Buprenorphine 101:Basic Background and

FrameworkDavid A. Fiellin, M.D.

Associate Professor of MedicineYale University School of Medicine

RWJ Foundation Generalist Physician Faculty ScholarChair, ASAM Buprenorphine Training

Overview• Opioid dependence

– Epidemiology– Neurobiology

• Treatment of opioid dependence– Rationale for opioid agonist treatment

• Drug Addiction Treatment Act of 2000 • Buprenorphine• Emerging issues in the use of buprenorphine

• Tolerance• Withdrawal• Larger amounts/longer period than intended• Inability to/persistent desire to cut down or control• Increased amount of time spent in activities

necessary to obtain opioids• Social, occupational and recreational activities given

up or reduced• Opioid use is continued despite adverse

consequences

Opioid Dependence (DSM-IV)(3 or more within one year)

Epidemiology• Office of National Drug Control Policy (1999)

– Opioid dependence• 810,000 persons• Only 170,000 receiving medication treatment

• National Household Survey on Drug Abuse (2002)– Heroin

• 1999: 2.4 million Americans reported using heroin at least once

• 2002: 166,000 current users– Non-Medical Use of Prescription Pain Relievers (opioids)

• Between 1990 and 2001, number of new users increased from 628,000 to 2.4 million

• In 2002, 4.4 million users• Drug Abuse Warning Network (1992 to 2001)

• Emergency department visits for heroin- Increased 47% from 63,000 to 93,000

• Emergency department visits for non-medical use of prescription pain relievers- Increased 117% from 42,000 to 90,000

Why does the brain prefer opium to broccoli?

Neurobiology

• Mu receptor mediates opioid effects– high affinity for enkephalins, beta endorphins, and opioids

• Dose dependent changes– Repeated exposure to short acting opioids– Neuronal cellular and receptor adaptations

• Mesolimbic dopamine system– Mediate tolerance, withdrawal, craving, self-administration– Explain chronic and relapsing nature of opioid dependence– Basis of pharmacotherapies to stabilize neuronal changes

What is it like to be opioid dependent?

Opioid Agonist Treatment• Rationale

– Cross-tolerance• prevent withdrawal

• relieve craving for opioids– Narcotic blockade

• block or attenuate euphoric effect of exogenous opioids

Bup 00 mg

Bup 02 mg

Bup 16 mg

Bup 32 mg0 -

4 -

MRI

BindingPotential(Bmax/Kd)

Effects of Buprenorphine Dose on µ-Opioid Receptor Availability in a Representative Subject

Slide Courtesy of Laura McNicholas, MD, PhD

Treatment vs. Addiction

MarkedAbsentEuphoria

3-6 hours24-36 hoursDuration

Immediate30 minutesOnset

IV, INOral, sublingualRoute

HeroinMethadone or buprenorphine

Withdrawal vs. Maintenance?

Retention in treatmentHeilig, Lancet 2003

Treatment duration (days)

Rem

aini

ng in

trea

tmen

t (n

r)

0

5

10

15

20

0 50 100 150 200 250 300 350

WithdrawalMaintenance

Buprenorphine RCT Mortality

Heilig, Lancet 2003

χ2=5.9; p=0.0150/20 (0%)4/20 (20%)Dead

Cox regressionMaintenanceWithdrawal

How effective is opioid agonist treatment?

HIV Seroconversion

• Metzger, 1993:– 2 cohorts of patients

• 103 out-of-treatment intravenous opiate users• 152 subjects receiving methadone treatment

– HIV antibody conversion, 18-months• 22% of those out-of-treatment• 3.5% of those receiving methadone treatment

Treatment outcomesBall and Ross, 1991

0%

10%

20%30%

40%

50%

60%

A B C D E F

Treatment Program

IV d

rug

use

Medication alone?

Psychiatric comorbidity

Brooner, 1997:716 opioid abusers seeking methadone treatment DSM-IIIR

assessments one month after admission

Lifetime Current• Any psychiatric comorbidity 47% 39%• Any Axis I disorder 24% 8%• Mood disorder 19% 4%

• major depression 16% 3%• anxiety disorder 8% 5%

• Any personality disorder 35%– anti-social 25%– avoidant 5%– borderline 5%

Effect of Counseling in Methadone Treatment

TreatmentRetention

Urine (-)> 16 weeks

Methadone alone

31% 0%

Methadone plus std counseling

59% 28%

Methadone plus enhanced counseling

81% 55%

Effect of counseling in buprenorphine treatment (Fiellin, 2002)

0

0.2

0.4

0.6

0.8

1

Induction week 2-4 week 5-7 week 8-10

Opi

oid

posi

tive

urin

es MMMM+DC

Federal Policy Changes• FDA and CSAT (2000)

• Created a process for exemptions for office-based care• To allow the transfer of stable patients from treatment

programs to physician’s offices• Congress (2000)

• Drug Addiction Treatment Act of 2000• Allows qualifying office-based physicians to use approved

schedule III-V narcotic medications (e.g. buprenorphine)

• FDA (2002)• Approves buprenorphine and buprenorphine/naloxone for

treatment of opioid dependence• DEA (2002)

• Buprenorphine and buprenorphine/naloxone schedule III

Practitioner requirements:“Qualifying physician”Has capacity to refer patients for

appropriate counseling and ancillary services

No more than 30 patients (individual or group practice)

Drug Addiction Treatment Act of 2000

The term “group practice” is defined under section 1877(h)(4) of the Social Security Act (42 U.S.C. § 1395nn(h)(4)) and further defined in regulations published by the Centers for Medicare and Medicaid Services (CMS) in the Federal Register on January 4, 2001 (66 FR 856). A brief summary of certain requirements of the definition of group practice is provided below; however, readers should not rely on this summary alone to determine whether they meet the requirements of the definition. Interested parties may refer to the statutory definition of “group practice” found at 42 U.S.C. § 1395nn(h)(4) and to the January 4, 2001, final rule, which may be accessed from the CMS website at http://www.cms.hhs.gov/medlearn/refphys.asp. In general, under section 1877(h)(4) of the Social Security Act and its implementing regulations, a “group practice” has the characteristicsidentified below. It is a single legal entity formed primarily for the purpose of being a physician group practice. The entity may be organized as a partnership, professional corporation, foundation, nonprofit corporation, faculty practice plan, or similar association. For example, a hospital that directly employs physicians (such as a VA hospital) generally is not a "group practice" for purposes of section 1877 of the Act, but it could establish a group practice that satisfies the definition. A group practice cannot be organized or owned in whole or in part by another medical practice that is a physician practice. The group practice has at least two physicians who are either owners of the group (directly or indirectly) or employees of the group (not independent contractors). Each physician who is a member of the group provides substantially the full range of services, which he or she routinely provides (e.g., medical care, diagnosis, and treatment) through the joint use of shared office space, equipment, and personnel. The term “member of the group” does not include independent contractors. At least 75% of the total patient care services of the group practice members are provided through the group and billed under a billing number assigned to the group, and receipts are treated as receipts of the group. This requirement does not apply to group practices located solely in a Health Professional Shortage Area (HPSA), as defined under section 332(a)(1)(A) of the Public Health Service Act. Members of the group personally conduct at least 75% of thephysician-patient encounters of the group practice. The group’s overhead expenses and income are distributed according to methods that are determined before the receipt of payment for the services that gave rise to the overhead expense or the income.Except for certain profit-sharing arrangements or productivity bonuses, no member of the group directly or indirectly receives compensation that is based on the volume or value of the referrals made by the physician. To the extent that a group of physicians that is not affiliated with an Opioid Treatment Program (i.e., methadone clinic) and that meets the definition of a group practice under section 1877(h)(4) of the Social Security Act wishes to provide maintenance or detoxification treatment for opioid-dependant patients from their general practice, each physician in that group practice would need to obtain a waiver from the annual registration requirement and the whole group would be subject to the 30-patient limitation.

Group Practice? http://buprenorphine.samhsa.gov/faq.html#9

“Qualifying physician”:A licensed physician who meets one or more of

the following:1. Board certified in Addiction Psychiatry2. Certified in Addiction Medicine by ASAM3. Certified in Addiction Medicine by AOA4. Investigator in buprenorphine clinical trials5. Has completed 8 hours training provided

by ASAM, AAAP, AMA, AOA, APA

New Federal DEA registration (XB1234567)

Drug Addiction Treatment Act of 2000

Medication:Approved by the FDA for use in

maintenance or detoxification treatment of opioid dependence

Schedule III, IV, or VMedication or combinations of

medications

Drug Addiction Treatment Act of 2000

Buprenorphine

Buprenorphine• Partial agonist at mu receptor • Effective therapy for opioid dependent

patients• Low abuse and diversion potential,

especially when combined with naloxone• Sub-lingual tablet - Buprenorphine/naloxone,

4:1• Effective in daily or thrice-weekly dosing

-10 -9 -8 -7 -6 -5 -40

10

20

30

40

50

60

70

80

90

100

Intrinsic Activity

Log Dose of Opioid

Full Agonist(Methadone)

Partial Agonist(Buprenorphine)

Antagonist (Naltrexone)

Intrinsic Activity: Full Agonist (Methadone), Partial Agonist (Buprenorphine), Antagonist (Naltrexone)

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

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%

PEAK EFFECTS – MEAN (±SD)

Bad Drug Sickness

0

20

40

60

80

100

Bad

Dru

g E

ffec

t (0-

100)

0

20

40

60

80

100

Sick

ness

Sca

le (0

-100

)

A Buprenorphine placebo, Naloxone placeboD Buprenorphine 0.2 mg, Naloxone 0.1 mgC Buprenorphine placebo, Naloxone 0.1 mg

A DCB

B Buprenorphine 0.2 mg, Naloxone placebo

A DCB

Adding Naloxone to Buprenorphine

• Does not diminish the effectiveness of sublingual buprenorphine but

• Attenuates opiate agonist effects in–Methadone patients–Untreated opioid dependent individuals

• Probably will have little effect on intravenous buprenorphine abuse in buprenorphine/naloxone treated patients

Potential medication interactions between buprenorphine and other medications

I. Cytochrome P450 3A4 inhibitorsAzole antifungalsMacrolide antibiotics

II. Cytochrome P450 3A4 inducersPhenobarbital, carbemazepine, phenytoin, rifampicin

III. Sedatives (e.g. benzodiazepines)

Potential medication interactions

I. Cytochrome P450 3A4 inhibitorsI. Azole antifungalsII. Macrolide antibiotics

III. Protease inhibitors (Ritonavir>Indinavir>Saquinavir inhibit buprenorphine N-dealkylation)

II. Cytochrome P450 3A4 inducersI. Phenobarbital, carbemazepine, phenytoin, rifampicin

III. Sedatives (e.g. benzodiazepines)

Note no controlled studies have directly examined these possible interactions

Training Resources• Components directed at physicians

– Standard Training Curriculum – Online Training Program (APA, AAAP)– CSAT Treatment Improvement Protocol #40

(Buprenorphine Practice Guideline)– DATA 2000 Training Societies

• ASAM , AAAP, AOA, APA, AMA

– Federation of State Medical Boards Model Policy Guideline

• Counselors training, 3-hour online• Physician Clinical Support Service

Use of Buprenorphine in the Pharmacologic Management of Opioid Dependence: Curriculum for physicians (Strain)Reference document and slidesRepresentatives from AAAP, AOAAM, ASAMSponsored by CSAT

Basic pharmacology Special treatment populationsPatient assessment Applied pharmacologyClinical Management Non-pharmacologic treatmentsPatient confidentiality Office managementMedical comorbidity Psychiatric comorbidity

The Curriculum

http://buprenorphine.samhsa.gov/Drug Addiction Act of 2000Waiver Notification formsBuprenorphine trainingsFrequently asked questions

Information line: 866-BUP-CSATM-F 8:30-5:00 EST

Email: info@buprenorphine.samhsa.gov

CSAT Buprenorphine Information

DATA 2000 Trainings• Over 68 completed in-person training events

(30-50 scheduled)• 4,414 physician trainees identified

– 3971 in-person trainees– 443 Web-based trainings completed

Waiver Notification Submissions

• 2,909 waiver notifications received• 2,675 waiver notifications approved• 1,760 waivers claimed a DATA-qualified

buprenorphine training • 1,998 physicians listed on Physician Locator

Buprenorphine Prescribing• Majority Psychiatry, followed by

Internal and Family Medicine

• Top 5 states– California, Pennsylvania, Florida, New

York, Texas

Three year evaluation periodHHS – efficacious, access, adverse

events DEA – violations, diversion

HHS and DEACan decide law should not remain in effectCease to be in effect in 60 days

Amended Controlled Substances Act

Emerging Issues

Logistical Issues• Group practice limitation –

– S-1887, Pending legislation to eliminate– SAMHSA Rulemaking Intent

• Coverage for medication costs• Reimbursement for physician services• Reimbursement for counseling

services

Special Populations• Pregnancy

• Hepatitis C

• Adolescents

• Acute and chronic pain

Patient Characteristics• Treatment seeking

• Opioid dependent

• No alcohol or sedative dependence

• No untreated Axis I disorders

• No acute medical conditions

• Transaminases

Treatment Characteristics• Daily or thrice weekly supervised dosing

• Solution and tablet

• Required counseling

• Opioid treatment program

Treatment Retention 3 month 6 monthJohnson, 1992 50% Kosten, 1993 68% 29% Strain, 1994 59% Johnson, 1995 72%, 58% Ling, 1996 55% 20% Ling, 1998 66% O’Connor, 1998 78%, 52% Johnson, 2000 72% Fudala, 2003 55%

Fiellin, unpub 46%

Summary• Opioid dependence is a chronic relapsing medical

condition• Profound neurobiologic changes accompany the

transition from opioid abuse to dependence• Buprenorphine combined with psychosocial

services can be effective in decreasing illicit opioid use and HIV risk

• Expansion of buprenorphine into HIV clinical settings poses unique challenges and opportunities inherent in blending two fields of medicine