Pharmacotherapy of Pharmacotherapy of Alcohol DependenceAlcohol Dependence

Department of Surgery Grand RoundsDepartment of Surgery Grand RoundsSt. Luke’s and Roosevelt HospitalsSt. Luke’s and Roosevelt HospitalsNew York, Wednesday, September 7, 2005New York, Wednesday, September 7, 2005

Petros Levounis, M.D.Petros Levounis, M.D.Director, The Addiction Institute of New YorkDirector, The Addiction Institute of New YorkChief, Division of Addiction Psychiatry atChief, Division of Addiction Psychiatry atSt. Luke’s and Roosevelt HospitalsSt. Luke’s and Roosevelt Hospitals

www.AddictionInstituteNY.orgwww.AddictionInstituteNY.org

4 HANDOUTS4 HANDOUTS

1.1. Mayo-Smith, M.F. (2003). Mayo-Smith, M.F. (2003). Management of Management of Alcohol Intoxication and Withdrawal.Alcohol Intoxication and Withdrawal. In In A. W. Graham, T. K. Shultz, M. F. Mayo-A. W. Graham, T. K. Shultz, M. F. Mayo-Smith, R. K. Ries, & B. B. Wilford (Eds.), Smith, R. K. Ries, & B. B. Wilford (Eds.), Principles of Addiction MedicinePrinciples of Addiction Medicine (3 (3rdrd ed., pp. ed., pp. 621-631). Chevy Chase, Maryland: 621-631). Chevy Chase, Maryland: American Society of Addiction Medicine.American Society of Addiction Medicine.

2.2. Fundamentals of Addiction MedicineFundamentals of Addiction Medicine

3.3. Addiction Institute BrochureAddiction Institute Brochure

4.4. These slidesThese slides

OUTLINEOUTLINE

1.1. IntroductionIntroduction

2.2. Alcohol IntoxicationAlcohol Intoxication

3.3. Alcohol WithdrawalAlcohol Withdrawal

4.4. Relapse PreventionRelapse Prevention

5.5. Co-Occurring DisordersCo-Occurring Disorders

6.6. New DirectionsNew Directions

11

INTRODUCTIONINTRODUCTION

EpidemiologyEpidemiology

207 million 207 million = US Population= US Population 18 million 18 million = Alcohol Use Disorders = Alcohol Use Disorders

(9%)(9%) 8 million 8 million = Alcohol Dependence (45%)= Alcohol Dependence (45%) 2 million 2 million = Ever treated (24%)= Ever treated (24%) 1.2 million 1.2 million = Ever seen an M.D. (60%)= Ever seen an M.D. (60%) .6 million .6 million = Ever given meds (50%)= Ever given meds (50%)

Grant BF et al. Arch Gen Psychiatry. 2004;61:807-816.Grant BF et al. Arch Gen Psychiatry. 2004;61:807-816.

http://imshealth.comhttp://imshealth.com

Neurotransmitter Neurotransmitter SystemsSystems

GABAGABA →→ CNS InhibitionCNS Inhibition GlutamateGlutamate →→ CNS ExcitationCNS Excitation OpioidOpioid →→ Euphoria/Euphoria/

RewardReward DopamineDopamine →→ AddictionAddiction SerotoninSerotonin →→ ImpulsivityImpulsivity

22

ALCOHOL ALCOHOL INTOXICATIONINTOXICATION

CharacteristicsCharacteristics

0-100 mg/dL0-100 mg/dL Well-beingWell-being 100-200 mg/dL100-200 mg/dL IncoordinationIncoordination 200-300 mg/dL200-300 mg/dL AtaxiaAtaxia 300-400 mg/dL300-400 mg/dL Stage I Stage I

AnesthesiaAnesthesia 400-600 mg/dL400-600 mg/dL ComaComa 600-800 mg/dL600-800 mg/dL DeathDeath

PharmacotherapyPharmacotherapy

Use IV thiamine and glucoseUse IV thiamine and glucose Do not use ipecac, activated Do not use ipecac, activated

charcoal, caffeine, charcoal, caffeine, amphetamines, or flumazenil.amphetamines, or flumazenil.

Treatment is supportive.Treatment is supportive.

33

ALCOHOL ALCOHOL WITHDRAWALWITHDRAWAL

Characteristics 1Characteristics 1

Following the last drink:Following the last drink:– 6 to 24 hours: 6 to 24 hours: Autonomic HyperactivityAutonomic Hyperactivity– 24 to 48 hours:24 to 48 hours: SeizuresSeizures– 48 to 96 hours:48 to 96 hours: Delirium tremensDelirium tremens

““Kindling effect” for seizures.Kindling effect” for seizures. Older patients are at higher risk of DTs.Older patients are at higher risk of DTs. Typically mild, occasionally severe, Typically mild, occasionally severe,

rarely fatal.rarely fatal.

Characteristics 2Characteristics 2

Autonomic Hyperactivity with:Autonomic Hyperactivity with:– Reduced GABA activity andReduced GABA activity and– Enhanced glutamate activity.Enhanced glutamate activity.

Characteristics 3Characteristics 3

Early signs of withdrawal:Early signs of withdrawal:

– TachycardiaTachycardia– Blood pressure elevationBlood pressure elevation– SweatingSweating– HyperthermiaHyperthermia– Tremor (6 to 8 cycles per second)Tremor (6 to 8 cycles per second)

AssessmentAssessment

Clinical Institute Withdrawal Clinical Institute Withdrawal Assessment for Alcohol (revised).Assessment for Alcohol (revised).

Mayo-Smith MF. JAMA. 1997;278:144-51.Mayo-Smith MF. JAMA. 1997;278:144-51.

CIWA-Ar CategoriesCIWA-Ar Categories[ Range of Scores: 0-7* [ Range of Scores: 0-7* ]]Neuropsych. Neuropsych. SymptomsSymptoms

Physical Physical SymptomsSymptoms

Perceptual Perceptual DisturbancesDisturbances

CLOUDED CLOUDED SENSORIUMSENSORIUM

NAUSEA/NAUSEA/

VOMITINGVOMITINGAUDITORYAUDITORY

ANXIETYANXIETY HEADACHEHEADACHE VISUALVISUAL

AGITATIONAGITATION TREMORSTREMORS TACTILETACTILE

SWEATSSWEATS * except 0-4 * except 0-4 for sensoriumfor sensorium

Adapted from www.asam.orgAdapted from www.asam.org

Practice GuidelinesPractice Guidelines

NoMedicationsS u pportiveTreatmen t

< 9M ild

W ith drawal

PRNMedications

O u tpatien t S ympt.Treatmen t

9 - 15M oderate

W ith drawal

StandingMedications

I n patien t M edicalTreatmen t

> 15S evere

W ith drawal

C IWA-ArSC ORE

Adapted from Mayo-Smith MF. JAMA. 1997;278:144-51.Adapted from Mayo-Smith MF. JAMA. 1997;278:144-51.

Pharmacotherapy 1Pharmacotherapy 1

Long-acting benzodiazepines (e.g., Long-acting benzodiazepines (e.g., chlordiazepoxide) are the chlordiazepoxide) are the treatment of choice.treatment of choice.

Short-acting benzodiazepines (e.g., Short-acting benzodiazepines (e.g., lorazepam) are preferred in liver lorazepam) are preferred in liver damage and the elderly.damage and the elderly.

Anticonvulsants are being studied.Anticonvulsants are being studied.

Holbrook AM et al. Can Med Assoc J. 1999;160:649-55. Bonnet U et al. J Clin Holbrook AM et al. Can Med Assoc J. 1999;160:649-55. Bonnet U et al. J Clin Psychopharmacol. 2003;23:514-9.Psychopharmacol. 2003;23:514-9.

Pharmacotherapy 2Pharmacotherapy 2

For symptom triggered medication, For symptom triggered medication, administer every hour when CIWA-administer every hour when CIWA-Ar >= 9:Ar >= 9:

– ChlordiazepoxideChlordiazepoxide 50 to 100 mg50 to 100 mg– Lorazepam Lorazepam 2 to 4 mg2 to 4 mg– Diazepam Diazepam 10 to 20 mg10 to 20 mg

Mayo-Smith MF. JAMA. 1997;278:144-51.Mayo-Smith MF. JAMA. 1997;278:144-51.

Pharmacotherapy 3Pharmacotherapy 3

For standing po chlordiazepoxide:For standing po chlordiazepoxide:

– Day 1:Day 1: 50 mg50 mg Q 4 hoursQ 4 hours– Day 2:Day 2: 50 mg50 mg Q 6 hoursQ 6 hours– Day 3:Day 3: 25 mg25 mg Q 4 hoursQ 4 hours– Day 4:Day 4: 25 mg25 mg Q 6 hoursQ 6 hours

Garbutt JC et al. JAMA. 1999;281:1318-25.Garbutt JC et al. JAMA. 1999;281:1318-25.

Pharmacotherapy 4Pharmacotherapy 4

For delirium tremens:For delirium tremens:

– 2 to 4 mg IV lorazepam followed by2 to 4 mg IV lorazepam followed by– 1 to 2 mg IV lorazepam every 5 1 to 2 mg IV lorazepam every 5

minutes until patient is calm.minutes until patient is calm.– Taper slowly over 4 to 5 days.Taper slowly over 4 to 5 days.

Adopted from Garbutt JC et al. JAMA. 1999;281:1318-25.Adopted from Garbutt JC et al. JAMA. 1999;281:1318-25.

Pharmacotherapy 5Pharmacotherapy 5

In general, for severe In general, for severe withdrawal:withdrawal:

1.1. Titrate to light sedation.Titrate to light sedation.

2.2. Have flumazenil ready.Have flumazenil ready.

3.3. Calculate daily dose.Calculate daily dose.

4.4. Decrease dose by 25% daily.Decrease dose by 25% daily.

44

RELAPSERELAPSE

PREVENTIONPREVENTION

DISULFIRAMDISULFIRAM

Introduced in 1954Introduced in 1954

Mechanism of ActionMechanism of Action

Alcohol → Acetaldehyde → AcetateAlcohol → Acetaldehyde → Acetate Disulfiram irreversibly binds to Disulfiram irreversibly binds to

acetaldehyde dehydrogenase acetaldehyde dehydrogenase inhibiting the metabolism of inhibiting the metabolism of acetaldehyde to acetate.acetaldehyde to acetate.

Acetaldehyde accumulates Acetaldehyde accumulates resulting in a violent reaction resulting in a violent reaction (nausea, vomiting, flushing).(nausea, vomiting, flushing).

EfficacyEfficacy

Double-blind, placebo-control Double-blind, placebo-control study design is not helpful as both study design is not helpful as both the medication and the placebo the medication and the placebo pills may (or may not) result in pills may (or may not) result in fear of drinking.fear of drinking.

Most studies are negative, but Most studies are negative, but disulfiram may be helpful in disulfiram may be helpful in highly structured settings.highly structured settings.

Fuller RK et al. JAMA. 1986;256:1449-55.Fuller RK et al. JAMA. 1986;256:1449-55.

Dosing and SafetyDosing and Safety

250-500 mg daily.250-500 mg daily. Medication costs approximately Medication costs approximately

$40 a month.$40 a month. Some liver toxicity; liver function Some liver toxicity; liver function

should monitored.should monitored. Inhibits hepatic microsomal Inhibits hepatic microsomal

enzymes and increases drug enzymes and increases drug levels.levels.

Physician’s Desk Reference. 59Physician’s Desk Reference. 59thth ed. Pp 2442-3. ed. Pp 2442-3.

NALTREXONENALTREXONE

Introduced in 1995Introduced in 1995

Mechanism of ActionMechanism of Action

Reduces positive reinforcement Reduces positive reinforcement (reward craving).(reward craving).

The patient does not experience The patient does not experience the full euphorogenic/reinforcing the full euphorogenic/reinforcing effect of alcohol.effect of alcohol.

Prevents a slip from becoming a Prevents a slip from becoming a full-blown relapse.full-blown relapse.

EfficacyEfficacy

Effective in reducing relapse to Effective in reducing relapse to heavy drinking ( >4 in men, >3 heavy drinking ( >4 in men, >3 drinks/day in women).drinks/day in women).

The Srisurapanont (2005) meta-The Srisurapanont (2005) meta-analysis found efficacy up to 12 analysis found efficacy up to 12 weeks but not after 12 weeks.weeks but not after 12 weeks.

Medication compliance may be a Medication compliance may be a limiting factor in treatment.limiting factor in treatment.

Mason BJ. Eur Neuropsychopharmacol. 2003;13:469-475. Srisurapanont M & Jarusuraisin N. Mason BJ. Eur Neuropsychopharmacol. 2003;13:469-475. Srisurapanont M & Jarusuraisin N. Cochrane Database Syst Rev 2005. Cochrane Database Syst Rev 2005.

Dosing and SafetyDosing and Safety

50 mg daily.50 mg daily. Medication costs $103 a month.Medication costs $103 a month. Liver toxicity; liver function Liver toxicity; liver function

should monitored closely.should monitored closely. Otherwise safe and well-tolerated.Otherwise safe and well-tolerated. No significant drug-drug No significant drug-drug

interactions.interactions.

http://ncadi.samhsa.gov/govpubs/BKD268/28c.aspxhttp://ncadi.samhsa.gov/govpubs/BKD268/28c.aspx

ACAMPROSATEACAMPROSATE

Introduced in 2005Introduced in 2005

Mechanism of ActionMechanism of Action

Reduces negative reinforcement Reduces negative reinforcement (abstinence craving).(abstinence craving).

Neuroadaptation and Neuroadaptation and upregulation of the glutamate upregulation of the glutamate system in alcoholism.system in alcoholism.

Acamprosate interferes with the Acamprosate interferes with the glutamatergic system.glutamatergic system.

EfficacyEfficacy

Effective in improving abstinence.Effective in improving abstinence. The Mann et al (2004) meta-The Mann et al (2004) meta-

analysis found a 50% analysis found a 50% improvement in 6-month improvement in 6-month abstinence (36% acamprosate vs. abstinence (36% acamprosate vs. 23% placebo).23% placebo).

Three times a day dosing may Three times a day dosing may compromise compliance.compromise compliance.

Sass et al. Arch Gen Psychiatry. 1996;53:673-680. Mann K et al. Alcohol Clin Exp Res. Sass et al. Arch Gen Psychiatry. 1996;53:673-680. Mann K et al. Alcohol Clin Exp Res. 2004;28:51-63.2004;28:51-63.

Dosing and SafetyDosing and Safety

666 mg three times a day.666 mg three times a day. Medication costs $110 a month.Medication costs $110 a month. Excreted by the kidneys - No liver Excreted by the kidneys - No liver

metabolism.metabolism. Mild diarrhea (16% acamprosate Mild diarrhea (16% acamprosate

vs. 10% placebo).vs. 10% placebo). No drug-drug interactions.No drug-drug interactions.

Physician’s Desk Reference. 59Physician’s Desk Reference. 59thth ed. Pp 3428-30. ed. Pp 3428-30.

55

CO-OCCURRING CO-OCCURRING DISORDERSDISORDERS

In GeneralIn General

Co-occurring alcohol dependence Co-occurring alcohol dependence and other psychiatric disorder(s) and other psychiatric disorder(s) typically require treatment for typically require treatment for both (all).both (all).

Treating patients under one roof Treating patients under one roof improves both addiction and improves both addiction and mental health outcomes.mental health outcomes.

Mariani JJ, Levin FR. Harvard Rev Psychiatry. 2004;12:351-66. Kranzler HR, Jaffe JH. In: Mariani JJ, Levin FR. Harvard Rev Psychiatry. 2004;12:351-66. Kranzler HR, Jaffe JH. In: Graham TK et al, eds. Principles of Addition Medicine. 3Graham TK et al, eds. Principles of Addition Medicine. 3rdrd ed. Chevy Chase, MD: American ed. Chevy Chase, MD: American Society of Addition Medicine. 2003:701-19.Society of Addition Medicine. 2003:701-19.

DepressionDepression

Antidepressants typically improve Antidepressants typically improve depressive symptoms.depressive symptoms.

However, they have limited However, they have limited impact on alcohol use.impact on alcohol use.

Nunez EV, Levin FR. JAMA. 2004;291:1887-96.Nunez EV, Levin FR. JAMA. 2004;291:1887-96.

Antidepressants’ Antidepressants’ Effect on DepressionEffect on Depression

From Nunez EV, Levin FR. JAMA. 2004;291:1893.From Nunez EV, Levin FR. JAMA. 2004;291:1893.

Antidepressants’ Antidepressants’ Effect on Substance Effect on Substance UseUse

From Nunez EV, Levin FR. JAMA. 2004;291:1893.From Nunez EV, Levin FR. JAMA. 2004;291:1893.

66

NEW DIRECTIONSNEW DIRECTIONS

New Delivery SystemsNew Delivery Systems

Long-acting naltrexone injection: Long-acting naltrexone injection: 100 μm diameter microspheres 100 μm diameter microspheres composed of naltrexone and PLG composed of naltrexone and PLG polymeric matrix.polymeric matrix.

Nausea, headache, and fatigue Nausea, headache, and fatigue are the prominent adverse are the prominent adverse effects.effects.

FDA decision expected in late ‘05.FDA decision expected in late ‘05.http://www.fda.govhttp://www.fda.gov

Please note: This agent is not approved by the FDA for use in alcohol dependence.Please note: This agent is not approved by the FDA for use in alcohol dependence.

Injectable NaltrexoneInjectable Naltrexone

0%

10%

20%

30%

40%

50%

(n=624)

Placebo

Naltrexone 190 mg

Naltrexone 380 mg

Heavy drinking days Heavy drinking days rates during a 24 rates during a 24 week treatment trial week treatment trial with injectable with injectable naltrexone 190 mg naltrexone 190 mg and 380 mg Qmonth.and 380 mg Qmonth.

Injectable naltrexone Injectable naltrexone reduced the rate of reduced the rate of heavy drinking by heavy drinking by 25% (25% (PP=.02).=.02).

Adapted from Garbutt et al. JAMA. 2005;293:1622.Adapted from Garbutt et al. JAMA. 2005;293:1622.

New CombinationsNew Combinations

Acamprosate and naltrexone have Acamprosate and naltrexone have different mechanisms of action different mechanisms of action and may work synergistically.and may work synergistically.

The COMBINE trial (n=1,375; 11 The COMBINE trial (n=1,375; 11 sites) will assess the medication sites) will assess the medication combination and two behavioral combination and two behavioral interventions for a total of 9 interventions for a total of 9 possible treatment formulations.possible treatment formulations.

COMBINE Study Research Group. Alcohol Clin Exp Res. 2003;27:1123-1131.COMBINE Study Research Group. Alcohol Clin Exp Res. 2003;27:1123-1131.

Naltrexone/Naltrexone/AcamprosateAcamprosate

0%

10%

20%

30%

40%

50%

60%

(n=160)

Placebo Naltrexone

Acamprosate Combination

Abstinence rates Abstinence rates during a 12-week during a 12-week treatment trial with treatment trial with naltrexone 50 mg QD naltrexone 50 mg QD and acamprosate 666 and acamprosate 666 mg TID.mg TID.

The The combinationcombination of of the two medications the two medications helped alcoholics stay helped alcoholics stay abstinent (abstinent (P=P=0.002) 0.002) better than each drug better than each drug alone.alone.

Adapted from Kiefer F et al. Arch Gen Psychiatry. 2003;60:96.Adapted from Kiefer F et al. Arch Gen Psychiatry. 2003;60:96.

New Pharmacological New Pharmacological AgentsAgents AnticonvulsantsAnticonvulsants

– TopiramateTopiramate– CarbamazepineCarbamazepine– Valproic AcidValproic Acid

GABA agonistGABA agonist– BaclofenBaclofen

Selective Serotonin Reuptake InhibitorsSelective Serotonin Reuptake Inhibitors Serotonin (5-HTSerotonin (5-HT33) antagonist) antagonist

– OndansetronOndansetron

Please note: These agents are not approved by the FDA for use in alcohol dependence.Please note: These agents are not approved by the FDA for use in alcohol dependence.

Where you can find usWhere you can find us

You can request an addiction You can request an addiction consultation by contacting:consultation by contacting:– Galen Cooper, Ph.D., x38409/pgr 35864 at Galen Cooper, Ph.D., x38409/pgr 35864 at

Roosevelt, orRoosevelt, or– Raisa Montalvo, M.A., x31743/pgr 39046 at Raisa Montalvo, M.A., x31743/pgr 39046 at

St. Luke’s.St. Luke’s. Our website: Our website:

www.AddictionInstituteNY.orgwww.AddictionInstituteNY.org Our 24-hour-line: 212-523-6491Our 24-hour-line: 212-523-6491