OF NEWER AND EMERGING DRUGS IN THE MANAGEMENT OF ALCOHOL DEPENDENCE
Sagar Karia1 Avinash De Sousa,2.Nilesh Shah,3Sushma
Research Associate 3Professor
And Head, 4addl. Professor
Psychiatry, Lomenta Tilak Municipal
Hospital, Sion, Mumbai – 22
dependence is a major health problem worldwide. Various pharmacological agents
have been used in the management of alcohol dependence. This present review looks
at the role of newer off label drugs like topiramate,
gabapentin, baclofen and levetiracetam along with
their proposed mechanism in alcohol dependence. The data available for each
drug is reviewed along with its side effect profile and potential for long term
use in the management of alcohol dependence. Future research and clinical needs
are discussed as well.
dependence, tiapride, baclofen, topiramate,
pregabalin, gabapentin, levetiracetam.
dependence constitutes the most serious alcohol use disorder (AUD) and is the
single most preventable cause of mortality and morbidity across the world.1
In addition to alcohol dependence, unhealthy alcohol consumption includes other
AUDs such as alcohol abuse and heavy drinking.2 Treatment of alcohol
dependence involves detoxification and rehabilitation phases. Detoxification manages the signs and symptoms of withdrawal, and
rehabilitation is intended to help the patient avoid future problems with
alcohol and prevention of relapse.3Alcohol withdrawal syndrome (AWS)
occurs when alcohol dependant patients decrease or discontinue their
consumption too suddenly and it is characterized by increase in blood pressure
and pulse rate, tremors, hyperreflexia, irritability,
anxiety and depression in mild to moderate forms and may progress to more
complicated forms characterized by delirium tremens, seizures and coma.4
Study of neurobiology of alcohol
withdrawal syndrome suggests role of
neurotransmitters and neuromodulaters like
glutamate, dopamine, noradrenaline, serotonin (5-HT), corticotropin-releasing
factor (CRF) and adenosine acetylcholine.5
exposure to alcohol causes adaptive changes in several neurotransmitter
systems, including gamma-aminobutyric acid (GABA)
receptors, glutamate receptors and central noradrenaline and dopamine activity.6
Glutamate represents the most common excitatory neurotransmitter in the
human brain, acting on several types of receptors in the central nervous
system. The one most affected by alcohol is the N-methyl-D-aspartate (NMDA)
receptor. GABA is the major inhibitory neurotransmitter, and binds to a
fast-acting receptor complex denoted as GABA-A, which hyperpolarizes the cell
membrane and thereby inhibits neural activity.7 GABA plays a key
role in mechanisms on the basis of intoxication, tolerance and withdrawal the
neurochemical mechanisms on the basis of intoxication, tolerance and
withdrawal.8 Thus there is need for drugs which act on these
neurotransmitters and pathways in brain involving them. A number of newer drugs
are now being used and have been found to be potentially useful in the long
term management of alcohol dependence.
is a sulfamate substituted analog of fructose
1-6-disphosphate and is an oxygen rich molecule and structurally similar to
acetazolamide.9 It is used as antiepileptic, prevention of migraine10
and to counteract weight gain by psychotropic medications.11 It
facilitates inhibitory action of gamma amino butyric (GABA) through non-benzodiazepine
receptor and reduces excitatory effect of glutamate in the alpha-amino-3
hydroxy-5 metylisoxazole-4 propionic (AMPA) receptor and the kainate receptors. In this way it reduces mesolimbic
cortical activity of dopamine and this seems the principal mechanism to
decrease rewarding effects of alcohol consumption.12 Topiramate is an
efficacious and potent anticonvulsant drug13-14 with proven neuro-protective effects.15-16 Topiramate has six important mechanisms of action viz. the
potentiation of inhibitory gamma amino butyric acid – A (GABA-A) mediated
currents at non-benzodiazepine sites on GABA-A receptors17-18 inhibition
of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate and kainate glutamate receptors19-20, inhibition of
L-type calcium channels and limitation of calcium-dependent second messenger
systems21, limits activity-dependent depolarization and excitation
of voltage-dependent sodium channels22, activation of potassium
conductance and weak inhibition of carbonic anhydrase isoenzymes
II and IV in neurons and peripheral tissues.18
have concluded that topiramate was more effective
than placebo after assessing clinical parameters like number of days to
relapse, severity of craving and laboratory markers. Also effect was
significant when topiramte was used at daily dose of
200-300mg.12 A 12 week clinical trial showed that topiramate improved odds of overall well being, reported
abstinence and overall life satisfaction. Also there was significant shift from
higher to lower drinking quartiles on percentage of heavy drinking days.23
Other studies have found topiramate helpful in
reducing liver function test values, plasma gamma glutamyl
transferases, plasma cholesterol, plasma bicarbonate
levels, systolic and diastolic blood pressure and body mass index.24
Trials comparing efficacy of topiramate to disulfiram25and
naltrexone26 have found favourable results
for topiramate. Topiramate
has been found effective as an add-on drug in non responders to naltrexone and
acamprosate.27 Side effect profile includes paresthesias,
memory problems, cognitive impairment in word finding, psychomotor slowing,
fatigue and confusion.28 Renal acidosis and kidney stones may arise
so adequate hydration is recommended for all patients.29
Tiapride, a substituted benzamide, has
a selective D2- and D3- dopamine receptor antagonist activity in limbic brain
areas or the locus coerulus.30 It has been used for AWS treatment
since the late 1970 s, especially in France.31 Main indications of tiapride are extrapyramidal symptoms or other dyskinesias, hyperkinesias, Huntington’s Chorea32 and
also geriatric agitation and restlessness.33 The common side effects
with tiapride are drowsiness, extrapyramidal
symptoms, dizziness, and orthostatic hypotension.34 Tiapride has no antihistaminic action and is known to
control psychomotor restlessness without causing considerable
benzodiazepine-like sedation.35 It also does not have a possibility of
dependence and abuse.
alcohol withdrawal, dopamine and N-methyl-D-aspartate (NMDA) levels are
increased and GABA is decreased.36 There is positive correlation
between withdrawal symptoms and peripheral dopamine levels on day 1 of
a detoxification treatment37; the D2 antagonist tiapride
reduces this possible dopamine hyperactivity. It does not have an antiepileptic
action so it is preferable to
combine tiapride with carbamazepine. The open label
study comparing efficacy of carbamazepine (upto 1200mg/day)
and tiapride (upto 1800 mg/day) with clomethiazole (upto
3840mg/day) and diazepam (upto 80mg/day) which had
127 patients who were analyzed after 9 days of treatment, found that tiapride had favourable results
upon mood variables and similar results in relation to safety (delirium and
seizure) as compared to standard medications i.e. diazepam and clomethiazole.38
A clinical open study involving 50
patients found good improvement in CIWA-A scores at lower doses of
carbamazepine (600mg) and tiparide (800mg) after 5
days of treatment and no cases of seizures or delirium were recorded.39
Baclofen, a gamma-aminobutyric acid
(GABA)-B receptor agonist, is a muscle relaxant introduced in the 1960s for the
treatment of muscle spasticity due to spinal cord injury, multiple sclerosis
and cerebral injuries resulting in spasticity.40-41 It is rapidly absorbed after oral administration and has a half-life of
approximately 3.5 hours. It is partially metabolized by the liver but largely
excreted by the kidneys, unchanged. Baclofen has been
found effective in treating patients with alcohol dependence in multiple
randomized controlled trials (RCT’s).43-45Experimental
evidence suggests that mesolimbic dopamine neurons are involved in the
mediation of alcohol intake and reinforcement.46 GABA-B receptors
are located both on the cell body of dopamine neurons and on the terminals of glutamatergic afferent neurons in the ventral tegmental
area. Their activation by GABA-B receptor agonists may exert an inhibitory
action on the dopamine neurons47 - the possible mechanism through
which baclofen suppresses alcohol stimulated dopamine release and, in turn,
dopamine mediated, alcohol reinforced and motivated behaviours.
It has been hypothesized that baclofen-induced activation of GABA-B receptors
might counterbalance AWS-associated, enhanced function of NMDA-mediated
glutamate excitatory neurotransmission and thus reducing symptoms of alcohol
two year observational study of 100 patients found baclofen was helpful in
effortless reduction in alcohol craving when used in dose range of 20-330mg/day.49
The incidence of adverse effects with oral baclofen
has been reported as 10–75% and that too at doses greater than 60mg/day.40
The most common side effects are sedation or somnolence, weakness, vertigo,
nausea, dry mouth and psychological disturbances which can be minimized by
initiating treatment with low doses and gradually titrating the dose upwards.
It may cause impairments of cognitive function, particularly confusion, memory
and attention.50 Rapid dose reduction or abrupt cessation of baclofen
leads to majority of
neuropsychiatric effects. A review51 found that such
psychiatric symptoms were consistent with delirium, and included hallucinations
(auditory, visual, tactile),delusional beliefs,
confusion, disorientation, fluctuating level of consciousness, anxiety,
agitation and formal thought disorder. These symptoms were associated with
autonomic changes, seizures, spasticity and sometimes dyskinesia.
Pregabalin (PRE), a structural analogue of GABA, is a novel
compound with broad-spectrum efficacy in the treatment of diabetic neuropathy52,
post-herpetic neuralgia53 and partial epilepsy54.
Different double-blind, placebo-controlled studies suggest that PRE may also be
efficacious in the treatment of general anxiety disorder.55-57 PRE
acts as a presynaptic modulator of the excessive release, in hyperexcited neurons, of excitatory neurotransmitters,
including glutamate58, substance P, calcitonin gene-related peptide
and monoaminergic neurotransmitters.59,60
It is inactive at GABA or benzodiazepines receptors. It neither binds to
serotonin receptors nor does it inhibit reuptake of serotonin or norepinephrine.61It
binds selectively to the α²-δ subunit protein of voltage gated
calcium channels, and rapidly reduces the influx of calcium, subsequently
reducing the exocytosis of synaptic vescicles in the
synaptic cleft. It has relatively little effect on neuronal function under
conditions of normal activity and its effect appears to be correlated strongly
with the degree of hyperexcitation of
the presynaptic neuron.62
Alcohol withdrawal is typically thought to encompass the
first 2–5 days after alcohol cessation but a more protracted phase may last for
weeks to months after the acute symptoms of withdrawal have subsided.63During
this protracted phase, patients experience sleep dysregulation,
irritability, and mood instability.64-65 PRE is useful as anxiolytic
both in acute as well as protracted phase of alcohol withdrawal. Being a novel
sleep modulator and ability to induce restorative sleep it may aid with the
sleep dysfunction experienced during and after acute alcohol withdrawal.66
Various double blind
controlled studies have found PRE used in dose range of 150-600mg/day efficacious in
management of alcohol withdrawal and also in relapse prevention of alcohol-dependent
subjects.67-69 Side effects include
dizziness and drowsiness,blurred vision, ataxia, memory
impairment, hypoaesthesia and hypotension.70
Gabapentin is structurally
analogous to GABA but, unlike GABA, crosses the blood-brain barrier when
administered systemically. The mechanism of action may be an increase in GABA-mediated
inhibition and inactivation of voltage-dependent sodium channels. Gabapentin may also exert
neuronal stabilization effects by binding to the L-amino acid transporter on the
plasma membrane or the subunit of voltage-gated calcium channels.
The above observations suggest that gabapentin may be a promising candidate for
the treatment of alcohol withdrawal symptoms. Open label reports as well as case
studies have shown the utility of gabapentin in managing alcohol withdrawal
symptoms and tonic clonic seizures that may occur
upon alcohol withdrawal. [73-75] Although
studies have shown a very modest effect of gabapentin in managing long-term
alcohol dependence, large-scale double-blind randomized controlled studies are
needed to strengthen these findings and look at relapse prevention.76
Levetiracetam is a newer
anti-epileptic drug with a multi-site mechanism of action, and is effective
against a variety of seizure types. It is currently being used especially in
the management of especially juvenile myoclonic seizures, Lennox Gastaut syndrome and refractory seizures in children and
adults. There is preclinical evidence that it may have potential benefit also
in anxiety disorders, stress, and mood disorders.77 To date, there
has been only one study with a negative outcome when levetiracetam
was used in the management of alcohol dependence with co-morbid anxiety.78
In an open label trial, levetiracetam was effective
in the management of alcohol withdrawal symptoms and prevention of seizures
during the withdrawal phase.79
Several recent reviews have
supported the role of topiramate in the management of
various phases of alcohol dependence, from the alcohol withdrawal syndrome to
long-term management and relapse prevention. In clinical practice I have often
found that in the management of alcohol withdrawal syndrome, particularly in
patients who suffer from both alcohol dependence and a comorbid antisocial personality
disorder, anticonvulsants act as mood stabilizers during withdrawal, thereby
reducing mood swings and irritability along with their anti-epileptic
potential. The role of topiramate in managing this
specific subset of alcohol dependence has not been investigated, and this
research is warranted. Alcohol dependence pharmacotherapy is at an interesting crossroads.
Increases in co-morbidity in alcohol dependence, in the form of mood disorders
as well as personality disorders, requires the use of poly-pharmacy when it
comes to the long-term management of alcohol dependence. It is well-known that depression
and bipolar disorder may exist at sub-threshold or subclinical levels in these
patients. It is here that a combination of drugs like disulfiram,
naltrexone, or acamprosate with anticonvulsant drugs
may help in sustaining abstinence and promoting the long-term management of
alcohol dependence. Further studies of various combinations of traditional
drugs with newer ones or newer ones alone in various populations across cultures
is required in order to judge the efficacy of these agents, as well as to reach
clear guidelines for their usage in alcohol dependence.
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