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Mary Jeanne Kreek, M.D. Professor and Head The Laboratory of the Biology of Addictive Diseases

40 th 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 Diseases The Rockefeller University Senior Physician

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Mary Jeanne Kreek, M.D. Professor and Head The Laboratory of the Biology of Addictive Diseases

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  1. 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 Diseases The Rockefeller University Senior Physician The Rockefeller University Hospital October 19, 2004 American Association for the Treatmentof Opioid Dependence Orlando, FL funded primarily by NIH-NIDA, NIHCRR and NYS OASAS

  2. 40th Anniversary of the Development of Methadone Maintenance Treatment –1964-2004 Initial 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

  3. 40th Anniversary of the Development of Methadone Maintenance Treatment –1964-2004 First publications describing methadone maintenance treatment research 1) Initial clinical research on mechanisms and treatment using methadone maintenance pharmacotherapyperformed 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. (also recorded in the Association of American Physicians meeting transcription of discussion) 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. 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

  4. 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

  5. Impact of Short-Acting Heroin versusLong-Acting Methadone Administered ona Chronic Basis in Humans - 1964 Study "High" Functional State(Heroin) (overdose) Functional State(Heroin) "Straight" "Sick" AM PM AM PM AM Days "High" Functional State(Methadone) "Straight" "Sick" AM PM AM H PM AM Dole, Nyswander and Kreek, 1966 Days

  6. 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 et al, 1973; 1984

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

  8. Methadone Maintenance Treatment for Opiate (Heroin) Addiction 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) Kreek, 1972; 1973; 2001; 2002, 2004; Inturrisi et al, in progress; Evans et al; in progress

  9. Opiate Addiction Treatment Outcome* 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% * 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

  10. Clinics/Treatment Programs Diagram Kreek, 1983; 1984; 1991; 2001

  11. 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”: • Provisions for “take home” medication have been extended to 31 days. • Participating office-based physicians will maintain formal relationships with OTPs and patients will be referred to the office-based physicians from the OTPs • Authoriations for this treatment model can be obtained from SAMHSA. Reviewed in Kreek & Vocci, J Sub Abuse Treatment, 2002

  12. Identification of HIV-1 Infection andChanging Prevalence in Drug UsersNew York City: 1978 – 1992; 1983 - 1984 Study 100 Percent of IV Drug Users Infected with HIV-1 75 % 50 25 0 1978 1979 1980 1981 1982 1983 1984 1985 1986 1987 1992 Kreek et al., 1984; Des Jarlais et al., 1984; 1989

  13. Prevalence of HIV-1 (AIDS Virus)Infection in Intravenous Drug UsersNew York City: 1983 - 1984 Study: Protective Effect of Methadone Maintenance Treatment 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 Kreek , 1984; Des Jarlais et al., 1984; 1989

  14. 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 • stress-responsivity • neurochemistry •synaptogenesis • behaviors • mRNA levels • peptides • proteomics Drug-Induced Effects(very high) Kreek et al., 2000; 2004

  15. OpioidReceptorTypes Mu Delta Kappa Opioid Classes Endorphins Enkephalins Dynorphins Endomorphins (?)    H2N S Extracellular fluid AA identical in 3 receptors S AA identical in 2 receptors AA different in 3 receptors cell membrane cell interior HOOC Endogenous Opioidsand their Receptors LaForge, Yuferov and Kreek, 2000

  16. Primary Site(s) of Major Drugs of Abuse 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 Kreek, 1978, 1987, 2001

  17. 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. Hypothesis — Atypical Responsivity to Stressors: A Possible Etiology of Addictions Kreek, 1972; 1987; 1992; 2001

  18. Hypothalamic-Pituitary-Adrenal Axis and the Endogenous Opioid System Have Interrelated Roles in the Biology of Addictive Diseases hypothalamus CRF anterior pituitary POMC b-End Endogenous Opioids (mu, kappa; delta ?) Cortisol ACTH adrenal Kreek et al., 1981; 1982; 1984; 1992; 2001

  19. Neuroendocrine Effects of Opiates, Cocaine, and Alcohol in Humans: Hormones Involved in HPA Axis Stress Response • 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) Suppression of HPA Axis Activation of HPA AxisNormalization of HPA Axis HPA – Hypothalamic-pituitary-adrenal axis (involved in stress response) Kreek, 1972; 1973; 1987; 1992; 2001

  20. 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

  21. [18F] Cyclofoxy (a Selective Opioid Antagonist) Binding in Human Brain: Normal Volunteer PET Study - NIH 116.25 82.50 48.75 Eckelman, Rice and the NIH PET group, 2000

  22. 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 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

  23. 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 Thl Amy Caud Ins ACg Put MT MFr Par Crb IT Hip WMt Region of Interest Kling et al., 2000

  24. Hypothesis: Genetic Variabilityand the Opioid System 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. LaForge, Yuferov and Kreek, 2000

  25. 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

  26. 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 Single Nucleotide Polymorphisms (SNPs) in Genes: Definitions Kreek (Rockefeller University) & Hassin (Columbia P&S), 2004

  27. Single Nucleotide Polymorphisms inCoding Region of Human Mu Opioid Receptor Gene with Allelic Frequency > 1% 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) * Nucleotide position 1 is first base of the start codon. Bond et al., 1998

  28. Human Mu Opioid Receptor Gene SNPs S4R A6V H2N N40D Synonymous mutation 50 Putative Glycosylation site extracellular fluid SNPvs with changed AA V234L S147C 300 N152D 150 200 250 cell membrane R260H R265P 350 100 cell interior S268P 400 HOOC Kreek, Yuferov and LaForge, 2000

  29. 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

  30. 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 0 30 60 90 120 150 180 240 Time (min) Post Capsule Time (min) Post Capsule King et al, 2002

  31. 24 1.0 N N A/A (n=29) 22 0.9 A/G (n=7) Naltrexone/ Asp40 Allele (A/G, G/G) (n=23) 20 0.8 18 Serum Cortisol (ug/dl) 0.7 N 16 Naltrexone/ Asn40 Allele (A/A) (n=48) 0.6 14 PI Placebo/ Asp40 Allele (A/G, G/G) (n=18) 0.5 12 N 10 Placebo/ Asn40 Allele (A/A) (n=41) 0.4 Cumulative Survival (Time to Relapse) 8 0.3 0 50 100 150 200 50 Time(min) 0.2 0.1 0.0 0 14 28 42 56 70 84 Days Physiogenetics and Pharmacogenetics Related to A118G Variant of Human Mu Opioid Receptor Gene

  32. Association Between a Functional Polymorphism in the mu Opioid Receptor Gene and Opiate Dependence in Central Sweden Thus, in the entire study group in this central Swedish population: Attributable Risk due to genotypes with a G allele in this population: 18%(with confidence interval ranges from 8.0 to 28.0%) Bart G , Heilig M, LaForge KS… Ott J, Kreek MJ, et al., 2004

  33. Opioid System Polymporphisms in Relation to Specific Addictive Diseases Opioid Receptor Genes Opioid Peptide Genes Mu Opioid ReceptorDynorphin Kappa Opioid Receptor Enkephalin Kreek, 2003

  34. 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

  35. The Laboratory of the Biology of Addictive DiseasesMary Jeanne Kreek, M.D. – Professor and Head2004 Laboratory Scientists Ann Ho K. Steven LaForge Eduardo Butelman Vadim Yuferov David Nielsen Yan Zhou Alexis Bailey Dmitri Proudnikov Brian Reed Stefan Schlussman Yong Zhang Clinical Scientists Gavin Bart Lisa Borg Heather Hofflich Scott Kellogg Charles Lilly Assistants for Research Johannes Adomako Julie Allen Lauren Bence Jason Choi Nicole Dankert Matthew Swift Clinical Adjunct Scientists Miriam Ochshorn Adelson James Kocsis Elizabeth Khuri Administrative Staff Kitt Lavoie Janesse Rojas Susan Russo Laboratory Adjunct Scientists Charles Inturrisi Roberto Picetti Virginia Pickel Ellen Unterwald Research Nurses Kathy Bell Elizabeth Ducat Dorothy Melia Laboratory Worker Laura Nunez The Laboratory of Statistical Genetics, Jurg Ott, Ph.D.– Professor and Head Jurg Ott, Suzanne Leal, Derek Gordon

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