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
Opioid Dependence
(DSM-IV, 3 or more within one year)
• 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
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.
Nonmedical Use
of Prescription Drugs
Past Month Users, Ages 12 and Older (in Millions)
Marijuana
14.6
Prescription Drugs
Cocaine
6.2
2.0
(incl. crack)
Crack
0.6
Ecstasy
0.7
Meth
0.6
Inhalants
0.6
Heroin
0.2
LSD
0.1
0
1
3
5
7
9
11
13
Source: SAMHSA, 2002 National Survey on Drug Use and Health.
15
Annual sales of prescription opioids
and unintentional overdose death
1990 - 2006
8
600
6
400
5
4
300
3
200
2
Deaths per 100,000
Opioid sales (mg per
person)
100
1
0
Sales in mg/person
500
'90
'91
'92
'93
'94
'95
'96
'97
'98
'99
'00
'01
'02
'03
'04
'05
'06
Crude rate per 100,000
7
0
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
Remaining in treatment (nr)
Kakko, Lancet 2003
20
15
10
Detoxification
5
Maintenance
0
0
50
100
150
200
250
Treatment duration (days)
300
350
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
Percent Retained
100
80
73% Hi Meth
60
58% Bup
40
53% LAAM
20
20% Lo Meth
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
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
Route
Methadone or
buprenorphine
Heroin
Oral, sublingual
IV, IN
30 minutes
Immediate
24-36 hours
3-6 hours
Absent
Marked
Onset
Duration
Euphoria
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
Intrinsic Activity: Full Agonist (Methadone), Partial
Agonist (Buprenorphine), Antagonist (Naloxone)
100
90
Full Agonist
(Methadone, oxycodone)
80
70
Intrinsic Activity 60
Partial Agonist
(Buprenorphine)
50
40
30
20
10
Antagonist (Naltrexone)
0
-10
-9
-8
-7
Log Dose of Opioid
-6
-5
-4
Effects of Buprenorphine Dose
on µ-Opioid Receptor Availability in a Representative Subject
MRI
Bup 00 mg
Binding
Potential
(Bmax/Kd)
Bup 02 mg
4Bup 16 mg
0-
Bup 32 mg
Federal Efforts to Increase Access
Fiellin 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 BuprenorphineNaloxone in Primary Care
Fiellin D et al. N Engl J Med 2006;355:365-374
Percent opioid negative
6 Weeks of Opioid Abstinence
60
50
40
30
20
10
0
Heroin only
Moore, JGIM, 2007
Heroin &
Prescription
Prescription
only
66 Physicians and 31 Treatment Programs
listed in Minnesota
Trained, Registered and
Prescribing Physicians
U.S. January 2009
8295
Alcohol Treatment
Patterns of Alcohol Use:
Epidemiology
1. Abstainers
2. Moderate Drinkers
3. At Risk
General
Population†
40%
35%
General Medical
Practice‡
-------
 20%
 20-35%
5%
5-10%
4. Alcohol Abuse
5. Alcohol Dependence
† 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:
> 14 drinks/week
> 4 drinks
/occasion
> 7 drinks/week
> 3
drinks/occasion
women:
What is a drink?
• 14 grams of alcohol
– 12 ounces of beer
– 5 ounces of wine
– 1.5 ounces of
distilled spirits
Alcohol Treatment
Pharmacotherapy
Disulfiram
ADH
Ethanol
ALDH
Acetaldehyde
Acetate
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 of
Yale 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
Project Combine: Design
Anton, R. F. et al. JAMA 2006;295:2003-2017.
Project Combine: Effect Size
Estimates and Hazard Ratios for
Primary Outcomes
Anton, R. F. et al. JAMA 2006;295:2003-2017.
Copyright restrictions may apply.
Injectable Naltrexone:
Mean Heavy Drinking Event Rate
Garbutt, J. C. et al. JAMA 2005;293:1617-1625.
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
Reduction in
number of heavy
drinking days
Increase in
abstinence days
(baselinewk 14)
Johnson BA, JAMA 2007
Topiramate
44%
Placebo
52%
p
0.002
10% to 38%
9% to 29%
0.002
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