Review Article

1, 1, *1
1

Alcohol Addiction, Alcohol Withdrawal Syndrome and Treatment

Araya Supawat1, Kutcharin Phunikhom1, Jintana Sattayasai*1
1Department of Pharmacology, Faculty of Medicine, Khon Kaen University,Thailand

(anticonvulsants)

anticonvulsant

Recently, there are many drugs for the treatment
of alcohol addiction and alcohol withdrawal syndrome.
However, several other drug candidates are currently
evaluated by the researcher for a long term therapy
and prevent relapse. The previous studies showed
that the researcher were interested the efficacy of
anticonvulsant drug group, according to variety mechanism
of action, to reduce alcohol addiction and alcohol withdrawal
syndrome. Therefore, anticonvulsant medical plants may be
promising candidates and modest pharmacological therapy for
alcohol dependence.
Keyword: alcohol addiction, alcohol withdrawal syndrome

2558; 30 (6): 618-629 Srinagarind Med J 2015; 30 (6): 618-629

.. 2554
17
15-24





1 ( 1)

618

(alcohol addiction)
(alcoholism)
3
mucosa
(heartburn)
(gastric content)
(gastroesophageal reflux)4

2558; 30 (6) Srinagarind Med J 2015; 30 (6)

Araya Supawat,et al.

()

28-40

28-43
(whiskey), (brandy), (Rum))
(beer)
3.5-6.4
(wine)
8-15
/
5-7

5-11

4-6
SMJ_58_046

28-40
(Cocktail)
3.5-43 (liver failure) 5
(alcoholic hepatitis) (cirrhosis)

(dilated cardiomyopathy)
*

(arrhythmias) (hypertension) (coronary heart

(alcoholic fatty liver)

30-90

(ovulatory

(impotence)

cycle)
disease) 5
6

(alcoholic hepatitis)

(
9598)

macrophages

(cirrhosis) (liver failure) 5

(amnesia)
(confusion)

(
0.7)
0.1)
(ataxia)

(cerebral atrophy)
(dilated

( 0.3) Syndrome

(dementia)
WernickeKorsakoff
(
vitamin B1) 7
cardiomyopathy) (arrhythmias)

(hypertension) (coronary1.

(metabolism)
acetaldehyde

5
heart disease) (impo3 alcohol dehydrogenase (ADH), catalase
30-90 (9598%)
tence) (ovulatory cycle)
2E1(CYP2E1)
aldehyde

(0.7%) (0.1%)
cytochrome
P450

6
(0.3%)

dehydrogenase
(ALDH)
acetaldehyde

acetaldehyde

dinucleotide
3 alcohol(NAD)
dehydrogenase (ADH),

acetate
nicotinamide
adenine
catalase
P450 2E1 (CYP2E1) aldehyde dehydrogenase (ALDH)
macrophages acetaldehyde
3 cytochrome
co-factor
Krebs cycle
acetate nicotinamide adenine dinucleotide (NAD) co-factor
4,5

(
( 1)
1)

Krebs
cycle
,
4-5

(amnesia)
(confusion) (ataxia)
(cerebral atrophy)
(dementia) WernickeKorsakoff Syndrome
( vitamin B1) 7
1. (metabolism)

1 5
1 (metabolic pathways of ethanol in human)
(metabolic pathways of ethanol in human)5
2558; 30 (6) Srinagarind Med J 2015; 30 (6)

619

2.
(central nervous system)



amino acid (amino
acid neurotransmitter systems) (excitatory
amino acids) glutamate (inhibitory
amino acids) - aminobutyric acid (GABA)
dopamine
2

Alcohol addiction, Alcohol Withdrawal Syndrome and Treatment

hyperpolarization


(stuporous)
(muscular incoordination)

(unconsciousness)

2.2
(central nervous
system)
incoordination)

2.1

(muscular




SMJ_58_046
(central nervous system)

(unconsciousness)

(chronicalcohol

consumption)
(acute
alcohol consumption) up-regulation NMDA receptor NMDA R2B
2. (central nervous system)
cerebral cortex, hippocampus, amygdala9
glutamatergic neurotransmission subunit
2.2

(central n


metabotropic
receptors
(mGluRs) presynaptic cell
amino acid (amino acid neurotransmitter systems)

(chronic al
NMDA
receptor acid
Na+ ion Ca2+ ion
(excitatory
amino

hippocampus
acids)glutamate
glutamate

(inhibitory
amino acids) up-regulation
- aminobutyric
NMDA
receptor NMDA R2B subunit cerebra

(GABA)
nucleus
accumbens

dopamine

(withdrawal)

NMDA receptor
2
N-methyl-D-aspartate (NMDA) receptor

GABA
system

2.1

(central
nervoushyperexcitability (
system)

3)

postsynaptic
cell

glycine
NMDA
(acute alcohol consumption)

hyperexcitability

(
3)
synapse

GABA system s
receptor

-Amino-3-hydroxy-5-methylisoxglutamatergic neurotransmission metabotropic receptors (mGluRs)

postsynaptic
neuron postsynaptic
neuron

GABA

azole-4-proprionic
acid (AMPA) receptors
presynaptic cell glutamate hippocampus nucleus accumbens
8,10
8,9
8-10
anxiety
glutamatergic
neurotransmission
( 2)(NMDA) receptorhyperexcitability
cell

N-methyl-D-aspartate

postsynaptic



GABA A
glycine NMDA
receptor
-Amino-3-hydroxy-5-methylisoxazole-4-proprionic
acid
8-9
(AMPA) receptors
neurotransmission
( 2)
receptor
Cl
glutamatergic
postsynaptic
cell

2.
glutamate system
8

3.

3 glutamate system

3.
(alcohol addiction and a
8
2

glutamate
system
postsynaptic
(withdrawal)

Cl-
cell

GABAA receptor
3.1 (pathophysiology)

hyperpolarization


(stuporous)
2558; 30 (6) Srinagarind
Med J 2015;
30 (6)
dependence)

(psychological dependence)
4
3.1.1 (physical dependence)

tolerance

620

3.
(alcohol addiction and alcohol withdrawal syndrome)

3.1 (pathophysiology)


(physical dependence)
(psychological dependence)

3.1.1 (physical
dependence)




tolerance GABA system
synapse GABA postsynaptic
neuron neuroadaptation
up-regulation NMDA receptor
glutamate cationic conductance


(withdrawal) hyper
excitability
neuron
withdrawal
symptoms (anxiety) (tremor)
(disorientation) (agitation)
(delirium) (hallucinations)
(grand mal seizures) 8-10

3.1.2 (psychological
dependence)




(pleasure) (reward)
(alcohol addiction)

(rewarding center) mesolimbic dopamine system (
ventral tegmental area (VTA), nucleus accumbens (NAc)
prefrontal cortex, amygdala, striatum hippocampus

Araya Supawat,et al.

-endorphin receptors
GABAergic neurons VTA GABAergic
transmission
glutamate GABAergic neurons
GABAergic neurons VTA
firing dopaminergic neurons
dopamine dopamine receptor
nucleus accumbens (NAc)11 ( 4A)

neuroadaptation (alcohol
dependence)
(alcohol withdrawal) glutamate GABAergic
neurons GABAergic neurons
dopamine VTA
( 4B) dopamine

craving8,12
(relapse)
dopaminergic neurons

glutamate dopamine
nucleus accumbens
(alcohol withdrawal) (alcohol
dependence) ( 4C)
8


depression, anxiety
serotonin

serotonin deficiency
5-HT 5-HT metabolites 13

3.2 (relapse)

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621

Alcohol
addiction, Alcohol Withdrawal Syndrome and Treatment
SMJ_58_046

glutamate craving

systems)

rewarding

4 (neurotransmitter
center8

dopamine
3.2 (relapse)

glutamate

surface
expression

glutamate
glutamate craving receptors

10 ( 5)

4.

dopamine

(treatment
of
alcohol
addiction
and
alcohol
withdrawal
glutamate surface expression
syndrome)
glutamate
receptors

10 ( 5)
4

(neuro 4
(neurotransmitter
systems) rewarding
center8

transmitter systems) rewarding center8

3.2 (relapse)


glutamate craving

dopamine
glutamate surface expression
glutamate receptors 10 ( 5)

5 (relapse) (abstinence)10

4.1 (pharmacological
therapy)




( 2)

4.1.1 Opioid receptor antagonists naltrexone, nalmefene

Naltrexone opioid receptor
antagonist mu kappa opioid
receptor competitive reversible
GABA transmission
GABAergic neurons VTA

622

dopamine nucleus accumbens (NAc)

8,14,15

Nalmefene opioid receptor
antagonist mu delta opioid receptor
partial agonist kappa opioid receptor
7
GABA neurons VTA
dopamine nucleus accumbens (NAc)
16


nalmefene 17,18
nalmefene
naltrexone nalmefene
naltrexone

2558; 30 (6) Srinagarind Med J 2015; 30 (6)

(alcohol dependent group) nalmefene

naltrexone
(craving)
19
4.1.2 Acamprosate

Acamprosate calcium salt
N-acetyl homotaurine glutamate,
GABA, glycine taurine acamprosate
ionotropic metabotropic glutamate receptors
NMDA receptor glutamatergic
neurotransmission type 5 metabotropic glutamate
receptors (mGluR5) glutamate
excitatory inhibitory
neurotransmitter hyperexcitability
hyperexcitability dopamine hyperexcitability nucleus accumbens alcohol
withdrawal 8, 17, 20

4.1.3 Disulfiram

Disulfiram (tetraethylthiurm disulfiram)
aldehyde dehydrogenase
(ALDH) nicotinamide adenine
dinucleotide (NAD) (co-factor) binding site
acetaldehyde acetate
acetaldehyde
5-10 alcohol metabolism
disulfiram ethanol reaction (DER)

(flushing)


(shortness of breath)
30


hypotension bradycardia, marked
tachycardia, cardiac arrest, cardiovascular collapse,
congestive heart failure

8, 17, 20

Araya Supawat,et al.

4.1.4 Baclofen

Baclofen presynaptic GABA-B
receptor agonist
(spasticity) baclofen
cortico-mesolimbic dopamine neurons17
baclofen
(voluntary ethanol intake)
baclofen
23

4.1.5 Dopaminergic drugs

dopamine
system brain reward circuit
dopamine
(alcohol addiction) dopamine
receptor antagonists quetiapine
dopamine
(clinical testing)17
4.1.6 Serotonergic drugs

serotonin
reuptake inhibitors, 5-HT1 partial receptor agonist, 5-HT2
receptor antagonist 5-HT3 receptor antagonists

- Selective serotonin reuptake
inhibitors (SSRIs)
reuptake 5-HT
knockout mice 5-HT transporter mice


24

- 5-HT1 partial receptor agonist
buspirone

buspirone anxiolytic effects
buspirone
17

- 5-HT 2 receptor antagonist
ritanserin, amperozide, FG5974

2558; 30 (6) Srinagarind Med J 2015; 30 (6)

623

ritanserin
(alcohol dependence)17

- 5-HT 3 receptor antagonists
ondansetron
5-HT3 receptor antagonists dopaminergic activity

early-onset alcohol dependence17
5-HT 3 receptor


4.1.7 Sedative/anxiolytics

benzodiazepines


delirium tremens (seizures)
benzodiazepine binding site
GABA receptor complex
GABAergic transmission
(long half-life benzodiazepine)
diazepam
(short half-life benzodiazepine) lorazepam

4.1.8 Anticonvulsants




brain reward circuit
alcohol dependence
carbamazepine, valproate, topiramate, levetiracetam,
gabapentin pregabalin

-Carbamazepine
alcohol withdrawal alcohol dependence voltage-gated
sodium channels sleep
disturbances, anxiety mood instability 25

-Valproate alcohol
addiction alcohol withdrawal syndrome
histone deacetylases

624

Alcohol addiction, Alcohol Withdrawal Syndrome and Treatment

glutamic acid decarboxylase

GABA
cortico-mesolimbic dopaminergic activity
(neuroprotection) neuronal
excitability25

-Topiramate

AMPA kainate receptor
topiramate GABA-A receptors
non-benzodiazepine sites GABAergic transmission dopamine meso-corticolimbic
pathway
hyperexitability
(seizure) alcohol withdrawal
syndrome topiramate
norepinephrine locus ceruleus
(anxiety) 17,20,21,25

-Gabapentin GABA

neuronal stabilization
GABAergic transmission voltage-gated sodium
channels L-amino acid transporter
plasma membrane 2 subunit
voltage-gated calcium channels excitatory
neurotransmitters26

-Pregabalin
2
subunit voltage-gated calcium channels
excitatory neurotransmitters glutamate monoaminergic
neurotransmitters27

-Levetiracetam

voltage-calcium channels Ca2+
intraneuronal stores28 open label
trial levetiracetam
anxiety disorders,
stress mood disorders29

2558; 30 (6) Srinagarind Med J 2015; 30 (6)

4.1.9 Novel pharmacological targets

vareniclin (partial agonist of nicotinic receptor), OSU6162
(novel class of dopamine stabilizers), verucerfont
peracerfont (corticotropin releasing factor-1; CRF1
antagonist), LY686017 (neurokininol antagonist)
30

4.2 (Herbal)

4.2.1 Pueraria lobata

Pueraria lobata Kudzu
isoflavone 2
daidzin daidzein Syrian Golden
hamster alcohol preferring rat

daidzin sleep time
acetaldehyde dehydrogenase (ALDH) disulfiram31
4.2.2 Tabernanthe iboga

Tabernanthe iboga
ibogaine indole alkaloid

ibogaine alcohol preferring
rats
ibogaine
(morphine) (cocain) 31

4.2.3 Panax ginseng

Panax ginseng

alcohol dehydrogenase (ADH)

31

Araya Supawat,et al.

4.2.4 Salvia miltiorrhiza

Salvia miltiorrhiza
(insomnia)


sP rats
31

4.2.5 Hypericumper foratum

Hypericumper foratum St. Johns wort

(antidepressant)
St. Johns wort
alcohol preferring rats sP rats
NMDA receptor31

Acorus calamus
anticonvulsant32-35

(alcohol addiction)

2558; 30 (6) Srinagarind Med J 2015; 30 (6)

625

Alcohol addiction, Alcohol Withdrawal Syndrome and Treatment

2
Study
Drugs
A multicentre,
randomized,
double-blind,
placebo-controlled
trial of naltrexone
in the treatment of
alcohol dependence
or abuse36
Effect of oral
acamprosate on
abstinence in
patients with alcohol
dependence in a
double-blind,
placebo-controlled
trial: The role of
patient motivation37
Efficacy and safety
of baclofen for
alcohol dependence:
a randomized,
double-blind,
placebo-controlled
trial38
Baclofen in the
treatment of alcohol
withdrawal
syndrome: a
comparative study
vs diazepam39

626

Study design No. of patients

Treatment

Comparators

Results

Multicentre, 175
randomized,
double-blind,
placebo-controlled trial

Naltrexone
50 mg/day
12

Placebo

Double-blind, 601
placebocontrolled
trial

Placebo

Acamprosate
2 g/day
3 g/day
6

(alcohol
dependence)

(alcohol
abuse)

(alcohol abstinence)

Randomized, 80
double-blind,
placebo-controlled trial

Baclofen
Placebo
30 mg/day
12

anxiety

(alcohol
dependence)

Comparative
Study

Baclofen
30 mg/day
10

Baclofen

alcohol withdrawal
syndrome

Diazepam

37

Diazepam
0.5-0.75 mg/
kg/day, 6

2558; 30 (6) Srinagarind Med J 2015; 30 (6)

Treatment of alcohol Open-label

90
dependence with
controlled trial
low-dose topiramate:
an open-label controlled study40

A double blind trial

of gabapentin vs.
lorazepam in the
treatment of alcohol
withdrawal41

Pregabalin, tiapride
and lorazepam in
alcoholwithdrawal
syndrome: a
multi-centre,
randomized,
single-blind
comparison trial42

Araya Supawat,et al.

Topiramate
75 mg/day (psychother 2
apy)
diazepam 5 mg

Topiramate
psychotherapeutic treatment
diazepam

(alcohol
craving)
alcohol
withdrawal syndrome
depression
anxiety
Double-blind, 100
Lorazepam 6
placebo Gabap- mg
controlled
entin
4
1,200
trial
900 mg
mg
1200 mg
alcohol
4
withdrawal syndrome

alcohol withdrawal
syndrome
Multicentre, 111 Pregabalin Tiapride
randomized,
450 mg/day 800 mg/day,
double-blind,
14
Lorazepam pregabplacebo-con10 mg/day
alin
trolled trial
alcohol
withdrawal syndrome
lorazepam
tiapride

2558; 30 (6) Srinagarind Med J 2015; 30 (6)

627

Herbs
A standardized
Kudzu extract
(NPI-031) reduces
alcohol
consumption
in non-treatment
seeking male heavy
drinkers43

Randomized, 21
double-blind,
placebo-controlled trial

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