Pharmacologic Treatment of Addiction Dr Andrew Mallon.
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Transcript of Pharmacologic Treatment of Addiction Dr Andrew Mallon.
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Pharmacologic Treatment of Addiction
Dr Andrew Mallon
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http://www.nida.nih.gov/scienceofaddiction/health.html
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Your Brain on Drugs Today
1-2 Min 3-4 5-6
6-7 7-8 8-9
9-10 10-20 20-30
YELLOW shows places in brain where cocaine goes (striatum)
Front of Brain
Back of Brain
Fowler et al., Synapse, 1989.
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Addiction as a Brain Disease
• Key brain pathways involve motivation, salience, memory, and reward
• Prolonged drug use is associated with changes brain function
• Changes are pervasive and persist after drug use stops
• Brain changes demonstrated at molecular, cellular, structural and functional levels
• These studies provide a rationale for medication-assisted treatment of addiction
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Drug Addiction Treatment• Scientific studies demonstrate that the right mix of behavioural therapy,
spiritual exploration, medication (when available), medical & social services can help addicted people navigate the road to recovery.
We Need to Treat theWe Need to Treat theWhole Person!Whole Person!
In Social ContextIn Social Context
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FDA Approved Treatments for Nicotine Addiction
• Chantix™ (Varenicline)
• Zyban
• Nicotine Replacement
Tobacco use is responsible for an
estimated 5 million deaths worldwide each year
http://www.drugabuse.gov/Infofacts/Tobacco.html
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Chantix™ (Varenicline)
• Non-nicotine aid for smoking cessation treatment + counseling
• When smoke is inhaled, nicotine attaches to brain receptors & sends a message to a different part of the brain to release dopamine = pleasure feeling for a short time.
• Chantix works by activating these receptors and blocking nicotine from attaching to them.
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Chantix™ (Varenicline)
Dual Mechanism of Action:
• Partial agonist effect through selective receptor binding & stimulates brain receptor-mediated activity, but at significantly lower level than nicotine (agonist effect).
• Blocks the ability of nicotine to activate the receptors & thus, to stimulate the central nervous mesolimbic dopamine sx, the neuronal mechanism underlying reinforcement and reward for smokers (antagonist effect). Use with caution in patients with hx psychosis
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Two Trials Comparing Quit Rates* with Chantix, Zyban and Placebo
CHANTIX 1 mg bid Zyban 150 mg bid Placebo
Gonzales et al (n=1025)
44.0%* 29.5%† 17.7%
Jorenby et al (n=1027)
43.9%* 29.8%‡ 17.6%
Quit Rates = Continuous abstinence (not even one puff of a cigarette) during weeks 9-12
JAMA. 2006; 296:47-55 & JAMA. 2006; 296:56-63
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Chantix (Varenicline)
• Dose: 0.5 mg q day x 3 days, then 0.5 mg BID on days 4-7, then 1 mg BID x 12 weeks +
• The most frequently reported adverse events (>10%) with CHANTIX were nausea, headache, insomnia and abnormal dreams.
• Nausea was reported by approximately 30% of patients treated with CHANTIX 1 mg bid, with approximately a 3% discontinuation rate during 12 weeks of treatment.
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FDA Approved Medications for Treatment of Alcoholism
• Disulfiram (Antabuse)• Acamprosate (Campral)• Naltrexone
NON-FDA Approved Medications • Topiramate (Topamax)• Modafinil• Prazosin (Minipress) - in clincial trials w/patients w/PTSD
• …and many more! www.clinicaltrials.gov
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Disulfiram (Antabuse)
• Used to support the treatment of chronic alcohol abuse by producing an acute sensitivity to alcohol
• Disulfiram should not be taken if alcohol has been consumed in the last 12 hours.
• Initial dose is 500 mg for 1 to 2 weeks, followed by a maintenance dose of 250 mg (range 125 mg - 500 mg) per day. The total daily dosage should not exceed 500 mg
• May cause liver toxicity so use w/caution in co-infected patients with chronic HBV and/or HCV
• Alcohol may be a potent cue for cocaine use. Often concurrent use
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Acamprosate (Campral)
• Blocks release of glutamate, which is associated with alcohol withdrawal
• Appears to be more helpful in preventing relapse than reducing drinking levels
• Does not prevent withdrawal symptoms
• Dose: .666 mg TID (can use 1/2 strength)
• Side effects: diarrhea, gas, upset stomach, loss of appetite, dry mouth, dizziness, itching, weakness. Monitor for depression. No liver toxicity
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Naltrexone• By blocking the µ-opioid receptors, naltrexone weakens the rewarding
effects of alcohol and reduces dopamine release and the inhibitory GABAergic output. Blocks the “high” feeling
• Appears to promote reduction in drinking level
• Dose: 50 mg q day. Side effect nausea is transient and transaminitis rare
• Extended-release naltrexone is the first once-a-month injection medication for alcohol dependence. May cause liver toxicity
Noeline C Latt, Stephen Jurd, Jennie Houseman and Sonia E Wutzke. "Naltrexone in alcoholdependence: a randomised controlled trial of effectiveness in a standard clinical setting.". The Medical Journal of Australia 176
(11): 530-534.
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Example of Medication Impact: Injectable Naltrexone
C o p y r i g h t r e s t r i c t i o n s m a y a p p l y .
G a r b u t t , J . C . e t a l . J A M A 2 0 0 5 ; 2 9 3 : 1 6 1 7 - 1 6 2 5 .
M e d i a n H e a v y D r i n k i n g D a y s p e r M o n t h f o r E a c h T r e a t m e n t G r o u p O v e r a l l a n d b y S e x
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Recent Opioid Trends
• Heroin related problems are stable
• Major increases in problems related to prescription opioid use and abuse:– Non-medical use– Emergency department visits– Addiction treatment admissions– Prescription opioid-related death
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New Non-medical Users of Pain Relievers Aged 12 or Older
Source: Office of Applied Studies. (2003). Results from the 2002 National Survey on Drug Use and Health: National findings (DHHS Publication No. SMA 03–3836, NHSDA Series H–22). Rockville, MD: Substance Abuse and Mental Health Services Administration. Nonmedical Use of Prescription Pain Relievers May 21, 2004
Mil
lio
ns
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Primary Drug at Entry to Opiate Treatment, King County WA
Heroin
94.6
83.2
Rx Opiate
3.0
14.4
0.0
20.0
40.0
60.0
80.0
100.0
1999 2000 2001 2002 2003 2004 2005
%
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Drug Caused Deaths, 1997-2005King County, WA
0
10
20
30
40
50
60
70
80
90
1997 1999 2001 2003 2005
# T
imes D
rug
Id
en
tifi
ed
Methadone
Oxycodone (e.g.Percocet,OxyContin)
Hydrocodone (e.g. Vicodin)
Propoxyphene
Fentanyl
Hydromorphone **
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Methadone Maintenance:Treatment Outcomes
• Methadone:– Reduces overall and overdose deaths
– Drug use
– Criminal behavior – Spread of infectious diseases (HIV, TB)
• Not a cure
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Swedish Methadone StudyBefore
Experimental Group(Methadone)
Control Group(No Methadone)
Gunne & Gronbladh, 1981
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Swedish Methadone Study After 2 Years
Experimental Group(Methadone)
Control Group(No Methadone)
Gunne & Gronbladh, 1981
d
a b
c
d d
a Sepsisb Sepsis and Endocarditisc Leg Amputationd In Prison
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Adapted from V. Dole (1989) JAMA, 282, p. 1881
Frequency of Heroin Use & Methadone Dose Level
0
10
20
30
40
50
60
70
80
90
10 20 30 40 50 60 70 80 90 100Daily Methadone Dose (in mgs.)
Past month IV drug use (%)
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Adapted from: Ball & Ross, 1991.
Reduction of Heroin Use By Duration of Methadone Treatment
8%
23%
97%
67%
0
20
40
60
80
100
120
Percent
Pre-treatment
Admission:< 6 months
stay
AverageStay: 6 to54 months
Long-term:> 54 months
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Adapted from: Ball & Ross, 1991.
Return to I.V. Drug Use Following Termination of Methadone Treatment
%
IV
USERS
28.9%
82.1%72.7%
57.6%
45.5%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
In Tx. 1 to 3 4 to 6 7 to 9 10 to 12
Months Since Dropout
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Methadone Maintenance:How Long?
• Randomized trial of 179 patients
• Maintenance versus 180-day psychosocially enriched detoxification
• Maintenance resulted in greater treatment retention and less heroin use
• No support for diverting resources from maintenance to long-term detoxification
JAMA 2000;283:1303-10
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Methadone Maintenance:Summary
• Limitations– Highly structured program (6 days/week)– Limited clinical flexibility and minimal medical
services– Expansion often opposed, stigma
• For patients in Methadone Maintenance– Ask about urine tests and encourage adequate
dose, take-home doses, and treatment retention
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Buprenorphine:A New Office-Based Option
• New medication for opioid dependence• Federal legislation (DATA 2000):
– Allows trained MDs to prescribe Schedule III-V drugs approved for addiction treatment
– Initially limited to 30 patients/group practice, but now each MD can treat up to 100 patients
• Safer than methadone• With naloxone, reduced abuse potential
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-10 -9 -8 -7 -6 -5 -40
10
20
30
40
50
60
70
80
90
100
Activity
Log Dose of Opioid
Full Agonist
Partial Agonist
Antagonist
Full Agonist vs Partial Agonist
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Zubieta et al., 2000
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Buprenorphine Maintenance versus Detoxification
• Randomized trial of 40 Swedish patients ineligible for methadone but >1 year of dependence
• Control group given buprenorphine taper (1 week)
• Both groups given weekly Cognitive Behavioral Therapy, individual counseling and assistance with social services
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Treatment duration (days)
Rem
aini
ng in
tre
atm
ent
(nr
)
0
5
10
15
20
0 50 100 150 200 250 300 350
Control
Buprenorphine
Buprenorphine Maintenance/Withdrawal: Retention
(Kakko et al., 2003)
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Placebo Buprenorphine Cox regression
Dead 4/20 (20%) 0/20 (0%) 2=5.9; p=0.015
Buprenorphine Maintenance/Withdrawal: Mortality
(Kakko et al., 2003)
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• Buprenorphine, methadone, LAAM comparison:
– 17 week outpatient randomized, double-blind clinical trial, single site (n=220)
– Four conditions with flexible dosing for three of the four: high dose methadone, LAAM (3x per week), buprenorphine (3x per week), and low dose methadone
Maintenance Treatment Using Buprenorphine
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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 (Johnson et al., 2000)
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Buprenorphine, Methadone, LAAM:Opioid Urine Results
Mea
n %
Neg
ativ
e
Study Week
All Subjects
Lo Meth
BupHi Meth
LAAM
1 3 5 7 9 11 13 15 170
20
40
60
80
100
19%
40%
39%
49%
(Johnson et al., 2000)
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Suboxone and HAART
• Buprenorphine is metabolized through CYP3A4
• Protease Inhibitors: RTV, but not NFV or LPV/R, increases buprenorphine AUC, but no opioid excess seen
• NNRTI: DLV increases and EFV decreases the buprenorphine AUC, but no clinically significant consequences
• Naloxone has no CYP3A4 metabolism, so no HAART interactions expected
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Buprenorphine Implementation
• Major efforts by CSAT to train physicians, provide mentoring, help patients find help
• Slow adoption by physicians• Difficulty integrating office-based treatment
and psychosocial services• Insurance coverage inconsistent and
generally not available for publicly funded patients
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Buprenorphine: Who Gets It?• CSAT Waiver Evaluation Results:
– 31% new to addiction treatment (60% new to medication assisted treatment)
– 60% addicted to non-heroin opioid – No reduction in patients seeking methadone
• Compared with a methadone treatment sample:– Younger, more white (92% vs 53%)– More employed (50% vs 29%) – More post-secondary education (56% vs 18%)– More non-heroin only users (40% vs 10%)
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Buprenorphine in Washington State
• Facilitate and evaluate the development and implementation of a pilot office-based buprenorphine program within the Washington State Medicaid program
• Funded by the RWJ Substance Abuse Policy Research Program
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WA State Buprenorphine Policy
• Medicaid Eligibility Limitations – CNP/GAX coupons only (“dual eligible” and
parents)– Not GAU, ADATSA (exception for special project)
• Clinical Requirements– Patients must be enrolled in addiction program– Limited to 6 months with one 6-month extension– Limited to two-week supply of medication
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Buprenorphine in WA State:Program Features
• Physician Recruitment– HMC clinics (AMC, FMC, Madison, PSC)– Community clinics
• Psychosocial Services– Evergreen Treatment Services– King County funding for CNP/GAX patients– Approximately 2 hours/month– RCKC for ADATSA patients
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Buprenorphine in WA State:Limitations
• Physician Issues – Many clinic directors not interested– Appointment scheduling difficult, especially induction
• Psychosocial Treatment Issues– Off site services cumbersome
• Patient Recruitment Issues– Many patients had wrong/no medical coupon– Access to methadone increased– Multiple steps prior to medication
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HMC Addictions Program: Suboxone Track
• Focus on HMC patients– Expedited access to assessment, induction– Still restricted to CNP/GAX patients
• Centralized Induction Services– Devoted physician FTE– Refer to primary care physicians once stabilized
• Collaborate with HMC Addictions Program– On site psychosocial services– Referrals: 744-9657 or call me
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Summary
• Buprenorphine has potential to expand treatment access and physician involvement in addiction treatment
• Substantial limitations exist, especially regulatory restrictions and cost
• Methadone maintenance remains an effective treatment option