50 Years of INRC: 1969 to 2019 – 55 Years of our Rockefeller University Research and 50 to 60 Years of Opioid Research Mary Jeanne Kreek, M.D. Patrick E. and Beatrice M. Haggerty Professor Head of Laboratory The Laboratory of the Biology of Addictive Diseases The Rockefeller University Senior Physician, The Rockefeller University Hospital International Narcotics Research Conference July 8, 2019 New York, NY Funded primarily by Dr. Miriam and Sheldon Adelson Medical Research Foundation, NIH-NIDA, NIH-NIAAA, NIH-CRR, Tri-Institutional Therapeutics Discovery Institute, Robertson Therapeutic Development Fund, and others International Narcotics Research Conference Founders Lecturers (First Awardee 1999) 1999 Eric J. Simon 2009 R. Alan North 2000 Brian M. Cox 2010 Masamichi Satoh 2001 Philip S. Portoghese 2011 Charles Chavkin 2002 Lars Terenius 2012 F. Ivy Carroll 2003 Bernard Roques 2013 Graeme Henderson 2004 Ji-Sheng Han 2014 Christopher Evans 2005 Mary Jeanne Kreek Brigitte Kieffer 2006 Huda Akil 2015 Gavril Pasternak (d. 2019) Stan Watson 2016 Lakshmi Devi 2007 Volker Hoellt 2017 John Traynor Horace Loh 2018 Macdonald Christie 2008 Jan van Ree 2019 Sol Snyder Kreek 2019 International Narcotics Research Conference Founders Lecturers at this 50th Anniversary Meeting 1999 Eric J. Simon 2009 R. Alan North 2000 Brian M. Cox 2010 Masamichi Satoh 2001 Philip S. Portoghese 2011 Charles Chavkin 2002 Lars Terenius 2012 F. Ivy Carroll 2003 Bernard Roques 2013 Graeme Henderson 2004 Ji-Sheng Han 2014 Christopher Evans 2005 Mary Jeanne Kreek Brigitte Kieffer 2006 Huda Akil 2015 Gavril Pasternak (d. 2019) Stan Watson 2016 Lakshmi Devi 2007 Volker Hoellt 2017 John Traynor Horace Loh 2018 Macdonald Christie 2008 Jan van Ree 2019 Sol Snyder Kreek 2019 Ji-Sheng Han cannot attend this 50th Anniversary meeting because of a family illness and sends his regards, along with this photo of him with his family. Ivy Carroll and Bernard Roques are unable to attend this year because of illness. Brigitte Kieffer and Huda Akil could not attend because of university business. All send their regards! Kreek 2019 Early Opioid Research of Martin (US) and Collier (UK) – 1961 Hypothesis and experimental evidence of the development of tolerance to and dependence on opiates with chronic exposure (heroin, morphine, methadone, other) Martin, W.R., Frasier, H.F. A comparative study of physiological and subjective effects of heroin and morphine administered intravenously in postaddicts. JPET, 133:388-99. (1961) Collier, H.O., Warner, B.T., Skerry, R. Multiple toe-pinch method for testing analgesic drugs. Br J Pharmacol Chemother. 17:28-40. (1961) (in rodents) Frasier, H.F., Van Horn, G.D., Martin, W.R., Wolbach, A.B., Isbell, H. Methods for evaluating addiction liability. (A) “Attitude” of opiate addicts toward opiate-like drugs. (B) a short-term “direct” addiction test. JPET, 133:371-87. (1961) Martin, W.R., Eades, C.G. Demonstration of tolerance and physical dependence in the dog following short-term infusion of morphine. JPET, 133:262-70. (1961) Kreek 2019 55th Anniversary of the Beginning of Our Rockefeller Institute (now University) Research: 1963-1964 Treatment of Heroin Addiction: Identification of Need, Formulation of Hypothesis, Basic Clinical and Related Laboratory Research, Translational Research, and Evaluations Autumn Vincent P. Dole, Jr., MD recruitment of two new staff 1963 members to his Laboratory of Physiology and Metabolism at The Rockefeller Institute for Medical Research: 1) Marie Nyswander, MD – psychiatrist, years of work with heroin addicts in New York City and Lexington, KY. Author of book The Addict as a Patient. 2) Mary Jeanne Kreek, MD – second year Resident in (Internal) Medicine (“PGY-2”) at Cornell-New York Hospital with experience in clinical and laboratory based research at NIH and Columbia P&S. January – New team formed and first patients admitted to the July 1964 Rockefeller Hospital; initial research on potential novel pharmacological treatment of heroin addiction, accomplished by July 1964. Kreek 2019 Development of Methadone Maintenance Treatment – 1964-1966 1964 HYPOTHESIS –NOW EVIDENCE-BASED FACT: 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. First publications describing methadone maintenance treatment research 1) 1964: Initial clinical research on development of treatment using methadone maintenance pharmacotherapy and on elucidating mechanisms of efficacy performed at The Rockefeller Hospital of The Rockefeller Institute for Medical Research: 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) 2) 1965: Translational applied clinical research performed at Manhattan General Hospital: Dole, V.P. and Nyswander, M.E.: A medical treatment for diacetylmorphine (heroin) addiction. JAMA, 193:646-650, 1965. Kreek 2019 Impact of Short-Acting Heroin versus Long-Acting Methadone Administered on a Chronic Basis in Humans (1964 through 1973 Studies): Opioid Agonist Pharmacokinetics – Heroin Versus Methadone “On-Off” Apparent Plasma Terminal "High" Drug or Half-life and Duration of Medication Desired Effects HEROIN 3 min for prodrug "Straight" 30 min for active (Heroin) "Sick" compound, mono-acetyl morphine (fast on-set and Functional Functional State AM PM AM PM AM off-set) Days “Steady State” 6 hours for active metabolites (morphine "High" and others) METHADONE 24h for racemic (rs) "Straight" medication (slow on-set and off-set – steady-state (Methadone) achieved) Functional Functional State "Sick" 48h for active (r) AM PM AM PM AM enantiomer Days H Dole, Nyswander and Kreek, 1966; Kreek et al., 1973; 2019 1973 Kreek, New York State Journal of Medicine, Vol. 73, No. 23, December 1, 1973 “On-Off” versus “Steady-State”: Relationship Between Blood (and Brain) Levels of Drugs of Abuse and Their Effects Disruption versus Normalization • levels of gene expression • receptor mediated events • physiology • behaviors 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, 1973 on, 2019 1965-1968: Early Expansion of Methadone Maintenance Treatment 1964-1967 – Initially all patients admitted as active or recently abstinent heroin addicts to the Rockefeller Hospital, unlocked research ward for inpatient induction into methadone maintenance treatment (minimum 6- 8 weeks). Follow-up in Rockefeller Hospital Outpatient Department. 1965-1966 – Replication of methadone maintenance treatment research model in an inpatient unit of the Manhattan General Hospital, a fee-for- service proprietary hospital (later to become the Bernstein Institute of Beth Israel Hospital), which had been engaged in 10-14 day detoxification “treatment” for opiates (“revolving door”). 1967-1968 – Introduction of outpatient induction into methadone maintenance treatment (at the Rockefeller Hospital clinic, Dr. MJ Kreek). Kreek 2019 Prospective studies of first 214 patients admitted to methadone maintenance research and treatment (January 1964 – July 1966, and followed-up for three years or more) and Retrospective Study of 1435 methadone maintenance patients. 1973 1967-1973: Further Expansion of Methadone Maintenance Treatment and FDA Approval 1967-1972 – Development of multiple satellite outpatient methadone maintenance treatment programs at Harlem, Beth Israel, St. Luke’s, Roosevelt, and Einstein Hospitals in New York City (Dole, Nyswander, Kreek, Lowinson, et al.). 1967-1972 – First replication of methadone maintenance program outside of New York City – Department of Psychiatry, University of Uppsala, Uppsala, Sweden (Dr. Lars Gunne and later Drs. Leif Grönbladh and Olof Blix). 1969-1973 – Opening of the “Adolescent Development Program” (self- administration for > three years in age 15-21) (Elizabeth Khuri and Robert Millman) and “Adult Program” (Aaron Wells) at New York Hospital- Cornell Medical Center. 1973 – Approval by US-FDA of long-term moderate to high dose methadone maintenance treatment for opiate addiction. Kreek 2019 Synthesis and Early Studies of Mu Opioid Receptor Antagonists Naloxone, and Subsequently Naltrexone and Nalmefene: Use in Reversal of Opiate Overdose and Later Treatment of Addictive Diseases (1967 onward) In 1967, Dr. Jack Fishman, a chemist and endocrinologist working with several institutions in New York City, visited with one of his former medical students (MJK) for lunch at The Rockefeller University. At that lunch, he shared that he had synthesized a new compound hoping that it would be a “non-addicting pain medication,” but in fact it did not relieve pain, instead it reversed the effect of short-acting opiate agonists such as heroin and morphine. “Would there be a clinical use for such a compound?” (JF) That compound was naloxone (Narcan™), which is now used world over for the reversal of opiate overdose, as well as planned narcotic effects during surgery and related procedures. Dr. Fishman also synthesized and assisted in the development of nalmefene and naltrexone. Naltrexone was studied and subsequently FDA