Alcohol Use Disorder Medications. Kavara Vaughn, MD ECHO Lecture Series September 22, 2016

Transcription

1 Alcohol Use Disorder Medications Kavara Vaughn, MD ECHO Lecture Series September 22, 2016

2 Drinking Levels De6ined At risk or heavy drinking Women > 3 drinks in a day OR > 7 drinks in a week Men > 4 drinks in a day OR > 14 drinks in a week U.S. standard drink = 14 grams WHO: -WHO standard drink = 10 grams -Max 2 drinks/day for both sexes Binge Drinking PaLern of drinking that brings BAC to 0.08 g/dl Typically 5 drinks for man and 4 drinks for woman, over 2 hours

3 Standard Drink (U.S.)

4 Number of Drinks in Different Containers Regular Beer (5% alcohol) Malt Liquor (7% alcohol) Table Wine (12% alcohol) 80-Proof Spirits (40% alcohol) 12 oz = 1 16 oz = oz = 2 40 oz = oz = oz = 2 22 oz = oz = ml (regular bolle) = oz glass ( shot ) = ml ( half-pint ) = ml ( pint or half-bolle ) = ml ( fiah ) = 17-1,000 ml ( liter ) = 22-1,750 ml ( half-gallon ) = 39

5 Associative Learning

6 Neurobiology of Alcohol Dependence Neurotransmitter Systems Reward circuits Dopamine Opiates Serotonin GABA Glutamate Stress circuits Cordcotrophin releasing factor (CRF) Neuropepdde Y

7 Neurobiology of Alcohol Dependence Reinforcement and Transition from Alcohol Use to Dependence Posidve reinforcement Rewarding sdmulus or experience increases probability of response Negadve reinforcement Probability of response increases if response alleviates aversive sdmulus Reladve contribudons change during transidon

8 Medications Naltrexone (ReVia, Vivitrol)* Acamprosate (Campral)* Disulfuram (Antabuse)* Gabapendn (Neurondn) Topiramate (Topamax) * = FDA approved

9 Study Outcomes Absdnence-based outcomes Rate of complete absdnence % days absdnent Time to first drink Heavy drinking-based outcomes Rate of heavy drinking % heavy drinking days Time to first heavy drinking day Heavy drinking importance Negadve health outcomes Trajectory = condnued reducdon, may achieve absdnence Increased self-efficacy Potendal value of trajectory analysis vs tradidonal summary outcomes

10 Naltrexone (ReVia, Vivitrol) MOA Compeddve antagonist at mu opioid receptor Reduces reinforcing properdes of alcohol Clinical effect Reduces posidve subjecdve effects of alcohol Reduces alcohol-related cue reacdvity Reduces severity of lapses Reduces craving -Primary efficacy = reduced heavy drinking -Also improves absdnence-based outcomes

11 Naltrexone Adverse Reactions Nausea/vomidng Decreased appedte Sedadon Dizziness Muscle cramps Insomnia Injecdon site reacdons Hepatotoxicity Depression Precipitated withdrawal Potendal for fatal opioid overdose

12 Vivitrol Warnings and Precautions

13 Vivitrol Blockade Reversal for Pain Management

14 Vivitrol Safety Card

15 Naltrexone Dosing Oral Naltrexone Usual dose = 50 mg daily Max dose = 150 mg daily Dosing: 50 mg, ½ tab daily x 7 days, then 1 tab daily Vivitrol 380 mg IM depot injecdon every 4 weeks (alt gluteal muscles) May give PO naltrexone for period of dme to assess tolerability Generally avoid if AST/ALT > 5 dmes upper limit normal Reanalysis of negadve studies showed that high compliance with PO naltrexone is necessary for efficacy (>80-90% of doses)

16 Naltrexone Initiation Checklist Must be absdnent from opioids before inidadon Short-acdng: 7-10 days Long-acdng (methadone, buprenorphine): 2 weeks Labs: liver enzymes/funcdon tests, renal funcdon tests, pregnancy test, urine drug screen

17 Naltrexone Patient Education Precipitated withdrawal Risk of fatal opioid overdose Hepatotoxicity signs/symptoms Blockade as it relates to pain control Necessity of lab monitoring

18 Naltrexone Lab Monitoring Liver enzymes/funcdon tests Baseline 1, 3, 6 months, then yearly thereaaer

19 Acamprosate MOA Modulates GABA/glutamate dysreguladon characterisdc of chronic alcohol use and withdrawal Clinical effect ALenuates protracted withdrawal symptoms Reduces cue-induced withdrawal Decreases cravings -Primary efficacy = absdnence-based outcomes -Some evidence of reduced drinking upon relapse

20 Acamprosate Dosing/Adverse Reactions/Monitoring Dosing: 333 mg, 2 tabs TID (low bioavailability) Renal disease Moderate: 333 mg TID Severe: contraindicated Diarrhea = most common adverse effect (may persist) Check renal funcdon at baseline, then every 6-12 months

21 Disulfuram (Antabuse) MOA Inhibits aldehyde dehydrogenase Elevated acetaldehyde à disulfuram ethanol reacdon Efficacy Absdnence-based outcomes Supervised dosing = more efficacious

22 Disulfuram-Ethanol Reaction

23 Disulfuram Contraindications & Cautions Contraindicadons Significant cognidve disorder Severe cardiac disease (reladve) Allergies: thiuram derivadves used in pesdcides and rubber vulcanizadon, sulfur, nickel Caudons Severe impulsivity Severe liver disease Epilepsy, cerebral damage Drug/exposure interacdons Metronidazole, paraldehyde, ethylene dibromide or its vapors (paint, paint thinner, varnish, shellac)

24 Disulfuram Adverse Reactions Rash/acne Mild drowsiness Fadgue Headache Metallic or garlic aaertaste Psychosis Opdc neurids Peripheral neurids, polyneurids, peripheral neuropathy Hepatotoxicity

25 Disulfuram Dosing Dosing Dose range: mg daily Usual dose: 250 mg daily If able to drink on 250 mg, increase to 500 mg ~ 24 hours absdnence before inidate (inpadent) MUST RECEIVE DETOX FIRST IF PHYSIOLOGIC DEPENDENCE Generally avoid if AST/ALT > 5 dmes upper limit normal Supervised ingesdon Increases compliance Recommended in guidelines Consider use if high-risk event, significant stressors, decompensadon

26 Disulfuram Initiation Checklist Appropriate padent is commiled to absdnence and has solid treatment plan/follow-up (and ideally has good support) Consider/review reladve contraindicadons with padent Be certain padent undergoes detox first if needed Labs: liver enzymes/funcdon tests, renal funcdon tests, pregnancy test

27 Disulfuram Patient Education Disulfuram ethanol reacdon and products/meds to avoid Symptoms of hepatotoxicity, neurids Advise to alert provider if change in health (pardcularly cardiac disease, cognidve disorder, liver disease) Necessity of lab monitoring

28 Disulfuram Lab Monitoring Liver enzymes/funcdon tests Baseline days aaer inidadon Monthly x 6 months Every three months thereaaer

29 Gabapentin MOA: GABA-moduladng agent Normalizes stress-induced GABA acdvadon in extended amygdala associated with alcohol dependence and negadve reinforcement Clinical effect Reduces protracted withdrawal symptoms and cravings Primary efficacy = reduced heavy drinking Studies Gabapen'n For Treatment of Alcohol Dependence: A RCT (JAMA IM, 2014)

30 Gabapentin Dose Titration (300 mg capsules) Morning ARernoon Evening Day Day Day 3 (900 mg) Day Day Day 6 (1,800 mg)* Rx #1: Rx #2: Neurondn 300 mg Neurondn 600 mg Take as directed 1 cap PO TID #21 #90 -No dose adjustment for hepadc impairment -Reduce dose for renal impairment * = Rx #2

31 Topiramate MOA Facilitates GABA acdvity (GABA-A receptor inhibidon) Antagonizes glutamate acdvity (AMPA and kainate receptors) Reduces cordcomesolimbic dopamine release Decreases alcohol reinforcement Clinical effect Reduces posidve subjecdve effect of alcohol Reduces craving Efficacy Reduced heavy drinking, increased absdnence Studies Muldple RCTs (JAMA, 2007) Meta-analysis of 7 RCTs (JCER, 2014) GRIK1 RCT (AJP, 2014) GRIK1 polymorphism moderates response (Genomind)

32 Topiramate Dose Titration Week Morning Night Total Daily Dose 1 N/A 25 mg 25 mg 2 25 mg 25 mg 50 mg 3 50 mg 50 mg 100 mg 4 75 mg 75 mg 150 mg 5* 100 mg 100 mg 200 mg Rx #1: Rx #2: Topiramate 25 mg Topiramate 100 mg Take as directed 1 tab PO BID #91 #60 -Mean Study Dose: ~170 mg -90% compliance Reduce dose for renal impairment * = Rx #2

33 Biomarkers of Alcohol Use Biomarker AST, ALT GGT MCV Carbohydrate-Deficient Transferrin (CDT) Ethyl Glucuronide (EtG), Ethyl Sulfate (EtS) Phosphaddyl Ethanol (PEth) Type of Drinking Characterized Unknown but heavy and lasdng several weeks At least 5 drinks/day for several weeks Unknown but heavy and lasdng several months At least 5 drinks/day for ~2 weeks May detect single drink 3 or 4 drinks/day for several days SensiWvity/Specificity Moderate/Moderate (screen for heavy use) Moderate/Moderate (screen for heavy use) Moderate/Moderate (screen for heavy use) Moderate/High (screen for heavy use) *FDA approved High/High (as relapse indicator) High/High (binge drinking?)

34 Window of Assessment for Alcohol Biomarkers

35 Alcohol Biomarkers By Particular Use Biomarker Screening for Heavy Drinking IdenWfy Relapse, Especially to Heavy Drinking Monitoring AbsWnence Time to Return to Normal With AbsWnence CDT 2-3 weeks AST/ALT 2-4 weeks GGT 2-4 weeks MCV Up to several months PEth 2-4 weeks EtG, EtS 1-3 days