8:00 a.m. - 8:45 a.m.
Keynote
Methadone Maintenance:
An Effective Treatment for Opioid Addiction
and for Chronic Pain
Mary Jeanne Kreek, MD
Senior Attending Physician
Patrick E. and Beatrice M. Haggerty Professor
Laboratory of the Biology of Addictive Diseases
The Rockefeller University
New York, NY
Methadone Maintenance: An Effective
Treatment for Opiate Addiction and
Chronic Pain
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
June 8, 2015
International Conference on Opioids
Boston, MA
funded primarily by
NIH-NIDA, NIH-NCRR and the Adelson Medical Research Foundation
Prevalence of Specific Drug Abuse and
Vulnerability to Develop Addictions 2015
National Household Survey and Related Surveys – 2007 – 2014
Alcohol Use – ever
~ 260 million
Alcoholism
~ 16.5 million
Marijuana Use – ever
Marijuana Daily Use
~ 104 million
~ 5.7 million
Cocaine Use – ever
Cocaine Addiction
~ 45.6 million
~ 2 to 3 million
Heroin Use – ever
Heroin Addiction
~ 5.7 million
~ 1 million
Illicit Use of Opiate Medication – ever
~ 37.1 million
(i.e., 14.2% of the population 12 and over)*
Dependence on Such Medication Use
~ 2 million
* 2007 National Survey on Drug Use and Health
SAMHSA National Survey on Drug Use and Health, 2014; NIDA Monitoring the Future 2014; Others, 2007-2015
Development of Addiction After
Self-Exposure to Specific Drugs
Alcoholism
~ 1 in 8 to 1 in 15
(12.5% to 6.5%)
Marijuana
~ 1 in 8 to 1 in 15
(12.5% to 5.5%)
(estimate)
Cocaine Addiction
~ 1 in 8 to 1 in 15
(12.5% to 6.5%)
Heroin Addiction
~ 1 in 3 to 1 in 5
(33.3% to 17.5%)
SAMHSA National Survey on Drug Use and Health, 2012; NIDA Monitoring the Future 2014; Others, 2007-2015
1
Number of Unintentional Drug Overdose Deaths Involving
Prescription Opiates, Heroin, and Cocaine (United States,
1999-2007) and Rate of Overdose (1970-2007)
Number of Unintentional Overdose Deaths
Rate of Overdose
10
12,000
Opioid Analgesic
10,000
Cocaine
8
Heroin
8,000
Rate*
Deaths
14,000
6,000
4,000
6
4
2,000
0
1999 2000 2001 2002 2003 2004 2005 2006 2007
2
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)
0
1.9 people die every day from heroin overdoses
in New York City. (NYC Dept of Health – 2013)
1970 1975 1980 1985 1990 1995 2000 2005
* Per 100,000 population
More than 1 person dies every
hour in the United States from
prescription opiate overdose.
(T Frieden, CDC – July 2014)
National Vital Statistics System; MMWR 61:1, 2012
Natural History of Drug and Alcohol
Abuse and Addictions
Primary
Prevention
Possible Utility of Vaccines
and Selected Medications
Initial Use of
Drug of Abuse
Sporadic
Intermittent
Use
Medications Useful
and Needed
Regular
Use
Addiction
70%-90% without
pharmacotherapy
relapse to addiction
Early
Protracted
Withdrawal Abstinence
(abstinence)
Progression
ADDICTION: Compulsive drug seeking behavior
and drug self-administration, without regard to
negative consequences to self or others
(adapted from WHO).
10-30% sustain
abstinence with no
specific medications
Adapted from Kreek et al., Nature Reviews Drug Discovery, 1:710, 2002; 2013
The Beginning: 1963-1964
Treatment of Heroin Addiction: Identification of Need, Formulation of
Hypothesis, Basic Clinical and Related Laboratory Research,
Translational Research, and Evaluations
Autumn
1963
Vincent P. Dole, Jr., MD recruitment of two new staff
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 –
July 1964
New team formed and first patients admitted to the
Rockefeller Hospital; initial research accomplished by
July.
AATOD 2013; EUROPAD 2014
2
50th Anniversary of Development of
Methadone Maintenance Treatment
Vincent P. Dole, Jr., MD; Marie Nyswander, MD; and Mary Jeanne Kreek, MD
1964: Initial clinical research at The Rockefeller Hospital on development of
treatment using methadone maintenance pharmacotherapy and on elucidating
mechanisms of efficacy.
Dole, V.P., Nyswander, M.E. and Kreek, M.J.: Narcotic blockade. Arch. Intern. Med., 1966.
What is Addiction?
Compulsive drug seeking behavior and
drug self-administration, without regard to
negative consequences to self or others.
(adapted from WHO)
“drug” = nicotine, alcohol – legal drugs
prescription opiates, marijuana (cannabis) – medicines (?)
heroin, cocaine – illegal drugs
2015
50th Anniversary of Development of
Hypothesis on Addictive Diseases
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.
Dole, V.P., Nyswander, M.E. and Kreek, M.J.: Narcotic blockade. Arch. Intern. Med., 1966.
3
Development of Methadone Maintenance
Treatment – 1964 Onward
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 (deceased 2006)
Marie Nyswander, M.D.
Guest Investigator – Joined Dole Lab in Winter 1964 (deceased 1986)
Mary Jeanne Kreek, M.D.
Guest Investigator – Joined Dole Lab in Winter 1964 (now Professor & Head of Laboratory)
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. AATOD 2013; EUROPAD 2014; MACAU 2015
Original basic clinical research at the
Rockefeller Hospital – January – July 1964
Dole, Nyswander, and Kreek, Arch. Intern. Med., 118:304,1966
Presented by
VP Dole at the
“Old Turks”
Meeting
(Association
of American
Physicians),
May 1966
…
…
Dole, Nyswander, and
Kreek: Narcotic
Blockade: a medical
technique for stopping
heroin use by addicts.
Trans. Assoc. Am. Phys.,
79:122-136,1966
4
1964-1966: 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, which had been
engaged in 10-14 day detoxification “treatment” for opiates
(revolving door).
Kreek, AATOD 2013; EUROPAD 2014
1967-1972: Continued Early Expansion
of Methadone Maintenance Treatment
1967-1968 – Introduction of outpatient induction into methadone
maintenance treatment (at the Rockefeller Hospital clinic, Dr. MJ Kreek).
1967-1972 – Development of multiple satellite outpatient methadone
maintenance treatment programs at Harlem, Beth Israel, St. Luke’s, and
Roosevelt Hospitals in New York City.
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).
1971 – Development of “Adolescent Development Program” in the
Department of Public Health of Cornell Medical College – New York
Hospital (Drs. Elizabeth Khuri and R. Millman).
1972 – Development of “Adult Clinic” in the Department of Medicine of
Cornell Medical College – New York Hospital (Dr. Aaron Wells).
Kreek, AATOD 2013 ; EUROPAD 2014
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)
along with retrospective study of 1435 methadone
maintenance patients and special studies in a smaller group.
1973
5
1973
Functional State
(Heroin)
Impact of Short-Acting Heroin versus Long-Acting
Methadone Administered on a Chronic Basis in Humans 1964 Study and Opioid Agonist Pharmacokinetics:
Heroin Versus Methadone (1973-mid-1980s)
"High"
"Straight"
Drug or
Medication
Apparent Plasma Terminal
Half-life and Duration of
Desired Effects
HEROIN
3 min for prodrug
30 min for active
compound (fast on-set
and off-set
"Sick"
AM
PM
AM
PM
AM
Functional State
(Methadone)
Days
6 hours for active
metabolites
"High"
METHADONE
"Straight"
"Sick"
24h for medication (slow
on-set and off-set)
48h for active half of
medication
AM
PM
AM
Days
H
PM
AM
Dole, Nyswander and Kreek, 1966; Kreek et al., 1973; 1976; 1977; 1979; 1982; Inturrisi et al, 1973; 1984; 2015
“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, 1978;1987;1991;1992; 2001
6
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, including especially brain function
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
30th Anniversary of Identification of HIV-1 Infection in Drug
Users in New York City and Protective Value of Methadone
Maintenance Treatment:
(1969 –) 1978 – 1992; 1983 – 1984 Study and Beyond
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
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 with Des Jarlais and others, 1984
Methadone Maintenance Treatment
for Opiate (Heroin) Addiction – 2015
Number of patients currently in treatment:
 USA: ~ 320,000
 Europe: ~ 600,000
~ 1.3 million worldwide
 Rest of world: ~400,000
Efficacy in “good” methadone treatment programs using adequate doses
(80 to 150mg/d) and adequate counseling:
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; 2014
7
Few Targeted Pharmacotherapies
Available for Specific Addictive Diseases
I.
Opiate Addiction (Heroin and Illicit Use of Opiate
Medications)
a.
b.
[c.
[d.
II.
METHADONE (50-80%)**
BUPRENORPHINE (+ NALOXONE) (40-50%)*
NALTREXONE ( <15%)**]
SUSTAINED RELEASE NALTREXONE (<15%)**]
Alcoholism
a. NALTREXONE (30-40%)*
b. ACAMPROSATE (low in USA)
c. NALMEFENE (approved in Europe only, 2012)
III. Nicotine Addiction (Primarily Tobacco Smoking)
NICOTINE – DIVERSE DELIVERY SYSTEMS (?)
BUPROPRION (?)
VARENICLINE (?)
a.
b.
c.
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 moderate to high success in eliminating specific drug use. Kreek, 2014
PHARMACOGENOMICS – P-glycoprotein (MDR1, ABCB1):
SNP 1236C>T (and Related Haplotype) Associated with
Higher Methadone Doses (>150 mg/day) in Caucasian
Maintenance Treatment Patients
1236C/T
Coding sequence
2 3
(-1)
4
5
8
9 12
rs3789243
rs2520464
Intronic
2677G/T
(A893S)
18
3435C/T
21
26 28
rs1922242 rs2235067
rs2032583 rs6949448
Methadone dose
TT
TT
CC
CC
< 150 mg/day >
CT
“Low”
“High”
CT
P = 0.007
P-gp is expressed in tissues with barrier function like
the endothelial cells lining of the Blood-Brain Barrier
Levran… Kreek, Hum. Mol. Genet., 17:2219, 2008
Methadone dose (mg/d)
100 150 200 250
PHARMACOGENOMICS – CYP2B6 SNPs are Associated with
Effective Methadone Dose (n=74) (516G>T and 785A>G)
TT
GT
GT
GG
GG
Number of subjects
50
25
150
mg/day
G/G
G/T
CYP2B6 rs3745274 (516G>T)
T/T
rs3745274 (516G>T)
20
15
10
5
Methadone dose (mg/d)
100 150 200 250
0
30 60 90 120 150 180 210 240 270
Methadone dose (mg/day)
GG
AG
AA
AA
50
AG
150
mg/day
A/A
A/G
G/G
Rs2279343 (785A>G)
Levran … Kreek, Addiction Biology, 2012
8
Opiate (Opioid) Analgesic Agents
~2008-2015
• Numerous – all mu opioid receptor-directed
• Diverse formulations – many long-acting (but also some still friable)
• Most available in oral, sublingual, or patch preparations
Examples – mostly short-acting
Sustained Release/Long-Acting(*)
Morphine
(e.g., MS Contin®)
Oxycodone
(e.g., OxyContin®)
Hydromorphone
(e.g., HydromorphoneContin®)**
Oxymorphone
Acetaminophen and Hydrocodone
(e.g., Vicodin®)
Fentanyl
(e.g., Duragesic®)
Meperidine
Codeine
Methadone* (long-acting)
(e.g., Dolophine®) – full mu agonist
Buprenorphine* (long-acting)
(e.g., Subatex® sl) – partial mu agonist
Buprenorphine-Naloxone* (long-acting)
(e.g., Suboxone® sl) – partial mu agonist
** Removed from market by FDA shortly after approval
Kreek, 2008; 2015
Use of Methadone as an Analgesic:
Doses Usually Range from 0.5mg tid to
10mg tid – Rarely Over 60 mg/d
• Very few indications for use of methadone in
management of acute pain – because of long-acting
pharmacokinetic properties, accumulation of
medication must be anticipated over the first four
days or longer. Accidental overdose deaths frequently
occur when methadone is so prescribed.
• Methadone is a superb (and often superior) opioid
analgesic for chronic pain, including neoplastic and
non-neoplastic pain – because tolerance develops
more slowly than to other opioid analgesics, steady
doses may be used over long periods of time and
escalation of dose may be gradual; no drowsiness,
no dulled responses.
Kreek, 1975 on; 2003; 2008; 2015
QTc Interval Prolongation Due to
Methadone
• First report of QTc prolongation due to methadone in late 1960s, with no
associated problems by Barry Stimmel, MD (cardiologist and director of
methadone treatment program).
• Over last decade, numerous reports of QTc interval prolongation with
cardiovascular complications attributed to methadone, primarily in
patients receiving multiple medications, including methadone for pain
management, or in poly-drug abusers.
• No reports of a serious outcome of prolongation of QTc interval
prolongation (torsades de pointe) in person receiving methadone
maintenance treatment in appropriate and registered programs in the
United States.
• Two prospective or cross-sectional studies during methadone
maintenance treatment identified QTc prolongation in most patients and
no related cardiovascular problems in any (Martel et al., Peles et al.) .
Martell et al., Ann Intern Med, 139: 154, 2002; Martell et al., Am J Cardiol, 95:915, 2005;
Peles et al., Addiction 102:289, 2007
9
QTc Interval Discussions
1964-1973-1993: New York City
Clinical Research – Laboratory of the Biology of
Addictive Diseases – The Rockefeller University)
Prospective, cross-sectional, and retrospective studies of former
heroin or other opiate addicts, with at least one year of opiate
addiction prior to entry into treatment, and in long-term methadone
maintenance treatment, in programs constituted according to the
US Federal guidelines, and approved as mandated:
No clinical evidence of:
a) Torsades de Pointes
b) Arrhythmias or other cardiovascular problems possibly
related to prolonged QTc interval
c) Death during treatment due to an unexplained cause or a
cause possibly related to QTc interval prolongation
Kreek, M.J., Proceedings of the Fourth National Conference on Methadone Treatment,
NAPAN-NIMH, 171, 1972; Novick et al., Drug Alcohol Depend., 33:2355,1993; Kreek, 2010
Informal Recommendations for Methadone Dose and
Monitoring Relevant to QTc Interval Issue (Requested
Response to American Pain Society by MJK Prior to
the Publication of their Methadone Guidelines)
1) EKG screening of new patients entering methadone
maintenance treatment needed only if there is a personal
history of severe cardiovascular disease or is under
medical care receiving a medication known to prolong QTc
intervals
2) EKG screening of any patient requiring methadone
maintenance dose >150 mg/d
3) EKG screening of any methadone maintenance patient
prior to receiving another medication known to have
significant QTc prolongation effects
4) Based on our studies, surveillance of any methadone
patient requiring a benzodiazapams
All mu opioid receptor agonists prolong QTc intervals. Many HIV
treatment agents, many cardiovascular treatment agents, and most
psychotropic medications prolong QTc intervals.
Factors Contributing to Vulnerability
to Develop a Specific Addiction
use of the drug of abuse essential (100%)
Genetic
(25-60%)
Environmental
(very high)
• DNA
• SNPs
• other
polymorphisms
• prenatal
• postnatal
• contemporary
• cues
• comorbidity
• stress-responsivity
• mRNA levels
• peptides
• proteomics
Drug-Induced Effects
(very high)
• neurochemistry
• synaptogenesis
• behaviors
Kreek et al., 2000; 2005
10
Development of an Addiction
• 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)
Endogenous Opioids (“Endorphins” – 3 classes)
and their Opioid Receptors (3 types)



Endorphin
peptide
H2N
extracellular
fluid
S
S
AA identical in
3 receptors
AA identical in
2 receptors
AA different in
3 receptors
cell membrane
cell interior
HOOC
LaForge, Yuferov and Kreek, 2000
Targets of Currently Approved
Treatments for Addictive Disorders
Kreek et al, Journal of Clinical Investigation, 12: 3387, 2012
11
Potential biological targets identified for
treatment of opioid/cocaine co-dependency
and opioid/alcohol co-dependency (e.g. KOPr)
• 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
addiction.
STRESS RESPONSIVITY:
Hypothesis – Atypical Responsivity to Stressors,
A Possible Etiology of Addictions – HPA Axis
Atypical responsivity to
stress and stressors may,
in part, contribute to the
–
Arginine
persistence of, and
CRF
Vasopressin
relapse to self+
administration of drugs of
anterior
pituitary
abuse and addictions.
+
–
Such atypical stress
POMC
responsivity in some
b-End
individuals may exist prior
to use of addictive drugs
Cortisol
ACTH
on a genetic or acquired
basis, and lead to the
+
adrenal
acquisition of drug
addiction.
hypothalamus
Endogenous
Opioids
(mu – inhibition)
(kappa – ? activation)
Kreek, 1972; 1981; 1982; 1984 … 2013
STRESS RESPONSIVITY –
Heroin, Cocaine, and Alcohol Profoundly Alter
Stress 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
Activation of HPA Axis
(increase levels of HPA
Hormones)
• Chronic effects of long-acting
opiate (e.g. methadone in
maintenance treatment)
Normalization of HPA Axis
* Our challenge studies have shown that a relative
and functional “endorphin deficiency” develops.
Kreek, 1972; 1973; 1987; 1992 … 2010
12
Specific Binding (ml plasma/ml tissue)
STRESS RESPONSIVITY – Normalization of Heroin Disrupted
Physiology During Methadone Maintenance Treatment: PET
Studies of mu Opioid Receptors in Human Brain Regions Using
the Antagonist [18F] Cyclofoxy
Normal volunteers n=14
MMTP volunteers n=14
16
(~20-30 percent reduction in
mu-opioid receptor binding
due to methadone occupancy)
14
12
10
8
6
4
2
0
Thl Amy Caud Ins ACg Put
MT
MFr
Par
Crb
IT
Area related to pain response
Region of Interest
Area with dopamine terminals involved in “reward”, mood, and decision-making
Area with dopamine terminals involved in memory, learning, and movement
Hip
WMt
Kling et al., . J.
Pharmacol. Exp.
Ther., 295, 2000
Genetic Vulnerability to (or Protection
from) Development of an Addiction
Genetic vulnerability to develop an addiction once
self-exposed probably due to:
• Multiple variants (SNPs and other types) of
• Multiple genes (as with any complex disorder, e.g.,
hypertension, diabetes)
• Probably both shared and also unique variants for
each specific addiction
• Genetic contributions of comorbid conditions and
personality types may play a role
No gene variant or group of variants causes an
addictive disease alone; self-administration of a
drug is essential.
Kreek, 2008
Single Nucleotide Polymorphisms of the Mu Opioid
Receptor in the Coding Region, Including the Functional
and Heroin Addiction Associated A118G (N40D) Variant
HYPOTHESIS
Gene variants:
(A118G)
• Alter physiology
“PHYSIOGENETICS”
• Alter response to
medications
“PHARMACOGENETICS”
• Are associated with
specific addictions
Bond, LaForge… Kreek, Yu, PNAS, 95:9608, 1998
13
Heroin Self-Administration (4h/d) in Male and Female
Wild-Type (A/A) and Genetically Modified (G/G) Mice:
A Murine Model of the Human A118G Mu Opioid
Receptor Functional Variant
10
Nosepokes
6
20
4
10
AA (15)
GG (12)
0
2
40
2
3
4
5
6
7
8
9
8
6
20
4
10
0
1
10
Females
30
AA (12)
2
GG (12)
0
10
Daily Heroin SA (mg/kg)
8
Daily Heroin Dose (mg/kg)
Males
30
Nosepokes
40
0
1
2
3
4
5
Day
6
7
8
9
10
Day
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
Males
Females
14
GG (6)
12
10
8
6
4
AA (6)
2
Dopamine (nM)
Dopamine (nM)
14
12
GG (6)
10
0
8
6
4
AA (7)
2
0
10mg/kg 20mg/kg
Heroin Heroin
10mg/kg 20mg/kg
Heroin Heroin
Zhang et al., Neuropsychopharmacology, in press, 2015
Basal plasma levels of cortisol significantly
higher in persons with the A118G variant.
Serum Cortisol (ug/dl)
Bart et al., 2006
P = Placebo
N = Naloxone
24
A/A (n=29)
A/G (n=7)
22
N
N
20
18
N
16
14
P
I
12
Cumulative Survival (Time to Relapse)
“Physiogenetics” and “Pharmacogenetics” Related
to A118G Variant of Human Mu Opioid Receptor Gene
– Altered Stress Responsivity
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
14
28
42
56
70
84
Days
N
Naltrexone/ A/G, G/G (n=23)
10
8
Naltrexone/ A/A (n=48)
Placebo/ A/G, G/G (n=18)
50
0
50
100
Time (min)
150
200
Wand et al., 2002
Placebo/ A/A (n=41)
Oslin et al., 2003
14
Association Between a Functional Polymorphism (SNP)
in the Mu Opioid Receptor Gene (A118G) and Opiate
Addiction and Also Alcoholism in Central Sweden
118G Allele Frequency
Opiate Dependent (n=139)
Control (n=170)
0.155
(15.5%)
0.074
(7.4%)
Odds Ratio=2.86
p=0.00025
In the entire study group in this central Swedish population:
Attributable Risk due to genotypes with a G allele: 18%
Bart et al., Molecular Psychiatry, 9:547-549, 2004
118G Allele Frequency *
Alcohol Dependent (n=389)
Control (n=170)
0.125
(12.5%)
0.074
(7.4%)
Odds Ratio=1.92
p=0.0074
* Overall 118G Allele Frequency = 0.109 (10.9%)
In the entire study group in this central Swedish population:
Attributable Risk due to genotypes with a G allele: 11.1%
Bart et al., Neuropsychopharmacology, 30:417, 2005
Major Issues/Problems Related to Physician
Prescribing of Long-Acting Mu Opioid Receptor
Agonists in Humans
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 conerning any
of the specific addictions and also medical approaches to assessing
persons with ongoing misuse, abuse, or addiction to drugs.
C. Secondary physician/healthcare worker and related enforcement
issues.
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.
Kreek, Invited Lecture for the Food and Drug Administration, 2003; 2015
Expansion of Methadone Maintenance Treatment in to
South East Asia: Data Presented at the Addiction and
Pain Treatment Meeting, Macau, China, April 18-19 2015
1) Methadone maintenance introduced into Hong Kong in 1975
by Dr. Robert Newman with information and data of Drs. Dole,
Nyswander, and Kreek. Now expanded to over 5 programs
and several thousand patients.
2) Methadone maintenance introduced into China by Dr. MJ
Kreek working with Dr. Qin, Military Medicine University, 1996
onward. Recent (~2005-2015) expansion of methadone
maintenance treatment with over 200,000 patients in
treatment, and further dramatic expansion expected.
3) Methadone maintenance treatment programs developed in
Macau (2005) with technical advice and education from Dr. A
Adelson and her staff; now expanded to over 5 clinics and
1000 patients.
4) Methadone maintenance introduced to Taiwan by Macau clinic
staff in 2007, with ~1000 patients in treatment.
15
Kreek Laboratory 2015
NOT PICURED: Vadim Yuferov, Brenda Ray, Derek Simon,
Sage Rahm, Josh Altschuler, Catherine Guariglia
16