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
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DOUBLE BLIND DOUBLE DUMMY PLACEBO CONTROLLED RANDOMIZED CLINCAL TRIAL OF IMPLANTABLE NALTREXONE (PRODETOXONE) FOR HEROIN ADDICTION Evgeny Krupitsky, MD,
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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).
• 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