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

Fu

nct

ion

al S

tate

(Met

had

on

e)

(ove

rdo

se)"High"

"Straight"

"Sick"

DaysAM PM AM PM AM

Fu

nct

ion

al S

tate

(Her

oin

)

Dole, Nyswander and Kreek, 1966H

Fu

nct

ion

al S

tate

(Her

oin

)

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

100

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

100

0

200

300

400

500

0 10 20 30 40 50 60 70 80 90

n=12

Time (min)

Pla

sma

Met

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eL

evel

s (n

g/m

l)

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

8

6

4

2

0

10

12

14

16

Thl Amy Caud Ins ACg Put MT MFr Par Crb IT Hip WMt

Region of Interest

Sp

ecif

ic B

ind

ing

(m

l pla

sma/

ml t

issu

e)

Kling et al., 2000

*

**

* *

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

100

80

60

40

20Pe

rce

nt

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d

0

1.0

0.5

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on

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Cu

rre

nt

Re

sp

on

se

0

Log [Endomorphin -1(M)]

-11 -10 -9 -8 -7

-10 -9 -8 -7 -6

100

80

60

40

20

0

Log [ Endorphin (M)]

-11 -10 -9 -8 -7

A118GPrototype

Bond et al., 1998

1.0

0.5

0

-9 -8 -7 -6

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

20

10

0

40

50

Naltrexone

Placebo

60FH+

Time (min) Post Capsule

AC

TH

(p

g/m

l)

0 30 60 90 120 150 180 240

30

20

10

0

40

50

Naltrexone

Placebo

60FH-

Naltrexone

Time (min) Post Capsule

Co

rtis

ol

(µg

/dl)

0 30 60 90 120 150 180 2400

15

10

5

20

25

PlaceboFH+

Time (min) Post Capsule

Co

rtis

ol

(µg

/dl)

0 30 60 90 120 150 1800

15

10

5

20

25 Naltrexone

PlaceboFH-

Physiogenetics and Pharmacogenetics Related to A118G Variant of Human Mu

Opioid Receptor Gene

24

22

20

18

16

14

12

10

8

50 0 50 100 150 200

Time (min)

Ser

um

Co

rtis

ol

(ug

/dl) N N

N

N

PI

A/A (n=29)A/G (n=7)

1.0

0.9

0.8

0.7

0.6

0.5

0.2

0.4

0.3

0.1

0.00 14 28 42 56 70 84C

um

ula

tive

Su

rviv

al (

Tim

e t

o R

elap

se)

Days

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