Download - Mary Jeanne Kreek, M.D. Professor and Head The Laboratory of the Biology of Addictive Diseases
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 DiseasesThe Rockefeller University
Senior PhysicianThe Rockefeller University Hospital
October 19, 2004American 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 –
1964-2004Initial 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 –
1964-2004First 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.
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., 79:122-136, 1966.
(also recorded in the Association of American Physicians meeting transcription of discussion)
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 (heroin) addiction. JAMA, 193:646-650, 1965. Kreek, 2004
Heroin (opiate) addiction is a disease – a “metabolicdisease” – of the brain with resultant behaviors of“drug hunger” and drug self-administration, despitenegative consequences to self and others. Heroinaddiction is not simply a criminal behavior or duealone to antisocial personality or some other personality disorder.
Hypothesis(1963–1964)
Dole, Nyswander and Kreek, 1966
Impact of Short-Acting Heroin versusLong-Acting Methadone Administered ona Chronic Basis in Humans - 1964 Study
"High"
"Straight"
"Sick"
DaysAM PM AM PM AM
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"Straight"
"Sick"
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tate
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Dole, Nyswander and Kreek, 1966H
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Opioid Agonist Pharmacokinetics:Heroin Versus Methadone
Compound Systemic Apparent Major
Bioavailability Plasma Terminal Route of
After Oral Half-life Biotrans-
Administration (t Beta) formation
Heroin Limited 3 m Successive(<30%) (30 m for active deacetylation
6-actyl-morphine and morphinemetabolite) glucuronidation(4-6 for activemorphine metabolite)
Methadone Essentially 24 h N-demethylationComplete (48 h for(>70%) active
l-enantiomer)
Kreek et al., 1973; 1976; 1977; 1979; 1982; Inturrisi et al, 1973; 1984
1/2
Disruption versus Normalization
• levels of gene expression
• receptor mediated events
• physiology
• behaviors
“On-Off” versus “Steady-State”
Kreek, 1987; 2001
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) 50 – 80%
Continuing use of illicit heroin 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)
Methadone Maintenance Treatment for Opiate (Heroin) Addiction
Kreek, 1972; 1973; 2001; 2002, 2004; Inturrisi et al, in progress; Evans et al; in progress
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%
Opiate Addiction Treatment Outcome*
* 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
Kreek, 1983; 1984; 1991; 2001Clinics/Treatment Programs Diagram
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”:
Reviewed in Kreek & Vocci, J Sub Abuse Treatment, 2002
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.
Identification of HIV-1 Infection andChanging Prevalence in Drug Users
New York City: 1978 – 1992; 1983 - 1984 Study
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75
50
25
0
%
1978 1979 1980 1981 1982 1983 1984 1985 1986 1987 1992
Percent of IV Drug Users Infected with HIV-1
Kreek et al., 1984; Des Jarlais et al., 1984; 1989
50 – 60% Untreated, street heroin addicts:Positive for HIV-1 antibody
9% Methadone maintained since<1978(beginning of AIDS epidemic):less than 10% positive for HIV-1 antibody
Prevalence of HIV-1 (AIDS Virus)Infection in Intravenous Drug Users
New York City: 1983 - 1984 Study: Protective Effect of Methadone Maintenance Treatment
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%)• DNA• SNPs• other polymorphisms
Drug-Induced Effects(very high)
Environmental(very high)• prenatal• postnatal• contemporary• cues• comorbidity• stress-responsivity
Kreek et al., 2000; 2004
• mRNA levels• peptides• proteomics
• neurochemistry• synaptogenesis• behaviors
Endogenous Opioidsand their Receptors
LaForge, Yuferov and Kreek, 2000
Extracellular fluid
cell interior
cell membrane
AA identical in 3 receptors
AA identical in 2 receptors
AA different in 3 receptors
HOOC
H2
NS
S
Opioid Classes
Endorphins
Enkephalins
Dynorphins
Endomorphins (?)
OpioidReceptorTypes
Mu
Delta
Kappa
Heroin Depressant • Acts primarily on endogenous
opioid system
• Also affects dopaminergic system
Cocaine Stimulant • Acts primarily on dopaminergic
system, as well as on serotonergic
and noradrenergic systems
• Also affects opioid system
Alcohol Stimulant & • Undefined primary site of action
Depressant • Affects dopaminergic, serotonergic
and opioid systems
Primary Site(s) of Major Drugs of Abuse
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 self-administration 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
Endogenous Opioids
(mu, kappa; delta ?)
-End
adrenal
CRF
POMC
Cortisol
hypothalamus
ACTH
anteriorpituitary
Kreek et al., 1981; 1982; 1984; 1992; 2001
• 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. methadonemaintenance treatment)
Neuroendocrine Effects of Opiates, Cocaine, and Alcohol in Humans:
Hormones Involved in HPA Axis Stress Response
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
116.25
82.50
48.75
[18F] Cyclofoxy (a Selective Opioid Antagonist) Binding in Human Brain: Normal Volunteer PET Study - NIH
Eckelman, Rice and the NIH PET group, 2000
Kling et al., 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
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n=12
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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
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Thl Amy Caud Ins ACg Put MT MFr Par Crb IT Hip WMt
Region of Interest
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Kling et al., 2000
*
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* *
normal volunteers n=14
MTP volunteers n=14
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.
Hypothesis: Genetic Variabilityand the Opioid System
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
Variant Exon Protein Corresponding Allele(nucleotide position) location domain amino acid change 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 2%mutation (6 heterozygous)
Single Nucleotide Polymorphisms inCoding Region of Human Mu Opioid
Receptor Gene with Allelic Frequency > 1%
* Nucleotide position 1 is first base of the start codon.
Bond et al., 1998
Human Mu Opioid Receptor Gene SNPs
extracellular fluid
cell interior
cell membrane
HOOC400
100
H2N50
S4R A6V
N40D
V234L
350
300
250200
150
S147C
N152D
R260H
R265P
S268P
Kreek, Yuferov and LaForge, 2000
SNPvs with changed AA
Synonymous mutation
Putative Glycosylation site
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
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Log [Endomorphin -1(M)]
-11 -10 -9 -8 -7
-10 -9 -8 -7 -6
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Log [ Endorphin (M)]
-11 -10 -9 -8 -7
A118GPrototype
Bond et al., 1998
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Log [Endomorphin -1(M)] Log [ Endorphin (M)]
240
ACTH and Cortisol Levels in Family History Positive (n=8) and Negative (n=7) Social
Drinkers after 50mg Oral Naltrexone
King et al, 2002
Time (min) Post Capsule
AC
TH
(p
g/m
l)
0 30 60 90 120 150 180 240
30
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40
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Naltrexone
Placebo
60FH+
Time (min) Post Capsule
AC
TH
(p
g/m
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0 30 60 90 120 150 180 240
30
20
10
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40
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Naltrexone
Placebo
60FH-
Naltrexone
Time (min) Post Capsule
Co
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(µg
/dl)
0 30 60 90 120 150 180 2400
15
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Time (min) Post Capsule
Co
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/dl)
0 30 60 90 120 150 1800
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PlaceboFH-
Physiogenetics and Pharmacogenetics Related to A118G Variant of Human Mu
Opioid Receptor Gene
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Time (min)
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A/A (n=29)A/G (n=7)
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Naltrexone/Asp40 Allele (A/G, G/G) (n=23)
Naltrexone/Asn40 Allele (A/A) (n=48)
Placebo/Asn40 Allele (A/A) (n=41)
Placebo/Asp40 Allele (A/G, G/G) (n=18)
Association Between a Functional Polymorphism in the mu Opioid Receptor Gene
and Opiate Dependence in Central Sweden
Bart G , Heilig M, LaForge KS… Ott J, Kreek MJ, et al., 2004
Attributable Risk due to genotypes with a G allele in this population:18%
(with confidence interval ranges from 8.0 to 28.0%)
cases controls
G/G, A/G 41 23
A/A 98 147
Thus, in the entire study group in this central Swedish population:
Genotype
All Subjects Swedish with Both Parents Swedish
Controls(n=170)
Opiate Dependent
(n=139)Controls(n=120)
Opiate Dependent(n=67)
A/A 147(0.865)
98(0.705)
104(0.867)
46(0.687)
A/G 21(0.123)
39(0.281)
15(0.125)
19(0.283)
G/G 2(0.012)
2(0.014)
1(0.008)
2(0/030)
RR= 2.86 2(1)= 13.403 P< 0.00025* RR= 2.97 2
(1)= 8.740 P< 0.0031*
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 DiseasesMary Jeanne Kreek, M.D. – Professor and Head
2004
Laboratory ScientistsAnn HoK. Steven LaForgeEduardo ButelmanVadim YuferovDavid Nielsen Yan Zhou Alexis Bailey Dmitri Proudnikov Brian ReedStefan SchlussmanYong Zhang
Laboratory Adjunct Scientists Charles InturrisiRoberto PicettiVirginia PickelEllen Unterwald
Clinical ScientistsGavin Bart Lisa BorgHeather HofflichScott KelloggCharles Lilly
Clinical Adjunct Scientists Miriam Ochshorn AdelsonJames Kocsis Elizabeth Khuri
Research Nurses Kathy Bell Elizabeth Ducat Dorothy Melia
Administrative StaffKitt LavoieJanesse RojasSusan Russo
Assistants for ResearchJohannes AdomakoJulie AllenLauren BenceJason ChoiNicole DankertMatthew Swift
Laboratory WorkerLaura Nunez
The Laboratory of Statistical Genetics, Jurg Ott, Ph.D.– Professor and HeadJurg Ott, Suzanne Leal, Derek Gordon