Transcript Buprenorphine

Buprenorphine:
A Slide Set With Teaching Notes
Sharon Stancliff, MD
New York State Department of Health
AIDS Institute
A Local Performance Site of the New York/New Jersey AETC
February 2004
Heroin Use: 2000
• 160,000 injection drug users in New York;
200,000 heroin users (estimates)- believed to be
increasing in 2003
• Among those admitted into treatment over half are
sniffing but transition to injection occurs for some
• Transition to injection: one study found 12% over
18 months
Frank MSJM 2000, Neaigus
Opioids: Heroin
• Use: nasal, injected, smoked and oral
• Why: Euphoria, sedation, reduce pain
• Negative: Dependence, overdose,
injection related illnesses
• Withdrawal: severe, not life threatening
• Pregnancy: Withdrawal dangerous to
fetus, maintain on methadone
Comments
• Overdose: most common when mixing drugs
or after period of abstinence
• Interactions with HAART
– In theory ritonavir may increase potency
– Analgesics are mixed with HAART
Sporer 1999, Farragon, in press
History of Maintenance
• Prior to 1914 opiates freely available
• 1914 Harrison Act: led to the end of
physician ability to maintain an addiction
• 1960s: redevelopment of maintenance
model
• 1972: FDA approval and strict regulation
of methadone
Joseph, 2000
2000: Drug Addiction
Treatment Act
• Allows for office based maintenance
with schedule III, IV or V medications
• Buprenorphine is the only approved
medication
Why was this legislation
passed?
• Methadone maintenance has been
shown to be highly effective in reducing
heroin use and the incidence of comorbidities such as HIV
• Access to methadone is limited by
regulation and stigma
HIV Prevention
• Methadone patients are 3-6 times
less likely to become HIV positive
when compared to out-of-treatment
heroin users, including the
population that continues to use
drugs.
Drucker, 1998
Methadone and HIV Prevention
• Methadone patients report less needle and
syringe sharing
• Methadone patients are 3-6 times less likely
to become HIV positive when compared to
out-of-treatment heroin users, including the
population who continues to use drugs
• Buprenorphine maintenance is hoped to have
a similar impact
•
De Castro S, 2003, Drucker 1998
Methadone and the HIV+ User
• Among HIV+ patients maintenance
is associated with more consistent
use of antiretrovirals and less
hospitalizations
Sambamoorthi 2000, Weber 1990, Laine 1998
Further Benefits
+ Reductions in lethal overdose- decrease
use and high tolerance
+Reductions in sex work
+Reductions in crime and presumably in
incarceration
Sporer 1999, Metzger 1993, Drucker 1998, NIH Consensus Panel 1998
Goals of Maintenance
Prevent drug withdrawal
Block the effects of heroin if taken
Prevent the powerful craving that
characterizes protracted withdrawal
Joseph, 2000
Protracted Abstinence Syndrome
• Heroin craving persists long after
withdrawal is over
• 80-90% of serious heroin users relapse
after detox
Hypothesis: opioid addiction is a
metabolic illness
Joseph 2000
Development of Protracted
Abstinence Syndrome
 Genetic predisposition
 Environmental factors may bring it out: use
of the drug, perhaps stress or other
influences
 Physiological changes possibly in the
receptors for endogenous opiates which are
long term and probably permanent
Nestler 1998
Maintenance Treatment
Substitution therapy:
may be compared to the treatment
of diabetes with insulin
How Can Methadone Help?
Abstinence: given a sufficient
dose virtually all heroin users will
stop using heroin
 Harm reduction: at lesser doses
heroin use is under more control
Side Effects
No known long term detrimental effects
Side effects: constipation, sweating
Longer acute withdrawal than heroin
Safe during pregnancy
Novick, Kandell
Methadone Dose
• Usual effective dose: 80-120 mg is
required to prevent craving
• Range: 5mg- >1000mg
• Affected by individual differences in
metabolism and by medication
interactions
Leavitt, MSJM 2000
Length of Treatment
• 80-90% of those stopping MMT will
return to heroin use - a treatment,
not a cure
• Not predictable by life stability
Magura MSJM 2000
Methadone: Restricted Access
Available only in methadone clinics
• Many areas lack sufficient methadone
treatment slots
• Many users do not enter methadone
programs, probably because of the
restrictions
Government Accounting Office 1990, NIH Consensus Statement 1998, Institute of Medicine 1995
New Federal Regulations
For those who meet strict criteria
• 1st 3 months: 5 days a week
• 2nd 3 months: 4 days a week
• 3rd 3 months: 3 days a week
• 4th 3 months: 1 day a week
• After 1 year: Every 2 weeks
• 2 years: monthly
Buprenorphine
Will be available by prescription
from qualified physician offices
–higher safety profile
–lower anticipated street value
Higher Safety Profile
Difficult to overdose on buprenorphine alone
“Partial agonist”- a ceiling effect above which
higher doses do not increase activity- respiratory
depression unlikely
Sublingual medication- low activity if swallowed,
therefore safer around children
Ling 2002
From Danyalearningcenter.com
Lower Street Value
• If used when “high” or “straight” on
heroin or methadone=severe withdrawal
• Mixed with naloxone (full antagonist)
which is activated if injected so there is
a reduced reward to opioid naïve misuser
Ling 2002
Lower Street Value
Effects on a person who is:
• Dependent on opioid: “high” or “straight” severe withdrawal whether taken under
tongue or injected
• Dependent on opioid: in withdrawal- relief
• An occasional user- gets high especially if
injecting but mixed with naloxone (full
antagonist) which is activated if injected so
reduced high
Ling 2002
To Prescribe Buprenorphine:
Be a qualified physician
Complete an 8 hour training
Or have
Certifications:
– Boarded in addiction psychiatry
– ASAM certified
– Boarded in addiction medicine by AOA
(Or participation in buprenorphine trials)
Other Physician Requirements
Register with the DEA
Register with NYS DOH (NY only)
Required to have access to appropriate
psychosocial services
Limited to 30 patients per doctor (or tax
ID)
Induction
• Patient presents in mild to moderate
withdrawal
• Test dose
• Follow up q1-3 days to titrate up to
maintenance
• In-person is recommended but
circumstances may vary, telephone or
e-mail contact may be sufficient
Maintenance
• Most patients can be stabilized on 1224mg. Because of a ceiling effect few will
be on >32mg.
• Some patients can dose q 2-3 days
• Frequency of visits determined by
MD/patient
• Training encourages urine testing but it is
not required by law
Detoxification
• 4-8 days
• 4- 16mg/day: example 6-8-10-8-4
• Additional medications are usually not
necessary
• No particular detoxification regime has been
shown to be more likely to lead to long term
abstinence
Side effects
• Similar to other opioids: constipation,
nausea, vomiting
• Precipitated withdrawal in agonist
dependent patient
• Pregnancy category C- studies are in
progress
Potential medication interactions
between buprenorphine and
other medications
•
Cytochrome P450 3A4 inhibitors
include:
Azoles, Macrolides, Nonnucleosides
and protease inhibitors
•
Cytochrome P450 3A4 inducers
include:
Phenobarbital, carbemazepine,
phenytoin, rifampicin
Drug Interactions
Chronic pain management : Chronic
opiate agonists contraindicated- may
necessitate transfer to methadone
Benzodiazepines: Increase potential for
fatal overdose
Which Patients?
• Those in areas with limited or no access to
methadone
• May draw in users earlier in drug use career
• Some studies suggest that buprenorphine is
most useful in those who are comfortable on
lower doses of methadone
Barnett 2001
Study: Buprenorphine vs.
Placebo
40 heroin users: 20 buprenophine, 20 placebo
Bupren
Placebo
Retention
75%
0
Drug use
25%
100%
Death
0
4
Kakko, 2003
Study:
Buprenorphine vs. Methadone
400 Pts. Randomized to flexible dose of
buprenorphine (2-32 mg) or methadone(10150mg)
• Morphine positive urine: no difference
• Self reported drug use: no difference
• Retention: methadone somewhat greater
Mattick 2003
The French Experience
• Licensed in 1995 by 2000 ~ 80,000 patients
receiving in primary care
• Dramatic decrease in heroin overdose
• Physicians report significant improvement in
health and social function
• Misuse- some injected but double enrollment
for prescription appears rare
Deveaux 2002, Vignau 1998
HAART-Buprenorphine Interactions
• Few formal studies to date
• No effect of buprenorphine on zidovudine
• CYP450 3A4 Metabolism of buprenorphine
would suggest possible interactions with PIs
and non-nucleosides
• In vitro ritonavir is potent inhibitor of BUP
metabolism (ritonavir > indinavir >
saquinavir).
• Clinicians need to be alert for potential
interactions
McCance-Katz AmJ Addic 2001;
Iribarne DrugMetDisp
Buprenorphine use in HIV-infected
persons: additional considerations
• One study found increases in AST, ALT
among pts. with hepatitis (Medians:ALT: 8.5 (12 to 54)AST: 9.5 (-8 to 32)
• 4 cases of severe hepatitis reported after
injection of Buprenorphine
• Possible relationship of buprenorphine to
hyperlactatemia in HIV-infected persons
on HAART- but small study, did not control
for HCV
•
Petry 2000, Berson 2001, Marceau 2003
Summary
Buprenorphine
• Moves addiction treatment into primary
care
• May bring patients into care before
various co-morbidities have an impact
• May increase use of and response to
HIV treatment
On-line Resources
• http://www.dhs.vic.gov.au/phd/buprenorphine/
• http://www.samhsa.gov/news/click_bupe.html