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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.

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Presentation on theme: "Long Acting Opioids: Challenges in Pharmacotherapy Mary Jeanne Kreek, M.D. The Laboratory of the Biology of Addictive Diseases The Rockefeller University."— Presentation transcript:

1 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

2 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

3 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

4 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*

5 National Household Survey and Related Surveys – 1996 – 1999 Alcohol Use – ever~177 million Alcoholism~15 million Cocaine Use – ever~26 million Cocaine Addiction~1 to 2 million Heroin Use – ever~2.5 to 3 million Heroin Addiction~0.5 to 1 million Development of Addiction After Self Exposure Alcoholism~1 in 10 to 1 in 20 Cocaine Addiction~1 in 10 to 1 in 20 Heroin Addiction~1 in 3 to 1 in 5 Prevalence of Specific Drug Abuse and Vulnerability to Develop Addictions NIDA, SAMHSA Reports

6 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

7 Opioid ClassesOpioid Receptor Types EndorphinsMu EnkephalinsDelta DynorphinsKappa Endomorphins (?) Endogenous Opioids and Their Receptors Kreek, 2001

8 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 H2NH2N S S 

9 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. Hypothesis (1963–1964) Dole, Nyswander and Kreek, 1966

10 Heroin Addiction: Functional State of a Typical Addict "High" "Straight" "Sick" Days AMPMAMPMAM Functional State Dole, Nyswander and Kreek, 1966 (overdose) (arrows indicate times of injection)

11 Goals and Rationale for Specific Pharmacotherapy for an Addiction 1.Prevent withdrawal symptoms 2.Reduce drug craving 3.Normalize any physiological functions disrupted by drug use 4.Target treatment agent to specific site of action, receptor, or physiological system affected or deranged by drug of abuse Kreek, 1978; 1991; 1992; 2001

12 Characteristics of an Effective Pharmacotherapeutic 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

13 Met had one /Mo rphi ne/ Her oin Che mic al Stru ctur e Kreek Lectures: 1967 onward

14 Methadone Maintenance: Functional State of a Former Addict Treated With Methadone Maintenance Functional State Dole, Nyswander and Kreek "High" "Straight" "Sick" AMPMAMPMAM 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.” MM H

15 HeroinMethadone Route of administrationintravenousoral Onset of actionimmediate30 minutes Duration of action3–6 hrs24–36 hrs Euphoriafirst 1–2 hrsnone Withdrawal symptomsafter 3–4 hrsafter 24 hrs Heroin versus Methadone* *effects of high dosages in tolerant individuals Kreek, 1973; 1976; 1987

16 Plasma Methadone Levels in an Individual Maintained on 100 mg/day Plasma levels (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 246824

17 Opioid Agonist Pharmacokinetics: Heroin Versus Methadone CompoundSystemicApparentMajor BioavailabilityPlasma TerminalRoute of After OralHalf-lifeBiotrans- Administration(t Beta) formation HeroinLimited3 mSuccessive (<30%)(30 m for activedeacetylation 6-actyl-morphineand morphine metabolite)glucuronidation (4-6 for active morphine metabolite) MethadoneEssentially24 hN-demethylation Complete(48 h for (>70%)active l-enantiomer) Kreek et al., 1973; 1976; 1977; 1979; 1982; Inturrisi, 1984 1/21/2

18 116.25 82.50 48.75 [ 18 F] Cyclofoxy (a Selective Opioid Antagonist) Binding in Human Brain: Normal Volunteer PET Study - NIH

19 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 0102030405060708090 n=12 Time (min) Plasma Methadone Levels (ng/ml)

20 Specific Binding of [ 18 F] 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 ThiAmyCaudInsACgPutMTMFrParCrbITHipWMt Region of Interest Specific Binding (ml plasma/ml tissue) Kling et al., 2000 * * * * * normal volunteers n=14 MTP volunteers n=14

21 Methadone Maintenance Treatment Allows Normalization of 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

22 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

23 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. Reinforcing or “Reward” Effects of Drugs of Abuse Kreek, 1987; 2001

24 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” Relationship Between Blood (and Brain) Levels of Drugs of Abuse and Their Effects on Events Related to Addictions Kreek, 1978; 1991, 1992; 2001

25 Disruption versus Normalization levels of gene expression receptor mediated events physiology behaviors “On-Off” versus “Steady-State” Kreek, 1987; 2001

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

27 Buprenorphine Hydrochloride* HO O N CH 3 O HO CH 3 C(CH 3 ) 3 HCl *Buprenex

28 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

29 Methadone Maintenance50 – 80% LAAM Maintenance50 – 80% Buprenorphine-Naloxone Maintenance 40 – 50%** Naltrexone Maintenance10 – 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

30 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

31 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

32 Oxycodone Hydrochloride* H 3 CO O O OH N H - Cl - CH 3 *OxyContin

33 Hydromorphone Hydrochloride HCl CH 2 CH 3 H H OH O O N

34 Fentanyl CH 3 CH 2 CONCH 2 N

35 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)* 2.7h12h 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)* 2.6h12h duration 3) Morphine (q 4h) (multiple) e.g., MSContin ® e.g., Kadian Reg ® (q 12h) (15, 30, 60, 100, 200mg)* 2 to 4h12h duration 4) Fentanyle.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.”

36 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

37 * All disrupted by chronic abuse of the short acting opiate, heroin Role of Mu Opioid Receptor and Related Endorphin Systems 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

38 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: 5%high or frequent M.J. Kreek, 2000

39 VariantExonProteinCorrespondingAllele (nucleotide position)locationdomainamino acid changefrequency A118G1N-terminusAsn 4 Asp (N40D)10.5% (26 heterozygous; 3 homozygous) C17T1N-terminusAla 6 Val (A6V)6.6% (14 heterozygous; 3 homozygous) G24A1N-terminusSynonymous2% mutation(6 heterozygous) G779A3CL3Arg 260 His (R260H)<1% (1 heterozygous) G942A3EL3Synonymous<1% mutation(1 heterozygous) Single Nucleotide Polymorphisms in Human Mu Opioid Receptor Gene * Nucleotide position 1 is first base of the start codon. Bond et al., 1998

40 Allelic Frequency Associations Opioid Dependence – C17T and A118G 2 2 (1) 2 2 2 *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

41 Human MOR Gene SNPs SNPvs with changed AA Synonymous mutation Putative Glycosylation site extracellular fluid cell interior cell membrane HOOC 400 100 H2NH2N 50 S4RA6V N40D V234L 350 300 250 200 150 S147C N152D R260H R265P S268P Kreek, Yuferov and LaForge, 2000

42 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 20 Percent Bound 0 1.0 0.5 Fraction Maximum Current Response 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 A118G Prototype Bond et al., 1998 1.0 0.5 0 -9-8-7-6 Log [Endomorphin -1(M)] Log [  Endorphin (M)]

43 24 22 20 18 16 14 12 10 8 50 0 100150200 Time (min) Serum Cortisol (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

44 240 “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 ACTH (pg/ml) 0306090120150180240 30 20 10 0 40 50 Naltrexone Placebo 60 FH+ Time (min) Post Capsule ACTH (pg/ml) 0306090120150180240 30 20 10 0 40 50 Naltrexone Placebo 60 FH- Naltrexone Time (min) Post Capsule Cortisol (µg/dl) 0306090120150180240 0 15 10 5 20 25 Placebo FH+ Time (min) Post Capsule Cortisol (µg/dl) 0306090120150180 0 15 10 5 20 25 Naltrexone Placebo FH-

45 Pharmacogenetics: Mu Opioid Receptor A118G Polymorphism— Naltrexone Treatment Response 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) *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

46 “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 0.0 0142842567084 Cumulative Survival (Time to Relapse) 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

47 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 adapted from K.S. LaForge, 2003

48 Ethnicity orBergen et al.Bond et al.Gelernter et al.Szeto et alTan et alBart et al population (1997)(1998)(1999)(2001)(2003)(2003) Asian Japanese0.485 (34) Han Chinese0.362 (297) Chinese 0.351 (208) Thai 0.438 (56) Malay0.446 (156) Indian0.442 (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) Hispanic0.142 (67) 0.117 (47) African American0.016 (31) 0.028 (144) Other (populations in Israel) Ethiopian0.170 (49) Bedouin0.080 (43) Ashkenazi0.210 (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, Yuferov and Kreek, 2003

49 Human Gene Diversity – SNPs and Other Polymorphisms in Coding Region of Opioid Receptor Genes # Polymorphisms Identified by our Laboratory* # of Additional Polymorphisms GeneTotal # Mu opioid receptor11617 Kappa opioid receptor819 Delta opioid receptor 022 *Without or with prior identification or later verification by other groups LaForge, Yuferov and Kreek, 2000; LaForge and Kreek, 2002

50 Laboratory ScientistsClinical ScientistsAdministrative Staff Ann HoGavin Bart Kitt Lavoie K. Steven LaForgeLisa BorgJanesse Rojas Eduardo ButelmanScott Kellogg Susan Russo Vadim YuferovCharles Lilly David Nielsen Assistants for Research Yan Zhou Clinical Adjunct Scientists Jonathan 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 SvingosLynette Benjamin Todd Harris Yong Zhang Elizabeth Khuri Lauren Hofmann Aaron Wells Elizabeth Oosterhuis Laboratory Adjunct Scientists Charles Inturrisi Research Nurses Laboratory Worker Roberto Picetti Kathy Bell Laura Nunez Virginia Pickel Elizabeth Ducat Ellen Unterwald Dorothy Melia Vanya Quinones-Jenab The Laboratory of the Biology of Addictive Diseases Mary Jeanne Kreek, M.D. – Professor and Head 2003

51 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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