AGONIST/PARTIAL AGONIST

Heroin: DSM IVTHE SIREN EFFECT (HOMER & THE ODYSSEY)

ORAL NALTREXONE

Good pharmacological efficacy

Poor Compliance

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

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

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

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)

Belt line

V shaped insertion lateral to the iliac crest

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

Implant Implant vv Oral (compliant) Oral (compliant)

Relationship Between:Relationship Between:

Blood Naltrexone levelsBlood Naltrexone levels

CravingCraving

Return to opioid useReturn to opioid use

ADVERSE AND SERIOUS ADVERSE EVENTSADVERSE AND SERIOUS ADVERSE EVENTS

Return to regular (most days/daily) heroin useReturn to regular (most days/daily) heroin use

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

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)

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

1.Blood Naltrexone2.CRAVING3. HEROIN USEINTERRELATIONSHIP

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

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

IMPLANT COMPARED TO COMPLIANT ORAL

NALTREXONE

INCREASED RISK ≥ WEEKLY HEROIN USE

NON COMPLIANT ORAL THAN ALL OTHERS

GREATER IN COMPLIANT ORAL THAN IMPLANT

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

IMPLANT COMPARED TO COMPLIANT ORAL

NALTREXONE

CRAVING ASSERSSED MONTHLY

IMPANT & COMPLIANT ORAL HAD LOW CRAVING

NON COMPLIANT ORAL HAD INCREASED CRAVING

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

?Clinically: why is craving so important?

CRAVINGCRAVING

Previous month craving Predictor of Previous month craving Predictor of subsequent heroin usesubsequent heroin use

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.

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

Classification of Implant Reaction

Three Dimensions REDNESS, SWELLING and TENDERNESS.

Each rated on a 4-point scale ZERO(no reaction) to THREE (severe).

200150100500

Days post implant

3

2

1

0

Site

redness

Placebo implantActive implant

Randomised group

200150100500

Days post implant

3

2

1

0

Site

tendern

ess

Placebo implantActive implant

Randomised group

200150100500

Days post implant

3

2

1

0

Sit

e s

wellin

g

Placebo implantActive implant

Randomised group

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