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 Rockefeller University

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 Heroin 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)

1.9 people die every day from heroin overdoses in New York City. (NYC Dept of Health – 2013)

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)

47,000 persons (15 per 100,000) in the United States died of overdose deaths in 2014.

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)

National Vital Statistics System; MMWR 61:1, 2012; CDC Vitalsigns (online), July 7, 2015

PREVENT People From Starting Heroin

Reduce prescription opioid painkiller abuse. Improve opioid painkiller prescribing practices and identify high-risk individuals early:

REDUCE Heroin Addiction

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

REVERSE Heroin Overdose

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

CDC Vitalsigns (online), July 7, 2015

• • • • • •

•

Factors Contributing to Vulnerabilityto Develop a Specific Addiction

use of the drug of abuse essential (100%)

Genetic (40-80%) • DNA • SNPs • other

polymorphisms

• • •

Environmental (very high)

prenatal postnatal epigenetics peer pressure cues comorbidity

(psychiatric) stress-responsivity

mRNA levels peptides proteomics Drug-Induced Effects

(very high)

• neurochemistry • synaptogenesis • neuroneogenesis • behaviors

Kreek et al., 2000; 2005; 2016

Natural History of Drug and Alcohol Abuse and Addictions

Primary Prevention

Possible Utility of Vaccines and Selected Medications

Medications Useful and Needed

60%-90% without pharmacotherapy relapse to addiction

Initial Use of Drug of Abuse

Sporadic Intermittent

Use

Regular Use

Addiction Early Withdrawal (abstinence)

Protracted Abstinence

Progression

ADDICTION: Compulsive drug seeking behavior and drug self-administration, without regard to negative consequences to self or others (adapted from WHO).

10%-40% sustain abstinence with no specific medications

Adapted from Kreek et al., Nature Reviews Drug Discovery, 1:710, 2002; 2016

50th Anniversary of First Research Paper onDeveloping 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 AgonistPharmacokinetics – Heroin Versus Methadone

Func

tiona

l Sta

te(H

eroi

n)

"High"

"Straight"

"Sick"

AM PM AM PM AM Days

Systemic Bioavailability

After Oral Apparent Plasma

Terminal Half-life Major Route of Biotrans-

Administration (t1/2 Beta) formation

Limited 3min Successive (<30%) (30min for active

- -6 acetyl morphine metabolite;

deacetylation and morphine

glucuronidation - 4 6h for morphine

and active - -morphine 6

glucuronide metabolite)

"High"

"Straight"

"Sick"

AM PM AM PM AM Days H

Func

tiona

l Sta

te(M

etha

done

)

Essentially 24h - N demethylation Complete (48h for active

(>70%) - [R](l) enantiomer)

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

Goals and Rationale for SpecificPharmacotherapy 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 PharmacotherapeuticAgent 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)

Continuing use of illicit heroin

50 – 80%

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, andExtended 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 PharmacotherapiesAvailable 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 StimulantsNONE

(%) 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 ApprovedTreatments 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); AlsoLocomotor Activity Study in C57BL/6J and 129/J Mice

0.0

0.2

Leve

ls (n

M)

C57BL/6J

Saline

1.61.6

1.4

1.4

Acute (1 day)

Chronic (13 day)

129/J

Saline

Tota

l Loc

omot

orE

xtra

cellu

lar D

opam

ine

Leve

ls (n

M) 1.2 1.2

1.0

0.8

0.6

1.0

0.8

0.6

0.4 0.4

0.2

0.0

500500500500 C57BL/6J Day 13 Cocaine

(15mg/kg x3)

129/J Day 13 Cocaine

(15mg/kg x3)400400400400

Cou

nts/

6-m

in B

in

Cou

nts/

6-m

in B

in

300300300300

200200 200200

100100 100100

0000

To

tal L

ocom

otor

Ext

race

llula

r Dop

amin

e

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

Control

1

Control

3

Cocaine

2

Cocaine

4

Atto

mol

es M

OR

mR

NA

/ µg

tota

l RN

A

FCx Brain Regions

Saline Cocaine (15 mg/kgx3x1 day)

0.0

0.2

1.0

1.2

1.4

0.4

0.6

0.8

1.6

NAc Amy CPu Hip Thal Hyp

*

**

fmol/mg Saline Cocaine (14d) Saline

Withdrawal Cocaine

Withdrawal (14d) Yuferov et al., Brain Res. Bull., 48:109 1999 Unterwald et al., Brain Res., 584:314 1

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 RECEPTOR­DYNORPHIN SYSTEM: Cocaine Increases Kappa Opioid

Receptor Density in Rat, But Kappa Opioid ReceptorDirected “Dynorphins” Also Increase

0

pg p

pDyn

mR

NA

/ µg

tota

l RN

A

Control

1

Control

3

Cocaine

2

Cocaine

4

7

6

5

4

1

Caudate Putamen Nucleus

Saline

14 day cocaine (15mg/kg x 3)

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

% o

f Sal

ine

Con

trol

ppDyn mRNA KOR mRNA

*

200 200

150

100

50 % o

f Sal

ine

Con

trol

150

100

50

*

0 0 Saline Morphine Saline Morphine

Saline

Morphine6.25 mg/kgx6x1 day Wang et al., 1999

Acute Intermittent Morphine IncreasesPreprodynorphin and Kappa Opioid Receptor

mRNA Levels in the Rat Brain

Natural Dynorphin A Lowers Basal and Cocaine Induced Dopamine Levels in Mouse Striatum

1-17

10 10

8

6

4

2

Dop

amin

e in

D

ialy

sate

(nM

) 8

6

4

2

0 0 60 120 180 60 120 180 Infusion Infusion Injection

20-min Sample 20-min Sample Dynorphin Dose (nmol)

0 1.0

2.0 4.4 4.4+nBNI (antagonist)

Dynorphin (4.4nmol) + Cocaine (15mg/kg)

Infusion and Injection Control Cocaine (15mg/kg)

D

ialy

sate

(nM

) D

opam

ine

in

Zhang, Butelman, Schlussman, Ho, and Kreek, Psychopharmacology, 172:422, 2004

•

•

•

•

Potential Biological Target Identifiedfor 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

Endogenous Opioids

(mu – inhibition) (kappa – ? activation)

β-End (↑)

hypothalamus

anterior pituitary

POMC

Cortisol (↑) ACTH (↑)

CRF

Mu Opioid Receptor Antagonists

adrenal

Arginine Vasopressin

++

+

Kreek, 1984; 1998; 2006; 2014

Heroin, Cocaine, and Alcohol Profoundly AlterStress Responsive Hypothalamic-Pituitary-Adrenal

(HPA) Axis: Normalization during methadone treatment • •

• • • •

•

Acute effects of opiates Chronic effects of short-acting opiates (e.g., heroin addiction)

Suppression of HPA Axis (decrease levels of HPA hormones)

Opiate withdrawal effects * Opioid antagonist effects Cocaine effects * Alcohol effects

Chronic effects of long-acting opiate (e.g. methadone in maintenance treatment)

Activation of HPA Axis (increase levels of HPA Hormones)

Normalization of HPA Axis

* Our challenge studies have shown that a relative and functional “endorphin deficiency” develops.

Kreek, 1972; 1973; 1987; 1992 … 2008

Nalmefene (mu/kappa Directed) Causes GreaterHPA Axis Activation Than Naloxone (mu Directed)

in Normal Human Volunteers (n=23)

=

40

35

30

25

20

15

AC

TH (p

g/m

l)

ACTH Cortisol 50 50

45 45

Cor

tisol

Lev

els

(µg/

dL)

40

35

30

25

20

15

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 receptorreceptor 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

Gene variants:

Alter physiology “PHYSIOGENETICS”

Alter response to medications

“PHARMACOGENETICS”

Are associated with specific addictions

(A118G)

(C17T)

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

1.0

0.5

Cur

rent

Res

pons

e Fr

actio

n M

axim

um

A118G Prototype

-11 -10 -9 -8 -7

80

60

40

20

0

A118G Prototype

-9 -8 -7 -6

0

Log [β Endorphin (M)] Log [β Endorphin (M)]

Perc

ent B

ound

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

24 22 20 18 16 14 12 10 8Se

rum

Cor

tisol

(ug/

dl) N = Naloxone

P I

A/A (n=29)A/G (n=7) N N

N

N

Cor

tisol

Lev

els

-AU

C

(9:3

0am

-10:

30am

+ 9

0min

) 2500 Cortisol

(no

food

for 9

hou

rs)

0

2000

1000

1500

40 19

Prototype A118G

P < 0.05

500

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” Relatedto A118G Variant of Human Mu Opioid Receptor Gene, Which AltersStress Responsivity: Positive Predictor of Response to Naltrexone

Treatment of Alcoholics

0 Cum

ulat

ive

Surv

ival

(Tim

e to

Rel

apse

) 1.0 0.9 0.8 0.7 0.6 0.5

0.2

0.4 0.3

0.1 0.0

Naltrexone/ A/G, G/G (n=23) Naltrexone/ A/A (n=48)

Placebo/ A/A (n=41) Placebo/ A/G, G/G (n=18)

% W

ith G

ood

Clin

ical

Out

com

e

Placebo 100 Naltrexone hydrochoride

90 80 70 60 50 40

n=126 n=115 n=35 n=31

Asn40 Asp40

30 20 10

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

N o

se p o

kes

4 0 1 0 4 0 1 0

8

6

4

2 D

ai l

y H

er o

i n D

o s

e (

m g

/ kg

)

N o

se

p o

ke

s

M a l e s F e m a l e s

D a

i l y

H e

r o i n

S A

( m

g / k

g )

A A ( 1 5 ) G G ( 1 2 )

3 0

2 0

1 0

3 0

A A ( 12)

G G ( 1 2 )

2 0

1 0

0 0 0 0 1 2 3 4 5 6 7 8 9 1 0 1 2 3 4 5 6 7 8 9 1 0

D a y D a y

2

4

6

8

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 ofDopamine after Heroin Injections

14

8 6 4 2

Females Males 14

GG (6) 12

Dop

amin

e (n

M) 12 GG (6)

10 10

AA (7) 2

8 6 4AA (6)

0 0

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

Dop

amin

e (n

M)

Zhang et al., Neuropsychopharmacology, in press, 2015

AIMS Markers and Gene Variants Associated with Long-Term Severe Opioid Addiction

African African cluster Descent

European European cluster Descent 12 genes

European sample

(24 genes)

African sample

(35 genes)

12 genes

Shared SNPs: DRD2: rs1076563

rs2587546

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

OPRM1 (mu opioid receptor)

OPRD1 (delta opioid receptor)

OPRK1 (kappa opioid receptor)

PDYN (dynorphin peptide)

Variant A118G (rs1799971)

rs2236861, rs3766951, rs2236857

NSV*

NSV*

Refs e.g, Bond… Kreek and Yu, 1998;

Stadlin et al., 2001; Haerian and Haerian, 2013 Levran et al., 2008; Beer et al., 2013;

Nelson et al., 2014 Yuferov et al., 2004; Levran et al., 2009;

Kumar et al., 2012 Wei et al., 2011; Clarke et al., 2012

AVPR1A (arginine vasopressin

receptor 1A)

FKBP5 (FK506-binding protein

51/ corticosterone chaperone)

GAL (galanin)

*NSV – N

rs11174811; rs1587097; rs10784339

rs1360780; rs3800373

rs694066

o Single Variant; replic

Maher et al., 2011; Levran et al., 2014

Levran et al., 2014a; Levran et al., 2014b

Maher et al., 2011, Levran et al., 2014

ation 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)

50

10

0 15

0 20

0 25

0

GGGT

TT

GG GT

250 30 60 90 120 150 180 210 240 270

Met

hado

ne d

ose

(mg/

d)

25

20

150

Num

ber o

f sub

ject

s

mg/day 15

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

rs3745274 (516G>T) 5

0

Methadone dose (mg/day)

50

100

150

200

A/A A/G G/G

GG

AA AG

AA AG

Met

hado

ne d

ose

(mg/

d)

150 mg/day

Rs2279343 (785A>G)

Levran … Kreek, Addiction Biology, 18: 709, 2012 Dobrinas…Eap, Pharmacogenet Genomics, 23:84, 2013

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