DOUBLE BLIND DOUBLE DUMMY PLACEBO CONTROLLED

RANDOMIZED CLINCAL TRIAL OF IMPLANTABLE NALTREXONE

(PRODETOXONE) FOR HEROIN ADDICTION

Evgeny Krupitsky, MD, PhD, D.Med.Sci.

St.-Petersburg Bekheterv Research Psychoneurological Institute and

St.-Petersburg Pavlov State Medical University

CONFLICT OF INTERESTS

• Supported with NIDA grant R01-DA-017317

• Dr. Krupitsky has received funding as a consultant for Alkermes, Inc.

PHARAMCOTHERAPY OF HEROIN DEPENDENCE

Full agonists (methadone, LAAM)Partical agonists-antagonists

(buprenorphin)Full antagonists (naltrexone,

nalmefene)

NALTREXONENALTREXONE

Different drug Different drug formulations:formulations:

1. Oral1. Oral

2. Implantable2. Implantable

3. Injectable3. Injectable

Background

• Our previous studies with oral naltrexone demonstrated its superiority over placebo, however, the rate of abstinence was relatively low in six month of medication (Krupitsky et al, J. Substance Abuse Treatment, 2002, 23:273-283)

• Combination of oral naltrexone with antidepressants improved abstinence insignificantly (Krupitsky et al, J. Substance Abuse Treatment, 2006, 31:319-328)

The major problem with oral naltrexone is a poor compliance

Is there way to improve naltrexone therapy ?

DIFFICULTY WITH ORAL NTXN:POOR COMPLIANCE

OPPORTUNITY:EXTENDED RELEASE

FORMULATIONS

“The pessimist sees difficulty in every opportunity. The optimist sees opportunity in every difficulty”

Winston Churchill

Implantable Naltrexone: Route and Dosage

PRODETOXONEPRODETOXONE, , tablets for implantationtablets for implantation 1000 mg of naltrexone1000 mg of naltrexone

Pharmacokinetics of ProdetoxonePharmacokinetics of Prodetoxone(data from the manufacturer)(data from the manufacturer)

Blood samples were collected in one week, one and two months after implantationBlood samples were collected in one week, one and two months after implantation

010 20 30 40 50 60 70

Time after implantation, days

Co

nce

ntr

atio

n, n

g/m

l

Naltrexone metabolite Naltrexone

METHODS 306 male and female heroin addicts after detoxification, giving

informed consent and passing a Naloxone challenge had been randomly assigned to one of three treatment groups (102 PATIENTS EACH).

Three cell study design:1. Naltrexone Implant (1000 mg) (3 times, every 2 months) + Oral Placebo (OP+NI).

2. Oral Naltrexone (50mg/day) + Implant Placebo (3 times, every 2 months) (ON+PI). 3. Implant Placebo (3 times, every 2 months) + Oral Placebo (OP+PI).

All patients received biweekly clinical management / compliance enhancement counseling.

Treatment lasted 6 months. Control of abstinence, compliance, psychiatric symptoms, and side

effects – every other week. All patients had at least one family member who was able to

supervise medication compliance. Study design: Double blind double dummy placebo controlled

randomized clinical trial.

Assessments Assessments have been done at

baseline, at each biweekly appointment, and at 3 and 6 months following the end of treatment.

Assessments included: Psychiatric rating scales, Riboflavine control of compliance, Urine drug tests, Naloxone challenge.

Primary outcomes: Treatment retention and relapse to heroin dependence.

Secondary outcomes: Opiate negative urines, HIV risk, psychiatric symptoms, and other measures of adjustment.

Recruitment details

358 approached309 met inclusion criteria306 got randomized

Demographics and Clinical Characteristics

Group

OP+PI ON+PI OP+NI

N 102 102 102

Gender (female) 27,5% 27,5% 27,5%

Age (M±SEM) 28,0±0,40 27,9±0,40 28,7±0,45

Duration of heroin dependence (M±SEM)

7,8±0,38 7,9±0,41 8,3±0,39

Number of previous treatments (M±SEM) 3,8±0,31 4,3±0,37 4,9±0,41

*

*

*

* P<0.01 to placebo

* *

* * ** * *

***

Weeks

** *

***

**

***

*

Retention in treatment (Remission) (% of patients)

+ + + ++

+ + + + + ++ + + + + + + +

+ P<0.01 to ON+PI

Log Rank (Mantel-Cox) Sig.

P(NI+OP)- (PO+PI)<0,001 P(NI+OP)- (PI+ON) <0,001 P(ON+PI)- (PO+PI)=0,069

Kaplan-Meier Survival Functions: Drop out

Retention: End of treatmernt (6 months)

OP+NI > OP+PI (P<0,001)

OP+NI > ON+PI (P<0,001)

(P<0,001)

(P<0,001)

Remissions in 3 & 6 months after treatment *

*Follow ups collected for 46,5% of those who was randomized

(End of Treatment) (3 Month Follow Up) (6 Month Follow Up)

Relapses in Naltrexone implant group

WEEKS

P<0,001

P<0,001

P<0,001

**

* *

**

*

**

* *

*

Opiate negative visits

*- P<0,01 Fisher's Exact Test to placebo + - P<0,01 Fisher's Exact Test to Ntxn implant group

Genetic Analysis Thomas Kosten, MDDavid Nielsen, PhD

Baylor College of Medicine

I). Gens of µ-opiate receptors:1) OPRM11, 2) OPRM12, 3) OPRM13 II). Gene of κ-opiate receptor:

OPRK1

III). Gene of the enzyme COMT:COMT

Effect of genotype on the completion of the treatment: Uncertainty Coefficients (I)

[OPRM13,COMT,OPRK1]

0,0

0,1

0,2

0,3

0,4

0,5

0,6

PO/NI (p=0.9) ON/PI (p=0.056) PO/PI (p=0.031)

[AAAGTT] or [AGAGTT] the others

Effect of genotype on the completion of the

treatment: Uncertainty Coefficients (II)

[OPRM11,COMT,OPRK1]

0

0,1

0,2

0,3

0,4

0,5

0,6

PO/NI (p=0.89) ON/PI (p=0.075) PO/PI (p=0.056)

[CCAGTT] or [CTAGTT] the others

Effect of genotype on the completion of the treatment: Kaplan-Meier Survival

Functions

Cu m u la ti ve P ro p o rti o n S u rvi vi n g (K a p la n -M e ie r)[O P RM 1 3 ,CO M T ,O P RK 1 ] p =0 .0 3 7 (Co x's F-te st)

Co m p le te Ce n so re d

A A A G T T A G A G T T

th e o th e rs0 5 1 0 1 5 2 0 2 5 3 0

T im e

0 ,1

0 ,2

0 ,3

0 ,4

0 ,5

0 ,6

0 ,7

0 ,8

0 ,9

1 ,0

Cu

mu

lativ

e P

rop

ort

ion

Su

rviv

ing

Cu m u la ti ve P ro p o rti o n S u rvi v i n g (K a p la n -M e ie r)[O P RM 1 1 ,CO M T ,O P RK 1 ] p =0 .0 2 (Co x's F-te st)

Co m p le te Ce n so re d

CCA G T T CT A G T T

th e o th e rs 0 5 1 0 1 5 2 0 2 5 3 0

T im e

0 ,1

0 ,2

0 ,3

0 ,4

0 ,5

0 ,6

0 ,7

0 ,8

0 ,9

1 ,0

Cu

mu

lativ

e P

rop

ort

ion

Su

rviv

ing

(p=0.02) (p=0.03)

Effect of genotype on the completion of the treatment: Treatment Effectiveness Score

p=0.063 p=0.043

Use of other drugs

Fisher's Exact Test P=0,005to placeboFisher's Exact Test P=0,049to ON+PI

Benzos

THC

Amphetamines

Anxiety and Depression

Depression (Beck scale)State Anxiety (Spielberger scale)

Physical Anhedonia Social Anhedonia

Anhedonia (Chapman at al.)

Anhedonia (J. Ferguson et al.)

LACK OF INTEREST LACK OF PLEASURE

HIV Risk Assessement Battery

RAB drug risk RAB sex risk

AE (non-surgical) (% visits)

AE (surgical) (% implants)

PON+IP=0.0001

POP+IP=0.005

Most common AE

1. Abdominal discomfort2. Nausea3. Drowsiness

• None of them required any special medication.

• Two patients in NI+OP group were terminated from the study because of side effects (wound infection).

SAE

The was only one serious adverse event in PI+OP group – the holecystectomia due to the stones in gallbladder which was considered as probably not related to the study medication

OD at the follow-up

• Through the phone calls to patients or their relatives follow-up information was collected on 261 patient (85,3% of the study patients). According to this information, five patients died during the 12 month follow-up period, all of them died of overdose, four of them were in the PI+OP (double placebo) group and one – the PI+ON group.

ALT & AST

SummaryImplantable naltrexone demonstrated

greater effectiveness in the treatment of heroin dependence in comparison to oral naltrexone and placebo.

Implantable naltrexone is basically comparable to oral naltrexone and placebo in terms of safety and tolerability except surgical adverse events.

Genotyping is helpful to determine responders to treatment.

LIMITATIONS for PRODETOXONE

1. Surgical procedure2. Wound infections (particularly in HIV+

individuals)3. Cosmetic defects 4. Relatively easy to take out within the

first few weeks after implantation5. Dos not provide 2 months long

blockade in some patients (small proportion)

AKNOWLEDGEMNET

E. Zvartau, E. Blokhina, V. Egorova, D. Masalov, А. Burakov, М. Tsoy, N. Bushara, Т. Romanova,

Е. Verbitskaya, A. Tyurina, V. Palatkin, Ch. О’Brian, G. Woody, T. Kosten, D. Nielsen

St.-Petersburg Pavlov State Medical University, St.-Petersburg Bekheterev Research

Psychoneurological Institute, University of Pennsylvania, Baylor College of Medicine

Supported with NIDA grant R01-DA-017317

•Thank you for your attention