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