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DOUBLE BLIND RANDOMIZED PLACEBO CONTROLLED STUDY OF EFFECTIVENESS OF IMPLANTABLE NALTREXONE (PRODETOXONE) FOR TREATMENT OF HEROIN ADDICTION (Interim analysis)

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Presentation on theme: "DOUBLE BLIND RANDOMIZED PLACEBO CONTROLLED STUDY OF EFFECTIVENESS OF IMPLANTABLE NALTREXONE (PRODETOXONE) FOR TREATMENT OF HEROIN ADDICTION (Interim analysis)"— Presentation transcript:

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2 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

3 Implantable Naltrexone: Route and Dosage PRODETOXONE, tablets for implantation 1000 mg of naltrexone PRODETOXONE, tablets for implantation 1000 mg of naltrexone

4 Pharmacokinetics of Prodetoxone (data from the manufacturer) Blood samples were collected in one week, one and two months after implantation 0 10203040506070 Time after implantation, days Concentration, ng/ml Naltrexone metaboliteNaltrexone

5 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.

6 Recruitment details  358 approached  309 met inclusion criteria  306 got randomized

7 Demographics and Clinical Characteristics Group OP+PION+PIOP+NI N102 Gender (female) 27,5% Age (M±SEM) 28,0±0,4027,9±0,4028,7±0,45 Duration of heroin dependence (M±SEM) 7,8±0,387,9±0,418,3±0,39 Number of previous treatments (M±SEM) 3,8±0,314,3±0,374,9±0,41

8 * * * * P<0.01 to placebo * * * * * * * * * * * Weeks * * * * * * * * * * * * Retention in treatment (Remission) (% of patients)

9 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

10 Kaplan-Meier Survival Functions: Relapse Log Rank (Mantel-Cox) Sig. P (PO+IN)- (PO+PI) <0,001 P ( ON+PI)- (PO+PI) =0,024

11 Retention: End of treatmernt (6 months) OP+NI > OP+PI (P<0,001) OP+NI > ON+PI (P<0,001) (P<0,001)

12 Relapses in Naltrexone implant group WEEKS

13 Treatment Effectiveness Score (TES): [ Heroin positive + Missed visits] (%) P<0,001 P=0,046 * * ** * * * * * * * * * - P<0,01 Fisher's Exact Test WEEKS Average TES per group

14 P<0,001 P=0,046 * * * * * * * * * ** * * - P<0,01 Fisher's Exact Test Opiate negative visits

15 Genetic Analysis Thomas Kosten, MD David 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

16 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

17 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

18 Effect of genotype on the completion of the treatment: Kaplan-Meier Survival Functions (p=0.02)(p=0.03)

19 Effect of genotype on the completion of the treatment: Treatment Effectiveness Score p=0.063 p=0.043

20 Use of other drugs Fisher's Exact Test P=0,003 Benzos Amphetamines THC

21 Craving for opiats

22 Anxiety and Depression Depression (Beck scale)State Anxiety (Spielberger scale)

23 Physical AnhedoniaSocial Anhedonia Anhedonia (Chapman at al.)

24 Anhedonia (J. Ferguson et al.) LACK OF INTEREST LACK OF PLEASURE

25 AE (non-surgical) (% patients) AT (surgical) (% patients) No SAE in either group

26 AE (non-surgical) (% visits) AE (surgical) (% implants) P OP+IP =0.02 P ON+IP =0.002 No SAE in either group

27 ALT & AST

28 Summary  Implantable 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.

29 LIMITATIONS for PRODETOXONE 1.Surgical procedure 2.Wound infections (particularly in HIV+ individuals) 3.Cosmetic defects 4.Relatively easy to take out within the first few weeks after implantation 5.Dos not provide 2 months long blockade in some patients (small proportion)


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