Behandeling van verslaving, het herwinnen van de controle?

8/10/2014

Behandeling van verslaving, het herwinnen van de controle? [email protected]

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

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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

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Model van de aanpassingen in automatische en gecontrolleerde processen bij verder gevorderd verslavingsgedrag (Wiers et al., 2006) Vermogen te stoppen / Heroriënteren/ Switchen



Emotie Regulatie

Negatieve ervaringen Alcohol/drug




sensitizatie

Alcohol / drugs Sociale context Geassocieerde stimuli

Verslaving 19-5-2010

Functioneel Model en Hersenstructuren

6

Volkow, 2006

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Piazza & DerocheGamonet, 2013, A multistep generl theory of transition to addiction.

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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.

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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 !

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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”

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Emotie Regulatie





sensitizatie


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Maar weten we er nu eigenlijk echt wel iets van ?

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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

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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 %

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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

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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 !

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Dubbel Diagnose

Verandering omgevingscontingenties

Spirituele morele incentives

Zelfcontrole technieken

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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

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Emotie Regulatie





sensitizatie


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Improving impulse control could be an important target for treating alcohol dependence.

Aanpakken hedonische dysregulatie

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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

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Laag frequente rTMS = blokkerend

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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.

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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

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(met Mike Rinck, RUN e.a.)

46

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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

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• http://mindsurfer.eu/jasmin_demo2/demos/cbm/config.html

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Cognitive online training ?




Emotie Regulatie





sensitizatie


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Versterken van de ruiter !

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rTMS • rTMS: Repetitieve transcraniele magnetische stimulatie (Hoog frequent = stimulerend). • rDCS: Direct Current Stimulation (Hoog & laag frequent)

Hoog frequente rTMS = activerend

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Transcraniele Magnetische Stimulatie bij Cocaineverslaafden

Een is misschien te weinig……..

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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

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N.D. Volkow et al. / NeuroImage 49 (2010) 2536–2543

mOFC

NAcc

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Goal management training

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Alfonso et al., 2011

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Alfonso et al., 2011 TRAINING

Polysubstance abusers

Improvement executive cognitive functioning

? Substance use outcome ?

Mindfulnes based

JAMA Psychiatry. 2014 May;71(5):547-56.

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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.

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HET VERSTERKEN VAN COGNITIEVE ZELFCONTROLE MET MODAFINIL EN DE RELATIE TOT HERVAL BIJ ALCOHOLAFHANKELIJKE PATIENTEN

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Alleen bij patiënten met slechte baseline inhibitie

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Schmaal et al. 2014 Psycholog Medic

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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)

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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

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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


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


T2

FU1

FU2

Time


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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

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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. • ??

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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 management 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…

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Pieter Bruegel

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Behandeling van verslaving, het herwinnen van de controle?

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