conflict of interest
Dr Keron Fletcher is a director of ZenaMed Ltd
ZenaMed Ltd distributes the Zenalyser
www.zenamed.co.uk
1
a new technique for
monitoring compliance
with disulfiram
Dr Keron Fletcher
Consultant Addictions Psychiatrist
South Staffordshire & Shropshire Healthcare NHS Foundation Trust
England
2
why monitor?
• to optimise
compliance
• to demonstrate
compliance
3
compliance
• compliance is central to the effectiveness
of any treatment
compliance on placebo > non-compliance on disulfiram
4
non-compliance
• patient doesn’t want disulfiram
(Wexberg, 1953; Hoft, 1961)
• patient doesn’t take disulfiram
(Baekeland et al, 1971; Fuller et al, 1986)
5
the patient doesn’t want disulfiram
problem
solution
• they don’t want to stop drinking
alcohol (despite multiple
harms)
• motivational work, cue cards,
listening and explanation
• exaggerated fear of side
effects
• reassure (mostly minor)
• exaggerated fear of the
disulfiram-ethanol reaction
(DER) including death
• reassure (about 700 times
less fatal than continuing to
drink alcohol!)
• fear that supervision will cause
increased conflict with partner
• reassure (opposite is true –
e.g.Chick et al, 1992)
6
the patient doesn’t take disulfiram
• attempts to improve compliance
–
–
–
–
–
–
implants
frequency of appointments
contingency management
community reinforcement
supervised administration
monitoring
7
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)
8
frequency of appointments
• % patients abstinent after 8 weeks
once weekly clinics
disulfiram
no disulfiram
7%
3%
twice weekly clinics
40%
9%
(Gerrein et al, 1973)
9
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)
10
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
– unsupervised disulfiram
– supervised disulfiram
– supervised disulfiram + CRA
single
6.75
8.0
28.3
married
17.4
30
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
• in-treatment
• post-treatment
9.8%
1.7%
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
15
monitoring
• methods of monitoring compliance
– urinary diethylamine
(Fuller & Niederhiser, 1981)
– riboflavin, urinalysis
(Fuller et al, 1983)
– exhaled carbon disulphide
(Paulson, 1977; Rychtarick, 1983)
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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
18
the Zenalyser
• all instrument criteria have
been met with the Zenalyser,
but……..
• does the Zenalyser produce
unequivocal results when
monitoring compliance?
• needed patient trials
19
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
Disulfiram
600
400
0
200
nmol
800
1,000
No Disulfiram
.
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 d = disulfiram
days post c = controls
dose
n=
sensitivity
(%)
specificity
(%)
1
12d
3c
100
100
2
20d
2c
84.6
100
3
22d
17c
88.2
100
23
readings sample
Disulfiram
No disulfiram
14
Zenalyser reading
12
10
8
6
4
2
0
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)
“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
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why monitor compliance?
• to optimise
compliance
• to demonstrate
compliance
25
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)
26
25
/0
4/
20
07
17
/0
5/
20
07
28
/0
6/
20
07
19
/0
7/
20
07
09
/0
8/
20
07
30
/0
8/
20
07
22
/0
9/
20
07
11
/1
0/
20
07
08
/1
1/
20
07
21
/1
2/
20
07
08
/0
2/
20
08
01
St
/
04
op
/
pe
20
d
08
di
su
lfir
am
06
/0
8/
20
08
01
/0
9/
20
08
26
/0
9/
20
08
27
/1
0/
20
08
07
/1
2/
20
08
02
/0
2/
20
09
15
/0
3/
20
09
11
/0
5/
20
09
19
/0
7/
20
09
21
/0
9/
20
09
28
/1
1/
20
09
10
/0
2/
20
10
27
/0
5/
20
10
22
/0
7/
20
10
Value
Zenalyser in practise
Pt Q - 3 year follow up
Zenalyser
GGT
250
200
150
100
50
0
Date
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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
29