Riunione Monotematica AISF 2017 Roma 5 Ottobre Management of Alcohol Use Disorders in Patients with Alcoholic Liver Disease

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1 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.

2 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

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5 Treatments for Addictions 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

6 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

7 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

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10 Neurochemical Systems and Drugs of Abuse Acetylcholine Neuron Enkephalin Inhibitory Neuron Nicotinic Receptors Glutamate Excitatory Input Dopamine Neuron Dopamine Receptors GABA Neuron m Opioid Receptors REWARD GABA Receptors GABA Inhibitory Feedback GABA Inhibitory Neuron Presynaptic Opioid Receptors (m, d?) Swift RM and Leggio L. Evidence-Based Addiction Treatment, 2009

11 Approved Medications Disulfiram Aldehyde dehydrogenase inhibitor When taken with alcohol: nausea, dizziness, headache, flushing Naltrexone (Oral and SR) Opioid receptor (mu-, -kappa, -delta) competitive full antagonist Binds to opioid receptors, thus blocking alcohol reward via modulation of the dopaminergic mesolimbic pathway Acamprosate Glutamate receptor modulator Helps maintain abstinence during post-acute withdrawal Nalmefene Opioid receptor antagonist (mu-, delta-) and partial agonist (kappa-) Approved in Europe only (EMA, 2013)

12 NNT was 12 for acamprosate and 20 for naltrexone

13 Statement of the Problem There is a need to develop novel medications for patients with alcohol use disorder

14 Use of Approved Pharmacotherapies for Alcohol Use Disorder in the context of Alcoholic Liver Disease Disulfiram may give hepatotoxicity Berlin, Alcohol Alcohol 1989 Chick, Addiction 2004 Naltrexone (Oral or SR) may give hepatotoxicity (Black Box Warning) acute hepatitis and liver failure represent contraindication Mosby s Drug Consult, 2005 Nalmefene no data on chronic administration in patients with liver failure Acamprosate 1-day administration tolerated in Child-Pugh class A and B cirrhosis patients Delgrange et al. Gastroenterol Clin Biol 1992 no data on chronic administration in patients with liver failure

15 Note: these medications are NOT approved for alcohol use disorder Topiramate Ondansetron Gabapentin Varenicline Baclofen increases GABAA-facilitated neuronal activity and simultaneously antagonizes AMPA and kainate glutamate receptor approved by the FDA for epilepsy and migraine 5-HT3 receptor antagonist approved by the FDA for nausea and vomiting GABA analog whose activity may involve interaction with voltage-gated calcium channels approved by the FDA for epilepsy and postherpetic neuralgia Nicotinic receptor partial agonist approved by the FDA for smoking cessation GABA-B receptor agonist approved by the FDA for spasticity

16 Note: these medications are NOT approved for alcohol use disorder Topiramate Ondansetron Gabapentin Varenicline Baclofen increases GABAA-facilitated neuronal activity and simultaneously antagonizes AMPA and kainate glutamate receptor approved by the FDA for epilepsy and migraine 5-HT3 receptor antagonist approved by the FDA for nausea and vomiting GABA analog whose activity may involve interaction with voltage-gated calcium channels approved by the FDA for epilepsy and postherpetic neuralgia Nicotinic receptor partial agonist approved by the FDA for smoking cessation GABA-B receptor agonist approved by the FDA for spasticity

17 Baclofen in Alcohol Use Disorder: Summary of Preclinical Studies In animal models, baclofen reduces: daily alcohol intake in alcohol-experienced rats Colombo et al. Alcohol Clin Exp Res 2000 extra-amount of alcohol consumed after a period of abstinence Colombo et al. Drug Alcohol Dep 2003 motivational properties of alcohol Colombo et al. Psychopharmacology 2003 self-administration of alcohol Liang et al. Neuropharmacology 2006 Walker & Koob. Alcohol Clin Exp Res 2007 severity of ethanol withdrawal Colombo et al. Alcohol Clin Exp Res 2000 Knapp et et al. Alcohol Clin Exp Res 2007

18 Baclofen in a double-blind controlled randomized study F treat (1,78)=5.65 p<0.05 F treat (1,78)=10.71; p<0.005 F treat (1,78)=4.60 p<0.05 F treat (1,78)=5.06 p<0.05 Addolorato et al. Alcohol Alcohol 2002

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20 Differences between European and US baclofen-treated alcoholic patients Leggio L, Garbutt JC, Addolorato G. CNS & Neurological Disorders - Drug Targets 2010

21 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

22 Trial Flow-chart and Results p = *CAD: 30.8 ± 5.5 p = *CAD: 62.8 ± 5.4 *CAD: Cumulative Abstinence Days

23 Baclofen and Liver Tests

24 Baclofen and Alcohol Use Disorder: Total alcohol abstinence evaluated according to the Child-Pugh classification

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26 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 reported Yamini et al. Alcohol Alcohol 2014

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30 Tobacco and Alcohol Use Disorders: A Very Common Comorbidity

31 Baclofen (80mg/day) vs. Placebo: Cigarettes per day (CPD) p<0.05

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33 Baclofen in alcoholic smokers: a randomized controlled study Baclofen increases alcohol-tobacco co-abstinence days in alcoholic smokers A. B.

34 Baclofen in alcoholic smokers: a randomized controlled study Severity of alcohol dependence moderated baclofen effect

35 Randomization A Pilot Human Lab Study Baclofen 30mg/day 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 Active Placebo after 40 minutes Day 0 Day 8

36 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

37 Mehdi Farokhnia, MD

38 Baclofen and Alcohol Subjective Effects

39 Baclofen and Alcohol PK Is this due to possible change in alcohol pharmacokinetics?

40 Baclofen in Alcohol Use Disorder: Summary 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

41 Beyond Baclofen: Addiction Medicine in Clinical Practice 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 Medicine Leggio and Lee, Am J Med 2017

42 Lee and Leggio, Am J Psychiatry 2015

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44 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.