Treatment of Alcohol Use Disorders New Options for Better Outcomes Wim van den Brink, MD PhD Amsterdam University Medical Centers, location AMC Amsterdam, The Netherlands Nordic Reform Conference 2019 Oslo, 20 September 2019 Disclosure Interest Name of organization Grants Alkermes Lundbeck, Merck Serono, Eli Lilly, Indivior, Pfizer, Honoraria Angelini Lundbeck, Merck Serono, Indivior, Mundipharma, Advisory Board/Consultant D&A Pharma, Bioproject, Novartis, Kinnov Therapeutics, Opiant Pharmaceuticals, Takeda Content • Addiction a treatable brain disorder • Many new neurobiological and psychological treatments • New treatment goals • Role of substitution treatment • Compliance, polypharmacy, and precision medicine • New paradigms • Conclusions Addiction a Treatable Brain Disorder Heritability estimates Heritability estimates for alcohol dependence, nicotine dependence, cannabis and other illicit drug use disorders across samples of twins Type of dependence Heritability 80 70 60 Alcohol 50–70% 50 40 Nicotine 50–75% 30 Heritability 20 10 (% of total variance) Cannabis 35–75% 0 Cocaine 35–80% Dutch Virginia Finnish twins Colorado twins twins Minnesotatwins twins Australiantwins Vietnamtwins era Heroin 40–60% Alcoholism Cannabis use disorder Nicotine dependence Any illicit drug use disorder Agrawal & Lynskey. Addiction 2008;103(7):1069–1081 Alcoholism Phenotype Social Alcoholism support spectrum Liability alcoholism Insight- oriented psychotherapy Conditioning Attentional bias Drug CBT Endophenotype Low alcohol Use Reward response Disinhibition deficiency Medication Conflict etc Neuromodulation monitoring Candidate genes Pharmaco- OPRM1 genetics DRD1 COMT GRIN2B GABRA6 Genotype DRD2 Gene SERT MAOA therapy CNR1 Ooteman et al (2006) adapted from: HTR1B Gottesman & Gould. Am J Psychiatry GABRB2 2003;160:636–645 GABRG2 Neurobiology of addiction Function Brain structures Neurotransmitters Naive Ventral tegmental area (VTA) Endorphins (μ-receptors) Reward deficiency Experimenting Nucleus accumbens (NAc) Dopamine moderate use Disinhibition DLPFC Noradrenalin, 5-HT Impulsivity ACC GABA, glutamate Binging NAc (ventral striatum) Dynorphins (κ-receptors) Abuse Conditioning Amygdala, Hippocampus Dopamine Craving Thalamus CRH Prefrontal cortex (OFC, ACC) Glutamate Attentional bias/ OFC Dependence Dopamine salience VMPFC (craving) Putamen, Nc caudatus Dopamine Habit formation (dorsal striatum) Addiction (compulsive use) Noradrenalin, CRH Withdrawal Locus coeruleus Glutamate Van Ree. 2002; de Vries & Schippenberg. 2002; Kreek et al. 2002; 7 Van den Brink. 2006; Volkow. 2004; Koob & Volkow. 2010 Alcoholism Fenotype Alcoholism spectrum Liability alcoholism IRISA: Hyperactive Conditioning Attentional bias Motivational system Endofenotype Deficient Reward Salience Disinhibition deficiency I Cognitive control system Conflict etc monitoring Candidate genes OPRM1 DRD1 COMT GRIN2B GABRA6 Genotype DRD2 SERT MAOA CNR1 Ooteman et al (2006) adapted from: HTR1B Gottesman & Gould. Am J Psychiatry GABRB2 2003;160:636–645 GABRG2 Brain Structures and Functions in Addiction 2006 Reward attentional bias cue-reactivity craving - deficient cognitive control - relapse Repeated reward Detection threshold Inhibition Attentional bias Cue-reactivity Craving Relapse Drug-related stimulus Conflict registration Neurobiology of addiction Function Brain structures Neurotransmitters Naive Ventral tegmental area (VTA) Endorphins (μ-receptors) Reward deficiency Experimenting Nucleus accumbens (NAc) Dopamine moderate use Disinhibition DLPFC Noradrenalin, 5-HT Impulsivity ACC GABA, glutamate Binging NAc (ventral striatum) Dynorphins (κ-receptors) Abuse Conditioning Amygdala Dopamine Craving Thalamus CRH Prefrontal cortex (OFC, ACC) Glutamate Attentional bias/ OFC Dependence Dopamine salience VMPFC (craving) Putamen, Nc caudatus Dopamine Habit formation (dorsal striatum) Addiction (compulsive use) Noradrenalin, CRH Withdrawal Locus coeruleus Glutamate Van Ree. 2002; de Vries & Schippenberg. 2002; Kreek et al. 2002; 11 Van den Brink. 2006; Volkow. 2004; Koob & Volkow. 2010 From reward to relief and from impulsive to compulsive impulsive compulsive Adapted from Heilig et al., 2010 Reward attentional bias cue-reactivity craving - deficient cognitive control - relapse Repeated reward Detection threshold Inhibition Attentional bias Cue-reactivity Craving Relapse Drug-related stimulus Conflict registration Reward attentional bias cue-reactivity craving - deficient cognitive control - relapse Repeated reward Detection threshold Inhibition Attentional bias Cue-reactivity Craving Relapse Drug-related stimulus STRESS WITHDRAWAL Conflict registration Conceptual Treatment Models Pharmacological Tx Model for Pharmacotherapy of Addiction Repeated reward Antagonist Agonis Detection threshold Inhibition t Cognitiv Attentional bias Cue-reactivity Craving e Relapse Anti-cra enhanc ving er medicati on Stress Conflict registration Drug-related stimulus Anti-stress medication 16 Pharmacotherapy Alcohol Use Disorder • HD Baclofen? Repeated reward • Sodium Oxybate? • Gabapentin? • Disulfiram • C H OH (alcohol) Antagonist • Naltrexone 2 5 • Nalmefene Agonis Detection threshold Inhibition t Cognitiv Attentional bias Cue-reactivity Craving e Relapse Anti-cra enhanc ving • Modafinil?er drug Conflict •registration LSD/Psilocybin? Stress • Acamprosate Drug-related stimulus • Topiramate? • LD Baclofen doxazosine • Varenicline?? Problems with potentially new medications • Many of the new medications are already out of patent • Testing new compounds for AUDs is risky for pharmaceutical industry • Not very likely that all these promising medications will be EMA/FDA registered • New role for professional, patient and political organisations • Non-registered medications with “enough” scientific support in guidelines! • Reimburse off-label prescriptions by specialist as off-label prescriptions! • Monitor the use, outcomes and potential18 adverse events! Conceptual Treatment Models Psychological Tx JSAD, 2011 20 ACER, 2011 “Change talk” vermindert activatie tijdens cue-reactivity regio’s tijdens kleine dosis voorkeursdrank en leidt tot minder craving 21 Model for Psychotherapy of Addiction Repeated reward Counterconditioni ng CM Detection threshold Inhibition CRA MET Attentional bias Cue-reactivity CET Craving Working Relapse (+DCS) Memory Act Training MBRP Stress EMDR? Conflict registration Drug-related stimulus CBT Mindfulness 22 Conclusions and remaining issues • Many pharmacological interventions for alcohol (nicotine and opioid) dependence • Very few pharmacological interventions for stimulant and cannabis dependence • Many psychological interventions for all addictions • BUT • Do patients and therapists want all these treatments? * abstinence vs. reduced/controlled drinking * agonists (often liked by patients) vs. antagonists (often liked by therapists) * change vs. acceptance of craving • How effective are these interventions? * compliance, polypharmacy, precision medicine • New paradigms ? New Treatment Goals Treatment gap in alcohol dependence (%) Treatment gap* Treatment Alcohol abuse and dependence have the widest treatment gap among all mental disorders – less than 10% of European patients with alcohol abuse and dependence are treated Kohn et al. Bull World Health Organ * Treatment gap=difference between number needing MH Tx and number receiving MH Tx 2004;82:858–866 Reasons for not seeking AD treatment Not ready to stop using Cost/insurance barriers Social stigma Access Did not think needed treatment/ thought could handle without treatment Did not know where to go for treatment Did not have time Treatment would not help Other barriers Percent SAMHSA 2007, National Survey on Drug Use and Health (NSDUH) Treatment Preference (UK & Canada) UK survey of patients with alcohol problems Canadian study of patients with chronic (n=742) alcoholism (n=106) Heather et al. Alcohol Alcohol 2010;45(2):128–135 Hodgins et al. Addict Behav 1997;22(2):247–255 Need for alcohol reduction intervention Effective Pharmacotherapy Alcohol Dependence Treatment Goal 1st Choice 2nd Choice 3rd Choice Acamprosate Disulfiram Baclofen? (NNT=11) (NNT=25; NS)* Sodium Oxybate? Abstinence Naltrexone?? (NNT=20) Gabapentin? Reduced Drinking Naltrexone# Modafinil?? (NNT=11) Topiramate? Varenicline? Nalmefene? Doxasozine?? * no supervision First choice registered reduced drinking medication? # off-label (and many 2nd and 3rd choice medications) treatment: months 1-4 post-treatment follow-up months 5-16 Witkiewitz et al., in press (Addiction): sustainability 29of reduced drinking independent of baseline severity Role of Substitution Treatment Sunday 17 December 2017 Western societies will 'give up alcohol' within a generation, leading drugs scientist claims Professor David Nutt, a former government drugs advisor teaching at Imperial College, said “alcosynth” will mimic the popular effects of alcohol – without the sickness and throbbing headache commonly experienced the following day. Will “alcosynth” look like GHB? 31 Position papers 2012 Requirements: * Agonist (effect) * Oral use with longer effect * Low toxicity Safety measures * Tx setting: specialist+support * Combine with psychosocial 2015 32 * Define outcomes * No effect on polydrug use Effective Pharmacotherapy Alcohol Dependence Treatment Goal 1st Choice 2nd Choice 3rd Choice Acamprosate Disulfiram Baclofen? (NNT=11) (NNT=25; NS)* Sodium Oxybate? Abstinence Naltrexone?? (NNT=20) Gabapentin? Reduced Drinking Naltrexone# Modafinil?? (NNT=11) Topiramate? Varenicline? Nalmefene?