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Alcohol Use Disorder

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Title: Alcohol Misuse Author: Philip Last modified by: Peer Created Date: 6/27/2013 1:40:41 PM Document presentation format: On-screen Show (4:3) Other titles – PowerPoint PPT presentation

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Title: Alcohol Use Disorder


1
Alcohol Use Disorder Latest Update on
Pharmacotherapy Options
  • Prof Philip Morris
  • MB BS, BSc med, PhD, FRANZCP, FAChAM, AmBPN,
    AmBIME
  • www.drphilipmorris.com
  • Visiting Professor of Psychiatry and Addiction
    Medicine
  • University of Malaya
  • Centre for Addiction Studies

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
  • 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)

4
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

5
Alcohol Use Disorder
  • Alcohol dependence (DSM-IV-TR)
  • The presence of three or more symptoms 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

6
Alcohol Use Disorder
  • Recognition and detection
  • Clinical suspicion
  • WHO Audit (and other questionnaires MAST)
  • How often, how much, more than 6 standard drinks
    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

7
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)

8
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

9
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

10
Alcohol Use Disorder
  • An approach to treatment of abuse and dependence
  • Simple vs. intensive interventions
  • Simple interventions (before dependence
    established)
  • safe drinking
  • harm minimization
  • Education about alcohol problems
  • Advice about safe levels
  • Promote and persuade safer drinking habits
  • Monitor use and encourage

11
Alcohol Use Disorder
  • An approach to treatment of abuse and dependence
  • Simple vs. intensive interventions
  • Intensive interventions (for severe abuse or
    established dependence)
  • abstinence model
  • 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

12
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
  • Drugs that diminish dopamine effects
  • Antipsychotics (D2 blockers)
  • Baclofen (blocks dopamine release)

13
Alcohol Use Disorder
  • Central nervous system and neurotransmitter
    actions of alcohol
  • Serotonin release increased by acute alcohol use,
    chronic use depletes serotonin stores (via dorsal
    raphe nucleus) implication for depressed mood
    in alcohol dependence
  • Drugs that modify serotonin effects
  • SSRI antidepressants
  • Ondansetron

14
Alcohol Use Disorder
  • Central nervous system and neurotransmitter
    actions of alcohol
  • Gamma-aminobutyric acid (GABA) inhibition
    increased by acute alcohol use
  • Drugs that affect GABA function
  • Benzodiazepines
  • Acamprosate
  • Topiramate

15
Alcohol Use Disorder
  • Central nervous system and neurotransmitter
    actions of alcohol
  • N-methyl-D-aspartate (NMDA) receptors inhibited
    by alcohol, chronic use produces enhanced
    sensitivity of NMDA receptors (to glutamate)
  • Drugs that diminish glutamate function
  • Acamprosate
  • Topiramate
  • Pregabalin

16
Alcohol Use Disorder
  • Central nervous system and neurotransmitter
    actions of alcohol
  • 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
  • Drugs that block opioid receptors
  • Naltrexone
  • Nalmefene

17
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

18
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)

19
Alcohol Use Disorder
  • Naltrexone
  • mu-Opioid receptor antagonist (receptor blocker)
  • 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

20
Alcohol Use Disorder
  • Nalmefene
  • Opioid receptor antagonist (universal receptor
    blocker against mu-, kappa-, and delta- opioid
    receptors)
  • Blocks pleasurable effects of alcohol mediated by
    endogenous opioids and dopamine
  • An anti-craving drug
  • Longer acting than naltrexone, no dose-dependent
    liver toxicity
  • Twice as potent than naltrexone dose is 20-25mg
    daily
  • Reduces relapse to heavy drinking and reduces
    alcohol consumption
  • Not as effective as naltrexone for maintaining
    abstinence
  • Can be used for reducing alcohol consumption on
    an as needed basis
  • Affects narcotic pain relief (patient should
    carry card)
  • Dose 20-25mg tablets, one tablet daily

21
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

22
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

23
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

24
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

25
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)

26
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)

27
Alcohol Use Disorder
  • 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
  • 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

28
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

29
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

30
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

31
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

32
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?

33
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.
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