Buprenorphine : A New Approach for Opioid Treatment Thomas E. Freese, Ph.D. Pacific Southwest...

Buprenorphine : A New Approach for Opioid Treatment

Thomas E. Freese, Ph.D.Pacific Southwest Addiction Technology Transfer Center

UCLA Integrated Substance Abuse Programs

National Conference on Problem Gambling

Kansas City, MO

June 8, 2007

My Opinions Concerning Medication Management

There are many strongly felt emotions held by addiction and other helping professionals towards medication management and the use of pharmacotherapies to treat substance dependence…

……What are yours?What are yours?

A Brief History of Opioid Treatment

A Brief History of Opioid Treatment

1964: Methadone is approved.

1974: Narcotic Treatment Act limits methadone treatment to specifically licensed Opioid Treatment Programs (OTPs).

1984: Naltrexone is approved, but has continued to be rarely used (approved in 1994 for alcohol addiction).

1993: LAAM is approved (for non-pregnant patients only), but is underutilized.

A Brief History of Opioid Treatment, Continued

2000: Drug Addiction Treatment Act of 2000 (DATA 2000) expands the clinical context of medication-assisted opioid treatment.

2002: Tablet formulations of buprenorphine (Subutex®) and buprenorphine/naloxone (Suboxone®) were approved by the Food and Drug Administration (FDA).

2004: Sale and distribution of ORLAAM® is discontinued.

Understanding DATA 2000

Drug Addiction Treatment Act of 2000 (DATA 2000)

Expands treatment options to include both the general health care system and opioid treatment programs.Expands number of available treatment

slotsAllows opioid treatment in office settingsSets physician qualifications for prescribing

the medication

DATA 2000: Physician Qualifications

Physicians must:Be licensed to practice by his/her stateHave the capacity to refer patients for psychosocial treatmentLimit their practice to 30 patients receiving buprenorphine at any given time Be qualified to provide buprenorphine and receive a license waiver

100 patients

A physician must meet one or more of the following qualifications:

Board certified in Addiction Psychiatry Certified in Addiction Medicine by ASAM or AOA Served as Investigator in buprenorphine clinical trials Completed 8 hours of training by ASAM, AAAP, AMA,

AOA, APA (or other organizations that may be designated by Health and Human Services)

Training or experience as determined by state medical licensing board

Other criteria established through regulation by Health and Human Services

DATA 2000: Physician Qualifications

Development of Subutex®/Suboxone®

U.S. FDA approved Subutex® and Suboxone® sublingual tablets for opioid addiction treatment on October 8, 2002.

Product launched in U.S. in March 2003

Interim rule changes to federal regulation (42 CFR Part 8) on May 22, 2003 enabled Opioid Treatment Programs (specialist clinics) to offer buprenorphine.

Treatment Admissions for Opioid Addiction

Who Enters Treatment for Heroin Abuse?

90% of opioid admissions in 2000 were for heroin

67% male

47% White; 25% Hispanic; 24% African American

65% injected; 30% inhaled

81% used heroin daily

SOURCE: SAMHSA, Treatment Episode Data Set, 1992-2000.

Who Enters Treatment for Heroin Abuse?

78% had at least one prior treatment episode; 25% had 5+ prior episodes

40% had a treatment plan that included methadone

23% reported secondary alcohol use; 22% reported secondary powder cocaine use


Who Enters Treatment for Other Opiate Abuse?

51% male

86% White

76% administered opiates orally

28% used opiates other than heroin after age 30

19% had a treatment plan that included methadone

44% reported no secondary substance use; 24% reported secondary alcohol use


(Non-prescription use of methadone, codeine, morphine, oxycodone, hydromorphone, opium, etc.)

Primary Heroin Treatment Admissions vs. Primary Other Opiate Treatment

Admissions: A Side-by-Side Comparison

0%10%20%30%40%50%60%70%80%90%

100%

% Male % White % Injected % Rec'dMethadone

Pe

rce

nt

of

Ad

mis

sio

ns

Heroin Admissions Other Opiate Admissions


Opioids and the Brain:Pharmacology and Half-Life

What Happens When You Use Opioids?

Acute Effects:

Results of Chronic Use:

Withdrawal Symptoms:

Let’s talk about each of these.

Possible Acute Effects of Opioid Use

Surge of pleasurable sensation = “rush”

Warm flushing of skin

Dry mouth

Heavy feeling in extremities

Drowsiness

Clouding of mental function

Slowing of heart rate and breathing

Nausea, vomiting, and severe itching

Consequences of Opioid UseAddiction

Overdose

Death

Use related (e.g., HIV infection, malnutrition)

Negative consequences from injection: Infectious diseases (e.g., HIV/AIDS, Hepatitis B and C) Collapsed veins Bacterial infections Abscesses Infection of heart lining and valves Arthritis and other rheumatologic problems

Opioid Withdrawal SyndromeIntensity varies with level & chronicity of use

Cessation of opioids causes a rebound in function altered by chronic use

First signs occur shortly before next scheduled dose

Duration of withdrawal is dependent upon the half-life of the drug used: Peak of withdrawal occurs 36 to 72 hours after last

dose Acute symptoms subside over 3 to 7 days Protracted symptoms may linger for weeks or months

Opioid Withdrawal Syndrome

Acute SymptomsPupillary dilation

Lacrimation (watery eyes)

Rhinorrhea (runny nose)

Muscle spasms (“kicking”)

Yawning, sweating, chills, gooseflesh

Stomach cramps, diarrhea, vomiting

Restlessness, anxiety, irritability

Opioid Withdrawal Syndrome

Protracted SymptomsDeep muscle aches and pains

Insomnia, disturbed sleep

Poor appetite

Reduced libido, impotence, anorgasmia

Depressed mood, anhedonia

Drug craving and obsession

An Overview of Buprenorphine

Development of Tablet Formulations of

BuprnorphineBuprenorphine is marketed for opioid treatment under the trade names of Subutex® (buprenorphine) and Suboxone® (buprenorphine/naloxone)

Over 25 years of researchOver 5,000 patients exposed during clinical trialsProven safe and effective for the treatment of opioid addiction

Buprenorphine: A Science-Based Treatment

Clinical trials have established the effectiveness of buprenorphine for the treatment of heroin addiction. Effectiveness of buprenorphine has been compared to:

Placebo (Johnson et al. 1995; Ling et al. 1998; Kakko et al. 2003) Methadone (Johnson et al. 1992; Strain et al. 1994a, 1994b; Ling et al. 1996; Schottenfield et al. 1997; Fischer et al. 1999) Methadone and LAAM (Johnson et al. 2000)

Buprenorphine as a Treatment for Opioid Addiction

A synthetic opioid

Described as a mixed opioid agonist-antagonist (or partial agonist)

Available for use by certified physicians outside traditionally licensed opioid treatment programs

The Role of Buprenorphine in Opioid Treatment

Partial Opioid AgonistProduces a ceiling effect at higher dosesHas effects of typical opioid agonists—these

effects are dose dependent up to a limitBinds strongly to opiate receptor and is long-

acting

Safe and effective therapy for opioid maintenance and detoxification

Partial vs. Full Opioid Agonist

Dose of Opiate

OpiateEffect

death

Full Agonist(e.g., methadone)

(e.g. Naloxone)Antagonist

Partial Agonist(e.g. buprenorphine)

1. Patient can participate fully in treatment activities and other activities of daily living easing their transition into the treatment environment

2. Limited potential for overdose

3. Minimal subjective effects (e.g., sedation) following a dose

4. Available for use in an office setting

5. Lower level of physical dependence

Advantages of Buprenorphine in the Treatment of Opioid Addiction

Combination tablet is being marketed for U.S. use

6. Discourages IV use

7. Diminishes diversion

8. Allows for take-home dosing

Advantages of Buprenorphine/Naloxone in the Treatment of Opioid Addiction

Disadvantages of Buprenorphine in the

Treatment of Opioid Addiction

1. Greater medication cost

2. Lower level of physical dependence (i.e., patients can discontinue treatment)

3. Not detectable in most urine toxicology screenings

Why was Buprenorphine/Naloxone Combination Developed?

• Developed in response to increased reports of buprenorphine abuse outside of the U.S.

• The combination tablet is specifically designed to decrease buprenorphine abuse by injection, especially by out of treatment opioid users.

What is the Ratio of Buprenorphine to Naloxone in the

Combination Tablet?Each tablet contains buprenorphine and naloxone in a 4:1 ratioEach 8 mg tablet contains 2 mg of naloxoneEach 2 mg tablet contains 0.5 mg of naloxone

Ratio was deemed optimal in clinical studiesPreserves buprenorphine’s therapeutic effects

when taken as intended sublinguallySufficient dysphoric effects occur if injected by

some physically dependent persons to discourage abuse.

Why Combining Buprenorphine and Naloxone Sublingually Works

Buprenorphine and naloxone have different sublingual (SL) to injection potency profiles that are optimal for use in a combination product.

SL Bioavailability Injection to Sublingual Potency

Buprenorphine 40-60% Buprenorphine ≈ 2:1

Naloxone 10% or less Naloxone ≈ 15:1

SOURCE: Amass et al., 2004.

Buprenorphine/Naloxone: What You Need to know

• Basic pharmacology, pharmacokinetics, and efficacy is the same as buprenorphine alone.

• Partial opioid agonist; ceiling effect at higher doses

• Blocks effects of other agonists• Binds strongly to opioid receptor, long

acting

The Use of Buprenorphine in the Treatment of Opioid Addiction

Induction

Maintenance

Tapering Off/Medically-Assisted Withdrawal

Induction

Induction Phase

Working to establish the appropriate dose of medication for patient to discontinue use of opiates with minimal withdrawal symptoms, side-effects, and craving

Buprenorphine is administered sublingually.

What will the tablets look like?How will they taste?

Light orange tablet

Flavor = natural lemon & lime Sweetener = acesulfame potassium

This is done to overcome the perceived bitterness of the naloxone hydrochloride in the Suboxone tablets. The orange color has been added to ensure clear differentiation between Subutex and Suboxone tablets.

Five Steps to Starting Bup/Nx

1. Have patient abstain or impose ~ 8 hr. interval between prior agonist use and buprenorphine administration

2. Mild withdrawal symptoms optimal

3. Verify that the urine sample is methadone-negative

4. Select appropriate substitution dose

5. Start with low dose and increase over several days

Direct Buprenorphine Induction from Long-Acting

Opioids Controlled trials are needed to determine optimal procedures for inducting these patients.

Data is also needed to determine whether the buprenorphine only or the buprenorphine/naloxone tablet is optimal when inducting these patients.

SOURCE: Amass, et al., 2004; Johnson, et al. 2003.

Direct Buprenorphine Induction from Long-Acting

OpioidsClinical experience has suggest that induction procedures with patients receiving long-acting opioids (e.g. methadone-maintenance patients) are basically the same as those used with patients taking short-acting opioids, except: The time interval between the last dose of medication and the

first dose of buprenorphine must be increased. At least 24 hrs should elapse before starting buprenorphine

and longer time periods may be needed (up to 48 hrs). Urine drug screening should indicate no other illicit opiate use

at the time of induction.

Stabilization and Maintenance

Stabilization Phase

Patient experiences no withdrawal symptoms, side-effects, or craving

Maintenance Phase

Goals of Maintenance Phase:Help the person stop and stay away from illicit drug use and problematic use of alcohol

1. Continue to monitor cravings to prevent relapse

2. Address psychosocial and family issues

Maintenance Phase

Psychosocial and family issues to be addressed:

a) Psychiatric comorbidity

b) Family and support issues

c) Time management

d) Employment/financial issues

e) Pro-social activities

f) Legal issues

g) Secondary drug/alcohol use

Buprenorphine Maintenance: Summary

Take-home dosing is safe and preferred by patients, but patient adherence will vary and this can impact treatment outcomes.

3x/week dosing with buprenorphine/naloxone is safe and effective as well (Amass, et al., 2001).

Counseling needs to be integrated into any buprenorphine treatment plan.

Medically-Assisted Withdrawal(a.k.a. Dose Tapering)

Buprenorphine Withdrawal

Working to provide a smooth transition from a physically-dependent to non-dependent state, with medical supervision

Medically supervised withdrawal (detoxification) is accompanied with and followed by psychosocial treatment, and sometimes medication treatment (i.e., naltrexone) to minimize risk of relapse.

Medically-Assisted Withdrawal (Detoxification)

Outpatient and inpatient withdrawal are both possible

How is it done?

Switch to longer-acting opioid (e.g., buprenorphine)

Taper off over a period of time (a few days to weeks depending upon the program)

Use other medications to treat withdrawal symptoms

Use clonidine and other non-narcotic medications to manage symptoms during withdrawal

Transferring Patients Onto Buprenorphine:

3 Ways Significant Withdrawal Could Occur

Insufficient agonist effects

Dose too low?

If dose is too low, the patient will experience withdrawal

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

10

20

30

40

50

60

70

80

90

100

Intrinsic Activity

Log Dose of Opioid

MaintenanceLevel

DosageLevel




Dose too low?

May notfully

substitute

Not full agonist

If the patient needs a high level of medication to achieve maintenance, the

ceiling effect of buprenorphine may result in withdrawal

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

10

20

30

40

50

60

70

80

90

100

Intrinsic Activity

Log Dose of Opioid

Maintenancelevel

Bup’s effect




Dose too low?

May notfully

substitute

Not full agonist

Ceiling effect

PrecipitatesWithdrawal

Buprenorphine will replace other opioids at the receptor site. The patient therefore

experiences withdrawal

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

10

20

30

40

50

60

70

80

90

100

Intrinsic Activity

Log Dose of Opioid

Currentintoxicationlevel

Bup’s effect

An Example of Detox Protocol: Results from 2 CTN Trials.

NIDA’s Clinical Trials Network

Established in 1999NIDA’s largest initiative to blend research and clinical practice by bringing promising therapies to community treatment providersNetwork of 17 University-based Regional Research and Training Centers (RRTCs) involving 116 Community Treatment Programs (CTPs) in 24 states, Washington D.C., and Puerto Rico

CTN RRTC

States with CTP

CTN NodesCTN Nodes

Regional Research &

Training Center

Community Treatment Program


Community Treatment Program Community

Treatment Program


CTN Node




The Research:CTN Protocols 0001 and 0002

The Two Buprenorphine-Naloxone Protocols

NIDA-CTN 0001:Buprenorphine-Naloxone vs. Clonidine for Short-Term

Inpatient Opiate Detoxification

NIDA-CTN 0002:Buprenorphine-Naloxone vs. Clonidine for Short-Term

Outpatient Opiate Detoxification

Initiated in 8 Regional Nodes and 12 Community Treatment Programs

PacificBetty Ford Center

Great LakesShar House Ohio Valley

Maryhaven

FloridaOperation PARCenter for DFL

Long IslandPhoenix House

Site Participation: NIDA-CTN 0001

PacificAegis

Ohio ValleyMidtown New York

ARTCBellevue

Delaware ValleyMercer

OregonKaiser Permanente

Site Participation: NIDA-CTN 0002

NIDA CTN 001/002 Buprenorphine-Naloxone Detoxification Protocols

• Two, open-label, randomized clinical trials• Compared Buprenorphine-Naloxone

(BUP/NX) and Clonidine for Short-Term (2 weeks) opioid Detoxification in Residential or Outpatient Settings

Community Treatment Programs

2 Therapeutic Communities1 Free-standing, Chemical

Dependency Hospital2 Detox Units with Integrated

Addiction and Mental Health Services

1 Long Term Residential

4 Opioid Treatment Programs1 HMO1 Community Mental Health

Center

6 Inpatient 6 Outpatient

Usual care approaches: 50% methadone, 50% clonidine

Usual care approaches: methadone in OTPs and clonidine in HMO

Study Schema

1. Obtain Informed Consent2. Perform Screening/Baseline Assessments

Follow-up at 1 month

Follow-up at 3 months

Randomize (2:1) and Enroll

N=240Buprenorphine/Naloxone

13 days detoxification

N=120 Clonidine

13 days detoxification

Follow-up at 6 months

Primary Efficacy Endpoint

It is hypothesized that BUP/NX detoxification, compared to clonidine, will be associated with a better treatment response.

A treatment responder = anyone who completes the 13-day detoxification and whose last urine specimen is negative for opioids.

So,

what did we find?

Bup/Nx Clonidine Total

Sex No. (%)

Male

Female

61

39

58

42

60

40

Race No. (%)

White

Black

Hispanic

Other

56

19

12

9

56

19

17

8

56

19

16

9

Age in Years: Mean(Range 21-61)

35.6 37.4 -

Employed (%) - - 66

Mean Education in Years (SD) - - 12.8 (1.7)

Mean Years of Heroin Use (SD) - - 6.6 (8.1)

Demographics 0001 (Inpatient)

Present and Opioid Negative0001 (Inpatient)

Present and opioid neg

Bup/Nx (N)

%Clonidine

(N)%

N 77 36

Day 3 or 4 52 67.5 16 44.4

Day 7 or 8 63 81.8 13 36.1

Day 10 or 11 56 72.7 10 27.8

Day 13 or 14 59 76.6 8 22.2

Present and Opioid Negative 0001 (Inpatient)

0

10

20

30

40

50

60

70

80

90

Day 3-4 Day 7-8 Day 10-11 Day 13-14

Clonidine Bup/Nx

Bup/Nx Clonidine Total

Sex No. (%)

Male

Female

73

27

69

31

72

28

Race No. (%)

White

Black

Hispanic

Other

40

36

21

3

40

28

13

3

40

37

20

3

Age in Years: Mean(Range 21-61)

38.3 40.0 -

Employed (%) - - 56.8

Mean Education in Years (SD) - - 12.4 (2.1)

Mean Years of Heroin Use (SD) - - 9.4 (9.6)

Demographics 0002 (Outpatient)

Present and Opioid Negative 0002 (Outpatient)

Present and opioid neg

Bup/Nx (N)

%Clonidine

(N)%

N 157 74

Day 3 or 4 37 23.6 5 6.8

Day 7 or 8 56 35.7 6 8.1

Day 10 or 11 52 33.1 5 6.8

Day 13 or 14 46 29.3 4 5.4

Present and Opioid Negative 0002 (Outpatient)

0

10

20

30

40

50

60

70

80

90

Day 3-4 Day 7-8 Day 10-11 Day 13-14

Clonidine Bup/Nx

NNT: Number Needed to Treat

NNT= Number of patients needed to treat

to achieve 1 treatment success

CTN 0001 (Inpatient)• NNT for Bup/Nx 77/59 = 1.31 • NNT for Clonidine 36/8 = 4.5

NNT Clonidine : BupNx = 3.44

CTN 0002 (Outpatient)• NNT for Bup/Nx: 157/46 = 3.4 • NNT for Clonidine: 74/4 = 18.5

NNT Clonidine : Bup/Nx = 5.44

Key Lessons Learned from the CTN Experience

Lessons Learned

1. Direct induction with BUP/NX is acceptable to a majority of opioid users. Ninety percent of patients completed induction, reaching a target dose of 16 mg within 3 days.

2. A substantial number of patients completed the short-term detox, regardless of setting or program philosophy. This program thus met a major goal of many programs to improve early treatment engagement. Short-term treatment can also help to establish an effective therapeutic alliance with local care providers.

3. Ancillary medications were provided to a majority of patients taking BUP/NX but mostly for protracted withdrawal symptoms common among patients withdrawing from opioids.

4. BUP/NX is safe for use in a wide range of community treatment settings. There were few serious adverse events and most were not related to BUP/NX.

Lessons Learned (continued)

Lessons Learned (continued)

5. Patient interest in the BUP/NX detox was high and some programs developed wait lists, suggesting that the combination mixture will not deter patients from seeking buprenorphine treatment.

6. All sites expected patients to attend counseling regularly. Whether short-term BUP/NX detox would fare as well in primary care or office based settings where such services are not on site is not known.

Who is Appropriate for Buprenorphine Treatment?

Patient Selection: Assessment Questions

Is the patient addicted to opioids?

Is the patient aware of other available treatment options?

Does the patient understand the risks, benefits, and limitations of buprenorphine treatment?

Is the patient expected to be reasonably compliant?

Is the patient expected to follow safety procedures?

Patient Selection: Assessment Questions

Is the patient psychiatrically stable?

Is the patient taking other medications that may interact with buprenorphine?

Are the psychosocial circumstances of the patient stable and supportive?

Is the patient interested in office-based buprenorphine treatment?

Are there resources available in the office to provide appropriate treatment?

Patient Selection: Issues Involving Consultation with the Physician

Several factors may indicate a patient is less likely to be an appropriate candidate, including:

Patients taking high doses of benzodiazepines, alcohol or other central nervous system depressantsSignificant psychiatric co-morbidityMultiple previous opioid addiction treatment episodes with frequent relapse during those episodes (may also indicate a perfect candidate)Nonresponse or poor response to buprenorphine treatment in the past

Several factors may indicate a patient is less likely to be an appropriate candidate, including:Active or chronic suicidal or homicidal ideation or attempts

Patient needs that cannot be addressed with existing office-based resources or through appropriate referrals

High risk for relapse to opioid use

Poor social support system


PregnancyCurrently buprenorphine is a Category C medication. This means it is not approved for use during pregnancy.Studies conducted to date suggest that buprenorphine may be an excellent option for pregnant women.Randomized trials are underway to determine the safety and effectiveness of using buprenorphine during pregnancy.


Patients with these conditions must be evaluated by a physician for appropriateness prior to buprenorphine treatment:SeizuresHIV and STDsHepatitis and impaired hepatic functionUse of alcohol, sedative-hypnotics, and

stimulantsOther drugs


Patient Selection: Additional Details

Suitability determined by a physician

What is the relevance to counselors?

Patient’s appropriateness may change during treatment

Potential patients or other providers may inquire about treatment

More useful and informed communication with physician

Patient Selection

Patients who do do not meet criteria for opioid addiction may still be appropriate for treatment with buprenorphinePatients who are risk of progression to

addiction or who are injecting

Patients who have had their medication discontinued and who are now at high risk for relapse

Use The SAMHSA Physician Locator Service To Find a

Physician Authorized To PrescribeBuprenorphine in Your State

www.buprenorphine.samhsa.gov.bwns_locator

Notice: The Drug Addiction Treatment Act of 2000 limits physicians or physician group practices to prescribing buprenorphine for opioid addiction to a maximum of 30 patients at one time. Because of this, some physicians listed on the Locator may not be accepting new patients at this time. If you are unable to find a physician within your area who is accepting new patients, please check our site later, as new physicians are being added weekly.

To locate the physician(s) authorized to prescribe Buprenorphine nearest you, find your State on the map below and click on it.

Challenges for Addiction Treatment Professionals

Not all physicians who are trained have consented to be listed on Physician locator. Community outreach is still critical.

Linking patients to primary care who have not been within the medical mainstream

Coordination with other professionals not accustomed to working with non-medical partners

Covering the cost of medication

Attributes of Successful Care Coordination

Understanding roles for each participant in the treatment team

Ongoing communication across professions

Personal contact between partners in the system

Barriers to Effective Care Coordination

Misunderstanding respective roles

Conflicting goals for treatment

Confidentiality restrictions

Control issues

Misconception of other professional perspectives

Thomas E. Freese, Ph.D.

[email protected]

www.psattc.org

www.uclaisap.org

www.buprenorphine.samhsa.gov.bwns_locator

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