Riunione Monotematica AISF 2017Roma – 5 Ottobre 2017

Management of Alcohol Use Disorders in Patients with Alcoholic Liver Disease

Lorenzo Leggio, M.D., Ph.D., M.Sc.

Lorenzo Leggio, M.D., Ph.D., M.Sc.

Il sottoscritto dichiara di non aver avuto negli ultimi 12 mesi

conflitto d’interesse in relazione a questa presentazione

e

che la presentazione contiene discussione di farmaci in studio

o ad uso off-label

Behavioral Treatments:

Brief Intervention

Motivational Interviewing (MI)

Motivational enhancement therapy (MET)

Contingency Management

Cognitive Behavioral Therapy (CBT), Skills Training

Mutual Help, Social Network, and Family/Couples Therapy

Treatments for Addictions

Pharmacotherapies may improve

Clinical Addiction Treatments

• Pharmacotherapies can normalize neuroadaptive changes due to chronic use of alcohol and/or drugs of abuse

• Pharmacotherapy improves clinical addiction treatments by enhancing abstinence, preventing relapse, and complementing behavioral interventions

Swift RM and Leggio L. Evidence-Based Addiction Treatment, 2009

Lingford-Hughes A, et al, Br Med Bull 2010

Addolorato G, et al. Neuropsychopharmacology 2012

Treatment of Alcoholic Liver Disease:

Focus on AUD

• Total alcohol abstinence represents the cornerstone in the treatment of alcoholic

liver disease

• Among patients with AUD and cirrhosis, 40% of them have 5-year survival if they

continue drinking, while 5-year survival increases to 77% if they stop drinking

• Abstinence from alcohol can lead to “re-compensation” in patients with

decompensated alcoholic liver disease and even to regression of compensated

disease (to a non-cirrhotic stage)

Hope et al., Oxford Handbook of Clinical Medicine 1998

Lee and Leggio, Am J Psychiatry 2015

Addolorato et al., J Hepatol 2016

Leggio and Lee, Am J Med 2017

Enkephalin

Inhibitory

Neuron

REWARD

Glutamate

Excitatory InputAcetylcholine

Neuron

GABA

Inhibitory

Neuron

GABA Inhibitory Feedback

Dopamine Neuron GABA

Neuron

Dopamine Receptors

GABA Receptors

Presynaptic

Opioid

Receptors (m, d?)

m Opioid

Receptors

Nicotinic

Receptors

Neurochemical Systems and Drugs of Abuse

Swift RM and Leggio L. Evidence-Based Addiction Treatment, 2009

Opioid receptor (mu-, -kappa, -delta) competitive full antagonist

Binds to opioid receptors, thus blocking alcohol reward via

modulation of the dopaminergic mesolimbic pathway

Naltrexone

(Oral and SR)

Aldehyde dehydrogenase inhibitor

When taken with alcohol: nausea, dizziness, headache, flushingDisulfiram

AcamprosateGlutamate receptor modulator

Helps maintain abstinence during post-acute withdrawal

Approved Medications

NalmefeneOpioid receptor antagonist (mu-, delta-) and partial agonist (kappa-)

Approved in Europe only (EMA, 2013)

NNT was 12 for acamprosate and 20 for naltrexone

There is a need to develop novel medications for

patients with alcohol use disorder

Statement of the Problem

Use of Approved Pharmacotherapies for Alcohol Use Disorder in the context of Alcoholic Liver Disease

Naltrexone (Oral or SR)

Disulfiram

Acamprosate

may give hepatotoxicityBerlin, Alcohol Alcohol 1989Chick, Addiction 2004

may give hepatotoxicity (Black Box Warning)

acute hepatitis and liver failure represent contraindication

Mosby’s Drug Consult, 2005

1-day administration tolerated in Child-Pugh class A and B cirrhosis patients

no data on chronic administration in patients with liver failure

Delgrange et al. Gastroenterol Clin Biol 1992

Nalmefene

no data on chronic administration in patients with liver failure

Note: these medications are NOT approved for alcohol use disorder

Ondansetron

Topiramate

Baclofen• GABA-B receptor agonist

• approved by the FDA for spasticity

• 5-HT3 receptor antagonist

• approved by the FDA for nausea and vomiting

• increases GABAA-facilitated neuronal activity and

simultaneously antagonizes AMPA and kainate glutamate receptor

• approved by the FDA for epilepsy and migraine

Varenicline• approved by the FDA for smoking cessation

• Nicotinic receptor partial agonist

Gabapentin

• GABA analog whose activity may involve interaction with

voltage-gated calcium channels

• approved by the FDA for epilepsy and postherpetic neuralgia

Note: these medications are NOT approved for alcohol use disorder

Ondansetron

Topiramate

Baclofen• GABA-B receptor agonist

• approved by the FDA for spasticity

• 5-HT3 receptor antagonist

• approved by the FDA for nausea and vomiting

• increases GABAA-facilitated neuronal activity and

simultaneously antagonizes AMPA and kainate glutamate receptor

• approved by the FDA for epilepsy and migraine

Varenicline• approved by the FDA for smoking cessation

• Nicotinic receptor partial agonist

Gabapentin

• GABA analog whose activity may involve interaction with

voltage-gated calcium channels

• approved by the FDA for epilepsy and postherpetic neuralgia

In animal models, baclofen reduces:

• daily alcohol intake in alcohol-experienced rats

• extra-amount of alcohol consumed after a period of abstinence

• motivational properties of alcohol

• self-administration of alcohol

• severity of ethanol withdrawal

Colombo et al. Drug Alcohol Dep 2003

Colombo et al. Alcohol Clin Exp Res 2000

Colombo et al. Alcohol Clin Exp Res 2000

Knapp et et al. Alcohol Clin Exp Res 2007

Liang et al. Neuropharmacology 2006

Walker & Koob. Alcohol Clin Exp Res 2007

Colombo et al. Psychopharmacology 2003

Baclofen in Alcohol Use Disorder:

Summary of Preclinical Studies

Ftreat(1,78)=5.65

p<0.05

Ftreat(1,78)=4.60

p<0.05

Ftreat(1,78)=5.06

p<0.05

Ftreat(1,78)=10.71; p<0.005

Baclofen in a double-blind controlled randomized study

Addolorato et al. Alcohol Alcohol 2002

Leggio L, Garbutt JC, Addolorato G. CNS & Neurological Disorders - Drug Targets 2010

Differences between European and US baclofen-treated

alcoholic patients

Baclofen, Alcohol Use Disorder and Liver Cirrhosis

Giovanni Addolorato, Lorenzo Leggio, Anna Ferrulli, Silvia Cardone, Luisa Vonghia,

Antonio Mirijello, Ludovico Abenavoli, Cristina D’Angelo, Fabio Caputo, Antonella

Zambon, Paul S Haber, Giovanni Gasbarrini

p = 0.0002

Trial Flow-chart and Results

*CAD: 30.8 ± 5.5 *CAD: 62.8 ± 5.4p = 0.001

*CAD: Cumulative Abstinence Days

Baclofen and Liver Tests

Baclofen and Alcohol Use Disorder:Total alcohol abstinence evaluated according to

the Child-Pugh classification

Pilot study at Royal Alexandria Hospital Paisley, Glasgow, UK

• Baclofen used ‘off label’ in > 50 patients

• the dose required was lower in those patients with advanced alcoholic liver

disease; patients reduce/stop drinking/craving. No side effects were reported

Heydtmann. Alcohol Clin Exp Res 2011

Pilot study at Loma Linda University Medical Center, US

• Baclofen used for 5-8 months in 14 patients with severe alcoholic hepatitis

• 13/14 patients completely stopped drinking/craving and one patient

reported a significant reduction in alcohol consumption

• There was a significant reduction in total bilirubin (p=.0057) and AST

(p=.0438) and there was a trend for reduced ALT (p=.083). No side effects

were reportedYamini et al. Alcohol Alcohol 2014

Tobacco and Alcohol Use Disorders:

A Very Common Comorbidity

Baclofen

(80mg/day)

vs.

Placebo:

Cigarettes per

day (CPD)

p<0.05

Baclofen in alcoholic smokers:

a randomized controlled study

A. B.

Baclofen increases alcohol-tobacco co-abstinence days in alcoholic smokers

Baclofen in alcoholic smokers:

a randomized controlled study

Severity of alcohol dependence moderated baclofen effect

Ra

nd

om

iza

tio

n

Alcohol

Cue-

Reactivity (CR)

- Neutral vs.

Alcohol Cues

Alcohol

Priming- Consumed

within 5 min.

- BrAC = 0.03

g/dl

Alcohol Self-

Administration

(ASA)- 2-hr Session

- 8 drinks available

- $3 per each drink not

consumed

Baclofen 30mg/day

Active

Placebo

after 40 minutes

Day 0 Day 8

A Pilot Human Lab Study

Amount of standard drink units (SDUs) ± SD consumed during the Alcohol Self-Administration

Leggio et al. Pharmacol Biochem Behav 2013

A Pilot Human Lab Study

Mehdi Farokhnia, MD

Baclofen and Alcohol Subjective Effects

Is this due to possible change in alcohol pharmacokinetics?

Baclofen and Alcohol PK

Baclofen is safe and may be effective to treat alcoholic patients, especially those with

liver disease

Some patients with AUD benefit from baclofen (e.g. alcoholic smokers, alcoholic

patients with high severity), however other patients do not, suggesting the need for

more work towards personalized approaches in the use of baclofen for AUD

Baclofen in Alcohol Use Disorder:

Summary

Beyond baclofen, this may serve as an example of integration among Medicine,

Addiction Medicine and Addiction Psychiatry fields and expertise toward a

multidisciplinary approach

Lee and Leggio, Am J Psychiatry 2015

This integration becomes more and more important, especially in a new area where

effective treatments for HCV are available

Addolorato et al. J Hepatol 2016

If the use of these new treatments for HCV will be accessible to all patients, it is likely

that AUD (and obesity) will represent one the main etiologies of advanced liver

disease in MedicineLeggio and Lee, Am J Med 2017

Beyond Baclofen:

Addiction Medicine in Clinical Practice

Lee and Leggio, Am J Psychiatry 2015

Riunione Monotematica AISF 2017Roma – 5 Ottobre 2017

Management of Alcohol Use Disorders in Patients with Alcoholic Liver Disease

Lorenzo Leggio, M.D., Ph.D., M.Sc.