Alcohol Use Disorder – Latest Update on Pharmacotherapy Options and Research Opportunities

1. Alcohol Use Disorder – Latest Update on Pharmacotherapy Options and Research Opportunities Prof Philip Morris MB BS, BSc med, PhD, FRANZCP, FAChAM (RACP), AmBPN, AmBIME Visiting Professor of Psychiatry, Bond University, Gold Coast, Australia Executive Director, Australian and New Zealand Mental Health Association

2. Alcohol Use Disorder • Q1. Acamprosate is most appropriate when controlled drinking is the goal of treatment.  Do you agree or disagree? • Q2. Naltrexone has no effect on liver function. Do you agree or disagree? • Q3. Serotonergic antidepressants have little place in treatment of Type I or A or Type II or B alcohol dependence.  Do you agree or disagree? • Q4. Naltrexone plus acamprosate is more effective than naltrexone alone. Do you agree or disagree? • Q5. The effect of ondansetron is independent of age of onset of alcohol dependence. Do you agree or disagree?

3. Alcohol Use Disorder Contents • Definitions and diagnosis – alcoholism, intoxication, excessive consumption, misuse, abuse, dependence • Detection and recognition • Assessment • Management • Dependence and abuse • Simple versus intensive treatment • Psychosocial treatments • Relapse prevention • Residential rehabilitation • Abstinence versus controlled drinking • Medications • Current pharmacotherapies • Promising pharmacotherapies • Novel research targets

4. Alcohol Use Disorder Alcoholism – outdated and non-specific term but still used widely! Other terms Alcohol intoxication, misuse, excessive consumption, alcohol abuse (harmful use), alcohol dependence, problem drinking (abuse plus dependence), alcohol withdrawal states

5. Alcohol Use Disorder Consumption (one standard drink = 10gm alcohol) Safe (up to 2 sd for women and men in daily regular consumption) versus Hazardous (3-6sd) and Harmful use (7 plus SD) Models of understanding Moral perspective (free will, punishment, prevent use in community – abolition approach) versus Medical perspective (disease concept, vulnerability to alcohol, stages of addiction, harm minimization approach) Prevalence One year prevalence 7-10%; males 14%, females 5% Type I or A (primary) – late onset, no family history Type II or B (secondary) – early onset, family history, antisocial personality traits Course Misuse – variable Dependence –irregular but downward spiral, chronic relapsing condition

6. Alcohol Use Disorder Causes - multifactor etiology Little known still - interacting factors (genes and environment) Genetic – familial - family history, twin studies, adoption studies Genetic - linkage studies – dopamine D2 alleles, chromosome 4 [near GABA gene] Genetic – genome-wide associations – up to 40 genes that confer genetic predisposition Tension - reduction hypothesis Pleasure – reward theory Learning addiction behaviours Personality – risk seeking behaviour, antisocial traits Psychiatric disorder Level of consumption in community and availability Religious and cultural attitudes

7. Alcohol Use Disorder Diagnosis Diagnosis required for prognosis and to indicate management Eight main elements of information needed – 1. Quantity, frequency, variability of use 2. Psychological dependence 3. Tolerance 4. Withdrawal symptoms 5. Loss of control over drinking 6. Adverse effect on mental, physical, social function 7. Continued drinking despite awareness of problems 8. Duration of problems (12 months at least)

8. Alcohol Use Disorder Alcohol abuse (DSM-IV-TR) Frequent (usually heavy) use of alcohol leading to – Recurrent role failure Use where physically hazardous Legal problems Continued use despite social or interpersonal problems

9. Alcohol Use Disorder Alcohol dependence (DSM-IV-TR) The presence of three or more of - Tolerance Withdrawal symptoms Loss of control over drinking Persistent desire or failed attempts to stop Becomes the focus of activity Social, occupational, interpersonal role failure Continued use despite awareness of problems

10. Alcohol Use Disorder Recognition and detection Clinical suspicion WHO Audit (and other questionnaires – MAST) How often, how much, more than 6 sd per day, cannot stop, role failure, morning drink, guilt or remorse, blackouts, injuries, concern of others Clinical associations (days off work, marital problems, legal/financial problems, gastritis, ulcers, liver disease, psychiatric conditions etc) Lab tests: GGT, MCV, CDT, BAC, positive urine alcohol.

11. Alcohol Use Disorder Assessment Drinking history Psychiatric complications (blackouts, amnesia, dementia, psychosis – paranoia/hallucinosis, Korsakoff psychosis, pathological jealousy, sexual problems, mood/anxiety disorder, personality change, suicide) Medical complications (end organ damage - cerebral and cerebellar atrophy, seizures, peripheral nerve/liver/heart damage; poor diet - vitamin deficiencies/Wernicke – Korsakoff syndrome; head injury; vascular disease; cancer; fetal alcohol syndrome) Social problems (family, education, work, legal)

12. Alcohol Use Disorder Detoxification – withdrawal Hospital – residential – home based Supportive medical and psychological care Thiamine and B group vitamins and folate Monitor alcohol withdrawal symptoms Long acting benzodiazepines (except in liver disease) Avoid anti-psychotics (seizure threshold) Be aware of delirium tremens, Wernicke encephalopathy and Korsakoff psychosis

13. Alcohol Use Disorder An approach to treatment of abuse and dependence Simple vs. intensive interventions Simple (before dependence established) Education about alcohol problems Advice about safe levels Promote and persuade safer drinking habits Monitor and encourage Intensive (for severe abuse or established dependence) Involve partner/family Specific goals and responsibilities Motivational interviewing and persuasion (begin early in course of addiction) – avoid being judgmental, roll with resistance, raise discrepancies in history, raise awareness - remember stages of change – pre-contemplation, contemplation, decision, action, maintenance, relapse and start again – to guide realistic expectations Cognitive behavioural therapy Relapse prevention – cue exposure Group therapy Alcoholics Anonymous Residential rehabilitation – establish drug-free lifestyle

14. Alcohol Use Disorder Abstinence versus controlled drinking Controlled drinking Controversial Only suitable before dependence or physical or psychiatric complications have been established, or in patients who refuse abstinence Abstinence Where dependence established or when end organ damage present

15. Alcohol Use Disorder Central nervous system and neurotransmitter actions of alcohol Dopamine enhancement (in ventral tegmental area) involved in pleasurable effects of acute alcohol use, chronic use increases dopamine receptors Serotonin release increased by acute alcohol use, chronic use depletes serotonin stores (via dorsal raphe nucleus) – implication for depressed mood in alcohol dependence Gamma-aminobutyric acid (GABA) inhibition increased by acute alcohol use N-methyl-D-aspartate (NMDA) receptors inhibited by alcohol, chronic use produces enhanced sensitivity of NMDA receptors (to glutamate) Alcohol stimulates production of endogenous opiate-like compounds (beta-endorphins) – produce pleasurable effects of alcohol via disinhibition of dopamine neurons in ventral tegmental area projecting to nucleus accumbens

16. Alcohol Use Disorder Current Medications Disulfiram (Antabuse) Used for over 50 years, but not as much recently Difficult to conduct blinded clinical trials – variable results in published studies, but many positive Blocks oxidation of alcohol – acetaldehyde accumulates – flushing reaction ensues An abstinence model medication Does not diminish cravings Requires close supervision and patient compliance over one year or more Avoid in heart disease, pregnancy, psychosis, liver disease Dose - 250 mg daily maintenance dose (125-500mg range) Should not be used for aversive conditioning – time lag and intensity of reaction is unpredictable

17. Alcohol Use Disorder Acamprosate GABA agonist and glutamate inhibitor Suppresses delayed sub-acute cravings by suppressing glutamatergic excitation associated with alcohol withdrawal Most research trial evidence is for maintaining abstinence (cumulative abstinence duration) Use soon after detoxification to encourage abstinence Few contraindications, not metabolized in liver Dose - 333 mg tablets, 2 tablets three times a day (weight >60kg)

18. Alcohol Use Disorder Naltrexone Opioid receptor antagonist Blocks pleasurable effects of alcohol mediated by endogenous opioids and dopamine An ‘anti-craving’ drug Supportive evidence base of clinical trials for mid-term use (up to 12 months) Reduces relapse to heavy drinking and reduces alcohol consumption Can be used in ‘controlled drinking’ models Most effective when high levels of craving, positive family history, and in patients with certain types of polymorphism of the mu-opioid receptor gene Affects narcotic pain relief (patient should carry card) Liver toxicity possible (>3x upper limit GGT) Dose - 50 mg tablets, one to two tablets daily Long-acting IM form now available (180 and 360mg IM monthly), dose response effect on reduced heavy drinking

19. Alcohol Use Disorder Is combination of naltrexone and acamprosate better than single use? Largest trial (COMBINE study) found no advantage of combining naltexone and acamprosate Best results found for combining medical management (MM) and naltrexone with cognitive behavioural intervention (CBI) In practice use acamprosate straight after detoxification and then add on naltrexone, not the other way around

20. Alcohol Use Disorder SSRI antidepressants May reverse serotonin depletion caused by chronic use of alcohol, reduce anxiety-tension Positive animal studies but conflicting human clinical trials (sertraline, fluoxetine, citalopram) Results dependent on Type of alcohol dependence, polymorphism of 5-HT transporter gene, and gender In summary – SSRIs have possible role in male non-depressed Type I (or A) alcohol dependence SSRIs may worsen Type II (or B) alcohol dependence Dose – usual antidepressant doses used

21. Alcohol Use Disorder Promising Pharmacotherapies Topiramate Anticonvulsant that enhances GABA activity and antagonizes glutamate receptors reducing dopamine release in nucleus accumbens and reduces neuronal hyper-excitability and withdrawal anxiety Recent short duration (12-14 week) studies show benefit on increased abstinent days, decreased heavy drinking days, and less craving for alcohol Pregnancy classification to Category D – cleft lip (do not use with pregnant women) Dose - 200 to 300mg daily

22. Alcohol Use Disorder Baclofen Anti-spasticity agent GABA(b) receptor agonist blocks dopamine release in central reward areas (ventral straitum and prefrontal cortex) Preliminary controlled trials and open-label studies showed improvements in cumulative abstinence duration and reduced alcohol cravings A recent controlled trial was not supportive Can be used in patients with liver disease Dose – 10mg three times daily Dose response effect observed – may need 20mg three times daily

23. Alcohol Use Disorder Ondansetron A 5-HT(3) receptor antagonist antiemetic affect the 5HT transported and down-regulates dopamine neurons reducing reward from alcohol A limited number of controlled trails of oral preparation show benefit in increasing days abstinent, reducing drinks consumed per day, and reduced alcohol cravings Results depended on age of onset of alcohol dependence (better in early onset) and genotype of the 5’regulatory region of the 5-HTT gene (better in the LL genotype) Dose – 0.25mg twice daily (or between 1 to 16mcg/kg twice daily)

24. Alcohol Use Disorder Aripiprazole New generation antipsychotic, binds to D2 receptors (partial agonism of dopamine autoreceptors), partial agonism of 5-HT1A, antagonism of 5-HT2A, and inverse agonism of 5-HT2B receptors Attenuates sedative effects of alcohol, reduces drinking in impulsive alcohol abuse Limited evidence base One trial showed reduced heavy drinking days but only at low doses of aripiprazole (5-15mg daily)

25. Alcohol Use Disorder Prazosin Noradrenalin alpha-1 blocker antihypertensive Used in PTSD, noted to reduce drinking of alcohol Decreases alcohol consumption in alcohol preferring rats Limited evidence base One controlled study using prazosin 16mg daily with medical management showed significant reduction in drinking days per week Pregabalin Neuropathic pain medication binds to calcium channels Inhibits release of excitatory neurotransmitters (glutamate, noradrenalin) Used in alcohol relapse prevention and alcohol withdrawal Reduced alcohol relapse in a few studies Dose – 150 to 450mg daily

26. Alcohol Use Disorder Future Targets of Pharmacotherapy for Alcohol Dependence Cannabinoid receptors Cannabinoid receptor CB1 agonists stimulate alcohol intake Cannabinoid receptor antagonists (rimonabant) may reduce alcohol intake Corticotropin-Releasing Factor (CRF) Hypothalamic messenger hormone Stress response (both HPA-axis and locus coeruleus-noradrenalin system) affects susceptibility for alcohol dependence and relapse Up regulated CRF and certain CRF polymorphisms associated with at-risk drinking behaviour

27. Alcohol Use Disorder Neuropeptide Y Hypothalamic peptide neurotransmitter CNS abundant neuron modulator Neuropeptide Y deficiency may be associated with anxiety and increased drinking behaviours and experience of alcohol withdrawal Ghrelin A gut peptide involved in stimulating appetite via hypothalamus and central reward systems Antagonism of ghrelin may reduce alcohol craving and drinking Gamma-hydroxybutyrate (GHB) All studies from Italy Decreased relapse rate, heavy drinking, and cravings

28. Alcohol Use Disorder Neurokinin receptors Substance P neurotransmitter involved in stress response via neurokinin-1 receptor (NK1R) Animal studies of deletion or blockade of NK1R inhibits responses to stress Genetically deficient mice have reduced preference for alcohol and increased sensitivity to sedation from alcohol NK receptor antagonism may reduce alcohol intake A NK receptor antagonist reduced alcohol craving in one study of recently detoxified alcohol dependent subjects Certain polymorphisms of NK1R are associated with development of alcohol dependence

29. Alcohol Use Disorder Genetically Targeted Pharmacotherapy Improved knowledge of the genetics of alcohol use disorders could lead to matching patients to specific treatments Opioid receptor genotypes can influence the effectiveness of naltrexone in preventing return or relapse to heavy drinking – the Asp40 allele associated with a better response to naltrexone Similar phenomena are being examined with dopamine receptor gene variations or alleles

30. Alcohol Use Disorder • Q1. Acamprosate is most appropriate when controlled drinking is the goal of treatment.  Do you agree or disagree? • Q2. Naltrexone has no effect on liver function. Do you agree or disagree? • Q3. Serotonergic antidepressants have little place in treatment of Type I or A or Type II or B alcohol dependence.  Do you agree or disagree? • Q4. Naltrexone plus acamprosate is more effective than naltrexone alone. Do you agree or disagree? • Q5. The effect of ondansetron is independent of age of onset of alcohol dependence. Do you agree or disagree?

31. Alcohol Use Disorder References and further reading Schuckit MA. Drug and Alcohol Abuse: A clinical guide to diagnosis and treatment. Springer 2005. Edwards SM et al. Current and promising pharmacotherapies, and novel research target areas in the treatment of alcohol dependence: A review. Current Pharmaceutical Design 2011; 17: 1323-1332.