1

conflict of interest

Dr Keron Fletcher is a director of ZenaMed Ltd

ZenaMed Ltd distributes the Zenalyser

www.zenamed.co.uk

2

a new technique for monitoring compliance

with disulfiram

Dr Keron FletcherConsultant Addictions Psychiatrist

South Staffordshire & Shropshire Healthcare NHS Foundation Trust

England

3

why monitor?

• to optimise compliance

• to demonstrate compliance

4

compliance

• compliance is central to the effectiveness of any treatment

compliance on placebo > non-compliance on disulfiram

5

non-compliance

• patient doesn’t want disulfiram(Wexberg, 1953; Hoft, 1961)

• patient doesn’t take disulfiram(Baekeland et al, 1971; Fuller et al, 1986)

6

the patient doesn’t want disulfiram

• they don’t want to stop drinking alcohol (despite multiple harms)

• exaggerated fear of side effects

• exaggerated fear of the disulfiram-ethanol reaction (DER) including death

• fear that supervision will cause increased conflict with partner

• motivational work, cue cards, listening and explanation

• reassure (mostly minor)

• reassure (about 700 times less fatal than continuing to drink alcohol!)

• reassure (opposite is true – e.g.Chick et al, 1992)

problem solution

7

the patient doesn’t take disulfiram

• attempts to improve compliance

– implants– frequency of appointments– contingency management– community reinforcement – supervised administration– monitoring

8

implants

• Wilson, 1975, Canada

– fail to release adequate levels of disulfiram

– adverse effects of implantation (infection, rejection)

– controlled studies do not show superior outcomes for patients given implants

(Bergstrom et al,1982; Morland et al, 1984; Johnsen et al. 1987)

9

frequency of appointments

• % patients abstinent after 8 weeks

once weekly clinics twice weekly clinics

disulfiram 7% 40%no disulfiram 3% 9%

(Gerrein et al, 1973)

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contingency management

• probation + disulfiram vs jail (Haynes, 1973; Brewer & Smith, 1983)

• money deposits – money given to charity if patient fails to attend for disulfiram

(Bigelow et al, 1976)

• termination of care if fail to take disulfiram(Sereny et al, 1986)

• for opiate and alcohol dependent patients disulfiram must be taken before methadone will be administered

(Liebson & Bigelow, 1972)

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community reinforcement

• Community Reinforcement Approach (CRA)• buddy• daily reporting procedure• group counselling• supervised disulfiram• “social motivation programme”

– 6 months follow-up, number of days alcohol free in previous month

single married – unsupervised disulfiram 6.75 17.4– supervised disulfiram 8.0 30– supervised disulfiram + CRA 28.3 30

(Azrin, 1976)

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supervised administration

• supervised disulfiram >>> placebo– Wright and Moore, 1990 – Kristenson, 1992 – Chick, 1992– Hughes & Cook, 1997– Anton, 2001– Mueser, 2003

• supervised disulfiram and employment outcomes– absenteeism rates

• pre-treatment 9.8%• in-treatment 1.7%• post-treatment 6.7%

(Robichaud et al, 1979)

• Krampe, 2006 - OLITA programme – multiple positive outcomes

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is supervised disulfiram superior to alternatives?

• recent comparative studies

– De Sousa, 2004 - disulfiram > naltrexone

– De Sousa, 2005 - disulfiram > acamprosate

– Petrakis, 2005 - disulfiram > naltrexone depressed patients

– De Sousa, 2008 - disulfiram > topiramate

– Laaksonen, 2008 - disulfiram > naltrexone and acamprosate

– Alho, 2009 - disulfiram > naltrexone and acamprosate

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monitoring

• available for use in every day clinical settings

– frequency of appointments– contingency management– community reinforcement– supervision

• optimising compliance– monitoring: improves compliance (which improves outcomes)

– monitoring: now available though new technology

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monitoring

• monitoring plus feedback > no monitoring• monitoring plus feedback > monitoring minus feedback

(Kofoed, 1987)

• 35% claiming compliance were not taking disulfiram• 20% receiving supervised disulfiram were not taking it

(Paulson, 1977)

• swap disulfiram for similar looking tablet• put disulfiram under tongue to spit out later• vomit dissolved disulfiram soon after administration• difficult to get a supervisor• supervisor threatened by patient to give false indication of compliance• even a good supervisor can be deceived

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monitoring

• methods of monitoring compliance

– urinary diethylamine (Fuller & Niederhiser, 1981)

– riboflavin, urinalysis (Fuller et al, 1983)

– exhaled carbon disulphide (Paulson, 1977; Rychtarick, 1983)

17

monitoring concept

• carbon disulphide + acetone (in patient’s breath)

= disulfiram

= compliance

= no alcohol

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ideal instrument

• breath analyser

• able to measure carbon disulphide and acetone

• hand held

• non-invasive

• instant results

• simple to operate

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the Zenalyser

• all instrument criteria have

been met with the Zenalyser,

but……..

• does the Zenalyser produce

unequivocal results when

monitoring compliance?

• needed patient trials

20

research

• study 1

– Zenalyser breath results from alcohol dependent patients

no disulfiram vs 200mgs disulfiram daily

– 489 breath samples

– was there any overlap in results between groups?

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study 1 - results

02

004

006

008

001

,000

No Disulfiram Disulfiram

nm

ol

.

Range: 27-40nmol/l Range: 374-518nmol/l

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research

• study 2

– what is the sensitivity and specificity of the Zenalyser?

– 391 breath samples from Edinburgh patients– tester blind to disulfiram status

• 54 patients on disulfiram

• 22 patients not taking disulfiram

– results sent to Shrewsbury for blind assessment

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study 2 - results

number of days post

dose

d = disulfiramc = controls

n =sensitivity

( % )specificity

( % )

1 12d 3c

100 100

2 20d 2c

84.6 100

3 22d 17c

88.2 100

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readings sample

“A breath test to assess compliance with disulfiram”K Fletcher, E Stone, MW Mohamad, GC Faulder, RM Faulder, K Jones, D Morgan, J Wegerdt,M Kelly, J Chick

Addiction, Volume 101, Issue 12,  pages 1705–1710, December 2006

0

2

4

6

8

10

12

14

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Time (seconds)

Zen

aly

ser

read

ingDisulfiram

No disulfiram

25

why monitor compliance?

• to optimise compliance

• to demonstrate compliance

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demonstrating compliance

• when patients want to prove compliance and abstinence status

– relationships

– employers• high risk – medical, military, “safety critical”• high absenteeism• high pay

– courts• child protection• drink-drive offences – Michigan USA• alcohol-related crime

• court-mandated disulfiram outcomes > voluntary disulfiram (Martin et al, 2004)

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Zenalyser in practise

Pt Q - 3 year follow up

0

50

100

150

200

250

Date

Val

ue

Zenalyser

GGT

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patient reactions to the Zenalyser

• patients have commented:

– that the “option” of missing some doses of disulfiram and having a few drinks was removed

– careful monitoring would stop them cheating

– pleased that doctors are making an effort to develop new ways of helping people with alcohol dependence

– relieved that compliance can now be demonstrated by the doctor

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summary

• disulfiram is an effective treatment for alcohol dependence and superior to other pharmacological alternatives when measures are taken to address compliance

• monitoring can optimise compliance

• the Zenalyser can objectively and accurately monitor disulfiram compliance with the potential

– to improve treatment outcomes– to improve the management of high risk situations