficacy of fluoxetine in alcoholic patients affected by depression; at a dose of 20
mg/day for the fi rst 2 weeks then 40 mg/day if necessary, fluoxetine has proved to be effective in reducing
depressive symptoms and alcohol consumption in these patients . Its efficacy, however, seems to decrease
in alcoholic patients without significant mood disorders. Fluvoxamine is a monocyclic SSRI, registered
worldwide for the treatment of depression and obsessive compulsive disorders. A double-blind multicenter
study showed no evidence that this drug helps prevent relapse in detoxified, abstinent or alcoholic patients.
There are some contrasting data on the efficacy of sertraline, citalopram (SSRI agents). It seems that SSRIs
might be useful in late-onset alcoholics, while ondansetron at a dose of 0.5–4 mg divided into two daily
doses for 6 weeks could be effective in early-onset alcoholics. Ondansetron (5HT3 receptor antagonist) is
able to increase dopamine level throughout the blocking action on 5HT3 receptor. This drug seems to be
effective to reduce craving and alcohol intake in early-onset alcoholics; moreover recent data showed the
efficacy of ondansetron in some genetic subtype of alcoholic patients.
MEDICAL MANAGEMENT OF ALCOHOL DEPENDENCE IN PATIENTS WITH ALD
Alcoholic liver disease (ALD) is one of the major medical complications of alcohol abuse. In particular,
80% of heavy drinkers develop steatosis, 10–35% develop alcoholic hepatitis, and approximately 10% will
develop cirrhosis. Possible factors that affect the development of liver injury include the dose, duration,
and type of alcohol consumption, drinking patterns, gender, ethnicity, and associated risk factors including
obesity, iron overload, concomitant infection with viral hepatitis, and genetic factors.
However, independent of the stage of ALD, abstinence from alcohol is the cornerstone of management,
since medical and surgical treatments for ALD have limited success when drinking continues. Accordingly,
total alcohol abstinence can improve the histology and/or survival of individuals with ALD and the clinical
outcome of all stages of ALD. On the contrary, persistent alcohol intake induce progression of liver damage
and, in those patients with alcoholic cirrhosis, is associated with a significant risk ratio of death due to
bleeding esophageal varices, infection, renal failure, and/or hepatic failure.
Psychological approach and counselling are essential components of therapy to promote abstinence in
these patients. However the efficacy of group and supportive psychotherapy is relatively low as monotherapy
(15-39%). As reported above, at present there are several medications able to reduce alcohol craving and,
consequently, to increase abstinence and prevent alcohol relapse. However trials investigating anti-craving
medications typically exclude individuals with high levels of transaminases and/or advanced liver disease,
for the concern that these medication might worsen liver disease. Infact, naltrexone is contraindicated in
those with liver disease due to its hepatic metabolism and reports of medication-related hepatic injury.
Acamprosate may induce hyperammoniemia; topiramate affect liver function and it may also induce
hyperammoniemia.
In the last few years, growing evidences suggest a role of baclofen in the management of ALD patients; at
present baclofen is the only drug tested in alcohol dependent patients affected by liver cirrhosis or acute
alcoholic hepatitis. Based on the safe profile of baclofen, summarized before, and considering baclofen’s
pharmacological profile (renal excretion and a small liver metabolism), a first randomized clinical trial was
conducted with a population of alcohol-dependent patients affected by liver cirrhosis. Inclusion criteria
consisted of both a current diagnosis of alcohol dependence and a diagnosis of cirrhosis. In this trial,
baclofen (10 mg t.i.d.) or placebo was administered for a 12-week period. Baclofen showed a significant
effect, compared to placebo, in reducing alcohol intake and craving. In particular, a significantly higher
number of patients treated with baclofen achieved and maintained abstinence (71.4%) compared to the
placebo group (28.6%; p=0.0002). The number of drop-outs was not statistically significantly different
between baclofen group (14.3%) and placebo group (31%; p=0.12). Cumulative Abstinence Duration
was approximately two-fold higher in baclofen- than placebo treated patients (p=0.001). Survival analysis
revealed a significantly greater chance in the baclofen group of remaining free of relapse to alcohol
consumption (p=0.006). There was also a significant reduction of OCDS craving scores (OCDS total score
and obsessive and compulsive OCDS subscores) in the baclofen group compared to the placebo group.
No patients had encephalopathy during the study period. Further, none showed hyperammonaemia or
significant changes in number connection test performance. Individuals allocated baclofen had significantly
reduced alanine aminotransferase, bilirubin, international normalised ratio, and γ glutamyltransferase from
baseline and significantly increased albumin. No serious systemic or single-organ event leading to drug
cessation was reported and no patient discontinued treatment because of a side-effect. Tolerability was fair
in all individuals. The safety of baclofen in patients with alcoholic liver disease has been confirmed by a
further study where baclofen was administered for at least 5 months in 14 patients with alcoholic hepatitis
(Avanesyan and Runyon, 2010). In this trial 13/14 patients completely stopped drinking/craving alcohol
since the start of baclofen and one patient reported a reduction in alcohol consumption from 50 to 3 drinks/
day. Those with the most severe illness were more willing to comply with medication, thus, showing the
most improvement. Total bilirubin was notably reduced. About 70% reduction was observed at 5 months
and 90% reduction after 8 months of baclofen use. Reduction in total bilirubin and AST were statistically
significant. No side effects were reported.
In conclusion baclofen, because of its anticraving action and safety, could have an important role for treatment
of alcohol-dependent patients with advanced liver disease, including those needing liver transplantation
(OLT), since the need of alcohol abstinence both before and after OLT.
In addition to dietary supplement therapy, several drugs have been tested to improve survival in patients
with ALD, including corticosteroids, propylthiouracil, S-adenosyl-L-methionine, infliximab and pentoxifylline.