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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
0.60.6
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.
Source: SAMHSA, 2002 National Survey on Drug Use and Health.
Nonmedical Use of Prescription Drugs
Nonmedical Use of Prescription Drugs
0
1
2
3
4
5
6
7
8
'90
'91
'92
'93
'94
'95
'96
'97
'98
'99
'00
'01
'02
'03
'04
'05
'06
Cru
de
ra
te p
er
10
0,0
00
0
100
200
300
400
500
600
Sa
les
in m
g/p
ers
on
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)
Rem
aini
ng in
tre
atm
ent
(nr
)
0
5
10
15
20
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
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
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
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)
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
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
0
10
20
30
40
50
60
Heroin only Heroin &Prescription
Prescriptiononly
Per
cen
t o
pio
id n
egat
ive
Moore, JGIM, 2007
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
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