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
SOURCE: SAMHSA, Treatment Episode Data Set, 1992-2000.
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
SOURCE: SAMHSA, Treatment Episode Data Set, 1992-2000.
(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
SOURCE: SAMHSA, Treatment Episode Data Set, 1992-2000.
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
Transferring Patients Onto Buprenorphine:
3 Ways Significant Withdrawal Could Occur
Insufficient agonist effects
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
Transferring Patients Onto Buprenorphine:
3 Ways Significant Withdrawal Could Occur
Insufficient agonist effects
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 Community
Treatment Program
Community Treatment Program
CTN Node
Community Treatment Program
Community Treatment Program
Community Treatment Program
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
Patient Selection: Issues Involving Consultation with the Physician
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.
Patient Selection: Issues Involving Consultation with the Physician
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: Issues Involving Consultation with the Physician
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.
www.psattc.org
www.uclaisap.org
www.buprenorphine.samhsa.gov.bwns_locator