Addiction Medicine 2014

(1)

Addiction

Medicine

2014

Update on Current/New/Anticipated

Medications for Alcohol Use Disorders

J.C. Garbutt, MD

Department of Psychiatry and Bowles Center for

Alcohol Studies

School of Medicine, University of North Carolina at

(2)

Objectives

• _Provide_a_perspective_on_current_efficacy_of_medications

for alcohol use disorders and prescribing practices

• Briefly review basic science concepts that should drive the

development of new medications

• _Provide_clinical_trial_data_on_medications_in_development

that show promise for alcohol use disorders.

• Provide information on the emerging effort to use

pharmacogenomics as a means to improve efficacy of

medications for alcohol use disorders.

• Provide some clinical perspective on pulling this all

(3)

(4)

Alcohol

Use

Disorders

• DSM‐V no longer includes alcohol dependence as

an alcohol use disorder, of interest to

pharmacotherapy as all FDA medications have

been approved for alcohol dependence as

defined by DSM‐IV and DSM‐III‐R. Is equivalence

moderate to severe alcohol use disorder?

• Use of pharmacotherapy for less severe alcohol

use disorders (abuse, binge drinking) not clear

(5)

Barriers

to

Medication

Use

• Of the estimated 10% of men and 5% of

women who will experience alcoholism in

their lifetime about 25% will receive

treatment, but, of those, only about 10% will

receive a medication for alcoholism.

• Mark et al (Drug and Alcohol Dependence 71:219, 2003)

examined why so few patients with alcoholism

(6)

Reasons

Given

for

Low

Medication

Use

(7)

How

Do

We

Move

Forward

• Education of physicians, counselors and

patients

• New molecules—preclinical research and

serendipity.

• The challenge of alcohol clinical trials given

disease heterogeneity and the issue of who

(8)

New

Molecules

(9)

The Pathophysiology of Alcoholism and Addiction

(10)

(11)

Effects

of

Naltrexone

on

Cue

‐

Induced

Activation

of

Ventral

Striatum

(Craving?)

(12)

Now or Later? An fMRI study of the effects of endogenous

opioid blockade on a decision‐making network

(13)

(14)

Withdrawal/Negative

Affect

• Acamprosate? Improvement in sleep

Staner et al, ACER,

30:1492, 2006 n=24

(15)

Potential

“New”

Medications

for

Alcohol

Use

Disorders

• Craving/Euphoria Anxiety/Withdrawal

• Baclofen ± +

• Gabapentin ± +

• Varenicline ± ‐

• Ondansetron + ±

(16)

Baclofen

‐First synthesized 1962

‐GABA_B agonist approved by the

FDA for treatment of spasticity.

‐In human use for many years so

safety profile well known

‐Animal testing has shown:

i) baclofen counters a variety of

drinking behaviors

ii)baclofen has anxiolytic

properties and can prevent the

anxiogenic effects of alcohol

(17)

Baclofen:

Effects

on

Alcohol

Withdrawal

Addolorato et al, Am J Med 119: 276, 2006

N=37, alcohol dependent

subjects with CIWA‐Ar scores

of ≥10. BAC dose of 30 mg/d

vs 0.5‐0.75 mg/kg diazepam. BAC equivalent to diazepam

(18)

Baclofen:

Effects

on

Consumption/Anxiety

Addolorato et al (2002)

• N=29, 4 week trial, 30 mg baclofen

P<.005

P<.05

(19)

Baclofen:

Effects

on

Consumption

Addolorato et

al

(2007)

N=84, subjects had

cirrhosis, 12 week trial,

30 mg baclofen

‐Baclofen well tolerated

in this population, no

negative effects on liver

function, no serious

(20)

Baclofen:

Effects

on

Consumption/Anxiety

Garbutt et al (2010)

• N=80, 12 week trial, 30 mg BAC

• Drowsiness (28% BAC, 10% PBO, p=.08)

P=.02 P=NS

(21)

Baclofen

Status

and

Directions

• Are higher doses more effective? Case reports of

improvement at higher BAC doses, up to 330

mg/d but more reports in the 90‐150 mg/d range

• BAC is 85% excreted by kidney with trials not

showing liver damage—agent of interest for

patients with liver disease including cirrhosis?

• Is severity of alcoholism an indicator of response?

• Current trials:

‐U.S. placebo‐30 mg‐90 mg/d

(22)

Gabapentin

‐ Discovered over 40 years ago

‐Complex mechanism of action

may affect multiple ion channels,

NMDA and GABA systems,

evidence of specific binding site in

brain.

‐FDA approved for epilepsy and

postherpetic neuralgia, safety

profile relatively well known

(23)

A double‐blind trial of gabapentin versus lorazepam

in the treatment of alcohol withdrawal.

Myrick et al, ACER 33:1582, 2009

• 100 subjects (lorazepam 8 mg, GBP 900mg, GBP

1200 mg tapered over 4 days)

GBP, 1200 mg, statistically superior to lorazepam

though clinically similar

• Post‐detox GBP subjects were less likey to drink

(24)

Gabapentin

combined

with

naltrexone

for

the

treatment

of

alcohol

dependence.

Anton et al, Am J Psych 168:709, 2011

• 150 subjects, 16 wks (50 NTX 50 mg; 50 PBO; 50 NTX

50 mg + Gabapentin 1200 mg for first 6 wks)

P=.03

Overall, the addition of

gabapentin to naltrexone

led to reductions in

drinking which faded

once gabapentin stopped.

The presence of

withdrawal sx or a history

of inpatient detox was

associated with positive

response to naltrexone +

gabapentin, effect

continued after

(25)

Gabapentin Treatment for Alcohol Dependence

A Randomized Clinical Trial

Mason et al, JAMA Int Med 174:70, 2014

• 150 randomized subjects

‐placebo

‐gabapentin 900 mg/d (300 mg tid)

‐gabapentin 1800 mg/d (600 mg tid)

• Subjects with CIWA scores >9 were excluded

(26)

(27)

• Effects on craving, sleep

and mood

(28)

Alcohol

and

Nicotine

• Alcohol Dependence associated with higher

rates of nicotine dependence in general

population (50%) and in treatment samples

(90%) compared to overall general population

(21%).

• Rates of nicotine dependence in general

population have dropped substantially but are

not dropping as fast in the alcohol dependent

(29)

Possible

Link

Between

Alcohol,

Dopamine

Release

and

Nicotine

Receptors

Hendrickson et al, Frontiers in Psychiatry 4:1, 2013

In the VTA, alcohol stimulates

DAergic neurons at least, in

part, via nAChR activation.

Ethanol increases ACh release

(red arrow, presumably through

cholinergic projection from the

LDT/PPTg) which in turn

activates nAChRs on DAergic neurons driving activity. In

addition, ethanol potentiates

Ach activation at high affinity

(30)

Varenicline: A Nicotine Receptor

Partial Agonist/Antagonist

Rollema et al, Trends Pharmacol, 28:316, 2007

Multiple forms of

nicotinic Ach receptor, α4β2 activates

dopamine release

Varenicline designed to

target α4β2 and

provide low‐level DA

activation while

(31)

A Double‐Blind, Placebo‐Controlled Trial

Assessing the Efficacy of Varenicline Tartrate for

Alcohol Dependence. Litten et al, J Addict Med 7:277 2013

N=200, PBO vs 1 mg

bid of varenicline. Randomization by

smoking.

Drinking improved

in both smokers

and non‐smokers. Cigarettes/day

dropped from 12 to

7 p=.002

(32)

Oxytocin

Nonapeptide released

by posterior pituitary

for uterine contraction,

milk ejection.

Oxytocin in brain

associated with pro‐

social and anxiolytic

properties and can

counteract physical

dependence to opiates

(33)

Intranasal Oxytocin Blocks Alcohol Withdrawal in Human Subjects

Pedersen et al, ACER 37:484, 2013

• Placebo‐controlled clinical trial

• Hospitalized subjects at risk for alcohol

withdrawal; CIWA‐Ar triggered lorazepam

• Oxytocin 24 IU intranasally bid (n=7), PBO

(n=4)

(34)

Intranasal Oxytocin Blocks Alcohol Withdrawal in Human Subjects Pedersen et al, ACER 37:484, 2013

0 2 4 6 8 10 12 14 16 18

CIWA-Ar Day 1 Lorazepam total mg Metric Placebo Oxytocin P<.0001 P=.0015

(35)

Alcoholism comes in many forms

(36)

Response

to

Naltrexone

and

Polymorphism

of

the

µ

‐

Opioid

Receptor

• A single nucleotide polymorphism in the µ‐opioid

receptor gene, Asn40Asp or G allele, confers change

in the response to ethanol:

N=28 (12 AG; 16 AA) Dopamine response

to ethanol assessed

with PET scans.

Ramchandani et al, Mol

Psych 16: 809, 2011

Frequencies of AG/GG

Genotype:

Caucasian 2.5‐15% African‐American 0‐5% Asian 25‐47%

(37)

Response

to

Naltrexone

and

AG/GG

Allele

(38)

Clinical and Biological Moderators of Response to

Naltrexone in Alcohol Dependence: A Systematic

(39)

Topiramate’s actions involve modulation of glutamate receptors

(40)

Response

to

Topiramate by

GRIK1

(41)

Ondansetron

• 5‐HT3 antagonist approved for nausea.

• Johnson et al (JAMA 284:963, 2000 and Am J Psych 168:265, 2011) found

efficacy in early onset alcoholism and in patients with L’L’‐

variant of serotonin transporter.

• Dose 4 μg/kg bid (about ¼ mg bid) with current formulation

being 4 mg for nausea, will need compounding pharmacy if

(42)

(43)

Determination of Genotype Combinations That Can Predict the Outcome of the Treatment of Alcohol

Dependence Using the 5‐HT3 Antagonist Ondansetron

(44)

Summary

in

Broader

Context

of

Recovery

• The use of medications should be considered when treating the patient with alcoholism.

• It makes sense to start with FDA approved medications: ‐disulfiram for the motivated patient who wants sobriety

‐naltrexonefor most patients and can consider long‐acting naltrexone if affordable ‐acamprosate may be considered for the patient with some established sobriety, may help with post‐withdrawal sleep problems as well.

• Off‐label medications

‐topiramateis top choice given evidence for efficacy

‐gabapentin is emerging as a potential good option either alone or as an adjunct to naltrexone and may help with sleep/anxiety/withdrawal

‐baclofen has mixed evidence but only drug with evidence in patients with

cirrhosis and may benefit anxiety/withdrawal, dose may need to be titrated up to 100‐150 mg/d, cautiously and can’t stop abruptly

‐varenicline data is still early but could consider in alcoholic patient with interest in smoking cessation

‐‐ondansetron has some positive evidence but may be limited to specific genetic pattern and not straightforward to formulate. • Pharmacogenomics an exciting new option but not quite ready for routine clinical use. • Medications are one tool in recovery. Patients should be encouraged to engage in counseling, attend AA or other meetings and realize recovery is more than taking a medication.