long acting opioids: challenges in pharmacotherapy mary jeanne kreek, m.d. the laboratory of the...
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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 CommitteeFood and Drug Administration
Bethesda, MD
funded primarily by NIH-NIDA, NIHCRR and NYS OASAS
Major Issues/ Problems Related to Physician Use/Prescribing of Long-Acting Mu Opioid
Receptor Agonists in Humans
1) 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.
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.
Kreek, 2003
Major Issues/ Problems Related to Physician Use/Prescribing of Long-Acting Mu Opioid Receptor Agonists in Humans (continued)
1) 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.
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.
Kreek, 2003
Major Issues/ Problems Related to Physician Use/Prescribing of Long-Acting Mu Opioid Receptor Agonists in Humans (continued)
1) Physicians (and related healthcare workers) with inadequate knowledge (and possibly inadequate access to information).
2) Physicians with inadequate time (due to HMO and related current healthcare system) to evaluate each patient carefully and to individualize care
3) Physicians desiring to (for profit) or willing to (for diverse reasons) become “prescription writers,” i.e., illicit practice of medicine.
4) Similar constraints of specific education and knowledge and time constraints often lead to inappropriate enforcement.
C. Secondary physician/healthcare worker and related enforcement issues.
Kreek, 2003
*majority of problems probably lay within these two realms*
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
Prevalence of Specific Drug Abuse and Vulnerability to Develop Addictions
NIDA, SAMHSA Reports
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
Kreek et al., 2000
• mRNA levels• peptides• proteomics
• neurochemistry• behaviors
Opioid ClassesOpioid Receptor Types
EndorphinsMu
EnkephalinsDelta
DynorphinsKappa
Endomorphins (?)
Endogenous Opioidsand Their Receptors
Kreek, 2001
Human Opioid Receptors , , and
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
H2N
S
S
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
Heroin Addiction: Functional State of aTypical Addict
"High"
"Straight"
"Sick"
Days
AM PM AM PM AM
Fu
nct
ion
al S
tate
Dole, Nyswander and Kreek, 1966
(ove
rdo
se)
(arrows indicate times of injection)
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 EffectivePharmacotherapeutic Agent for
Treatment of an Addictive Disease
• Orally effective
• Slow onset of action
• Long duration of action
• Slow offset of action
Kreek, 1978; 1991; 1992; 2001
Methadone/Morphin
e/Heroin Chemical
Structur
e
Kreek Lectures: 1967 onward
Methadone Maintenance: Functional State of a Former Addict Treated With
Methadone Maintenance
Fu
nct
ion
al S
tate
Dole, Nyswander and Kreek
"High"
"Straight"
"Sick"
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.”
M MH
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
Heroin versus Methadone*
* effects of high dosages in tolerant individuals
Kreek, 1973; 1976; 1987
Plasma Methadone Levels in anIndividual Maintained on 100 mg/day
Pla
sma
leve
ls (
ng
/ml)
MJ Kreek, MD, 1994 (from Kreek, MJ, NY State J. Med. (73), 1973)
500
0
Time (hours after dose)
400
300
200
100
0
2 4 6 8 24
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, 1984
1/2
116.25
82.50
48.75
[18F] Cyclofoxy (a Selective Opioid Antagonist) Binding in Human Brain: Normal Volunteer PET Study - NIH
Kling et al., 2000
Plasma Methadone Levels in Long-Term, Methadone-Treatment Patients Sampled Across
the 90-min PET Scan Session
100
0
200
300
400
500
0 10 20 30 40 50 60 70 80 90
n=12
Time (min)
Pla
sma
Met
had
on
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
Thi 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
Methadone Maintenance Treatment Allows Normalizationof Endogenous Opioid-Related Physiological Functions
Disrupted During Chronic Heroin Use
Neuroendocrine Function– Hypothalamic-Pituitary-Adrenal Axis – Stress Responsivity
levels 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
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)
Methadone Maintenance Treatment for Opiate (Heroin) Addiction
Kreek, 1972; 1973; 2001; 2002; Inturrisi et al, in progress; Evans et al; in progress
Initial exposure to a drug of abuse may produce effects which areinterpreted 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 theirreward or reinforcing effects have been identified as specific brain regions, rich in dopamine nerve terminals or cell bodies, themesolimbic and mesocortical dopamine systems especially thenucleus accumbens, as well as the amygdala and the anteriorcingulate.
Reinforcing or “Reward” Effects of Drugs of Abuse
Kreek, 1987; 2001
Rates of rise of blood (and presumable brain) levels of drugs of abuse are related positively to their reinforcingeffects
Rates of fall of blood (and presumably brain) levels of drugs of abuse are related positively to the onset ofwithdrawal symptoms and/or acute “craving”
Relationship Between Blood (and Brain) Levels of Drugs of Abuse and Their Effects
on Events Related to Addictions
Kreek, 1978; 1991, 1992; 2001
Disruption versus Normalization
• levels of gene expression
• receptor mediated events
• physiology
• behaviors
“On-Off” versus “Steady-State”
Kreek, 1987; 2001
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
O
N
CH3O
HOCH3
C(CH3)3
HCl
*Buprenex
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
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)
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.
Kreek, 1996; 2001; 2003
Continuing Urgent Medical Needs
1) 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.
2) 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
1) Is this mu opioid agonist medication and/or this specific formulation short- or long-acting?
2) Is the patient opioid naïve, modestly exposed, or long-term exposed and, thus, tolerant?
3) 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
O
O
OH
NH-Cl-
CH3
*OxyContin
Hydromorphone Hydrochloride
HCl
CH2
CH2
CH3
HH
OH
O
O
N
Fentanyl
CH3 CH2 CON CH2 CH2N
Generic Name
(Trade Name of Immediate Release Preparation)
(Dosing Interval)
(Dosage)
Trade Name(s) of Extended Release Preparation
(Dosing Interval)
(Dosages)
(higher doses for tolerant individuals only)
Plasma t½ (h)
Dynamics/Duration of Extended Release Formulation
1) Oxycodone
(q 4h)
(5mg; 10mg)
e.g., OxyContin®
(q 12h)
(10, 20, 40, 80mg)*
2.7h 12h duration (t½ absorption—bimodal, e.g., 0.6 and 6.9h)
2) Hydromorphone
(e.g., Dilaudid ®)
(q 4h)
(2mg; 4mg)
e.g., Hydromorphin Contin ®
(q 12h)
(8, 16, 32, 64mg)*
2.6h 12h duration
3) Morphine
(q 4h)
(multiple)
e.g., MSContin ®
e.g., Kadian Reg ®
(q 12h)
(15, 30, 60, 100, 200mg)*
2 to 4h 12h duration
4) Fentanyl e.g., Duragesic ®
(q 72h)
(25, 50, 75, 100μg/h)*
(2.5, 5.0, 7.5, 10mg)
3-12h (?) 72h duration
Kreek, 2003
*“Taken broken, chewed, crushed xxx (compound formulations 1, 2, or 3) could lead to rapid release… toxic dose.”
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.
Hypothesis
* All disrupted by chronic abuse of the short acting opiate, heroin
Role of Mu Opioid Receptor and Related EndorphinSystems in Normal Physiological Functions*
• Neuroendocrine Functions– Stress responsive systems including
hypothalamic-pituitary-adrenal axis– Reproductive function including
hypothalamic-pituitary-gonadal axis
• Response to Pain• Immunological Function• Gastrointestinal Function• Cardiovascular Function• Pulmonary Function• ? Mood, Affect; Cognition
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 rare1–5% intermediate>5% high or frequent
M.J. Kreek, 2000
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)
Single Nucleotide Polymorphisms inHuman Mu Opioid Receptor Gene
* Nucleotide position 1 is first base of the start codon.
Bond et al., 1998
Allelic Frequency AssociationsOpioid Dependence – C17T and A118G
2
2(1)
2
2
(1)
2(1)
* This finding is similar to that obtained by Berrettini et al. (1997) = 4.1 [p=0.05]
† 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 = 8.22 [p=0.0041])
Dependent
Non-dependent
Yate's corrected =
C
207(0.916)
77(0.987)
T
19(0.084)
1(0.013)
Total
226
78
A
206(0.912)
66(0.846)
G
20(0.088)
12(0.154)
3.70 (p = 0.054)* 1.98 (p = 0.159)†
Bond et al., 1998
Human MOR Gene SNPs
SNPvs with changed AA
Synonymous mutation
Putative Glycosylation siteextracellular 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
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
Bo
un
d
0
1.0
0.5
Fra
cti
on
Ma
xim
um
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)]
24
22
20
18
16
14
12
10
850 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)
“Physiogenetics”—Cortisol Levels After Incremental Naloxone Administration:
Mu Opioid Receptor A118G Heterozygote Individuals
Kreek, 1999; Wand et al, 2002
240
“Physiogenetics”?– Pharmacogenetics–ACTH and Cortisol Levels in Family History Positive (n=8) and
Negative (n=7) Social Drinkers after 50mg Oral Naltrexone
Kreek 1999;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-
Pharmacogenetics:Mu Opioid Receptor A118G Polymorphism—
Naltrexone Treatment ResponseStudy 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 placeboc) 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) placeboc) nefazine (up to 600mg/day)
*All subjects consented for genetics studies either at the time of naltrexone study or at a later date
Oslin, Berrettini, Volpicelli, Kranzler, O’Brien, et al., 2003
“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
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 84
Cu
mu
lati
ve S
urv
ival
(T
ime
to 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)
Oslin, Berrettini, Volpicelli, Kranzler, O’Brien, et al., 2003
Mu Opioid Receptor Gene: Evidence of Association or Linkage With AddictionsAlcohol 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
adapted from K.S. LaForge, 2003
Ethnicity or Bergen et al. Bond et al. Gelernter et al. Szeto et al Tan et al Bart et alpopulation (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).
Allelic Frequencies of the Variant Allele of the A118G Single Nucleotide Polymorphism of the Human -Opioid
Receptor Gene in Diverse Populations
LaForge, Yuferovand Kreek, 2003
Human Gene Diversity – SNPs and OtherPolymorphisms in Coding Region of
Opioid Receptor Genes
# PolymorphismsIdentified by our
Laboratory*
# of AdditionalPolymorphisms
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
Laboratory Scientists Clinical Scientists Administrative StaffAnn Ho Gavin Bart Kitt LavoieK. Steven LaForge Lisa Borg Janesse RojasEduardo Butelman Scott Kellogg Susan RussoVadim Yuferov Charles LillyDavid Nielsen Assistants for ResearchYan Zhou Clinical Adjunct Scientists Jonathan BallAlexis Bailey Paola Piccolo Lauren BenceThomas Kroslak Joan Culpepper-Morgan Jason ChoiDmitri Proudnikov Lawrence Brown Wan-Xin FengBrian Reed James Kocsis David Fussell Stefan Schlussman Mark Green Rob GianottiAdena Svingos Lynette Benjamin Todd HarrisYong Zhang Elizabeth Khuri Lauren Hofmann
Aaron Wells Elizabeth OosterhuisLaboratory Adjunct Scientists Charles Inturrisi Research Nurses Laboratory WorkerRoberto Picetti Kathy Bell Laura NunezVirginia Pickel Elizabeth Ducat Ellen Unterwald Dorothy MeliaVanya Quinones-Jenab
The Laboratory of the Biology of Addictive DiseasesMary Jeanne Kreek, M.D. – Professor and Head
2003
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-RR00102GCRC – The Rockefeller University Hospital