Henning Krampe Department of Anaesthesiology and Intensive Care Medicine

1. Long-term disulfiram treatment and mechanisms of effectiveness 10th Stapleford International Addiction Conference Stapleford Athens 2011 Henning Krampe Department of Anaesthesiology and Intensive Care Medicine Campus Virchow-Klinikum and Campus Charité Mitte Charité - Universitätsmedizin Berlin C C C CHARITÉ CAMPUS VIRCHOW-KLINIKUM und CAMPUS CHARITÉ MITTE KLINIK FÜR ANÄSTHESIOLOGIE m. S. OPERATIVE INTENSIVMEDIZIN

2. 60 years of treatment outcome research on DSF Promising early RCTs on supervised DSF: Gerrein et al 1973, Azrin et al 1982 Large scale RCT on unsupervised DSF:Fuller et al 1986 1990s: Disulfiram "The obsolete medication" Only 2 RCT on supervised DSF in the 90s: Chick et al 1992, Tønnesen et al 1999 → Beneficial results Research on Naltrexone, Acamprosate – Economic interestsCurrent trends:Topiramate, GHB, Baclofen ??? Wise reviews on DSF, e.g. Banys 1988; Brewer 1993, 2005; Brewer et al 2000; Chick 1999; Kristenson 1995

3. Revival of disulfiram between 2000 and 2011 No evidence for sufficient efficacy of primarily pharmacotherapeutic treatment of AUD Recent RCT and nonrandomized clinical studies: Supervised DSF is the most successful pharmacological adjunct to psychotherapay in AUD DIS has some effect as pharmacological adjunct in psychosocial treament of cocaine dependence New clinical studies e.g. De Sousa & De Sousa 2004, 2005, 2008a, b; Krampe et al 2006; Laaksonen et al 2008; Petrakis et al 2005 New reviews, e.g.Brewer 2005, Suh et al. 2006, Barth & Malcom 2010, Krampe & Ehrenreich 2010

4. Long-term effects and long-term use Azrin (1976) 2-year follow-up of CRA: Patients were 90% of the time abstinent (N=9) Ojehagen et al. (1991) Long-term, not intensive outpatient treatment (19 sessions / 2 years, N=50): Favorable drinking outcomes in 75% of long-term DSF users vs 31% of short-term DSF users Mueser et al. (2003) Chart review on 33 patients with psychosis and AUD who were on DSF for average 2 years: 1-year remission in 21 patients, 2-year remission in 10 patients

5. Supervised DSF in OLITA(Outpatient Longterm Intensive Therapy for Alcoholics) • 9-year follow-up study in 180 chronic alcohol dependent patients • Explicit psychotherapeutic application of supervised DSF Krampe & Ehrenreich, CPD 2010; Krampe et al, ACER, 2006

6. OLITA Outpatient Longterm Intensive Therapy for Alcoholics • Unusually long duration of program: 2 years • Frequent short term contacts -gradual tapering... • Crisis interventions • Social re-integration • Alcohol deterrents (AD) / control • Regular urine analyses • Aggressive aftercare • Therapist rotation Celina Polanski (contemporary)

7. OLITA: Outpatient Four-Step Program of Care Ehrenreich et al, Eur Arch Psychiatry Clin Neurosci, 1997

8. 1.0 .8 .6 Abstinence Probability .4 .2 .0 1000 0 2000 3000 OLITA: Patient characteristics and outcome (N=180) Relapses = 72 Abstinence probability after 9 years = .52 Days from first outpatient contact Krampe et al, Alcohol Clin Exp Res, 2006

9. 1.0 For comparison: Best results reported in the literature upon 2 years observation: 30% .8 .6 Abstinence Probability .4 .2 .0 1000 0 2000 3000 OLITA: Patient characteristics and outcome (N=180) Relapses = 72 Abstinence probability after 9 years = .52 Days from first outpatient contact Krampe et al, Alcohol Clin Exp Res, 2006

10. 1.0 .8 .6 Abstinence Probability .4 .2 .0 1000 0 2000 3000 Days from first outpatient contact Supervised DSF in OLITA: Long-term use – long-term effects On average … 733 abstinent days with DSF 521 abstinent days without DSF 9-year abstinence probability=.52 Krampe & Ehrenreich, CPD 2010; Krampe et al, ACER, 2006

11. 1.0 .8 .6 Probability to be free of relapse .4 Sham-AD (n=15): Probability .86 Verum-AD (n=165): Probability .49 (log rank statistic 4.73, df=1, p=.03) + + .2 .0 0 1000 2000 3000 4000 1.0 .8 .6 Probability to be free of lapse .4 Sham-AD (n=15): Probability .25 Verum-AD (n=165): Probability .25 (log rank statistic 1.06, df=1, p=.30) + .2 + .0 0 1000 2000 3000 4000 Days from first outpatient contact Probability to be free of relapse Probability to be free of lapse Krampe et al, Alcohol Clin Exp Res, 2006

12. 1.0 .8 AD > 20 months (n=74): Probability to be free of relapse .75 AD 13–20 months (n=41): Probability to be free of relapse .50 (log rank statistic 13.43, df=1, p<.001) + .6 Probability to be free of relapse + .4 .2 .0 366 1000 2000 3000 4000 Days from first outpatient contact (presentation starting from month 13) Time to relapse for patients who took alcohol deterrents (AD) for more than 20 months versus patients who stopped AD intake between months 13 and 20 Krampe et al, Alcohol Clin Exp Res, 2006

13. Before entering OLITA During / after OLITA 70 Percentage of warned patients 60 ** 50 Percent (%) 40 30 ** ** 20 10 0 Unemployed Temporarily employed Employed Krampe et al, Dialogues Clin Neurosci, 2007 Employment of OLITA patients(N = 180; p<.0001 vs. before entering OLITA)

14. 70 60 50 * 40 At least one Axis I disorder (%) ** 30 20 * ** 10 0 Month 24 Month 1 Month 6 Month 12 Two-year course of comorbid depression & anxiety (p<.0001; bold bracket p<.01; thin bracket p<.05) Wagner et al, J Psychiatr Res, 2004

15. Supervised DSF Long-term use – long-term effects What is the principal mode of action? Krampe & Ehrenreich, CPD 2010

16. Qualitative review of 13 clinical trials on DSF from 2000 to 2008 (Krampe & Ehrenreich, Current Pharmaceutical Design 2010) DSF: Effective therapeutic tool in all studies [11 with, 2 without supervised administration] BETTER OUTCOMES: Therapy programs make use of psychological effects of DSF, no evidence for an effect of dose Fuller et al (1986) - Outcomes of the compliant patients (20%): 12-month abstinence rates of 50%, 38%, and 43% in treatment groups with 1 mg / day, 250 mg / day, and no DSF respectively OLITA: no impact of pharmacological mechanisms of DSF on alcohol abstinence (dose,tolerability of medication,verum vs sham AD)

17. Reviewed studies suggest psychological effects as principal mode of action However, the assumed effects have never been properly investigated Krampe & Ehrenreich, CPD 2010

18. Application of DSF as psychotherapeutic tool Elaborated as a standardized procedure of OLITA: Integrated in comprehensive bio-psycho-social therapy program Long-term low dose DSF (100 mg/ day): Together with regular medical examination and blood tests Psychotherapeutic procedure: Initial and advanced psychoeducation Training to use DSF as a coping skill, Extension of the repertoire of coping skills Replacing DSF by effective measures of behavior control Krampe & Ehrenreich, CPD 2010

19. Application of DSF as psychotherapeutic tool Specific psychological effects (1) Deterrence (2) (Auto-)suggestion (3) Therapeutic ritual around (4) A frequently renewed active decision process (5) Continuous reinforcement of a sober lifestyle (6) Development, training and maintenance of new coping skills Broader perspective of learning and behavior therapy Supervised DSF as a method of exposure and response prevention Krampe & Ehrenreich, CPD 2010

20. Disulfiram: Irreversible inhibition of acet-aldehyd dehydrogenase for 1-2 weeks CH3CH2OH Ethanol CH3CHO Acetaldehyde CH3COOH Acetate Alcohol dehydrogenase Acetaldehyde dehydrogenase In case of alcohol consumption:Accumulation of acetaldehyde in blood, so-called disulfiram ethanol reaction (DER), starting approximately after 10 min from 5g alcohol, duration 60-180 min Pharmacological action of disulfiram Krampe & Ehrenreich, CPD 2010

21. Example: advanced psychoeducation on DSF as standardized procedure within psychotherapeutic application of supervised DSF Therapist repeats psychoeducation about disulfiram as often as possible in the first therapy sessions Therapist lets the patient repeatedly explain the effect, function and therapeutic application of disulfiram • Most important questions: • Why are you taking disulfiram? • How is the medication working? • How long does disulfiram act? • How does disulfiram work when you drink alcohol? • Which role is disulfiram playing for you in maintaining alcohol abstinence? • What are you thinking when you take the medication? How does it feel? • How is disulfiram working in case you do not drink alcohol? • What do you have to do if you want to resume alcohol consumption? Therapist corrects patient's answers and lets him/her repeat answers until they understand the effect and therapeutic function of disulfiram Important: Therapist supports patients when they explain disulfiram by prompting(e.g. "very good, what you said is right, and then there is also ….") Therapist shapes patient's answer by praising and correcting each trial to explain disulfiram effect Do not forget: Repeat psychoeducation regularly during therapy Krampe & Ehrenreich, CPD 2010

22. Example: advanced psychoeducation on DSF as standardized procedure within psychotherapeutic application of supervised DSF • Most important questions: • Why are you taking disulfiram? • How is the medication working? • How long does disulfiram act? • How does disulfiram work when you drink alcohol? • Which role is disulfiram playing for you in maintaining alcohol abstinence? • What are you thinking when you take the medication? How does it feel? • How is disulfiram working in case you do not drink alcohol? • What do you have to do if you want to resume alcohol consumption? Krampe & Ehrenreich, CPD 2010

23. Example: advanced psychoeducation on DSF as standardized procedure within psychotherapeutic application of supervised DSF Therapist repeats psychoeducation about disulfiram as often as possible in the first therapy sessions Therapist lets the patient repeatedly explain the effect, function and therapeutic application of disulfiram • Most important questions: • Why are you taking disulfiram? • How is the medication working? • How long does disulfiram act? • How does disulfiram work when you drink alcohol? • Which role is disulfiram playing for you in maintaining alcohol abstinence? • What are you thinking when you take the medication? How does it feel? • How is disulfiram working in case you do not drink alcohol? • What do you have to do if you want to resume alcohol consumption? Therapist corrects patient's answers and lets him/her repeat answers until they understand the effect and therapeutic function of disulfiram Important: Therapist supports patients when they explain disulfiram by prompting(e.g. "very good, what you said is right, and then there is also ….") Therapist shapes patient's answer by praising and correcting each trial to explain disulfiram effect Do not forget: Repeat psychoeducation regularly during therapy Krampe & Ehrenreich, CPD 2010

24. Patient Therapist 6 6 5 5 4 4 3 3 2 2 1 1 abstinent (n=29) abstinent (n=29) relapsed (n=20) relapsed (n=20) 0 0 1 2 3 4 5 6 7 8 3 4 5 6 7 9 12 1 2 3 4 5 6 7 8 3 4 5 6 7 9 12 Weeks Months Weeks Months Basis of supervised DSF: Trustful and stable therapeutic alliance Helping Alliance Questionnaire Krampe et al, Journal of Psychiatric Research 2008

25. Summary and conclusion • Qualitative review: Supervised DSF proved to be an effective therapeutic tool in all clinical studies from 2000 to 2008 • DSF seems to be superior to other pharmacological adjuncts to the treatment of AUD • Long-term use + integration in CBT leads to long-term effects • Therapy programs that make use of psychological effects of supervised DSF have best results • Psychological effects as principal mode of action • Standardized procedure in OLITA: Psychotherapeutic application of supervised low-dose DSF (not more than 100 mg /day) • Future clinical studies needed • I have no conflict of interest to declare