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Stato dell’arte dei trattamenticontributo di VEdeTTE

Pier Paolo PaniMedicina TossicodipendenzeSer.T. AUSL 8, Cagliari

PREVALENZA USO DI DROGHE NELLA POPOLAZIONE GENERALE

(USO NELLA VITA ITALIA 2004)

Cannabis

CocainaEroina

0

15

30

45Prevalenza %

Uso nella vita

EroinaCocaina(USA) Cocaina

(Olanda)

0

20

40

60

80

100

%

DIPENDENZA: PREVALENZA FRA I CONSUMATORI

dipendenza

uso

Cohen, 1990; NSDUH, 2003.

AddictionA chronic but A chronic but

treatabletreatable conditioncondition

But “relapses” are common But “relapses” are common ----like some medical problems!like some medical problems!

August Vollmer, Police Administrator, 1936

OPIOID ADDICTION: GENERAL STATEMENT

Any treatment (methadone maintenance, therapeuticcommunity, drug-free treatment) is better thennothing.

The effects of treatment tend to be less evident after leaving the program.

Myths about the treatment of addiction Charles P O'Brien, A Thomas McLellan

The Lancet 1996; 347: 237-40

COSTO DELLA TOSSICODIPENDENZA

0

100

200

300

Euro al giorno

strada carcere Ser.T. Comunità

Components of Comprehensive Components of Comprehensive Drug Addiction TreatmentDrug Addiction Treatment

www.drugabuse.gov

Drug Abuse Reporting ProgramFirst National Evaluation of Treatment Effectiveness

Funded by the Funded by the National National

Institute on Institute on Drug AbuseDrug Abuse

Sells, Simpson, Sells, Simpson, DemareeDemaree, & Joe , & Joe 6 books & 150 papers published (funded 19706 books & 150 papers published (funded 1970--19901990))

1969-7335 Cities

139 Programs~44,000 Patients

All treatment typesFollow-ups: 1,3,6,12 Yrs

Drug Abuse Treatment Outcome StudiesThird National Evaluation of Treatment Effectiveness

Funded by the Funded by the National National

Institute on Institute on Drug AbuseDrug Abuse

1991-9311 Cities

96 Programs~10,000 Patients

All treatment typesFollow-up: 1 & 5 Yrs

60 Studies Published (or In Press)60 Studies Published (or In Press) ––Psychology of Addictive BehaviorsPsychology of Addictive Behaviors (Dec 97)(Dec 97)

Drug and Alcohol DependenceDrug and Alcohol Dependence (Dec 99) (Dec 99) Archives of General PsychiatryArchives of General Psychiatry (June 99; In press)(June 99; In press)

Journal of Adolescent Research Journal of Adolescent Research (In press)(In press)

53

64

52

29

53

3343 42

30

0

20

40

60

80

100

Daily Opioid Use: % in Year 1 After Discharge

0Days

(IntakeOnly)

1-30Days inDetoxOnly

1-3 3+Mos in

TherapeuticCommunity*

1-3 3+Mos in

OutpatientDrug-Free*

1-3 3-12 12+Mos in

MethadoneMaintenance*

N=3,248; Simpson & Sells, 1982 (AASA)

*p<.01

ComparisonGroups Same for criminality !

Long-Term Residential (LTR) TreatmentChanges from Before to After Treatment

66

2217

6

40

19

41

16

8877

24

13

0

20

40

60

80

100

Cocaine (Weekly)*

Heroin (Weekly)*

Heavy Alcohol*

Illegal Activity*

No FTWork*

SuicidalIdeation*

Pre Post

% of DATOS Sample (N=676)*p<.001

Hubbard, Craddock, Flynn, Anderson, & Etheridge, 1997 (PAB)

Outpatient Drug-Free (ODF) TreatmentChanges from Before to After

Treatment

42

1825

9

31

1522

14

8276

1911

0

20

40

60

80

100

Cocaine (Weekly)*

Marijuana (Weekly)*

Heavy Alcohol*

Illegal Activity*

No FTWork*

SuicidalIdeation*

Pre Post

% of DATOS Sample (N=764)*p<.001


42

22

89

28

15 16

29

14

85 82

1713

0

20

40

60

80

100

Cocaine (Weekly)*

Heroin (Weekly)*

Heavy Alcohol

Illegal Activity*

No FTWork

SuicidalIdeation

Pre Post

% of DATOS Sample (N=727)

Outpatient Methadone Treatment (OMT)Changes from Before to After Treatment

*p<.001


METHADONE EFFECTIVENESS

There is strong evidence from clinical trials that heroin-dependent individualshave much better outcomes in terms of illicit drug consumption and othercriminal behavior when they are maintained on methadone than when they arenot treated at all, when they are simply detoxified and released, or whenmethadone is tapered down and terminated arbitrarily.

Methadone clinics have significantly higher retention rates among opioid-dependent populations than do other treatment modalities for similar patients.

When assessed following discharge from methadone treatment, patients who stayed in treatment longer have better outcomes than patients who left earlier.

Patients do much better, generally, when they are stabilized on higher rather than lower doses.

THERAPEUTIC COMMUNITY EFFECTIVENESS

TC patients end virtually all illicit drug taking and other criminal behaviorwhile in residence.

They perform better (in terms of reduced drug taking and other criminalactivity and increased social productivity) after discharge than beforeadmission.

They also have better outcomes at follow-up than individuals who simplyundergo detoxification or who contact but do not enter a TC program.

The length of stay is the strongest predictor of outcomes at follow-up, with graduates having the best outcomes at that point.

Attrition from TCs is typically high—above the rates for MM but belowthe rates for OPNM treatment.).

L’OTTIMIZZAZIONE DEL TRATTAMENTO

• Ritenzione

• Dose dei farmaci agonisti

• integrazione e personalizzazione

Comparison of Year 1 Outcomes by Length of Stay in LTR

55

28

53

19 159

54

24

0

20

40

60

80

100

Cocaine (Any Use)*

UA+ (Any Drug)*

Alcohol (Daily Use)*

Any Jail*

< 90 Days 90+ Days

% of Sample*p<.001

N=342; Simpson, Joe, & Brown, 1997 (PAB)

MMTP EFFECT OF THE DOSE OF METHADONE

0.21

0.47

2.2

OR / RR

0.12 - 0.38<60 vs >80

0.33 - 0.67drop-out<60 vs 60-80Caplehorn etal., 1994

use of heroin80 vs 40Caplehorn etal., 1993

IC 95%OutcomeDose

METHADONE:ANTIWITHDRAWAL AND ANTICRAVING EFFECT

Time

Plas

ma

conc

entr

atio

n

INTOXICATION

ABSTINENCE

TOLERANCE

AnticravingAnticraving DoseDose

AntiwithdrawalAntiwithdrawal DoseDose

METHADONE DOSAGES:FREQUENCE DISTRIBUTION

05

101520253035404550

0-25 25-50 50-75 75-100 100-125 125-150 150-175 > 175

Methadone (mg)

METHADONE PHARMACOKINETIC:DOSE- CONCENTRATION RELATIONSHIP

0100200300400500600700800900

1000

0 25 50 75 100 125 150 175 200 225 250

methadone (mg)

Plas

ma

conc

entr

atio

n (n

g/m

l)

FACTORS INVOLVED IN DETERMINATION METHADONE DOSE

• Tolerance level• Genetic factors (metabolic)• Physiologic factors (diet, pregnancy)• Pharmacological interferences• Physical pathology• Psychic pathology

RATS MAINTAINED CHRONICALLY ON BUPRENORPHINE SHOW REDUCED HEROIN AND COCAINE SEEKING IN TESTS OF EXTINTION AND

DRUG-INDUCED REINSTATEMENTSorge et al. Neuropsychopharmacol. 2005

Inc re a s e in e xtra c e llo la r do pa m ine in nuc le us a c c um be ns in re s po ns e to a c ute inje c t io ns o f

he ro in.

0

100

200

300

400

-40 0 40 80 120Tim e

B UP 3B UP 1.5B UP 0

Inc re a s e in e xtra c e llo la r do pa m ine in nuc le us a c c um be ns in re s po ns e to a c ute inje c t io ns o f

c o c a ine .

0

400

800

1200

-40 0 40 80 120Tim e

B U P 3B U P 1.5B U P 0



Ext in tio n s e s s io n: he ro in.

0

5

10

15

20

25

30

35

40

45

50

55

60

1 2 3 4 5 6

Mea

n resp

onse

s on a

ctive

leve

r in 3

h B UP 3B UP 0

Ext int io n s e s s io n: c o c a ine .

0

5

10

15

20

25

30

35

40

45

50

55

60

1 2 3 4 5 6

Mea

n resp

onses

on ac

tive l

ever

B U P 3B U P 0



Reinstatement session: heroin.

05

1015202530354045505560657075

Heroin Cocaine Stress

Mea

n resp

onse

s on a

ctive

leve

r in 3

h B UP 3B UP 0

Reinstatement session: cocaine.

05

1015202530354045505560657075

Heroin1 Cocaine Stress

Mea

n resp

onses

on ac

tive l

ever

B U P 3B U P 0

FOUR DOMAINS IN THE EVALUATION OF TREATMENT

LA PERSONALIZZAZIONE DEL TRATTAMENTO

Il clinico vorrebbe sapere come può aiutare al meglio il suo paziente e in che modo la conoscenza della

condizione dello stesso può aiutarlo a mettere assieme il

migliore programma di trattamento.

COSA AGGIUNGE VEDETTE

• Ci informa su aspetti non esplorabili daitrial clinici.

• Permette di verificare cosa accade nellarealtà del trattamento.

Methadone Maintenance 50 – 80%

LAAM Maintenance 50 – 80%

Buprenorphine-Naloxone Maintenance 40 – 50%**

Naltrexone Maintenance 10 – 20%

“Drug Free” (non-pharmacotherapeutic) 5 – 20%

Short-term Detoxification (any mode) 5 – 20% (limited data)

Opiate Addiction Treatment Outcome*

* One year retention in treatment and/or follow-up with significant reduction or elimination of illicit use of opiates

** Maximum effective dose (24mgsl) equal to 60 to 70 mg/d methadone. Data base on 6 month follow-up only.

Kreek, 1996; 2001; 2003

The “Black Box” of Treatment?The “Black Box” of Treatment?The “Black Box” of Treatment?

Retention Predicts Outcomes• Findings Consistent from National

Studies1970s (44,000 admissions in DARP)1980s (11,000 admissions in TOPS)1990s (10,000 admissions in DATOS)

Also in England’s NTORS (1990s)!

• Conclusions from Major ReviewsInstitute of Medicine (’90, ’96, & ’98)

Patient Retention Rates for Programs(beyond minimum “thresholds”)

65%75% 76%

21% 16% 15%3+ Mos inLong-TermResidential

(n=17)

3+ Mos in Outpatient Drug-Free

(n=14)

12+ Mos inOutpatient

Methadone (n=10)

Simpson, Joe, Broome, Hiller, Knight, Rowan-Szal, 1997 (PAB)

BestProgram

PoorestProgram

Patient Problems in LTR Programs

6782

9686 86

75

416

42 33 44 29

Alcohol

Poly-Drug

Criminal In

vl

Psychological

Family/Friends

Unemployment

Highest %

Lowest %

Programs with Lower Retention had more “troubled” caseloads!

Admissions to these programs had --–More cocaine & alcohol problems–More time in previous treatments –More psychological problems

But these patient problems did not explainall program differences in retention rates!

Simpson, Joe, Broome, Hiller, Knight, Rowan-Szal, 1997 (PAB)

Elements of a “Model”for Treatment Process?

SufficientRetentionSufficientSufficientRetentionRetention

PosttreatmentPosttreatment

Drug UseDrug UseDrug Use

CrimeCrimeCrime

Social AdjSocial AdjSocial Adj

?PatientFactorsPatientPatientFactorsFactors

PsychologicalPsychologicalFunctioning,Functioning,

MotivationMotivation,,

& Problem& ProblemSeveritySeverity

Conclusions•• Treatment Treatment reducesreduces drug use & crimedrug use & crime

–– Problem severity & retention of patientsProblem severity & retention of patients–– Setting, program functioning, & staff skillsSetting, program functioning, & staff skills

•• Treatment programs are Treatment programs are differentdifferent–– Types of patients servedTypes of patients served–– Engagement & retention of patientsEngagement & retention of patients–– Readiness for change & resources availableReadiness for change & resources available

•• Pressing issuesPressing issues for treatment fieldfor treatment field–– “Treatment process” (quality & “Treatment process” (quality &

performance)performance)–– “Technology transfer” (research“Technology transfer” (research--toto--

0

50

100

1 4 8 12 16 20 24Time (months)

Perc

enta

ge re

mai

ning

in p

rogr

am

SCL-90 < 1.3SCL-90 > 1.3

Psychiatric Severity and Treatment Response in Methadone Maintenance Treatment Programmes: New EvidencePani PP, Trogu E, Carboni G, Palla P, Loi A. Heroin Add & Rel Clin Probl 2003

URINE POSITIVENESS FOR MORPHINE (PCC)URINE POSITIVENESS FOR MORPHINE (PCC)

0

20

40

60

80

100

1 2 3 4 54 month periods

Perc

enta

ge o

f urin

alys

es p

ositi

ve

SCL-90 < 1.3SCL-90 > 1.3


URINE POSITIVENESS FOR COCAINE PER MONTHURINE POSITIVENESS FOR COCAINE PER MONTH

0

20

40

60

80

100

1 2 3 4 5 64 months- period

Perc

enta

ge o

f urin

alys

es p

ositi

ve

SCL-90 < 1.3SCL-90 > 1.3


BASELINE BASELINE –– ENDPOINT HEROIN CRAVINGENDPOINT HEROIN CRAVING

0

20

40

60

80

100

Baseline Endpoint

Her

oin

crav

ing

SCL-90 < 1.3SCL-90 > 1.3


BASELINEBASELINE--ENDPOINT CHANGES IN SCLENDPOINT CHANGES IN SCL--9090

0.0000.0000.521.100.290.35Interper sensitivity

0.0050.0010.751.220.320.37Anxiety

0.0010.0000.971.710.380.52Somatization

0.0060.0000.621.070.310.42Paranoidism0.0000.0080.170.500.130.06Phobic anxiety0.0110.0020.531.020.400.45Anger-hostility

0.0000.0000.661.290.350.44Total

0.0010.0070.520.920.290.24Psychoticism

0.0000.0000.921.650.430.55Depression

0.0000.0000.731.410.460.52Obsess-compuls

EndpointBaselineEndpointBaselineGroup-timeTimeHigh severityLow severity

PROSPECTIVE PSYCHIATRIC SEVERITY STUDYPROSPECTIVE PSYCHIATRIC SEVERITY STUDY

BASELINE BASELINE –– ENDPOINT SCLENDPOINT SCL--90: 90: TOTALTOTAL

0

2

Baseline Endpoint

SCL

-90

Tot

al

SCL-90 < 1.3SCL-90 > 1.3

HEROIN ADDICTION: PLASMA VARIATIONS FOR HEROIN AND METHADONE

0

20

40

60

80

100

7 8 9

Time (days)

Plas

ma

conc

entr

atio

ns

Heroin Methadone

METHADONE:ANTIWITHDRAWAL AND ANTICRAVING EFFECT

Time

Plas

ma

conc

entr

atio

n

INTOXICATION

ABSTINENCE

TOLERANCE

AnticravingAnticraving DoseDose

AntiwithdrawalAntiwithdrawal DoseDose

RELATIONSHIP BETWEEN THE DOSE OF RELATIONSHIP BETWEEN THE DOSE OF METHADONE AND THE USE OF HEROINMETHADONE AND THE USE OF HEROIN

0,1

1,0

10,0

40 80

dose of methadone (mg)

use

of

her

oin

(O

R)

Clinical guidelines for the use of methadoneConsensus panel on methadone treatment,

Pietrasanta 2001

“In a range between 80 - 120 mg/day usuallywe get the therapeutic response in terms of

control of heroin use”.

METHADONE DOSAGES:FREQUENCE DISTRIBUTION

05

101520253035404550

0-25 25-50 50-75 75-100 100-125 125-150 150-175 > 175

Methadone (mg)


0100200300400500600700800900

1000

0 25 50 75 100 125 150 175 200 225 250

methadone (mg)

Plas

ma

conc

entr

atio

n (n

g/m

l)

FACTORS INVOLVED IN DETERMINATION METHADONE DOSE

• Tolerance level• Genetic factors (metabolic)• Physiologic factors (diet, pregnancy)• Pharmacological interferences• Physical pathology• Psychic pathology

Methadone dose of heroin addicts with Axis I Methadone dose of heroin addicts with Axis I psychiatric psychiatric comorbiditycomorbidity (Maremmani, (Maremmani, etet al.,al.,. J Addict . J Addict DisDis, 2000), 2000)..

99

Mean

154

Mean

TOnly heroin addicted patients

Dually diagnosed patients

P <.0014984Methadone dose

SDSD


0100200300400500600700800900

1000

0 25 50 75 100 125 150 175 200 225 250

methadone (mg)

Plas

ma

conc

entr

atio

n (n

g/m

l)

METHADONE INTERFERENCES: CLINICAL CASE

0100200300400500600700800900

1000

0 25 50 75 100 125 150 175 200 225 250

Methadone dose (mg)

Pla

sma c

on

cen

trati

on

(n

g/m

l)

A.Y.Methadone = 100 mgPlasma concentration = 57 ng/ml (14 hours after intake)Craving = 80 (range: 0 – 100). Medications: carbamazepine

X.J.Methadone = 180 mgPlasma concentration = 52 ng/mlCraving = 70 for cocaine, 0 forheroin.Medications: carbamazepine

MEDICATIONS INTERFERING WITH METHADONE

INCREASE PLASMA CONCENTRATION:

Surefluvoxaminefluconazolchetoconazol

PossibleCimetidinciprofloxacinfluoxetineNefazodoneparoxetine

REDUCE PLASMA CONCENTRATION:

SureBarbituratescarbamazepinefenitoinerifampicineamprenavirabacavirefavirenznevirapina

Possiblealcooldidanosineritonavirstavudineascorbic acid ed other urine acidifiants.

FIG. 2 REGRESSION PLASMA METHADONE CONCENTRATION (FPIA) BY DOSE TAKEN

0100200300400500600700800900

1000

0 25 50 75 100 125 150 175 200 225 250

Methadone dose (mg)

Pla

sma c

on

cen

tra

tion

(n

g/m

l)

A 17 fold variation has been found in the dose of methadone needed to obtain a 250 ng/ml plasma concentration of R-methadone (Eap etal., 2000).

METHADONE CONCENTRATION TRESHOLD

0100200300400500600700800900

1000

0 25 50 75 100 125 150 175 200 225 250

Methadone dose (mg)

Pla

sma

con

cen

trati

on

(n

g/m

l)

Treshold R-S,(Eap et al., 2002)

Treshold R-S,(Dole, 1988; Loimer 1992

)

PHARMACOLOGY OF BUPRENORPHINE

Buprenorphine acts asPartial agonist for µ receptors

Antagonist for κ receptors

Buprenorphine has a high affinity for µand (less) for κ receptors

OPIOID RECEPTORS

κδµ

OPIOID ACTIVITY

antagonistpartialagonist

agonist

AFFINITY

Buprenorphine Morphine

Opioidreceptor

Buprenorphine is reinforcing but does not produce “rush”-like effects

PHARMACOLOGY OF BUPRENORPHINE

Buprenorphine does not induce significant physicaldependence

The possibility of buprenorphine lethal overdoseis remote

Buprenorphine effectively suppresses heroinself-administration

Buprenorphine may be administered sublingually

EFFICACY OF BUPRENORPHINE FOR THE TREATMENT OF OPIOID DEPENDENCE: EFFECT OF THE DOSE

BUPRENORPHINE: DOSE EFFECT RELATIONSHIP

Dose

Effe

ct

Methadone

Buprenorphine

BUPRENORPHINE PLASMA CONCENTRATION: CRONIC ADMINISTRATION

0

1

2

3

4

5

6

7

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 25 26 27 28 29 30 31 32 33 34 35 36 37 38

Time (hours)

Conc

entra

tion

(ng/

ml)

SUBLINGUAL BUPRENORPHINE (8 mg liquid): VARIABILITY IN PLASMA CONCENTRATION

Schuh et al., 1999 (modified).

0

2

4

6

8

10

12

14

24h 15m 30m 60m 120m 180m 360m

Time

Conc

entra

tion

(ng/

ml)

OPIOID AGONISTS IN HEROIN ADDICTION: APPROPRIATE DOSE

• No withdrawal complains• No use of heroin• No craving• No sedation, euforia

• In Italy, a widepublic treatment network (500 services) givescurrently assistance to about 150.000heroin addicts.

METHADONE MAINTENANCE COST

020406080

100120140160180200

Euro/day

meth street Jail

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