Baclofen

Treatment of Alcohol Dependence

Standard Drink Measure

Drinking Episodes Defined

(National Household Survey)

Binge Drinking as 5 or more drinks per occasion Heavy alcohol use as 5 or more drinks for 5 or more days per month

Historical Trends: 1850-1997

3 2.5 2 1.5 1 0.5 0

Gallons Ethanol

Spirits Wine Beer

Year
Source: Nephew et al., 1999

Alcohol Dependence or Alcoholism

A progressive chronic disorder that both American Medical Association and American Psychiatric Association recognize as a disease.

What contributes to the development of a problem with drinking?

Neurochemical factors,

Genetic factors, and

Emotional factors, among others

It is a common disorder posing a heavy burden on patients, their families and the society

Definition of Alcohol Dependence

Maladaptive alcohol use causes clinically important distress or impairment, shown in a single 12-month period by three or more of the following:

Tolerance or withdrawal Amount/duration of use greater than intended. Unsuccessful efforts to control or reduce use Spending much time using alcohol, recovering from its effects, or trying to obtain it.

Reducing or abandoning important work, social or leisure activities because of alcohol use. Continued alcohol use despite knowing that it has probably caused ongoing physical or psychological problems.

Icon of Alcohol
In addition to enhancing GABA inhibition and reducing Glutamate excitation, alcohol also enhances euphoric effects by releasing opiates and cannabinoids

Alcohol
+ GABA

Overview of Treatment

Treatment of Alcoholism STEP 1

Alcohol Detoxification

STEP 2

Maintaining Abstinence, Preventing Relapse

Early Onset
Diathesis Externalizing Wx sx Reverse Neuro Adaptation Relapse Prevention - Relapse Triggers -Social support -Monitoring -Safety net Involve sig. others Supportive Therapy ? Directive & Prescriptive Behav. Marital etc. Dealing with fallout

Atomoxetine Bupropion + Behavioral Training -Cog train -Brain train -Prob solving -Coping skills

BZDZ Thiamine H2 blockers Other prn Acamprosate ve Affect state

Naltrexone Ondansetron Baclofen

Topiramate
+ Unchain habits Structure ADL Baclofen 30-60 mg/d Alternative highs Phys. Exercise

-Contingency Contracting
-Regular F/U -Single therapist

Bipolar (esp BP II) very common ask and treat appropriately

Late Onset
Precursor event / condition
Wx sx
BZDZ Thiamine H2 blockers Supportive and/ Individual Therapy prn
SSRIs etc.

Reverse Neuro Adaptation

SSRISertraline Acamprosate Topiramate + Unchain habits Structure ADL Alternative highs Yoga/ relaxation tech

Relapse Prevention

Dealing with fallout

Relapse Triggers -Social support -Monitoring -Safety net -Contingency Contracting -Regular F/U -Single therapist

Involve sig. others

Supportive Therapy ? Directive & Prescriptive
Behav. Marital etc.

Acamprosate ve Affect state

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Depression and anxiety very common ask and treat appropriately

Baclofen- promising new therapy for alcohol withdrawal.

Baclofen is a GABA-B receptor agonist.

In several studies, it reduced moderate and severe symptoms in alcohol withdrawal syndrome, and it had a more favorable side effect profile than benzodiazepines. Baclofen exhibits less addictive properties and may be more effective than benzodiazepines at helping to maintain abstinence in alcoholics.

Before widespread can be recommended, larger studies comparing it directly to benzodiazepines are needed.

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Treating Alcohol Addiction: A Pill Instead of Abstinence?

They call it "the switch." Alcoholics who take an anticraving medication called baclofen say the drug allows them to resist the most powerful triggers of relapse: former drinking buddies, a favorite bar, the sight of alcohol or even the most potent drinking cue of all, having a single drink.

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Baclofen - History

Dr. Olivier Ameisen, professor of medicine at Cornell University, reported in 2004 in the journal Alcohol and Alcoholism that he successfully used Baclofen to completely suppress his own alcohol addiction.

His therapeutic model was reproduced by Dr. William Bucknam, (case report in Alcohol and Alcoholism) and by Roberta Agabio et al. (case reportin Journal of Clinical Psychopharmacology).

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Mechanism of action

VTA is modulated by GABAergic inputs. GABAB receptors inhibit VTA cell bodies, i.e., when stimulated, hyperpolarize the membrane potential and decrease firing rates of VTA neurons.

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Mechanism of action

Different lines of experimental evidence suggest that

mesolimbic dopamine neurons are involved in the

mediation of alcohol intake and reinforcement

Interestingly, GABAB receptors are located in the ventral tegmental area (the area where mesolimbic dopamine neurons originate), both on the cell body of dopamine neurons and on the terminals of glutamatergic afferent neurons

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Mechanism of action

Their activation by GABAB receptor agonists may exert an

inhibitory action on the dopamine neurons.

This is the possible mechanism through which baclofen suppresses alcohol- stimulated dopamine release and, in turn, dopamine mediated, alcohol-reinforced and -motivated behaviors.

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Baclofen Efficacy in alcohol dependence

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18

Garbutt JC, et al. Alcohol Clin Exp Res. 2010; 34(11): 1849-57.

Study design

80 subjects randomized

36 Females

44 Males

18 Assigned to Baclofen

18 Assigned to Placebo

22 Assigned to Baclofen

22 Assigned to Placebo

19

Garbutt JC, et al. Alcohol Clin Exp Res. 2010 Nov; 34(11): 1849-57.

Study results
Reduction in percentage of heavy drinking days

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Garbutt JC, et al. Alcohol Clin Exp Res. 2010 Nov; 34(11): 1849-57

Increased percentage of abstinent days with baclofen treated patients

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Garbutt JC, et al. Alcohol Clin Exp Res. 2010 Nov; 34(11): 1849-57.

Reduction in craving, anxiety, and depression with baclofen treated patients vs. placebo

22

Garbutt JC, et al. Alcohol Clin Exp Res. 2010 Nov; 34(11): 1849-57.

Increased percentage of individuals maintaining abstinence during trial by drug condition.

23

Garbutt JC, et al. Alcohol Clin Exp Res. 2010 Nov; 34(11): 1849-57.

24

Addolorato G,et al. Alcohol Alcohol. 2002 Sep-Oct; 37(5): 504-8.

Study design
Diagram on recruitment, group allocation, treatment retention and success in achieving and maintaining complete abstinence.

25
Addolorato G,et al. Alcohol Alcohol. 2002 Sep-ct; 37(5): 504-8.

Study results

A significantly higher number of patients who achieved and maintained abstinence throughout the experimental period was found in the group of patients treated with baclofen (14 out of 20, corresponding to 70.0%) compared to subjects treated with placebo (four out of 19, or 21.1%) .

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Addolorato G,et al. Alcohol Alcohol. 2002 Sep-Oct; 37(5): 504-8.

Significant effects of treatment and time on both compulsive and obsessive drinking subscales of OCDS, with scores in the baclofen groups constantly lower than those of the placebo group throughout T1T4.

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Addolorato G,et al. Alcohol Alcohol. 2002 Sep-Oct; 37(5): 504-8.

Conclusion
The results of the present preliminary double-blind study confirm that baclofen, because of its anti-craving and anti-reward action on the one hand, and safety on the other, may have an important role in the treatment of patients with alcohol problems.

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Baclofen for Alcohol Dependence in Patients with Liver Cirrhosis

Addolorato G, et al. Lancet. 2007; 370(9603): 19151922.

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Background

In developed countries, alcohol is the most frequent cause

of liver cirrhosis.

Currently, few specific therapies for alcoholic liver disease exist.

However, abstinence is single most important intervention since continued alcohol ingestion is important risk factor for progression of disease. Abstinence is also important for patients who may eventually require liver transplantation.

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Methods

Between October 2003 to November 2006, alcoholdependent patients with liver cirrhosis at the Institute of Internal Medicine of Catholic University in Rome, Italy were assessed for the study.

Patients were referred to the institute (which has both a

liver unit and an alcohol addiction unit).

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Inclusion Criteria

Methods

Exclusion Criteria

Age 18-75 ETOH dependence per DSM-IV criteria Liver cirrhosis (Diagnosed by histological findings, PE, lab tests, imaging studies) Alcohol intake: at least 2 heavy drinking days/week and >21 drinks/week men, >14 drinks/week women for 4 weeks prior to study. Family member available for assistance during study

Severe heart or lung disease Abnormal renal function, hepatorenal syndrome or both Malignant disease Metabolic diseases Hepatic encephalopathy Treatment with interferon or corticosteroids in last 2 mo. Psychopathologic disease on treatment Epilepsy Addiction to other drugs other than nicotine

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Addolorato G, et al. Lancet. 2007; 370(9603): 19151922

Methods

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Addolorato G, et al. Lancet. 2007; 370(9603): 19151922.

Primary Outcome Measures

TOTAL ABSTINENCE FROM ALCOHOL Based on patients self-evaluation and family member interview. Blood, urine alcohol content also measured. CUMULATIVE ABSTINENCE DURATION Total number of days abstinent from alcohol -Relapse: Daily ETOH intake of >4drinks or an overall consumption of >14 drinks per week -Lapse: Any episode of ETOH consumption not classified as relapse

Secondary Outcome Measures

DIFFERENCE IN CRAVING MEASURES Evaluated by Obsessive compulsive drinking scale at start of study and at every visit. This scale is validated and measures obsessive and compulsive components of craving.

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Results
Significant alcohol abstinence in Baclofen group vs. Placebo.

Alcohol abstinence in Baclofen group 30/42 (71%) vs. Placebo group 14/42 (29%). Odds ratio 6.3. NNT=2.5 Cumulative abstinence duration twofold higher in Baclofen group. Mean 62.8 days versus 30.8 days. Dropouts in Baclofen group 6/42 (14%) vs. Placebo group 13/42 (31%). p=0.12.
Addolorato G, et al. Lancet. 2007; 370(9603): 19151922.

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Baclofen significantly reduced craving scores

1.

Graphs to right: Mean total craving score Obsessive subscale Compulsive subscale

2.

3.

36

Addolorato G, et al. Lancet. 2007;370(9603):19151922.

Study results

Biological liver variables were also measured during 12-week study period. Patients with baclofen had significantly reduced alanine aminotransferase, bilirubin, INR, and -glutamyl transferase from baseline and significantly increased albumin. No difference seen for aspartate aminotransferase, mean cellular volume, and creatinine values.

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Biological liver variables

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Addolorato G, et al. Lancet. 2007 ;370(9603): 19151922.

Side effects
Baclofen=headache (4), tiredness (1), vertigo (2), sleepiness (1).

Placebo=headache (4), tiredness (1), vertigo (1) Treatment adherence did not differ between groups. Placebo (79.5%) and Baclofen (82.8%).

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Conclusion

Study suggest that give reduction in self-reported alcohol use and with significant reductions in clinical markers, enough evidence suggests that oral administration of baclofen is significantly more effective than placebo in maintaining alcohol abstinence.

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41

Suppressing effect of baclofen on alcohol withdrawal : a comparative study versus diazepam

25 20 CIWA_Ar score 15 10 5 0 1 2
_ _

Baclofen Diazepam

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Time (days)

10

Addolorato G, et al. Am J Med. 2006 Mar; 119(3): 276.e13-8

Baclofen Trials summary

Baclofen administration in human alcoholics have a significant efficacy - to induce alcohol abstinence - to reduce alcohol intake - to reduce alcohol craving -in obsessive component -in compulsive component - to induce the remission of alcohol withdrawal syndrome -delirium tremens Baclofen seems to be very manageable also showing general safety, even when administered to patients with severe liver disease 43

Baclofen Dosage used in clinical Trials

Therapy usually started with an initial low dose of about 30 mg daily and gradually titrated up in a stepwise fashion until symptomatic relief occurs.

The usual maximum dose is 80 mg per day.

However Addolorato et al and our group have found that 5060 mg/day is efficacious.

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Baclofen- side effects

Common

Constipation; dizziness; drowsiness; fatigue; headache; nausea; sleeplessness

Severe (Uncommon)

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); agitation; chills; inability to urinate; loss of muscle tone; seizures.

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Withdrawal syndrome

Abrupt withdrawal can result in severe withdrawal symptoms resembling benzodiazepine / alcohol withdrawal. Can be stopped by recommencing baclofen More likely if used for long periods of time (>couple of months) and can occur from low or high doses. Severity depends on rate of discontinuation. To minimise withdrawal symptoms taper down slowly

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Summary

Effective in reducing drinking and promoting abstinence

Effectiveness started at about the 10 mg per day

Reduced craving, comorbid anxiety and depression Combats craving by inhibiting alcohol-induced release of dopamine in the midbrain Adverse effects were of mild intensity Can be administered in patients with advanced liver disease

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Conclusion

Bolder approaches should at least be considered where the scientific rationale is compelling and the putative therapeutic medication is known to be safe and preferably approved for human use Baclofen is safe and effective medication for treatment of alcoholism Baclofens development for treatment of alcoholism should garner scientific interest, since few effective medications are available for this condition

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Thank You