Riunione Monotematica AISF 2017 Roma – 5 Ottobre 2017 Management of Alcohol Use Disorders in Patients with Alcoholic Liver Disease Lorenzo Leggio, M.D., Ph.D., M.Sc.
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.