Alcohol Use Disorder – Latest Update on Pharmacotherapy Options

Alcohol Use Disorder – Latest Update on Pharmacotherapy Options

Prof Philip MorrisMB 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?


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 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


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


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


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


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


An approach to treatment of abuse and dependenceSimple 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


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)



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



Gamma-aminobutyric acid (GABA) inhibition increased by acute alcohol use

Drugs that affect GABA function –

Benzodiazepines

Acamprosate

Topiramate



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 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


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)


Naltrexonemu-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


NalmefeneOpioid 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


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)


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

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


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.

Documents

Alcohol Use Disorder – Latest Update on Pharmacotherapy Options