WISAM 2018 Annual Conference Sept. 27‐28, 2018
1
Pharmacotherapies and Associated Genetics for Alcohol Use Disorders
Jonathan Covault, MD, PhDUConn Alcohol Research Center
Disclosures
• No financial conflict disclosures to declare
• No pharmaceutical company research support
• Not on any speaker bureaus
• I will discuss off‐label use of medications for alcohol use disorder (e.g. topiramate, gabapentin, zonisamide, dutasteride)
• NIAAA has supported clinical research at the UConn Alcohol Research Center for past 40 years including study of naltrexone, depot naltrexone, topiramate, zonisamide and most recently dutasteride.– Victor Hesselbrock ‐ Center Director
– Henry Kranzler, Albert Arias, Jonathan Covault ‐ clinical trail investigators
2
WISAM 2018 Annual Conference Sept. 27‐28, 2018
2
Learning Objectives
• Review evidence supporting the use of FDA approved medications for alcohol use disorder (AUD).
• Identify at least two medications approved for other conditions which for which RCTs support their use in treatment of AUD.
• Identify potential benefits of genetically informed treatment matching.
3
Sobering Measures of Alcohol Use Disorder 70% of alcohol in US is consumed by 10% of the population
• Despite evidence supporting medications for AD, < 10% of Alcohol Dependent patients are prescribed medications to prevent relapse to heavy drinking 4
WISAM 2018 Annual Conference Sept. 27‐28, 2018
3
Hazardous Drinking -
• NIAAA defines hazardous drinking as:
– more than 14 drinks in a typical week or 5 or more drinks on any day (HDD) for men <65yo:
– more than 7 drinks in a typical week or 4 or more drinks on any day (HDD) for women or men >65yo:
• Among those drinking more than the daily and weekly limit – 50% have Alcohol Dependence
* US drink = 14 gr ethanol
12 oz beer, 5 oz wine, 1.5 oz spirits
5
Part I –Data supporting use of FDA approved medications for alcohol dependence
6
WISAM 2018 Annual Conference Sept. 27‐28, 2018
4
FDA Approved Medications for Treatment of Alcohol Dependence
• Disulfiram (Antabuse™): 1949
• Naltrexone (Revia™): 1994
• Acamprosate (Campral™): 2004
• Long‐Acting Naltrexone (Vivitrol™): 2006
It’s statistically significant – But does the difference matter?- Common effect size measures
• Cohen’s d= group 1 mean – group 2 mean / s.d. of means– d=0.2 small effect– d=0.5 medium effect– d=0.8 large effect
• Meta‐analysis is a statistical analysis that combines the results of multiple scientific studies to generate a more representative comparison of treatments. Pooling effect sizes from individual studies.
• Number needed to treat for 1 additional responderNNT = 100 / % responders group1‐group2
– * NNT for typical antidepressant = 7‐9
WISAM 2018 Annual Conference Sept. 27‐28, 2018
5
Disulfiram (Antabuse™ 1949)
• Irreversible inhibitor of acetaldehyde dehyrogenase• Slows the breakdown of acetaldehyde, a noxious
metabolite of alcohol
Ethanol Acetaldehyde Acetate
• Disulfiram is an alcohol-sensitizing medication that results in unpleasant sensations if alcohol is used - flushing, sweating, nausea, vomiting, ↓BP and HR
• Efficacy is based on the expectation of highly unpleasant effects if alcohol consumed and requires patients learn and use coping skills to remain abstinent.
l
disulfiram
• In double blind study designs placebo subjects would be expected to respond equivalently to active disulfiram– Meta-analysis clearly demonstrates this
• 7 blinded studies d = 0.01 ns• 17 un-blinded studies d = 0.7 (medium to large effect size)
– Disulfiram should work best with observed / supervised dosing• 5 no supervision un-blinded studies d = 0.26 (small effect)• 12 supervised medication use un-blinded studies d = 0.82 (large effect
size)
• In head to head trials comparing disulfiram to naltrexone or acamprosate, disulfiram was more effective in maintaining abstinence in open label supervised medication use studies – naltrexone d=0.8 (7 studies)– acamprosate d=0.8 (3 studies)
Skinner et al., 2014 Plos One, V9(2) e87366
WISAM 2018 Annual Conference Sept. 27‐28, 2018
6
FDA Approved Medications for Treatment of Alcohol Dependence
www.zenamed.co.uk
Alcohol and Alcoholism, Volume 50, Issue 2, 1 March 2015, Pages 255–256,
Disulfiram – FDA label “management of selected chronic alcohol patients who want to remain in a state of enforced sobriety”
• Irreversible inhibitor of acetaldehyde reductase very unpleasant reaction including flushing, sweating, nausea, ↓BP and HR with alcohol.
• Concomitant use of alcohol or alcohol‐containing preparations; coronary artery disease; severe myocardial disease
• Hepatic cirrhosis or insufficiency; cerebrovascular disease; psychoses (current or history);
• Disulfiram‐alcohol reaction, Rare‐hepatotoxicity, optic neuritis, peripheral neuropathy, psychotic reactions.
• Metallic after‐taste; drowsiness.
• 250 – 500 mg / day; Warn patient not to take disulfiram for at least 12 hours after drinking and that a disulfiram‐alcohol reaction can occur up to 2 weeks after the last dose; recommend pt carry emergency wallet card
• Best with supervised use or highly motivated patient
Action
Contraindications
Precautions
Serious adverse reactions
Common side effects
Usual dosage
WISAM 2018 Annual Conference Sept. 27‐28, 2018
7
Naltrexone (Revia™ 1994)
• Non-selective antagonist of mu, delta, and kappa opioid receptors
• Naltrexone was initially approved in 1984 for treatment of opioid dependence as it blocks the effect of heroin or opioid pain pills
• Naltrexone blocks endogenous opioids associated with both the expectation of drinking and with alcohol use that enhance dopamine release in the nucleus accumbensreduced craving
• Very limited preclinical studies in 1980s led to pivotal clinical trials of naltrexone
– low priming doses of morphine increase drinking in rodents
– opiate receptor antagonists reduce stress induced drinking in rodents
WISAM 2018 Annual Conference Sept. 27‐28, 2018
8
• UPenn 12 wk naltrexone 50 mg vs. placebo
– 70 recently abstinent male veterans entering an outpatient day treatment alcohol rehab program
• Yale / UConn 12 wk naltrexone 50 mg vs. placebo
– 104 treatment seeking recently abstinent outpatients
– Combined with weekly individualsupportive or coping skills/relapse prevention psychotherapy
• Outcomes similar for both– Naltrexone significantly reduced
relapse to heavy drinking (23% vs. 54% and 40% vs 80%), particularly for those with a slip.
– No main effect of medication on increasing abstinence
• Among placebo groups, 90% of those who had slip progressed to heavy drinking vs. 50% for naltrexone subject groups
Efficacy of Naltrexone in AD – meta-analysis
Meta-analysis of 14 placebo controlled studies involving >2,000 patients:
– Non-significant effect of naltrexone on increasing abstinence rate [OR: 1.26 (0.97,1.64), P=0.08].
– Clear effect of naltrexone on decreasing risk of relapse to heavy drinking [OR: 0.62 (0.52, 0.75), P<0.001]
– Small effect size d=0.2 for reducing heavy drinking– NNT= 9 in order to prevent relapse to heavy
drinking in 1 individual
Bouza et al., Addiction, 2004; Maisel et al., Addiction 2013 108:275
WISAM 2018 Annual Conference Sept. 27‐28, 2018
9
Naltrexone – reduction of heavy drinking
Maisel et al., Addiction 2013 108:275
Naltrexone-FDA approved for treatment of AD and opioid dependence
• Blocks opioid receptors. Thought to reduce dopamine release associated with both the expectation of alcohol and drinking.
• Recent opioid use; anticipated need for opioid analgesics; acute hepatitis or liver failure
• Hepatic disease; renal impairment
• Acute opioid withdrawal if dependent on opioids;
• Rarely ‐ hepatotoxicity at higher than recommended doses
• Black Box warning has been removed from label
• Nausea, decreased appetite, fatigue, insomnia
• 50‐100 mg daily (oral); 380 mg monthly IM (gluteus)
• IM naltrexone (Vivitrol™) is a great choice for patients with co-morbid opioid and alcohol dependence
Action
Contraindications
Precautions
Serious adverse reactions
Common side effects
Usual dosage
WISAM 2018 Annual Conference Sept. 27‐28, 2018
10
Acamprosate (Campral™) 2004
• Pharmacologic effects of acamprosate are not fully understood.
• Acamprosate is a NMDA glutamate-receptor antagonist and an allosteric positive modulator of GABAA receptors
– the normal balance between these systems is altered by chronic drinking.
– In animals trained to drink alcohol, acamprosate reduces withdrawal-induced drinking.
19
Efficacy of Acamprosate (Campral™)
• Meta analysis of 11 European placebo controlled clinical trials (> 3,300 patients; Bouza 2004):Significantly improved abstinence rates following detoxification OR = 1.88 (1.57, 2.25), P < 0.001], but not reduction of heavy drinking
• In US studies acamprosate effects were limited / absent
– large multi-site US studies showed no benefit vs. placebo for entire sample, but with possible benefit for subjects having a goal of abstinence
– European studies recruited subjects from detoxification centers with goal of abstinence.
– US studies recruited from ambulatory populations
• Acamprosate may be more helpful for patients with physical dependence, anxiety and a goal to stop drinking;
WISAM 2018 Annual Conference Sept. 27‐28, 2018
11
2013 Maisel et al; Addiction; Meta‐analysis naltrexone and acamprosate for AD
Meta-analysis of Placebo controlled RCT of Acamprosate for Alcohol Use Disorder
Small to medium effect size for abstinence composite(abstinence rate, % days abstinent and time to first drink)
US study
Acamprosate -FDA approved for maintenance of abstinence in patients with AD
• Effects on glutamate‐NMDA activity; GABA positive modulator, ethanol related effects unknown. May reduce symptoms of protracted withdrawal ‐insomnia, anxiety, restlessness, dysphoria.
• Severe renal impairment (eGFR ≤ 30 mL/min).
• Moderate renal impairment (1/2 dose for eGFRbetween 30 and 50 mL/min); depression or suicidal ideation.
• None, no drug interactions, no hepatoxicity, renal excretion
• Diarrhea.
• 666 mg TID
Action
Contraindications
Precautions
Serious adverse reactions
Common side effects
Usual dosage
WISAM 2018 Annual Conference Sept. 27‐28, 2018
12
23
Are combinations of medications and behavioral treatment more effective than either alone?
11 US academic sites randomized 1,383 AD subjects
(outpatient recruitment, sober for 4 days) to nine treatments arms
9 treatment conditions – 150 patients each
Medical management (MM) MM + Combined Behavioral Intervention (CBI)(encourage pill use & abstinence) (integrates CBT, 12‐step, Motivational enhancement)
placebo capsules placebo capsulesnaltrexone naltrexoneacamprosate acamprosatenaltrexone + acamprosate naltrexone + acamprosate
CBI alone (no pills / no medical management)
24
WISAM 2018 Annual Conference Sept. 27‐28, 2018
13
Outcomes:Patients receiving medical management with naltrexone, behavioral counseling, or both had fewer heavy drinking days.
‐ NNT for good clinical outcome was 7 for naltrexone; naltrexone + CBI or CBI alone
No additional benefit from combining naltrexone with acamprosate.
Acamprosate showed no evidence of efficacy, with or without behavioral counseling
This was first study to suggest that naltrexone with only medical management may be effective in non‐specialist (eg PCP) settings, potentially serving AD patients who might otherwise not receive medication treatment.
25
Part II –Emerging medications for AUD
26
WISAM 2018 Annual Conference Sept. 27‐28, 2018
14
Partial list of medications approved to treat other disorders that have been evaluated for AD
• topiramate (Topamax™)• gabapentin (Neurontin™)• zonisamide (Zonegran™)• dutasteride (Avodart™)
• baclofen (Lioresal ™)• ondansetron (Zofran™)• Selective Serotonin Reuptake Inhibitors (SSRIs)
These medication are not FDA‐approved for treatment of alcohol use disorders
Pharmacology of topiramate (Topamax™)
• Topiramate is FDA approved for migraine prophylaxis, epilepsy, and weight loss (in combination with phentermine)
• Topiramate antagonizes AMPA and kainate subtypes of glutamate receptors and facilitates GABAA receptor activity. These effects would counter the effects of chronic alcohol on glutamate and GABA signaling.
– Other actions include inhibition of L-type Ca+ channels and weak inhibition of carbonic anhydrase type CA-II and CA-IV.
• Topiramate is not FDA approved for treatment of alcohol dependence
WISAM 2018 Annual Conference Sept. 27‐28, 2018
15
2014 Blogett et al; Alcoholism Clin Exp Res; Meta‐analysis Topiramate for AD
Meta-analysis of Placebo controlled RCT of Topiramate for Alcohol Use Disorder
Moderate effect size for abstinence and reduction of heavy drinkingNNT = 6 (7 studies involving 1,125 participants)
Topiramate -Off label use for AUD
• Antagonizes AMPA and kainate glutamate receptors, facilitates GABA(A) receptor activity. Clinically patients report less interest in alcohol and less alcohol craving.
• Renal calculi,
• Slow dose titration by 50 mg / week to avoid side effects.
• Rare‐secondary angle closure glaucoma.
• Paresthesia, altered taste, weight loss, fatigue, mental slowing and reduction in verbal fluency memory (dose related and reversible)
• For AD 100‐150 mg BID (begin 25 mg BID). Once daily sustained release formulation now available = Qudexy XR and Troxendi XR;
• FDA‐approved dosage for migraine headaches is 50 mg BID and for seizure disorder 200 mg BID
Action
Contraindications
Precautions
Serious adverse reactions
Common side effects
Usual dosage
WISAM 2018 Annual Conference Sept. 27‐28, 2018
16
Gabapentin (Neurontin™)
• Gabapentin’s anticonvulsant, analgesic, and anxiolytic effects are via inhibition of α2-δ-subunit containing voltage dependent calcium channels (VDCCs) and subsequent effects on neurotransmitter release.
• Despite it’s name, gabapentin does not activate GABA receptors or effect GABA re-uptake, synthesis or metabolism
• FDA-approved as adjunct for treatment of partial seizures and for post-herpetic neuralgia
• Off-label evidence supports use as first line treatment for diabetic neuropathy.
• Well tolerated, no hepatic interactions
• Gabapentin is not FDA approved for treatment of alcohol withdrawal or dependence
31
• Single‐site (Scripps – La Jolla CA), 12‐week study with 150 patients randomly assigned to treatment with
placebo, or gabapentin 900 or 1800 mg/day dosed TID
• Alcohol dependent outpatients abstinent for 3‐30 days prior to randomization
• Results – gabapentin reduced relapse to heavy drinking, increased abstinence rates, and improved sleep quality.
2014 JAMA Internal Med 174: 70‐77
WISAM 2018 Annual Conference Sept. 27‐28, 2018
17
• Linear gabapentin dose effects on HDD, abstinence, alcohol craving, quality of sleep and mood
Mason et al., 2014 JAMA Internal Med 174(1): 70‐77
• Scheduled or symptom triggered dosing of benzodiazepines has long been the standard of care for the management of alcohol withdrawal symptoms.
– Benzodiazepines can be challenging to use for outpatient detoxification due to potentially serious interactions with alcohol and opiates. For inpatients they have risk of delirium and falls particularly in medically ill. High doses can require prolonged taper.
• Gabapentin, in comparison to benzodiazepines, is relatively safe in combination with alcohol and opiates.– Renal elimination, low binding to plasma proteins, no hepatic or
hematologic effects, non‐scheduled medication– In contrast to gabapentin, other anticonvulsants examined for
management of AWS have more significant potential for medical side effects
Gabapentin for Alcohol Withdrawal
WISAM 2018 Annual Conference Sept. 27‐28, 2018
18
Myrick et al., Alcoholism: Clinical Exper Res 2009 33: 1582‐1588
• Single‐site (MUSC) ‐ 100 treatment seeking outpatients. • Baseline Clinical Institute Withdrawal Assessment for Alcohol‐Revised
(CIWA‐AR) >10 • Randomly assigned to 3 groups:
– Lorazepam 2 mg TID for 3 days then 2 mg BID day 4– Gabapentin 300 mg TID for 3 days then 300 mg BID day 4– Gabapentin 400 mg TID for 3 days then 400 mg BID day 4
Outcomes:• The 1200 mg / day gabapentin group had the lowest CIWA‐AR scores
both during detox and for the 3 days following detox
• Lorazepam treated subjects had higher alcohol craving and were more likely to drink alcohol during detox (25% vs. 8% for gabapentin).
Leung et al., Psychosomatics 2018 PMID: 29735241
• Mayo Clinic in Rochester has adopted a gabapentin based alcohol detoxification protocol on medical services beginning in 2015.
• Gabapentin dose schedule for management of AWS: – Gabapentin 900 mg TID for 4 days then, 600 mg TID for 3 days then 300 mg
TID for 2 days (9 day taper)
– For renal impairment (eGFR 30‐60 cc/min) dosage reduced to 600, 300 and 100 mg
– Adjunctive treatment with clonidine or valproate but not benzodiazepines are part of protocol
• A retrospective chart review of 77 hospitalized patients treated with the gabapentin detox protocol vs. 77 matched cases using former lorazepam detox protocol was recently reported.
WISAM 2018 Annual Conference Sept. 27‐28, 2018
19
Leung et al., Psychosomatics 2018 PMID: 29735241
• Gabapentin protocol patients had lower CIWA‐AR scores on days 2 and 3 of detox.
• No difference in length of stay for gabapentin vs. lorazepam detox (4.2 days for gabapentin vs. 5 days for lorazepam)
Outcomes:
• No gabapentin protocol patients required transfer to critical care / ICU levels of care.
Gabapentin - FDA approved for neuropathic pain and as adjunctive Tx for epilepsy. Not approved for AUD
Binds to the 2‐ subunit of the voltage‐activated Ca+2‐channel modulating neurotransmitter release.
• Severe renal impairment (eGFR ≤ 30 mL/min).
• Moderate renal impairment (half dose for eGFR 30 ‐ 50 mL/min);
• Pros: No drug interactions, renal excretion, no hepatic effects;
• Suicidal ideation. Rare: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multi‐organ hypersensitivity
• Dizziness, sedation, peripheral edema
• 600‐900 mg TID with taper for management alcohol withdrawal symptoms; 600 mg TID for relapse prevention;
Action
Contraindications
Precautions
Serious adverse reactions
Common side effects
Dosage
WISAM 2018 Annual Conference Sept. 27‐28, 2018
20
• Zonisamide is a broad‐spectrum anti‐seizure medication FDA approved for adjunctive treatment of partial seizures
• Zonisamide has overlapping pharmacology with topiramate
• Compared with topiramate, zonisamide has reduced frequencies of – Paresthesia, metabolic acidosis and mental slowing
• Two small RCT’s reported medium effect size for reducing heavy drinking– In conjunction with Dr. Arias at Virginia Commonwealth UConn
is one 3 sites for a larger RCT of zonisamide for AD
Zonisamide (Zonegran™) not FDA approved for AUD
Arias et al., J Clin Psychopharmacol. (2010). Knapp et al. J Clin Psychopharmacol (2015)
Benzodiazepines, Barbiturates and Neuroactive steroids are positive allosteric modulators of GABAA
receptors
The effect of GABA is increased by these agents without directly activating the receptor
40
Alcohol and neuroactive steroidsGABAA receptor – multiple allosteric modulators
Reddy, D.S., Woodward, R NeuroscienceVolume 138, Issue 3, 27 March 2006, Pages 911–920
WISAM 2018 Annual Conference Sept. 27‐28, 2018
21
Chemical structures of several endogenous GABAergicneuroactive steroids
41
Progesterone
TestosteroneDeoxycorticosterone
5a-DHP5a-DHT
5a-DHDOC
5R
3HSD
Neuroactive steroids are thought to mediate some of alcohol’s effects
Dutasteride, FDA approved to treat Benign Prostatic Hypertrophy inhibits 5AR in both the brain and peripherally, is being examined as a
potential treatment for heavy drinking.
42
Progesterone
TestosteroneDeoxycorticosterone
5a-DHP5a-DHT
5a-DHDOC
5R
3HSD
dutasteride
Neuroactive steroids are thought to mediate some of alcohol’s effects
WISAM 2018 Annual Conference Sept. 27‐28, 2018
22
Covault, Tennen et al. 2018 unpublished
Dutasteride treatment to reduce drinking in men
-Dutasteride treated subjects had greater reduction in the number of drinks per week and HDD /wk compared with placebo (p<0.001 and p=0.001, respectively),
d=0.4 for wks 9-12
- During the last 4 weeks of treatment 33% of subjects in the dutasteride arm had no HDDs compared with 11% of pbo-treated subjects (p=0.02; OR=4.0). NNT = 5
A sample of 109 non‐smoking male heavy drinkers were randomized to placebo or 1 mg / day dutasteride for 12 weeks.
Dutasteride is not FDA approved for this indication
Covault, Tennen et al. 2018 unpublished
Dutasteride was particularly helpful for patients reportingabove average levels of baseline anxiety
Large treatment effect size of d=0.7 for higher anxiety group of patients
WISAM 2018 Annual Conference Sept. 27‐28, 2018
23
Part III –Pharmacogenetic studies in AUD
45
Pharmacogenetics and personalized medicine
• Treatment responses to existing pharmacotherapies are in the small to medium range. Yet, some patients respond very well to a given medication while others have no benefit. We need reliable predictors to better match treatment to patients.
• Genetic polymorphisms may identify subjects more likely to respond to a given medication – Candidate genes include those encoding protein targets for medication
(naltrexone, topiramate, odansetron), medication pathways or associated with risk of AUD (topiramate, acamprosate).
• Promising findings have been reported for four medications– naltrexone
– topiramate
– acamprosate
– odansetron
Batki and Pennington (2014) Am J Psychiatry 171(4):391
WISAM 2018 Annual Conference Sept. 27‐28, 2018
24
Naltrexone
• Antagonist at ‐opiate receptors (encoded by OPRM1 gene)
– The OPRM1 gene single nucleotide polymorphism (SNP) A118G generates an amino acid substitution – Asparagine 40 Aspartic acid 40 in the extracellular domain of ‐opiate receptor protein (28% of Caucasians are Asp40 carriers)
– A physiologic impact of the Asp40 variant can be demonstrated by IV administration of the ‐opiate receptor antagonist naloxone to block tonic inhibition of HPA activation by endogenous endorphin ‐opiate receptor agonists
• Naloxone triggers a greater release of ACTH and cortisol in Asp40 carriers
naltrexone morphine
Endogenous -opiate receptor agonists tonicallyinhibit HPA axis activation.
– IV administration of naloxone triggers a time limited release of ACTH and cortisol
• ‐opiate receptor Asp40 carriers have enhanced HPA axis response following naloxone infusion indicating more robust tonic inhibition in Asp40 carriers
IV‐naloxone /Pbo
Hernandez et al 2003, 2007; Wand et al 2002;
WISAM 2018 Annual Conference Sept. 27‐28, 2018
25
Naltrexone treatment and moderation by OPRM1 A118G genotype (Asn40Asp)
• Two naltrexone (100 mg/day) treatment studies (Oslin et al 2003 and Anton et al 2008 Combine) reported reduced drinking among ‐opioid receptor Asp40 carriers compared with Asn/Asn homozygotes.
• Other studies have failed to find this effect (e.g. Gelernter et al 2007; although this study did not find a main effect of medication).
• A meta‐analysis including results from 6 studies suggests a 2‐fold reduction in odds of relapse for Asp‐carriers (Chamorro et al 2012)
Topiramate – GluK1 subunit gene GRIK1 as pharmacogenetic candidate gene
– Our group tested several variants in glutamate receptors for association with AD and found that a GRIK1 gene polymorphism (rs28332407 C-allele) was associated with alcohol dependence (Kranzler et al., 2009)
– Topiramate is an antagonist for kainate subtype of glutamate receptors containing the GluK1-subunit protein encoded by the GRIK1 gene
http://www.bristol.ac.uk/synaptic/receptors/kar/
WISAM 2018 Annual Conference Sept. 27‐28, 2018
26
• Two‐site (UCHC / U Penn), 12‐week study
• 138 patients randomly assigned to treatment with placebo or 200 mgtopiramate (122 Caucasians)
• Alcohol dependent outpatients abstinent for 3‐30 days prior to randomization.
• Genotype measured retrospectively at the AD‐risk allele rs26332407 in the GRIK1gene
Topiramate Treatment for Heavy Drinkers:Moderation by a GRIK1 Polymorphism
Am J Psychiatry 2014; 171:445‐452
Kranzler, Covault, et al; Am J Psychiatry 2014; 171:445‐452
a Significant main effect of medication (p<0.001) and interaction of medication group‐by‐treatment week (p<0.0001). SEM is represented.
At end of Treatment, placebo subject 5x more likely to experience a heavy drinking day.
N=71
N=67
Topiramate Treatment for Heavy Drinkers:Moderation by a GRIK1 Polymorphism
WISAM 2018 Annual Conference Sept. 27‐28, 2018
27
Kranzler, Covault, et al; Am J Psychiatry 2014; 171:445‐452
a Significant medication group‐by‐genotype interaction (p=0.004). SEM is represented.
Topiramate response vs. placebo was only observed among CC subjects (42% of sample)For CC subjects NNT = 2.3 (vs. 5.3 for entire sample)
N=51 N=53 N=18
Topiramate Treatment for Heavy Drinkers:Moderation by a GRIK1 Polymorphism
WISAM 2018 Annual Conference Sept. 27‐28, 2018
28
Covault, Tennen et al. 2018 unpublished
a Significant 3‐way interaction of medication group‐by‐anxiety‐by‐FKBP5 genotype (p<0.001). SEM is represented.
Dutasteride treatment for reducing drinking:The greatest efficacy was for anxious drinkers with
the stress sensitive FKBP5 genotype
AUD medication effect size summary from meta-analysis
• Reduction of heavy drinking– Topiramate d=0.4 NNT=6
– Gabapentin (1 study) NNT=5
– Naltrexone d=0.20 NNT=9
– Acamprosate ns
• Abstinence– Disulfiram d=0.8 supervised;
d=0.26 unsupervised use
– Topiramate d=0.46 NNT=5
– Acamprosate d=0.36 NNT=8
– Gabapentin (1 study) NNT=8
– Naltrexone d=0.12 NNT=20
* NNT for typical antidepressant = 7‐9
d=0.2 small; d=0.5 medium; d=0.8 large effect
2014 Skinner et al., Plos One, V9(2) e87366; 2014 Blogett et al; Alcoholism Clin Exp Res; 2013 Maisel et al; Addiction
WISAM 2018 Annual Conference Sept. 27‐28, 2018
29
Medication Recommendation SummaryEvidence for use of disulfiram in relapse prevention is highly dependent on
medication adherence. With supervised dosing it can be very effective.
Naltrexone reduces the probability of relapse and the amount of heavy drinking following a slip by blocking craving / reward feedback mechanisms. Effect size small. Depot formulation available. It may work best for those with reward > relief motivations to drink.
Acamprosate has some benefit for increasing the probability of abstinence when initiated at time of detox, but not relapse to heavy drinking. Addition of acamprosate to naltrexone provides no added benefit.
Topiramate and gabapentin are off label medications with strong and moderate support respectively for use in AUD. Topiramate requires titration but has a medium effect size for both increasing abstinence and reducing heavy drinking. Gabapentin is relatively easy to dose and generally well tolerated. Gabapentin can be useful both for relapse prevention as well as inpatient and outpatient detox.
Pharmacogenetic guidance for medication choice remains in early stages, but in the future may contribute to personalized treatment.
57APA practice guideline for AUD – Reus et al., 2018 Am J Psychiatry 175:86‐90VA practice guideline –www.healthquality.va.gov/guidelines/MH/sud/VADoDSUDCPGFinal1.pdf
Thanks for your attention.