Alcohol use disorder

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Alcoholism – outdated and non-specific term but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.