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

Alcohol Use Disorder – Latest Update on Pharmacotherapy Options and

Research Opportunities

Prof Philip MorrisMB 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

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?


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


Alcoholism – outdated and non-specific term but still used widely!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


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

CourseMisuse – variable

Dependence –irregular but downward spiral, chronic relapsing condition


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


DiagnosisDiagnosis 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 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 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


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.


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)


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


An approach to treatment of abuse and dependenceSimple 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


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


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


Current MedicationsDisulfiram (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


AcamprosateGABA 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)


NaltrexoneOpioid 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


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


SSRI antidepressantsMay 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


Promising Pharmacotherapies

TopiramateAnticonvulsant 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


BaclofenAnti-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


OndansetronA 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)


AripiprazoleNew 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)


PrazosinNoradrenalin 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

PregabalinNeuropathic 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


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


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


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


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


• 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?


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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