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Implantable Naltrexone: Route and Dosage

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

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Implantable Naltrexone: Route and Dosage

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  1. 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. WoodySt.-Petersburg Pavlov State Medical University,University of PennsylvaniaSupported by NIDA Grant R01-DA-017317

  2. Implantable Naltrexone: Route and Dosage PRODETOXONE, tablets for implantation1000 mg of naltrexone

  3. Pharmacokinetics of Prodetoxone(data from the manufacturer) Concentration, ng/ml 0 10 20 30 40 50 60 70 Time after implantation, days Naltrexone metabolite Naltrexone Blood samples were collected in one week, one and two months after implantation

  4. 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.

  5. Recruitment details 358 approached 309 met inclusion criteria 306 got randomized

  6. Demographics and Clinical Characteristics

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

  8. Kaplan-Meier Survival Functions: Drop out Log Rank (Mantel-Cox) Sig. P(PO+IN)- (PO+PI)<0,001 P(ON+PI)- (PO+PI)=0,069

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

  10. 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)

  11. Relapses in Naltrexone implant group WEEKS

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

  13. Genetic AnalysisThomas Kosten, MDDavid Nielsen, PhDBaylor College of Medicine I). Gens of µ-opiate receptors: • OPRM11, 2) OPRM12, 3) OPRM13 II). Gene of ζ-opiate receptor: OPRK1 III). Gene of the enzyme COMT: COMT

  14. [OPRM13,COMT,OPRK1] 0,6 [AAAGTT] or [AGAGTT] the others 0,5 0,4 0,3 0,2 0,1 0,0 PO/NI (p=0.9) ON/PI (p=0.056) PO/PI (p=0.031) Effect of genotype on the completion of the treatment: Uncertainty Coefficients (I)

  15. [OPRM11,COMT,OPRK1] 0,6 [CCAGTT] or [CTAGTT] the others 0,5 0,4 0,3 0,2 0,1 0 PO/NI (p=0.89) ON/PI (p=0.075) PO/PI (p=0.056) Effect of genotype on the completion of the treatment: UncertaintyCoefficients (II)

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

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

  18. Use of other drugs Fisher's Exact Test P=0,003

  19. Anhedonia (Chapmanat al.) Physical Anhedonia Social Anhedonia

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

  21. AE(non-surgical) (% visits) AE (surgical) (% implants) POP+IP=0.02 No SAE in either group PON+IP=0.002

  22. ALT & AST

  23. 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.

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

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