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Alcohol Addiction

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Anna Dang

on 13 May 2015

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Transcript of Alcohol Addiction

Study Population Sample
At a single site outpatient facility at Scripps Research Institute

150 participants (> 18 years old)

Alcohol dependence volunteers
Meet the Diagnostic and Statistical Manual criteria for alcohol dependence
Abstinent from alcohol for at least 3 days prior to randomization

Exclude
Dependence on substance other than alcohol
Significant medical or psychiatric disorders


http://assets.bizjournals.com/milwaukee/study%20population*304.jpg?v=1
Alcohol
Addiction
Lilian Situ
Kimberly Ly
Anhthu Dang
Si Chen
Clarissa Marquez
Joy Kim
Solhee Han


(NIH 2015)
By
Disulfiram
Naltrexone
Acamprosate
Varenicline
Gabapentin
Approved Treatments
Disulfiram

Disulfiram Background
Antabuse/ Antabus

First medication approved by FDA

Alcohol sensitizing agent
Increases alcohol toxicity


Mechanism of Action
Most Efficacious
Most beneficial towards:
Self-motivated and want to achieve abstinence
Understand the effects from alcohol consumption under disulfiram use


Able to have supervision with each dosing

Naltrexone


Acamprosate
Naltrexone Background
Revia/ Vivitrol

Oral Naltrexone
Low rate retention and adherence
For highly motivated individuals or ones with supervised daily dosing

Extended-release injectable Naltrexone
FDA approved for treatment of AUD 2006

Fewer side effects taking naltrexone when abstinent
Also safe under clinically supervised withdrawal or actively drinking
Gabapentin
FDA approved for epileptic seizures and neuropathic pain

GABA analog

Blocks the specific alpha-2d subunit of the voltage-gated Ca2+ channel

Varenicline Background
A partial α4β2 nicotinic acetylcholine agonist used in aiding smoking cessation

Nicotinic acetylcholine receptors may play a significant role in the rewarding effects of both nicotine and alcohol

Study Design
Phase 2 clinical trial

Conducted clinical and telephone visits

Follow up telephone interview 2 weeks after the study

The medication was dispensed using a double-blind method

Randomly assigned either varenicline or placebo
Study Design
Dosage per patient:
Day 1-3: 0.5mg
Day 4-7: 0.5 mg twice a day
Week 2-13: 1.0 mg twice a day

Study Population
Population criteria:
At least 18 years of age
Have specific drinking averages
Not dependent on other psychoactive substances
No history of psychiatric disorder and cardiovascular disease

Study Population
Total patients: 461
Received placebo or varenicline: 200
Excluded: 261

Reasons for not meeting the criteria:
1. Positive urine toxicology
2. Psychiatric disorder
3. Discontinued medication

Study Results
The weekly treatment effects varied significantly and were consistently greatest and most significant during the last 5 week of trial.





Strengths
Randomized, double-blind, placebo-controlled, parallel-group study

Observed effects among smokers and nonsmokers

Provided more evidence to show Varenicline efficacy and safety

Continuous outcomes were measured at multiple time points



Limitations
Adverse effects include: nausea, abnormal dreams, and constipation

Did not include patients who have psychiatric disorders.

Unknown effects on patients suffer from cardiovascular disease

Varenicline binds to multiple nicotinic receptor subtypes

Missing drinking data was imputed as heavy drinking days

Future Studies
Observe effect of Varenicline on patients with psychiatric and cardiovascular disorders.

More research is needed to fully understand the complex interaction of alcohol with the nicotinic system

Conclusion
Varenicline significantly reduced measures of alcohol use

Positive effects of Varenicline on drinking were observed in alcohol dependent patients

Varenicline treated patients showed significantly reduced alcohol craving


Main Use:
Act as an incentive against alcohol consumption
ALDH inhibitor
Disulfiram
http://www.scielo.cl/fbpe/img/jcchems/v54n4/fig22.1.jpj
http://www.gaba-supplement.com/wp-content/uploads/2013/12/Gabapentin1.jpj
http://yourlinkpost.com/image/551f9d540d740. jpg
Gabapentin Mechanism
Objective: to determine if gabapentin:
Increases rates of sustained alcohol abstinence and decreases heavy drinking
Decreases abstinence related symptoms in sleep, mood and craving
12-week, double blind, placebo controlled, randomized dose ranging
3 groups:
(1) Gabapentin 900mg
(2) Gabapentin 1800mg
(3) Placebo
Gabapentin of various dosages with weekly counseling
To increase motivation, abstinence, and medication compliance
Post-treatment (week 13-24)

Study Design
Varenicline Mechanism
http://media.salon.com/2013/08/mystery_pills-1280x960. jpg
Weekly Assessments
Alcohol Use
Daily record of standard drink
14g ethanol, 12 ounce beer
Validate by weekly breathalyzer




Mood
Self- report Beck Depression Inventory



Naltrexone Mechanism of Action
Blocks dopaminergic receptors in mesolimbic pathway

Prevents release of dopamine
Lessens pleasure from alcohol consumption
Drinking urges/craving
Self-report Alcohol Craving Questionnaire
Sleep disturbance
Self-report Pittsburgh Sleep Quality Index

Safety Evaluations
Vital signs, urine screening, specimen
Benefits
Those who have history of opioid use disorder (substance abuse) and those seeking treatment
Those with cravings for alcohol and opioids
Patients with intense cravings during treatment
Patients with family history of alcohol use disorders
People with Asp40 allele of gene encoding the mu opioid receptor (OPRM1)
http://adai.washington.edu/instruments/pdf/Alcohol_Craving_Questionnaire_Short_Form_Revised_20.pdf
Acamprosate Background
Campral
FDA approved 2004
Post-withdrawal maintencence and prolonging abstinence
Cochrane review of 24 studies had moderate effects in preventing relapse and prolonging abstinence
http://www.chemspider.com/Chemical-Structure.64300.html
Cochrane – nonprofit organization that prepares, maintains and promotes accessibility to the systematic reviews of the effects of health care
Mechanism of Action
GABA agonist
NMDA-R Antagonist
Benefits
Most effective in those wanting to achieve complete abstinence
Best for those post-withdrawal maintenance
Particularly useful in people:
With liver disease
Treated with opioids for pain or addiction
No adverse effects with exogenous or endogeouous opioids
Those taking multiple drugs
No significant drug-drug interactions
http://www.newdruginfo.com/pharmacopeia/usp28/v28230/usp28nf23s0_m27690.htm
http://www.dana.org/Publications/ReportDetails.aspx?id=44308
Acamprosate prevents excess glutamate release
Results: Gabapentin vs. Placebo
Makes GABA receptors more sensitive
Significant linear dose effect
Increasing rates of complete abstinence
No heavy drinking

Gabapentin 1800mg = Greatest effect!
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3920987/bin/nihms-533947-f0002. jpg
Results: Gabapentin vs. Placebo
Gabapentin showed significant linear decrease in
#of days of heavy drinking per week
# of drinks consumed per week
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3920987/bin/nihms-533947-f0003. jpg
Results: Gabapentin vs. Placebo
Significant linear dose effects on
Alcohol craving
Mood
Sleep disturbances
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3920987/bin/nihms-533947-f0004. jpg
Safety and Tolerability
Well tolerated, no deaths

No serious drug-related adverse events
Only common side effects : fatigue, headache, insomnia

Only 9 out of 150 participants ended treatment due to adverse events

Future Studies
1) Find the mechanism of how Gabapentin works to treat alcohol dependence
2) Larger studies in more diverse populations of patients with alcohol dependence
Needed to replicate and extend these findings


3) Increased implementation of treatment of alcohol dependence in primary care
VTA ---> Nucleus Accumbens
Conclusion
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3920987/
1) Gabapentin is effective at treating:
Alcohol dependence
Increases rate of abstinence & decreases heavy drinking
Relapse-related symptoms
Craving, mood, and sleep

2) Linear dose effect
1800mg is more effective than 900mg

3) Favorable safety profile

Summary: Approved Treatments

Disulfiram
Naltrexone
Acamprosate
Alcohol Dependence
Chronic, relapsing compulsive alcohol use

Withdrawal syndrome emerge upon cessation

Long term abstinence causes relapsing symptoms
Alcohol craving
Mood
Sleep disturbance

most effective for those who fear the toxic side effects
for those who crave the high alcohol gives
best for post-withdrawal maintenence
Worldwide Prevalence

Medications for alcohol dependence are prescribed for fewer than 9% of alcohol dependence patients in the US

Pathological alcohol use is one of the largest avoidable risk factors for the worldwide burden of disease
http://www.treatobacco.net/en/uploads/image/nic_vs_varenicline. jpg
http://en.citizendium.org/images/b/b6/Varenicline. png
Multisystem Reaction
Reaction severity dependent on both amount alcohol and drug taken
http://placebocures.com/wp-content/uploads/2012/10/placebo-same-as-antidepressant. jpg
http://tmedweb.tulane.edu/pharmwiki/doku.php/alcohol_alcohol_addictionv
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Chronic alcohol consumption desensitized GABA-A
Background

Alcohol use disorders affect 18 million Americans, causing a wide range of medical, psychological, social, personal, and economic problems

Heterogeneous disorder is characterized by compulsive alcohol use and an inability to stop drinking despite harmful consequences

3rd leading risk factor for global burden of disease and injury

$224 billion annually for alcohol consumption

http://www.kofusion.com/wp-content/uploads/2009/02/featured_drinks. jpg
Prealence

Alcohol Use Disorder

Previous alcohol addiction diagnosis separated into two categories:
Alcohol abuse
Alcohol dependence

Current diagnosis :
Alcohol abuse and alcohol dependence now collectively called Alcohol Use Disorder (AUD)
Varying degrees of severity - mild, moderate, and severe based on 11 criteria for detecting substance abuse

CAGE Test
Cutting down
Have you ever felt you should cut down on drinking?
Annoyed
Are you annoyed when others comment on your drinking?
Guilty
Do you feel guilty when you’re drinking?
Eye-opener
Eye-opener : Do you drink to calm yourself or to get rid of a hangover?
AUDIT Test

Score of 8 or higher indicate harmful/hazardous drinking habits
http://www.industrialpsychiatry.org/article.asp?issn=0972-6748;year=2013;volume=22;issue=2;spage=100;epage=108;aulast=Kattimani
http://what-when-how.com/neuroscience/behavioral-and-psychiatric-disorders-integrative-systems-part-3/
Smptoms哦发阿拉coHOLu
http://pubs.niaaa.nih.gov/publications/arh28-2/78-79.htm
Two endpoints were measured:
Percent of heavy drinking days
Drinking and non drinking outcomes
drinks/day, abstinence, cigarettes/day and cravings
References
Diagnosis
Criteria for diagnosing severity of Alcohol Use Disorders:

1. Taking the substance in larger amounts or for longer than you meant to
2. Wanting to cut down or stop using the substance but not managing to
3. Spending a lot of time getting, using, or recovering from use of the substance
4. Cravings and urges to use the substance
5. Not managing to do what you should at work, home or school, because of substance use
6. Continuing to use, even when it causes problems in relationships
7. Giving up important social, occupational or recreational activities because of substance use
8. Using substances again and again, even when it puts you in danger
9. Continuing to use, even when you know you have a physical or psychological problem that could have been caused or made worse by the substance
10. Needing more of the substance to get the effect you want (tolerance)
11. Development of withdrawal symptoms, which can be relieved by taking more of the substance.

Alcohol in the Brain
Alters neuronal membranes, receptors, enzymes, and ion channels
Alcohol binds to serotonin (5-HT), GABA, Acetylcholine (AcH), and NMDA receptors for glutamate
For GABA synapse
GABA’s job is to reduce neural activity by allowing Cl to to enter post-synaptic neuron
Cl has negative charge therefore making neuron less excitable
When alcohol binds to GABA receptors these ion channels stay open longer, increasing the time Cl can enter the post-synaptic neuron and reducing neuronal activity
alcohol is a depressant in this sense
Also reduces glutamate’s excitatory effect on NMDA receptors
Chronic consumption leads to hypersensitive NMDA receptors and desensitized GABAergic receptors
This adaptive quality leads to the “excited state” characteristic of alcohol withdrawal

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