John Strang National Addiction Centre (The Maudsley & Institute of Psychiatry) London

1. Supervised heroin treatment for entrenched hard-to-treat heroin addicts: major benefits and cost-effectiveness in RIOTT and other randomised trials John Strang National Addiction Centre (The Maudsley & Institute of Psychiatry) London (on behalf of RIOTT research, clinical and related colleagues)

2. Declaration (personal & institutional) • NHS provider (community & in-patient); history with Phoenix House, Lifeline, Clouds House, KCA (Kent Council on Addictions). • DH, NTA, Home Office, NACD, EMCDDA, WHO, UNODC, FDA, NIDA. • Consultation and work with pharmaceutical companies re actual or potential development of new medicines for use in the addiction treatment field, including (past 3 years) Martindale Pharma, Reckitt-Benkiser/Indivior, MundiPharma, Alkermes, Rusan/iGen, Braeburn. • UKDPC (UK Drug Policy Commission), SSA (Society for the Study of Addiction); and two Masters degrees (taught MSc and IPAS) and an Addictions MOOC. • Work also with several charities (and received support) including Action on Addiction, and also with J Paul Getty Charitable Trust (JPGT) and Pilgrim Trust. • The university (King’s College London) has registered intellectual property on a novel buccal naloxone, and JS has been named in a patent registration by a Pharma company as inventor of a concentrated nasal naloxone spray formulation. 

3. 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:

4. 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 Clinical Trial Pharmacist Glynis Ivin, Maudsley Hospital Godwin Achunine, London clinic Diamorphine suppliers DiaMo Narcotics GmbH, Switzerland Auralis, UK 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 Randomisation Clinical Trials Unit, IoP Pathology Dr Andy Marsh & Richard Evers, Kings College Hospital RIOTT Team & Collaborators

5. Credit where credit’s due • Ambros Uchtenhagen and Swiss Ministry of Health - public health policy drive • Wim Van den Brink and Dutch CCHB – serious research trial (and Germans and Canadians) • UK Government Drug Strategy 2002 & 2008 – ‘blueprint’; and 2012 service specs from DH/PHE

6. Structure of today’s talk • history of heroin policy; and new scrutiny • The RIOTT trial – origins, conduct and results • The supervised heroin clinic – how it works • Analyses – effectiveness, cost-effectiveness • Cost-limits, time-limits, cuts and damage done

7. The Rolleston Report, 1926 • The legitimacy and authority of the medical versus law enforcement perspective • “maintenance” (not termed thus) with injectable morphine (or sometimes diamorphine (heroin)) is legitimate medical practice • Sets UK apart from post-1920s US policy • Largely overtaken by evidence-driven oral methadone maintenance treatment (& bup) as main modality of treatment response

8. The Second Brain Report, 1965 For the first time, seen as a growing problem amongst the young A ‘socially transmissable condition’ Entirely based on prescribed or diverted pharmaceutical injectables (from small number of independent doctors) Creation of a new network of drug treatment centres (esp around London) The new clinics take over all injectable prescribing

9. WHAT INJECTABLE PRODUCTS? • Two products: • - heroin ampoules (dry amps) - methadone ampoules (wet amps) (historically also morphine by injection)

10. Changes in the UK in the 1970s & 1980s • initial optimism for therapeutic power; growing disillusionment over the years • The growing status of oral methadone • The withering of injectable heroin • Intermediate years of injectable methadone

11. IOT in the UK at turn of century • Diminishing treatment modality in UK • Calls from Government to increase heroin prescribing • Drugs Strategy 2002: prescribed heroin for ‘all in need’ • Parliamentary Select Committee 2002 • NTA Guidance Report May 2003 • expert committee on injectable heroin/methadone prescribing • Influence of studies emerging from mainland Europe

12. WHAT INJECTABLE PRODUCTS?(n.b. predominantly an English phenomenon) • Today - two products: • - heroin ampoules (dry amps) (less than 1%) - methadone ampoules (wet amps) (maybe 1%)

13. Structure of today’s talk • history of heroin policy; and new scrutiny • The RIOTT trial – origins, conduct and results • The supervised heroin clinic – how it works • Analyses – effectiveness, cost-effectiveness • Cost-limits, time-limits, cuts and damage done

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

16. 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

17. 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 • Overviews – EMCDDA Monograph 2012; meta-analysis and systematic review BJPsych 2015

18. Structure of today’s talk • history of heroin policy; and new scrutiny • The RIOTT trial – origins, conduct and results • The supervised heroin clinic – how it works • Analyses – effectiveness, cost-effectiveness • Cost-limits, time-limits, cuts and damage done

19. 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

26. Structure of today’s talk • history of heroin policy; and new scrutiny • The RIOTT trial – origins, conduct and results • The supervised heroin clinic – how it works • Analyses – effectiveness, cost-effectiveness • Cost-limits, time-limits, cuts and damage done

27. 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)

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

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

30. Primary outcome measure

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

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

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

36. Findings - 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

37. So what are the main findings on(i) ‘responder’ (reduced use of street-heroin)?(ii) ‘abstinent from street-heroin’?

38. RIOTT - data on ‘responders’ and ‘non-responders’ – broken down as % - at baseline (OOM, SIM, SIH)

39. RIOTT - data on ‘responders’ and ‘non-responders’ – broken down as % - at Months 4-6 (OOM, SIM, SIH)

40. RIOTT - data on ‘responders’ and ‘non-responders’ – broken down as % - at Months 4-6 (OOM, SIM, SIH)

41. RIOTT - data on ‘responders’ and ‘non-responders’ – broken down as % - at Months 4-6 (OOM, SIM, SIH)

42. RIOTT - data on ‘responders’ and ‘non-responders’ – broken down as % - at Months 4-6 (OOM, SIM, SIH)

43. Percentage of participants not using illicit heroin by week (ITT sample)

44. Percentage of participants not using illicit heroin by week (ITT sample)

45. Percentage of participants not using illicit heroin by week (ITT sample)

46. Operating costs • …….. • Optimised oral methadone maintenance – c 5k pppa • Supervised injectable methadone maintenance – c 10k pppa • Supervised injectable heroin maintenance – c 15k pppa • …..

47. Operating costs • ‘bog-standard’ oral methadone maintenance – c 3k pppa • DTTO/DIP methadone treatment + monitoring – c 10k pppa • Optimised oral methadone maintenance – c 5k pppa • Supervised injectable methadone maintenance – c 10k pppa • Supervised injectable heroin maintenance – c 15k pppa • Prison – c 44k pppa

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