Transcript Alcohol Misuse - Dr Philip Morris

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
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?
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)
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
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
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
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)
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
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
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
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
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)
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
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
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
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
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
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)
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 (>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
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
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
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
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
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
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)
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 5HT2B 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)
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
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 coeruleusnoradrenalin system) affects susceptibility for alcohol
dependence and relapse
Up regulated CRF and certain CRF polymorphisms associated
with at-risk drinking behaviour
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
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
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
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?
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.