agonist/partial agonist heroin: dsm iv the siren effect (homer & the odyssey)
TRANSCRIPT
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AGONIST/PARTIAL AGONIST
Heroin: DSM IVTHE SIREN EFFECT (HOMER & THE ODYSSEY)
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ORAL NALTREXONE
Good pharmacological efficacy
Poor Compliance
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Pharmacotherapy WorksPharmacotherapy Works
PHARMACOTHERAPY WORKSPHARMACOTHERAPY WORKS
But only if you actually getBut only if you actually get
the right the right medicationmedication
into the right patient into the right patient
most of the timemost of the time
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DEPOT NALTREXONE• Therapeutic naltrexone blood levels above 1-
2 ng/ml suggested
• Remove onus for oral compliance
• Objective: facilitate stable opiate-based abstinent lifestyle
•Available Depot Preparations 4-6 weeks•Biotek, Inc. (Depotrex®) {Comer, 2002}; Drug Abuse Sciences (Naltrel®) {Kranzler, 2004}; Alkermes, Inc. (Vivitrol®) {Garbutt, 2005} FDA Approved
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Randomised (70 DSM IV Heroin Dependent
Persons) double-blind placebo controlled clinical
trial compared to oral naltrexone
Hulse, GK; Tait, RJ; Ngo, HT; Morris N; Arnold-Reed D
Funded: National Health & Medical Research Council
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GoMedical naltrexone implant pellet in a bevelled syringe ready for subcutaneous insertion
GoMedical Industries (Perth, WA)GoMedical Industries (Perth, WA)
Naltrexone in microspheres encapsulated in polyNaltrexone in microspheres encapsulated in poly--DLDL--lactide lactide compressed into a pallet ( x10 tablets)compressed into a pallet ( x10 tablets)
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Belt line
V shaped insertion lateral to the iliac crest
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Clinical EfficacyClinical Efficacy
Survival Survival – – – return to regular (most days / daily) heroin usereturn to regular (most days / daily) heroin use
Patterns of heroin usePatterns of heroin use– cumulativecumulative
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Implant Implant vv Oral (compliant) Oral (compliant)
Relationship Between:Relationship Between:
Blood Naltrexone levelsBlood Naltrexone levels
CravingCraving
Return to opioid useReturn to opioid use
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ADVERSE AND SERIOUS ADVERSE EVENTSADVERSE AND SERIOUS ADVERSE EVENTS
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Return to regular (most days/daily) heroin useReturn to regular (most days/daily) heroin use
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Return to regular (most days/daily) heroin useReturn to regular (most days/daily) heroin use
versus versus > 1-3 times / month> 1-3 times / month
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Return to regular (most days/daily) heroin useReturn to regular (most days/daily) heroin useor lost to follow-upor lost to follow-up
Hulse, G.K., Morris, N., Arnold-Reed, D., Tait R.J. (2009). Treating heroin dependence: Randomised Trial of oral or implant naltrexone. Archives of General Psychiatry Manuscript 66(10): 1-8 (impact factor 14.2)
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Cumulative (worst) heroin use outcomesCumulative (worst) heroin use outcomesover the studyover the study
NB 4 lost to follow-up
5 new treatment
NB 4 lost to follow-up
2 new treatment
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1.Blood Naltrexone2.CRAVING3. HEROIN USEINTERRELATIONSHIP
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Findings from Challenge studies:Findings from Challenge studies:
2.8ng/ml blocks 500mg of diamorphine 2.8ng/ml blocks 500mg of diamorphine (Brewer(Brewer 2002)2002)
≥ ≥ 2ng/ml blocks 25mg IV heroin 2ng/ml blocks 25mg IV heroin (Navaratnam, (Navaratnam, 1994, Verebey, 1976)1994, Verebey, 1976)
1 ng/ml blocks15mg morphine 1 ng/ml blocks15mg morphine (Chiang, 1985)(Chiang, 1985)
Identifying the Therapeutic Blood Naltrexone Level for the Management of
Heroin Dependence
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NALTREXONE BLOOD LEVEL RISK FOR NALTREXONE BLOOD LEVEL RISK FOR
≥≥ WEEKLY HEROIN USE WEEKLY HEROIN USE
2.5 risk below 0.5 ng/ml
Each 1ng/ml increase = 35% decrease risk heroin use
Above 3ng/ml can be confident of absence or low level use
Data Suggest: Minimum Therapeutic Blood Naltrexone level =1ng/ml
No need to exceed 3ng/ml
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IMPLANT COMPARED TO COMPLIANT ORAL
NALTREXONE
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INCREASED RISK ≥ WEEKLY HEROIN USE
NON COMPLIANT ORAL THAN ALL OTHERS
GREATER IN COMPLIANT ORAL THAN IMPLANT
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Heroin Craving
Craving assessed with 10 item survey scale scored 1 to 7 (Tiffany, 1993)
Implant significantly lower craving at month 5
Overall, implant show less craving than oral Naltrexone
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IMPLANT COMPARED TO COMPLIANT ORAL
NALTREXONE
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CRAVING ASSERSSED MONTHLY
IMPANT & COMPLIANT ORAL HAD LOW CRAVING
NON COMPLIANT ORAL HAD INCREASED CRAVING
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OTHER STUDY CRAVING PREDICTORS
i. High craving at baseline
ii. Increased years of heroin use
iii.Being Female
iv.Being Younger Older Persons Have Lower Craving
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?Clinically: why is craving so important?
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CRAVINGCRAVING
Previous month craving Predictor of Previous month craving Predictor of subsequent heroin usesubsequent heroin use
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Study Adverse & Serious Adverse Events
Independent monitoring Committee: Professor of Psychiatry, Professor of Public Health, Two Addiction Specialists (Fellows of the Australasian College of Addiction Medicine)
Events were classified as: "unexpected" (but probably related to the device/procedure), "expected" (and probably related to the device/procedure), "pre-existing" (i.e. present at the time of enrolment), or "unrelated".
TGA guidelines based on International Conference on Harmonization policies.
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Treatment Category Days Summary
Implant Related expected 0 Wound hematoma - bleeding, swelling, pain proximal to implant site
Implant Pre-existing 108 Psychotic episode
Implant Pre-existing 110 Substance abuse (‘alcoholic binge’)
Implant Pre-existing 128 Psychosis
Implant Pre-existing 131 Suicide attempt
Implant Pre-existing 141 Depression
Implant Unrelated 0 Bradycardia and collapse – allergic reaction to clonidine
Implant Unrelated 28 Drug overdose (Risperadone) requiring hospital admission
Implant Unrelated 35 Abscess on neck
Implant Unrelated 161 Miscarriage (septic abortion) at 7 weeks gestation
Tablet Pre-existing 0 patient had commenced opioid withdrawal days prior to presentation
Tablet Pre-existing 6 Depression and suicide ideation
Tablet Unrelated 19 Possible spinal nerve damage referred right leg and ankle
Tablet Unrelated 56 Poly drug overdose (Buprenorphine, Serepax) hospital admission †
Tablet Unrelated 61 Poly drug overdose (Buprenorphine, Serepax) hospital admission †
Tablet Unrelated 84 Pneumonia (left basal) and pleurisy
Summaries of all the serious adverse events
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Classification of Implant Reaction
Three Dimensions REDNESS, SWELLING and TENDERNESS.
Each rated on a 4-point scale ZERO(no reaction) to THREE (severe).
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200150100500
Days post implant
3
2
1
0
Site
redness
Placebo implantActive implant
Randomised group
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200150100500
Days post implant
3
2
1
0
Site
tendern
ess
Placebo implantActive implant
Randomised group
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200150100500
Days post implant
3
2
1
0
Sit
e s
wellin
g
Placebo implantActive implant
Randomised group
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