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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