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Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University...

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Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine
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Page 1: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

Pharmacological Treatment of Addiction

David A. Fiellin, M.D.

Professor of Medicine

Yale University School of Medicine

Page 2: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

Overview

• Epidemiology of opioid dependence

• Treatment of opioid dependence– Buprenoprhine– Office-based treatment

• Epidemiology of alcohol problems

• Treatment of alcohol problems– Naltrexone, acamprosate, disulfiram

Page 3: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

• Physical Dependence– Tolerance– Withdrawal

• Loss of control (addiction)– Larger amounts/longer period than intended– Inability to/persistent desire to cut down or control– Increased amount of time spent in activities necessary to

obtain opioids– Social, occupational and recreational activities given up or

reduced– Opioid use is continued despite adverse consequences

Opioid Dependence (DSM-IV, 3 or more within one year)

Page 4: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

Epidemiology• Prescription opioids

– National Survey on Drug Use and Health, 2006• > 12 million reported non-medical use of prescription opioids • Estimated 1.6 million met criteria for prescription opioid abuse or

dependence

• Heroin– National Household Survey on Drug Abuse, 2006

• > 500,000 reported past year heroin use• Approximately 323,000 individuals met criteria for heroin abuse or

dependence

• Combined, 2 million opioid dependent in U.S.– In 2005 only 331,000 individuals entered treatment for opioid

dependence

Page 5: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

Prescription of Opioids• Between 1994 & 2003, prescriptions for:

– Non-controlled drugs increased by 57%

– Controlled substances increased by 154%.

Trescot et al. Pain Physician, 2008; 11: S5-62.

Page 6: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

0.10.1

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LSDLSD

HeroinHeroin

InhalantsInhalants

MethMeth

EcstasyEcstasy

CrackCrack

CocaineCocaine

Prescription DrugsPrescription Drugs

MarijuanaMarijuana

(incl. crack)(incl. crack)

Past Month Users, Ages 12 and Older (in Millions)Past Month Users, Ages 12 and Older (in Millions)

Source: SAMHSA, 2002 National Survey on Drug Use and Health.

Source: SAMHSA, 2002 National Survey on Drug Use and Health.

Nonmedical Use of Prescription Drugs

Nonmedical Use of Prescription Drugs

Page 7: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.
Page 8: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

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Opioid sales (mg perperson)

Annual sales of prescription opioids and unintentional overdose death

1990 - 2006

Source: Paulozzi, CDC, Congressional testimony, 2007

Page 9: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

Brain’s Reward pathways

Page 10: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.
Page 11: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

Changes in Neurobiology

• Repeated exposure to short acting opioids leads to neuronal adaptations– Mesolimbic dopaminergic system

• adaptations in G protein-coupled receptors• up regulation of cyclic cAMP second messenger pathway

• changes in transcription and translation

• Adaptations– Mediate tolerance, withdrawal, craving, self-adminstration– Provide insight into the chronic and relapsing nature of

opioid dependence– Form basis of pharmacotherapies to stabilize neuronal

circuits

Page 12: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

Opioid Treatment

Page 13: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

Pharmacologic Treatment of Opioid Dependence

• Pharmacologic withdrawal - “detoxification”

• Opioid antagonist treatment

– Naltrexone

• Opioid agonist treatment

– Methadone

– Buprenorphine

Page 14: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

Poor results with detoxification Kakko, Lancet 2003

Treatment duration (days)

Rem

aini

ng in

tre

atm

ent

(nr

)

0

5

10

15

20

0 50 100 150 200 250 300 350

Detoxification

Maintenance

Page 15: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

Opioid Agonist Treatment

• Rationale

– Cross-tolerance

• prevent withdrawal

• relieve craving for opioids

– Narcotic blockade

• block or attenuate euphoric effect of exogenous opioids

Page 16: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

How effective is opioid agonist treatment?

Page 17: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

Buprenorphine, Methadone, LAAM: Treatment Retention

Per

cent

Ret

aine

d

0

20

40

60

80

100

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

20% Lo Meth

58% Bup

73% Hi Meth

53% LAAM

Study Week

Page 18: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.
Page 19: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.
Page 20: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.
Page 21: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

HIV Seroconversion

• Metzger, 1993:– 2 cohorts of patients

• 103 out-of-treatment intravenous opiate users

• 152 subjects receiving methadone treatment

– HIV antibody conversion, 18-months• 22% of those out-of-treatment

• 3.5% of those receiving methadone treatment

Page 22: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

Treatment vs. Addiction

MarkedAbsentEuphoria

3-6 hours24-36 hoursDuration

Immediate30 minutesOnset

IV, INOral, sublingualRoute

HeroinMethadone or buprenorphine

Page 23: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

Buprenorphine

• Partial agonist at mu receptor

• Low abuse and diversion potential, especially when combined with naloxone

• Can be prescribed from the office by a physician

• Sub-lingual tablet

• Daily or thrice weekly dosing

Page 24: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

-10 -9 -8 -7 -6 -5 -40

10

20

30

40

50

60

70

80

90

100

Intrinsic Activity

Log Dose of Opioid

Full Agonist(Methadone, oxycodone)

Partial Agonist(Buprenorphine)

Antagonist (Naltrexone)

Intrinsic Activity: Full Agonist (Methadone), Partial Agonist (Buprenorphine), Antagonist (Naloxone)

Page 25: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

Bup 00 mg

Bup 02 mg

Bup 16 mg

Bup 32 mg0 -

4 -

MRI

BindingPotential(Bmax/Kd)

Effects of Buprenorphine Dose on µ-Opioid Receptor Availability in a Representative Subject

Page 26: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

Federal Efforts to Increase AccessFiellin and O’Connor, NEJM 2002

• Congress (2000)• Drug Addiction Treatment Act

• Allows qualifying physicians to use approved schedule III-V medications

• Qualifying physician either certified in Addiction Medicine/Psychiatry or complete 8 hour training

• FDA and DEA (2002)• Approves buprenorphine and

buprenorphine/naloxone for treatment of opioid dependence, schedule III

Page 27: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

How effective is office-based buprenorphine treatment?

Page 28: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

Self-Reported Frequency of Illicit Opioid Use in Opioid-Dependent Patients Receiving Buprenorphine-Naloxone in Primary Care

Fiellin D et al. N Engl J Med 2006;355:365-374

Page 29: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

Retention among Opioid-Dependent Patients Receiving Buprenorphine-Naloxone in Primary Care

Fiellin D et al. N Engl J Med 2006;355:365-374

Page 30: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

6 Weeks of Opioid Abstinence

0

10

20

30

40

50

60

Heroin only Heroin &Prescription

Prescriptiononly

Per

cen

t o

pio

id n

egat

ive

Moore, JGIM, 2007

Page 31: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

66 Physicians and 31 Treatment Programs listed in Minnesota

Page 32: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

Trained, Registered and Prescribing Physicians

U.S. January 2009

8295

Page 33: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

Alcohol Treatment

Page 34: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

Patterns of Alcohol Use: Epidemiology

GeneralPopulation†

General MedicalPractice‡

1. Abstainers 40% ----

2. Moderate Drinkers 35% ----

3. At Risk

4. Alcohol Abuse 20% 20-35%

5. Alcohol Dependence 5% 5-10%

† National Longitudinal Alcohol Epidemiology Study 1992, National Comorbidity Study, 1992‡ Wallace; BMJ 1988;297:663-8, Flemming JAMA 1997;277:1039-45

Page 35: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

Terminology For Alcohol Use Behaviors

Term Description Moderate Drinking

men: women: over 65:

< 2 drinks/day < 1 drink/day < 1 drink/day

At Risk Drinking men: women:

> 14 drinks/week > 4 drinks /occasion > 7 drinks/week > 3 drinks/occasion

Page 36: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

What is a drink? 

• 14 grams of alcohol– 12 ounces of beer– 5 ounces of wine– 1.5 ounces of

distilled spirits

Page 37: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

Alcohol TreatmentPharmacotherapy

Page 38: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

Disulfiram

Ethanol Acetaldehyde AcetateADH ALDH

Build up of acetaldehyde causes:-Flushing-Headache-Nausea-Dizziness-Palpitations

Page 39: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

Disulfiram Efficacy

• In a large double-blinded study, disulfiram was no better than placebo in helping patients remain abstinent

• A subset of relapsed patients, who were older and more socially stable, drank less

frequently when given disulfiram

• Greater efficacy has been shown with supervised disulfiram administration

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

Page 40: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

Prescribing Disulfiram

• Start at 250mg daily and titrate to 500mg daily• Contraindications:

– Recent alcohol use– Pregnancy– Cognitive impairment

• Side effects:– Hepatotoxicity– Neuropathy

Page 41: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

Naltrexone

1. Mechanism of Action: opioid receptor blockade

2. Effects: decreased craving and alcohol consumption

3. Dose: 50 mg/day

4. Side Effects: nausea (10%), headache

5. Contraindications: opioid dependence

severe liver disease

Page 42: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

Combined Analysis ofYale and U Penn Studies of Naltrexone

• 12 week, double-blind, placebo controlled

• Concurrent Psychotherapy:

– Once weekly individual therapy (Yale)

– Day Hospital (1 month), twice weekly

group (2 months) (U Penn)

• Abstinence rates:

Naltrexone: 54%

Placebo: 31%

-------------O’Malley et al., Psychiatric Annals 1995;25:681-88.

Page 43: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

Naltrexone: Efficacy• Meta-analysis of 14 studies*

– Relapse to heavy drinking• Naltrexone 428/1142 (37%), control 445/930 (48%)

– Odds ratio for relapse• 0.62 (95% CI 0.52,0.75)

• COMBINE Study† (Naltrexone X 16 w, n=302)– Increased abstinence over placebo (81% vs. 75%)– Reduced risk of a heavy drinking day (HR 0.72,

p<0.02)

*Carmen B, Addiction 2004; † Anton RF, JAMA, 2004

Page 44: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

Prescribing Naltrexone

• 25 to 50 mg daily taken after a meal for at least 3-4 months

• Depot form available doses studied 190-380 mg– 25% reduction in heavy drinking days

• Contraindications:– Opioid use– Pregnancy

• Side Effects:– Nausea

Garbutt JC, JAMA, 2005, Anton R, NEJM, 2008

Page 45: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

Anton, R. F. et al. JAMA 2006;295:2003-2017.

Project Combine: Design

Page 46: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

Copyright restrictions may apply.

Anton, R. F. et al. JAMA 2006;295:2003-2017.

Project Combine: Effect Size Estimates and Hazard Ratios for

Primary Outcomes

Page 47: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

Garbutt, J. C. et al. JAMA 2005;293:1617-1625.

Injectable Naltrexone:Mean Heavy Drinking Event Rate

Page 48: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

Acamprosate

• Alcohol is an agonist at the inhibitory GABA receptors and antagonist at excitatory glutamate receptors

• Acamprosate modulates alcohol effects:– GABA-analogue– Modulates action at NMDA receptor

Page 49: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

Acamprosate: Efficacy• Meta-analysis of 7 placebo controlled trials*

– Acamprosate (n=1195), placebo (n=1027)– Proportion of patients continually abstinent at one

year 23% for acamprosate group, 15% for placebo group

• COMBINE study† (Acamprosate arm, n=300)– No significant effect on drinking over placebo

*Carmen B, Addiction 2004; †Anton, RF, JAMA 2004

Page 50: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

Prescribing Acamprosate

• 666 mg po TID; start after a period of abstinence

• Contraindications– CrCl < 30 cc/min– Pregnancy

• Side effects– Diarrhea

Page 51: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

Topiramate

• Reduces corticomesolimbic dopamine release– Agonist at GABA– Antagonist at glutamate

• Not FDA approved

Page 52: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

Topiramate: Efficacy• N=371, double blind randomized placebo

controlled trial• Intention-to-treat analysis

Topiramate Placebo pReduction in number of heavy drinking days

44% 52% 0.002

Increase in abstinence days (baselinewk 14)

10% to 38% 9% to 29% 0.002

Johnson BA, JAMA 2007

Page 53: Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

Summary• Opioid and alcohol problems are common• Effective therapies for opioid dependence

and alcohol use disorders exist• Office-based treatment of addictive disorders

may help increase access to treatment and decrease stigma


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