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DOUBLE BLIND RANDOMIZED PLACEBO CONTROLLED STUDY OF EFFECTIVENESS
OF IMPLANTABLE NALTREXONE (PRODETOXONE) FOR TREATMENT OF HEROIN ADDICTION (Interim analysis)
Е. Krupitsky, E. Zvartau, V. Egorova, D. Masalov, А. Burakov, М. Tsoy, N. Bushara, Т. Romanova, Е. Verbitskaya, Ch. О’Brian,
G. Woody
St.-Petersburg Pavlov State Medical University,
University of Pennsylvania
Supported by NIDA Grant R01-DA-017317
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Implantable Naltrexone: Route and Dosage
PRODETOXONE, tablets for implantation 1000 mg of naltrexone
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Pharmacokinetics of Prodetoxone(data from the manufacturer)
Blood 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
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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.
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Recruitment details
· 358 approached· 309 met inclusion criteria· 306 got randomized
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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
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0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 18 19 20 22 230
0.2
0.4
0.6
0.8
1
1.2
PO+PION+PIPO+NI
*
*
*
* P<0.01 to placebo
* *
* * ** * *
***
Weeks
** *
***
**
***
*
Retention in treatment (Remission) (% of patients)
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Log Rank (Mantel-Cox) Sig.
P(PO+IN)- (PO+PI)<0,001 P(ON+PI)- (PO+PI)=0,069
Kaplan-Meier Survival Functions: Drop out
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Kaplan-Meier Survival Functions: Relapse
Log Rank (Mantel-Cox) Sig.
P(PO+IN)- (PO+PI)<0,001 P(ON+PI)- (PO+PI)=0,024
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PO+PI ON+PI PO+NI0%
10%
20%
30%
40%
50%
60%
11%
16%
53%
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)
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Relapses in Naltrexone implant group
WEEKS
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Treatment Effectiveness Score (TES): [Heroin positive + Missed visits] (%)
P<0,001
P<0,001
P=0,046
0 2 4 6 8 10 12 14 16 18 20 22 240%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
PO+PI
ON+PI
PO+NI
**
* *
**
*
*
** *
*
* - P<0,01 Fisher's Exact Test
WEEKS
Average TES per group
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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 ζ-opiate receptor:
OPRK1
III). Gene of the enzyme COMT:COMT
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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
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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
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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)
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Effect of genotype on the completion of the treatment: Treatment Effectiveness Score
p=0.063 p=0.043
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Use of other drugs
Fisher's Exact Test P=0,003
Benzos Amphetamines
THC
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Physical Anhedonia Social Anhedonia
Anhedonia (Chapman at al.)
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Anhedonia (J. Ferguson et al.)
LACK OF INTEREST LACK OF PLEASURE
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PO+PI ON+PI PO+NI0%
1%
2%
3%
4%
5%
6%
1%
0%
5%
n
AE (non-surgical) (% visits)
AE (surgical) (% implants)
POP+IP=0.02
PON+IP=0.002
PO+PI ON+PI PO+NI0.0%
0.5%
1.0%
1.5%
2.0%
2.5%
3.0%
3.5%
3%
1%
3%
PON+IP=0.002
No SAE in either group
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ALT & AST
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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.
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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)