Practical ApplicationsPractical Applications

OfOf

Neuroscience ResearchNeuroscience Research

February 16, 2007

Charles P. O’Brien, MD, PhDUniversity of Pennsylvania

Philadelphia VA Medical Center

Search: Non-addicting medSearch: Non-addicting medfor severe pain NIH (NIDA)for severe pain NIH (NIDA)

Opiate Receptors 1973

Endogenous opioids “endorphins”

Enkephalin 1975 ∂

B-Endorphin µ

Dynorphin k

Nociceptin OFQ/NOC 1990’s

Post-SynapticNeuron

KappaKappa Mu Mu Delta Delta

Affinity for Opiate ReceptorAffinity for Opiate Receptor

TXTX

TXTX

TXTX

Opiate ReceptorsOpiate Receptors

KappaKappa MuMu DeltaDelta

NaltrexoneNaltrexone 406 406 108 108 54 54 MorphineMorphine 1 1 1 1 1 1

MORMOR

MORMOR

MORMOR

MOR

MOR

..

..

..

..

NOCNOC

NN

New Concepts:New Concepts:agonistagonistantagonistantagonistpartial agonistpartial agonistinverse agonistinverse agonist

Opiate receptor antagonistsOpiate receptor antagonists1970s1970s

Naloxone

reverse opiate analgesia

treat opiate overdose

Naltrexone

block heroin relapse (FDA 1984)

treat babies born with excess endorphins

treat form of infertility by stimulating gonadotrophins

Naltrexone treatment of opiate addictionNaltrexone treatment of opiate addiction

Little use for heroin addiction

Treatment of choice for physicians and other

“white collar” addicts

Successful treatment of parolees and probationers

Block revolving door: heroin-prison-heroin

SubstanceSubstance Oral Nltx Oral Nltx Control Control Sig.Sig.

(N=34)(N=34) (N=17) (N=17)

OpiateOpiate 8%8% 30%30% p<.05p<.05

CocaineCocaine 33%33% 49%49% NSNS

AmphetamineAmphetamine 0%0% 1%1% NSNS

BenzodiazepineBenzodiazepine 2%2% 6%6% NSNS

MarijuanaMarijuana 13%13% 19%19% NSNS

AlcoholAlcohol 2%2% 4%4% NSNS

ParoleesParolees

Mean Percent Positive UrinesMean Percent Positive Urines

Re-Incarceration at 6 monthsRe-Incarceration at 6 months

0

20

40

60

80

100

NaltrexoneNaltrexone ControlControl

Per

cen

t su

bje

cts

Per

cen

t su

bje

cts

26%26%

56%56%

P<.05P<.05

Study in Parolees with Study in Parolees with History of Opiate AddictionHistory of Opiate Addiction

Six sites

Providence, RI

NYC (Columbia)

NYC (NYU)

Philadelphia

Baltimore

Richmond

Relapse Rate to Heroin Addiction

Re-incarceration Rate

Alcohol stimulates endogenous opioidsAlcohol stimulates endogenous opioidsUnexpected finding from animal modelsUnexpected finding from animal models

Monkeys 1979

Rats 1980s

First study in human alcoholics, Philadelphia VAMC

1983-90

Family history positive alcoholics

Opiate-like euphoria from alcohol

High craving for alcohol

Subjective “high” in Naltrexone and Subjective “high” in Naltrexone and Placebo SubjectsPlacebo Subjects

Naltrexone PlaceboNaltrexone Placebo

mea

n “

hig

h”

rati

ng

mea

n “

hig

h”

rati

ng

0.1

0

- 0.1

- 0.2

- 0.3

- 0.4

- 0.5 **

* p<.05* p<.05

Non-relapse “Survival”Non-relapse “Survival”

Volpicelli et al, Arch Gen Psychiatry, 1992; 49: 876-880Volpicelli et al, Arch Gen Psychiatry, 1992; 49: 876-880

No. of Weeks Receiving MedicationNo. of Weeks Receiving Medication

10 2 3 4 5 6 7 8 9 10 11 120.0

0.1

0.2

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0.3Naltrexone HCL (N=35)Naltrexone HCL (N=35)

Placebo (N=35)Placebo (N=35)

Cu

mm

ulat

ive

Pro

port

ion

wit

h N

o R

elap

seC

um

mul

ativ

e P

ropo

rtio

n w

ith

No

Rel

apse

Rates of Never Relapsing According to Rates of Never Relapsing According to Treatment Group (n=97)Treatment Group (n=97)

O’Malley et al, Arch of Gen Psychiatry, Vol 49, Nov 1992

Naltrexone/coping skillsNaltrexone/supportive therapyPlacebo/coping skillsPlacebo/supportive therapy

Days

0

20

40

60

80

100

n=97

0 20 40 80 60

Naltrexone treatment of alcoholismNaltrexone treatment of alcoholism

Philadelphia VA results replicated 1992

FDA approval 1994

Naltrexone used throughout the world

for alcoholism

Does not work for all alcoholics

Genetics of alcoholismGenetics of alcoholism

Genetic variant of µ opiate receptor “G allele”

Increased euphoria from alcohol

Euphoria blocked by Naltrexone

Increased risk of opiate addiction

Increased risk of alcoholism

G allele: 20-25% of European-Americans

Poor outcome randomized to placebo treatment

& counseling

Excellent results with naltrexone & counseling

Days

8470564228140

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

Naltrexone /Asp40 Allele (A/G, G/G)

Naltrexone Asn40 Allele (A/A)

Placebo /Asp40 Allele (A/G, G/G)

Placebo /Asn40 Allele (A/Al)

Days

8470564228140

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

Naltrexone /Asp40 Allele (A/G, G/G)

Naltrexone Asn40 Allele (A/A)

Placebo /Asp40 Allele (A/G, G/G)

Placebo /Asn40 Allele (A/Al)

Days

8470564228140

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

Naltrexone /Asp40 Allele (A/G, G/G)

Naltrexone Asn40 Allele (A/A)

Placebo /Asp40 Allele (A/G, G/G)

Placebo /Asn40 Allele (A/Al)

Pro

po

rtio

n N

on

rela

pse

d

Relapse Rate by Genotype

Replication studyReplication study

NaltNalt A/G, GG A/G, GG 95%95% N = 28N = 28

Nalt Nalt A/A A/A 73%73% N = 86N = 86

Plac.Plac. A/G, GG A/G, GG 63%63% N = 60N = 60

Plac.Plac. A/A A/A 65%65% N = 205N = 205

Odds ratio, nalt good regs, GVA = 10.25 (95% CI 1.31 - 80.0 P= .03)Odds ratio, nalt good regs, GVA = 10.25 (95% CI 1.31 - 80.0 P= .03)

“Good” Results

New delivery systemNew delivery system

One injection each month

Slow release

Blocks opiates and endogenous opioids for one month

Alcoholism: FDA approved 2006

Opiate addiction: in clinical trial

SummarySummary

Search for non-addicting pain reliever

Discovery of opiate receptors

Discovery of endogenous opioids

Development of opiate antagonists

New treatment for opiate addiction

New treatment for alcoholism

Endophenotype of alcoholism

? Reduced re-incarceration of heroin addicts

Institutionalization in the United States Institutionalization in the United States (per 100,000 adults)(per 100,000 adults)

0

100

200

300

400

500

600

700

1928193419401946195219581964197019761982198819942000

___ Total RateTotal Rate __ __ __ Prison RatePrison Rate _ _ _ Mental Hospital RateMental Hospital Rate