8/10/2014
Behandeling van
verslaving, het
herwinnen van de
controle?
geert.dom@uantwerpen.be
Ziekte ?
• “Seeing addiction for what it is: a pathological condition that should
be explained by a pathophysiological process and not the use of a
“normal” behavioral response to a nonnatural reward”
• >> Disease as any other psychiatric disorder!
• Koob & LeMoal
1
8/10/2014
Ik ben vermoedelijk een beetje
pessimistisch over de
neurowetenschappen…
Model van het begin van verslavingsgedrag (Wiers et al., 2006)
Vermogen te stoppen /
Heroriënteren/
Switchen
Gecontroleerde processen
« Cool & slow »
Motivatie om te
reguleren
Emotie
Regulatie
Automatische processen « hot & fast »
Alcohol – drugs als
emotionele stimulus
« approach »
Actie tendens
Alcohol of
Drug gebruik
sensitizatie
Alcohol / drugs
Sociale context
2
8/10/2014
Model van de aanpassingen in automatische en gecontrolleerde processen bij verder gevorderd verslavingsgedrag (Wiers et
al., 2006)
Vermogen te stoppen /
Heroriënteren/
Switchen
Gecontroleerde processen
« Cool & slow »
Motivatie om te
reguleren
Emotie
Regulatie
Negatieve ervaringen
Alcohol/drug
Automatische processen « hot & fast »
Alcohol – drugs als
emotionele stimulus
« approach »
Actie tendens
Alcohol of
Drug gebruik
sensitizatie
Alcohol / drugs
Sociale context
Geassocieerde stimuli
Verslaving 19-5-2010
Functioneel Model en Hersenstructuren
6
Volkow, 2006
3
8/10/2014
Piazza &
DerocheGamonet,
2013, A
multistep
generl
theory of
transition
to
addiction.
4
8/10/2014
Mens en dier
• Ongeveer 90% kan leren drugs te gebruiken
• Transitie naar regelmatig gebruik bij een behoorlijk % spreiding harmonisch- waarbij sterk beïnvloedbaar door
beschikbaarheid en regelmaat gebruik.
• Slechts 17% gaat naar stadium Controle verlies en
uitgesproken verslaving.
Samenvatting (dieren)
experimenteel onderzoek (Piazza
et
al., 2013)
• “full addiction is not a purely human phenomenon but also
exists in laboratorium rats”
• Despite the use of a large amount of drug over a prolonged
period, most individuals are resistent to addiction
• Individual vulnerabilities seem to be a nescessary condition
• Independent, different, vulnerabilities play a role in both risk
transition to sustained drug use (e.g. Locomotor recation to
stress, anxiety-like behavior, impulsivity) and transition to loss
of control.
5
8/10/2014
Impulsiviteit:
Intolerance Delay
Reward (DDT)
“Impuls”
gebruik
Reward/Ris
k
evaluation
(IGT, CGT)
Regelmatig
gebruik
Impulsiviteit:
- Behavioral
Disinhibition
- Impuls control
Controle
verlies
1. Sensitisatie DA systemen
2. Increase GR activation >>
sensitisatie DA systeem Nac
3. 1 + 2 = “Desire”
4. Hedonic set-point = “Need”
Transitie naar echt controle verlies
nog weinig onderzocht !
6
8/10/2014
Synaptic plasticity
• Long-term potentiation (LTP) & Depression (LTD)
• “Represents the ability of the brain to strengthen or depress neuronal
circuits in order to maintain adaptive behavior responses to changes in
environmental contingencies (Nieman & Loewenstein, 2013)”
Plasticity and Loss of Control
• “The only biological modification yet specifically associated with loss of
control of drug intake is a loss of synaptic plasticity (Kasanetz et al., 2010,
2012)”.
• Piazza et al.;
• After 18 days of cocaine use (before addiction-like behavior) a loss of
NMDA-dependent LTD in the Nac of all self-administrating animals.
• Later, after 60 days, return to normal LTD in those animals (majority)
that remained control over intake, while animals with LoC addiction like
behaviors continued impaired NMDA and GluR2/3-dependent LTD in
Nac & PFC.
• Vulnerability for addiction can be conceptualized as a degree of
“anaplasticity”, the inability to recover a lost function.
• Addicted animals (humans) remain “frozen” in a behavioral repertoire
although the reward contingencies have changed dramatically.
• “Imprisoned - Frozen in the behavior”
7
8/10/2014
Model van de aanpassingen in automatische en gecontrolleerde processen bij verder gevorderd verslavingsgedrag (Wiers et
al., 2006)
Vermogen te stoppen /
Heroriënteren/
Switchen
Gecontroleerde processen
« Cool & slow »
Motivatie om te
reguleren
Emotie
Regulatie
Negatieve ervaringen
Alcohol/drug
Automatische processen « hot & fast »
Alcohol – drugs als
emotionele stimulus
« approach »
Actie tendens
Alcohol of
Drug gebruik
sensitizatie
Alcohol / drugs
Sociale context
Geassocieerde stimuli
8
8/10/2014
Maar weten we er nu
eigenlijk echt wel
iets van ?
9
8/10/2014
Middel
Jaarprevalentie gebruikers
Jaarprevalentie verslaafden
Verslavingszorg
Verslaafden in
huisartsenpraktijk
Aantal 12+
%18+
Aantal 18+
Aantal
% van ver-slaafden
Per 2500
Per 150
Tabak
34
4.400.000
17
2.000.000
Nihil
Nihil
425
25
Alcohol
73
9.800.000
3,7
280.000
28.000
10
90
6
Benzodiazepinen
4
500.000
3,3
250.000
Nihil
Nihil
80
Cannabis
3
400.000
0,5
35.000
3.500
9
10
XTC
0,3
65.000
?
?
< 300
?
?
?
Heroïne
0,2
28.000
0,3
25.000
17.500
70
5-10
<1
Cocaïne
> 0,4
> 50.000
> 0,3
> 20.000
7.000
< 30
> 10
1
Verslaving 19-5-2010
% 12+
5
<1
19
A spectrum of responses to alcohol problems
None
Hazardous
drinking
Harmful
drinking
Moderately
dependent
drinking
Reduced risk drinking
Severely
dependent
drinking
Abstinence
More intensive
specialist treatment
Less-intensive treatment in generalist or specialist settings
Extended brief interventions in generalist settings
Simple brief interventions in generalist settings
Public health programmes – primary preventions
Rastrick et al. 2006; Adapted from Institute of Medicine. 1990
10
8/10/2014
Bias !
• Beeldvorming bij de onderzoeker, clinicus en publiek wordt
bepaald door de, kleine, groep van chronische patiënten.
• Op basis daarvan extrapoleren ze opinies over “verslaving” !
• >> The “Clinician’s Illusion” Cohen & Cohen, 1984, Arch Gen
Psych.
• In realiteit lijken mensen er best wel in te slagen hun
verslaving, “psychiatrische ziekte” onder controle te houden!
Van welke psychiatrische
aandoening wordt de prevalentie
en schade zo door de omgeving
bepaald?
1960
2014
80%
23 %
11
8/10/2014
Addiction: Quitting is the rule not
the exception !
• ECA study (1980s): n = 19.000. Among those who had become
dependent on drugs at age 24, more than half later reported
not a single drug-related symptom. By age 37, roughly 75%
reported no drug symptom.
• NCS & NESARC (N = 43.000) 77% & 86 % reported no more
substance problems one year before survey.
• !those who did report more likely to have psychiatric comorbidity.
• !Relapse rates of treated drug-addicted patients 40-60%. = the
chronic-relapsing patients.
N = 42.000 US GP
16% van de mensen met
een current
afhankelijkheidsdiagnose
was in behandeling (zelfhulp
/professioneel)
De overgrote
meerderheid van de
mensen stopt zonder
enige vorm van
hulpverlening
12
8/10/2014
Cantin et al., 2011
• Virtually all rats preferred saccharin over intravenous cocaine.
• The preference for saccharin sweet taste was not surmountable by
increasing doses of cocaine and was observed despite either cocaine
intoxication, sensitization or intake escalation – the latter being a hallmark
of drug addiction.
• In addition, in several cases (85%), the preference for saccharin emerged
in rats which had originally developed a strong preference for the cocainerewarded lever.
• Such reversals of preference clearly show that in our setting, animals are
not stuck with their initial preferences and can change them according to
new reward contingencies.
• Finally, the preference for saccharin was maintained in the face of
increasing reward price or cost, suggesting that rats did not only prefer
saccharin over cocaine (‘liking’) but they were also more willing to work
for it than for cocaine (‘wanting’).
Factoren die een rol spelen bij
stoppen (of “uit de diagnose
vallen”)
• Afwezigheid psychiatrische en medische co-morbiditeit.
•
•
•
•
•
•
•
Relationele status (gehuwd > single)
Economische druk
Angst juridische consequenties
Bezorgd over respect verlies bij kinderen en familie
Hoger inkomen
Opleidingsniveau
“mensen met verslavingsproblemen geven vaak aan dat ze stopten met
gebruik om een betere ouder te zijn, familie trots te maken, en geen
schaamtevolle dingen meer te willen doen”
• >> Drijfveren om te stoppen zijn dus voornamelijk de praktische en morele
bezwaren die een rol spelen bij majeure beslissingen/keuzes.
• <> heel andere drijfveren dan die een rol spelen bij andere medische (brein)
aandoeningen: Alzheimer – Schizofrenie – diabetes –
• Het ene voordeel vervangen door een
ander beter !
13
8/10/2014
Dubbel Diagnose
Verandering
omgevingscontingenties
Spirituele
morele
incentives
Zelfcontrole technieken
14
8/10/2014
Huidige vormen van
behandeling
farmacotherapie
Psychosociaal:
zelfhulp
Behandeling
alcohol
Medications for Relapse Prevention
Addicted Brain
Non-Addicted
Brain
Interfere with drug’s
reinforcing effects
Vaccines
Enzymatic degredation
Naltrexone
DA D3 antagonists
CB1 antagonists
Executive function/
Inhibitory control
Biofeedback
Modafinil
Bupropion
Stimulants
Control
Control
Saliency
Saliency
prefrontalGO Strengthen
STOP
striatal communication
Drive
Drive
Memory
Memory
Adenosine
A2 antagonists
DA D3 antagonists
Interfere with conditioned
memories (craving)
Antiepileptic GVG
N-acetylcysteine
Teach new memories
Cycloserine
Counteract stress responses CRF antagonists
that lead to relapse
Orexin antagonists
15
8/10/2014
Model van de aanpassingen in automatische en gecontrolleerde processen bij verder gevorderd verslavingsgedrag (Wiers et
al., 2006)
Vermogen te stoppen /
Heroriënteren/
Switchen
Gecontroleerde processen
« Cool & slow »
Motivatie om te
reguleren
Emotie
Regulatie
Negatieve ervaringen
Alcohol/drug
Automatische processen « hot & fast »
Alcohol – drugs als
emotionele stimulus
« approach »
Actie tendens
Alcohol of
Drug gebruik
sensitizatie
Alcohol / drugs
Sociale context
Geassocieerde stimuli
16
8/10/2014
Improving impulse control could be an important target for treating
alcohol dependence.
Aanpakken hedonische dysregulatie
17
8/10/2014
HDD/TAC: change from baseline in the 1-year study: Patients with at least high
DRL at baseline and randomisation
Herwinnen controle maar dan moet patiënt de pil wel nemen !!
SENSE: change in HDDs
SENSE: change in TAC
19 HDDs
100 g/day
Difference:
-3.6 HDDs, p=0.0164
7 HDDs
MMRM (OC) FAS estimates and SE; *p<0.05;
MMRM=mixed-effect model repeated measure;
OC=observed cases; FAS=full analysis set; SE=standard error
Difference:
-17.3 g/day, p=0.0129
33 g/day
van den Brink et al. SENSE. Poster at EPA 2013
van den Brink et al. J Psychopharmacol, in press
Summary of effect sizes.
Leucht S et al. BJP 2012;200:97-106
©2012 by The Royal College of Psychiatrists
18
8/10/2014
19
8/10/2014
Laag frequente rTMS = blokkerend
20
8/10/2014
Diepe Brein Stimulatie
geschiedenis
• Sinds jaren 1990 vooral Parkinson
• Gemerkt dat verslavingsgedrag
bij Parkinson pat. Veranderd
• Vanaf 2005 ook psychiatrische
indicaties (OCD)
• Case series Bechara & insula
infarct.
• Momenteel +/- 4 studies
specifiek op verslaving.
©2012 by Cleveland Clinic
DHS bij alcohol afhankelijkheid
N=6
• Vier jaar opvolging
• Vermindering craving
• 2 van de 6 patienten
bleven abstinent
gedurende de volledige
opvolgingsduur.
21
8/10/2014
Future Research
Immunotherapies for Addiction Treatment (i.e., Vaccines)
Antibodies Can Reduce Brain Concentrations
VACCINE
Binding Site
Antibodies
Capillary
Blood Flow
Brain
Targeting the drugs,
not the receptors
Capillary
Blood Flow
Brain
22
8/10/2014
(met Mike Rinck, RUN e.a.)
46
23
8/10/2014
Klinische Re-training
(Schoenmakers et al. )
37 alcoholisten: 4 x trainen in alcohol-kliniek (Attentional Retraining of
placebo-training).
* Effecten op Attentional Bias
+ voorzichtige indicaties
Klinische effecten (minder
Terugval; kortere succesvolle
behandelduur
47
• http://mindsurfer.eu/jasmin_demo2/demos/cbm/config.html
24
8/10/2014
Cognitive online training ?
Model van de aanpassingen in automatische en gecontrolleerde processen bij verder gevorderd verslavingsgedrag (Wiers et
al., 2006)
Vermogen te stoppen /
Heroriënteren/
Switchen
Gecontroleerde processen
« Cool & slow »
Motivatie om te
reguleren
Emotie
Regulatie
Negatieve ervaringen
Alcohol/drug
Automatische processen « hot & fast »
Alcohol – drugs als
emotionele stimulus
« approach »
Actie tendens
Alcohol of
Drug gebruik
sensitizatie
Alcohol / drugs
Sociale context
Geassocieerde stimuli
25
8/10/2014
Improving impulse control could be an important target for treating
alcohol dependence.
Versterken van de ruiter !
26
8/10/2014
rTMS
• rTMS: Repetitieve transcraniele magnetische stimulatie (Hoog
frequent = stimulerend).
• rDCS: Direct Current Stimulation (Hoog & laag frequent)
Hoog frequente rTMS = activerend
27
8/10/2014
Transcraniele Magnetische
Stimulatie bij Cocaineverslaafden
Een is misschien te weinig……..
28
8/10/2014
Kan men craving “reguleren”?
DCRAVING
CRAVING INDUCTION IN A PET SETTING
5
4
3
2
1
0
-1
N = 13
Neutral
Cocaine
Conditioned
Association
STIMULI
2.5
2.0
1.5
1.0
.5
0
Nature Video
Cocaine Video
Childress et al., Am. J. Psychiatry, 1999
29
8/10/2014
N.D. Volkow et al. /
NeuroImage 49 (2010) 2536–2543
mOFC
NAcc
30
8/10/2014
Versterken van de ruiter !
Goal management training
31
8/10/2014
Alfonso et al., 2011
32
8/10/2014
Alfonso et al., 2011
TRAINING
Polysubstance
abusers
Improvement
executive
cognitive
functioning
? Substance use
outcome ?
Mindfulnes based
JAMA Psychiatry. 2014
May;71(5):547-56.
33
8/10/2014
Bowen et al., 2014
TAU = 12-step
28-day inpatient
8-weeks
after care
RP (= CBT)
3/6/12 m.
follow up
90-day intensive outpatient
RPMB
Bowen et al., 2014.
• For individuals in aftercare following initial treatment for substance
use disorders, RP and MBRP, compared with TAU, produced
significantly reduced relapse risk to drug use and heavy drinking.
• Relapse prevention delayed time to first drug use at 6-month followup, with MBRP and RP participants who used alcohol also reporting
significantly fewer heavy drinking days compared with TAU
participants.
• At 12-month follow-up, MBRP offered added benefit over RP and
TAU in reducing drug use and heavy drinking.
• Targeted mindfulness practicesmay support long-term outcomes by
strengthening the ability to monitor and skillfully cope with
discomfort associated with craving or negative affect, thus
supporting long-term outcomes.
34
8/10/2014
Improving impulse control could be an important target for treating
alcohol dependence.
35
8/10/2014
Versterken van de ruiter !
HET VERSTERKEN VAN COGNITIEVE ZELFCONTROLE MET MODAFINIL EN DE
RELATIE TOT HERVAL BIJ ALCOHOLAFHANKELIJKE PATIENTEN
36
8/10/2014
Alleen bij patiënten met slechte baseline inhibitie
37
8/10/2014
Schmaal et al. 2014 Psycholog
Medic
38
8/10/2014
Method: protocol
Inclusion
Baseline
Week 0
Follow-up (FU)
Interview by phone
Treatment Modafinil/Placebo – 10 weeks
1
2
3
4
5
6
7
8
9
10
3 months
Screenin
g and
baseline
Testing
during
treatmen
t
Testing
after
treatmen
t
T0
T1
T2
6 months
FU1
FU2
Results: Complete abstinence
Groups did not significantly differed in abstinence rates
• Abstinence rates
60
X²: p=.416
Percentage abstinence
50
40
X²: p=.214
30
Modafinil
Placebo
20
10
0
End of treatment
(10 weeks)
End of follow-up
(6 months)
39
8/10/2014
Results: Primary outcome
measures
Modafinil improved self-reported state impulsivity
• Primary outcome measures:
MMRM: Time by treatment: p=.001
Modafinil
Placebo
45
Total STIMP scores
• Alcohol use
• % abstinent days (T )
• % heavy drinking days (T )
• Impulsivity
• Self-reported state impulsivity
• Response inhibition (SST) (T )
• Delay discounting (DDT)
40
35
30
25
T0
T1
Time
T2
Results: mediation analyses
Redundant
Modafinil
treatment
X
Alcohol
use
Changes in
impulsive
behaviour
40
8/10/2014
Bi-directional effects in subgroups
Percentage Abstinent Days (MMRM 3-way: p<.001)
Good Response Inhibition
(n=41)
Placebo
Modafinil
100
100
90
90
80
80
% Abstinent Days
% Abstinent Days
Modafinil
Poor Response Inhibition
(n=42)
70
60
50
Placebo
70
60
50
40
40
T2
FU1
FU2
T2
FU1
Time
FU2
Time
MMRM: time by treatment: p=.002
MMRM: time by treatment: p=.066
Bi-directional effects in subgroups
Percentage Heavy Drinking Days (MMRM 3-way: p=.001)
Good Response Inhibition
(n=41)
Placebo
Modafinil
45
45
40
40
35
35
% Heavy Drinking Days
% Heavy Drinking Days
Modafinil
Poor Response Inhibition
(n=42)
30
25
20
15
30
25
20
15
10
10
5
5
0
Placebo
0
T2
FU1
FU2
Time
MMRM: time by treatment: p=.003
T2
FU1
FU2
Time
MMRM: time by treatment: p=.656
41
8/10/2014
Combinatie therapieen ?
• Werken op ruiter & paard
Therapie x medicatie
• Werken op twee systemen; bv. Craving x zelfcontrole:
• rTMS x nalmefene/campral/naltrexon: ??
• CBT x naltrexone: COMBINE studie (Compliance bij patiënten met
psychiatrische co-morbiditeit)
• BRENDA x Nalmefene: compliance
• Of proberen een systeem dubbel te beïnvloeden:
• CBT x modafinil
42
8/10/2014
Gilleen et al., 2014
• Rate of new-language learning was significantly enhanced
with modafinil, and effects were greatest over the first five
sessions. Modafinil improved within-day learning rather than
between-day retention.
• No enhancement of gains with modafinil was observed in
working memory nor rate of verbal learning. Gains in all tasks
were retained post drug administration, but transfer effects to
broad cognitive abilities were not seen.
• ??
43
8/10/2014
Verandering
omgevingscontingenties
Spirituele
morele
incentives
Zelfcontrole technieken
Verandering
omgevingscontingenties
Spirituele
morele
incentives
Zelfcontrole technieken
44
8/10/2014
45
8/10/2014
And…..
• Participants who received the contingency management
intervention were 2.4 times as likely as those in the control
condition to submit a stimulant-negative urine sample during
treatment
• The cost of urine testing and reinforcers was $256 per
participant for the entire treatment group ($864 for
individuals with $8 weeks of abstinence).
• individuals assigned to the contingency management
condition experienced 138 fewer days of psychiatric
hospitalization than those in the control condition.
• Our data suggest that an effect of contingency manage- ment
on stimulant abstinence persisted after treatment was
discontinued.
Besluit
• Groot deel van de mensen met verslavingsproblemen herwinnen op
eigen kracht de controle over hun gebruik.
• Ongekend terrein waar we nog veel van kunnen leren.
• Een klein deel “zwaar verslaafden “ meestal met psychiatrische comorbiditeit beantwoord aan het chronisch (brein) ziekte model.
• Werken aan zelfcontrole is werken aan zowel het drive deel (paard)
als het controle (ruiter).
• Individuele matching (profilering) staat nog in kinderschoenen.
• Combinatie therapieën gericht op beide dimensies onderzoek naar
de toekomst.
• Veranderen van omgevingscontingenties en stress management…
46
8/10/2014
Pieter Bruegel
47