Presentation on theme: "Alcohol Use Disorder – Latest Update on Pharmacotherapy Options and Research Opportunities Prof Philip Morris MB BS, BSc med, PhD, FRANZCP, FAChAM (RACP),"— Presentation transcript:
1 Alcohol Use Disorder – Latest Update on Pharmacotherapy Options and Research Opportunities Prof Philip MorrisMB BS, BSc med, PhD, FRANZCP, FAChAM (RACP), AmBPN, AmBIMEVisiting Professor of Psychiatry,Bond University, Gold Coast, AustraliaExecutive Director, Australian and New Zealand Mental Health Association
2 Alcohol Use DisorderQ1. 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 Detection and recognition Assessment Management Alcohol Use DisorderContentsDefinitions and diagnosis – alcoholism, intoxication, excessive consumption, misuse, abuse, dependenceDetection and recognitionAssessmentManagementDependence and abuseSimple versus intensive treatmentPsychosocial treatmentsRelapse preventionResidential rehabilitationAbstinence versus controlled drinkingMedicationsCurrent pharmacotherapiesPromising pharmacotherapiesNovel research targets
4 Alcoholism – outdated and non-specific term but still used widely! Alcohol Use DisorderAlcoholism – outdated and non-specific term but still used widely!Other termsAlcohol intoxication, misuse, excessive consumption, alcohol abuse (harmful use), alcohol dependence,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) versusHazardous (3-6sd) and Harmful use (7 plus SD)Models of understandingMoral perspective (free will, punishment, prevent use in community – abolition approach)versusMedical perspective (disease concept, vulnerability to alcohol, stages of addiction, harm minimization approach)PrevalenceOne year prevalence 7-10%; males 14%, females 5%Type I or A (primary) – late onset, no family historyType II or B (secondary) – early onset, family history, antisocial personality traitsCourseMisuse – variableDependence –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 studiesGenetic - linkage studies – dopamine D2 alleles,chromosome 4 [near GABA gene]Genetic – genome-wide associations – up to 40 genes that confer genetic predispositionTension - reduction hypothesisPleasure – reward theoryLearning addiction behavioursPersonality – risk seeking behaviour, antisocial traitsPsychiatric disorderLevel of consumption in community and availabilityReligious and cultural attitudes
7 Diagnosis Alcohol Use Disorder Diagnosis required for prognosis and to indicate managementEight main elements of information needed –1. Quantity, frequency, variability of use2. Psychological dependence3. Tolerance4. Withdrawal symptoms5. Loss of control over drinking6. Adverse effect on mental, physical, social function7. Continued drinking despite awareness of problems8. Duration of problems (12 months at least)
8 Alcohol abuse (DSM-IV-TR) Alcohol Use DisorderAlcohol abuse (DSM-IV-TR)Frequent (usually heavy) use of alcohol leading to –Recurrent role failureUse where physically hazardousLegal problemsContinued use despite social or interpersonal problems
9 Alcohol dependence (DSM-IV-TR) Alcohol Use DisorderAlcohol dependence (DSM-IV-TR)The presence of three or more of -ToleranceWithdrawal symptomsLoss of control over drinkingPersistent desire or failed attempts to stopBecomes the focus of activitySocial, occupational, interpersonal role failureContinued use despite awareness of problems
10 Recognition and detection Alcohol Use DisorderRecognition and detectionClinical suspicionWHO 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 othersClinical 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.
12 Detoxification – withdrawal Hospital – residential – home based Alcohol Use DisorderDetoxification – withdrawalHospital – residential – home basedSupportive medical and psychological careThiamine and B group vitamins and folateMonitor alcohol withdrawal symptomsLong 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 interventionsSimple (before dependence established)Education about alcohol problemsAdvice about safe levelsPromote and persuade safer drinking habitsMonitor and encourageIntensive (for severe abuse or established dependence)Involve partner/familySpecific goals and responsibilitiesMotivational 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 expectationsCognitive behavioural therapyRelapse prevention – cue exposureGroup therapyAlcoholics AnonymousResidential rehabilitation – establish drug-free lifestyle
14 Abstinence versus controlled drinking Controlled drinking Alcohol Use DisorderAbstinence versus controlled drinkingControlled drinkingControversialOnly suitable before dependence or physical or psychiatric complications have been established, or in patients who refuse abstinenceAbstinenceWhere dependence established or when end organ damage present
15 Central nervous system and neurotransmitter actions of alcohol Alcohol Use DisorderCentral nervous system and neurotransmitter actions of alcoholDopamine enhancement (in ventral tegmental area) involved in pleasurable effects of acute alcohol use, chronic use increases dopamine receptorsSerotonin release increased by acute alcohol use, chronic use depletes serotonin stores (via dorsal raphe nucleus) – implication for depressed mood in alcohol dependenceGamma-aminobutyric acid (GABA) inhibition increased by acute alcohol useN-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 Current Medications Disulfiram (Antabuse) Alcohol Use Disorder Used for over 50 years, but not as much recentlyDifficult to conduct blinded clinical trials – variable results in published studies, but many positiveBlocks oxidation of alcohol – acetaldehyde accumulates – flushing reaction ensuesAn abstinence model medicationDoes not diminish cravingsRequires close supervision and patient compliance over one year or moreAvoid in heart disease, pregnancy, psychosis, liver diseaseDose mg daily maintenance dose ( mg range)Should not be used for aversive conditioning – time lag and intensity of reaction is unpredictable
17 Acamprosate GABA agonist and glutamate inhibitor Alcohol Use DisorderAcamprosateGABA agonist and glutamate inhibitorSuppresses delayed sub-acute cravings by suppressing glutamatergic excitation associated with alcohol withdrawalMost research trial evidence is for maintaining abstinence (cumulative abstinence duration)Use soon after detoxification to encourage abstinenceFew contraindications, not metabolized in liverDose mg tablets, 2 tablets three times a day (weight >60kg)
18 Naltrexone Alcohol Use Disorder Opioid receptor antagonist Blocks pleasurable effects of alcohol mediated by endogenous opioids and dopamineAn ‘anti-craving’ drugSupportive evidence base of clinical trials for mid-term use (up to 12 months)Reduces relapse to heavy drinking and reduces alcohol consumptionCan be used in ‘controlled drinking’ modelsMost effective when high levels of craving, positive family history, and in patients with certain types of polymorphism of the mu-opioid receptor geneAffects narcotic pain relief (patient should carry card)Liver toxicity possible (>3x upper limit GGT)Dose - 50 mg tablets, one to two tablets dailyLong-acting IM form now available (180 and 360mg IM monthly), dose response effect on reduced heavy drinking
19 Is combination of naltrexone and acamprosate better than single use? Alcohol Use DisorderIs combination of naltrexone and acamprosate better than single use?Largest trial (COMBINE study) found no advantage of combining naltexone and acamprosateBest 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 SSRI antidepressants Alcohol Use Disorder May reverse serotonin depletion caused by chronic use of alcohol, reduce anxiety-tensionPositive animal studies but conflicting human clinical trials (sertraline, fluoxetine, citalopram)Results dependent on Type of alcohol dependence, polymorphism of 5-HT transporter gene, and genderIn summary –SSRIs have possible role in male non-depressed Type I (or A) alcohol dependenceSSRIs may worsen Type II (or B) alcohol dependenceDose – usual antidepressant doses used
21 Promising Pharmacotherapies Alcohol Use DisorderPromising PharmacotherapiesTopiramateAnticonvulsant that enhances GABA activity and antagonizes glutamate receptors reducing dopamine release in nucleus accumbens and reduces neuronal hyper-excitability and withdrawal anxietyRecent short duration (12-14 week) studies show benefit on increased abstinent days, decreased heavy drinking days, and less craving for alcoholPregnancy classification to Category D – cleft lip (do not use with pregnant women)Dose to 300mg daily
22 Baclofen Alcohol Use Disorder 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 cravingsA recent controlled trial was not supportiveCan be used in patients with liver diseaseDose – 10mg three times dailyDose response effect observed – may need 20mg three times daily
23 Dose – 0.25mg twice daily (or between 1 to 16mcg/kg twice daily) Alcohol Use DisorderOndansetronA 5-HT(3) receptor antagonist antiemetic affect the 5HT transported and down-regulates dopamine neurons reducing reward from alcoholA limited number of controlled trails of oral preparation show benefit in increasing days abstinent, reducing drinks consumed per day, and reduced alcohol cravingsResults 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 DisorderAripiprazoleNew 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 receptorsAttenuates sedative effects of alcohol, reduces drinking in impulsive alcohol abuseLimited evidence baseOne trial showed reduced heavy drinking days but only at low doses of aripiprazole (5-15mg daily)
25 Prazosin Pregabalin Alcohol Use Disorder Noradrenalin alpha-1 blocker antihypertensiveUsed in PTSD, noted to reduce drinking of alcoholDecreases alcohol consumption in alcohol preferring ratsLimited evidence baseOne controlled study using prazosin 16mg daily with medical management showed significant reduction in drinking days per weekPregabalinNeuropathic pain medication binds to calcium channelsInhibits release of excitatory neurotransmitters (glutamate, noradrenalin)Used in alcohol relapse prevention and alcohol withdrawalReduced alcohol relapse in a few studiesDose – 150 to 450mg daily
26 Future Targets of Pharmacotherapy for Alcohol Dependence Alcohol Use DisorderFuture Targets of Pharmacotherapy for Alcohol DependenceCannabinoid receptorsCannabinoid receptor CB1 agonists stimulate alcohol intakeCannabinoid receptor antagonists (rimonabant) may reduce alcohol intakeCorticotropin-Releasing Factor (CRF)Hypothalamic messenger hormoneStress response (both HPA-axis and locus coeruleus-noradrenalin system) affects susceptibility for alcohol dependence and relapseUp regulated CRF and certain CRF polymorphisms associated with at-risk drinking behaviour
27 Alcohol Use Disorder Neuropeptide Y Hypothalamic peptide neurotransmitterCNS abundant neuron modulatorNeuropeptide Y deficiency may be associated with anxiety and increased drinking behaviours and experience of alcohol withdrawalGhrelinA gut peptide involved in stimulating appetite via hypothalamus and central reward systemsAntagonism of ghrelin may reduce alcohol craving and drinkingGamma-hydroxybutyrate (GHB)All studies from ItalyDecreased relapse rate, heavy drinking, and cravings
28 NK receptor antagonism may reduce alcohol intake Alcohol Use DisorderNeurokinin receptorsSubstance P neurotransmitter involved in stress response via neurokinin-1 receptor (NK1R)Animal studies of deletion or blockade of NK1R inhibits responses to stressGenetically deficient mice have reduced preference for alcohol and increased sensitivity to sedation from alcoholNK receptor antagonism may reduce alcohol intakeA NK receptor antagonist reduced alcohol craving in one study of recently detoxified alcohol dependent subjectsCertain polymorphisms of NK1R are associated with development of alcohol dependence
29 Genetically Targeted Pharmacotherapy Alcohol Use DisorderGenetically Targeted PharmacotherapyImproved knowledge of the genetics of alcohol use disorders could lead to matching patients to specific treatmentsOpioid 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 naltrexoneSimilar phenomena are being examined with dopamine receptor gene variations or alleles
30 Alcohol Use DisorderQ1. 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 References and further reading Alcohol Use DisorderReferences and further readingSchuckit 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:
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