The Modern Science of Addiction Mary Jeanne Kreek, M.D. Patrick E. and Beatrice M. Haggerty Professor Head of Laboratory The Laboratory of the Biology of Addictive Diseases The Senior Physician, The Rockefeller University Hospital

Science Board – Food and Drug Administration Silver Spring, Maryland March 1, 2016

Funded primarily by NIH-NIDA (P50-05130), The Adelson Medical Research Foundation, NIH-NCRR (RUH – Dr B. Coller) Prevalence of Drug Abuse in United States and Vulnerability to Develop Addictions National Household Survey and Related Surveys – 2007 – 2013 Alcohol Use – ever ~ 260 million Alcoholism ~ 16.5 million

Marijuana Use – ever ~ 104 million Marijuana Daily Use ~ 5.7 million

Cocaine Use – ever ~ 45.6 million Cocaine Addiction ~ 2 to 3 million

Heroin Use – ever ~ 5.7 million Addiction ~ 1 million

Illicit Use of Opiate Medication – ever ~ 37.1 million (i.e., 14.2% of the population 12 and over)* Development of Addiction After Self Exposure (meta-analyses) Alcoholism, Cocaine, Marijuana Addictions ~ 1 in 8 to 1 in 15 Heroin Addiction ~ 1 in 3 to 1 in 5 * 2007 National Survey on Drug Use and Health SAMHSA National Survey on Drug Use and Health, 2012; NIDA Monitoring the Future 2014; Others, 2007-2016 Number of Unintentional Drug Overdose Deaths Involving Prescription Opiates, Heroin, and Cocaine (United States, 1999-2007) and Rate of Heroin Overdose Deaths (2002-13)

More than 3 people die every hour in the United States from illicit opiate overdose (2014). (T Frieden, Center for Disease Control and Prevention, 2015)

1.9 people die every day from heroin overdoses in . (NYC Dept of Health – 2013) 47,000 persons (15 per 100,000) in the United States died of overdose deaths in 2014. 23.5 million persons aged 12 and older needed treatment for an illicit drug or alcohol abuse problem. Only 2.6 million received treatment at a specialized facility. (SAMHSA 2009) National Vital Statistics System; MMWR 61:1, 2012; CDC Vitalsigns (online), July 7, 2015 PREVENT Reduce prescription opioid painkiller abuse. People From Improve opioid painkiller prescribing practices Starting Heroin and identify high-risk individuals early:

Ensure access to Medication-Assisted Treatment (MAn. REDUCE Treat people addicted to heroin or prescription opioid painkillers with MAT which combines the Heroin Addiction use of medications {, buprenorphine, or naltrexone) with counseling and behavioral therapies.

Expand the use of naloxone. REVERSE Use naloxone, a life-saving drug that can reverse the effects of an opioid overdose when administered Heroin Overdose in time.

CDC Vitalsigns (online), July 7, 2015 Factors Contributing to Vulnerability to Develop a Specific Addiction

use of the drug of abuse essential (100%)

Genetic Environmental (40-80%) (very high) • DNA • prenatal • SNPs • postnatal • other • epigenetics polymorphisms • peer pressure • cues • comorbidity (psychiatric) • stress-responsivity

• mRNA levels • neurochemistry • peptides • synaptogenesis • proteomics Drug-Induced Effects • neuroneogenesis (very high) • behaviors Kreek et al., 2000; 2005; 2016 Natural History of Drug and Alcohol Abuse and Addictions

60%-90% without Primary Possible Utility of Vaccines Medications Useful pharmacotherapy Prevention and Selected Medications and Needed relapse to addiction

Initial Use of Sporadic Regular Addiction Early Protracted Drug of Abuse Intermittent Use Withdrawal Abstinence Use (abstinence)

Progression 10%-40% sustain ADDICTION: Compulsive drug seeking behavior abstinence with no and drug self-administration, without regard to specific medications negative consequences to self or others (adapted from WHO). Adapted from Kreek et al., Nature Reviews Drug Discovery, 1:710, 2002; 2016 50th Anniversary of First Research Paper on Developing Methadone Maintenance Treatment HYPOTHESIS: 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. Vincent P. Dole, Jr., MD; Marie Nyswander, MD; and Mary Jeanne Kreek, MD

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: First research paper describing methadone maintenance treatment research Dole, V.P., Nyswander, M.E. and Kreek, M.J.: Narcotic blockade: a medical technique for stopping heroin use by addicts. Transactions of the Association of American Physicians (May 1966), 79:122-136, 1966. (including discussion)

Dole, V.P., Nyswander, M.E. and Kreek, M.J.: Narcotic blockade. Arch. Intern. Med., 118:304-309, 1966. Dole, Nyswander and Kreek, 1966, 2006, 2016 Impact of Short-Acting Heroin versus Long-Acting Methadone Administered on a Chronic Basis in Humans – 1964 through 1978 Studies: Opioid Agonist Pharmacokinetics – Heroin Versus Methadone Systemic Bioavailability Apparent Plasma Major Route After Oral Terminal Half-life of Biotrans- Administration formation (t1/2 Beta)

Limited 3min Successive "High" (<30%) (30min for active deacetylation 6 --acetyl and morphine metabolite; glucuronidation "Straight" 4 -6h for morphine and active

(Heroin) morphine --6 "Sick" glucuronide

Functional State metabolite) AM PM AM PM AM Days

"High" Essentially 24h N- demethylation Complete (48h for active "Straight" (>70%) [R](l) -enantiomer) (Methadone) "Sick" Functional State

AM PM AM PM AM Days H Dole, Nyswander and Kreek, 1966; Kreek et al., 1973; 1976; 1977; 1979; 1982; Inturrisi et al, 1973; 1984

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

Characteristics of an Effective Pharmacotherapeutic Agent for Treatment of an Addictive Disease

1. Orally effective 2. Slow onset of action 3. Long duration of action 4. Slow offset of action

Kreek, 1978; 1991; 1992; 2001

Methadone Maintenance Treatment for Opiate (Heroin) Addiction – 2016

Number of patients currently in treatment: ~ 1.3 million worldwide

 USA: ~ 330,000  Europe: ~ 600,000  Rest of world: ~400,000 Efficacy in “good” methadone 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 medication (24h half-life for racemate in humans) provides steady levels of opioid at specific receptor sites. • methadone found to be a full mu opioid receptor agonist which internalizes like endorphins (beta-endorphin and enkephalins) • methadone also has modest NMDA receptor complex antagonism Kreek, 1972; 1973; 2016 Status of Methadone, Buprenorphine, and Extended Release Naltrexone Treatments in the United States – 2013 (SAMHSA, 2015)

Methadone Maintenance Treatment Facilities 1,282 Patients 330,308

Buprenorphine Maintenance Treatment Facilities 3,113 Patients 48,148

Extended Release Naltrexone Treatment Facilities 1,718 Patients 3,781

Source: Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration. National Survey of Substance Abuse Treatment Services (N- SSATS), 2003 -2014 Communication from: Cathie E. Alderks, PhD, Federal Project Officer, Behavioral Health Services Information System, Center for Behavioral Health Statistics and Quality, SAMHSA, 2015 Limited Targeted Pharmacotherapies Available for Specific Addictive Diseases I. Opiate Addiction (Heroin and Illicit Use of Opiates) a. METHADONE (50-80%)** b. BUPRENORPHINE (+ NALOXONE) (40-50%)* [c. NALTREXONE / SUSTAINED RELEASE NALTREXONE (<15%)*]

II. Alcoholism a. NALTREXONE (30-40%)* b. NALMEFENE (approved in Europe only, 2012) c. ACAMPROSATE (low in USA)

III. Nicotine Addiction (Primarily Tobacco Smoking) a. NICOTINE – DIVERSE DELIVERY SYSTEMS (?) b. BUPROPRION (?) c. VARENICLINE (?)

IV. Cocaine, Amphetamines and Other Stimulants NONE

(%) is % of unselected persons with specific addictions who can be retained voluntarily in treatment for 3 months (*) or 12 months (**), with success in eliminating specific drug use. Kreek, 2016 Targets of Currently Approved Treatments for Addictive Disorders

Kreek et al, Journal of Clinical Investigation, 12: 3387, 2012 Development of an Addiction: Neurobiology

• Drugs alter normal brain networks and chemicals

• “Rewarding” or “pleasurable” effects of drugs (the so-called “reinforcing effects”) involve: – Dopamine – Endorphins (acting at Mu Opioid Receptors)

• “Countermodulatory” response to reward involves: – Dynorphins (acting at Kappa Opioid Receptors)

Bidirectional-Translational Research: Novel and Conventional Animal Models to Mimic Human Patterns of Abuse • “Binge” Pattern Cocaine Parenteral Administration Model: Constant or Ascending Dose (mimics most common pattern of human use in addiction)

• Intermittent Heroin (Morphine) Parenteral Administration Model: Constant or Ascending Dose (mimics most common pattern of human use in addiction)

• “Binge” Pattern Oral Ethanol Administration Model: (mimics common pattern of human excessive use)

• Intravenous Pump Methadone Administration Model: (converts short-acting pharmacokinetic properties of opioid agonist in rodent to long-acting human pharmacokinetic profile)

• Intravenous Self-Administration (Mouse) Without or With High-Dose (also, extended access 4 h)

• Extended Access (10 or 18 hours) Intravenous Self-Administration (Rat) with Individual Selection of Dose Escalation

Kreek et al., 1987; 1992; 2001; 2005; 2015 REWARD – DOPAMINE: Attenuated Basal and Cocaine-Induced Increases in Extracellular Dopamine Levels in Nucleus Accumbens After Chronic “Binge” Pattern Cocaine (Microdialysis); Also Locomotor Activity Study in C57BL/6J and 129/J Mice

C57BL/6J 129/J Acute (1 day) 1.6 1.6 Chronic (13 day)

1.4 1.4

1.2 1.2 1.0 1.0 0.8 0.8 0.6 0.6 Levels (nM) Levels Levels (nM) Levels 0.4 0.4

Extracellular Dopamine Extracellular 0.2 0.2 0.0 Dopamine Extracellular 0.0

Saline 500500 Saline 500500 C57BL/6J 129/J Day 13 Cocaine Day 13 Cocaine

(15mg/kg x3) 400400 400400 (15mg/kg x3)

300300 300300 min Bin min Bin

200200 200200 Total Locomotor Total Total Locomotor Total - Counts/6 100100 100100 - Counts/6

00 00

Zhang et al., Synapse, 50:191, 2003 2003; Schlussman et al., Pharmacol. Biochem. Behav., 75:123, 2003 REWARD — MU OPIOID RECEPTOR-ENDORPHIN SYSTEM: Chronic Cocaine in Rat Increases Mu Opioid Receptor Gene Expression Density, But With No Increase in Mu Endorphins: A Persistent Effect After Withdrawal

1.6 Saline 1 2 Cocaine (15 mg/kgx3x1 day) 1.4

* 1.2 * g total RNA µ

1.0 Control Cocaine 0.8 3 4

0.6

* 0.4

0.2

AttomolesMOR mRNA / 0.0 Control Cocaine FCx NAc Amy CPu Hip Thal Hyp Brain Regions Yuferov et al., Brain Res. Bull., 48:109 1999 Unterwald et al., Brain Res., 584:314 1 Saline Cocaine fmol/mg Saline Cocaine (14d) Withdrawal Withdrawal (14d)

Bailey et al., Brain Res. Mol. Brain Res. 137:258 2005 REWARD — MU OPIOID RECEPTOR-ENDORPHIN SYSTEM: Mu Opioid Receptor Knock-Out Mice

• No morphine or other mu agonist analgesia • No heroin or morphine self-administration • No heroin or morphine induced conditioned place preference • Attenuated self-administration of cocaine • Attenuated self-administration of alcohol

[Different knock-out constructs and multiple research groups, including Kieffer, Uhl, Yu, Pintar, Loh, with, e.g., Maldonado, Pasternak, Hoellt, Roberts]

Reviewed in Kreek et al., Nature Reviews Drug Discovery, 1:710-726, 2002; 2010

COUNTERMODULATION – KAPPA OPIOID RECEPTOR­ DYNORPHIN SYSTEM: Cocaine Increases Kappa Opioid Receptor Density in Rat, But Kappa Opioid Receptor Directed “Dynorphins” Also Increase

7 1 2 Saline

14 day cocaine (15mg/kg x 3) 6

Control Cocaine 5

3 4

4

1

pg ppDyn mRNA pg ppDyn mRNA totalRNA / µg Control Cocaine 0 Caudate Putamen Nucleus Accumbens Dynorphin Acting at the Kappa Opioid Receptor Lowers Dopamine Levels and Prevents Surge After Cocaine

Spangler, Ho, Zhou, Maggos, Yuferov, and Kreek , Mol. Brain Res., 38:71, 1996; Unterwald, Rubenfeld, and Kreek , NeuroReport, 5:1613, 1994 Acute Intermittent Morphine Increases Preprodynorphin and Kappa Opioid Receptor mRNA Levels in the Rat Brain

ppDyn mRNA KOR mRNA

*

200 200 *

150 150

100 100

% of Saline Control 50 % of Saline Control 50

0 0 Saline Morphine Saline Morphine

Saline Morphine 6.25 mg/kgx6x1 day Wang et al., 1999

Natural Dynorphin A1-17 Lowers Basal and Cocaine Induced Dopamine Levels in Mouse Striatum

10 10

8 8

6 6

4 4 Dopamine in Dopamine Dopamine in Dopamine (nM) Dialysate 2 (nM) Dialysate 2

0 0

Infusion 60 120 180 Infusion Injection60 120 180 20-min Sample 20-min Sample Dynorphin Dose (nmol) Infusion and Injection 0 2.0 Control 1.0 4.4 Cocaine (15mg/kg) 4.4+nBNI Dynorphin (4.4nmol) (antagonist) + Cocaine (15mg/kg)

Zhang, Butelman, Schlussman, Ho, and Kreek, Psychopharmacology, 172:422, 2004 Potential Biological Target Identified for Novel Pharmacotherapies (KOPr-Dynorphin System)

• Need: Compounds selective for this target KOPr (agonist, biased agonist, partial agonist, and antagonist).

• Major Clinical Concern with High Efficacy Kappa Agonist: Dysphoria; psychotomimesis

• Actual Concern of Research Clinician: None. Tolerance develops to psychotomimetic effects. One recent study showed little to no problems in persons with long term addictions.

• Potential Use in Treatments: Cocaine addiction; alcoholism; opiate addiction with concomitant cocaine or alcohol addiction Kreek 2016 STRESS RESPONSIVITY – Dissecting the Hypothalamic-Pituitary-Adrenal Axis in Humans: Selective Opioid Antagonist Testing

hypothalamus Arginine CRF Vasopressin anterior pituitary Endogenous + + Opioids POMC (mu – inhibition) (kappa – ? activation) β-End (↑)

Mu Opioid Receptor Cortisol (↑) Antagonists ACTH (↑)

adrenal +

Kreek, 1984; 1998; 2006; 2014 Heroin, Cocaine, and Alcohol Profoundly Alter Stress Responsive Hypothalamic-Pituitary-Adrenal (HPA) Axis: Normalization during methadone treatment

• Acute effects of opiates Suppression of HPA Axis • Chronic effects of short- (decrease levels of HPA acting opiates (e.g., heroin hormones) addiction)

• Opiate withdrawal effects * Activation of HPA Axis • Opioid antagonist effects (increase levels of HPA • Cocaine effects * Hormones) • Alcohol effects

• Chronic effects of long-acting opiate (e.g. methadone in Normalization of HPA Axis maintenance treatment) * Our challenge studies have shown that a relative and functional “endorphin deficiency” develops. Kreek, 1972; 1973; 1987; 1992 … 2008 Nalmefene (mu/kappa Directed) Causes Greater HPA Axis Activation Than Naloxone (mu Directed) in Normal Human Volunteers (n=23)

ACTH Cortisol

50 50

45 45

40 40 g/dL)

35 µ 35

30 30

25 25

ACTH (pg/ml) 20 20

15 15 Cortisol Levels (

10 10

0 10 20 30 40 50 60 75 90 120 150 180 240 0 10 20 30 40 50 60 75 90 120 150 180 240

Time after injection (min) Time after injection (min) 30 mg nalmefene 30 mg naloxone placebo (n= 23) 10 mg nalmefene 10 mg naloxone (n=10 for each antagonist condition) (mu and kappa opioid (mu opioid receptor receptor directed) directed)

Schluger, Ho, Borg, Porter, Maniar, Gunduz, Perret, King, and Kreek, Alcohol. Clin. Exp. Res., 22,1430, 1998 Genetic Variants of the Human Mu Opioid Receptor: Single Nucleotide Polymorphisms in the Coding Region Including the Functional A118G (N40D) Variant

HYPOTHESIS (C17T)

Gene variants: (A118G) • Alter physiology “PHYSIOGENETICS”

• Alter response to medications “PHARMACOGENETICS”

• Are associated with specific addictions

Bond, LaForge… Kreek, Yu, PNAS , 95:9608, 1998; Kreek, Yuferov and LaForge, 2000

FUNCTIONAL MOP-r (A118G) VARIANT – Binding and Coupling to G Protein-Activated, Inwardly Rectifying K+(GIRK) Channels by Beta-Endorphin at the Prototype A118A and A118G Variant of the Mu Opioid Receptor

100 A118G A118G

1.0 Prototype Prototype 80

60

0.5 40

20 Percent Bound Percent Fraction Maximum Current Response 0 0

-11 -10 -9 -8 -7 -9 -8 -7 -6 Log [β Endorphin (M)] Log [β Endorphin (M)]

Bond, LaForge… Kreek, Yu, PNAS , 95:9608, 1998; Kreek, Yuferov and LaForge, 2000

FUNCTIONAL MOP-r (A118G) VARIANT – “Physiogenetics” Related to A118G Variant of Human Mu Opioid Receptor Gene – Altered Stress Responsivity in Healthy Control Volunteers

P = Placebo N = Naloxone

2500 Cortisol 24 A/A (n=29) 22 A/G (n=7) N N 2000 P < 0.05 20 - AUC

1500 18 16 N 1000

14 P

500 40 19 12 I N 10 (no food for 9 hours) Cortisol Levels Levels Cortisol

0 Serum (ug/dl) Cortisol 8 (9:30am-10:30am (9:30am-10:30am + 90min) Prototype A118G 50 0 50 100 150 200

Time (min)

Bart et al. Neuropsychopharmacology, Wand et al., Neuropsychopharmacol, 26:106, 2002 31:2313-2317, 2006 Chong…Wand, Neuropsychopharmacology, 31:204, 2006 FUNCTIONAL MOP-r (A118G) VARIANT –“Pharmacogenetics” Related to A118G Variant of Human Mu Opioid Receptor Gene, Which Alters Stress Responsivity: Positive Predictor of Response to Naltrexone Treatment of Alcoholics

1.0

100 Placebo 0.9 Naltrexone hydrochoride

0.8 90 80 0.7 70 0.6 60 0.5 50 0.4 40 0.3 Naltrexone/ A/G, G/G (n=23) 30 n=126 n=115 n=35 n=31 Naltrexone/ A/A (n=48) 0.2 20 Placebo/ A/G, G/G (n=18) 10 0.1 Placebo/ A/A (n=41) With % Good Clinical Outcome 0.0 0 Cumulative Relapse) to Cumulative Survival (Time Asn40 Asp40 0 14 28 42 56 70 84 Days OPRM1 Genotype

Oslin et al., Neuropsychopharmacology, 28: 1546, 2003; Anton… Goldman et al., Arch Gen Pscyh, 65:135, 2008 Association Between a Functional Polymorphism in the mu Opioid Receptor Gene and Opiate Addiction and also Alcoholism in Central Sweden Opiate Dependent (n=139) Control (n=170) G/G; A/G 41 23 A/A 98 147 118G Allele Frequency 0.155 0.074 Thus, in the entire study group in this central Swedish population: Attributable Risk due to genotypes with a G allele: 18% (with confidence interval ranges from 8.0 to 28.0%) Bart G , Heilig M, LaForge KS… Ott J, Kreek MJ, et al., Molecular Psychiatry, 9:547-549, 2004

Alcohol Dependent (n=389) Control (n=170) G/G; A/G 90 23 A/A 299 147 118G Allele Frequency * 0.125 0.074 * Overall 118G Allele Frequency = 0.109 Thus, in the entire study group in this central Swedish population: Attributable Risk due to genotypes with a G allele: 11.1% (with confidence interval ranges from 3.6 to 18.0%)

Bart G , Kreek MJ, LaForge KS… Ott J, Heilig M, Neuropsychopharmacology, 30:417, 2005

Heroin Self-Administration (10 d; 4h/d) in Male and Female Wild-Type (A/A) and Genetically Modified A112G (G/G) Mice: A Model of the Human A118G Mu Opioid Receptor Functional Variant

40 10 40 10 M ales F em ale s 8 8 30 30

6 6 20 20 4 4 N o se p o kes o p se o N N o se p o kes o p se o N 10 A A (15) 10 A A (12) 2 2

GG (1 2 ) G G (12 ) )kg / g m A ( S n i o r e y H l ai D D ai l y H er o i n D o se ( m g / kg ) kg / g m se ( o n D i o er y H l ai D 0 0 0 0 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 D ay D ay

Zhang et al., Neuropsychopharmacology, 40:1091, 2015 Microdialysis in Striatum of Prototype A112A versus Genetically Modified G112G Mice: Absolute Dopamine Levels of Three Baseline Samples and Levels of Dopamine after Heroin Injections

Females Males 14 14

GG (6) 12 12 GG (6) 10 10

8 8 6 6 4 AA (6) 4 AA (7) 2 2 Dopamine (nM) Dopamine Dopamine (nM) Dopamine 0 0

10mg/kg 20mg/kg 10mg/kg 20mg/kg Heroin Heroin Heroin Heroin

Zhang et al., Neuropsychopharmacology, in press, 2015 AIMS Markers and Gene Variants Associated with Long-Term Severe Opioid Addiction

African Descent African cluster

European European cluster Descent 12 genes

European African Shared SNPs: sample 12 sample DRD2: rs1076563 genes (24 (35 rs2587546 genes) genes)

Kreek 2016, after Levran 2015 Variants of Opioid and Stress Related Genes Associated with Opiate Addiction in Caucasians Which Have Been Replicated (7 of over 15) Genes Variant Refs OPRM1 A118G (rs1799971) e.g, Bond… Kreek and Yu, 1998; (mu opioid receptor) Stadlin et al., 2001; Haerian and Haerian, 2013 OPRD1 rs2236861, rs3766951, Levran et al., 2008; Beer et al., 2013; (delta opioid receptor) rs2236857 Nelson et al., 2014 OPRK1 NSV* Yuferov et al., 2004; Levran et al., 2009; (kappa opioid receptor) Kumar et al., 2012 PDYN NSV* Wei et al., 2011; Clarke et al., 2012 (dynorphin peptide) AVPR1A rs11174811; Maher et al., 2011; Levran et al., 2014 (arginine vasopressin rs1587097; receptor 1A) rs10784339 FKBP5 rs1360780; rs3800373 Levran et al., 2014a; Levran et al., 2014b (FK506-binding protein 51/ corticosterone chaperone) GAL rs694066 Maher et al., 2011, Levran et al., 2014 (galanin) *NSV – No Single Variant; replication is on association of entire genes

Kreek 2016; adapted from Reed et al., Current Psychiatry Reports,16(11): 504, 2014 PHARMACOGENOMICS – CYP2B6 SNPs are Associated with Effective Methadone Dose (n=74) (516G>T and 785A>G) (Replication)

TT

GT GG GT GG

25 Methadone dose (mg/d)

20

50 100 150 200 250 150 mg/day 15

CYP2B6 rs3745274 (516G>T) G/G G/T T/T 10

rs3745274 (516G>T) Number of subjects 5

0 30 60 90 120 150 180 210 240 270 250

Methadone dose (mg/day)

GG AG AA AA AG Methadone dose (mg/d)

150 50 100 150 200 mg/day

Levran … Kreek, Addiction Biology, 18: 709, 2012

A/A A/G G/G Dobrinas…Eap, Pharmacogenet Genomics, 23:84, 2013 Rs2279343 (785A>G) Gadel et at., Drug Metab Dispos, 41: 709, 2013 September 10, 2003 – FDA Presentation “Major Issues Related to Physician Prescribing of Long-Acting Mu Opioid Receptor Agonists” 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.

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

C. Stigma, ingrained in physicians and other healthcare workers by their formal health-related education, against the addictive diseases, the persons suffering from addictive diseases, the providers of healthcare services to those with addictive diseases, and the medications used to treat addictive diseases (e.g., methadone and buprenorphine-naloxone). Kreek, adapted from Long Acting Opioids: Challenges in Pharmacotherapy presented at the FDA September 10, 2003