Transcript Pharmacologic Treatment of Addiction Madison Clinic Lunch & Learn June 2007 http://www.nida.nih.gov/scienceofaddiction/health.html Your Brain on Drugs Today Front of Brain Back of Brain 1-2 Min 3-4 5-6 6-7 7-8 8-9 9-10 10-20 20-30 Fowler et.

Pharmacologic Treatment of Addiction
Madison Clinic
Lunch & Learn
June 2007
http://www.nida.nih.gov/scienceofaddiction/health.html
Your Brain on Drugs Today
Front of Brain
Back of Brain
1-2 Min
3-4
5-6
6-7
7-8
8-9
9-10
10-20
20-30
Fowler et al., Synapse, 1989.
YELLOW shows
places in brain
where cocaine goes
(striatum)
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 medicationassisted treatment of addiction
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.
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
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.
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
Two Trials Comparing Quit Rates*
with Chantix, Zyban and Placebo
CHANTIX 1 mg bid Zyban 150 mg bid Placebo
Gonzales et al 44.0%*
(n=1025)
29.5%†
17.7%
Jorenby et al
(n=1027)
29.8%‡
17.6%
43.9%*
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
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.
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
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
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
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 alcohol
dependence: a randomised controlled trial of effectiveness in a standard clinical setting.". The Medical Journal of Australia 176
(11): 530-534.
Example of Medication Impact:
Injectable Naltrexone
Median Heavy Drinking Days per Month for Each Treatment Group Overall and by Sex
Garbutt, J. C. et al. JAMA 2005;293:1617-1625.
Copyright restrictions may apply.
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
Millions
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
Primary Drug at Entry to Opiate Treatment,
King County WA
100.0
94.6
Heroin
80.0
83.2
60.0
%
40.0
20.0
14.4
Rx Opiate
3.0
0.0
1999
2000
2001
2002
2003
2004
2005
Drug Caused Deaths, 1997-2005
King County, WA
# Times Drug Identified
90
80
Methadone
70
Oxycodone (e.g.Percocet,
OxyContin)
60
Hydrocodone (e.g. Vicodin)
50
Propoxyphene
40
Fentanyl
30
Hydromorphone **
20
10
0
1997
1999
2001
2003
2005
Methadone Maintenance:
Treatment Outcomes
• Methadone:
– Reduces overall and overdose deaths
– Drug use
– Criminal behavior
– Spread of infectious diseases (HIV, TB)
• Not a cure
Swedish Methadone Study
Experimental Group
(Methadone)
Gunne & Gronbladh, 1981
Before
Control Group
(No Methadone)
Swedish Methadone Study
Experimental Group
(Methadone)
After 2 Years
Control Group
(No Methadone)
a
b
c
d
d
d
Gunne & Gronbladh, 1981
a
b
c
d
Sepsis
Sepsis and Endocarditis
Leg Amputation
In Prison
Frequency of Heroin Use & Methadone
Dose Level
90
80
Past
month
IV drug
use (%)
70
60
50
40
30
20
10
0
10
20
30
40
50
60
70
80
Daily Methadone Dose (in mgs.)
Adapted from V. Dole (1989) JAMA,
282, p. 1881
90
100
Reduction of Heroin Use By Duration of
Methadone Treatment
120
100
97%
P
e 80
r
c 60
e
n 40
t
67%
23%
20
8%
0
Pretreatment
Admission:
< 6 months
stay
Average
Stay: 6 to
54 months
Adapted from: Ball & Ross, 1991.
Long-term:
> 54 months
Return to I.V. Drug Use Following
Termination of Methadone Treatment
90%
%
80%
I
V
70%
82.1%
72.7%
60%
57.6%
50%
U
S
E
R
S
40%
45.5%
30%
20%
28.9%
10%
0%
In Tx.
1 to 3
4 to 6
7 to 9
Months Since Dropout
Adapted from: Ball & Ross, 1991.
10 to 12
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
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
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
Full Agonist vs Partial Agonist
100
90
Full Agonist
80
70
Activity
60
50
Partial Agonist
40
30
20
10
Antagonist
0
-10
-9
-8
-7
-6
-5
Log Dose of Opioid
-4
Zubieta et al., 2000
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
Remaining in treatment (nr)
Buprenorphine Maintenance/Withdrawal:
Retention
20
15
10
Control
5
Buprenorphine
0
0
50
100
150
200
250
Treatment duration (days)
300
350
(Kakko et al., 2003)
Buprenorphine Maintenance/Withdrawal:
Mortality
Dead
Placebo
Buprenorphine
Cox regression
4/20 (20%)
0/20 (0%)
2=5.9; p=0.015
(Kakko et al., 2003)
Maintenance Treatment Using Buprenorphine
• Buprenorphine, methadone, LAAM
comparison:
– 17 week outpatient randomized, doubleblind 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
Buprenorphine, Methadone, LAAM:
Treatment Retention
Percent Retained
100
73% Hi Meth
80
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
(Johnson et al., 2000)
Buprenorphine, Methadone, LAAM:
Opioid Urine Results
100
All Subjects
Mean % Negative
80
LAAM
49%
60
Bup
Hi Meth
40%
40
39%
Lo Meth
20
19%
0
1
3
5
7
9
11
Study Week
13
15
17
(Johnson et al., 2000)
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
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
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%)
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
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
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
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
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
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
To Learn More:
buprenorphine.samhsa.gov