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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