Buprenorphine: A Slide Set With Teaching Notes

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BuprenorphineA Slide Set With Teaching Notes

• Sharon Stancliff, MD
• New York State Department of Health
• AIDS Institute
• May 2004

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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

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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

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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, Faragon, 2003

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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

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2000 Drug Addiction Treatment Act

• Allows for office based maintenance with schedule
  III, IV or V medications
• Buprenorphine is the only approved medication

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Why was this legislation passed?

• Methadone maintenance has been shown to be highly
  effective in reducing heroin use and the
  incidence of co-morbidities such as HIV
• Access to methadone is limited by regulation and
  stigma

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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

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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

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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

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Goals of Maintenance

• Prevent drug withdrawal
• Block the effects of heroin if taken
• Prevent the powerful craving that characterizes
  protracted withdrawal
• Joseph, 2000

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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

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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

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Maintenance Treatment

• Substitution therapy
• may be compared to the treatment of diabetes
  with insulin

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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

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Side Effects

• No known long term detrimental effects
• Side effects constipation, sweating
• Longer acute withdrawal than heroin
• Safe during pregnancy
• Novick, Kandell

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Methadone Dose

• Usual effective dose 80-120 mg is required to
  prevent craving
• Range 5mg- gt1000mg
• Affected by individual differences in metabolism
  and by medication interactions
• Leavitt, MSJM 2000

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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

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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

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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

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Buprenorphine

• Will be available by prescription from qualified
  physician offices
• higher safety profile
• lower anticipated street value

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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

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• From Danyalearningcenter.com

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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

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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)

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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)

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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

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Maintenance

• Most patients can be stabilized on 12-24mg.
  Because of a ceiling effect few will be on gt32mg.
• 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

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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

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Side effects

• Similar to other opioids constipation, nausea,
  vomiting
• Precipitated withdrawal in agonist dependent
  patient
• Pregnancy category C- studies are in progress

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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

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Drug Interactions

• Chronic pain management Chronic opiate agonists
  contraindicated- may necessitate transfer to
  methadone
• Benzodiazepines Increase potential for fatal
  overdose

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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

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Study Buprenorphine vs. Placebo

• 40 heroin users 20 buprenophine, 20 placebo

Kakko, 2003
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Study Buprenorphine vs. Methadone

• 400 Pts. Randomized to flexible dose of
  buprenorphine (2-32 mg) or methadone(10-150mg)
• Morphine positive urine no difference
• Self reported drug use no difference
• Retention methadone somewhat greater
• Mattick 2003

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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

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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 gt indinavir gt saquinavir).
• Clinicians need to be alert for potential
  interactions

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Buprenorphine use in HIV-infected persons
additional considerations

• One study found increases in AST, ALT among pts.
  with hepatitis (MediansALT 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

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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

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On-line Resources

• http//www.dhs.vic.gov.au/phd/buprenorphine/
• http//www.samhsa.gov/news/click_bupe.html

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For more HIV-related resources, please visit
www.hivguidelines.org