baclofen in alcohol dependence

Baclofen

Treatment of Alcohol Dependence

2

Standard Drink Measure

3

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

4

Historical Trends: 1850-1997

00.5

11.5

22.5

3

1850

1916

-19

1940

1955

1975

1985

1995

Year

Gal

lon

s E

than

ol

SpiritsWineBeer

Source: Nephew et al., 1999

5

Alcohol Dependence or Alcoholism

A progressive chronic

disorder that both American

Medical Association and

American Psychiatric

Association recognize as a

disease.

It is a common disorder

posing a heavy burden on

patients, their families and

the society

What contributes to the

development of a problem

with drinking?

Neurochemical

factors,

Genetic factors, and

Emotional factors,

among others

6

Definition of Alcohol DependenceDefinition of Alcohol Dependence

Tolerance or withdrawalTolerance or withdrawal Amount/duration of use Amount/duration of use

greater than intended.greater than intended. Unsuccessful efforts to control Unsuccessful efforts to control

or reduce useor reduce use Spending much time using Spending much time using

alcohol, recovering from its alcohol, recovering from its effects, or trying to obtain it.effects, or trying to obtain it.

Reducing or abandoning Reducing or abandoning important work, social or important work, social or leisure activities because of leisure activities because of alcohol use.alcohol use.

Continued alcohol use Continued alcohol use despite knowing that it has despite knowing that it has probably caused ongoing probably caused ongoing physical or psychological physical or psychological problems.problems.

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

7

Icon of Alcohol

+GABA

+Mu

opiates

_GLU

Alcohol

+

Cannabi

noids

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

8

Overview of Treatment

Maintaining Abstinence, Preventing

Relapse

Alcohol Detoxification

Treatment of Alcoholism

STEP 1

STEP 2

9

Early Onset

Wx sxWx sx

BZDZThiamine

H2 blockersOther prn

AcamprosateAcamprosate –ve Affect

state

AcamprosateAcamprosate –ve Affect

state

Baclofen30-60 mg/d

DiathesisExternalizing

AtomoxetineBupropion

+Behavioral

Training-Cog train

-Brain train-Prob solving-Coping skills

Reverse Reverse NeuroNeuroAdaptationAdaptation

NaltrexoneOndansetron

Baclofen

Topiramate

+Unchain habits

Structure ADL

Alternative highs

Phys. Exercise

Relapse Relapse PreventionPrevention

- Relapse - Relapse TriggersTriggers

-Social support Social support -MonitoringMonitoring-Safety netSafety net

-Contingency Contingency ContractingContracting

-Regular F/URegular F/U-Single Single

therapisttherapist

Dealing with fallout

Involve sig. others

Supportive Therapy

? Directive & Prescriptive

Behav. Marital etc.

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

10

Late Onset

Wx sxWx sxWx sxWx sx

BZDZThiamine

H2 blockers

AcamprosateAcamprosate –ve Affect

state

AcamprosateAcamprosate –ve Affect

state

Precursor Precursor event / event /

conditioncondition

Precursor Precursor event / event /

conditioncondition

Supportive and/

Individual Therapy prn

SSRI’s etc.

Reverse Reverse NeuroNeuroAdaptationAdaptation

Reverse Reverse NeuroNeuroAdaptationAdaptation

SSRI–Sertraline

AcamprosateTopiramate

+Unchain habitsStructure ADLAlternative highs

Yoga/ relaxation tech

Relapse Relapse PreventionPrevention

Relapse Relapse PreventionPrevention

- - Relapse Relapse TriggersTriggers

-Social support Social support -MonitoringMonitoring-Safety netSafety net

-Contingency Contingency ContractingContracting

-Regular F/URegular F/U-Single Single

therapisttherapist

Dealing with fallout

Dealing with fallout

Involve sig. others

Supportive Therapy

? Directive & Prescriptive

Behav. Marital etc.

Depression and anxiety very common – ask and treat appropriately

11

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. 

12

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.

13

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).

14

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.

15

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

16

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.

17

Baclofen – Efficacy in alcohol dependence

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

19

Study design

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

20

Reduction in percentage of heavy drinking days

Study results

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

21

Increased percentage of abstinent days with baclofen treated patients

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

22

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

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

23

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

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.

25

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

Study design

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

26

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%) .

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

27

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 T1–T4.

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

28

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.

Conclusion

29

Baclofen for Alcohol Dependence in Patients with Liver Cirrhosis

Addolorato G, et al. Lancet. 2007; 370(9603): 1915–1922.

30

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.

31

Methods

Between October 2003 to November 2006, alcohol-

dependent 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).

32

MethodsInclusion 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

Exclusion Criteria

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

Addolorato G, et al. Lancet. 2007; 370(9603): 1915–1922

33

Methods

Addolorato G, et al. Lancet. 2007; 370(9603): 1915–1922.

34

Primary Outcome MeasuresTOTAL ABSTINENCE FROM ALCOHOL

Based on patient’s self-evaluation and family member interview. Blood, urine alcohol content also measured.

CUMULATIVE ABSTINENCE DURATIONTotal 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 MEASURESEvaluated 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.

35

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.

Significant alcohol abstinence in Baclofen group vs. Placebo.

Results

Addolorato G, et al. Lancet. 2007; 370(9603): 1915–1922.

36

Graphs to right:

1. Mean total

craving score

2. Obsessive

subscale

3. Compulsive

subscale

Baclofen significantly reduced craving scores

Addolorato G, et al. Lancet. 2007;370(9603):1915–1922.

37

Study results

Biological liver variables were also measured during 12-week study period.

Patients with baclofen had significantly reduced alanine aminotransferase, bilirubin, INR, and ϒ-glutamyl transferase from baseline and significantly increased albumin.

No difference seen for aspartate aminotransferase, mean cellular volume, and creatinine values.

38

Biological liver variables

Addolorato G, et al. Lancet. 2007 ;370(9603): 1915–1922.

39

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%).

40

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.

41

42

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

1 2 3 4 5 10

5

25

20

15

10

0

_

_

Baclofen

Diazepam

CIW

A_A

r sc

ore

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

43

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

44

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 50-

60 mg/day is efficacious.

45

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.

46

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

47

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

48

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

Baclofen’s development for treatment of alcoholism

should garner scientific interest, since few effective

medications are available for this condition

Thank You