Office-Based Opioid Therapy:
Methadone/Buprenorphine Nexus
Edwin A. Salsitz, M.D., FASAM
Medical Director Office-Based Opioid Therapy
Beth Israel Medical Center, NYC
esalsitz@chpnet.org
Financial Disclosure
• Reckitt Benckiser Speaker Honoraria
• Pfizer
Speaker Honoraria
• PriCara
Speaker Honoraria
• Purdue Pharma
Adv.Board Honoraria
MEDICATION ASSISTED
ADDICTION TREATMENT
“All Treatments Work For Some
People/Patients”
“No One Treatment Works for All
People/Patients”
Alan I. Leshner, Ph.D
Former Director NIDA
OPIATE AGONIST THERAPY
Addiction Regulatory
Pharmacology
Stigma
Destitution Political
The Lexington Narcotic Farm
The first facility opened on May 25, 1935, outside Lexington, Ky. The 1,050acre site included a farm and dairy, working on which was considered
therapeutic for patients.
With the increased availability of state and local drug abuse treatment
programs, the hospital was closed in February 1974.
Drs. Kolb, Himmelsbach, Wikler, Jaffe, Kleber, Vaillant
JAMA Classics: Celebrating 125 Years
Methadone Maintenance 4 Decades Later
Thousands of Lives Saved But Still Controversial
Commentary by Herbert D. Kleber, MD
JAMA. 2008;300(19):2303-2305
JAMA. 1965;193(8):646-650
Exclusion: non-opioid addiction/misuse, severe psychiatric problems
Opiate Addiction Treatment
Outcome*
Methadone Maintenance
50 – 80%
Naltrexone Maintenance
10 – 20%
“Drug Free” (non-pharmacotherapeutic)
LAAM Maintenance
5 – 30%
50 – 80%
Buprenorphine-Naloxone Maintenance
40-50%**
Short-term Detoxification (any mode)
5 – 20% (limited data)
* One year retention in treatment and/or follow-up with significant
reduction or elimination of illicit use of opiates
** Maximum effective dose (24mgsl) equal to 60 to 70 mg/d
methadone. Data base on 6 month follow-up only.
Kreek, 1996; 2001
Methadone
• Synthetic Opioid 1937 Germany
• T ½ 24—36 hrs. Inherent
• Onset of Action 30 min. Peak 3-4 hrs.
• R/S(l/d) racemic mixture mu/NMDA antag
• CYP3A4, 2D6 Drug/Drug No Active Metab
• Renal and biliary excretion
• Dosing QD for addiction, Q6H for Pain
Functional State
(Heroin)
Impact of Short-Acting Heroin versus
Long-Acting Methadone Administered on
a Chronic Basis in Humans - 1964 Study
"High"
"Straight"
"Sick"
AM
PM
AM
PM
AM
PM
AM
Functional State
(Methadone)
Days
"High"
"Straight"
"Sick"
AM
PM
AM
Days
H
Dole, Nyswander and Kreek, 1966
Acc
VTA
GLU
FCX
Amphetamine
Cocaine
Opiates
Cannabinoids
Phencyclidine
Ketamine
HIPP
AMYG
CRF
GLU
5HT
GABA
OPIOID
OPIOID
GABA
GABA
DYN
5HT
ENK
VP
OFT
BNST
Opiates
DA
GABA
NE LC
ABN
HYPOTHAL
ICSS
MesoLimbic Dopaminergic Circuit
Pleasure/Reward Center
H2O, Food, Sex, Parenting, Social
NE
LAT-TEG
Opiates
Ethanol
Barbiturates
Benzodiazepines
Nicotine
Cannabinoids
PAG
END
5HT
Raphé
To
dorsal
horn
RETIC
Molecular and Cellular
Basis of Addiction
Science 3 October
1997:
Eric J. Nestler,
George K. Aghajanian
Figure 2. Scheme illustrating opiate actions in the locus coeruleus. Opiates acutely inhibit locus coeruleus neurons by increasing
the conductance of an inwardly rectifying K+ channel through coupling with subtypes of Gi/o, as well as by decreasing a Na+dependent inward current through coupling with Gi/o and the consequent inhibition of adenylyl cyclase. Reduced concentrations
of cAMP decrease PKA activity and the phosphorylation of the responsible channel or pump. Inhibition of the cAMP pathway also
decreases phosphorylation of numerous other proteins and thereby affects many additional processes in the neuron. For example,
it reduces the phosphorylation state of CREB, which may initiate some of the longer-term changes in locus coeruleus function.
Upward bold arrows summarize effects of chronic morphine administration in the locus coeruleus. Chronic morphine increases
concentrations of types I and VIII adenylyl cyclase (AC I and VIII), PKA catalytic (C) and regulatory type II (RII) subunits, and
several phosphoproteins, including CREB. These changes contribute to the altered phenotype of the drug-addicted state. For
example, the intrinsic excitability of locus coeruleus neurons is increased by enhanced activity of the cAMP pathway and Na+dependent inward current, which contributes to the tolerance, dependence, and withdrawal exhibited by these neurons. Upregulation of type VIII adenylyl cyclase is mediated by CREB, whereas up-regulation of type I adenylyl cyclase and of the PKA
39 wk
39wk
137wk
Cerebral
phosphorus
metabolite
abnormalities in
opiate-dependent
polydrug abusers
in methadone
maintenance
Psychiatry
Research:
Neuroimaging
Volume 90, Issue 3 ,
30 June 1999, Pages
143-152
Kaufman,M
Phosphorous MR Spectroscopy
Fig. 3. Metabolite levels in control subjects (n=16) and in short- (n=7) and long-term
(n=8) methadone maintenance treatment (MMT) subgroups. Shown are means±S.D.
of percent metabolite measures. Post hoc Scheffé test results: *P<0.05 vs. control
subjects; **P<0.01 vs. control subjects; ***P<0.0001 vs. control subjects ;†P<0.05
vs. long-term MMT group
From these data, we conclude that polydrug
abusers in MMT have 31P-MRS results consistent
with abnormal brain metabolism and phospholipid
balance. The nearly normal metabolite profile in
long-term MMT subjects suggests that prolonged
MMT may be associated with improved
neurochemistry.
Psychiatry Research:
Neuroimaging
Volume 90, Issue 3 , 30
June 1999, Pages 143-152
Distribution of Opioid Treatment Programs (OTPs)
2002
SAMHSA/CSAT
581 Male Heroin Addicts Followed for 33yrs
The natural history of narcotics addiction among a male sample (N = 581).
From: Yih-Ing, et. al., 2001. A 33-Year Follow-up of Narcotics Addicts. Archives of General
Psychiatry, 58:503-508)
Medical Maintenance
Admission Criteria
• At least 4 years in MMTP
• Negative urines for last 3 years
• Working/School etc.
• Adequate income for fees
• Recommendation from clinic
• Not in military reserves
• Stable and safe storage environment
Medical Maintenance
Procedures
• Patient given 28 day supply of methadone,
by MD,in disket form, every 4 weeks.
• Medication prepared by hospital pharmacy
in usual Rx type bottle and label
• Routine urine toxicologies
• Patient returns before “run out” date
• Primary care provided
Methadone Maintenance
Total duration in years
N = 233 patients
60
50
40
30
No of patients
20
10
0
0-5
6-10
11-15
16-20
21-25
26-30
31-35
36-40
4/05
Duration in years
Medical Maintenance
Total Duration in Years
N= 233 patients
100
90
80
70
60
50
40
30
20
10
0
No. of patients
0-5
6-10
11-15
Duration in years
16-20
4/05
Medical Maintenance--Dosage
• Average = 75mg./day
• Median = 80mg./day
• Range = 5mg.----200mg./day
• 30% Split Dose
04/05
N=223
Medical Maintenance
1983 - Present
347 =Total Enrolled
Withdrew
22 (6%)
TransferMMTP
7
Pain
9
Revised –06/16/09
MMTP
41(12%)
Cocaine
19
Cause
22
Deaths
59 (17%)
23
14
4
9
4
1
2
1
1
- Tobacco
- Hepatitis C
- Lymphoma
- Medical
- HIV
-Old Age
-Homi/Suicide
-Prostate Ca
Leukemia
Active
184 (53%)
Buprenorphine 24
Deaths: 1 Tob
1 Hep C
9 liver transplants
8 patients
4 alive
Prevalence of HIV-1 (AIDS Virus)
Infection in Intravenous Drug Users
New York City: 1983 - 1984 Study: Protective
Effect of Methadone Maintenance Treatment
50 – 60%
9%
Untreated, street heroin addicts:
Positive for HIV-1 antibody
Methadone maintained since<1978
(beginning of AIDS epidemic):
less than 10% positive for HIV-1 antibody
Kreek , 1984; Des Jarlais et al., 1984; 1989
New York Times
Dry Mouth Decay, Crave Sugary Drinks, Brushing/Flossing, Caustic Ingredients
Grinding/Clenching Teeth,
STIGMA--METHADONE
• “My Wife’s Opinion Is That
Methadone Maintenance
Treatment Is As Close To Evil As
You Can Get, Without Killing
Someone.”
A “successful” methadone patient quoting his wife’s attitude
toward methadone treatment
U.S. Drug Enforcement Administrative Agent Joanne Masur,
one of the last government witnesses in the case against
Shinderman, took the stand Friday in U.S. District Court in
Portland.
Masur, whose job is preventing the diversion of prescription
drugs to the black market, said she consulted with
Shinderman on at least two occasions. But she said she had
no bias against him or his clients, although she said she may
have referred to them as "dirt bags."
"That is a term I use," she said. "But it's not necessarily
derogatory."
Portland Press Herald, 7/15/06
Crane collapses in busy New York street, killing seven in worst construction
accident in recent memory'
SUBSTITUTION
TREATMENT
???????
Helpful/Harmful
“Substituting one addiction for
another”
3/19/08
Critics say methadone simply replaces one dependency with another, and some say
methadone can be even harder to quit than heroin.
Scottish Conservative Party justice spokesman, Bill Aitken, recently described many of those
in methadone programmes in Scotland as “sitting fat, dumb and happy" on the drug.
Percent Change in Distribution of
Methadone and Three Comparison Drugs,
1998--2002
Methadone
Oxycodone
Morphine
Hydrocodone
Percent Change from
Baseline Year 1998
300%
250%
200%
150%
100%
50%
0%
1999
2000
2001
2002
Center for Substance Abuse Treatment, Methadone-Associated Mortality: Report of
a National Assessment, May 8-9, 2003. SAMHSA Publication No. 04-3904.
Rockville, MD: Center for Substance Abuse Treatment, SAMHSA, 2004.
54%
390%
Methadone Deaths Not Linked to Misuse of
Methadone from Treatment Centers
• The consensus report, “Methadone-Associated Mortality, Report of a
National Assessment”, concludes that “although the data remain
incomplete, National Assessment meeting participants concurred
that methadone tablets and/or diskettes distributed through
channels other than opioid treatment programs most likely are the
central factor in methadone-associated mortality.”
• The panel based it conclusion that methadone is coming from other
sources on data showing that the greatest growth in methadone
distribution in recent years is associated with its use as a
prescription analgesic prescribed for pain, primarily in solid tablet or
diskette form, and not in the liquid formulations that are the
mainstay of opioid treatment programs that treat patients with
methadone for abuse of heroin or prescription pain killers.
• The experts surmise that current reports of methadone deaths
involve one of three scenarios: illicitly obtained methadone used in
excessive or repetitive doses in an attempt to achieve euphoric
effects; methadone, either licitly or illicitly obtained, used in
combination with other prescription medications, such as
benzodiazepines (anti-anxiety medications), alcohol or other opioids;
or an accumulation of methadone to harmful serum levels in the
first few days of treatment for addiction or pain, before tolerance is
developed
SAMHSA--2004
JAMA 2000:283:1303-1310
Survival Function by Treatment Group
Sees, K. L. et al. JAMA 2000;283:1303-1310.
Copyright restrictions may apply.
Proportion of Participants Using Heroin and Mean Days of Heroin Use in Previous 30 Days
Sees, K. L. et al. JAMA 2000;283:1303-1310.
Copyright restrictions may apply.
Remaining in treatment (nr)
Buprenorphine Maintenance/Withdrawal:
Retention
20
15
10
Control
5
Buprenorphine
0
0
50
100
150
200
250
Treatment duration (days)
300
350
(Kakko et al., 2003)
Kakko et al, Lancet Feb 22, 2003
Buprenorphine Maintenance/Withdrawal:
Mortality
Placebo
Dead
4/20
(20%)
Buprenorphine
Cox
regression
2=5.9;
0/20 (0%)
p=0.015
Transitioning Stable
Methadone Maintenance
Patients to Buprenorphine
Maintenance
Edwin A. Salsitz, M.D., FASAM
Beth Israel Medical Center
New York City
Why Transition From
Methadone?
•
•
•
•
•
Office-based availability
Less than monthly visits
Different side effect profile
Possible diminished stigma
Geographic Flexibility
Why Not Transition?
• May not be as effective for individual
• Fear of destabilization
• Transition difficult
– Opioid withdrawal required
– May precipitate withdrawal
•
•
•
•
Less social and psychological services
Insurance/cost
Satisfied with methadone
“If it Ain’t Broke….”
Subjects
• MMM eligibility requirements
– 4 years in Methadone Maintenance
Treatment Program (MMTP)
– 3 years of illicit drug abstinence
– No excessive drinking
– Employment/Education, etc.
– Emotional stability
• 6/03 - 1/08 patients on methadone
≤ 80 mg/day offered transition to
buprenorphine
Johnson RE, Chutuape MA, et al. A comparison of levomethadyl acetate,
buprenorphine, and methadone for opioid dependence. N Engl J Med. 2000;343:1290–
1297.
Transfer
• Patients given option to taper
methadone to 30-40 mg/day
• Standard protocol used
– Patients abstained from methadone for
48-72 hours
– First buprenorphine/naloxone dose given
when Clinical Opiate Withdrawal Scale
(COWS) score indicated withdrawal
• Stabilized over following week
Center for Substance Abuse Treatment. Clinical guidelines for the use of
buprenorphine in the treatment of opioid addiction. Treatment Improvement Protocol
Series (TIPS) 40. Department of Health and Human Services Publication #SMA04-3939.
Rockville, MD: Substance Abuse and Mental Health Services Administration, 2004.
Study Participants
• 102 MMM patients offered
buprenorphine
• 23 (22.5%) accepted
• Two stable MMTP patients referred
• 104 patients total-25 (24.0%) accepted
• Reasons for not wanting to switch
– no perceived advantage of switching
– concern about efficacy
– concern about side effects (withdrawal)
Outcomes
• 25/25 patients successfully stabilized
on buprenorphine (100%)
• Average buprenorphine dose- 10.9
mg (S.D. 7.6)
• Average time on buprenorphine
maintenance- 30.3 months (S.D.
16.5)
Final buprenorphine dose mg/day
Methadone Dose Compared
to Buprenorphine Dose
40
35
30
25
20
15
10
5
0
0
10
20
30
40
50
60
70
80
90
Baseline methadone dose mg/day
Low-moderate correlation - Spearman rank
order coefficient = 0.46, p = 0.02
Positive Experiences
• No stabilized subjects elected to
return to methadone
• Less frequent office visits
– every 1 - 6 months, not monthly
– several patients moved further away
from program
• 24/25 patients reported feeling
“clearer”
Unsuccessful Transfers
• 5 initially reluctant patients agreed to
attempt conversion
• All unsuccessful
• Duration of buprenorphine treatment
- 1 dose to 5 days
• Returned to methadone without event
• 2 cases - “dysphoria”
• 3 cases – no reason listed
Study Strengths
• Subjects
– Unique population in research
– Findings applicable to stable methadone
maintained patients seeking transfer to
Buprenorphine
• Very long follow-up period - absence
of negative outcomes
CONCLUSIONS
• Buprenorphine is viable maintenance
treatment for stable patients on
methadone doses up to 80 mg/day
• Transitioning generally well tolerated
• Buprenorphine efficacious and safe
long-term
• Low to moderate association between
methadone and buprenorphine doses
Admission EKG QTc~ 600 msec.
QTc ~ 440 msec.
Bupe started
Off methadone x 1 Week
Russia Scorns Methadone for Heroin
Addiction Science Times 7-22-08, Michael Schwartz
• After the conference in February, which Dr. Mendelevich
•
•
helped organize, Moscow’s legislature began an inquiry into
whether he had engaged in “drug propaganda,” and it called
on prosecutors to open a case against him, he said
At the same AIDS conference, Dr. Gennady G. Onishchenko,
the country’s chief sanitary doctor, the equivalent of surgeon
general, said health officials “are not convinced that this is
effective,” and added, “There is little optimism for legalizing
methadone therapy in the near future.”
“Scientific arguments, evidence-based data, are not
convincing them,” said Evgeny M. Krupitsky, the head of a
laboratory that conducts research on drug addiction at St.
Petersburg State Pavlov Medical University. Russian
methodology regarding opiate addiction “is not evidencebased,” but relies on “subjective opinions of major leaders in
this field.
DRUG PROBLEM Patients in a program for heroin addiction in Yekaterinburg,
Russia, run by a nongovernmental group.
MEDICATION ASSISTED
ADDICTION TREATMENT
“All Treatments Work For Some
People/Patients”
“No One Treatment Works for All
People/Patients”
Alan I. Leshner, Ph.D
Former Director NIDA