Transcript Слайд 1 - CTN Dissemination Library

Emergence of Medication Assisted
Therapy (MAT) in Addiction
Treatment
George Woody, MD
Department of Psychiatry, Treatment Research
Institute, and Delaware Valley Node of NIDA Clinical
Trials Network
University of Pennsylvania
Disclosures
• NIDA funding
• Reckitt Benckiser provided medication for
buprenorphine studies via NIDA
• Alkermes is providing VIVITROL® (naltrexone for
extended-release injectable suspension) &
matching placebo for amphetamine treatment
project
• Some slides from Drs. O’Brien, Ling and Dackis
Overview of Presentation
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Background
Counseling & medications
Alcohol medications
Opioid medications
Amphetamine medications
Nicotine medications
Cocaine medications
Vaccines
Psychiatric medications for co-morbidities
Most Important Point of Talk
(If you remember nothing else)
• New medications are being developed
• Old medications are being used and
studied for new indications
• Keep informed about what is going on and
try to apply it
• Though there is no “magic bullet”, these
medications can help your patients
Background
• The Big Book says members should take advantage of
medical advances
• Somehow, this message changed to a “no medication”
philosophy, probably based on:
– Observations that abuseable substances often
precipitate relapse, even if used in small amounts
– Ambivalence about addiction as a
personality/social/motivational problem rather than a
medical disorder
– Historical absence of medical profession from
addiction treatment
Background (continued)
• Result was generalization to any medication, even those
with no addiction risk (lithium, antidepressants, others)
• Addiction treatment became based (entirely) on
psychosocial therapies + 12-Step participation
• But, with two exceptions
– Benzodiazepines for alcohol withdrawal
• Evidence it prevents DTs
– Antabuse for preventing relapse to alcohol
• Things have been changing (slowly!)
– “Evidence-based medicine” an important factor
Background (continued)
• Methadone maintenance the first “breakthrough”
– But opposition continues
– Not allowed in a few states and countries
• Data show no real problem combining psychosocial
therapy with medication
• In fact, medication magnifies counseling effect
– i.e. Methadone and Suboxone – no meds=no patients
• And, counseling magnifies medication effects
– Especially for patients with many psychosocial
problems
Example: Methadone Only vs. Methadone +
Counseling in Maintenance Rx - Positive Urines
Previous Slide Example of Counseling
Magnifying Methadone Effect
• But – important to consider:
– Patients were veterans; many had psychiatric,
medical, family/social, legal problems
– 30% did OK with methadone alone
– Probably those with fewer co-morbidities
• Patients seeking Suboxone may be more similar to these
30% and do fine with medication alone because:
– More working
– Shorter period of addiction
– Fewer co-morbidities
Alcohol Medications
• Benzodiazepines for withdrawal
• Antabuse - not popular with patients or most clinicians:
– Drug interactions – inhibits drug metabolism
– Cardiovascular events possible if drink
• Naltrexone for relapse prevention
– Attenuates reward by reducing transmission in the
dopamine/endorphin system
– Works best if used after patient detoxified
– Seems to work mainly in persons with a certain
genetic alteration, not in those without it
Pharmacological Treatments for
Alcoholism
Craving Scores by Week
0
1
2
3
4
5
6
7
8
Weeks on Medication
9 10 11 12
Subjective “high” in Naltrexone and
Placebo Subjects
0.1
0
- 0.1
- 0.2
- 0.3
- 0.4
- 0.5
*
Naltrexone
Placebo
* p<.05
Cummulative Proportion with No Relapse
Non-relapse “Survival”
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
Naltrexone HCL (N=35)
Placebo (N=35)
0.2
0.1
0.0
0
1
2
3
4
5
6
7
8
9
10 11 12
No. of Weeks Receiving Medication
Volpicelli et al, Arch Gen Psychiatry, 1992; 49: 876-880
Rates of Never Relapsing According to Treatment Group
(n=97)
Naltrexone/coping skills
Naltrexone/supportive therapy
Placebo/coping skills
Placebo/supportive therapy
100
80
60
40
n=97
20
0
0
20
40
60
80
Days
O’Malley et al, Arch of Gen Psychiatry, Vol 49, Nov 1992
Hypothesis: Why it Works
Dopamine release necessary for “rewarding”
effects of alcohol
Alcohol causes release of endogenous opioids
which release dopamine
Naltrexone blocks endogenous opioid release
Change in b Endorphin Levels
after Alcohol Consumption
Minutes after alcohol consumption
Relapse Rate by Genotype
1.0
Proportion Nonrelapsed
.9
Naltrexone /
Asp40 Allele (A/G, G/G)
.8
.7
Naltrexone
Asn40 Allele (A/A)
.6
.5
Placebo /
Asp40 Allele (A/G, G/G)
.4
Placebo /
Asn40 Allele (A/Al)
.3
.2
.1
0.0
0
14
28
42
56
Days
70
84
Alcohol Medications (cont.)
Topiramate
Multiple mechanisms of action
1. Na+ and CA++ channel blockade
2. GABA potentiation
3. Glutamate antagonism
4. Carbonic anhydrase inhibition
Results: alcohol use
Days of Alcohol Use
Days of Alcohol Use
14
(in Heavy Drinkers)
10.6
12
10
8
9.5
7.6
6
4
2.9
2
0
Topiramate
Baseline
Placebo
End of study
P = .04
Results: abstinence rates
% Abstinent 3 Weeks
% Patients with 3 Consecutive Abstinent Weeks
70%
60%
59%
50%
40%
26%
30%
20%
10%
0%
Topiramate
Placebo
p < .05
Conclusions
• Topiramate
– Well tolerated with slow dose titration
– Reduces cocaine use & promotes stable
abstinence
– May be beneficial in cocaine /alcohol
dependence
Alcohol Medications (cont.)
• Acamprosate (Campral) - A synthetic compound similar
to homotaurine, a naturally-occurring amino acid
• Reduces CNS excitability associated with alcohol
withdrawal, possibly by blocking glutamatergic (excites)
N-methyl-D-aspartate receptors (NMDA) while activating
gamma-aminobutyric acid (GABA; calms) receptors
– NMDA receptors excite; GABA receptors calm
• European studies show relapse prevention effect
– U.S. studies do not
• Possibly because most European patients had
residential rx before outpatient rx
Final Thought on Alcohol
Medications
• A way to “controlled drinking” for some?
– BIG controversy!
• VIVITROL® - extended release naltrexone
– Blood level for 28 days
– Aetna found it reduced ER and other
expensive services for a net saving
Opioid Addiction Medications
• Methadone and Suboxone (buprenorphine/naloxone)
- Work for maintenance & detox
• When used for maintenance
– Reduce drug use, HIV risk, overdose death, crime
– Improve quality of life, psychiatric symptoms
• Buprenorphine implants for maintenance (Probuphine)
– Inserted under skin on inner part of arm
– Last 6 months; must be removed
– Effective in one study & 2nd underway
– May get FDA approval
Opioid Addiction Medications: Detox
• Methadone & buprenorphine work best in short term
• Poor results in long-term
• Other medications
– Clonidine (an antihypertensive)
• sedating; suppresses autonomic signs of
withdrawal but not subjective distress
– Lofexidine – similar to clonidine
• Less hypotension
• Approved in Europe but not in U.S.
Clonidine vs. Buprenorphine: Percent Present and
Clean from Inpatient detox at Days 13-14 (Ling et al)
Clonidine vs. Buprenorphine: Percent Present and
Clean from Outpatient Detox at Days 13-14 (Ling et al)
Opioid Addiction – Relapse Prevention
• Naltrexone – oral, injectable (VIVITROL® ), and implant
(Vivitrol only approved for alcohol dependence; no
naltrexone implants approved in US)
• Interest and adherence to oral naltrexone in US has
been low except for:
– Highly motivated patients
– Those threatened by severe consequenses if relapse
(health care professionals in monitoring programs,
probation/parole)
Opioid Relapse Prevention:
Naltrexone Implants –Emerging Data
• NIDA sponsored implant studies in early 1970s,
but no preparations were safe and effective
• New technologies improved the situation
• Example: PRODETOXONE - Approved in
Russia, 2005 - 1000 mg naltrexone
- 2-3 cm incision; insert under skin of
abdominal wall
- Blocks opioids for 3 months
Naltrexone Implant Study in St. Petersburg
(Interim analysis of 191 patients)
• 6- month randomized trial
– Ntx implant + ntx oral placebo
– Ntx oral + ntx implant placebo
– Ntx oral placebo/ntx implant placebo
6 Month Relapse Rate (end of treatment)
OP+NI < OP+PI (P<0,001)
OP+NI < ON+PI (P<0,001)
60%
40%
20%
68%
60%
15%
OP+PI
ON+PI
OP+NI
0%
Naltrexone Implants (cont)
• Effects similar in final sample of 306 patients
• No serious adverse events
– But, more superficial infections in implant patients
• Australia, China also have implants
– Australian implant used in over 3000 patients
– None yet approved by their governments
• Alkermes study of Vivitrol for relapse prevention to opioid
addiction recently completed in Russia
– Results show strong effect of Vivitrol over placebo
– Could result in US approval for opioid relapse prevention
Amphetamine Medications
• No pharmacotherapy found effective until recent
Swedish trial
• Significant effect with oral naltrexone in
randomized, placebo-controlled trial of 80
patients (Jayaram-Lindstrom et al, 2008)
Amphetamine in Iceland:
Dependent Patients Admitted to Vogur: 19842008
% of Patients Admitted to Vogur with
Diagnosis of Amphetamine Addiction: 19842008
Iceland Study
(NIDA Funding; Vivitrol Provided by Alkermes)
• 100 amphetamine dependent patients starting outpatient
treatment
• Randomized 1:1 to VIVITROL® or VIVITROL® placebo
• Randomization stratified according to male/female;
injecting/non-injecting
• Medication continued for 6 months
• Primary outcome – proportion of amphetamine negative
urine tests during weeks 1-24 of outpatient treatment
• Results available in 2 years
Other Outcomes: HIV Risk
• Results should provide signal if Vivitrol helps
prevent relapse to amphetamine addiction
• Some in Iceland are injecting
• Though HIV prevalence low in Iceland, it can
change rapidly if injecting continues
• Effective treatments reduce HIV risk
• Best shown for methadone, but any effective
treatment will do it
• Example - naltrexone
HIV Risk Assessment Battery Data: Naltrexone
for Relapse to Opioid Addiction in St. Petersburg
Sex risk
Drug risk
8,00
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6,00
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4,00
2,00
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remission relapse
remission
relapse
Cocaine Addiction Medications
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Meds may be different than those for amphetamine
Many studies & leads
No clearly positive results
Very important problem, so we keep trying
Most promising current medication is modafinil (Provigil)
Releases dopamine, norepinephrine and histamine
Low abuse liability – Schedule IV
Approved for treatment of narcolepsy but being used “off
label” to counteract daytime sleepiness, fatigue, etc
Modafinil
Efficacy in Cocaine Dependence
and Abuse Potential
University of Pennsylvania - Center for Studies in Addiction
Modafinil for Cocaine Dependence
Blocks cocaine-induced euphoria
Three controlled human laboratory studies
Reverses cocaine-induced neuroadaptations
Agonist Therapy
Minimal abuse potential
Promotes abstinence in 2/3 clinical trials
Not effective in alcohol dependence
Possible gender effect
Abuse Characteristics of Modafinil
Dopamine transporter antagonist
Slow onset after oral administration (4 hrs to peak)
Low water solubility (IV not feasible)
Unstable at high temperatures (Smoking not feasible)
Relatively low potency vs psychostimulants
Methylphenidate 20 mg vs. modafinil 200 mg
Low potency DAT antagonist with a slow onset of action
Modafinil Subjective Effects in
Humans
6
Amphetamine 15 mg
Modafinil 300 mg
Caffeine 300 mg
Placebo
5
4
3
2
1
-1
0
1
2
3
4
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Hours Postdose
6
7
8
Warot 1993
Post-Marketing Experience with Modafinil
Post-marketing modafinil surveillance
1) Modafinil has little potential for abuse
2) Limited reports of euphoric effects
3) Increased mainstream publicity
4) Extensive Internet postings on off-label use
5) Several reports of decreased efficacy over time
“Information to date continues to support the conclusion
that the abuse liability of modafinil, if it exists, is low.”
Myrick 2004
Nicotine Addiction Medications
• “Smoking is the leading preventable
cause of disease and death in the
United States”
–440,000 premature deaths per year
–Cost to the nation, $157 billion dollars
Report of Surgeon General on the Health Effects of Smoking, 2004
Pharmacology of nicotine addiction
% of Individuals Exposed to a Drug Who Become
Addicted
O’Brien, Goodman and Gillman, 1996
Current treatments
• Cold turkey
• Self-help
• Cessation counseling
• Medications
– Nicotine replacement
– Bupropion SR (Zyban®)
– Varenicline (Chantix®)
• Combination of counseling + medication
Current treatments
Self-help approaches
–Cold turkey
• 5% long-term abstinence*
–Leaflets, internet, posters
• 3-14% long-term abstinence**
*Fiore et al., JAMA, 288(14):1768-71, 2002
**Curry et al., J.Consult. & Clin. Psychology, 61(5):305-19 1993
Current treatments
Effectiveness of Non-Pharmacologic
Treatments
% Quit
at 12months
Lerman, Patterson, & Berrittini, 2005.
Current treatments
Abstinence Rates Varenicline vs. Bupropion vs.
Placebo
Nides et al. Am J Health Behav 32: 664-675, 2008
The Future? - Vaccines
• Bind to cocaine or nicotine molecules and
prevent them from attaching to receptors
• Or, facilitate metabolism so the drug never
has a chance to exert its full effects
• Positive results in early pilot studies
• Interesting and could be “game changing”
if can develop vaccines that are safe and
long-acting
Dual Diagnosis
• Substance-induced vs. independent disorders a
very important differential to make before
prescribing
• Shift to outpatient gives less time to make that
distinction
• Use same meds as would use in absence of a
SUD, but increase caution
– Benzodiazepines
– Any others with abuse liability
Conclusion
• New medications being developed
• Other than methadone, buprenorphine and
naltrexone, all have mild/moderate effects
– Those opioid medications have strong effects if
patients take them
• Psychosocial therapies magnify effect of
medications, and vice-versa, particularly for
patients with co-morbidities
Conclusion (cont.)
• Staff need to keep up to date on new
developments since a lot is going on
• Training on medication indications, efficacy and
side effects important
• Attitudinal barriers to use medications need to
be overcome
• Administrators need to find ways to include MAT
options in treatment
Medication Assisted Treatment
Administrator’s Workshop
Salon A
Yngvild Olsen, MD
Medical Director,
Baltimore Substance Abuse Systems,
Inc.
Clinician’s Workshop
Salon D
Marc Fishman, MD
Medical Director,
Maryland Treatment Centers
Clinician’s Workshop
Salon E
Michael Fingerhood, MD
Johns Hopkins Bayview Chemical
Dependency Clinic