Il trattamento farmacologico del poliabuso nell'Addiction da eroina

Dr. Angelo G. I. MaremmaniDirigente Medico, Azienda USL Toscana Nord-Ovest (Zona Versilia)

Dottorando di Ricerca di Biochimica e Biologia Molecolare, Università degli Studi di SienaMaster di II Livello in "Dipendenze Farmaco-Tossicologiche e Comportamentali", Università di Pisa

Abilitato alle funzioni di Professore Universitario di Seconda Fascia

CongressoNazionaleSITD.Roma,24/11/2017

Outline

• The role of bipolarity in addiction and polyabuse

• Heroin Use Disorder + Sedatives (Alcohol / BZDs)

• Heroin Use Disorder + Cocaine

• Treatment implications

Psychiatric Comorbidity in Addiction

%

Mood Disorders 33-90

Anxiety Disorders 1-36

Personality Disorders 3-91

Violence and Impuls Control Disorder 10-45

Suicide 10-20

Schizophrenia 0.2-19

(Maremmani et al., Heroin Addiction and Related Clinical Problems, 2003)

Substance Use Disorder (Lifetime) in Bipolar Disorder patients

Author (year) N Alcohol Cannabis Amphet Cocaine Sub Ab

Regier, 1990 20291 61%

Strakowski, 1993 60 26.7%

Keck,1998 134 32.8%

Angst, 1998 56 21.4% 16.1%

Pini, 1999 125 15.2% 18.4% 5.6%

Goldberg, 1999 204 28% 21% 12% 34%

Chengappa, 2000 71 58%

Cassidy, 2001 392 48.5% 36% 5.1% 24.2% 59%

Maremmani, 2000 19 78.9% 73.7%

0

10

20

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60

70

Cocaina Amfetamine Oppiacei Allucinogeni Inalanti Cannabinoidi Alcol Benzodiazepine

Distrubo Bipolare Schizofrenia

Maremmani A. G., Bacciardi S., Gehring N. D., Cambioli L., Schutz C., Jang K., Krausz M. (2017): Substance Use Among HomelessIndividuals With Schizophrenia and Bipolar Disorder. The Journal of nervous and mental disease. 205(3): 173-177.

* p<0.05*

**

*

**

*

0

10

20

30

40

50

60

70

80

90

Alcohol BZDs Amphetamines

Heroin Addiction + Bipolar Disorder Heroin Addiction

P=0.009

P=0.017

P=0.05

Polyabuse in Heroin Addiction and Bipolarity

Maremmani et al., 2000. Heroin Addiction and Related Clinical Problems 2, 35-42.

Maremmani I., Maremmani A. G. I. el al., (2012): Clinical presentations of substance abuse in bipolar heroin addicts at time of treatment entry. Ann Gen Psychiatry. 11(1): 23.

0

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80

90

100

depressive episode hypomanic episode manic episode mixed episode

heroin

alcohol

anxiolytics-hypnotics

cocaine-amphetamins

cannabinoid

*

p<0.5

*

*

* **

*

*

Pacini M., et a.. (2015):. Alcohol alcohol.

new cases all cases

2004 15/99 (15.1%)

2005 22/159 (13.8%) 37/258 (14.5%)

2006 16/151 (10.5%) 53/409 (13.1%)

2007 27/98 (27.5%) 80/507 (15.8%)

Data collected at the Centre for the Assessment and Treatment of Alcohol- Related Pathology, La Sapienza University, at the Umberto I University Hospital in Rome, Italy

Why looking at former heroin use disorder in alcoholics?

Addiction history, social adjustment and physical complications of Former Heroin Addicts-Alcohol Use Disorder (FHA-AUD) and

Alcohol Use Disorder patients (AUD)

FHA-AUD

N=60

AUD

N=388 p

Age alcohol first use 15.17±4.8 15.70±5.1 nsAge alcohol misuse 24.27±6.4 24.02±7.2 nsDrinking duration 28.22±8.2 28.44±10.6 nsAlcoholism duration 19.15±8.6 20.12±10.7 nsInitial alcohol Units/daily 9.78±9.1 7.02±7.5 0.003Max alcohol Units/daily 25.13±11.6 21.55±10.1 0.016Physical severe complications 16 (26.7) 64 (16.5) 0.056Problematic social adjustment 28 (46.7) 157 (40.5) ns

Heroin Addiction and Treatment History of 60 Former Heroin Addicts-Alcohol Use Disorder patients

Heroin addiction historyAge at heroin continuous use (M±sd) (range) 22.12±8.2 (13-49)

Stage 3 reached – revolving door phase (N (%)) 53 (88.3%)

Heroin dependence length in years (M±sd) (range) 9.38±5.5 (1-21)

Age at heroin use stopping (M±sd) (range) 34.09±7.2 (26-48)

Heroin free for almost 2 years (N (%)) 36 (60.0%)

Treatment historyPast opioid agonist treated (N (%)) 18 (30.5%)

AOT length in years (M±sd) (range) 5.30±4.0 (1-12)

Age at last AOT (Years) (M±sd) (range) 33.92±8.1 (25-50)Blocking doses (at least 80mg of methadone and 16 mg of buprenorphine) not reached (N (%))

34 (56,6%)

Age at alcohol treatment request (M±sd) (range) 43.38±6.3 (22-58)

Cocaine abuse and the bipolar spectrum in 1090 heroin addicts: Clinical observations and a proposal of a pathophysiologic model

1,21 1,15 1,14 1,181,31

0,91

1,531,63

1,541,46 1,51

0,95

1,37 1,39 1,34 1,321,41

0,93

0

1

2

DD Bipolarspectrum

Psychoticdisorder

Lovingproblems

Legalproblems

Ageofonset

Odd

ratio

s

PREDICTORS

Criterion: presence of “concomitant use of cocaine”

Min

Max

Oddratio

Maremmani, I., M. Pacini, et al. (2008). "." Journal of Affective Disorders 106: 55-61.

176161

122 119

0

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120

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200

Stop Cocaine (n=31) Continue Cociane (n=14) Start Cocaine (n=25) Never Use Cocaine (n=242)

methadone dosagesANOVA, F = 15.6,

p < 0.0005

High methadone dose may reduce cocaine use in patients addicted to bothheroin and cocaine (1 years of treatment)

Combined Treatment

• Heroin plus alcohol: “masked heroinism”– under treatment? Enhance methadone dosages– add GHB

• Heroin plus benzodiazepine:– under treatment? Enhance methadone dosages– add Clonazepam Maintenance Treatment

• Heroin plus Cocaine– enhance methadone dosages– add DA-ergic, Glutammatergic medications (?)

Terapia disponibili per il Disturbo da Uso di Oppiacei

Metadone

• Metadone Cloridrato• Levometadone (L-Polamidon)

• Agonista Mu

• Metabolismo: Enzimi epatici, influenzato dalla funzione epatica

Buprenorfina

• Buprenorfina (Subutex)• Buprenorfina/Naloxone (Suboxone)

• Agonista Parziale Mu • Antagonista Kappa

• Metabolismo: Enzimi epatici + coniugazione, minore influenza della funzione epatica

CYP3A4: ruolo primario nel metabolismo del metadone. CYP2D6: ruolo secondario nel metabolismo del metadone.

CYP1A2 2C9 2C19 2B6: ruolo non definito (ancora in studio)

• Formulazione commerciale formata:• 50% R-Met *• 50% S-Met

Forma racemica

R-Met S-Met

frazione libera 14% 10%

emivita 38h 29h

clearance media 158 nl/min 129 nl/min

• R-Met: • affinità al recettore Mu 2x S-Met• potenza analgesica 50x S-Met• variazione interindividuale 16-17x (250ng/ml sono raggiunti con 55mg/die oppure con

900mg/die)• S-Met:

• antagonismo non competitivo NMDA che blocca l’iperalgesia NMDA-indotta e la tolleranza alla morfina

Kristensen, K., et al.,1996. Therapeutic drug monitoring 18, 221-227.

• Variabilità interindividuale:– D,L-Metadone 35x 400ng/ml– L-Metadone 17x 250ng/ml

• 150 – 600 ng/ml

FarmacocineticaConcentrazione plasmatica

Meini, M., et al., 2015. Eur J Pharmacol 760, 1-6.

D,L-Methadone Vs L-Methadone

• Same efficacy after switching from D,L- to L-Methadone (with ratio 2:1)– Sherbaum et al., 1996 Pharmacopsychiatry 29, 212-215– de Vos et al., 1998 Eur Addict Res 4, 134-141– Meini et al., 2015 Eur J Pharmacol 760, 1-6– Verthein et al., 2005 Drug and alcohol dependence 80, 267-271

• Better safety of cardiological ground (QTc)– Ansermot et al., 2010 Archives of internal medicine 170, 529-536

• Reduction in craving • Reduction in concomitant substance use• Better compliance to treatment

Thank you for your attention!

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Versilia (Italy), Photo from Tonfano’s Pier, Winter 2016