High-dose baclofen for the treatment of alcohol addiction * A double-blind, randomized, placebo-controlled study

First animal studies showed a reduction of alcohol drinking behavior and a
decrease of the intensity of withdrawal signs in alcohol-preferring rats caused
by the administration of baclofen (Colombo et al., 2000; 2003; Stromberg, 2004;
Liang et al., 2006). Consistent with animal research, two open label studies
showed that the administration of 30 mg/day of baclofen for 27 days or 12 weeks
increased abstinence and reduced alcohol intake and craving for alcohol in
alcohol-dependent patients (Addolorato et al., 2000; Flannery et al., 2004).
The efficacy of baclofen was further evaluated in two double-blind randomized
controlled studies, in which the positive effects of 30 mg/day baclofen could
be replicated (Addolorato et al., 2002; Addolorato et al., 2006). In summary,
although one recent double blind randomized controlled study failed to find any
evidence for the efficacy of low dose baclofen (Garbutt et al., 2010), overall,
literature supports the potential value of baclofen in the treatment of AD.

Although, the efficacy of low doses of baclofen has been studied, randomized
controlled studies examining higher doses of baclofen are lacking. Two case
studies demonstrated that the administration of higher doses (up to 270 mg) of
baclofen can completely suppress alcohol craving (Ameisen, 2005; Bucknam,
2007). These studies suggest the use of higher doses of baclofen in the
treatment of alcohol dependence. To date, no randomized controlled studies have
been done comparing high-dose baclofen with placebo treatment. Furthermore,
studies aiming to examine of possible other factors, which could play a role in
the effectiveness of baclofen are missing. Based on earlier literature,
potential predictors of treatment response could be the individual*s anxiety
level, motives to drink, role of family history, genetic endowments or
personality (Garbutt et al., 2010; Addolorato et al., 2002; 2006; Flannery et
al., 2004; Cooper et al., 1995; Lesch & Walter, 1996; Monterosso et al., 2001;
Rohsenow et al., 2007; Oslin et al., 2003; Anton et al., 2008).

The primary goal of the present study is to examine the efficacy of high dose
baclofen for the treatment of patients with AD in a double-blind, randomized,
placebo controlled study. Therefore high dose baclofen will be compared with
placebo.

Furthermore, as a secondary study objective, factors, which may predict the
treatment response of baclofen are investigated. In order to assess which
patients benefit the most of the treatment with baclofen, it is proposed to
examine the role of:
- anxiety
- motives to drink
- personality
- family history and age of onset of AD
- genetic endowments

Additionally, as a third goal, the effect of baclofen on cognitive biases
concerning alcohol will be assessed. The following cognitive biases will be
examined:
- attentional bias
- approach/ avoidance bias
- affective associations

In order to test the efficiency of baclofen a double blind, randomized, placebo
controlled study will be conducted. There will be an intervention.
It is planned to recruit 130 patients. 65 patients will receive treatment with
a high dose of baclofen (150 mg, 120 mg or 90 mg) and 65 participants will
receive placebo.
The study is conducted in six clinics: SolutionS Center, Ready for Change,
U-Center, The Home Clinic and the Stichting voor Alcoholverslavingszorg, Clear
Mind Amsterdam. Furthermore, patients who followed a treatment at SolutionS
without success get the possibility to get a ambulant treatment with baclofen
at SolutionS Center.

Baclofen or placebo will be administered for the duration of 16 weeks.
Thereafter the medication will be decreased. All participants receiving
baclofen will start with a dose of 30 mg/day. In the high dose group, the
dosage will be increased up to a maximum of 150 mg within six weeks. From the
start of the second week, the dosage will be increased with 30 mg every seven
days. In order to ensure a slow habituation the dosage is increased with 10 mg
every other day. Every seven days possible side effects are assessed by means
of a questionnaire. In case of prolonged side effects, the dosage will be
decreased to the former 30 mg step and will be slowly increased again. If no
side effects occur, the dosage will be increased to the following 30 mg step.
If side effects occur during the six days, a physician from the clinic can
decide not to administer the additional tablets for increasing the dosage.
After six weeks the final dosage is reached and patients are stabilized on this
dose. In the high dose group it is possible to reach 90 mg, 120 mg or 150 mg.
In the placebo group the dosage will be increased with placebo pills. Patients
continue taking one of these dosages until week 16, thereafter the dosage will
be slowly decreased.

Baclofen is administered in 10 mg pills. All tablets will be identical in
appearance. Participants in all groups will start with three tablets per day
and can end up taking a maximum of 15 tablets, depending on the occurrence of
side effects. Pills are taken orally three times a day.

Paticipants are tested three times. The first testing session is scheduled
after detoxification. Testing will take place at SolutionS, Ready for Change,
U-Center, at home (via The Home Clinic), in the office of the Stichting voor
Alcoholveslavingszorg, Clear Mind Amsterdam or in the office of Terwille. After
signing the informed consent, participants are asked to fill in questionnaires
in order to collect information about about alcohol use, alcohol drinking
history, family history, use of other drugs, psychological problems and
personality. Participants are asked to conduct three behavioral tasks on a
computer. Each task will take about 12 minutes.The first testing session will
take about 60 - 90 minutes.
After 4 and 16 weeks participants are asked to repeat the same procedure. Each
session will take about 60 to 90 minutes. After 6 month, participants are
contacted by phone in order to ask questions about alcohol use, craving and
wellbeing. This phone calls will take about 10 minutes each.
Participants are asked to give twice a blood sample of 30 ml in order to
determine biological markers of alcohol consumption.
Furthermore, in order to test for alcohol use, breath alcohol concentration
will be measured prior to the screening session and prior to therapy sessions
during the out-patient period. DNA will be collected through saliva samples.

Risks:
- The negative mood induction and the fear inducing pictures may evoke negative
thoughts in participants. In order to diminish possible negative affect, a
positive mood is induced at the end of each session. Additionally, participants
get the possibility to talk to a psychiatrist, if desired.
- The use of baclofen can cause various side-effects, although side effects do
not occur in all users and many users have no, or minor, side effects. Very
frequently (>10%) occurring side effects include sedation, drowsiness, and
nausea. Frequently (1-10%) occurring side effects include decrease in cardiac
output, dizziness, headache, ataxia, tremor, nystagmus, coordination disorder,
reduction in acuity, breath depression, hypotension, vomiting, weakness, dry
mouth, constipation, diarrhea, hyperhidrosis, skin rash, pollakisuria,
enuresis, dysuria, fatigue, confusion, euphoria, depression, hallucination,
muscle weakness, and myalgia. Rarely (0.01-0.1%) occurring side effects include
paresthesia, dysartria, urinary retention, erectile dysfunction, dysgeusia, and
abdominal pain. Very rarely (< 0.01%) occurring side effects include
hypothermia.