# Presentation: 621316

## Long Acting Opioids:Challenges in Pharmacotherapy

**Mary Jeanne Kreek, M.D.**
**The Laboratory of the Biology of Addictive Diseases**
**The Rockefeller University**
**September 10, 2003**
**Anesthetic Life Support Drugs Advisory Committee**
**Food and Drug Administration**
**Bethesda, MD**
***funded primarily by NIH-NIDA, NIHCRR and NYS OASAS***

## Major Issues/ Problems Related to Physician Use/Prescribing of Long-Acting Mu Opioid Receptor Agonists in Humans

**Decrease in formal medical education in classical pharmacology and lack of continuing medical education in pharmacology.**
**2)   Discovery (synthesis) and development of intrinsically long-acting mu opioid agonists for treatment of opioid addiction and for treatment of chronic pain (1964 onward).**
**3)   Increase in numbers of short-acting mu opioid agonists now formulated to be long-acting opioids for use in management of pain.**

**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.**

***Kreek, 2003***

## Major Issues/ Problems Related to Physician Use/Prescribing of Long-Acting Mu Opioid Receptor Agonists in Humans (continued)

**Lack of awareness of prevalence of specific additions (10% to 20% in all US population with one or more addiction).**
**2)   Lack of knowledge concerning, e.g., genetic vulnerabilities; predictable chronic drug use induced changes in brain; environmental (e.g., set and setting, peer pressure, availability) and host factors (e.g., psychiatric comorbidity, medical comorbidity, chronic pain) contributing to the vulnerability to develop an addiction.**

**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.**

***Kreek, 2003***

## Major Issues/ Problems Related to Physician Use/Prescribing of Long-Acting Mu Opioid Receptor Agonists in Humans (continued)

**Physicians (and related healthcare workers) with inadequate knowledge (and possibly inadequate access to information).**
**Physicians with inadequate time (due to HMO and related current healthcare system) to evaluate each patient carefully and to individualize care**
**Physicians desiring to (for profit) or willing to (for diverse reasons) become “prescription writers,” i.e., illicit practice of medicine.**
**Similar constraints of specific education and knowledge and time  constraints often lead to inappropriate enforcement.**

**C. Secondary physician/healthcare worker and related enforcement issues.**

***Kreek, 2003***

***majority of problems probably lay within these two realms***

## Prevalence of Specific Drug Abuse and Vulnerability to Develop Addictions

**	**Alcohol Use – ever	~	177 millionAlcoholism	~	15 million
- 	Cocaine Use – ever	~	26 millionCocaine Addiction	~	1 to 2 million
- 	Heroin Use – ever	~	2.5 to 3 millionHeroin Addiction	~	0.5 to 1 million
**Development of Addiction After Self Exposure**
**	**Alcoholism	~	1 in 10 to 1 in 20Cocaine Addiction	~	1 in 10 to 1 in 20Heroin Addiction	~	1 in   3 to 1 in   5

**Prevalence of Specific Drug Abuse and Vulnerability to Develop Addictions**

*NIDA, SAMHSA Reports *

## Factors Contributing to Vulnerability to Develop a Specific Addiction

**use of the drug of abuse essential (100%)**

**Genetic****(25-50%)**
**• ****DNA**
**• ****SNPs**
**• ****other **
**   ****polymorphisms**

**Drug-Induced Effects****(very high)**

**Environmental****(very high)**
**• ****prenatal**
**• ****postnatal**
**• ****contemporary**
**• ****cues**
**• ****comorbidity**

***Kreek et al., 2000***

**• ****mRNA levels**
**• ****peptides**
**• ****proteomics**

**• ****neurochemistry**
**• ****behaviors**

## Endogenous Opioidsand Their Receptors

**Endorphins****	****	****Mu**
**Enkephalins****	****	****Delta**
**Dynorphins****	****	****Kappa**
**Endomorphins (?)**

**Endogenous Opioids****and Their Receptors**

*Kreek, 2001*

## Human Opioid Receptors , , and 

*LaForge, Yuferov and Kreek, 2000*

- extracellular fluid

- cell interior

- cell membrane

**AA identical in 3 receptors**

**AA identical in **
**2 receptors**

**AA different in **
**3 receptors**

- HOOC

- H2N

- S

- S

****

****

****

## Hypothesis(1963–1964)

**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.**
** **

**Hypothesis****(1963–1964)**

*Dole, Nyswander and Kreek, 1966*

## Heroin Addiction: Functional State of aTypical Addict

**"High"**

**"Straight"**

**"Sick"**

**Days**

- AM

- PM

- AM

- PM

- AM

**Functional State**

*Dole, Nyswander and Kreek, 1966*

**(overdose)**

- (arrows indicate times of injection)

## 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 **

*Kreek, 1978; 1991; 1992; 2001*

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

**   ****Orally effective**
**   ****Slow onset of action**
**   ****Long duration of action**
**   ****Slow offset of action **

*Kreek, 1978; 1991; 1992; 2001*

## Methadone/Morphine/Heroin Chemical Structure

***Kreek Lectures: 1967 onward***

## Methadone Maintenance: Functional State of a Former Addict Treated With Methadone Maintenance

**Functional State**

*Dole, Nyswander and Kreek*

**"High"**

**"Straight"**

**"Sick"**

- AM

- PM

- AM

- PM

- AM

**Days**

- “Functional state of a patient blockaded with methadone (a single oral dose each morning).  The effect of an intravenous injection of heroin in the blocked patient is shown in the second day. The dotted line (---) indicates the course if methadone is omitted.”

- M

- M

- H

## Heroin versus Methadone*

**Route of administration****	****intravenous****	****oral**
**Onset of action****	****immediate****	****30 minutes**
**Duration of action****	****3–6 hrs****	****24–36 hrs**
**Euphoria****	****first 1–2 hrs****	****none**
**Withdrawal symptoms****	****after 3–4 hrs****	****after 24 hrs**

**Heroin versus Methadone***

****	**effects of high dosages in tolerant individuals*

*Kreek, 1973; 1976; 1987*

## Plasma Methadone Levels in anIndividual Maintained on 100 mg/day

**Plasma levels (ng/ml)**

*MJ Kreek, MD, 1994 (from Kreek, MJ, *_*NY State J. Med.*_* (73), 1973)*

**500**

**0**

**Time (hours after dose)**

**400**

**300**

**200**

**100**

**0**

**2**

**4**

**6**

**8**

**24**

## Opioid Agonist Pharmacokinetics:Heroin Versus Methadone

**Compound****	****Systemic****	****	****Apparent****	****	****Major**
**	****	****	****Bioavailability****	****Plasma Terminal****	****Route of**
**	****	****	****After Oral****	****Half-life****	****	****Biotrans-**
**	****	****	****Administration****	****(t****      ****Beta)****	****	****   formation**
**	**

**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, 1984*

**1****/****2**

## [18F] Cyclofoxy (a Selective Opioid Antagonist) Binding 

**82.50**

**48.75**

**[****18****F] Cyclofoxy (a Selective Opioid Antagonist) Binding **
**in Human Brain: Normal Volunteer PET Study - NIH**

## Plasma Methadone Levels in Long-Term, Methadone-Treatment Patients Sampled Across the 90-min PET Scan Session

**Plasma Methadone Levels in Long-Term, Methadone-Treatment Patients Sampled Across the 90-min PET Scan Session**

**100**

**0**

**200**

**300**

**400**

**500**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**n=12**

**Time (min)**

**Plasma Methadone****Levels (ng/ml)**

## 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

- 8

- 6

- 4

- 2

- 0

- 10

- 12

- 14

- 16

**Thi**

**Amy**

**Caud**

**Ins**

**ACg**

**Put**

**MT**

**MFr**

**Par**

**Crb**

**IT**

**Hip**

**WMt**

**Region of Interest**

**Specific Binding (ml plasma/ml tissue)**

*Kling et al., 2000*

- *

- *

- *

- *

- *

- normal volunteers n=14

- MTP volunteers n=14

## Methadone Maintenance Treatment Allows Normalizationof Endogenous Opioid-Related Physiological FunctionsDisrupted During Chronic Heroin Use

**Neuroendocrine Function**
**Hypothalamic-Pituitary-Adrenal Axis**** – ****Stress Responsivity****levels and circadian rhythm of release of POMC peptides****(******** Endorphin; ACTH and cortisol)**
**Hypothalamic-Pituitary-Gonadal Axis**** – ****Reproductive Biology**** levels and pulsatile release of LH and testosterone levels**
**Immune Function**
**Natural Killer Cell Activity**
**Absolute Numbers of Cells**** — T cells; T cell subset levels;****B cells; NK cells**
**Immunoglobin Levels (M and G)**

*Kreek, 1972; 1973; 1978; 1987; 1992; 2001; Novick et al., 1989*

## Methadone Maintenance Treatment for Opiate (Heroin) Addiction

**Efficacy in “good” treatment programs using adequate doses:**
**     ****Voluntary retention in treatment *****(1 year or more)*****	****60 – 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)***
**     **

**Methadone Maintenance Treatment for Opiate (Heroin) Addiction**

***Kreek, 1972; 1973; 2001; 2002; Inturrisi et al, in progress; Evans et al; in progress***

## Reinforcing or “Reward” Effects of Drugs of Abuse

**interpreted by the individual as ****“desirable”**** or ****“pleasurable”****, i.e.,**
**“****rewarding”****. These effects may lead to ****“craving”**** or ****“hunger”**** for **
**the drug, with resultant spontaneous activity or work for ****drug **
**acquisition**** and ****self-administration****.**
**Primary sites of actions of drugs of abuse with respect to their**
**reward or reinforcing effects have been identified as specific **
**brain regions, rich in ****dopamine nerve terminals or cell bodies****, the**
**mesolimbic and mesocortical dopamine systems especially the**
**nucleus accumbens****, as well as the amygdala and the anterior**
**cingulate. **
** **

**Reinforcing or “Reward” Effects of ****Drugs of Abuse**

*Kreek, 1987; 2001*

## Relationship Between Blood (and Brain) Levels of Drugs of Abuse and Their Effects on Events Related to Addictions

**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”**

**Relationship Between Blood (and Brain) ****Levels of Drugs of Abuse and Their Effects ****on Events Related to Addictions**

*Kreek, 1978; 1991, 1992; 2001*

## “On-Off” versus “Steady-State” 

**             **
**          ****	****•  ****levels of gene expression**
**	****•  ****receptor mediated events**
** ****	****•  ****physiology**
**	****•  ****behaviors**

**“****On-Off” *****versus***** “Steady-State” **

*Kreek, 1987; 2001*

## Pharmacokinetics of LAAM(l--acetyl-methadol)

**Orally effective**
**Long-acting**
**Long duration of action due, in part, to two biologically****active metabolites**
**P450 related hepatic enzymes involved in metabolism**
**Apparent ******** terminal half-life in humans**
**LAAM****	****:2.6 days**
**norLAAM****	****:2    days**
**dinorLAAM****	****:4    days**

## Buprenorphine Hydrochloride*

***Buprenex**

## Buprenorphine— Pharmacokinetics and Dynamics in Humans

**Mu opioid receptor partial agonist.**
**No oral preparation— (ineffective: “first pass” rapid biotransformation by GI mucosa and by liver).**
**Sublingual preparation– (without, and with, naloxone to reduce intravenous abuse liability).**
**Approved by FDA– maximum 16mg/day for treatment of opiate addiction (only); no approval for management of pain yet.**
**Maximal dose effective in humans 24 to 32mg.**
**Sublingual liquid or tablet; tablet ~55% plasma levels of liquid.**
**Plasma ****β**** terminal half-life: “3 to 5 hours.”**
**Around 120 minutes to peak after sublingual dose.**
**Pharmacodynamic sustained mu opioid effect, 24 to 48 hours due to very long mu opioid receptor occupancy.**
**Mu opioid agonist effects NOT reversible with opioid antagonist naloxone (because of very high affinity to and quasi-irreversible binding at mu opioid receptor.**

***Kreek, 2003***

## Opiate Addiction Treatment Outcome*

**LAAM Maintenance****	****	****	****	****50** **–** **80%**
**Buprenorphine-Naloxone Maintenance****	****               40** **–** **50%****
**Naltrexone Maintenance****	****	****	****	****10 – 20%**
**“****Drug Free” (non-pharmacotherapeutic)****	****	****  5 – 20%**
**Short-term Detoxification (any mode)****	****	****  5 – 20% ****(limited data)**
**	**

**Opiate Addiction Treatment Outcome***

****	**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.*

***Kreek, 1996; 2001; 2003***

## Continuing Urgent Medical Needs

**To provide the most effective treatment for a major addictive disease, long term heroin (or other short-acting opiate) addiction, the use of long-acting mu opioid agonists or partial agonists is usually essential.**
**To provide the most effective treatment for chronic pain, neoplastic or other, the use of long-acting mu opioid agonists or partial agonists are often essential.**

***Kreek, 2003***

## Specific Critical Questions

**Is this mu opioid agonist medication and/or this specific formulation short- or long-acting?**
**Is the patient opioid naïve, modestly exposed, or long-term exposed and, thus, tolerant?**
**Does this patient already have a problem with some type of drug abuse or addiction or other indicators suggesting risk of increased vulnerability to develop an addiction?**

***Kreek, 2003***

## Oxycodone Hydrochloride*

***OxyContin**

## Hydromorphone Hydrochloride

## Fentanyl

## Kreek, 2003

| Generic Name
(Trade Name of Immediate Release Preparation)
(Dosing Interval)
(Dosage) | Trade Name(s) of Extended Release Preparation
(Dosing Interval)
(Dosages)
(higher doses for tolerant individuals only) | Plasma t1⁄2 (h) | Dynamics/Duration of Extended Release Formulation |
| --- | --- | --- | --- |
| Oxycodone
       (q 4h)
       (5mg; 10mg) | e.g., OxyContin®
(q 12h)
(10, 20, 40, 80mg)* | 2.7h | 12h duration (t1⁄2 absorption—bimodal, e.g., 0.6 and 6.9h) |
| Hydromorphone
       (e.g., Dilaudid ®)
       (q 4h)
       (2mg; 4mg) | e.g., Hydromorphin                Contin ®
(q 12h)
(8, 16, 32, 64mg)* | 2.6h | 12h duration |
| 3)    Morphine
       (q 4h)
       (multiple) | e.g., MSContin ®
e.g., Kadian Reg ®
(q 12h)
(15, 30, 60, 100, 200mg)* | 2 to 4h | 12h duration |
| 4)    Fentanyl | e.g., Duragesic ®
(q 72h)
(25, 50, 75, 100μg/h)*
(2.5, 5.0, 7.5, 10mg) | 3-12h (?) | 72h duration |

***Kreek, 2003***

****“Taken broken, chewed, crushed xxx (compound formulations 1, 2, or 3)***
***   ******could lead to rapid release... toxic dose.”***

## Hypothesis

**Also, individual differences in responses to endogenous opioids (“physiogenetics”) or treatment pharmacotherapies (“pharmacogenetics”) may be mediated by variant forms of the mu opioid receptor.****                                                                                                                   **

**Hypothesis**

## Role of Mu Opioid Receptor and Related EndorphinSystems in Normal Physiological Functions*

**Role of Mu Opioid Receptor and Related Endorphin****Systems in Normal Physiological Functions***

**  ****Neuroendocrine Functions**
**Stress responsive systems including****hypothalamic-pituitary-adrenal axis**
**Reproductive function including****hypothalamic-pituitary-gonadal axis**
**  ****Response to Pain**
**  ****Immunological Function**
**  ****Gastrointestinal Function**
**  ****Cardiovascular Function**
**  ****Pulmonary Function**
**  ****? Mood, Affect; Cognition**

*Kreek, 2000*

## Human Gene Diversity: Single Nucleotide Polymorphisms (SNPs) in Genes: Definitions

**SNP — a single nucleotide polymorphism, that is, one nucleotide or base of any base pair that is different from the “usual”, “prototypic”, (or first identified and recorded base)**
**Coding region — that part of a gene which codes for a peptide (protein)**
**Allelic Frequency:****	****<1%****	****low or rare****	****	****	****1–5%****	****intermediate****	****	****	****>5%****	****high or frequent**

***M.J. Kreek, 2000***

## Single Nucleotide Polymorphisms inHuman Mu Opioid Receptor Gene

**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)**
**G779A****	****	****3****	****CL3****	****	****Arg 260 His (R260H)****	****<1%**
**	****	****	****	****	****	****	****(1 heterozygous)**
**G942A****	****	****3****	****EL3****	****	****Synonymous****	****<1%**
**	****	****	****	****	****mutation****	****	****(1 heterozygous)**

**Single Nucleotide Polymorphisms in****Human Mu Opioid Receptor Gene**

** Nucleotide position 1 is first base of the start codon.*

*Bond et al., 1998*

## Allelic Frequency AssociationsOpioid Dependence – C17T and A118G

**2**

** **

** **

**2**

**(1)**

** **

** **

**2**

**2**

**(1)**

**2**

**(1)**

*****

**This finding is similar to that obtained by Berrettini et al. (1997) **

****

** ****= 4.1 [p=0.05]**

**†**

**However, within the Hispanic study subjects groups (total n=67), the A118G variant allele was present in a significantly higher proportion of non-opioid dependent subjects compared to opioid dependent subjects. **
**(Yates corrected Chi-square**

****

** ****= 8.22 [p=0.0041])**

**Dependent**

**Non-dependent**

**Yate's corrected **

****

** ****=**

**C**

**207**

**(0.916)**

**77**

**(0.987)**

**T**

**19**

**(0.084)**

**1**

**(0.013)**

**Total**

** ****226**

**78**

**A**

** ****206**

**(0.912)**

**66**

**(0.846)**

**G**

**20**

**(0.088)**

**12**

**(0.154)**

** ****3.70 (p = 0.054)***

** ****1.98 (p = 0.159)**

**†**

*Bond et al., 1998*

## Human MOR Gene SNPs 

**SNPvs with changed AA**

**Synonymous mutation**

**Putative Glycosylation site**

- extracellular fluid

- cell interior

- cell membrane

- HOOC

- 400

- 100

- H2N

- 50

- S4R

- A6V

- N40D

- V234L

- 350

- 300

- 250

- 200

- 150

- S147C

- N152D

- R260H

- R265P

- S268P

*Kreek, Yuferov and LaForge, 2000*

## 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**

**80**

**60**

**40**

**20**

**Percent Bound**

**0**

**1.0**

**0.5**

**Fraction Maximum Current Response**

**0**

**Log [Endomorphin -1(M)]**

**-11**

**-10**

**-9**

**-8**

**-7**

**-10**

**-9**

**-8**

**-7**

**-6**

**100**

**80**

**60**

**40**

**20**

**0**

**Log [******** Endorphin (M)]**

**-11**

**-10**

**-9**

**-8**

**-7**

**A118G**

**Prototype**

*Bond et al., 1998*

**1.0**

**0.5**

**0**

**-9**

**-8**

**-7**

**-6**

**Log [Endomorphin -1(M)]**

**Log [******** Endorphin (M)]**

## “Physiogenetics”—Cortisol Levels After Incremental Naloxone Administration:Mu Opioid Receptor A118G Heterozygote Individuals

- 24

- 22

- 20

- 18

- 16

- 14

- 12

- 10

- 8

- 50

- 0

- 50

- 100

- 150

- 200

**Time***** *****(min)**

**Serum Cortisol (ug/dl)**

**N**

**N**

**N**

**N**

**PI**

**A/A (n=29)**

**A/G (n=7)**

**“****Physiogenetics”—****Cortisol Levels After Incremental Naloxone Administration:****Mu Opioid Receptor A118G Heterozygote Individuals**

***Kreek, 1999; Wand et al, 2002***

## “Physiogenetics”?– Pharmacogenetics–ACTH and Cortisol Levels in Family History Positive (n=8) and Negative (n=7) Social Drinkers after 50mg Oral Naltrexone

**“****Physiogenetics”?– Pharmacogenetics–****ACTH and Cortisol Levels in Family History Positive (n=8) and Negative (n=7) Social Drinkers after 50mg Oral Naltrexone**

***Kreek 1999;***
***King et al, 2002***

**Time (min) Post Capsule**

**ACTH (pg/ml)**

**0**

**30**

**60**

**90**

**120**

**150**

**180**

**240**

**30**

**20**

**10**

**0**

**40**

**50**

**Naltrexone**

**Placebo**

**60**

**FH+**

**Time (min) Post Capsule**

**ACTH (pg/ml)**

**0**

**30**

**60**

**90**

**120**

**150**

**180**

**240**

**30**

**20**

**10**

**0**

**40**

**50**

**Naltrexone**

**Placebo**

**60**

**FH-**

**Naltrexone**

**Time (min) Post Capsule**

**Cortisol (μg/dl)**

**0**

**30**

**60**

**90**

**120**

**150**

**180**

**240**

**0**

**15**

**10**

**5**

**20**

**25**

**Placebo**

**FH+**

**Time (min) Post Capsule**

**Cortisol (μg/dl)**

**0**

**30**

**60**

**90**

**120**

**150**

**180**

**0**

**15**

**10**

**5**

**20**

**25**

**Naltrexone**

**Placebo**

**FH-**

## Pharmacogenetics:Mu Opioid Receptor A118G Polymorphism—Naltrexone Treatment Response

_**Study 1**_**:****	****UPENN (Monterosso *****et al.*****, 2001)***
**	****	******** ****183 alcohol dependent outpatient subjects**
**	****	******** ****Randomized to 3 groups:**
**	****	****	****a) 9 months of naltrexone  (100mg/day)**
**	****	****	****b) 12 weeks of naltrexone (100mg/day),****	**
**	****	****	****     ****followed by 6 months of placebo**
**	****	****	****c) 9 months of placebo**
_**Study 2**_**:****	****UPENN (unpublished)***
**	****	******** ****240 alcohol dependent outpatient subjects**
**	****	******** ****Randomized to 6 groups:**
**	****	****	****a) either naltrexone (100mg/day) for 24 weeks or**
**	****	****    ****	****b) placebo for 24 weeks**
**	****	****    ****	****c) all subjects in (a) or (b) randomized to 3 different**
**	****	****	****     ****psychosocial interventions**
_**Study 3**_**:****	****University of Connecticut Health Center (Kranzler *****et al.*****, 2000)***
**	****	******** ****183 alcohol dependent outpatient subjects**
**	****	******** ****After Initial treatment of 1 week single-blind placebo, randomized**
**	****	****     ****to 3 groups:**
**	****	****	****a) naltrexone (50mg/day)**
**	****	****	****b) placebo**
**	****	****	****c) nefazine (up to 600mg/day)**

***All subjects consented for genetics studies either at the time of naltrexone study or at a later date**

***Oslin, Berrettini, Volpicelli, Kranzler, O’Brien, et al., 2003***

## “Pharmacogenetics”—Naltrexone Treatment Response:Survival Analyses for Time to Relapse in Subjects With One or Two Copies of the Asp40 Allele vs. Those Homozygous for the Asp40 Allele by Medication Group

**Cumulative Survival (Time to Relapse)**

**Days**

***Oslin, Berrettini, Volpicelli, Kranzler, O’Brien, et al., 2003***

## Mu Opioid Receptor Gene: Evidence of Association or Linkage With Addictions

_**Alcohol Dependence**_** **
**For: Town, et al., 1999**
**No Evidence For: Bergen, et al., 1997; Kranzler et al., 1998; Sander et al., 1998; Gelernter et al., 1999; Gscheidel et al., 2000.**
_**Opioid Dependence**_
**For: Bond et al., 1998; Szeto et al., 2001; Shi et al., 2002; Tan et al., 2003; ****Bart et al., 2003**
**No Evidence For: Kranzler et al., 1998; Li et al.,2000; Franke et al., 2001.**
_**Mixed Drug Dependence**_
**For: Berrettini et al., 1997; Hoeho et al., 1997; Hoehe et al., 2000,****Schinka et al., 2002; Luo et al, 2003**
**No Evidence for: Kranzler et al., 1998; Gelernter et al., 1999**

***adapted from K.S. LaForge, 2003***

## Allelic Frequencies of the Variant Allele of the A118G Single Nucleotide Polymorphism of the Human -Opioid Receptor Gene in Diverse Populations

**population ****	**** (1997)****	****(1998)****	****(1999)****	****(2001)****	****(2003)****	****(2003)**
**Asian**
**   ****Japanese****	****	****	****0.485 (34)**
**   ****Han Chinese****	****	****	****	****0.362 (297)**
**   ****Chinese****	****        ****	****	****	****	****0.351 (208)**
**   ****Thai****	****         ****	****	****	****	****0.438 (56)**
**   ****Malay****	****	****	****	****	****0.446 (156)**
**Indian****	****	****	****	****	****0.442 (137)**
**Southwest Native ****	****	****	****0.163 (367)****American**
**Caucasian**
**   ****European American ****	****    0.105 (100)      0.115 (52)        ****	****0.141 (543)****Finnish Caucasian****	****    0.122 (324)**
**   ****Swedish Caucasian** **	****	****	****	****	****	**** 0.107 (187)*** *
**	**
**Hispanic****	****	****0.142 (67)        ****	****0.117 (47)**
**African American****	****	****0.016 (31)        ****	****0.028 (144)**
**Other (populations in Israel)**
**   ****Ethiopian****	****	****	****0.170 (49)**
**   ****Bedouin****	****	****	****0.080 (43)**
**   ****Ashkenazi****	****	****	****0.210 (93)**
**	****	**

- Allele frequency for the variant allele is shown for various study populations.  Numbers in parentheses are the number of subjects whose genotype was ascertained in each study.  A study of Han Chinese found the 118G allele at a frequency of 0.321, and no occurrence of the 17T allele in 540 subjects (Li et al., 2000).

**Allelic Frequencies of the Variant Allele of the A118G Single Nucleotide Polymorphism of the Human ********-Opioid Receptor Gene in Diverse Populations**

***LaForge, Yuferov***
***and Kreek, 2003***

## Human Gene Diversity – SNPs and OtherPolymorphisms in Coding Region ofOpioid Receptor Genes

**# Polymorphisms**
**Identified by our**
**Laboratory***

**# of Additional**
**Polymorphisms**

**Gene **

**Total #**

**Mu opioid receptor****	****11****	****6****	****17**
**Kappa opioid receptor****	****8****	****1****	****9**
**Delta opioid receptor****	**** 0****	****2****	****2**

**  **

**Without or with prior identification or later verification by other groups*

***LaForge, Yuferov and Kreek, 2000; LaForge and Kreek, 2002***

## The Laboratory of the Biology of Addictive DiseasesMary Jeanne Kreek, M.D. – Professor and Head2003

**Ann Ho****	****Gavin Bart ****	****Kitt Lavoie**
**K. Steven LaForge****	****Lisa Borg****	****Janesse Rojas**
**Eduardo Butelman****	****Scott Kellogg ****	****Susan Russo**
**Vadim Yuferov****	****Charles Lilly****	**
**David Nielsen**** ****	****	**_**Assistants for Research**_
**Yan Zhou ****	**_**Clinical Adjunct Scientists**_** ****	****Jonathan Ball**
**Alexis Bailey ****	****Paola Piccolo ****	****Lauren Bence**
**Thomas Kroslak** **	****Joan Culpepper-Morgan ****	****Jason Choi**
**Dmitri Proudnikov ****	****Lawrence Brown ****	****Wan-Xin Feng**
**Brian Reed** **	****James Kocsis ****	****David Fussell **
**Stefan Schlussman ****	****Mark Green ****	****Rob Gianotti**
**Adena Svingos****	****Lynette Benjamin ****	****Todd Harris**
**Yong Zhang ****	****Elizabeth Khuri ****	****Lauren Hofmann**
**	****Aaron Wells ****	****Elizabeth Oosterhuis**
_**Laboratory Adjunct Scientists**_** ****	****	**
**Charles Inturrisi** **	**_**Research Nurses**_** ****	**_**Laboratory Worker**_
**Roberto Picetti**** ****	****Kathy Bell ****	****Laura Nunez**
**Virginia Pickel ****	****Elizabeth Ducat ****	**
**Ellen Unterwald** **	****Dorothy Melia****	****	**
**Vanya Quinones-Jenab ****	**

**The Laboratory of the Biology of Addictive Diseases****Mary Jeanne Kreek, M.D. – Professor and Head****2003**

## NIH-NIDA K05-DA00049

**	****“****Addictive Drugs: Pharmacology and Physiology”**
**NIH-NIDA P60-DA05130**
**	****“****Treatment of Addictions: Biological Correlates”**
**NIH-NIDA R01-DA09444**
**	****“****Mu Opioid Receptor Gene in Heroin Addicts”**
**NIH-NIDA R01-DA11113**
**	****“****Effects of Systematically Administered Dynorphins”**
**NIH-NIDA R01-DA12848**
**	****“****Addictions: Genotypes, Polymorphisms and Function”**
**NIH-NIDA U10-DA13046**
**	****“****NIDA Clinical Trials Network – NYC”**
**New York State OASAS**
**NIH-NCRR M01-RR00102**
**	****GCRC – The Rockefeller University Hospital**