Alcohol Use Disorder

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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

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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

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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• Alcoholism outdated and non-specific term but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

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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

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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

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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)

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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

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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

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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.

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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)

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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

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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

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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

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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

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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

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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 gt60kg)

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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 (gt3x 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

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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

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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

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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

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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

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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 5regulatory region of the 5-HTT gene
  (better in the LL genotype)
• Dose 0.25mg twice daily (or between 1 to
  16mcg/kg twice daily)

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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)

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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

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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

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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

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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

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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.