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National Evaluation of
Pharmacotherapies for
Opioid Dependence
(NEPOD)
Main findings and recommendations
Richard P. Mattick, Erol Digiusto, Chris Doran, Susannah O’Brien, Marian Shanahan, Jo
Kimber, Nicky Henderson, Courtney Breen, James Shearer, Jenny Gates, Anthony
Shakeshaft and NEPOD Trial Investigators*.
This presentation was funded by the Australian Government Department of Health and Ageing under the
National Illicit Drug Strategy.
STRUCTURE OF PRESENTATION
o Introduction
o Methodology
o Results
o Recommendations
INTRODUCTION
Opioid dependence is a chronic,
relapsing condition, requiring longterm care strategies
Treatment works - reducing heroin
use, mortality rates and crime
NEPOD background and aims
o Commissioned by MCDS, funded by DOH&A
o NEPOD was a three year national evaluation of the:
o effectiveness
o safety
o cost and cost-effectiveness
of pharmacotherapies for opioid dependence
o Trials funded by State/Territory and NH&MRC
o Historical context of NEPOD
Trial chief investigators
ACT: Dr Gabriele Bammer, A/Prof Nick Glasgow
Vic:
Dr Nick Lintzeris, Dr Alison Ritter
SA:
Dr Robert Ali, Prof Jason White
WA: Dr Allan Quigley
Qld: Dr Lynn Hawken, Prof John B. Saunders
NSW: Dr James Bell, Prof Richard P. Mattick
Pharmacotherapies investigated
A range of opioid detoxification procedures and
maintenance treatments were evaluated involving:
Methadone, Buprenorphine, Naltrexone,
and LAAM
Methadone
Methadone (methadone hydrochloride) is
o An opioid receptor agonist with similar
pharmacological actions to morphine
o Oral syrup – strength 5mgs/mL in Australia
o Used to treat opioid dependence in Australia
since 1969. Up until 2000, the only
maintenance treatment option available
Buprenorphine
Buprenorphine (buprenorphine hydrochloride) is
o An opioid receptor partial agonist, giving an
opioid effect, yet reducing the effects of
additional opioid use
o Sublingual tablet – 0.4mgs, 2mgs, 8mgs
o Registered in Australia (as Subutex®) in October
2000 for the treatment of opioid dependence,
including detoxification and maintenance
Naltrexone
Naltrexone (naltrexone hydrochloride) is
o A pure opioid receptor antagonist, displacing
opioids if present and blocking the effects of
subsequent use. It produces no opioid agonist
effects
o Oral tablet – 50mg
o Registered in Australia (as ReVia®) for use as an
adjunctive therapy to maintain abstinence
following detoxification from opioids. Not
currently registered for use in detoxification
LAAM
LAAM (levo-alpha-acetyl methadol) is
o An opioid receptor agonist, chemically related to
methadone, with pharmacological actions
qualitatively similar to morphine and methadone
o Oral syrup
o Not currently registered for use in Australia.
Registered in the USA since 1993 (ORLAAM®)
but no longer being sold or distributed due to
safety concerns (as at 2003)
Scale of the project
o 13 treatment trials
o 1,425 participants (355 already in MMT)
o More than 250 clinical & research staff
o Approximately $7 million funding
(mostly spent on providing treatment)
METHODOLOGY
o Trials collected a ‘core data set’
o Quasi-experimental nature of NEPOD
o advantages and disadvantages
o Generalisability of NEPOD results
o treatment under trial conditions not ‘real-life’
(e.g. explicit selection criteria, close
monitoring, cooperative participants)
o participants may not have received preferred
treatment
RESULTS
The 1,070 heroin dependent participants
o first used heroin at 20 years
o ‘habit’ first developed at 23
o At time of entering treatment:
o 30 years old, 66% male and 71% not employed
o high levels of depression and other mental health problems
o In month prior to entering treatment:
o only 3 of 28 days ‘heroin-free’
Short-term heroin detox outcomes
% achieving initial 7 days heroin-free
60%
58%
24%
12%
Rapid
Rapid
detoxification detoxification
under sedation
under
(24/40)
anaesthesia
(44/76)
4%
Conventional Buprenorphine Conventional
inpatient
outpatient
outpatient
detoxification detoxification detoxificaton
(12/50)
(19/158)
(2/56)
Post-detoxification treatment
o Detoxification is a starting point
o Advantage of buprenorphine detoxification in
engaging participants in ongoing treatment
o When given a choice
o 5% chose naltrexone
o 60% chose methadone or buprenorphine
Retention in treatment
methadone, buprenorphine & LAAM vs naltrexone
Heroin-free days in past 28 days
Trial participants still in treatment at 6 months
22
22
3
3
Methadone
(n=282) (n=102)
Buprenorphine
(n=250) (n=77)
Entry to treatment
28
25
4
2
LAAM
(n=41) (n=23)
Naltrexone
(n=283) (n=8)
In sixth month
Criminal activity in past month
Trial participants still in treatment at 6 months
24%
23%
13%
8%
8%
1%
Property crime
Drug dealing
Entry to treatment (n=748)
Fraud
In sixth month (n=206)
Serious Adverse Events (SAEs)
Rates per 100 person-years
o Overall rate of SAEs during treatment low - 14
per 100 person-years
o SAE rates increased after participants left
treatment - approximately three times higher
o Heroin overdose the most common SAE, with
higher rates among participants entering
naltrexone than agonist treatment
Costs of detoxification
$2,879
$489
$605
Buprenorphine
outpatient
detoxification
(n=158)
Conventional
outpatient
detoxification
(n=56)
$2,056
$2,073
Conventional
inpatient
detoxification
(n=50)
Rapid
detoxification
under sedation
(n=25)
Rapid
detoxification
under
anaesthesia
(n=76)
Cost-effectiveness ratios for detoxification
The cost of achieving initial 7 days heroin-free
$16,945
$3,317
$4,056
$4,645
Rapid
detoxification
under sedation
Buprenorphine
outpatient
detoxification
Rapid
detoxification
under
anaesthesia
$5,824
Conventional
inpatient
detoxification
Conventional
outpatient
detoxification
% achieving initial 7 days heroin-free
60%
12%
58%
24%
4%
Cost-effectiveness of detoxification
The cost of achieving initial 7 days heroin-free
o Rapid detoxification under sedation appears the
most cost-effective detoxification procedure
o Buprenorphine outpatient detoxification appears
more cost-effective than conventional procedures
o Detoxification through a conventional outpatient
setting is the least cost-effective method
Costs of maintenance treatment
Weekly cost for 6 months
$112
$67
Methadone (n=287)
$75
LAAM (n=44)
$85
Naltrexone (n=171)
Buprenorphine
(n=250)
Cost-effectiveness ratios for treatment
Cost per extra heroin-free day in sixth month
$318
$353
$195
$89
$118
LAAM
(n=32)(n=12)
$106
Methadone
(n=61) (n=226)
G.P. setting
$133
Buprenorphine
(n=37) (n=213)
Naltrexone
(n=151)
Specialist clinic
Cost-effectiveness of treatment
The cost of an extra heroin-free day
o Methadone appears the most cost-effective
treatment currently available
o Naltrexone treatment is the least cost-effective
o Treatment in G.P. (shared-care) setting appears
more cost-effective than in specialist clinics
RECOMMENDATIONS
Recommendations regarding clinical practice
1. Continue to support methadone
o
o
the most cost-effective treatment available
but look for cost-efficiencies with buprenorphine
2. Provide a range of effective treatment
options
o
all treatments provide benefits
Recommendations regarding clinical practice
Improve retention
3.
o
o
o
o
range of treatments
provide incentives (convenient treatment pathways
from clinics to G.P. care to abstinence)
eliminate disincentives (e.g., costs to patients)
address psychosocial needs
Encourage GP shared-care model
4.
o
o
cost-effective
accessible
Recommendations regarding clinical practice
5. Link detoxification to continuing treatment
6. Use buprenorphine for outpatient
detoxification
7. Provide rapid detoxification under sedation
o
o
o
for patients who want naltrexone treatment
anaesthesia is not necessary
naltrexone is not registered for rapid detoxification
Recommendations regarding further research
o
Buprenorphine in pregnancy & ‘medical maintenance’
o
Combined buprenorphine / naloxone tablet (Suboxone®)
o
Transfer from buprenorphine to naltrexone
o
Naltrexone retention – sustained release preparations?
o
GP shared-care costs & effects
o
LAAM
o
Cost-benefit of treatment – crime
o
Monitor implementation of buprenorphine
Contacts for further information
o For further information regarding the NEPOD
Project, contact the:
National Drug and Alcohol Research Centre
(NDARC) on (02) 9385 0333
http://ndarc.med.unsw.edu.au
o For further details regarding individual trials,
refer to the published articles, or contact the
investigators who conducted the research