H Krampe Henning Krampe Department of Anaesthesiology and Intensive Care Medicine Campus Virchow-Klinikum and Campus Charité Mitte Charité - Universitätsmedizin

H Krampe

Henning Krampe

Department of Anaesthesiology and Intensive Care Medicine Campus Virchow-Klinikum and Campus Charité Mitte

Charité - Universitätsmedizin Berlin

CHARITÉ CAMPUS VIRCHOW-KLINIKUM und CAMPUS CHARITÉ MITTE KLINIK FÜR ANÄSTHESIOLOGIE m. S. OPERATIVE INTENSIVMEDIZINC CC

Long-term disulfiram treatment and mechanisms of effectiveness

Long-term disulfiram treatment and mechanisms of effectiveness

10th Stapleford International Addiction ConferenceStapleford Athens 2011

H Krampe

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 interests Current trends: Topiramate, GHB, Baclofen ???

Wise reviews on DSF, e.g. Banys 1988; Brewer 1993, 2005;

Brewer et al 2000; Chick 1999; Kristenson 1995

H Krampe

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 studiese.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

H Krampe

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

H Krampe

Supervised DSF in OLITA(Outpatient Longterm Intensive Therapy for Alcoholics)

(1) 9-year follow-up study in 180 chronic alcohol dependent patients

(2) Explicit psychotherapeutic application of supervised DSF

Krampe & Ehrenreich, CPD 2010; Krampe et al, ACER, 2006

H Krampe

OLITAOutpatient Longterm Intensive Therapy for Alcoholics

Celina Polanski (contemporary)

• 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

H Krampe

OLITA: Outpatient Four-Step Program of Care

Period Duration ContactsMedication

Each Contact

Urine Analysis

Inpatient period detoxification

2-3 weeks15 min, daily, including

weekendsdisulfiram daily 100 mg

each contact

Outpatient period I intensive phase

3 months15 min, daily, including

weekendsdisulfiram daily 100 mg

each contact

Outpatient period II stabilizing phase

3-4 months15 min, 3 / week

(max. interval 2 days)

disulfiram 400 mg

3 times a week

each contact

Outpatient period III weaning-off phase

6 months30 min, 2 / week

(max. interval 4 days)

disulfiram 400 mg

twice a week

each contact

Outpatient period IV aftercare phase

6 months

30 min, 1 / week

+

90 min, OLITA-group 1 / week

disulfiram 400 mg

once a week

each contact

6 months 90 min, OLITA-group 1 / week -each

contact

Ehrenreich et al, Eur Arch Psychiatry Clin Neurosci, 1997

H Krampe

OLITA: Patient characteristics and outcome (N=180)

Days from first outpatient contact1000

Abs

tinen

ce P

roba

bilit

y

0 2000 3000 .0

.2

.4

.6

.8

1.0

Krampe et al, Alcohol Clin Exp Res, 2006

Age (years)

Duration of alcohol dependence (years)

Inpatient detoxifications (N)

Alcohol intake (g/day)

Addiction severity score (EuropASI)

43.6 (7.7)* 18.2 (7.0)* 7.3 (8.5)* 437.1 (161.6) 0.8 (0.1)*

Relapses = 72Abstinence probability after 9 years = .52

H Krampe

OLITA: Patient characteristics and outcome (N=180)


Abs

tinen

ce P

roba

bilit

y

0 2000 3000 .0

.2

.4

.6

.8

1.0


Age (years)

Duration of alcohol dependence (years)

Inpatient detoxifications (N)

Alcohol intake (g/day)

Addiction severity score (EuropASI)

43.6 (7.7)* 18.2 (7.0)* 7.3 (8.5)* 437.1 (161.6) 0.8 (0.1)*

Relapses = 72Abstinence probability after 9 years = .52

For comparison: Best results reported in the literature upon 2 years observation: 30%

H Krampe

Supervised DSF in OLITA: Long-term use – long-term effects


Abs

tinen

ce P

roba

bilit

y

0 2000 3000 .0

.2

.4

.6

.8

1.0

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

H Krampe

Sham-AD (n=15): Probability .86

Verum-AD (n=165): Probability .49

(log rank statistic 4.73, df=1, p=.03)+

+

0 1000 2000 3000 4000

.0

.2

.4

.6

.8

1.0

Pro

ba

bili

ty t

o b

e f

ree

of

rela

ps

e

0 1000 2000 3000 4000

.0

.2

.4

.6

.8

1.0

Pro

ba

bili

ty t

o b

e f

ree

of

lap

se

Days from first outpatient contact

+

+

Sham-AD (n=15): Probability .25

Verum-AD (n=165): Probability .25

(log rank statistic 1.06, df=1, p=.30)

Probability to be free of relapse

Probability to be free of lapse


H Krampe

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)

Days from first outpatient contact(presentation starting from month 13)

+

+

Pro

babi

lity

to b

e fr

ee o

f rel

apse

1000 2000 3000 4000

.0

.2

.4

.6

.8

1.0

366

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


H Krampe

Employment of OLITA patients(N = 180; p<.0001 vs. before entering OLITA)

****

**

Pe

rce

nt

(%)

Unemployed Temporarily employed Employed

0

10

20

30

40

50

60

70

Before entering OLITA

During / after OLITA

Percentage of warned patients

Krampe et al, Dialogues Clin Neurosci, 2007

H Krampe

*

**

***

Month 1 Month 6 Month 12 Month 240

10

20

30

40

50

60

70

At l

east

one

Axi

s I d

isor

der

(%)

Two-year course of comorbid depression & anxiety(p<.0001; bold bracket p<.01; thin bracket p<.05)

Wagner et al, J Psychiatr Res, 2004

H Krampe

Supervised DSFLong-term use – long-term effects

What is the principal mode of action?

Krampe & Ehrenreich, CPD 2010

H Krampe

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)

H Krampe

Reviewed studies suggest psychological effects as principal mode of action

However, the assumed effects have never been properly investigated


H Krampe

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


H Krampe

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


H Krampe

Disulfiram: Irreversible inhibition of acet-aldehyd dehydrogenase for 1-2 weeks

CH3CH2OHEthanol

CH3CH2OHEthanol

CH3CHOAcetaldehyde

CH3CHOAcetaldehyde

CH3COOHAcetate

CH3COOHAcetate

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

Alcohol dehydrogenase

Alcohol dehydrogenase

AcetaldehydedehydrogenaseAcetaldehyde

dehydrogenase

Pharmacological action of disulfiram


H Krampe

Therapist lets the patient repeatedly explain the effect, function and therapeutic application of disulfiram

Therapist repeats psychoeducation about disulfiram as often as possible in the first therapy sessions

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

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?

Do not forget:Repeat psychoeducation regularly during therapy

Example: advanced psychoeducation on DSF as standardized procedure within psychotherapeutic application of supervised

DSF


H Krampe

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?

Example: advanced psychoeducation on DSF as standardized procedure within psychotherapeutic application of supervised DSF


H Krampe

Therapist lets the patient repeatedly explain the effect, function and therapeutic application of disulfiram

Therapist repeats psychoeducation about disulfiram as often as possible in the first therapy sessions

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

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?

Do not forget:Repeat psychoeducation regularly during therapy

Example: advanced psychoeducation on DSF as standardized procedure within psychotherapeutic application of supervised DSF


H Krampe

Helping Alliance Questionnaire

Patient Therapist

0

1

2

3

4

5

6

1 2 3 4 5 6 7 8 3 4 5 6 7 9 12Weeks Months

1 2 3 4 5 6 7 8 3 4 5 6 7 9 12Weeks Months

0

1

2

3

4

5

6

abstinent (n=29)

relapsed (n=20)

abstinent (n=29)

relapsed (n=20)

Krampe et al, Journal of Psychiatric Research 2008

Basis of supervised DSF: Trustful and stable therapeutic alliance

H Krampe

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

Documents

H Krampe Henning Krampe Department of Anaesthesiology and Intensive Care Medicine Campus Virchow-Klinikum and Campus Charité Mitte Charité - Universitätsmedizin