New Developments in Tx of alcohol dependence: Baclofen and sodium oxybate

Wim van den Brink, MD PhD Amsterdam University Medical Centers, location AMC Amsterdam, The Netherlands

Colloque International “Addictions, Toxicomanies, Hepatites, SIDA” (ATHS) Biarritz, 2 October 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 disease

• Pharmacological Treatments of Alcohol Dependence

• Substitution Treatment

• Baclofen, Sodium Oxybate, and C2H5OH

• Conclusions and recommendations Addiction a Treatable Brain Disease History of the concept of alcoholism

1. Moral model 6. Social model

2. Pharmacological 7. Brain disease model model

5. Learning model

4. Disease model 3. Symptomatic model 1976: Edwards & Gross Biopsychosocial Model 5 Alcohol dependence syndrome Addiction is (also) a treatable brain disease

Nora Volkow

Charles O’Brien Heritability estimates

Heritability estimates for alcohol dependence, nicotine dependence, cannabis and other illicit drug use disorders across samples of twins

80 Type of dependence Heritability 70 60 Alcohol 50–70% 50 40 30 Nicotine 50–75%

Heritability Heritability 20

(% of total variance) total of(% 10 Cannabis 35–75% 0

Cocaine 35–80%

Heroin 40–60% Alcoholism Cannabis use disorder Nicotine dependence Any illicit drug use disorder Agrawal & Lynskey. Addiction 2008;103(7):1069–1081 Phenotype Alcoholism Social Alcoholism support spectrum

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 Fenotype Alcoholism Alcoholism spectrum

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 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 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 STRESS WITHDRAWAL Conflict registration Conceptual Treatment Models Pharmacological Tx Model for Pharmacotherapy of Addiction

Repeated reward

Antagonist Detection threshold Inhibition Agonist

Attentional bias Cue-reactivity Craving Cognitive Relapse enhancer Anti-craving medication Stress Conflict registration Drug-related stimulus Anti-stress medication

14 Pharmacotherapy Alcohol Use Disorder

• HD Baclofen? Repeated reward • Sodium Oxybate? • Gabapentin? • Disulfiram • C H OH (alcohol) Antagonist • Naltrexone 2 5 • Nalmefene Detection threshold Inhibition Agonist

Attentional bias Cue-reactivity Craving Cognitive Relapse enhancer Anti-craving drug • Modafinil? Conflict •registrationLSD/Psilocybin?? Stress • Acamprosate Drug-related stimulus • Topiramate? • Varenicline? doxazosine Effective Pharmacotherapy Alcohol Dependence

Treatment Goal 1st Choice 2nd Choice 3rd Choice

Acamprosate Disulfiram Baclofen? (NNT=11) Abstinence (NNT=25; NS)* Sodium Oxybate? Naltrexon?? (NNT=20)

Gabapentin? Reduced Drinking Naltrexon# Topiramaat? Modafinil?? (NNT=11) Varenicline? Doxasozine??

* no supervision # off-label Substitution Treatment in Alcohol Dependence Position papers

2012 Requirements: * Agonist (effect) * Oral use with longer effect * Low toxicity

Safety measures * Tx setting: specialist+support * Combine with psychosocial * Define outcomes

2015 * No effect on polydrug use 18 Effective Pharmacotherapy Alcohol Dependence

Treatment Goal 1st Choice 2nd Choice 3rd Choice

Acamprosate Disulfiram Baclofen? (NNT=11) Abstinence (NNT=25; NS)* Sodium Oxybate? Naltrexone?? (NNT=20)

Gabapentin? Naltrexone# Reduced Drinking Modafinil?? (NNT=11) Topiramate? Varenicline? Nalmefene? Doxasozine??

* no supervision # off-label Third choice substitution medications Recent Consensus Statements

Sodium oxybate (GHB)

Addict Biol. 2018 Jul;23(4):969-986. Baclofen (LD/HD)

Front Psychiatry. 2019 Jan 4;9:708. Lancet Psychiatry. 2018 Dec;5(12):957-960. 2019

Gabapentin probably only effective in reducing the % of heavy drinking days  Can gabapentin really be regarded21 to be a substitution treatment? Lower total alcohol intake 6 MAPs  Idem + Fewer emergency room admissions improved functioning Fewer police reports Baclofen Baclofen Efficacy * Clinical studies show conflicting results * Baclofen is often used off-label for AD  Review by researchers and clinicians (a) Evidence efficacy from all studies (b) Description two treatment strategies (c) Clinical use today 15 baclofen RCTs

2

4 meta-analyses

2014 2018 2018 2018 15 baclofen RCTs

4 meta-analyses First meta-analysis (2014)

Design: Fixed-effect meta-analysis of 5 early (2002-2010) LD Baclofen RCTs. Results: Compared to placebo, baclofen was associated with a significant increase of 179% in percentage of abstinent patients at the end of the trial. For secondary outcome measures, no significant effect of baclofen was observed compared to placebo. Conclusions. Our meta-analysis brings weak support towards an efficacy of low dosages

of baclofen on the maintenance of abstinence28 in alcohol-dependent patients. Studies and Findings Lasouef et al., 2014

Fixed-effect meta-analysis of 3 small LD baclofen29 studies shows effect on abstinence 15 baclofen RCTs

4 meta-analyses February 2018

Random-effects meta-analysis including 12 RCTs Overall significant effect of baclofen on abstinence rate (n=6: OR=2.67; NNT=8); No sign. effect on any of the other alcohol outcomes, craving, anxiety, depression No stratified analysis for HD vs. LD!! 31 15 baclofen RCTs

4 meta-analyses 2018

• Systematic search RCTs baclofen vs placebo  13 RCTs • Dose (# studies) * LD baclofen (n=7), HD baclofen (n=4); LD en HD baclofen (n=2) • Outcomes (# studies; # patients) * TTL = Time To Lapse (n=8; N=852) * PDA = Percent abstinence Days (n=7; N=457) * PAE = Percent Abstinent at Endpoint (n=8; N=1244) • Statistics * Random effect model with evaluation over complete study period * Stratification for dose (≤ 60 mg/day vs. > 60 mg/day) * Meta-regression for alcohol use at intake33 2018

34 2018

also: Rombouts et al., 2019

35 Small study (N=42) with significant effects of baclofen only in the subgroup of patients with a life-time anxiety disorder36 (also: CC genotype of GABAB1 receptor gene). Baclofen and GABA-B receptor subunit 1 gene

Article Title: Moderation of baclofen response by a GABAB receptor polymorphism: Results from the BacALD study

Authors: Kirsten C Morley; Natasha Luquin; Andrew Baillie; Isabel Fraser; Ronald J Trent; Glenys Dore; Nghi Phung; Paul S Haber

Addiction. 2018 Dec;113(12):2205-2213

Tx * genotype interaction is significant: p=0.049

a) GABBR1 genotype CC  relapse HR=0.32  large effect b) GABBR1 genotype G-  relapse HR=1.07  no effect

Relatively small study showing strong interaction effect with baclofen only being effective in patients with CC genotype of37 GABAB1 gene (or lifetime anxiety disorder?) Baclofen Safety Strong increase baclofen poisoning in Western France between 2010 & 2013; often combined with benzo’s and alcohol and more often in patients with psychiatric comorbidity. Dose: mean 325 mg (range 10-3100 mg)!! Alcohol Alcohol. 2019 Jan 1;54(1):73-78

Increasing prescription of baclofen is paralleled by increasing number of self- poisenings

77% needed medical care 35% with GCS<9 19% needed ventilation

53% with 0ne or more coingestants

Baclofen only prescribed by (GP) experts and not for impulsive patients (e.g. BPD) 40 EMS in 20% of all patients

VAS ≥ 7/10

AWAC en DDB both associated with EMS, but AWAC stronger than DDB Interaction of AWAC with DDB on risk of EMS

Interaction (p=0.047): AWAC>35 22% more risk of EMS with each 20mg extra baclofen 42 Frequent AEs in HD baclofen: somnolence,insomnia, dizziness, headache,43 memory/concentration problems, excitation/hypomania. 50% persistent! More AEs of HD baclofen among women Fewer AEs of HD baclofen in patients with psychosis/antipsychotic medication 44 Baclofen Conclusions * Baclofen not (yet) licensed for Tx alc. dep. * Most experience with baclofen after detox * Baclofen is (in principle) 2nd/3rd line treatment * Dose dependent on effect, tolerability, safety * Start low (15mg), go slow (5-10mg/3 days) * No evidence for baclofen during withdrawal * Most side effects are dose dependent * Baclofen Tx should not be abruptly stopped 46 Sodium Oxybate Sodium Oxybate Efficacy Addict Biol. 2018 Jul;23(4):969-986.

49 Sodium Oxybate Efficacy

2018 Pilotstudies (1992-2007)

Sodium oxybate (Alcover®) more effective than placebo and NTX in reaching abstinence 50 Sodium Oxybate Efficacy

2018 Phase III trials

GATE 2 Study RCT, double-blind, placebo-controlled N=314 Significant longer CAD at month 6 and 12

SMO032 RCT, double-blind, placebo-controlled N=496 12 weeks treatment + 1 week FU 4 different doses (0.75-2.25 g t.i.d.) Post-hoc analyses (DRL) No sign. effect (high placebo response) 51 Sodium Oxybate Efficacy

2018 Phase III trials: SMO023

Significant effect (abstinence, HDD, TAC) of 52Sodium Oxybate in subgroup with H/VH DRL Sodium Oxybate Safety Sodium Oxybate

2018 Safety

* Overall the incidence of SAEs and AEs was low. * Of the 100 abuse/misuse cases in the clinical trials, 64 were in patients with severe psychiatric comorbidity and or comorbid cocaine/heroin dependence. * In this specific subgroup, abuse/misuse 54was 12%!  be careful! Sodium Oxybate Conclusions Conclusions

• Indications for efficacy especially in H/VH DRLs

• Extensively used and registered in Austria and Italy

• No indication of serious abuse/misuse or SAEs

56 Conclusions and Recommendations Conclusions and recommendations

• Alcohol use disorder (AUD) is (also) a treatable brain disease

• Many pharmacological treatments with limited effect size available

• New alcohol substitution treatments available, including off-label use of baclofen and sodium oxybate as 2nd/3rd line treatments

• Careful dosing (titration/tapering): side-effects/overdose, withdrawal

• Prescription only by (GP) addiction experts in non-comorbid cases? Thank You

Wim van den Brink: [email protected]