Transcript MMT-Belfast

Supervised heroin treatment for
refractory chronic heroin addicts:
development, research study and
clinical provision in the UK
John Strang, Nicola Metrebian and
Rob vanderWaal
National Addiction Centre (The Maudsley & Institute of Psychiatry)
London
(on behalf of RIOTT research, clinical and related colleagues)
Research into the causes,
consequences and influences
upon Addictions
Development and pilot
testing of new
Prevention and
Treatment Interventions
Policy analysis
and input into
Policy formation
Second-line use of injectable maintenance
Rx-seeking
dependent
heroin user
Treat with oral
good-quality
maintenance
repeated
treatment ‘failure’
Poor benefit with
oral maintenance
‘Optimisation box’
still treatment
‘failure’
minimal
benefit
Still poor benefit
with oral
Brief test trial of
‘RIOTT’
treatment
Good benefit
Immersion in full
‘RIOTT’
treatment
Structure of today’s talk

history of heroin policy; and new scrutiny
 The
RIOTT trial – origins, conduct and results
 The
trial - and dialogue with government
 Ongoing
current analyses
Supervised heroin treatment for
refractory chronic heroin addicts:
development, research study and
clinical provision in the UK
John Strang, Nicola Metrebian and
Rob vanderWaal
National Addiction Centre (The Maudsley & Institute of Psychiatry)
London
(on behalf of RIOTT research, clinical and related colleagues)
Declaration (personal & institutional)

DH, NTA, Home Office, NACD, EMCDDA, WHO, UNODC, NIDA

NHS provider (community & in-patient); also Phoenix House, Lifeline, Clouds
House, KCA (Kent Council on Addictions)

Reckitt-Benckiser, Schering-Plough, Genus-Britannia, Napp, Titan, Martindale,
Catalent, Auralis, Lundbeck, Astra-Zeneca, Alkermes, UCB, Fidelity, Rusan,
Mundipharma Europe, Lannacher, Lightlake & others, including trying to work
with possible pharma-manufacturers

UKDPC (UK Drug Policy Commission), SSA (Society for the Study of Addiction);
and two Masters degrees (taught MSc and IPAS)

Work also with several charities (and received support) including Action on
Addiction, and also with J Paul Getty Charitable Trust (JPGT) and Pilgrim Trust
RIOTT funding support & declarations

Research Funding
 Community Fund (Big Lottery) & Action on Addiction & Hedley Foundation

Clinical Services Funding
 National Treatment Agency, Department of Health, and Home Office
 Local DATs & PCTs

Medications:
 Diamo, Switzerland; Cardinal, UK; Auralis, UK; also Genus, UK

Other support
 The Band Trust – DVD
 EMCDDA – European analysis and ‘Insights’ report

Clinical colleagues:
 Marina House, Maudsley; Darlington; Brighton

Service users/patients/study subjects:
RIOTT Team & Collaborators

Investigators/trial coordination
 Prof John Strang
 Dr Nicholas Lintzeris
 Dr Nicola Metrebian

Local Investigators
 Dr Deborah Zador / Dr James Bell
 Dr Tom Carnwath/Dr Soraya Mayet
 Dr Hugh Williams


Research staff
 Vikki Charles
 Luciana Forzisi
 Teodora Groshkova
 Chris Hallam
 Anthea Martin

RIOTT clinical team leaders
 Rob van der Waal, London
 Anne McNutt, Darlington
 Ian Wilson, Brighton

Trial co-ordination
 National Addiction Centre, Institute of
Psychiatry, KCL

Statistician
 Laura Potts, Clinical Trials Unit,
Institute of Psychiatry, KCL

Health Economics
 Dr Sarah Byford Institute of
Psychiatry, KCL
 Barbara Barrett, Institute of
Psychiatry
Clinical Trial Pharmacist
 Glynis Ivin, Maudsley Hospital
 Godwin Achunine, London clinic
Diamorphine suppliers
 DiaMo Narcotics GmbH, Switzerland
 Auralis, UK
Randomisation
 Clinical Trials Unit, IoP

Pathology
 Dr Andy Marsh & Richard Evers,
Kings College Hospital
Credit where credit’s due
 Ambros
Uchtenhagen and Swiss Ministry of
Health - public health policy drive
Van den Brink and Dutch CCHB – serious
research trial (and Germans and Canadians)
 Wim
Government Drug Strategy 2002 & 2008 –
‘blueprint’ and service specs
 UK
Structure of today’s talk

history of heroin policy; and new scrutiny
 The
RIOTT trial – origins, conduct and results
 The
trial - and dialogue with government
 Ongoing
current analyses
Sir Humphry Davy Rolleston,
(President of Royal College of Physicians, 1922-1936)
 The
legitimacy and authority of the medical
versus law enforcement perspective
 “maintenance”
(not termed thus) with injectable
morphine or diamorphine (heroin) legitimate
medical practice
 Sets
UK apart from post-1920s US policy
CHANGES IN THE UK IN THE 1970s

initial optimism for therapeutic power in the
new drug clinics post-1968; but then growing
disillusionment over the next decade or so
 The
growing status of oral methadone
 The
withering of injectable heroin
 Intermediate
years of injectable methadone
WHAT INJECTABLE PRODUCTS?
(n.b. predominantly an English phenomenon)
 Two
-
-
products:
heroin ampoules
(dry amps) (less than 1%)
methadone ampoules
(wet amps) (maybe 1%)
(historically also morphine by injection)
Structure of today’s talk

history of heroin policy; and new scrutiny
 The
RIOTT trial – origins, conduct and results
 The
trial - and dialogue with government
 Ongoing
current analyses
To complement the development of existing services,
heroin should be available on prescription
to all those who have a clinical need for it.
The number of people receiving heroin will increase as
overall numbers in treatment grow.
The administration of prescribed heroin for
those with a clinical need will take place in
safe, medically supervised areas with clean
needles. Strict and verifiable measures will
be in place to ensure there is no risk of
seepage into the wider community.
UK Government Drug Strategy, 2002
Unsupervised vs Supervised

‘Old’ (unsupervised)

Long history

But minimal research
evidence base

Internationally isolated

Mainly for the stable

‘New’ (supervised)
Supervised vs unsupervised

‘Old’ (unsupervised)

‘New’ (supervised)

Long history

Increasingly strong
research evidence base

But minimal research
evidence base

In line internationally

Internationally isolated

Public safety

Mainly for the stable

Accords with Drug
Strategy 2002 & 2008

For the repeatedly
‘failing’
My starting observations
 The
‘Old British System’ of injectable maintenance
and the new supervised treatment are extremely
different.
 The
evidence base for ‘Old British System’ is
extremely weak scientifically (although not
necessarily negative).
 The
evidence base for ‘Swiss-style’ supervised
injectable maintenance (as used in all recent
RCTs) is increasingly strong.
Accumulating body of evidence

Perneger et al, 1998, BMJ – Switzerland

Van den Brink et al, 2003, BMJ – Netherlands

March et al, 2006, JSAT – Spain

Haasen et al, 2007, B J Psych - Germany

Oviedo-Joekes et al (NAOMI), 2009, NEJM - Canada

Strang et al (RIOTT), 2010, Lancet; BJPsych 2013 - England
Supervised injecting clinics
Characteristics of new clinics
7
days per week; under supervision
 no
take-home injections / adequate daily doses
 oral
take-home supplements
 flexible
prescribing - oral take-home conversion on
request
 dedicated
facility - specific function
Supervised heroin treatment for
refractory chronic heroin addicts:
development, research study and
clinical provision in the UK
John Strang, Nicola Metrebian and
Rob vanderWaal
National Addiction Centre (The Maudsley & Institute of Psychiatry)
London
(on behalf of RIOTT research, clinical and related colleagues)
Research into the causes,
consequences and influences
upon Addictions
Development and pilot
testing of new
Prevention and
Treatment Interventions
Policy analysis
and input into
Policy formation
Declaration (personal & institutional)

DH, NTA, Home Office, NACD, EMCDDA, WHO, UNODC, NIDA

NHS provider (community & in-patient); also Phoenix House, Lifeline, Clouds
House, KCA (Kent Council on Addictions)

Reckitt-Benckiser, Schering-Plough, Genus-Britannia, Napp, Titan, Martindale,
Catalent, Auralis, Lundbeck, Astra-Zeneca, Alkermes, UCB, Fidelity, Rusan,
Mundipharma Europe, Lannacher, Lightlake & others, including trying to work
with possible pharma-manufacturers

UKDPC (UK Drug Policy Commission), SSA (Society for the Study of Addiction);
and two Masters degrees (taught MSc and IPAS)

Work also with several charities (and received support) including Action on
Addiction, and also with J Paul Getty Charitable Trust (JPGT) and Pilgrim Trust
RIOTT funding support & declarations

Research Funding
 Community Fund (Big Lottery) & Action on Addiction & Hedley Foundation

Clinical Services Funding
 National Treatment Agency, Department of Health, and Home Office
 Local DATs & PCTs

Medications:
 Diamo, Switzerland; Cardinal, UK; Auralis, UK; also Genus, UK

Other support
 The Band Trust – DVD
 EMCDDA – European analysis and ‘Insights’ report

Clinical colleagues:
 Marina House, Maudsley; Darlington; Brighton

Service users/patients/study subjects:
RIOTT Team & Collaborators

Investigators/trial coordination
 Prof John Strang
 Dr Nicholas Lintzeris
 Dr Nicola Metrebian

Local Investigators
 Dr Deborah Zador / Dr James Bell
 Dr Tom Carnwath/Dr Soraya Mayet
 Dr Hugh Williams


Research staff
 Vikki Charles
 Luciana Forzisi
 Teodora Groshkova
 Chris Hallam
 Anthea Martin

RIOTT clinical team leaders
 Rob van der Waal, London
 Anne McNutt, Darlington
 Ian Wilson, Brighton

Trial co-ordination
 National Addiction Centre, Institute of
Psychiatry, KCL

Statistician
 Laura Potts, Clinical Trials Unit,
Institute of Psychiatry, KCL

Health Economics
 Dr Sarah Byford Institute of
Psychiatry, KCL
 Barbara Barrett, Institute of
Psychiatry
Clinical Trial Pharmacist
 Glynis Ivin, Maudsley Hospital
 Godwin Achunine, London clinic
Diamorphine suppliers
 DiaMo Narcotics GmbH, Switzerland
 Auralis, UK
Randomisation
 Clinical Trials Unit, IoP

Pathology
 Dr Andy Marsh & Richard Evers,
Kings College Hospital
Credit where credit’s due
 Ambros
Uchtenhagen and Swiss Ministry of
Health - public health policy drive
Van den Brink and Dutch CCHB – serious
research trial (and Germans and Canadians)
 Wim
Government Drug Strategy 2002 & 2008 –
‘blueprint’ and service specs
 UK
Structure of today’s talk

history of heroin policy; and new scrutiny
 The
RIOTT trial – origins, conduct and results
 The
trial - and dialogue with government
 Ongoing
current analyses
What was the aim & design
of the trial?
Target population
Entrenched heroin addicts who have
repeatedly been found to fail to
benefit from existing treatments
(despite treatment, continuing to inject
heroin on all/most days per month)
Second-line use of injectable maintenance
Rx-seeking
dependent
heroin user
Treat with oral
good-quality
maintenance
repeated
treatment ‘failure’
Poor benefit with
oral maintenance
‘Optimisation box’
still treatment
‘failure’
minimal
benefit
Still poor benefit
with oral
Brief test trial of
‘RIOTT’
treatment
Good benefit
Immersion in full
‘RIOTT’
treatment
RIOTT trial
Computer generated randomisation
Injecting heroin
User in opioid
Maintenance
Treatment for
6 months
Diamorphine iv/im
+/- oral methadone
Methadone
Ampoules iv/im
+/- oral methadone
Enhanced
Oral
Methadone
What were our measures of
effective treatment?
Primary outcome measure
Primary outcome
Measures
Reduction in street heroin The proportion of subjects in each
use
group who cease regular street
heroin use
Metabolism of “illicit” Heroin
Diamorphine
Noscapine
Papaverine
HO
CH3
HO
O
CH3
O
N
H3C
O
O
H3C
N
O
O
O
CH3
N
O
O
O
CH3
CH3
O
H3C
HO
Codeine
H3C
O
Meconine
6-Monoacyl morphine
6-Hydroxypapaverine
HO
HO
CH3
O
N
H3C
O
O
O
HO
N
CH3
O
OH
HO
O
H3C
Morphine
6- Desmethylmeconine
4,6-Dihydroxypapaverine
Outcome measures
Secondary outcomes
Measures
Other illicit drug use
UDS & self-report
Treatment retention
Clinic records (& self report)
Injecting practices
Frequency, risk & complications
Psychosocial functioning & Quality
of Life Measures
SF-36, EQ-5D, OTI
Crime
Self-report (drug related
expenditure & criminal activity)
Safety
Adverse events
Patient satisfaction
Semi-structured Q’s
Cost effectiveness
Service costs (internal & external)
Treatments to be investigated
Supervised Injectable Heroin (SIH)
Supervised Injectable Methadone (SIM)
Optimised Oral Methadone (OOM)
Sample to be analysed
Intention-To-Treat (ITT) sample
Per-Protocol (PP) sample
Primary outcome
Retention in treatment Χ
Reducing/quitting ‘street heroin’
Other drug use; well-being;
Criminal behaviour ?
Wider recovery
‘responder’ or ‘abstinent’?
Major reduction in frequency of use
of ‘street heroin’
Completely abstinent from ‘street
heroin’
Which measure of primary outcome?
Urine test results
Observations and measurements
Self-report
What were the benefits?
To begin at the end
Four important conclusions, as I see them
•
SIH (heroin) group strongest achievement
•
SIM (inj methadone) better than OOM group
•
OOM (optimised oral) – still show benefit
•
Rapid onset of benefit and gain
So what are the main findings on
(i) ‘responder’ (reduced use of street-heroin)?
(ii) ‘abstinent from street-heroin’?
RIOTT - data on ‘responders’ and ‘non-responders’ –
broken down as % - at baseline (OOM, SIM, SIH)
100%
non-responder
90%
80%
responder
70%
60%
50%
100
100
100
0
0
0
OOM
SIM
SIH
40%
30%
20%
10%
0%
RIOTT treatment group
RIOTT - data on ‘responders’ and ‘non-responders’ –
broken down as % - at Months 4-6 (OOM, SIM, SIH)
100%
90%
27
80%
70%
60%
responder
72
67
50%
40%
73
30%
20%
10%
non-resp - some clean
28
33
OOM
SIM
0%
SIH
RIOTT treatment group
RIOTT - data on ‘responders’ and ‘non-responders’ –
broken down as % - at Months 4-6 (OOM, SIM, SIH)
non-responder
100%
90%
27
responder - only one dirty
responder - all clean
80%
70%
60%
72
67
50%
54
40%
30%
20%
10%
0%
31
19
7
2
OOM
SIM
SIH
RIOTT treatment group
RIOTT - data on ‘responders’ and ‘non-responders’ –
broken down as % - at Months 4-6 (OOM, SIM, SIH)
non-responder
100%
90%
27
80%
70%
60%
72
responder - > one dirty
responder - only one dirty
responder - all clean
67
35
50%
40%
19
30%
20%
10%
0%
19
24
7
7
2
OOM
SIM
19
SIH
RIOTT treatment group
RIOTT - data on ‘responders’ and ‘non-responders’ –
broken down as % - at Months 4-6 (OOM, SIM, SIH)
non-responder
100%
90%
27
80%
70%
60%
72
67
50%
16
responder - >2 dirty
responder - only 2 dirty
responder - only one dirty
responder - all clean
19
40%
19
30%
20%
17
24
10%
2
7
0
7
2
19
OOM
SIM
SIH
0%
RIOTT treatment group
How quickly does this marked
advantage show itself?
Percentage of participants not using
illicit heroin by week (ITT sample)
Percentage of participants not using
illicit heroin by week (ITT sample)
Percentage of participants not using
illicit heroin by week (ITT sample)
Other outcomes
Retention in treatment
Other drug use
Well-being
Serious Adverse events
Criminal behaviour
Serious Adverse Events
OOM
9 SAE
SIM
4 SAE
9 unrelated
0 related
1 related
(1 x O/D)
1 in 5551
injections
SIH
7 SAE
2 related
(2 x O/D)
1 in 6613
injections
5 unrelated
3 unrelated
How real an issue? SAEs
 Injected
diamorphine –
 2 x rapid overdose requiring emergency naloxone as
well as oxygen (incl. unconscious and unrousable)
 Injected
methadone –
 1 x rapid overdose requiring emergency naloxone plus
oxygen
Oxygen saturation: IV versus IM
IM
IV
SpO2 (%)
96
94
92
90
0
10
20
30
40
Minutes post-injection
50
60
Oxygen saturation: case study
96
SpO2 (%)
93
90
87
Male, age 49
Intravenous diamorphine (6 years)
This dose = 120 mg
Daily dose = 400mg
84
0
10
20
30
40
Minutes post-injection
50
60
Structure of today’s talk

history of heroin policy; and new scrutiny
 The
RIOTT trial – origins, conduct and results
 The
trial - and dialogue with government
 Ongoing
current analyses
“… rolling out the prescription of injectable
heroin and methadone to clients who do
not respond to other forms of treatment,
subject to the findings, due in 2009, of
pilots exploring the use of this type of
treatment”.
(H.M.Government Drug Strategy, 2008)
Structure of today’s talk
 history
of heroin policy; and new scrutiny
 The
RIOTT trial – origins, conduct and results
 The
trial - and dialogue with government
 Ongoing
current analyses
15000
Figure 3&4: SIH vs OOM:
bootstrapped cost and
effectiveness pairs: (i)
primary outcome, (ii)
quality adjusted life years
10000
0
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
-5000
-10000
-15000
-20000
-25000
-30000
Incremental effect - proportion >50% heroin free weeks 14 to 26
15000
10000
5000
Incremental cost (£)
Incremental cost (£)
5000
0
-0.15
-0.1
-0.05
0
-5000
0.05
0.1
0.15
-10000
-15000
-20000
-25000
-30000
Incremental effect - quality adjusted life years
0.2
0.25
0.3
RIOTT Research conclusions
Four important conclusions, as I see them
•
SIH (heroin) group strongest achievement
•
SIM (inj methadone) better than control group
•
OOM (optimised oral) – notable benefit
•
Rapid onset of benefit and gain
RIOTT Clinical conclusions
And four important clinical conclusions, also
•
Intensive-care – high-dose, high-level care
•
High-risk – be prepared
•
The most severe cases (?5-10%)
•
International critical mass with supervised
injectable maintenance treatment modality
 Thank
you