Treatment of Heroin Addiction in The Netherlands

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1 Treatment of Heroin Addiction in The Netherlands Wim van den Brink Amsterdam Institute for Addiction Research Academic Medical Center University of Amsterdam Sixth Interdisciplinary Substitution Treatment Symposium Montreal, 3 November 1 December 26 Content General treatment principles in heroin addiction History of heroin addiction in The Netherlands History of substitution treatment in the Netherlands Current situation in The Netherlands * General treatment organization * Methadone maintenance treatment in The Netherlands * Heroin assisted treatment in The Netherlands Remaining problems and potential solutions Conclusions 1

2 Herion Addiction and General Treatment Principles 33 jaar follow-up van heroineverslaafden (Hser et al., 21) Onbekend Dood Gedetineerd Dagelijks gebruik Methadon Onregelmatig gebruik Abstinent % 2% 6% 7% 4% 48% % N Age 24.5 (3.9) 36.8 (5.4) 47.6 (5.1) 57.4 (4.) 2

3 A 33 year FU of narcotic addicts (Hser et al., 21) Unknown Dead Incarcerated Daily use MMT Occasional use Abstinence Theodore Dalrymple 22% 2% 6% 7% 4% 48% % N Age 24.5 (3.9) 36.8 (5.4) 47.6 (5.1) 57.4 (4.) Treatment Career and Treatment Goals General Model TYPE Crisis Intervention Cure Care Palliation GOAL Immediate Survival Stable Abstinence Stabilization Harm Reduction Pain Relieve PROCESS - Reanimation - Motivation - Detoxification - Relapse Prevention - Reduction Illicit Drug Use - Psychosocial Support - Provide Drug of Abuse - Support 3

4 Treatment Career and Treatment Goals Applied General Model TYPE GOAL PROCESS MEDICATION Crisis Intervention Immediate Survival - Reanimation Antagonist Cure Care Stable Abstinence Stabilization Harm Reduction - Motivation - Detoxification - Relapse Prevention - Reduction Ill Drug Use - Support Agonist tapering Part Agonist tapering Symptomatic Antagonist maintenance Agonist maintenance Part Agonist maintenance Palliation Pain Relieve - Provide Abused Drug Agonist maintenence Goals and Interventions Heroin Addiction Type Goal Process Medicine EBM Crisis Intervention Survival Reanimation - Naloxone +++ Cure Abstinence Detoxification Relapse prevention - Methadone reduction Buprenorphine reduction Clonidine/Lofexidine Naltrexone (ROD/UROD) - Naltrexone maintenance (implants/depot) ±/- Care Stabilization Harm reduction Reduction ill drug use Secundary prevention - Methadone maintenance HD LAAM Buprenorphine maintenance Methadone maintenance LD Heroin maintenance Palliation Pain relieve Provide abused drug - Methadone/Heroin na Van den Brink and Haasen, 26; Lingford-Hughes et al., 24, Vocci et al., 25; O Brien, 25 4

5 History of Heroin Addiction in The Netherlands History Heroin Addiction in NL (NL: 16.. inhabitants; Amsterdam: 75.) 1972 Introduction heroin to the Netherlands 1975 Independence of Suriname; n = 2. heroin addicts 1977 n = 1. heroin addicts 1985 n = 2. heroin addicts 1985 HIV introduction to the Netherlands 1995 n = 25. heroin addicts: 4% injectors, 6% smokers 26 n = 25. heroin addicts: 1% injectors, 9% smokers 5

6 Heroin Addicts in Amsterdam (GGD Amsterdam, 25; number ) Age Heroin Addicts in Amsterdam (GGD Amsterdam, 25: 28 yrs 45 yrs, i.e. 17 yrs within 2 years) Heroin addicts = stable, ageing population with few new cases and relatively low mortality 6

7 Mortality Heroine Addicts Amsterdam (GGD Amsterdam, 25) Mortality per 1 MMT patients/year Survival rates heroin addicts (and smokers) Mortality and excess mortality increase with time/age; 5% ever IDU die before 55 Excess mortality among heroin inhalers much lower and LTE better demand for care! History of Substitution Treatment in The Netherlands 7

8 History Substitution Tx in NL 1968 Introduction methadone for Tx of morphine addiction 1972 Introduction of heroin to the Netherlands Methadone reduction and methadone maintenance Experiment with Morphine i.v. (n=37) 1985 Introduction HIV to the Netherlands Low Threshold MMT (low dosages, no sanctions) Experiment with Methadone i.v. (n=3 AIDS patients) Experiment Dextramoramide p.o. (n=53) Experiment High Methadone Doses (n=225: >85 mg/day) Experiment Heroin Assisted Treatment (n=549) Routine treatment with MMT and HAT 26 Registration heroin as a medicinal product? 27 Registration Suboxone as a medicinal product? Substitution Tx coverage in EU (EMCDDA, 22) high estimate low estimate UK POR NOR FIN SWE AUS IT DK GER IRL BE LUX FR NL SP Since

9 Available Treatments in Europe (EMCDDA, 25) Agonist Maintenance Tx in Europe (EMCDDA, 25) In methadone Tx In buprenorphine Tx In substitution Tx Total opioid addicts

10 Methadone Maintenance in Europe (EMCDDA, 23) CEECs = Central and East European Countries Assistance Drug Users Prison in EU (EMCDDA, 22) HIV prevention substitution drug free UK POR NOR FIN SWE AUS IT DK GER IRL BE LUX FR NL SP 1

11 Current Situation in The Netherlands General Treatment Organization Methadone Maintenance Treatment Heroin Assisted Treatment Current Situation in The Netherlands General Treatment Organization Methadone Maintenance Treatment Heroin Assisted Treatment 11

12 General Treatment Organization Netherlands: 16.. inhabitants (41. km 2 ); 25. heroin addicts BNP = 5 billion Health Care Spending 45 billion (9% BNP) Canada: 32.. inhabitants (1.. km 2 ); 9. opioid addicts BNP = 85 billion Health Care Spending 1 billion (12% BNP) Organization Treatment Services 14 regional addiction treatment centers 6. patients in treatment/year 17. heroin addicts in treatment/year Increasing integration addiction and mental health services 12

13 Financial Aspects Treatment Netherlands: BNP = 5 billion 45 billion spent on health care per year (9% 1%) 3.6 billion spent on mental health care per year (8%) 35 million spent on addiction treatment services per year (.8%) 175 million spent on drug addiction treatment per year (.4%) 5 million spent on MMT and 6 million spent on HAT Current Situation in The Netherlands General Treatment Organization Methadone Maintenance Treatment Heroin Assisted Treatment 13

14 Substitution Tx coverage in EU (EMCDDA, 22) high estimate low estimate UK POR NOR FIN SWE AUS IT DK GER IRL BE LUX FR NL SP Since 1968 Methadone dosages NL 24 (LADIS/IVZ, 24) 62% with dosages < 6 mg/day 14

15 Substitution Tx coverage EU (EMCDDA, 22) Amsterdam high estimate low estimate Coverage Amsterdam 7% UK POR NOR FIN SWE AUS IT DK GER IRL BE LUX FR NL SP since 1968 Heroin Addicts in Amsterdam (Capture-Recapture: GGG Amsterdam, 25: ) Buitenlanders NL Allochtoon NL Autochtoon

16 Methadone Tx in Amsterdam (GGD Amsterdam, 25: ) Jellinek GP GGD Jellinek GP GGD MMT Dosages and Compliance (GGD Amsterdam, 25) mg/day mg/day GGD GP Jellinek 54% < 6 mg/day 69% < 6 mg/day 57% < 6 mg/day Compliance better with higher dosages 16

17 IDU, HIV and NE in Amsterdam (GGD Amsterdam, 25) Number of new HIV cases over time Number of exchanged needles x 1. Reductions in IV drug use and prevention measures seem to lead to a lower HIV incidence and reductions in needles exhanged; HIV prelalence Amsterdam = 7% Treatment Heroin Addicts in The Netherlands TOTAL N=24, 15% injectors, 85% smokers In Treatment N=17, Not in Treatment N=7, METHADONE MAINTENANCE N=12,5 DRUGFREE TREATMENT N=4, Integrated N=4,5 Not Integrated N=5, Extremely Problematic N=3, 17

18 Health Council of the Netherlands (1995) Continuation existing programmes * drugfree, methadone reduction, methadon maintenance Improving liaison between legal and treatment system * diversion, drugfree prison programmes Ultrarapid detoxification with/without anesthesia High dosage methadone maintenance Controlled medical prescription of heroin Ultrarapid NTX Assisted Detox (De Jong et al., 25) 24% of patients successfully detoxified with NTX were still abstinent 12 months later Very selective group with no polydrug use and good social integration 18

19 Health Council of the Netherlands (1995) Continuation existing programmes * drugfree, methadone reduction, methadon maintenance Improving liaison between legal and treatment system * diversion, drugfree prison programmes Ultrarapid detoxification with/without anesthesia High dosage methadone maintenance Controlled medical prescription of heroin High dosages of Methadone (Driessen et al., submitted) RCT N=225 Baseline methadone dose: 53 mg/day Exp = > 85 mg/day mean 12 mg/day after 22 months Con = < 85 mg/day mean 66 mg/day after 22 months Daily Illegal Heroin * High Dose 56% 17% - 39% * Low Dose 5% 31% -19% High dose group also better in physical functioning 19

20 Health Council of the Netherlands (1995) Continuation existing programmes * drugfree, methadone reduction, methadon maintenance Improving liaison between legal and treatment system * diversion, drugfree prison programmes Ultrarapid detoxification with/without anesthesia High dosage methadone maintenance Controlled medical prescription of heroin Current Situation in The Netherlands General Treatment Organization Methadone Maintenance Treatment Heroin Assisted Treatment 2

21 Basic Principles Dutch Heroin Trials Separate RCTs for inhalable and intravenous heroin Explicit inclusion and exclusion criteria Standardized assessment procedures Pre-defined measure of effect + pre-specified analysis plan Adequate statistical power Quality assurance according to GCP Design of the Study Phase 1 2 months Randomization Phase 2a 6 months Phase 2b 6 months Phase 3 6 months Target Group 1. Inhaling M (N=375) 1A (N=135) 1B (N=115) 1C (N=125) M M+H (inh) M M M+H (inh) M+H (inh) M+H (inh) appropriate appropriate 2. Injecting M (N=25) 2A (N=135) 2B (N=115) M M+H (iv) M M+H (iv) M+H appropriate M=oral methadone; H=heroin; inh=inhalable; iv=intravenous 21

22 Experimental and Control Treatment Control Treatment oral methadone < 15 mg/day standard psychosocial offer Experimental Treatment oral methadone < 15 mg/day standard psychosocial offer heroin inhalable or intravenous: * -7 days/week * -3 times/day * < 4 mg/administration * < 1 mg/day dosages individually titrated no prescription of other illicit drugs Inclusion and Exclusion Criteria chronic, treatment-resistant heroin addicts Inclusion Criteria Exclusion Criteria DSM-IV heroin dep > 5 yrs registered in MMT last 12 mths >3-5 visits to MMT last 6 mths >5-6 mg meth > 4 wks last 5 yrs (nearly) daily use of heroin poor social integration and/or poor physical and/or mental health age > 25 yrs legal resident in The Netherlands registered in area > 3 yrs willing to be randomized written informed consent not meeting ALL inclusion criteria illness with high safety risk illness or behaviour likely to interfere with study completion pregnant or lactating awaiting long imprisonment other drugs dominating heroin dep short life-time expectancy voluntary abstin > 2 mths past yr requiring > 15 mg oral methadone requiring > 1 mg heroin participating in other study 22

23 Patient Characteristics Age 39 years Female patients 19 % Dutch/Western 86 % Heroin 16 years 26 days Methadone 12 years 29 days Cocaine 1 years (92%) 18 days (86%) Poly drug use 17 years 29 days Physical problems 66 % Psychiatric problems 6 % Social problems 72 % Participation in the trial Injectable heroin: 174 patients randomized (25 planned) Inhalable heroin: 375 patients randomized (375 planned) Injectable heroin: 93% month 12 endpoint assessments Inhalable heroin: 94% month 12 endpoint assessments 23

24 Response definition 4% improvement in physical health or 4% improvement in mental status or 4% improvement in social functioning and no serious deterioration (4% in any domain) and no increase in cocaine (or other drug) use FILM 24

25 Heroin Assisted Treatment in The Netherlands Van den Brink et al. 23, BMJ 1% 12 months methadone 12 months methadone + heroin percentage responders 8% 6% 4% 2% OR= OR= % injectable heroin inhalable heroin percentage multi-domain responders 1% 8% 6% 4% 2% % Effectiveness of heroin assisted traetment multi-domain responders 1 domain 2 domains 3 domains =25% = 23% 32% 57% 25% 48% 5 27 methadone heroin methadone heroin injectable heroin inhalable heroin 25

26 Changes among Responders 2 physical health 1 mental status M A P - HSS score SCL- 9 score = baseline = 12 months 3 illegal activities 3 no contact non-drug users 3 cocaine use num ber of days num ber of days num ber of days Discontinuation completers 217 responders 115 (53%) deteriorated responders 94 (82%) 26

27 Changes among deteriorated responders 2 physical health 1 mental status M A P - HSS score SCL-9 score = baseline = 12 months = 14 months 3 illegal activities 3 no contact non-drug users 3 cocaine use num ber of day s num ber of days num ber of days Long-term course responders (24 months: n = 128; 36 months: n = 95; 48 months: n = 79) MAP-HSS score physical health S CL-9 score mental status = baseline = 12 month exp = 24 months nat = 36 months nat = 48 months nat 3 illegal activities 3 no contact non-drug users 3 cocaine use num ber of day s num ber of day s num ber of day s

28 Cost-Effectiveness HA Treatment Dijkgraaf et al, 25, BMJ Type of Costs M+H Difference M Medical Maintenance Other Health Care Juridical Police, prosecution, jail Damage Victims: persons, companies Total Difference Cost-Effectiveness HA-Treatement Dijkgraaf et al (25), BMJ Better and More Expensive Better and Cheaper Better and Cheaper Cost-Effectiveness Plane 28

29 Current Situation and Plans HAT Approximately 3 patients in 6 cities in HA treatment Registration file for injectable and inhalable heroin under review at Dutch registration authority Approved plans for extension of HA treatment to 8 patients in cities RCT contingency management within contexts of HA treatment to further reduce cocaine abuse and to enhance treatment effectiveness Application for Registration 29

30 heroin assisted treatment units in the Netherlands old centres new centres planned centres 5-7 patients 25-5 patients 25-3 patients Contingency Management Cocaine Heroin-treatment + CM Heroin-treatment alone Experimental group Heroin-treatment randomisation Heroin-treatment alone Heroin-treatment + CM Control group Heroin-treatment Naturalistic comp. group 3

31 Contingency Management Cocaine Contingency Management Cocaine 31

32 Treatment Goals and Modalities in NL Therapeutic Residential Community Treatment ABSTINENCE ORIENTED Inpatient DETOX Psychiatric 4 5 Treatment Drug Free Prison Treatment (VOL) Outpatient Drug Counseling Outpatient DETOX Methadone Reduction Employment Training VOLUNTARY Employment Training 12 5 Methadon Maintenance Budgeting Diversion Motivation Centre Day Care Night Care Needle Exchange Heroin Maintenance HARM Methadone in Prison USER ROOMS REDUCTION Prison TC Drug Free Prison Treatment (COM) Forensic Drug Abuse Treatment COMPULSORY Treatment Goals and Modalities VOLUNTARY ABSTINENCE ORIENTED HARM REDUCTION COMPULSORY 32

33 Agonist treatment and the risk of increased incidence Nordt & Stohler, Lancet, 26 MMT HAT The harm reduction policy of Switzerland and its emphasis on the medicalisation of the heroin problem seems to have contributed to the image of heroin as unattractive for young people. Remaining Problems and Potential Solutions 33

34 Conclusions and Remaining Issues Heroin Addiction Treatment Conclusions Detoxification without RP useless and dangerous Antagonist treatments have very high drop-out rates Naltrexone assisted detox with anesthesia useless and dangerous Maintenance treatments are much more effective than tapering regimens Remaining issues Efficacy heroine, methadone iv, and morphine SR? No consensus about treatment of pregnant heroin addicted women Patient-Treatment Matching unresolved Attention Comorbid drug use Comorbid psychiatric disorders Comorbid somatic disorders Treatment of Drug Addicts in NL (LADIS/IVZ, 25) Opiaten Cocaine Amfetamine Cannabis Reduction heroin, strong increase cocaine, increase cannabis 34

35 Treatment Seeking Cocaine (LADIS?IVZ, 24) 24% Snorting 76% Base Coke/Crack 56% Cocaine + Heroine Beyond Heroin Addiction - Beyond MMT Comorbid drug use (Gossop, 24) Stimulant use 4-9%, stimulant dependence 4-8% Alcohol use 9%, alcohol dependence 2-4% Cannabis use 5-75%, cannabis dependence 1-2% Comorbid psychiatric disorders (Kranzler & Tinsley, 24) Depression 25-4% ADHD 15-2% Psychosis 5-1% Comorbid physical ailments (Sullivan & O Connor, 24) HIV 5-35%; HCV 5-9% Comorbid social problems Housing 35

36 MMT and Comorbid Substance Use Alcohol use 9%, alcohol dependence 2-4% Stimulant use 4-9%, stimulant dependence 4-8% Cannabis use 5-75%, cannabis dependence 1-2% MMT and Alcohol Use/Dependence Findings Alcohol dependence in MMT often is associated with lower abstinence levels from illicit opioids (Gossop et al., 22), with increased levels of criminality (Roszell et al., 1986), and increased risk of a fatal overdose (Darke et al., 1996) BUT Alcohol dependence in MMT sometimes associated with higher heroin abstinence and with increased use of cocaine (Chatham et al., 1997). Primary cocaine dependence? Conclusion Integrated treatment necessary with attention for heroin, stimulant and alcohol dependence (Kipnis et al., 21) Alcohol treatment through CM, CBT, CRA (including disulfiram)? 36

37 MMT and Cocaine Use/Dependence Comorbid cocaine use is a negative predictor for the effect of MMT on illicit opioid use (e.g. Wasserman et al., 1998) MMT is more effective than BMT in patients with comorbid cocaine use: better retention, larger reductions of both illicit opioids and cocaine (Schottenfeld et al., 25; Strain et al., 1994) Inconsistent findings with regard to the effect of higher dosages of methadone or buprenorphine on illicit cocaine use: pos. Peles et al., 26; neg. Schottenfeld et al Positive effects of CM and CBT on illicit heroin and/or cocaine use during MMT (e.g. Silverman et al., 1996, 1999; Rawson et al., 22; Schottenfeld et al., 25; Poling et al., 26; Pierce et al., 26). Positive effects of bupropion, modafinil and disulfiram on cocaine use? Schottenfeld et al., 25 MMT vs BMT with/without CM: retention drug-free urines Treatment retention/reduction drug use better in METH than BUP; short-term effect CM 37

38 Schottenfeld et al, 25 MMT vs BMT with/without CM: cocaine-free urines Positive short-term effects of CM (during increase incentives), but no long-term effects of CM Silverman et al Effect of CM voucher magnitude on cocaine use in MMT max 3 max 3 max CM effective but expensive 38

39 Pierce et al. (26) MMT with/without CM (low-cost/lottery: $ 12/pt) on stimulant and alcohol 39

40 Rawson et al. (22) MMT with/without 16 weeks CM and/or CBT directed at cocaine use 8 7 % of cocaine-free urine samples CBT CM CBT + CM MMT alone weeks 26 weeks 52 weeks CM more short-term effective, CBT more long-term effective MMT and Cannabis Use/Dependence Findings: Most studies show no negative effect of (heavy) cannabis use on retention and outcome in MMT/BMT with or without CM * Saxon et al., 1993; Nirenberg et al., 1996; Budney et al., 1998; Epstein & Preston, 23 Conclusion Cannabis use needs not be a focus of attention from the point of view of MMT. It may be focus in and by itself. 4

41 Epstein & Preston (Addiction, 23) All 3 studies in MMT + CM directed to either illicit opioid or cocaine use % neg urines for targetd drug No effect of (heavy) cannabis use on retention or perc drug-free targets of MMT+CM MMT and Comorbid Mental Disorders Double Trouble Depression 25-4% ADHD 15-2% Psychosis 5-1% 41

42 MMT and Depression Chronic opioid use seems to lead to depression and depression seems to increase opioid use Comorbid depression is a negative predictor in MMT (McLellan et al., 1983, 1997) SSRIs (fluoxetine, sertraline) are not effective in Tx of depression in MMT patients (Petrakis et al., 1998; Dean et al, 22; Carpenter et al., 24) Tricyclics (doxepin, imipramine) might be effective in Tx of depression in MMT patients (Woody et al., 1975; Nunes et al., 1998) Nunes et al. (1998) RCT Imipramine vs Placebo in Depressed MMT patients Imipamine effective for depression (57% vs 7% response), no difference in drug use outcomes 42

43 MMT and ADHD Effect of ADHD on MMT outcome not consistent (Schubiner et al., 2) Methylphenidate reduced effect on ADHD Sx in cocaine dependent patients, and no effect on cocaine use is inconsistent (Levin et al., 1998; Schubiner et al., 22; Carpentier et al., 25) No indications of abuse of prescribed (exetende release) stimulants in addicted patients with ADHD. Methylphenidate and bupropion are NOT affective in the Tx of MMT patients with ADHD (Levin et al., 26) Psycho-education plus higher dosages of methylphenidate or dexamphetamine? Levin et al. (26) Placebo, Methylphenidate, and Bupropion in MMT patients with ADHD No effect of MPH or BRP on ADHD Sx or drug use indicators 43

44 MMT and Schizophrenia Classical anti-psychotics often less effective in schizophrenic patients with substance use disorders and no or negative effect on substance abuse (e.g. Bowers et al., 199; Sokolsky et al., 1994; D Mello et al., 1995; Swofford et al., 2) Atypical anti-psychotics (risperidone, olanzapine, clozapine) generally have a normal positive effect on schizophrenic Sx and sometimes on substance abuse (e.g. Buckley et al., 1994; Kelly et al., 23; Conley et al., 1998; Littrell et al., 21; Albanes et al., 21). Some indications for superiority of clozapine over other atypical antipsychotics (Zimmet et al., 2; Green et al., 23; Brunette et al., 26). Cave epileptic seizures! Integrated psychosocial treatments reduce drug use in patienst with schizophrenia (Barrowclough et al., 21; Bellack et al., 26) Bellack et al. (26) RCT 6 months Integrated vs Separate Substance Abuse Program (no data available in MMT) Intregated program results in better retention and greater reduction of drug use 44

45 Conclusions Conclusions Abstinence oriented Txs are relatively ineffective and should be reserved for small group of stable, well-functioning opioid addicts. MMT is the best studied and most effective first line Tx Not all patients respond favorably to MMT, but other opioid agonists (BUP, SROM, HAT) are good alternatives in these patients Prison = window of opportunity for harm-reduction and maintenance Tx. Agonist maintenance Tx should always be combined with * psychosocial support, CM or CBT if indicated, and * attention to polydrug use, and mental, somatic and social omorbidity 45

46 Selected References van den Brink W, Hendriks VM, van Ree JM (1999) Medical co-prescription of heroin to chronic, treatment-resistant methadone patients in the Netherlands: a randomized clinical trial. Journal of Drug Issues, 29, van den Brink W, Hendriks VM, Blanken P, van Zwieten BJ, van Ree JM (23) Medical prescription of heroin to chronic, treatment-resistant heroin dependent patients: two randomised controlled trials. BMJ, 327, Dijkgraaf MGW, van der Zanden BP, Borgie CAJM, Blanken P, van Ree JM, van den Brink W (25) Cost utility of medical co-prescription of herroin compared with methadone maintenance treatment for chronic, treatment resistant heroin addicts. BMJ, 33, van den Brink W, Haasen C (26) Evidence-based treatment of opioid dependent patients. Canadian Journal of Psychiatry, 51,

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