1. MHRN & Addictions
1-2-3
(MHRN Annual Conference, March 2013)
Professor John Strang
National Addiction Centre, London, UK
(comprising Addictions Department, IoP, Kings College London,
and Soutn London & Maudsley NHS Foundation Trust)
within Kings Health Partners Academic Health Sciences Centre

2. Declaration - general
• 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
• 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 have received support) including Action on
Addiction, and also with J Paul Getty Charitable Trust (JPGT) and Pilgrim Trust

3. Addictions area 1;
Addictions area 2;
Addictions area 3

4. Addictions area 1:
RIOTT: randomised trial of supervised heroin
prescribing for chronic refractory heroin addicts
Addictions area 2:
ConMan: Contingency management techniques
to improve benefit in Addictions treatments
Addictions area 3:
N-ALIVE: randomised trial of take-home
naloxone to prevent post-prison overdose deaths

5. Addictions area 1:
RIOTT: randomised trial of supervised heroin
prescribing for chronic refractory heroin addicts

6. 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:

7. RIOTT Team & Collaborators
 Investigators/trial coordination • RIOTT clinical team leaders
– Prof John Strang – Rob van der Waal, London
– Dr Nicholas Lintzeris – Anne McNutt, Darlington
– Dr Nicola Metrebian – Ian Wilson, Brighton
• Local Investigators • Trial co-ordination
– Dr Deborah Zador / Dr James Bell – National Addiction Centre, Institute of
– Dr Tom Carnwath/Dr Soraya Mayet Psychiatry, KCL
– Dr Hugh Williams
• Statistician
• Research staff – Laura Potts, Clinical Trials Unit,
– Vikki Charles Institute of Psychiatry, KCL
– Luciana Forzisi
– Teodora Groshkova • Health Economics
– Chris Hallam – Dr Sarah Byford Institute of
– Anthea Martin Psychiatry, KCL
– Barbara Barrett, Institute of
Psychiatry
• Clinical Trial Pharmacist
– Glynis Ivin, Maudsley Hospital
– Godwin Achunine, London clinic Randomisation
– Clinical Trials Unit, IoP
Diamorphine suppliers
 DiaMo Narcotics GmbH, Switzerland • Pathology
 Auralis, UK – Dr Andy Marsh & Richard Evers,
Kings College Hospital

8. Operating costs
• ‘An ineffective service is inefficient
and cannot be cost-effective, no
matter how cheaply it is provided’
• Cochrane, 1972

9. 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)

10. Second-line use of injectable maintenance
Rx-seeking Treat with oral
dependent good-quality
heroin user maintenance
repeated
treatment ‘failure’
Poor benefit with
oral maintenance
‘Optimisation box’
still treatment
minimal
‘failure’ benefit
Still poor benefit
with oral
Brief test trial of Immersion in full
‘RIOTT’ treatment ‘RIOTT’ treatment
Good benefit

11. Computer generated randomisation
Injecting heroin
User in opioid
Maintenance
Treatment for
6 months
Methadone
Enhanced
Diamorphine iv/im Ampoules iv/im
Oral
+/- oral methadone +/- oral methadone
Methadone

12. Treatments to be investigated
Supervised Injectable Heroin (SIH)
Supervised Injectable Methadone
(SIM)
Optimised Oral Methadone (OOM)

13. Sample to be analysed
Intention-To-Treat (ITT) sample
Per-Protocol (PP) sample

14. Primary outcome
Retention in treatment Χ
Reducing/quitting ‘street heroin’
Other drug use; well-being;
Criminal behaviour ?

15. ‘responder’ or ‘abstinent’?
Major reduction in frequency of
use of ‘street heroin’
Completely abstinent from
‘street heroin’

16. Which measure of primary outcome?
Urine test results
Observations and
measurements
Self-report

17. To begin at the end
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

18. 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
40%
30%
20%
10%
0 0 0
0%
OOM SIM SIH
RI OTT t r eat m ent group

19. RIOTT - data on ‘responders’ and ‘non-
responders’ – broken down as % - at Months 4-
6 (OOM, SIM, SIH)
100%
90% non-resp - some clean
27
80% responder
70%
72 67
60%
50%
40%
73
30%
20%
28 33
10%
0%
OOM SIM SIH
RI OTT t r eat m ent group

20. RIOTT - data on ‘responders’ and ‘non-
responders’ – broken down as % - at Months 4-
6 (OOM, SIM, SIH)
non-responder
100% responder - only one dirty
90% responder - all clean
27
80%
70%
72 67
60%
50%
54
40%
30%
20% 31
10% 19
7 2
0%
OOM SIM SIH
RI OTT t reat m ent gr oup

21. RIOTT - data on ‘responders’ and ‘non-
responders’ – broken down as % - at Months 4-
6 (OOM, SIM, SIH)
non-responder
100% responder - > one dirty
90% responder - only one dirty
27
responder - all clean
80%
70%
72 67
60%
35
50%
40%
30% 19
20% 19 24
10% 7 19
7 2
0%
OOM SIM SIH
RI OTT t r eat m ent group

22. RIOTT - data on ‘responders’ and ‘non-
responders’ – broken down as % - at Months 4-
6 (OOM, SIM, SIH)
non-responder
100% responder - >2 dirty
90% responder - only 2 dirty
27
responder - only one dirty
80%
responder - all clean
70%
72 67 16
60%
50% 19
40%
30% 19
20% 17 24
2 0
10% 7 19
7 2
0%
OOM SIM SIH
RI OTT t r eat m ent group

24. “… 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)

25. Addictions area 2:
ConMan: Contingency management techniques
to improve benefit in Addictions treatments

26. The ConMan Research Programme:
Developing a UK evidence base for
contingency management in drug treatment
Funding: NIHR (National Institute for Health Research) Programme
Chief Investigators
Prof John Strang (Kings, NAC / SLaM)
Dr Tim Weaver (Imperial / CNWL)
Prof Steve Pilling (UCL / Camden & Islington)
Programme Co-ordinator: Dr Nicola Metrebian
CM Psychologists: Dr Luke Mitcheson (SLaM) & Dr Frank Ryan (CNWL & C&I)
Researchers: Vikki Charles, Dilkushi Poovendran & Nicholas Little
Statistical and Health Economic Analysis: Jenny Hellier
Prof Sarah Byford & Hiong Tie
Prof Alan Brennan & Rachid Rafia University of Sheffield

27. The Research Programme
Module 1: Cross Cutting Themes
Organisational
analysis & Theme A: Theme B:
intervention Management, The service user
modelling Workforce & perspective
Training
Module 2:
CM & completion
of Hep B
Vaccination
Module 3:
CM & Retention in
treatment and
Abstinence from
Street Drugs
Time (5 year programme)

28. The Research Programme
Module 1: Cross Cutting Themes
Organisational
analysis & Theme A: Theme B:
intervention Management, The service user
modelling Workforce & perspective
Training
Module 2:
CM & completion
of Hep B
Vaccination
Module 3:
CM & Retention in
treatment and
Abstinence from
Street Drugs
Time (5 year programme)

29. Module 2:
Contingency Management &
completion of Hep B
Vaccination

30. Aims & Study Hypotheses
Aim:
Measure the effectiveness of two CM schedules in
improving completion of Hep B vaccination (when
compared with clients offered no incentive).
Hypotheses:
• The proportions of clients who complete Hep B
vaccination will be highest amongst groups offered
incentives when compared to a control group to
whom no incentives are offered.
• Reward schedules with the same aggregate value
but with different incentive schedules (i.e. fixed or
escalating) will achieve different completion rates.

31. Clinical Assessment, BBV Vaccination & Research
Assessments
Staff member assesses new client – Provides client with
information about trial & obtains informed consent
Research Interview – Baseline assessment
& disclosure of research allocation
Outcome Data
Recording: Hep B vacc - Day 0
1st vaccination (+/- incentive)
Record client’s
compliance
with the Hep B vacc – Day 7
vaccination 2nd vaccination (+/- incentive)
schedule.
Audio-recording Hep B vacc– Day 21
consultations 3rd vaccination (+/- incentive)

32. Clinical Assessment, BBV Vaccination & Research
Assessments
Staff member assesses new client – Provides client with
information about trial & obtains informed consent
Research Interview – Baseline assessment
& disclosure of research allocation
Outcome Data
Recording: Hep B vacc - Day 0
1st vaccination (+/- incentive)
Record client’s
compliance
with the Hep B vacc – Day 7
vaccination 2nd vaccination (+/- incentive)
schedule.
Audio-recording Hep B vacc– Day 21
consultations 3rd vaccination (+/- incentive)

33. Module 2: Cluster Randomised Trial Design
12 sites
Arm 1: (4 sites) Arm 2: (4 sites) Arm 3: (4 sites)
Hep B Vaccination Hep B Vaccination + Hep B Vaccination +
(Treatment as usual) fixed CM schedule escalating CM schedule
(No incentive) (£10, £10, £10) (£5, £10, £15)
Recruitment: 16 – 20 clients per site (64 per arm, 192 in total)
Trial Research
Researcher - Baseline interview with each client.
BBV Nurse - Record compliance with vaccination schedule & audio-recording
of consultations

34. ConMan HepB trial
Cluster Randomised trial of
CM-fixed or CM-esc
vs
control (TAU)

35. Results
• Still being prepared for submission etc
• In strict confidence and not for reporting
without authors’ explicit permission

36. ConMan HepB trial
Cluster Randomised trial of CM-
fixed or CM-esc vs control (TAU)
Payment by Results?
Results by Payment?

37. Addictions area 3:
N-ALIVE: randomised trial of take-home naloxone
to prevent post-prison overdose deaths

38. The MRC N-ALIVE Pilot Trial:
NALoxone InVEstigation
• N-ALIVE Chief Investigators
– Prof. John Strang
– Prof. Mahesh Parmar
– Prof. Sheila Bird
• N-ALIVE CTU Trial Team
– Dr. Angela Meade – Scientific Lead
– Laura Nichols – Trial Manager
– Lizzie Armstrong – Clinical Project Manager
– Tracey Pepple – Data Manager
• Funding and support: MRC with research support from MHRN.

39. n

40. n

41. Background
• Heroin-related deaths account for 8% of all
UK deaths in individuals aged 15-44 yrs.
• One in 200 prisoners with a history of
heroin use by injection dies from a drugs-
related death (DRD) within 2 – 4 weeks of
leaving prison.
• Current prevention approaches have not
resolved this high rate of overdose death
soon after release.

42. Drug-related deaths in England and
Wales 1997 – 2002 (ONS)
Drug Prevalence in general No. of deaths in the
population (use in last last 5 years
year, age 16-59)
Cannabis 10.8% 78
Cocaine 2.4% 508
Amphetamine 1.5% 436
Ecstasy 2% 200
Opiates (inc Heroin, 0.2% 6,194
morphine &
methadone)

43. Drug-related deaths in England and
Wales 1997 – 2002 (ONS)
Drug Prevalence in general No. of deaths in the
population (use in last last 5 years
year, age 16-59)
Cannabis 10.8% 78
Cocaine 2.4% 508
Amphetamine 1.5% 436
Ecstasy 2% 200
Opiates (inc Heroin, 0.2% 6,194
morphine &
methadone)

44. Excess mortality ratio for different time periods post-release by
cause of death (Singleton, Farrell, Marsden et al 2003)
45
40
35 Drug-related deaths Not drug-related
30
Excess mortality ratio
25
20
15
10
5
0
to 1 to 2 to 4 to 8 3 6 2 = 52 otal
p to 1 p to 2 p to 5 > T
U 1 up 2 up 4 up 8 up 13 u 26 u
Time since release (w eeks)

47. Background
• The N-ALIVE pilot, a prison-based
Naloxone-on-release randomised
controlled prevention trial.
•
• Naloxone - opiate antagonist reverses
heroin overdose.
• pilot N-ALIVE – feasibility; 10% sample
(n=5,600).

48. Eligibility Criteria
Inclusion criteria Exclusion criteria
• History of heroin use by • History of anaphylactic reaction to
injection Naloxone
• Aged 18-44 years • Pregnant or planning to become
• Have been in prison for at least pregnant within 6 months
seven days • Resident outside of Scotland,
• Likely release date within three England and Wales
months • Most recent N-ALIVE release date is
• Not previously randomised and within 6 months
then withdrawn their consent • Most recent N-ALIVE release date
prior to release missing but participant was
• Written informed consent randomised in the past year
N.B. Participants receiving OST not
excluded from participating in N-ALIVE

49. N-ALIVE Process Chart

51. MHRN Networks & N-ALIVE Sites

52. MHRN Networks & N-ALIVE
Sites

53. N-ALIVE Site Progress
Total No.
Sites Open MHRN Hub N-ALIVE Workers Open Date
Randomised
Sites in Set-up
Elizabeth Andrew
HMP Nottingham East Midlands 28th May 2012 59
Amy Shuttlewood
HMP Doncaster
South London
HMP Winchester Joanne McCarthy 12th October 2012 17
and South East
HMP Dorchester
Anne Chafer
HMP Lincoln East Midlands 08th October 2012 6
Diane Brennan HMP Liverpool
HMP Becca Bishop
Exeter/Channings West 29th October 2012 33 HMP Styal
Wood/Dartmoor Dave Bright
HMP Gloucester Genevieve Riley
HMP Highpoint North and
West 2nd November 2012 11
South
(now closed) Emma Page, Simon Ball
Kim Thompson
HMP Dovegate East Midlands 26th November 2012 1 HMP Blunsden
Tim Lewington
Sheila Shatford
HMP Bristol West 27th November 2012 26 HMP Eastwood Park
Karen Alloway
Total Recruitment (175 up to 15th March) 153

54. N-ALIVE recruitment
N = 175 and rising daily
We still need extra prison release sites:
Contact Laura Nichols at MRC CTU at
lln@ctu.mrc.ac.uk or
nalivepilot@ctu.mrc.ac.uk

55. Acknowledgments
• The N-ALIVE Trial Management Group wishes to
acknowledge the support and contribution of MHRN staff to
date. MHRN staff from 5 MHRN hubs are helping to get the
trial initiated and in some cases taking on the key role of
N-ALIVE worker; building strong relationships with prison
staff, introducing the trial to potential participants,
obtaining informed consent and managing the trial locally.

56. Addictions area 4:
Naltrexone Enhanced Addiction Treatment (NEAT)
for opioid dependence: RCT of implanted
extended-release naltrexone vs oral naltrexone

57. Addictions area 1:
RIOTT: randomised trial of supervised heroin
prescribing for chronic refractory heroin addicts
Addictions area 2:
ConMan: Contingency management techniques
to improve benefit in Addictions treatments
Addictions area 3:
N-ALIVE: randomised trial of take-home
naloxone to prevent post-prison overdose deaths

58. Thank you