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Long Acting Opioids: Challenges in Pharmacotherapy. Mary Jeanne Kreek, M.D. The Laboratory of the Biology of Addictive Diseases The Rockefeller University September 10, 2003 Anesthetic Life Support Drugs Advisory Committee Food and Drug Administration Bethesda, MD

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long acting opioids challenges in pharmacotherapy
Long Acting Opioids:Challenges in Pharmacotherapy

Mary Jeanne Kreek, M.D.

The Laboratory of the Biology of Addictive Diseases

The Rockefeller University

September 10, 2003

Anesthetic Life Support Drugs Advisory Committee

Food and Drug Administration

Bethesda, MD

funded primarily by NIH-NIDA, NIHCRR and NYS OASAS

slide2
Major Issues/ Problems Related to Physician Use/Prescribing of Long-Acting Mu Opioid Receptor Agonists in Humans

A. Lack of adequate or updated medical education concerning pharmacokinetics and pharmacodynamics of long-acting (intrinsic or by formulation) mu opioid receptor agonists and partial agonists.

  • Decrease in formal medical education in classical pharmacology and lack of continuing medical education in pharmacology.

2) Discovery (synthesis) and development of intrinsically long-acting mu opioid agonists for treatment of opioid addiction and for treatment of chronic pain (1964 onward).

3) Increase in numbers of short-acting mu opioid agonists now formulated to be long-acting opioids for use in management of pain.

Kreek, 2003

slide3
Major Issues/ Problems Related to Physician Use/Prescribing of Long-Acting Mu Opioid Receptor Agonists in Humans (continued)

B. Lack of adequate (or any) medical school education conerning any of the specific addictions and also medical approaches to assessing persons with ongoing misuse, abuse, or addiction to drugs.

  • Lack of awareness of prevalence of specific additions (10% to 20% in all US population with one or more addiction).

2) Lack of knowledge concerning, e.g., genetic vulnerabilities; predictable chronic drug use induced changes in brain; environmental (e.g., set and setting, peer pressure, availability) and host factors (e.g., psychiatric comorbidity, medical comorbidity, chronic pain) contributing to the vulnerability to develop an addiction.

Kreek, 2003

slide4
Major Issues/ Problems Related to Physician Use/Prescribing of Long-Acting Mu Opioid Receptor Agonists in Humans (continued)

C. Secondary physician/healthcare worker and related enforcement issues.

  • Physicians (and related healthcare workers) with inadequate knowledge (and possibly inadequate access to information).
  • Physicians with inadequate time (due to HMO and related current healthcare system) to evaluate each patient carefully and to individualize care
  • Physicians desiring to (for profit) or willing to (for diverse reasons) become “prescription writers,” i.e., illicit practice of medicine.
  • Similar constraints of specific education and knowledge and time constraints often lead to inappropriate enforcement.

*majority of problems probably lay within these two realms*

Kreek, 2003

prevalence of specific drug abuse and vulnerability to develop addictions
Prevalence of Specific Drug Abuse and Vulnerability to Develop Addictions

National Household Survey and Related Surveys – 1996 – 1999

Alcohol Use – ever ~ 177 millionAlcoholism ~ 15 million

Cocaine Use – ever ~ 26 millionCocaine Addiction ~ 1 to 2 million

Heroin Use – ever ~ 2.5 to 3 millionHeroin Addiction ~ 0.5 to 1 million

Development of Addiction After Self Exposure

Alcoholism ~ 1 in 10 to 1 in 20Cocaine Addiction ~ 1 in 10 to 1 in 20Heroin Addiction ~ 1 in 3 to 1 in 5

NIDA, SAMHSA Reports

factors contributing to vulnerability to develop a specific addiction
Factors Contributing to Vulnerability to Develop a Specific Addiction

use of the drug of abuse essential (100%)

Genetic(25-50%)

• DNA

• SNPs

• other

polymorphisms

Environmental(very high)

• prenatal

• postnatal

• contemporary

• cues

• comorbidity

• neurochemistry

• behaviors

• mRNA levels

• peptides

• proteomics

Drug-Induced Effects(very high)

Kreek et al., 2000

endogenous opioids and their receptors
Endogenous Opioidsand Their Receptors

Opioid ClassesOpioid Receptor Types

Endorphins Mu

Enkephalins Delta

Dynorphins Kappa

Endomorphins (?)

Kreek, 2001

human opioid receptors and
Human Opioid Receptors , , and 

H2N

extracellular fluid

S

AA identical in 3 receptors

S

AA identical in

2 receptors

AA different in

3 receptors

cell membrane

cell interior

HOOC

LaForge, Yuferov and Kreek, 2000

hypothesis 1963 1964
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

heroin addiction functional state of a typical addict
Heroin Addiction: Functional State of aTypical Addict

"High"

(overdose)

Functional State

"Straight"

"Sick"

(arrows indicate times of injection)

AM

PM

AM

PM

AM

Days

Dole, Nyswander and Kreek, 1966

goals and rationale for specific pharmacotherapy for an addiction
Goals and Rationale for SpecificPharmacotherapy for an Addiction

1. Prevent withdrawal symptoms

2. Reduce drug craving

3. Normalize any physiological functions disruptedby drug use

4. Target treatment agent to specific site of action,receptor, or physiological system affected orderanged by drug of abuse

Kreek, 1978; 1991; 1992; 2001

characteristics of an effective pharmacotherapeutic agent for treatment of an addictive disease
Characteristics of an EffectivePharmacotherapeutic Agent forTreatment of an Addictive Disease
  • Orally effective
  • Slow onset of action
  • Long duration of action
  • Slow offset of action

Kreek, 1978; 1991; 1992; 2001

methadone maintenance functional state of a former addict treated with methadone maintenance
Methadone Maintenance: Functional State of a Former Addict Treated With Methadone Maintenance

"High"

"Straight"

Functional State

"Sick"

H

M

M

AM

PM

AM

PM

AM

Days

“Functional state of a patient blockaded with methadone (a single oral dose each morning). The effect of an intravenous injection of heroin in the blocked patient is shown in the second day. The dotted line (---) indicates the course if methadone is omitted.”

Dole, Nyswander and Kreek

heroin versus methadone
Heroin versus Methadone*

Heroin Methadone

Route of administration intravenous oral

Onset of action immediate 30 minutes

Duration of action 3–6 hrs 24–36 hrs

Euphoria first 1–2 hrs none

Withdrawal symptoms after 3–4 hrs after 24 hrs

* effects of high dosages in tolerant individuals

Kreek, 1973; 1976; 1987

plasma methadone levels in an individual maintained on 100 mg day
Plasma Methadone Levels in anIndividual Maintained on 100 mg/day

500

400

300

Plasma levels (ng/ml)

200

100

0

0

2

4

6

8

24

Time (hours after dose)

MJ Kreek, MD, 1994 (from Kreek, MJ, NY State J. Med. (73), 1973)

opioid agonist pharmacokinetics heroin versus methadone
Opioid Agonist Pharmacokinetics:Heroin Versus Methadone

Compound Systemic Apparent Major

Bioavailability Plasma Terminal Route of

After Oral Half-life Biotrans-

Administration (tBeta) formation

1/2

Heroin Limited 3 m Successive

(<30%) (30 m for active deacetylation

6-actyl-morphine and morphine

metabolite) glucuronidation

(4-6 for active

morphine metabolite)

Methadone Essentially 24 h N-demethylation

Complete (48 h for

(>70%) active

l-enantiomer)

Kreek et al., 1973; 1976; 1977; 1979; 1982; Inturrisi, 1984

slide18

[18F] Cyclofoxy (a Selective Opioid Antagonist) Binding

in Human Brain: Normal Volunteer PET Study - NIH

116.25

82.50

48.75

slide19
Plasma Methadone Levels in Long-Term, Methadone-Treatment Patients Sampled Across the 90-min PET Scan Session

500

400

300

Plasma MethadoneLevels (ng/ml)

200

100

n=12

0

0

10

20

30

40

50

60

70

80

90

Time (min)

Kling et al., 2000

slide20

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

*

Specific Binding (ml plasma/ml tissue)

8

*

*

6

*

4

2

0

Thi

Amy

Caud

Ins

ACg

Put

MT

MFr

Par

Crb

IT

Hip

WMt

Region of Interest

Kling et al., 2000

slide21

Methadone Maintenance Treatment Allows Normalizationof Endogenous Opioid-Related Physiological FunctionsDisrupted During Chronic Heroin Use

Neuroendocrine Function

  • Hypothalamic-Pituitary-Adrenal Axis – Stress Responsivitylevels and circadian rhythm of release of POMC peptides( Endorphin; ACTH and cortisol)
  • Hypothalamic-Pituitary-Gonadal Axis – Reproductive Biology levels and pulsatile release of LH and testosterone levels

Immune Function

  • Natural Killer Cell Activity
  • Absolute Numbers of Cells — T cells; T cell subset levels;B cells; NK cells
  • Immunoglobin Levels (M and G)

Kreek, 1972; 1973; 1978; 1987; 1992; 2001; Novick et al., 1989

methadone maintenance treatment for opiate heroin addiction
Methadone Maintenance Treatment for Opiate (Heroin) Addiction

Number of patients in treatment: 179,000

Efficacy in “good” treatment programs using adequate doses:

Voluntary retention in treatment (1 year or more) 60 – 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)

Kreek, 1972; 1973; 2001; 2002; Inturrisi et al, in progress; Evans et al; in progress

reinforcing or reward effects of drugs of abuse
Reinforcing or “Reward” Effects of Drugs of Abuse

Initial exposure to a drug of abuse may produce effects which are

interpreted by the individual as “desirable” or “pleasurable”, i.e.,

“rewarding”. These effects may lead to “craving” or “hunger” for

the drug, with resultant spontaneous activity or work for drug

acquisition and self-administration.

Primary sites of actions of drugs of abuse with respect to their

reward or reinforcing effects have been identified as specific

brain regions, rich in dopamine nerve terminals or cell bodies, the

mesolimbic and mesocortical dopamine systems especially the

nucleus accumbens, as well as the amygdala and the anterior

cingulate.

Kreek, 1987; 2001

slide24
Relationship Between Blood (and Brain) Levels of Drugs of Abuse and Their Effects on Events Related to Addictions

Rates of rise of blood (and presumable brain) levels of

drugs of abuse are related positively to their reinforcing

effects

Rates of fall of blood (and presumably brain) levels of

drugs of abuse are related positively to the onset of

withdrawal symptoms and/or acute “craving”

Kreek, 1978; 1991, 1992; 2001

on off versus steady state
“On-Off” versus “Steady-State”

Disruption versus Normalization

• levels of gene expression

• receptor mediated events

• physiology

• behaviors

Kreek, 1987; 2001

pharmacokinetics of laam l acetyl methadol
Pharmacokinetics of LAAM(l--acetyl-methadol)
  • Orally effective
  • Long-acting
  • Long duration of action due, in part, to two biologicallyactive metabolites
  • P450 related hepatic enzymes involved in metabolism
  • Apparent  terminal half-life in humans
  • LAAM :2.6 days
  • norLAAM :2 days
  • dinorLAAM :4 days
buprenorphine hydrochloride

HO

HCl

O

N

CH3O

CH3

HO

C(CH3)3

Buprenorphine Hydrochloride*

*Buprenex

buprenorphine pharmacokinetics and dynamics in humans
Buprenorphine— Pharmacokinetics and Dynamics in Humans
  • Mu opioid receptor partial agonist.
  • No oral preparation— (ineffective: “first pass” rapid biotransformation by GI mucosa and by liver).
  • Sublingual preparation– (without, and with, naloxone to reduce intravenous abuse liability).
    • Approved by FDA– maximum 16mg/day for treatment of opiate addiction (only); no approval for management of pain yet.
    • Maximal dose effective in humans 24 to 32mg.
    • Sublingual liquid or tablet; tablet ~55% plasma levels of liquid.
  • Plasma β terminal half-life: “3 to 5 hours.”
    • Around 120 minutes to peak after sublingual dose.
  • Pharmacodynamic sustained mu opioid effect, 24 to 48 hours due to very long mu opioid receptor occupancy.
  • Mu opioid agonist effects NOT reversible with opioid antagonist naloxone (because of very high affinity to and quasi-irreversible binding at mu opioid receptor.

Kreek, 2003

opiate addiction treatment outcome
Opiate Addiction Treatment Outcome*

Methadone Maintenance 50 – 80%

LAAM Maintenance 50–80%

Buprenorphine-Naloxone Maintenance 40–50%**

Naltrexone Maintenance 10 – 20%

“Drug Free” (non-pharmacotherapeutic) 5 – 20%

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; 2003

continuing urgent medical needs
Continuing Urgent Medical Needs
  • To provide the most effective treatment for a major addictive disease, long term heroin (or other short-acting opiate) addiction, the use of long-acting mu opioid agonists or partial agonists is usually essential.
  • To provide the most effective treatment for chronic pain, neoplastic or other, the use of long-acting mu opioid agonists or partial agonists are often essential.

Kreek, 2003

specific critical questions
Specific Critical Questions
  • Is this mu opioid agonist medication and/or this specific formulation short- or long-acting?
  • Is the patient opioid naïve, modestly exposed, or long-term exposed and, thus, tolerant?
  • Does this patient already have a problem with some type of drug abuse or addiction or other indicators suggesting risk of increased vulnerability to develop an addiction?

Kreek, 2003

oxycodone hydrochloride

H3CO

OH

O

H-Cl-

N

CH3

O

Oxycodone Hydrochloride*

*OxyContin

slide35

*“Taken broken, chewed, crushed xxx (compound formulations 1, 2, or 3)

could lead to rapid release… toxic dose.”

Kreek, 2003

hypothesis
Hypothesis

Some of the individual genetic variability in susceptibility to the development and persistence of, or relapse to, opiate addiction may be due to polymorphism at the mu opioid receptor.

Also, individual differences in responses to endogenous opioids (“physiogenetics”) or treatment pharmacotherapies (“pharmacogenetics”) may be mediated by variant forms of the mu opioid receptor.

role of mu opioid receptor and related endorphin systems in normal physiological functions
Role of Mu Opioid Receptor and Related EndorphinSystems in Normal Physiological Functions*
  • Neuroendocrine Functions
    • Stress responsive systems includinghypothalamic-pituitary-adrenal axis
    • Reproductive function includinghypothalamic-pituitary-gonadal axis
  • Response to Pain
  • Immunological Function
  • Gastrointestinal Function
  • Cardiovascular Function
  • Pulmonary Function
  • ? Mood, Affect; Cognition

* All disrupted by chronic abuse of the short acting opiate, heroin

Kreek, 2000

human gene diversity single nucleotide polymorphisms snps in genes definitions
SNP — a single nucleotide polymorphism, that is, one nucleotide or base of any base pair that is different from the “usual”, “prototypic”, (or first identified and recorded base)

Coding region — that part of a gene which codes for a peptide (protein)

Allelic Frequency: <1% low or rare 1–5% intermediate >5% high or frequent

Human Gene Diversity: Single Nucleotide Polymorphisms (SNPs) in Genes: Definitions

M.J. Kreek, 2000

single nucleotide polymorphisms in human mu opioid receptor gene
Single Nucleotide Polymorphisms inHuman Mu Opioid Receptor Gene

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)

G779A 3 CL3 Arg 260 His (R260H) <1%

(1 heterozygous)

G942A 3 EL3 Synonymous <1%

mutation (1 heterozygous)

* Nucleotide position 1 is first base of the start codon.

Bond et al., 1998

allelic frequency associations opioid dependence c17t and a118g
Allelic Frequency AssociationsOpioid Dependence – C17T and A118G

C

T

A

G

Total

207

19

206

20

226

Dependent

(0.916)

(0.084)

(0.912)

(0.088)

77

1

66

12

78

Non-dependent

(0.987)

(0.013)

(0.846)

(0.154)

c

3.70 (p = 0.054)*

1.98 (p = 0.159)

Yate\'s corrected

=

2

(1)

c

= 4.1 [p=0.05]

*

This finding is similar to that obtained by Berrettini et al. (1997)

2

2

However, within the Hispanic study subjects groups (total n=67), the A118G variant allele was present in a significantly higher proportion of non-opioid dependent subjects compared to opioid dependent subjects.

(Yates corrected Chi-square

c

2

= 8.22 [p=0.0041])

2

(1)

(1)

Bond et al., 1998

human mor gene snps
Human MOR Gene SNPs

S4R

A6V

H2N

N40D

SNPvs with changed AA

50

Synonymous mutation

extracellular fluid

Putative Glycosylation site

V234L

S147C

300

N152D

150

200

250

cell membrane

R260H

R265P

350

100

cell interior

S268P

400

HOOC

Kreek, Yuferov and LaForge, 2000

slide42

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

Percent Bound

40

40

20

20

0

0

-11

-10

-9

-8

-7

-11

-10

-9

-8

-7

Log [Endomorphin -1(M)]

Log [ Endorphin (M)]

A118G

1.0

1.0

Prototype

Fraction Maximum Current Response

0.5

0.5

0

0

-10

-9

-8

-7

-6

-9

-8

-7

-6

Log [Endomorphin -1(M)]

Log [ Endorphin (M)]

Bond et al., 1998

slide43
“Physiogenetics”—Cortisol Levels After Incremental Naloxone Administration:Mu Opioid Receptor A118G Heterozygote Individuals

24

A/A (n=29)

N

22

N

A/G (n=7)

20

18

Serum Cortisol (ug/dl)

N

16

14

PI

12

N

10

8

0

50

100

150

200

50

Time(min)

Kreek, 1999; Wand et al, 2002

slide44

“Physiogenetics”?– Pharmacogenetics–ACTH and Cortisol Levels in Family History Positive (n=8) and Negative (n=7) Social Drinkers after 50mg Oral Naltrexone

60

60

Naltrexone

Naltrexone

FH-

FH+

Placebo

Placebo

50

50

40

40

ACTH (pg/ml)

ACTH (pg/ml)

30

30

20

20

10

10

0

0

0

30

60

90

120

150

180

240

0

30

60

90

120

150

180

240

Time (min) Post Capsule

Time (min) Post Capsule

25

Naltrexone

Naltrexone

25

FH-

FH+

Placebo

Placebo

20

20

15

15

Cortisol (µg/dl)

Cortisol (µg/dl)

10

10

5

5

0

0

0

30

60

90

120

150

180

240

Kreek 1999;

King et al, 2002

0

30

60

90

120

150

180

240

Time (min) Post Capsule

Time (min) Post Capsule

pharmacogenetics mu opioid receptor a118g polymorphism naltrexone treatment response
Pharmacogenetics:Mu Opioid Receptor A118G Polymorphism—Naltrexone Treatment Response

*All subjects consented for genetics studies either at the time of naltrexone study or at a later date

Study 1: UPENN (Monterosso et al., 2001)*

 183 alcohol dependent outpatient subjects

 Randomized to 3 groups:

a) 9 months of naltrexone (100mg/day)

b) 12 weeks of naltrexone (100mg/day),

followed by 6 months of placebo

c) 9 months of placebo

Study 2: UPENN (unpublished)*

 240 alcohol dependent outpatient subjects

 Randomized to 6 groups:

a) either naltrexone (100mg/day) for 24 weeks or

b) placebo for 24 weeks

c) all subjects in (a) or (b) randomized to 3 different

psychosocial interventions

Study 3: University of Connecticut Health Center (Kranzler et al., 2000)*

 183 alcohol dependent outpatient subjects

 After Initial treatment of 1 week single-blind placebo, randomized

to 3 groups:

a) naltrexone (50mg/day)

b) placebo

c) nefazine (up to 600mg/day)

Oslin, Berrettini, Volpicelli, Kranzler, O’Brien, et al., 2003

slide46

1.0

0.9

Naltrexone/

Asp40 Allele (A/G, G/G) (n=23)

0.8

0.7

Naltrexone/

Asn40 Allele (A/A) (n=48)

0.6

Placebo/

Asp40 Allele (A/G, G/G) (n=18)

0.5

Placebo/

Asn40 Allele (A/A) (n=41)

0.4

0.3

0.2

0.1

0.0

0

14

28

42

56

70

84

“Pharmacogenetics”—Naltrexone Treatment Response:Survival Analyses for Time to Relapse in Subjects With One or Two Copies of the Asp40 Allele vs. Those Homozygous for the Asp40 Allele by Medication Group

Cumulative Survival (Time to Relapse)

Days

Oslin, Berrettini, Volpicelli, Kranzler, O’Brien, et al., 2003

mu opioid receptor gene evidence of association or linkage with addictions
Alcohol Dependence

For: Town, et al., 1999

No Evidence For: Bergen, et al., 1997; Kranzler et al., 1998; Sander et al., 1998; Gelernter et al., 1999; Gscheidel et al., 2000.

Opioid Dependence

For: Bond et al., 1998; Szeto et al., 2001; Shi et al., 2002; Tan et al., 2003; Bart et al., 2003

No Evidence For: Kranzler et al., 1998; Li et al.,2000; Franke et al., 2001.

Mixed Drug Dependence

For: Berrettini et al., 1997; Hoeho et al., 1997; Hoehe et al., 2000,Schinka et al., 2002; Luo et al, 2003

No Evidence for: Kranzler et al., 1998; Gelernter et al., 1999

Mu Opioid Receptor Gene: Evidence of Association or Linkage With Addictions

adapted from K.S. LaForge, 2003

slide48

Allelic Frequencies of the Variant Allele of the A118G Single Nucleotide Polymorphism of the Human -Opioid Receptor Gene in Diverse Populations

Ethnicity or Bergen et al. Bond et al. Gelernter et al. Szeto et al Tan et al Bart et al

population (1997) (1998) (1999) (2001) (2003) (2003)

Asian

Japanese 0.485 (34)

Han Chinese 0.362 (297)

Chinese 0.351 (208)

Thai 0.438 (56)

Malay 0.446 (156)

Indian 0.442 (137)

Southwest Native 0.163 (367)American

Caucasian

European American 0.105 (100) 0.115 (52) 0.141 (543)Finnish Caucasian 0.122 (324)

Swedish Caucasian 0.107 (187)

Hispanic 0.142 (67) 0.117 (47)

African American 0.016 (31) 0.028 (144)

Other (populations in Israel)

Ethiopian 0.170 (49)

Bedouin 0.080 (43)

Ashkenazi 0.210 (93)

Allele frequency for the variant allele is shown for various study populations. Numbers in parentheses are the number of subjects whose genotype was ascertained in each study. A study of Han Chinese found the 118G allele at a frequency of 0.321, and no occurrence of the 17T allele in 540 subjects (Li et al., 2000).

LaForge, Yuferov

and Kreek, 2003

human gene diversity snps and other polymorphisms in coding region of opioid receptor genes
Human Gene Diversity – SNPs and OtherPolymorphisms in Coding Region ofOpioid Receptor Genes

# Polymorphisms

Identified by our

Laboratory*

# of Additional

Polymorphisms

Gene

Total #

Mu opioid receptor 11 6 17

Kappa opioid receptor 8 1 9

Delta opioid receptor 0 2 2

*Without or with prior identification or later verification by other groups

LaForge, Yuferov and Kreek, 2000; LaForge and Kreek, 2002

the laboratory of the biology of addictive diseases mary jeanne kreek m d professor and head 2003
The Laboratory of the Biology of Addictive DiseasesMary Jeanne Kreek, M.D. – Professor and Head2003

Laboratory ScientistsClinical ScientistsAdministrative Staff

Ann Ho Gavin Bart Kitt Lavoie

K. Steven LaForge Lisa Borg Janesse Rojas

Eduardo Butelman Scott Kellogg Susan Russo

Vadim Yuferov Charles Lilly

David NielsenAssistants for Research

Yan Zhou Clinical Adjunct ScientistsJonathan Ball

Alexis Bailey Paola Piccolo Lauren Bence

Thomas Kroslak Joan Culpepper-Morgan Jason Choi

Dmitri Proudnikov Lawrence Brown Wan-Xin Feng

Brian Reed James Kocsis David Fussell

Stefan Schlussman Mark Green Rob Gianotti

Adena Svingos Lynette Benjamin Todd Harris

Yong Zhang Elizabeth Khuri Lauren Hofmann

Aaron Wells Elizabeth Oosterhuis

Laboratory Adjunct Scientists

Charles InturrisiResearch NursesLaboratory Worker

Roberto Picetti Kathy Bell Laura Nunez

Virginia Pickel Elizabeth Ducat

Ellen Unterwald Dorothy Melia

Vanya Quinones-Jenab

slide51

NIH-NIDA K05-DA00049

“Addictive Drugs: Pharmacology and Physiology”

NIH-NIDA P60-DA05130

“Treatment of Addictions: Biological Correlates”

NIH-NIDA R01-DA09444

“Mu Opioid Receptor Gene in Heroin Addicts”

NIH-NIDA R01-DA11113

“Effects of Systematically Administered Dynorphins”

NIH-NIDA R01-DA12848

“Addictions: Genotypes, Polymorphisms and Function”

NIH-NIDA U10-DA13046

“NIDA Clinical Trials Network – NYC”

New York State OASAS

NIH-NCRR M01-RR00102

GCRC – The Rockefeller University Hospital

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