Post on 13-Jan-2016
Charles P. O’Brien, MD, PhDUniversity of Pennsylvania
Depriving Patients of Medication: Is this ethical ?
DisclosuresConsultant to
Embera (Research)
Alkermes (Depot Naltrexone,
no patent, no stock)
Gilead (drug development)
Reckit (drug development)
Recent Alcoholism Patient Recent Alcoholism Patient
40 yo married female40 yo married femaleDiscussed naltrexoneDiscussed naltrexoneReferred to excellent residential Referred to excellent residential program for detox and maintenanceprogram for detox and maintenance
6 weeks later…6 weeks later…Call from husbandCall from husband
RelapseRelapseDid she stop meds? No, counselor Did she stop meds? No, counselor
told her she shouldn’t take medicationtold her she shouldn’t take medication
CNN Special CNN Special Addiction: Life on the edgeAddiction: Life on the edge
5 patients followed for one year5 patients followed for one yearDifferent parts of countryDifferent parts of country
AdmissionsAdmissions
GraduationsGraduations
RelapsesRelapses
Interviews with counselors at Interviews with counselors at famous programsfamous programs
Sanjay Gupta, MDSanjay Gupta, MDInterviews, patients, families, reasons for Interviews, patients, families, reasons for relapsesrelapses
Last show:Last show:Tall patient from Brown UniversityTall patient from Brown University
Not one of the 5 index patientsNot one of the 5 index patients
Interviewed near end of seriesInterviewed near end of series
Apparently Apparently onlyonly patient treated with patient treated with medicationmedication
GUPTA: And so he tried again. He checked himself into an experimental program run by Brown University. This time he got counseling once a week and a daily pill. A medicine called naltrexone. About two months into it, Walter Kent suddenly noticed the world around him looked and felt different.
KENT: And I had just turned around and I said, this is really something for the first time in my life that I never had this sensation where I didn't want a drink. And this, to me, was like a godsend because of the fact that for someone who had to have a drink, now all of a sudden I don't need that -- I don't have that feeling anymore.
GUPTA: He hasn't had a drink in more than eight years. Even after his doctor stopped the medication. He's healthy, back at work, fixing up carburetors. And now he's part of a running debate. Is addiction an illness you can treat with a pill or a character flaw to be tackled with therapy and self-help?
Addiction: Life on the Edge – CNN Correspondent Dr. Sanjay Gupta aired April 19, 2009
GUPTA: Despite the evidence, most fancy rehab centers use medication only rarely, if at all. The focus is much more on therapy.
Head Counselor Minnesota: “With the health care professional staff here at Hazelden, our experience tells us having that network of support in recovery is what really makes the difference.
GUPTA: More so than medication?
CLARK: More so than just medication, exactly.
GUPTA: And that's the conventional wisdom.”
Addiction: Life on the Edge – CNN Correspondent Dr. Sanjay Gupta aired April 19, 2009
California Program
GUPTA: What about medications?
Head Counselor California Program: “We do not use them at the Betty Ford Center.”
No comment from the interviewer, no follow up questions.
Addiction: Life on the Edge – CNN Correspondent Dr. Sanjay Gupta aired April 19, 2009
UPenn Teaching on addictionUPenn Teaching on addiction
Medical students, required course, Medical students, required course, year 1, all students (n=165)year 1, all students (n=165)
Lectures, seminars, recovering Lectures, seminars, recovering physicians, 12 step meeting, patient physicians, 12 step meeting, patient interviews:interviews:Exam on all aspects of addiction:Exam on all aspects of addiction:
Psychological, Psychological, pharmacological, emphasis on AA pharmacological, emphasis on AA as collaborator with MDsas collaborator with MDs
UPenn Teaching on addictionUPenn Teaching on addiction
Psychiatry residents: seminars & Psychiatry residents: seminars & pt. supervision, multi disciplinary pt. supervision, multi disciplinary recruit for addiction residencyrecruit for addiction residency
Addiction psychiatry residencyAddiction psychiatry residency
Research NIDA post doc T32Research NIDA post doc T32
Minority internshipMinority internship
Clinical TrialsClinical Trials
• PsychotherapyPsychotherapy• Voucher based reinforcementVoucher based reinforcement• PharmacotherapyPharmacotherapy• Addiction Severity IndexAddiction Severity Index
Treatment Research InstituteTreatment Research InstituteTranslation of research findingsTranslation of research findings
Private PracticePrivate Practice
• Evidence based treatmentEvidence based treatment• Psychotherapy including family Psychotherapy including family
therapytherapy• Pharmacotherapy when indicatedPharmacotherapy when indicated
Hypertension (High Blood Pressure)Hypertension (High Blood Pressure)
• Thiazide diuretics• Alpha receptor blockers • Beta receptors blockers• Angiotension II receptor blockers• Calcium channel blockers• Angiotension converting enzyme blockers
Alcohol (ethyl alcohol)Alcohol (ethyl alcohol)
• Depressant: Acetyl choline, GABA, serotonin, NMDA receptors
• Motivation to consume: Release of Endogenous opioids (endorphins)
Why is endorphin effect of alcohol often ignored?
FDA Approved MedicationsFDA Approved Medications
• Disulfiram (Antabuse)• Naltrexone (generic)• Acamprosate (Campral)• Depot Naltrexone (Vivitrol)
-60-50-40-30-20-10
010203040
1 to 5 5 to 10 10 to 15
Naltrexone 1.0 mg/kg
Naltrexone 3.0 mg/kg
Naltrexone 5.0 mg/kg
Naltrexone decreases Alcohol preference*Naltrexone decreases Alcohol preference*
Days NaltrexoneDays Naltrexone* Altshuler 1980* Altshuler 1980
% C
han
ge
fro
m S
alin
e P
retr
eatm
ent
% C
han
ge
fro
m S
alin
e P
retr
eatm
ent
Res
po
nse
Lev
els
(10
day
mea
n)
Res
po
nse
Lev
els
(10
day
mea
n)
Brain Reward System
PrefrontalCortex
Nucleus Accumbens
Arcuate Nucleus Ventral
TegmentalArea
Nestler and Malenka. The Addicted Brain. Scientific American. March, 2004.
–
GABA
Ventral Tegmental AreaArcuate Nucleus
Dopamine
-Endorphin Neuron
Long Loop
Nucleus Accumbens
Dopamine
–
Alcohol
Gianoulakis. Alcohol-Seeking Behavior: The Roles of the Hypothalamic-Pituitary-Adrenal Axis and the Endogenous Opioid System. Alcohol Health and Research World. 1998;22(3).
DopamineOpioid Antagonism
–
GABA
Ventral Tegmental AreaArcuate Nucleus
-Endorphin Neuron
Nucleus Accumbens
–
Alcohol
Dopamine
Gianoulakis. Alcohol-Seeking Behavior: The Roles of the Hypothalamic-Pituitary-Adrenal Axis and the Endogenous Opioid System. Alcohol Health and Research World. 1998;22(3).
Alcohol effects become conditioned to environmental cues
Naltrexone blocks cue induced relapse better than stress induced
70
80
90
100
110
120
130
140
150
10 20 30 40 50 60 70
Time (minutes)
Do
pa
min
e (
% b
as
eli
ne)
Saline, N=13
Naltrexone, N=16
Pre-AlcoholPre-Alcohol “Craving”“Craving”
Alcohol - Beverage Condition
Insula
Cingulate
Nucleus Accumbens
Z=1.645 Ex .05
Alcoholics (n=10) Controls (n=10)
Ventral Tegmental Area
Cingulate
Z=1.645 Ex .05
Alcohol - Beverage Condition
Alcoholics (n=10) Controls (n=10)
Philadelphia VA Hospital
• 70 chronic alcoholics
• All received intensive day hospital, AA, psychotherapy
• Half received Naltrexone 50 mg/day
• Half received identical placebo
• Weekly craving scores
• “slips” measured (not a relapse)
• Relapse defined
(Treatment staff resisted the study)
Pharmacological Treatments for Pharmacological Treatments for AlcoholismAlcoholism
Mea
n (
SE
M)
Cra
vin
g S
c ore
(0-
9)M
ean
(S
EM
) C
ravi
ng
Sco
re (
0 -9)
0
1
2
3
4
5
Placebo
Naltrexone
0 1 2 3 4 5 6 7 8 9 10 11 120 1 2 3 4 5 6 7 8 9 10 11 12
Weeks on MedicationWeeks on Medication
Craving Scores by WeekCraving Scores by Week
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
0
20
40
60
80
Any Alcohol DrinkingAny Alcohol Drinking
Naltrexone PlaceboNaltrexone Placebo
Per
cen
t o
f S
ub
ject
sP
erce
nt
of
Su
bje
cts
0.0
0.2
0.4
0.6
0.8
1.0
Days DrinkingDays Drinking
Naltrexone PlaceboNaltrexone Placebo
Ave
rag
e D
rin
kin
g D
ays
Ave
rag
e D
r in
kin
g D
ays
per
wee
kp
er w
eek
A.A. coming to treatment appointment coming to treatment appointment with a blood alcohol concentration with a blood alcohol concentration
> 100 mg%> 100 mg%oror
B.B. self report of drinking five or more self report of drinking five or more days within one weekdays within one week
oror
C.C. self report of five or more drinks during self report of five or more drinks during one drinking occasionone drinking occasion
Alcohol RelapseAlcohol Relapse
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 12
0.0
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
ula
tive
Pro
po
rtio
n w
ith
No
Rel
apse
Cu
mm
ula
tive
Pro
po
rtio
n w
ith
No
Rel
apse
Rates of Never Relapsing According to Treatment Group Rates of Never Relapsing According to Treatment Group (n=97)(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
Per
cent
With
out R
elap
se
0 20 40 80 60
Studies supporting efficacyStudies supporting efficacy Studies not supporting efficacyStudy # Ss Notes Study # Ss Notes
Volpicelli, et al 1992 70 None Kranzler, et al 1999
183 None
O’Malley, et al 1992 97 None Krystal, et al 2002 627 None
Mason, et al 1994 [Nalmefene]
21 None
Oslin, et al 1997 44 Elderly
Volpicelli, et al 1997 97 None
Mason, et al 1999 [Nalmefene]
105 None
Kranzler, et al 1998 20 Depot
Anton, et al 2000 131 None
Chick, et al 2000 (UK) 169 Adherence
Monterosso, et al 2001 183 None
Morris, et al 2001 (Australia)
111 None
Heinala, et al 2001 (Finland)
121 Nonabstinent
Lee, et al 2001 (Singapore)
Kiefer et al 2003 (Germany)
53
160
None
None
Studies supporting efficacy Studies not supporting efficacy
Study # Ss Notes Study # Ss Notes
Latt et al 2002 107 Family Prac
Balldin et al 2003 118 None
Feeney et al 2001 50 Hist. cont
Rubio et al 2001 157 v. Acamp.
Rubio et al 2002 30 Cont. Drink.
Gastpar et al 2002 105 Neg. in self report
Pos. GGT
Gastpar et al 2002 105 Neg. in self
report
Pos. GGT
Guardia et al 2002 202 Relapse
Kranzler et al 2003 153 Heavy drinkers
O’Malley et al 2002 18 Human lab
Anton et al 2006 1383 RCT, depot
Results: Heavy Drinking Days
Baseline
Placebo
Vivitrex 190 mg
Vivitrex 380 mg
75th Percentile
25th Percentile
Med
ian
Hea
vy
Dri
nki
ng
Da
ys p
er M
on
th
0
5
10
15
20
25
30
Overall Male Female
19.3
7.05.6
4.94.0
2.1
5.4
19.3
3.1
5.94.4
21.5
Why do many alcoholics respond to naltrexone, but others show no response?
% D
ays
Hea
vy D
rin
kin
g
(PACS < 5) (PACS 6-15) (PACS > 15)
0
2
4
6
8
10
12
14
16
Low Crave Mod Crave High Crave
NTX
PLAn = 44
n = 72
n = 57
PACS = Penn Alcohol Craving Scale
Baseline Craving Scores
Family History and Naltrexone EfficacyFamily History and Naltrexone Efficacy%
Day
s H
eavy
Dri
nki
ng
% D
ays
Hea
vy D
rin
kin
g
0
2
4
6
8
10
12
14
16
NXTPLA
< 25% Alc Problem 25%-50% Alc Problem > 50% Alc Problem
Density of Familial Alcohol Problems
n = 77 n = 73
n = 29
Baseline b-Baseline b-Endorphin Levels in Low- and Levels in Low- and High-Risk, and Abstinent Alcoholic PatientsHigh-Risk, and Abstinent Alcoholic Patients
0
10
20
30
40
50
Low Risk High Risk Abstinent
Pla
sma
Pla
sma
-E
nd
orp
hin
Lev
els
(pg
/ml
-En
do
rph
in L
evel
s (p
g/m
l)
Gianoulakis. Gianoulakis. Eur J Pharmacol.Eur J Pharmacol. 1990;180:21-29 1990;180:21-29.
0
20
40
60
80
100
120
140
160
180
0 20 40 60 80 100 120
High Risk
Low Risk
Minutes after alcohol consumptionMinutes after alcohol consumption
% c
han
ge
in p
lasm
a b
-en
do
rph
in le
vels
% c
han
ge
in p
lasm
a b
-en
do
rph
in le
vels
Change in b- Endorphin Levels after Alcohol Change in b- Endorphin Levels after Alcohol
ConsumptionConsumption
0
5
10
15
20
25
FH+
FH-
0
5
10
15
20
25
BAES Stimulation Scores BAES Stimulation Scores Among FH+ and FH SubjectsAmong FH+ and FH Subjects
PlaceboPlacebo NaltrexoneNaltrexone
Base 2 30 min 60 min 120 minBase 2 30 min 60 min 120 min Base 2 30 min 60 min 120 minBase 2 30 min 60 min 120 min
Key effect: Sensitivity of Endogenous Opioid system to alcohol
One source of individual variability in response to ethyl alcohol
OPRM1 PROTEIN STRUCTURE
LIGAND BINDING
EXTRACELLULARNH2 TERMINUS
A118G
COOH TERMINUS
N40D, N is anN-glycosylation site
Human Mu Opioid Receptor Gene
PROMOTOR 5’UTR EXON 1 EXON 2 EXON 3 EXON 4 3’UTR
10 variants
4 5’UTR
SNPs
2 SNPs 1 SNP
6 INTRON 2 SNPs6 INTRON 2 SNPs
1 INTRON 1 INTRON
3 SNP3 SNP1 3’UTR
SNP6.6 kb of OPRM1 gene sequence was determined in ~200 persons; 25 variants occurred at a frequency >1%.
The 118 A>G exon 1 SNP increases OPRM1 affinity for beta-endorphin. The functional significance of other variants remains unknown.
05
101520253035404550
0.02 0.04 0.06
AA alleleAG allele
Se
lf-r
e po
rte
d S
tim
ula
t io
n (
SH
AS
)
Breath Alcohol ConcentrationBreath Alcohol Concentration
Alcohol effects by genotypeAlcohol effects by genotype
Ethnicity & A118G Allele Frequency
• Based on multiple studies, allele frequencies differ markedly across ethnicities for the A118G SNP in the mu opioid receptor gene. It arose after the out-of-Africa migration.
• Crowley et al, 2003• Gelernter et al,
1999• Tan et al, 2003• Bart et al, 2004
African 1% Koreans 31%
African-
American
3% Chinese 35%
Swedish 17% Malaysian 45%
European-
origin US
15% Indian 47%
ETHNICITY f(G) ETHNICITY f(G)
OPRM1 A118G and Opioid DependenceOPRM1 A118G and Opioid Dependence
Bart et al (Mol Psychiatry 9:547, 2004) studied opioid addicts in
Sweden for A118G.
0
20
40
60
80
100
120
140
160
controls opioidaddicts
A/A
A/G, G/G
There was a significant (Chi squared = 13, p = 0.00025)increase in A/G, G/G genotypeamong opioid addicts. The attributable
risk for the G allele is ~ 18%, suggesting
that ~ 18% of Swedish opioid addicts have disease in part due to the G allele.
OPRM1 A118G and AlcoholismOPRM1 A118G and Alcoholism
Bart et al (Neuropsychopharmacol, 2005) studied alcoholics in Sweden for the A118G.
0
50
100
150
200
250
300
controls alcoholics
A/A
A/G, G/G
There was a significant (Chi squared = 7.2, p = 0.007)increase in A/G, G/G genotypeamong alcoholics. In this study the attributable risk for the G
allele is ~ 11%, suggesting that
~ 11% of Swedish alcoholics have disease in part due to the G allele.
Relapse Rate by GenotypeRelapse Rate by Genotype
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)
847070564228140
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)
8484565642422828141400
1.01.0
.9.9
.8.8
.7.7
.6.6
.5.5
.4.4
.3.3
.2.2
.1.1
0.00.0
Naltrexone /Naltrexone /Asp40 Allele (A/G, G/G)Asp40 Allele (A/G, G/G)
Naltrexone Naltrexone Asn40 Allele (A/A)Asn40 Allele (A/A)
Placebo /Placebo /Asp40 Allele (A/G, G/G)Asp40 Allele (A/G, G/G)
Placebo /Placebo /Asn40 Allele (A/Al)Asn40 Allele (A/Al)
Pro
po
rtio
n N
on
rela
pse
dP
rop
ort
ion
No
nre
lap
sed
DaysDays
COMBINE Study
• N = 1383; 9 randomized groups– MM + Placebo
– MM + Naltrexone
– MM + Acamprosate
– MM + Naltrexone + Acamprosate• CBI only
• At least 4 days abstinence at baseline• Endpoints
– Percent days abstinent
– Time to first heavy drinking day
+/- CBI
CBI = cognitive behavioral intervention;MM = medical managementAnton et al. JAMA. 2006;295:2003.
Combine: NIAAACombine: NIAAAGood OutcomeGood Outcome
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)
*VA multi-site study: sample size with G allele small*VA multi-site study: sample size with G allele small
Sub-sample of VA coop. study (original report was
negative)
Those who gave blood for DNA
Naltrexone sig. outcome better than placebo, but no genetic
association.
Finnish study with Nalmefene- Naltrexone superior to
placebo, but no genetic association
Two PROSPECTIVE studies in progress
Genotype first, then randomize
EndophenotypeEndophenotypeEndorphin Dependent AlcoholismEndorphin Dependent Alcoholism
• AlcoholAlcohol Endogenous Opioids Endogenous Opioids
• Euphoria/StimulationEuphoria/Stimulation
• Sensitive µ ReceptorsSensitive µ Receptors
• Family HistoryFamily History
• Alcohol CravingAlcohol Craving
05
101520253035404550
0.02 0.04 0.06
AA alleleAG allele
Se
lf-r
e po
rte
d S
tim
ula
t io
n (
SH
AS
)
Breath Alcohol ConcentrationBreath Alcohol Concentration
Alcohol effects by genotypeAlcohol effects by genotype
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
Sertraline + Naltrexone for Co-Occurring Depression & Alcohol Dxs
% Alcohol Dx Patients with Complete Abstinence In-Trial
Hamilton Score Change From Baseline
A “new” treatment based on animal models
Abstinence v. reduction in heavy drinking1979: Naltrexone reduces alcohol drinking in monkeys1980: Rat models of alcohol drinking: decrease1983: First studies of heroin medication in alcoholics1988: First clinical efficacy reports1990: First publication1992: Replication1994: FDA “surprise” approval2006: FDA approval of depot version for alcoholism2010: Cost benefit advantages
Why so infrequently used?
Arguments against medicationsArguments against medications
• They are just a “crutch”• You have to work the program yourself –
no chemical aids• They get in the way of the 12 steps• I’ve been sober for 10 years and I never
took medication• They have side effects• You’ll become addicted to them• Etc…
Why has it been so difficult to obtain acceptance of opioid aspects of alcoholism?
Best TreatmentBest Treatment
• Medications
Plus
• Psychosocial Intervention
Do we as therapists have the right to deprive our patients of the opportunity to see if they get a good response to medication?
Penn/VA Center TeamPenn/VA Center Team
Joe Volpicelli James McKayWade Berrettini A. Thomas McLellanJohn Cacciola David MetzgerAnna Rose Childress David OslinJames Cornish Helen PettinatiCharles Dackis Michael StrombergRonald Ehrman Elmer YuTeresa Franklin George WoodyKyle Kampman Arthur Alterman
FOR MORE INFORMATIONFOR MORE INFORMATION
http://www.med.upenn.edu/csa/http://www.med.upenn.edu/csa/or or
obrien@mail.trc.upenn.eduobrien@mail.trc.upenn.edu
Measures of CravingMeasures of Craving
• 100 mm Visual Analog Scale100 mm Visual Analog Scale• Anton’s Obsessive Compulsive Anton’s Obsessive Compulsive
Drinking ScaleDrinking Scale• Alcohol Urge QuestionnaireAlcohol Urge Questionnaire• Penn Alcohol Craving ScalePenn Alcohol Craving Scale
OPRM1 A118G EFFECTON TRANSLATION
Zhang et al, JBC, 2005
Lotsch et al, 2006
Naltrexone Affinity at Opioid Naltrexone Affinity at Opioid Receptor SubtypesReceptor Subtypes
Receptor Binding Ki (nM) Mu Delta Kappa
________________________________________________Antagonist:
Naltrexone 0.37 9.4 4.8________________________________________________Agonists:
Morphine (m ) 38 510 1,900DADL-enke (d) 150 1.8 >10,000(-)-EKC (k) 2.3 5.2 2.2
Schmidt, W.K., et al., Drug Alcohol Depend, 1985;14:339-362.
Receptor Blockade with Naltrexone (50mg)
Study Naltrexone Time Receptor Dose (hr) Blockade (%)
Lee et al, 50 mg 48 91 1988* 72 80
120 48 168 30
* Lee, MC, et al J Nuc Med, 1988, 29(7) 1207-1211
Receptor Blockade with Naltrexone in Alcoholics (50mg)
93% blockade of µ receptors, 24 hours, all SS C 11 carfentanil
Variable (22.8 +/- 12%) blockade of ∂ receptors C 11 N methyl naltrindole, 24 hrs.
* McCaul et al 2004