Buprenorphine on the Cutting Edge: Advanced Issues in the Clinical Use of Buprenorphine

1
Buprenorphine on the Cutting Edge Advanced
Issues in the Clinical Use of Buprenorphine

• Eric D. Collins, M.D.
• Michael Weaver, M.D.
• Hendree Jones, Ph.D.
• Ed Salsitz, M.D.

2
Outline

• Buprenorphine and Pain Management
• Dr. Weaver
• Transitioning Patients from Methadone Maintenance
  to Buprenorphine Maintenance
• Dr. Salsitz
• Buprenorphine as a Bridge to Naltrexone
  Maintenance
• Dr. Collins
• Buprenorphine in Pregnancy
• Dr. Jones

3
Buprenorphine on the Cutting EdgeBuprenorphine
and Pain Management

• Michael Weaver, MD, FASAM
• Virginia Commonwealth University

4
MOA

• Mu opioid receptor partial agonist
• Kappa antagonist
• Limited spinal analgesia
• Psychotomimetic effects
• Possible partial agonist at ORL-1
• Opioid receptor-like receptor
• Endogenous ligand is Orphanin FQ
• May contribute to analgesic effect

5
Metabolism

• Cytochrome P-450 enzyme 3A4
• Nor-buprenorphine
• Analgesic activity 25 of buprenorphine
• During surgical anesthesia, clearance is lower
• Due to reduced hepatic blood flow
• Lower plasma concentrations of bup and nor-bup
  with hepatic impairment
• No dose adjustment in mild to moderate hepatic
  impairment

6
Metabolism

• Glucuronidated
• Conjugated with glucuronic acid in liver
• Allows for excretion by kidney
• Metabolism and clearance not affected by renal
  impairment
• Same dose in patients on hemodialysis

7
Pre-clinical (animal) studies

• Guinea pig and rat paw pressure tests
• Antinociceptive potency of buprenorphine gt
  morphine
• Post-injury pain model
• Formalin test
• Bup 10x more potent than morphine
• Rat hot plate
• Bell-shaped dose-response curve
• Not seen in humans up to 32 mg sublingual

8
Analgesia

• Indicated for moderate to severe pain
• Lower doses for analgesia than for addiction
  treatment (tolerance)
• Bup 0.3 mg IV morphine 10 mg IV

9
Side effects

• Typical opioid side effects
• Nausea, sedation, dizziness, constipation
• More SE than with morphine IV
• No adverse hepatic effects reported at analgesic
  doses
• Overdose
• Supportive care (mechanical ventilation)
• Large doses of naloxone
• Adverse event rate slightly lower than other
  opioids when used for chronic pain in Europe

10
Ceiling effect

• Limits abuse potential
• Limits respiratory depression
• Up to 7 mg IV does not reduce resp rate
• 32 mg SL reduces RR by 4 breaths/min.
• May limit analgesic potential
• Cancer pain

11
Malignant/Non-malignant pain

• Nociceptive pain
• Neuropathic pain
• Higher doses
• Drug interactions
• HIV-related pain
• Drug interactions
• Cancer pain
• Less useful, especially end-stage

12
Drug Interactions

• Anticonvulsants
• Carbamazepine, phenytoin
• HIV medications
• Antiretrovirals
• Erythromycin, Rifampin
• Opioid rotation
• Taper down pure mu opioid first
• Methadone very long-acting

13
Dosage Forms

• Parenteral
• Sublingual
• Buccal strip
• Transdermal
• Intranasal
• Epidural
• Intrathecal
• Caudal
• Intra-articular
• Subcutaneous
• Ganglion injection

14
Parenteral

• Buprenex
• Only FDA-approved form for analgesia
• IV or IM
• Up to 90 bioavailability
• Peak plasma levels in lt5 minutes
• Duration of action 3-6 hrs

15
Sublingual

• Suboxone, Subutex
• Liquid, tablet
• Buccal strip
• 30 bioavailability
• Peak plasma conc. in 30-120 minutes
• Duration of action around 28 hours
• Sequestering in oral mucosa

16
Transdermal patch

• 3-day delivery
• 35, 52.5, or 70 mcg/hr
• 12-24 hrs to peak analgesic effect
• Change every 3 days
• Approved in Europe
• 7-day delivery
• 5, 10, or 20 mcg/hr
• Milder pain
• Higher strength larger patch size
• same bup concentration in all patch strengths

17
Other routes of administration

• Intranasal
• 50 bioavailability
• Peak plasma conc. in 10-30 minutes
• Uses PEG vehicle
• Spinal
• 12-24 hour pain relief
• Intra-articular
• Analgesia after knee arthroscopy
• Subcutaneous
• Ganglion injection

18
Acute vs. Chronic pain

• Acute
• ROA
• Parenteral
• Intranasal
• Sublingual
• Spinal
• Intra-articular
• Subcutaneous
• Lots of research

• Chronic
• ROA
• Transdermal
• Sublingual
• Less research
• Concerns
• Abuse, diversion
• Ceiling effect (cancer)

19
Summary

• Buprenorphine used for acute analgesia for
  decades
• May have better safety profile than full mu
  opioid agonist analgesics
• Lower doses for analgesia than addiction
• Indicated for moderate to severe pain
• Multiple potential dosage forms

20
Buprenorphine on the Cutting Edge Using
Buprenorphine as a Bridge to Naltrexone
Maintenance

• Eric D. Collins, M.D.
• Columbia University Medical Center

21
Background

• Buprenorphine
• Available as Subutex, Suboxone, and Buprenex
  (parenteral analgesic)
• partial mu receptor agonist kappa receptor
  antagonist
• high affinity for opioid receptors
• long receptor half-life
• many studies demonstrate its utility in both
  detoxification and maintenance treatments
• FDA approval for treatment of heroin dependence
  in U.S. October 2002

22
Methods

• Study Overview
• Patients enrolled between 4/2000 and 7/2003
• Screening over 1 to 3 weeks
• Randomization prior to one of three
  detoxifications
• anesthesia-assisted rapid opioid detoxification
  (AROD)
• buprenorphine-assisted rapid opioid
  detoxification (BROD)
• clonidine-assisted opioid detoxification (COD)
• 72 hour hospitalization Monday (day 0) to
  Thursday (day 3)

23
Methods

• Study Overview
• Naltrexone induction on day 1 in AROD, day 2 in
  BROD, and day 7 in COD
• Naltrexone maintenance (strongly recommended)
  with twice weekly relapse prevention
  psychotherapy for 12 weeks
• Urine toxicology 2x/week
• Major outcome variables retention in aftercare
  opiate abstinence in aftercare withdrawal
  severity scores (SOWS, OOWS, CINA) induction
  onto naltrexone

24
Timeline of Study Procedures
Collins et al., JAMA. Aug 24 2005294(8)903-913
25
Methods

• Buprenorphine-assisted rapid opioid detox (BROD)
• Positive control arm, with buprenorphine used to
  facilitate induction onto naltrexone
• Clonidine titrated to blood pressure, other
  medications (including benzos) utilized
• Buprenorphine 8 mg tablet SL on day of admission
  (day 0), after mild to moderate withdrawal is
  observed
• natlrexone begun on day 2 (Wednesday) in 12.5 mg
  dose, with increasing doses on day 3 (25 mg) and
  day 4 (50 mg after discharge)

26
Methods

• Detoxification medications in all three
  detoxification approaches
• clonidine
• clonazepam
• ketorolac tromethamine
• ondansetron
• prochlorperazine
• octreotide
• After discharge
• desyrel and/or zolpidem for sleep

27
Patients
Collins et al., JAMA. Aug 24 2005294(8)903-913
28
Patients Substance Use
Collins et al., JAMA. Aug 24 2005294(8)903-913
29
Mean SOWS Withdrawal Scores
Collins et al., JAMA. Aug 24 2005294(8)903-913
30
Mean OOWS Withdrawal Scores
Collins et al., JAMA. Aug 24 2005294(8)903-913
31
Mean CINA Scores
Collins et al., JAMA. Aug 24 2005294(8)903-913
32
Treatment Retention
Collins et al., JAMA. Aug 24 2005294(8)903-913
33
Results
Collins et al., JAMA. Aug 24 2005294(8)903-913
34
Results

• Urine toxicology done twice weekly during
  follow-up
• Tested for THC, phencyclidine, benzodiazepine,
  methadone, cocaine, barbiturate, and amphetamine
• No differences among groups in opioid-positive
  urine samples
• No differences among groups in samples positive
  for any drug tested

35
Summary

• Withdrawal scores suggest that AROD produces
  withdrawal symptoms comparable to BROD and COD
• Naltrexone maintenance and retention in treatment
  appear to be comparable (but poor) in both AROD
  and BROD, probably worse in COD
• Induction onto naltrexone can be accomplished
  with manageable discomfort using buprenorphine as
  a bridge

36
Treating Opioid Dependent Pregnant Women Update
on Buprenorphine
Hendrée E. Jones, Ph.D. Johns Hopkins
University, School of Medicine, Department of
Psychiatry and Behavioral Sciences
37
Acknowledgements

• NIDA R01 DA015764
• Center for Addiction and Pregnancy patients and
  staff
• Co-investigators
• Rolley Johnson, Donald Jasinski, Kevin
  OGrady, Chris Chisholm, Robin Choo, Michael
  Crocetti, Robert Dudas, Cheryl Harrow, Marilyn
  Huestis, Lauren Jansson, Mike Lantz, Barry
  Lester, Lorraine Milio.

38
OUTLINE

• I. The Problem
• II. Role of agonist therapies in treatment
• III. Future Directions

39
National Survey on Drug Use and Health 2002
Women aged 15-44
40
Pregnancy can be a promising time to evaluate
behavior change
TREATMENT
CAP
41
Drug addiction in women often starts before
pregnancy and occurs in context of complex
medical, psychosocial and environmental factors
42
Medical Complications Observed in Heroin
Dependent Pregnant Women

• Infections
• Anemia, Diabetes mellitus, Hypertension
• Sexually Transmitted Diseases
• Fetal Wastage
• Premature Labor and delivery
• Placental abruption or insufficiency

43
Fetal Complications of Heroin Exposure

• Cycles of withdrawal contribute to
• Decreased oxygen supply to the fetus
• Intermittent hypoxia and passage of meconium
• Fetal growth restriction

44
Medical Complications Observed in Drug Exposed
Neonates

• Higher rates of microcephaly
• Small for gestational age
• Low birth weight
• Sudden Infant Death Syndrome
• Increased neonatal and perinatal death
• Meconium aspiration syndrome
• Premature birth
• Heroin is not considered a physical teratogen

45
Psychosocial and Environmental Factors Influence
Mother Child Outcomes

• Exposure to violence and trauma
• Multiple drug exposure
• Poor maternal/child attachment
• Child abuse
• Psychological status of caregiver
• Stable caregiver and environment
• Nutrition

46
I. The Problem SUMMARY

• Some women spontaneously quit substance use when
  pregnant
• Pregnancies complicated by heroin addiction are
  often closely associated with a multitude of
  environmental factors that can contribute to
  adverse maternal, fetal and neonatal consequences

47
OUTLINE
OUTLINE

• I. The Problem
• II. Role of agonist therapies in treatment
• III. Future Directions

48
Medications to Treat Dependence

• OPIOID
• Naltrexone/naloxone
• Methadone
• Buprenorphine
• Morphine (long and short acting)
• Tramadol
• Rimonabant
• Lofexidine

• COCAINE
• Aripiprazole
• Naltrexone
• Baclofen
• Tiagabine
• Disulfiram
• Topiramate
• Modafinil
• Vaccine

49
Medication Treatment Works Best When

• Given in appropriate doses to prevent maternal
  withdrawal and minimize illicit opioid use
• Given in the context of prenatal care
• Given as a part of women-centered treatment

50
Medication TreatmentGoals
(1) Cessation of opioid use (2) Reduce
drug seeking and related behaviors (3) Blocks
effects of illicit opioids (4) Fetal safety
(5) Increased compliance with prenatal care
(6) Enhanced pregnancy outcomes
51
RiskBenefits of Agonist Medication During
Pregnancy
Potential Benefits
Greater birth weight
Treatment retention Reduced
exposure to unknown chemicals from cutting
agents Opportunity to engage in other medical
and psychosocial interventions
Potential Risks
Fetal exposure to psychoactive
substance Potential for neonatal withdrawal

52
What if Opioid Dependent Pregnant Women are Not
Treated?
Maternal and fetal complications
Intrauterine growth restriction low birth
weight Infant morbidity
53
Methadone Can be Safely Used to Treat Pregnant
Opioid Dependent Women

• Methadone is recommended for the treatment of
  opioid dependent women
• Over 30 years of experience and research
• Not appear to have teratogenic potential

54
Neonatal Abstinence Syndrome (NAS)

• Neuralgic excitability (hyperactivity,
  irritability, sleep disturbance)
• Gastrointestinal dysfunction
• (uncoordinated sucking/swallowing, vomiting)
• Autonomic Signs (fever, sweating, nasal
  stuffiness)

55
NAS of Methadone Exposed Neonates

• NAS is a treatable condition
• 55-90 exhibit NAS
• Onset within 45 to 72 hours after birth
• Peak 40 to 120 hours after birth
• Subacute signs for a year
• Methadone dose relationship to NAS severity is
  inconsistent

56
Number of Cigarettes Plays Role in Severity of
Methadone associated NAS Adapted from Choo et
al., 2004 Drug Alcohol Depend



n13
n16
n16
n13
57
Treatment of NAS

• Research literature inconsistent
• Wide range of mediations, dosing and weaning
  procedures
• Assessment tools vary
• Symptoms driving the management ability are the
  CNS irritability and GI dysfunction
• American Academy of Pediatrics (AAP) Committee on
  Drugs Pediatrics Vol. 101 No. 6, June 1998

58
Long Term Outcome of Prenatal Drug Exposure

• Effects of poverty
• Effects of other drug use, dose and timing
• Quality of caregiving is a major determinant of
  resilience

59
Buprenorphine

• A derivative of thebaine
• Subutex or Suboxone

Full
Full
Antagonist
Agonist
Heroin
Buprenorphine
Nalmefene
Naloxone
Morphine
Naltrexone
Methadone
60
Buprenorphine Potential Alternative for Treating
Opioid Dependent Pregnant Women

• Birth outcomes improved with methadone compared
  to untreated heroin dependence
• Associated methadone withdrawal in the neonate
  can pose a clinical challenge
• Buprenorphine reported to produce less physical
  dependence in adults

61
Studies of Buprenorphine in Pregnancy

• Since 1995, over 30 published reports
• Approximately 457 babies and number of cases
  ranged from 1 to 159 (median13)
• Two RCTs, one prospective multi-center trial,
  nine other prospective reports and eighteen case
  reports

62
NAS Comparison
Methadone 55-90 70 45 to 72 hrs 40 to 120
hrs Subacute signs for a year
Buprenorphine 61 50 12-48 hrs 66-96
hrs 120-168 hrs
NAS signs Requiring treatment NAS appears NAS
peaks Duration
Methadone and buprenorphine dose relationship to
NAS severity is inconsistent
63
Purpose

• Compare methadone and buprenorphine in pregnant
  opioid-dependent women and to provide preliminary
  safety and efficacy data for a larger
  multi-center trial

64
Randomized Controlled Study

• Double-blind (staff and patient)
• Double-dummy (two medications)
• Two groups Methadone or Buprenorphine
• Flexible dosing
• Methadone 20-100 mg
• Buprenorphine (Subutex) 4-24 mg

65
Criteria

• Inclusion
• 18 - 40 years of age
• Gestational age 16 - 30 weeks
• Opioid dependent (DSM-IV, SCID I)
• Opioid positive urine

66
Criteria

• Exclusion
• Methadone positive urine at admission
• DSM IV axis I current diagnosis other than
  psychoactive substance use
• Serious medical or psychiatric illness
• Diagnosis of preterm labor
• Congenital fetal malformation
• Current alcohol abuse/dependence
• Benzodiazepine use
• (8 or more times/month and/or 2 or more times
  /week)

67
Primary Outcome MeasuresNeonate

• Neonatal Abstinence Syndrome (NAS)
• Length of Hospital Stay (LOS)

68
Selected Secondary Outcome Measures

• Maternal
• Days of treatment
• Prenatal care visits
• Illicit drug use
• Infant
• Physical birth parameters

69
Non-Pharmacotherapy Treatments

• Vouchers contingent upon drug negative biological
  samples
• Vouchers contingent upon compliance with
  treatment
• Counseling
• Medical Care
• Obstetric services
• Non-Obstetrical medical care (e.g., psychiatric)

70
Patient Flow
Number screened 1490
Not Qualify Initially 1433
Qualify and sign consent 57
Randomized 30
Buprenorphine 15
Methadone 15
Buprenorphine 9
Methadone 11
Adapted from Jones, H.E. et al., 200579, 1-10.
Drug Alcohol Depend
71
Induction

• Patients stabilized on immediate release morphine
  (IRM) prior to randomization
• Is transition from IRM to methadone or
  buprenorphine similar?
• Withdrawal scores over first 3 days appeared mild
  for both medications

72
Induction
Methadone
Buprenorphine Morphine Dose (mg) 268
(214-322) 208 (161-254) Dose (mg)
54 (49-58) 11(10-12)
Adapted from Jones, H.E. et al., 2005 7833-38.
Drug Alcohol Depend
73
Maternal Drug Use
Methadone N11
Buprenorphine N9
Urine Samples
opioid 15.6 16.7 cocaine 11.2 15.2 ampheta
mine 0.0 0.0 barbiturates 0.0
0.0 benzodiazepine 0.4 2.5 THC 7.5
0.0
Adapted from Jones, H.E. et al., 200579, 1-10.
Drug Alcohol Depend
74
Maternal Characteristics
Methadone N11
Buprenorphine N9
African-American 63.6 88.9 Gestation
(weeks) 23.6 22.8 Education
(yrs) 10.0 10.3 Employed 0.0 0.0 Age
(yrs) 30.3 30.0 Smoked Cigarettes 81.8 77.8
Adapted from Jones, H.E. et al., 200579, 1-10.
Drug Alcohol Depend
75
Maternal Outcomes
Methadone N11
Buprenorphine N9
Days in Treatment 99.9 115.6 Prenatal
care visits 3.4 3.6 LOS mom 2.2
2.2 C section 9.1 11.1 Tox. delivery
(mom) 9.1 0.0 Normal presentation 100
100 Preterm birth 9.1 0.0 Gestational
age delivery 38.8 38.8 Ave. dose at delivery
(mg) 79.1 18.7
Adapted from Jones, H.E. et al., 200579, 1-10.
Drug Alcohol Depend
76
Birth Outcomes
Methadone N11
Buprenorphine N9 deliveries (10 babies)
Treated for NAS 45.5 20.0 Morphine
Drops 93.1 23.6 Birth Weight (gm)
3001.8 3530.4 LOS baby 8.1 6.8
NICU treatment 18.0 10.0 APGAR 1 8.3
8.1 APGAR 5 8.9 8.7 Length
(cm) 49.6 52.8 Head Cir. (cm) 33.2 34.9
data safety monitoring board recommended
removing twin data from these variables
Adapted from Jones, H.E. et al., 200579, 1-10.
Drug Alcohol Depend
77
Study Limitations

• Small sample size
• I/E criteria limits generalizability
• Nicotine exposure and effect on NAS needs more
  study
• Long-term outcomes beyond scope of study

78
Conclusions of the Pilot Study

• Both methadone and buprenorphine provide positive
  benefits to mothers
• 100 of infants had NAS signs/symptoms
• Tendency for fewer buprenorphine-exposed babies
  to be treated for NAS
• Significantly fewer days of hospitalization with
  buprenorphine exposure

79
Bottom Line

• Both medications have strong support to document
  safety and efficacy for mother and infant
• NAS is only part of the complete riskbenefit
  ratio
• A greater range of medication options will
  improve the treatment of pregnant women

80
OUTLINE

• I. The Problem
• II. Role of agonist therapies in treatment
• III. Future Directions

81
Current DirectionsMOTHER N370

• Johns Hopkins U. Baltimore, MD (60)
• Medical U. of Vienna, Vienna, Austria (52)
• St. Josephs Hlth Ctr. Toronto, Canada (30)
• T. Jefferson U., Philadelphia, PA (60)

• University of VT, Burlington, VT (48)
• Vanderbilt UMC, Nashville, TN (60)
• Wayne State U., Detroit, Michigan (40)
• Women Infants, Providence, RI (20)

Coordinating Center Center for Substance Abuse
Research, (CESAR) U. of Maryland
82
Current Directions

• 8 site multi-center trial comparing methadone and
  buprenorphine
• May provide data needed to change FDA labeling
  for methadone and buprenorphine
• Develop infrastructure for studying other
  medications and womens health issues during
  pregnancy

83
Questions for Future Study Mother

• Pharmacokinetics and pharmacodynamics of
  buprenoprhine pre- and post-partum
• Treatment matching and transitioning from one
  medication to another
• Pain management during labor, delivery and
  post-partum
• Amount of medication exposure during breast
  feeding

84
Transition from Methadone to BuprenorphineSubject
ive Withdrawaladapted from Jones et al., Am J
Addict 2006 15, 61-70.
85
Questions for Future Study Child

• NAS
• Tools to measure NAS
• Medications to treat NAS
• Role of concomitant drug exposure in NAS
  expression
• Short and long term outcome
• Growth, learning, development, behavior
• Role of environmental variables as protective
  factors

86
Take Home Messages
Opioid addiction during pregnancy often occurs
in context of multiple complex medical,
psychosocial and environmental factors
Medications can play an important role in the
treatment of opioid addiction during pregnancy
Greater medication options will help to improve
the treatment of opioid addicted pregnant
patients