Treatment of Addiction Treatment of Addiction

as HIV Preventionas HIV Prevention

August 6, 2008

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

DisclosuresDisclosures

Consultant toConsultant to

Forest (Campral)Forest (Campral)

Alkermes/Cephalon (Naltrexone)Alkermes/Cephalon (Naltrexone)

Merck (medication development)Merck (medication development)

18%

13%

21%

39%

51%

21%

0%

10%

20%

30%

40%

50%

60%

B 6 12 18 24 30 36 42 48 60 72

Baseline through 36 Months

Percent Testing Positive

In Treatment Out of Treatment

HIV Infection Rates by Treatment Status at Time of Enrollment

Fig. 1

Incidence of drug addictions in the Leningrad Region (Number of first time registered drug addicts per 100.000 of general population)

1 1,64,7

7,2 6,811,8 11,6

21,3

33,8

51,1 51,3

19,4

0

10

20

30

40

50

60

1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002

Prevalence of drug addictions in the Leningrad Region (Total number of registered drug addicts per 100.000 of general population)

7,9 8,7 12,4 19,8 27,439,3

5069,5

102,5

152,4

204,1216,7

0

50

100

150

200

250

1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002

Prevalence of IV drug users (%) among HIV positive individuals registered within a year

In the Leningrad Region

67 67

9491

82

66

0

10

20

30

40

50

60

70

80

90

100

1997 1998 1999 2000 2001 2002

In the city of St. Pe tersburg

20

56

8680

76

0

10

20

30

40

50

60

70

80

90

100

1997 1998 2000 2001 2002

Prevalence of HIV positive individuals (%) among drug addicts

In the Leningrad Regional Center of Addictions

0,00% 0,00% 1,00%

37,70%

33,40%

18,00%

1997 1998 1999 2000 2001 2002

In the St. Petersburg City Center of Addictions

0,00% 0,04% 0,45%

8,20%

18,70%

1997 1998 1999 2000 2001

Drug CategoriesHeroinStimulants

cocainemethamphetamine

AlcoholNicotineSedativesMarijuanaAnabolic SteroidsInhalantsClub Drugs

New Medications

BuprenorphineBup/Naloxone (Suboxone)

LAAM Naltrexone for alcoholism

Depot NaltrexoneAcamprosateTopiramate, Baclofen, GVGRimonabantOndansatronModafinilBupropion

Manual Guided Therapies

Cognitive Behavioral (CBT)Drug Counseling (DC)Twelve Step Facilitation (TSF)Motivation Enhancement Therapy (MET)BRENDA (Biopsychosocial, Nurse)Interpersonal Therapy (IPT)Family TherapyGroup Therapy

Drug Free TherapeuticCommunity

ExpensiveNot widely available nor covered by

insuranceMany addicts not willing to participateThose who graduate have 50% relapse

rate in one year

Post-SynapticNeuron

KappaKappa Mu Mu Delta Delta

Affinity for ReceptorAffinity for 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

MO

RM

OR

..

..

..

..

NOCNOC

NN

-10 -9 -8 -7 -6 -5 -40

10

20

30

40

50

60

70

80

90

100

Intrinsic Activity

Log Dose of Opioid

Full Agonist(Methadone)

Partial Agonist(Buprenorphine)

Antagonist (Naloxone)

Intrinsic Activity: Full Agonist (Methadone), Partial Agonist (Buprenorphine), Antagonist (Naloxone)

Methadone MaintenanceMethadone Maintenance

Methadone MaintenanceMethadone Maintenance

<45 mg<45 mg 27.9% positive27.9% positive

46 mg - 8046 mg - 80 5.4%5.4%

0

20

40

60

80

100

Impact of Methadone Maintenance Impact of Methadone Maintenance Treatment on IV Drug Use of 388 Male Treatment on IV Drug Use of 388 Male Methadone Patients in Six ProgramsMethadone Patients in Six Programs

Last Addiction PeriodLast Addiction Period

In-Treatment PeriodIn-Treatment Period

AdmissionAdmission

Pre-Admission 1st Year 2nd Year 3rd Year 4th YearPre-Admission 1st Year 2nd Year 3rd Year 4th Year periodperiod

100%100%

81.4%81.4%

63.3%63.3%

41.7%41.7%

28.9%28.9%

...

. .

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10 11 12

Relapse to IV Drug Use after Relapse to IV Drug Use after Methadone Maintenance Treatment of Methadone Maintenance Treatment of 105 Male Patients who left Treatment105 Male Patients who left Treatment

In-Treatment RateIn-Treatment Rate

Months Since Drop OutMonths Since Drop Out

28.9%28.9%

45.5%45.5%

57.6%57.6%

72.7%72.7%82.1%82.1%

Co-occurring mental disorders• Depression• Anxiety• Schizophrenia• Bipolar disorder• TREATMENT:Psychotherapy

+

Psychoactive medication

“Dose” of Psychotherapy

• Hold methadone dose constant• Randomize among

– 1. No counseling– 2. Standard counseling– 3. Enhanced counseling

Opiate Positive Urines

69% terminated

0

10

20

30

40

50

60

70

B 1 2 3 4 5 6

Percent Meeting Protective Termination Criterion

0

10

20

30

40

50

60

70

80

Percent

Group 1 Group 2 Group 3

Group 1 Group 2 Group 3

BuprenorphineBuprenorphine

Partial agonistPartial agonist

Very safeVery safe

Combined with naloxone Combined with naloxone

(Suboxone)(Suboxone)

New law allows New law allows

treatment in physician’s treatment in physician’s

officeoffice

0

1

2

3

4

5

0 20 40 60 80 100 120 140 160 180

0 mg1 mg2 mg4 mg8 mg16 mg32 mg

””How much do you feel the drug?”How much do you feel the drug?”

Time (minutes)Time (minutes)

An

alo

g S

core

(cm

)A

nal

og

Sco

re (

cm)

S. Walsh, et al 1994, Clinical Pharmacology & Experimental TherapeuticsS. Walsh, et al 1994, Clinical Pharmacology & Experimental Therapeutics

BuprenorphineBuprenorphine

NaltrexoneNaltrexone

Complete antagonistComplete antagonist

Blocks receptorsBlocks receptors

Also blocks alcohol highAlso blocks alcohol high

““IMPOSSIBLE” to relapse on IMPOSSIBLE” to relapse on

naltrexonenaltrexone

Available as a monthly Available as a monthly

injectioninjection

Philadelphia prison system

18 % of parolees have history of opiate addiction

Relapse should/could result in re-incarceration

Approximately 1 Million opiate addicts in US

Most support habit by crime

2.1 Million Americans in prison

Substance Oral Nltx Control Sig.

(N=34) (N=17)

Opiate 8% 30%p<.05

Cocaine 33% 49% NS

Amphetamine 0% 1% NS

Benzodiazepine 2% 6% NS

Marijuana 13% 19% NS

Alcohol 2% 4% NS

Mean Percent Positive Urines

Re-Incarceration at 6 months

NALTREXONE CONTROL

26%

56%

0%

20%

40%

60%

80%

100%P

erce

nt

Su

bje

cts

P<.05

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

A new delivery systemBetter adherenceLower monthly doseSteady brain levels

*Garbutt et al 2005

Dean RL. Front Biosci. 2005 Jan 1;10:643-655. Dunbar JL, et al. Alc Clin Exp Res. 2006;30:480-490.Data on File, Alkermes, Inc.

Plasma Concentrations

Results: Heavy Drinking DaysBaseline

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

Comer, S. D. et al. Arch Gen Psychiatry 2006;63:210-218

Retention in treatment by study week and treatment group

Comer, S. D. et al. Arch Gen Psychiatry 2006;63:210-218

Percentage of urine samples negative for various drugs of interest

Medications for Cocaine AddictionMedications for Cocaine Addiction

• GABA-ergic medicationsGABA-ergic medications– VigabatrinVigabatrin

– BaclofenBaclofen

– TopiramateTopiramate

• Block cocaine withdrawalBlock cocaine withdrawal– Methylphenidate - negative Methylphenidate - negative

– Amphetamine - negativeAmphetamine - negative

– Modafinil - positive studies, also blocks cocaine euphoriaModafinil - positive studies, also blocks cocaine euphoria

Modafinil Blunts Cocaine Euphoria

Cocaine-induced euphoria was (ARCI Amphetamine Scale) was significantly blunted (P = 0.02) after modafinil pretreatment (n=6)

ARCI AMPHETAMINE

0

1

2

3

4

5

6

7

8

-15 15 90 120

Cocaine Infusion

ARCI Score

Placebo LD HD

Infusion Time

Dackis CA, et al.: Modafinil and Cocaine: A Double-Blind, Placebo-Controlled Drug Interaction Study. Drug & Alcohol Dependence 70:29-37, 2003

Results: Abstinence (Urine Testing)

Longitudinal GEE models showed a significant main effect for cocaine abstinence in

the modafinil group (odds ratio = 2.41, 95% CI 1.09-5.31, p = 0.03)

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

50%

1 2 3 4 5 6 7 8

Placebo Modafinil

Study Week

Dackis, C.A., et al., A double-blind, placebo-controlled trial of modafinil for cocaine dependence. Neuropsychopharmacology, 2005. 30(1): p. 205-11.

Results: Prolonged AbstinenceResults: Prolonged Abstinence

More of the modafinil-treated subjects (33% v. 13%; p < 0.05) provided 9 consecutive clean urines (perfect attendance)

0%

5%

10%

15%

20%

25%

30%

35%

MOD PLAC

% Ss with Protracted Abstinence

Results: Abstinence at Study EndResults: Abstinence at Study End

More of the modafinil-treated subjects (67% v. 22%) provided

3 consecutive clean urines at the end of their medication trial

0%

10%

20%

30%

40%

50%

60%

70%

MOD PLAC

% Ss Whose Last 3 Urines Were Clean

Dackis, C.A., et al., A double-blind, placebo-controlled trial of modafinil for cocaine dependence. Neuropsychopharmacology, 2005. 30(1): p. 205-11.

Results: Abuse / Overuse

Return rate in modafinil & placebo groups was not different

(chi2 = 0.01, p = 0.93) Dackis et al. A Double-Blind, Placebo-Controlled Trial of Modafinil for Cocaine Dependence. Neuropsychopharmacology (in press).

Abuse Potential of Modafinil

Hours post-dose

ARCI:amphetamine

scale

Warot. Eur Psychiatry. 1993;8:201

-1 0 1 2 3 4 5 6 7 8

1

2

3

4

5

6 Amphetamine 15 mgModafinil 300 mgCaffeine 300 mgPlacebo

Penn/VA Center TeamPenn/VA Center Team

Arthur Alterman 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 Joe Volpicelli

obrien@mail.trc.upenn.edu

http://www.uphs.upenn.edu/trc