40th Anniversary of Opioid Agonist Pharmacotherapy
for Heroin and Related Opiate Addiction:
Perspectives and Expectations for the Future
Mary Jeanne Kreek, M.D.
Professor and Head
The Laboratory of the Biology of Addictive Diseases
The Rockefeller University
Senior Physician
The Rockefeller University Hospital
October 19, 2004
American Association for the Treatment
of Opioid Dependence
Orlando, FL
funded primarily by NIH-NIDA, NIHCRR and NYS OASAS
40th Anniversary of the Development of
Methadone Maintenance Treatment –
1964-2004
Initial clinical research on mechanisms and treatment using methadone
maintenance pharmacotherapy at The Rockefeller Hospital of The Rockefeller
Institute for Medical Research (by the mid-1960s, The Rockefeller University)
performed by the team of:
Vincent P. Dole, Jr., M.D.
Professor & Head of the Laboratory of Physiology and Metabolism
The Rockefeller University
(now Professor Emeritus)
Marie Nyswander, M.D.
Guest Investigator, The Rockefeller University
Joined Dole Lab in Winter 1964
(now deceased)
Mary Jeanne Kreek, M.D.
Guest Investigator, The Rockefeller University
Joined Dole Lab in Winter 1964
(now Professor & Head of the Laboratory of the Biology of Addictive Diseases)
Kreek, 2004
40th Anniversary of the Development of
Methadone Maintenance Treatment –
1964-2004
First publications describing methadone maintenance treatment research
1) Initial clinical research on mechanisms and treatment using methadone
maintenance pharmacotherapy performed at The Rockefeller Hospital of The
Rockefeller Institute for Medical Research by Dole, Nyswander, and Kreek in the
winter, spring, and early summer of 1964 (presented at the Association of
American Physicians by Vincent P. Dole, MD in 1966):
Dole, V.P., Nyswander, M.E. and Kreek, M.J.: Narcotic blockade. Arch. Intern.
Med., 118:304-309, 1966.
(also recorded in the Association of American Physicians meeting transcription of discussion)
Dole, V.P., Nyswander, M.E. and Kreek, M.J.: Narcotic blockade: a medical
technique for stopping heroin use by addicts. Trans. Assoc. Am. Phys., 79:122136, 1966.
2) Translational applied clinical research performed at Manhattan General Hospital
(to become Bernstein Institute of Beth Israel Medical Center) in late 1964 and 1965
by Dr. M. Nyswander and Dr. V.P. Dole, and joined there by Dr. J. Lowinson,
including one-year follow-up studies on study subjects admitted to The
Rockefeller Hospital in the first half of 1964, as well as new patients admitted to
Manhattan General Hospital:
Dole, V.P. and Nyswander, M.E.: A medical treatment for diacetylmorphine
Kreek, 2004
(heroin) addiction. JAMA, 193:646-650, 1965.
Hypothesis
(1963–1964)
Heroin (opiate) addiction is a disease – a “metabolic
disease” – of the brain with resultant behaviors of
“drug hunger” and drug self-administration, despite
negative consequences to self and others. Heroin
addiction is not simply a criminal behavior or due
alone to antisocial personality or some other
personality disorder.
Dole, Nyswander and Kreek, 1966
State
Functional
FunctionalState
(Heroin)
(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
Opioid Agonist Pharmacokinetics:
Heroin Versus Methadone
Compound
Systemic
Bioavailability
After Oral
Administration
Apparent
Plasma Terminal
Half-life
(t 1/ Beta)
Major
Route of
Biotransformation
2
Heroin
Limited
(<30%)
3m
Successive
(30 m for active
deacetylation
6-actyl-morphine
and morphine
metabolite)
glucuronidation
(4-6 for active
morphine metabolite)
Methadone
Essentially
Complete
(>70%)
24 h
(48 h for
active
l-enantiomer)
N-demethylation
Kreek et al., 1973; 1976; 1977; 1979; 1982; Inturrisi et al, 1973; 1984
“On-Off” versus “Steady-State”
Disruption versus Normalization
• levels of gene expression
• receptor mediated events
• physiology
• behaviors
Kreek, 1987; 2001
Methadone Maintenance Treatment
for Opiate (Heroin) Addiction
Number of patients in treatment:
225,000
Efficacy in “good” treatment programs using adequate doses (80 to 150mg/d):
Voluntary retention in treatment (1 year or more)
Continuing use of illicit heroin
50 – 80%
5 – 20%
Actions of methadone treatment:
• Prevents withdrawal symptoms and “drug hunger”
• Blocks euphoric effects of short-acting narcotics
• Allows normalization of disrupted physiology
Mechanism of action: Long-acting narcotic provides steady levels of
opioid at specific mu receptor sites (methadone found to be a full mu
opioid receptor agonist which internalizes like endorphins and which
also has modest NMDA receptor complex antagonism)
Kreek, 1972; 1973; 2001; 2002, 2004; Inturrisi et al, in progress; Evans et al; in progress
Opiate Addiction Treatment Outcome*
Methadone Maintenance (~225,000 people in US)
50 – 80%
Buprenorphine-Naloxone Maintenance (~8,000 people in US)
40 – 50%**
LAAM Maintenance (~3,100 people in US)
50 – 80%
Naltrexone Maintenance
10 – 20%
“Drug Free” (non-pharmacotherapeutic)
5 – 30%
Short-term Detoxification (any mode)
5 – 20%
* 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; current estimate of up to another 55,000 in buprenorphine detox
***Use curtailed because of limited manufacture in U.S. (2003); use stopped in much of
Europe because of concern about QT-interval prolongation in some patients
Kreek, 1996; 2001; 2004
Clinics/Treatment Programs Diagram
Kreek, 1983; 1984; 1991; 2001
Regulatory Reform of the Narcotic Treatment
Programs or Methadone Programs – 1999; 2001
(Opiate Treatment Programs (OTPs)):
“Office Based Opioid Treatment”
•
Proposed in a Notice of Proposed Rule Making (NPRM) in the
Federal Register (FR) in July 22, 1999.
•
Secretary of the Department of Heath and Human Services
requested comment on the NPRM was “office based opioid
treatment.”
•
The preamble to the final rule, published in the FR on January 17,
2001 and effective May 17, 2001 (Federal Register, 2001),
announced administrative measures to facilitate the treatment of
patients under a “medical maintenance model”:
1)
Provisions for “take home” medication have been extended
to 31 days.
2)
Participating office-based physicians will maintain formal
relationships with OTPs and patients will be referred to the
office-based physicians from the OTPs
3)
Authoriations for this treatment model can be obtained from
SAMHSA.
Reviewed in Kreek & Vocci, J Sub Abuse Treatment, 2002
Identification of HIV-1 Infection and
Changing Prevalence in Drug Users
New York City: 1978 – 1992; 1983 - 1984 Study
100
Percent of IV Drug Users Infected with HIV-1
75
%
50
25
0
1978
1979
1980
1981
1982
1983
1984
1985
1986
1987
1992
Kreek et al., 1984; Des Jarlais et al., 1984; 1989
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
Factors Contributing to Vulnerability
to Develop a Specific Addiction
use of the drug of abuse essential (100%)
Genetic
(25-50%)
Environmental
(very high)
• DNA
• SNPs
• other
polymorphisms
• prenatal
• postnatal
• contemporary
• cues
• comorbidity
• stress-responsivity
• mRNA levels
• peptides
• proteomics
• neurochemistry
• synaptogenesis
• behaviors
Drug-Induced Effects
(very high)
Kreek et al., 2000; 2004
Endogenous Opioids
and their Receptors
Opioid Classes
Opioid
Receptor
Types
Endorphins
Mu
Enkephalins
Delta
Dynorphins
Kappa



H2
N
S
Extracellular
fluid
S
AA identical in
3 receptors
AA identical in
2 receptors
Endomorphins (?)
AA different in
3 receptors
cell membrane
cell interior
HOOC
LaForge, Yuferov and Kreek, 2000
Primary Site(s) of Major Drugs of
Abuse
Heroin
Depressant
•
•
Cocaine
Stimulant
•
•
Alcohol
Stimulant & •
Depressant •
Acts primarily on endogenous
opioid system
Also affects dopaminergic system
Acts primarily on dopaminergic
system, as well as on serotonergic
and noradrenergic systems
Also affects opioid system
Undefined primary site of action
Affects dopaminergic, serotonergic
and opioid systems
Kreek, 1978, 1987, 2001
Hypothesis — Atypical Responsivity to
Stressors: A Possible Etiology of Addictions
Atypical responsivity to stress and stressors may, in part,
contribute to the persistence of, and relapse to selfadministration of drugs of abuse and addictions.
Such atypical stress responsivity in some individuals may
exist prior to use of addictive drugs on a genetic or acquired
basis, and lead to the acquisition of drug addiction.
Genetic, environmental and direct drug effects may each
contribute to this atypical stress responsivity.
Kreek, 1972; 1987; 1992; 2001
Hypothalamic-Pituitary-Adrenal Axis and the Endogenous
Opioid System Have Interrelated Roles in the Biology of
Addictive Diseases
hypothalamus
CRF
anterior
pituitary
POMC
b-End
Endogenous
Opioids
(mu, kappa; delta ?)
Cortisol
ACTH
adrenal
Kreek et al., 1981; 1982; 1984; 1992; 2001
Neuroendocrine Effects of Opiates, Cocaine, and
Alcohol in Humans:
Hormones Involved in HPA Axis Stress Response
• Acute effects of opiates
• Chronic effects of short-acting
opiates (e.g. heroin addiction)
•
•
•
•
Opiate withdrawal effects
Opioid antagonist effects
Cocaine effects
Alcohol effects
• Chronic effects of long-acting
opiate (e.g. methadone
maintenance treatment)
Suppression of
HPA Axis
Activation of
HPA Axis
Normalization of
HPA Axis
HPA – Hypothalamic-pituitary-adrenal axis (involved in stress response)
Kreek, 1972; 1973; 1987; 1992; 2001
Metyrapone Testing:
a Chemically-Induced “Stress”
•
•
•
•
•
Heroin addicts
– hyporesponsive
Methadone maintained former heroin addicts
– euresponsive
Drug-free, opioid medication-free former heroin addicts
– hyperresponsive
Cocaine addicts- recently abstinent
– hyperresponsive
Cocaine addicted, methadone maintained former heroin
addicts
– hyperresponsive
Kreek, 1972; 1973; 1984; 1987; 1992;
Kreek et al., 1984; Schluger et al., 2001
[18F] Cyclofoxy (a Selective Opioid Antagonist) Binding
in Human Brain: Normal Volunteer PET Study - NIH
116.25
82.50
48.75
Eckelman, Rice and the NIH PET group, 2000
Plasma Methadone Levels in Long-Term,
Methadone-Treatment Patients Sampled Across
the 90-min PET Scan Session: 22.5 to 24h After
Last Oral Dose of Methadone
Plasma Methadone
Levels (ng/ml)
500
400
300
200
100
n=12
0
0
10
20
30
40
50
60
70
80
90
Time (min)
Kling et al., 2000
Specific Binding (ml plasma/ml tissue)
Specific Binding of [18F] Cyclofoxy (mean + S.E.M.) in 13
Brain Regions of Normal Volunteers and Long-Term,
Methadone Treated Former Heroin Addicts - PET Study
normal volunteers n=14
16
MTP volunteers n=14
14
12
10
*
*
8
*
6
*
*
MT
MFr
4
2
0
Thl
Amy
Caud
Ins
ACg
Put
Par
Crb
IT
Hip
WMt
Region of Interest
Kling et al., 2000
Hypothesis: Genetic Variability
and the Opioid System
Some of the individual genetic variability in
susceptibility to the development and persistence of,
or relapse to, opiate addiction may be due to
polymorphisms of the mu opioid receptor.
Also, individual differences in responses to
endogenous opioids (“physiogenetics”) or
pharmacotherapies (“pharmacogenetics”) may be
mediated by variant forms of the mu opioid receptor.
LaForge, Yuferov and Kreek, 2000
The Human Genome
(as currently understood)
• In the human genome,
there are ~3 billion
bases (nucleotides)
• In humans, there are
estimated to be ~30,000
genes (many but not all
identified and
annotated)
• Each gene is a
sequence of bases or
nucleotides
Kreek (Rockefeller University) & Hassin (Columbia P&S), 2004
Single Nucleotide Polymorphisms
(SNPs) in Genes: Definitions
• SNP — a single
nucleotide
polymorphism, that is,
one nucleotide or base
of any base pair
• Allelic Frequency:
<1% low or rare
1–5% intermediate
>5% high, frequent
Kreek (Rockefeller University) & Hassin (Columbia P&S), 2004
Single Nucleotide Polymorphisms in
Coding Region of Human Mu Opioid
Receptor Gene with Allelic Frequency > 1%
Variant
Exon
(nucleotide position) location
Protein
domain
Corresponding
amino acid change
Allele
frequency
A118G
1
N-terminus
Asn 4 Asp (N40D)
10.5%
(26 heterozygous;
3 homozygous)
C17T
1
N-terminus
Ala 6 Val (A6V)
6.6%
(14 heterozygous;
3 homozygous)
G24A
1
N-terminus
Synonymous
mutation
2%
(6 heterozygous)
* Nucleotide position 1 is first base of the start codon.
Bond et al., 1998
Human Mu Opioid Receptor Gene SNPs
S4R A6V
H2N
N40D
Synonymous mutation
50
Putative Glycosylation site
extracellular fluid
SNPvs with changed AA
V234L
S147C
300
N152D
150
200
250
cell membrane
R260H
R265P
100
cell interior
HOOC
400
350
S268P
Kreek, Yuferov and LaForge, 2000
Fraction Maximum Current Response
Percent Bound
Binding and Coupling to G Protein-Activated, Inwardly
Rectifying K+(GIRK) Channels by Endogenous Opioid Peptides
to the Prototype and A118G Variant Mu Opioid Receptor
100
100
80
80
60
60
40
40
20
20
0
0
-11
-10
-9
-8
-7
-11
-10
Log [Endomorphin -1(M)]
1.0
0.5
0.5
0
0
-9
-8
-7
Log [Endomorphin -1(M)]
-8
-7
Log [b Endorphin (M)]
1.0
-10
-9
-6
A118G
Prototype
-9
-8
-7
-6
Log [b Endorphin (M)]
Bond et al., 1998
ACTH and Cortisol Levels in Family History
Positive (n=8) and Negative (n=7) Social
Drinkers after 50mg Oral Naltrexone
60
Placebo
ACTH (pg/ml)
50
ACTH (pg/ml)
60
Naltrexone
FH+
40
30
20
10
Placebo
50
40
30
20
10
0
0
30
60
90 120 150 180
0
240
0
60
90 120 150 180
25
Naltrexone
FH+
FH-
Placebo
240
Naltrexone
Placebo
Cortisol (µg/dl)
Cortisol (µg/dl)
25
30
Time (min) Post Capsule
Time (min) Post Capsule
20
15
10
20
15
10
5
5
0
Naltrexone
FH-
0
0
30
60
90
120 150 180
Time (min) Post Capsule
240
0
30
60
90
120 150 180
Time (min) Post Capsule
240
King et al, 2002
24
A/A (n=29)
A/G (n=7)
22
N
N
20
18
N
16
14
P
I
12
N
10
8
50
0
50
100
Time (min)
150
200
Cumulative Survival (Time to Relapse)
Serum Cortisol (ug/dl)
Physiogenetics and Pharmacogenetics
Related to A118G Variant of Human Mu
Opioid Receptor Gene
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
14
28
42
56
70
Days
Naltrexone/
Asp40 Allele (A/G, G/G) (n=23)
Naltrexone/
Asn40 Allele (A/A) (n=48)
Placebo/
Asp40 Allele (A/G, G/G) (n=18)
Placebo/
Asn40 Allele (A/A) (n=41)
84
Association Between a Functional
Polymorphism in the mu Opioid Receptor Gene
and Opiate Dependence in Central Sweden
Genotype
All Subjects
Opiate
Controls Dependent
(n=170)
(n=139)
147
(0.865)
21
(0.123)
2
(0.012)
A/A
A/G
G/G
RR= 2.86
2(1)= 13.403
Swedish with Both Parents Swedish
98
(0.705)
39
(0.281)
2
(0.014)
P< 0.00025*
Controls
(n=120)
Opiate Dependent
(n=67)
104
(0.867)
15
(0.125)
1
(0.008)
46
(0.687)
19
(0.283)
2
(0/030)
RR= 2.97
cases
controls
G/G, A/G
41
23
A/A
98
147
2(1)= 8.740
P< 0.0031*
Thus, in the entire study group in this central Swedish population:
Attributable Risk due to genotypes with a G allele in this population:
18%
(with confidence interval ranges from 8.0 to 28.0%)
Bart G , Heilig M, LaForge KS… Ott J, Kreek MJ, et al., 2004
Opioid System Polymporphisms in
Relation to Specific Addictive Diseases
Opioid Receptor Genes
Opioid Peptide Genes
Mu Opioid Receptor
Dynorphin
Kappa Opioid Receptor
Enkephalin
Kreek, 2003
Predictions for the Future
• Progressive changes in regulations governing opioid
agonist and partial agonist treatment, recognizing the
need for clinics and specialists for management of
complex cases, but also the need for office-based
practice.
• Increasing acceptance and reimbursement for
behavioral therapy and pharmacotherapy for both
addictive diseases and for coexisting disorders (HIV;
hepatitis C).
• Utilization of genetics and genomics, including
physiogenetic and pharmacogenetic information, to
guide the selection of treatment approaches for
individual patients.
Kreek, 2004
The Laboratory of the Biology of Addictive Diseases
Mary Jeanne Kreek, M.D. – Professor and Head
2004
Laboratory Scientists
Ann Ho
K. Steven LaForge
Eduardo Butelman
Vadim Yuferov
David Nielsen
Yan Zhou
Alexis Bailey
Dmitri Proudnikov
Brian Reed
Stefan Schlussman
Yong Zhang
Clinical Scientists
Gavin Bart
Lisa Borg
Heather Hofflich
Scott Kellogg
Charles Lilly
Laboratory Adjunct Scientists
Charles Inturrisi
Roberto Picetti
Virginia Pickel
Ellen Unterwald
Research Nurses
Kathy Bell
Elizabeth Ducat
Dorothy Melia
Clinical Adjunct Scientists
Miriam Ochshorn Adelson
James Kocsis
Elizabeth Khuri
Assistants for Research
Johannes Adomako
Julie Allen
Lauren Bence
Jason Choi
Nicole Dankert
Matthew Swift
Administrative Staff
Kitt Lavoie
Janesse Rojas
Susan Russo
Laboratory Worker
Laura Nunez
The Laboratory of Statistical Genetics, Jurg Ott, Ph.D.– Professor and Head
Jurg Ott, Suzanne Leal, Derek Gordon