psychiatry clinical reviews...bhanu prakash kolla md, mrcpsych october 6-8, 2016 intercontinental...

Mayo School of Continuous Professional Development

Psychiatry Clinical Reviews Treatment Updates in Substance Use Disorders

Bhanu Prakash Kolla MD, MRCPsych October 6-8, 2016

Intercontinental Chicago Magnificent Mile Chicago, IL

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Disclosure

Relevant Financial Relationships

None

Off-Label/Investigational Uses

Off-label use of gabapentin, varenicline, baclofen in AUD

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Outline/Objectives

• Understand current pharmacotherapy for alcohol use disorders

• Discuss potential emerging treatment options

• Recognize emerging evidence regarding other off-label treatment options

• Develop appropriate treatment selection for patients with AUD

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Substance Use Disorders

• Taken in larger quantities/ longer periods

• Desire/unsuccessful efforts to cut down

• Time spent obtaining/using

• Failure to fulfill role obligations

• Use despite social/interpersonal problems

• Recurrent use in physically hazardous situations

• Important social, occupational/recreational activities given up

• Use despite physical/psychological problems

• Tolerance

• Withdrawal

• Craving

Mild: 2-3

Moderate: 4-5

Severe: >6

DSM-5

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Alcohol Use Disorders

• Prevalence of 12.4% of adult men and 4.9% of women in the US

• 3.8% of global deaths are attributable to alcohol

• Pharmacotherapy reserved for moderate/severe use disorders

DSM-5

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Who to Treat-pharmacotherapy

• Some degree of motivation to address drinking (contemplators)

• No medical contraindication

• Moderate/severe AUD

• Not a choice between psychological vs medical treatment

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Nalmefene

Varenicline Gabapentin

Baclofen

Naltrexone

Acamprosate

Disulfiram

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Nalmefene

• Opioid antagonist (mu and delta) with partial agonist action on kappa receptors

• Has European Medicines Agency (EMA) approval for alcohol dependence to help reduce alcohol consumption in adults who consume >60 g of alcohol per day (for men) or >40 g per day (for women)

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Nalmefene

• It has a unique indication and this is based on pooled secondary analyses data

• Also, this medication was studied in an as needed situation – days patients thought they were at high risk of drinking

• The main adverse effects seem to be dizziness and insomnia

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Palpacuer et al PloS 2015

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Nalmefene

• This meta-analyses of 2,567 randomized participants in five RCTs indicates some benefit with a slight reduction in HDD and total alcohol consumption

• About 1.65 fewer heavy drinking days per month

• Sensitivity analyses did not show benefit over placebo

• No head-to-head comparisons with naltrexone

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Naltrexone vs. Nalmefene

Naltrexone

• Mu, delta and kappa antagonist

• Risk of hepatotoxicity-this is very low and can monitor LFTs

• Evidence only for daily use; no studies on as needed use

Nalmefene

• Antagonist at mu and delta; partial agonist at kappa

• No hepatotoxicity risk

• Can be used as needed to reduce heavy drinking

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Varenicline

• Partial α4β2 nicotinic acetylcholine agonist used in aiding smoking cessation

• Earlier concerns about suicidality and criminality have not been substantiated

• Minimal drug-drug interactions

• Examined in an RCT of 200 subjects with AD who were heavy drinkers (41% Vs. 38% were smokers)

• Smoking rates among AD can be as high as 70%

Anthenelli et al Lancet 2016; Fazel et al Lancet 2015; Litten et al

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Heavy Drinking Days

Litten et al; J Addict Med.

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Varenicline

• Single study showed good efficacy in reducing heavy drinking days in AUD

• Varenicline did not increase suicidal ideation, mood changes, behavior/thinking changes, hostility or agitation

• Improvements in drinks/day and drinks/drinking day

• No difference in abstinence rates

• The average treatment effect for the primary outcome did not significantly vary by baseline smoking status

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Gabapentin

• This is an α-2-δ subunit blocker

• FDA approved for seizures and neuropathic pain

• Building evidence base for use for alcohol withdrawal

• Here we discuss use to reduce drinking in alcohol use disorder

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Gabapentin

• Single site study that recruited patients with AUD

• Patients needed to abstinent for 3 days prior to randomization

• 1:1:1 randomization to placebo, 900 mg or 1800 mg

• Patients followed for 12 weeks

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Gabapentin

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Gabapentin

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Gabapentin

• Limitations

• Mean stay in study was 9 weeks

• Community dwelling volunteer patients

• Patients were able to self taper for 3 days prior to randomization

• High drop out rate

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• 150 alcohol-dependent individuals randomized to

• Sixteen weeks of naltrexone alone (50 mg/day [N= 50])

• Naltexone with gabapentin (up to 1200 mg/day [N=50] for the first six weeks), or

• Double placebo (N= 50) while receiving medical management

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Survival curves for heavy drinking

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Heavy drinking days

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Gabapentin

• Limitations

• Again voluntary patients who could self taper off alcohol for 4 days prior to randomization

• Single site

• There was worsening of sleep and increased drinking after gabapentin was discontinued

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Gabapentin

• Some more evidence from smaller RCTs

• Current multi-center trial with gabapentin enacarbil-Horizant™ underway

• Potential concerns for abuse/misuse of gabapentin

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Baclofen

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Baclofen

• A GABA-B agonist that works as a muscle relaxant

• Commonly used doses for spasticity are 80 mg/day

• Case report suggested use of as much as 230 mg/day

• Initial studies examined doses of 30-60 mg/day

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Mean dose reached for the baclofen group was 180 mg/day

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Baclofen

• During the 12-week high-dose phase, significantly more patients assigned to baclofen remained abstinent compared to those assigned to placebo (15/22, 68.2% vs. 5/21, 23.8%; p=0.014).

• During the entire medication phase significantly more patients also maintained alcohol abstinence in the baclofen group compared to placebo (12/28, 42.9% vs. 4/28, 14.3%; p=0.037)

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Baclofen

• Limitations

• No changes in AST, ALT, GGT

• Small single site study

• Other studies have used doses between 30 mg/day to 60 mg/day

• Garbutt et al; 30 mg/day (n=80): -ve

• Morley et al; 30-60 mg/day(n=42):-ve

• Addolorato et al; 10 mg tid(n=84): increased abstinence rates at 12 weeks

Morley et al, Alcohol Alcohol. 2014; Garbutt et al, Alcohol Clin Exp 2010; Addolorato et al, Lancet. 2007;

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Naltrexone

• µ receptor blocker

• Can be initiated while still drinking

• Usual dosage is 50 mg once daily(50mg >100mg)

• Available as IM 380 mg every 4 weeks

• Obtain liver enzymes prior to starting

• AE: nausea, headache, dizziness and elevation of liver enzymes

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Naltrexone-Efficacy

• Meta analyses of 50 RCTs with 7793 patients shows it improves some outcomes related to drinking

• It shows a reduced risk of return to heavy drinking

• (83% of placebo) and number of drinking days (by 3%)

• No difference in return to any drinking

• Secondary measures showed a reduction in heavy drinking days (3%), alcohol consumed on drinking days and GGT (10 units)

• Reduced heavy drinking in COMBINE

• Mostly confirmed in a more recent meta analyses (n=9140; NNT=20 for any drinking and 12 for heavy drinking)

Rosner et al 2010; Anton et al 2006

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Naltrexone- Efficacy • Meta-analyses of 4 studies (n=739) examining injectable

preparations does not show efficacy

• Some evidence that Asn40Asp SNP variants of OPRM1 gene might influence response to naltrexone- some non-replication

• Asp40 allele were significantly more likely not to relapse to heavy drinking with naltrexone treatment (73.9%) than individuals homozygous for the Asn40 allele (49.0%)

• Recent RCT randomly(n=221) assigned to study treatment based on the presence of 1 or 2 copies of the Asp40 allele compared with those homozygous for the Asn40 allele

Jonas et al 2014

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From: Naltrexone vs Placebo for the Treatment of Alcohol Dependence: A Randomized Clinical Trial

JAMA Psychiatry. 2015;72(5):430-437. doi:10.1001/jamapsychiatry.2014.3053

The Proportion of Participants With Any Heavy Drinking Within a Given Treatment Week Separated by Genotype and Treatment

Group. There were no significant differences in outcomes among the 4 groups when adjusting for site and baseline rates of heavy

drinking.

:

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Acamprosate

• Modulates glutamatergic transmission

• Patients do better if abstinent prior to starting the medication (c.f. naltrexone)

• Usual dosage is 666 mg tid- reduced in renal failure

• AE: diarrhea, nervousness and fatigue

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Acamprosate-Efficacy

• A meta analyses of 24 RCTs with 6915 patients found evidence for efficacy

• Showed reduced risk of returning to any drinking (86% of placebo) and increased duration of abstinence ( mean 10 days)

• No impact on GGT or heavy drinking

• No difference from placebo in COMBINE study

• Mostly confirmed in a more recent meta analyses (n=7519; NNT=12 for any drinking)

Jonas et al 2014; Rosner et al 2010

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Disulfiram

• Aldehyde dehydrogenase inhibitor

• Requires complete abstinence before starting and up to 14 days after discontinuation

• AEs: Fatigue, headache, psychosis, hepatitis

• CI: Psychosis and liver failure

• A meta analyses of 492 patients showed no difference from placebo

• An RCT of supervised Rx showed reduction in heavy drinking days, time to first drink, weekly alcohol consumption and number of abstinent days

Laaksonen et al 2008; Jonas et al 2014

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Summary

• Naltrexone and acamprosate are reasonable first line options with no meaningful differences between the two

• Potential predictors of +ve response to naltrexone include strong cravings and family history (gene mutations not ready for primetime)

• For acamprosate, anxiety, physiologic dependence and female sex are potential predictors of response-longer period of abstinence

• Placebo effect is also important

Monterosso et al 2001; Rosner et al 2008; Verheul et al 2005

psychiatry clinical reviews...bhanu prakash kolla md, mrcpsych october 6-8, 2016 intercontinental...

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