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

Overview

• Epidemiology of opioid dependence

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

• Epidemiology of alcohol problems

• Treatment of alcohol problems– Naltrexone, acamprosate, disulfiram

• 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)

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

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.

0.10.1

0.20.2

0.60.6

0.70.7

0.60.6

2.02.0

6.26.2

14.614.6

00 11 33 55 77 99 1111 1313 1515

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.

Nonmedical Use of Prescription Drugs

Deaths per 100,000

Opioid sales (mg perperson)

Annual sales of prescription opioids and unintentional overdose death

1990 - 2006

Source: Paulozzi, CDC, Congressional testimony, 2007

Brain’s Reward pathways

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

Opioid Treatment

Pharmacologic Treatment of Opioid Dependence

• Pharmacologic withdrawal - “detoxification”

• Opioid antagonist treatment

– Naltrexone

• Opioid agonist treatment

– Methadone

– Buprenorphine

Poor results with detoxification Kakko, Lancet 2003

Treatment duration (days)

0 50 100 150 200 250 300 350

Detoxification

Maintenance

Opioid Agonist Treatment

• Rationale

– Cross-tolerance

• prevent withdrawal

• relieve craving for opioids

– Narcotic blockade

• block or attenuate euphoric effect of exogenous opioids

How effective is opioid agonist treatment?

Buprenorphine, Methadone, LAAM: Treatment Retention

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

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

Treatment vs. Addiction

MarkedAbsentEuphoria

3-6 hours24-36 hoursDuration

Immediate30 minutesOnset

IV, INOral, sublingualRoute

HeroinMethadone or buprenorphine

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

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

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)

Bup 00 mg

Bup 02 mg

Bup 16 mg

Bup 32 mg0 -

BindingPotential(Bmax/Kd)

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

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

How effective is office-based buprenorphine treatment?

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

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

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

6 Weeks of Opioid Abstinence

Heroin only Heroin &Prescription

Prescriptiononly

Moore, JGIM, 2007

66 Physicians and 31 Treatment Programs listed in Minnesota

Trained, Registered and Prescribing Physicians

U.S. January 2009

Alcohol Treatment

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

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

What is a drink?

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

distilled spirits

Alcohol TreatmentPharmacotherapy

Disulfiram

Ethanol Acetaldehyde AcetateADH ALDH

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

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

Prescribing Disulfiram

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

– Recent alcohol use– Pregnancy– Cognitive impairment

• Side effects:– Hepatotoxicity– Neuropathy

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

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.

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

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

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

Project Combine: Design

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

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

Injectable Naltrexone:Mean Heavy Drinking Event Rate

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

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

Prescribing Acamprosate

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

• Contraindications– CrCl < 30 cc/min– Pregnancy

• Side effects– Diarrhea

Topiramate

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

• Not FDA approved

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

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

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

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