[REVIEW]

by VANIA MODESTO-LOWE, MD, MPh; JESSICA HUARD, BS; and CYNTHIA CONRAD, MD, PhD

Dr. Modesto-Lowe is Assistant Professor and Dr. Conrad is Associate Professor from the Department of Psychiatry, University of Connecticut School of Medicine and
both are from Connecticut Valley Hospital; Ms. Huard is Master’s Physician Assistant Student, Quinnipiac University—All from Middletown, Connecticut.

Alcohol Withdrawal
Kindling: Is There a Role for
Anticonvulsants?
ABSTRACT
Animal and clinical studies
supporting the kindling hypothe-
sis of alcohol withdrawal suggest
the need to revisit current treat-
ment concepts. While traditional
approaches have emphasized
symptom reduction and preven-
tion of complications, novel
approaches include slowing
progress of clinical severity asso-
ciated with multiple withdrawals.
Currently, it is unclear if medica-
tions can halt cumulative neuro-
toxicity associated with multiple
withdrawals. However, the ability
of anticonvulsants to improve the
course of alcohol withdrawal and
their neuroprotective effects may
be of interest. The use of anti-
convulsants as probes in animal
models of kindling and controlled
trials examining the efficacy of
newer anticonvulsants in the
treatment of alcohol withdrawal
may improve understanding of
alcohol withdrawal kindling and
its treatment. ADDRESS CORRESPONDENCE TO:
Vania Modesto-Lowe, MD, MPH, Connecticut Valley Hospital, Addiction Service Division, Merrit Hall, PO Box 351,
Middletown, CT 06457; Phone: (860) 521-2604; E-mail: Vania.Modesto-Lowe@po.state.ct.us

[MAY] Psychiatry 2005 25

 INTRODUCTION
Alcohol dependence, a chronic
relapsing disorder, affects 14 per-
cent of Americans causing signifi-
cant morbidity and mortality.1
Chronic heavy drinking leads to
central nervous system (CNS) neu-
roadaptations. Discontinuation of
alcohol following chronic use may
result in CNS over-excitation clini-
cally manifested by the signs and
symptoms of alcohol withdrawal.2
For many alcohol-dependent
patients, detoxification is the first
step of treatment. Alcoholics with
adequate social support, mild to
moderate alcohol withdrawal, and
stable medical and psychiatric sta-
tus may be suitable candidates for
outpatient management.3
In the United States, benzodi-
azepines have become the gold
standard pharmacological treatment
of alcohol withdrawal.4 However,
the potential for benzodiazepine
misuse and the interactions with
alcohol complicate its use in outpa-
tient detoxification.5 To protect
against unnecessary prescriptions
of benzodiazepines for withdrawal,
decisions can be based upon quanti-
tative ratings of alcohol withdrawal
symptom severity.6,7 The approach
of monitoring symptoms while with-
holding benzodiazepines has been
widely endorsed for cases of mild
alcohol withdrawal.4,8 Yet, the poten-
tial for subclinical neurotoxicity
during each episode of untreated
alcohol withdrawal suggests that
there may be a role for a more
aggressive pharmacological inter-
vention.9,10
According to the kindling
hypothesis, multiple episodes of
alcohol withdrawal not only cause
immediate neurotoxicity, but also
cumulative changes in neuronal
excitability.11 This phenomenon of
neural sensitization, referred to as
“kindling,” appears to clinically
manifest itself by progressive wors-
ening of subsequent withdrawal
episodes, particularly the predispo-
sition to experience alcohol with-
drawal seizures.9 The question of
whether benzodiazepines can pre-
26 Psychiatry 2005 [ M A Y ]
vent neurotoxicity associated with
repeated alcohol withdrawal by
blocking early withdrawal reactions
has recently received some atten-
tion.12,13 There has also been grow-
ing interest in the potential neuro-
protective effects of anticonvulsants
in preclinical models with cerebral
ischemia and traumatic brain
injuries.14 These medications may
exert neuroprotective effects by
either interacting directly with neu-
rotransmitter receptors or via ion
channels (e.g., voltage sensitive cal-
cium channels).15,16 Clinical trials
demonstrating that anticonvulsants
improve the course of alcohol with-
drawal suggest neuroprotective
effects may be relevant to the
pathophysiology of alcohol with-
drawal states.20
This article examines the poten-
tial for increasing the use of anti-
convulsants in the outpatient treat-
ment of alcohol withdrawal in view
of the kindling hypothesis. First, we
will discuss the empirical basis for
the kindling hypothesis of alcohol
withdrawal. Second, we will review
the effects of alcohol and selected
anticonvulsants on major excitatory
and inhibitory neurotransmitter sys-
tems, as well as possible neurobio-
logical correlates of the kindling
hypothesis. Third, we will examine
clinical trials evaluating the efficacy
of selective anticonvulsants for mild
to moderate alcohol withdrawal.
Lastly, we will conclude by identify-
ing directions for future research on
the kindling model and highlighting
therapeutic implications.
ALCOHOL WITHDRAWAL AND
KINDLING
The kindling concept is derived
from epilepsy animal models and
refers to a sensitization phenome-
non by which stimuli of neural sites
with no initial epileptogenic effect
will, if repeated over time, result in
the development of seizures.21 In
alcohol withdrawal, the kindling
model is used to demonstrate the
association between the number of
withdrawal episodes and the severi-
ty of subsequent withdrawal reac-
tions.9,20 Specifically, repeated
episodes of ethanol withdrawal are
thought to promote changes in neu-
ronal excitation, leading to cumula-
tive neuronal damage clinically
manifested by an increasing severi-
ty of the withdrawal syndrome in
subsequent episodes; this includes a
higher risk for seizures.
Mice studies comparing the
severity of withdrawal and pharma-
cologically induced seizures after
single and multiple withdrawal reac-
tions are of interest in this
regard.23,24,26 Specifically, withdrawal
seizures are significantly more
severe in mice tested after multiple
withdrawals compared to mice test-
ed after a single withdrawal.23
Similarly, mice exposed to multiple
cycles of ethanol withdrawal display
significantly enhanced sensitivity to
the pharmacologically induced con-
vulsions in comparison to mice the
experience a single withdrawal
episode.24–26 Animal electroen-
cephalogram (EEG) studies also
show that repeated alcohol with-
drawal results in epileptiform
abnormalities that worsen during
successive withdrawals.27,28
Specifically, at baseline, all mice
display low levels of brief spindle
episode activity. During periods of
ethanol withdrawal, mice exhibit a
significant increase in activity,
which is potentiated during subse-
quent withdrawal episodes.29
Human studies showing a positive
relationship between the number of
previous withdrawal reactions and
the risk of developing seizures dur-
ing subsequent episodes of alcohol
withdrawal provide further support
for the kindling hypothesis.30–32
Although the precise mecha-
nisms involved in kindling need fur-
ther elucidation, long-term changes
in N-methyl-D-aspartate (NMDA)
and gamma aminobutyric acid
(GABA-±) receptor functioning fol-
lowing repeated episodes of alcohol
withdrawal may be implicated.29
The development of experimental
models sensitive to the effects of
repeated withdrawals has shed
some light on the neurobiology of
sensitized withdrawal seizures and
neurotoxicity resulting from repeat-
ed alcohol withdrawal. Next, we will
review alcohol effects on NMDA
and GABA systems and speculate
how it may relate to kindling. We
will also discuss candidate mecha-
nisms of anticonvulsants putative
neuroprotective effects on these
systems.
ETHANOL AFFECTS THE
GLUTAMATE NMDA RECEPTOR
SYSTEM
The glutamate NMDA receptor
complex is a ligand-gated ion chan-
nel that mediates the influx of calci-
um ions when activated. The NMDA
receptor complex and voltage-gated
calcium currents are both involved
in controlling neuronal excitability.33
Animal studies show that acute
administration of ethanol disrupts
glutamatergic neurotransmission,
Animals withdrawing from ethanol exhibit a marked increase in
glutamatergic function...This glutamatergic overactivity is likely
to mediate withdrawal symptoms (e.g., seizures)
as well as the neurotoxic effects of ethanol.
causing potent and selective inhibi-
tion of the function of the NMDA
subtype of glutamate receptor.34
Chronic alcohol exposure results
in prolonged NMDA inhibition and
compensatory increases in the
number of NMDA receptors (upreg-
ulation) in several areas of the
brain.34,35 Similarly, acute ethanol
exposure inhibits voltage-sensitive
calcium channels while chronic
ethanol exposure results in an
increase in the number of voltage
sensitive calcium channels.36,37
Animals withdrawing from
ethanol exhibit a marked increase
in glutamatergic function, including
an increase in glutamate release
combined with functional overactiv-
ity of the NMDA receptors.38–40 This
glutamatergic overactivity is likely
to mediate withdrawal symptoms
(e.g. seizures) as well as the neuro-
toxic effects of ethanol.41
Interestingly, the anticonvulsant
carbamazepine has been shown to
depress NMDA-receptor-mediated
responses.42,43 Several other anticon-
vulsants including valproate and
gabapentin also attenuate gluta-
matergic neurotransmission.44
Glutamatergic-induced neurotoxici-
ty occurring during ethanol with-
drawal is thought to be due in part
to excessive amounts of calcium
ions entering the hyperexcitable
neurons and has been implicated in
cumulative neuronal damage associ-
ated with repeated ethanol with-
drawal.45
Evidence for involvement of the
glutamate NMDA receptors in kin-
dling derives from animal studies
indicating that a history of multiple
withdrawal episodes correlates with
increased sensitivity to NMDA-
induced seizures.46 Efforts to inhibit
glutamatergic excitability and neu-
rotoxicity associated with alcohol
withdrawal focused on acam-
prosate.47 This medication, which
was approved for the treatment of
alcohol dependence in Europe and
recently approved in the US, exerts
a weak inhibitory effect on the glu-
tamatergic system via the gluta-
mate/NMDA receptors resulting in
reduced NMDA receptor function.48
In at least two in-vitro studies,
acamprosate had protective effects
against glutamate-induced neuro-
toxicity in ethanol-withdrawn cul-
tures.49,50 While these effects do not
correlate with acamprosate’s effects
on calcium entry, anticonvulsants
may exert their neuroprotective
effects by interacting with voltage-
gated calcium currents.49,51
One in-vitro study has shown
that the anticonvulsants oxcarba-
mazepine and lamotrigine consis-
tently inhibit voltage-activated calci-
um currents.15 The anticonvulsant
gabapentin inhibits neuronal calci-
um influx in a concentration-
dependent manner.52 If decreased
calcium influx indeed reduces exci-
tatory glutamate release, anticon-
vulsants may indeed exert neuro-
protective effects during alcohol
withdrawal. Because current under-
standing of the full spectrum of the
biological effects of alcohol, anticon-
vulsants, and neurotransmitter sys-
tems are incomplete, both animal
and human models of kindling
require further development.
Perhaps the use of anticonvulsants
as pharmacological probes in animal
kindling models may improve the
understanding of kindling neurobio-
logical substrates as well as the
development of alternative pharma-
cological treatments for alcohol
withdrawal.
ETHANOL EFFECTS ON GABA
Acutely, ethanol consumption
acts at the benzodiazepine GABA-±-
chloride receptor complex, potenti-
ating its inhibitory effects and sup-
pressing neuronal activity in several
areas of the brain.53 Specifically,
activation of GABA-± receptors
results in the entrance of chloride
ions into the neuron. This increase
in intraneuronal chloride concentra-
tion dampens neural activity.
Conversely, chronic ethanol admin-
istration may alter GABA-± recep-
tor functioning by decreasing either
the number or the expression of the
GABA-± receptor subunit.54,55 Both
GABA-± downregulation and con-
[MAY] Psychiatry 2005 27
 formational changes in the config-
uration GABA-± subunits associat-
ed with chronic ETOH exposure
may influence neuronal responsivi-
ty to alcohol and the development
of hyperexcitability during ethanol
withdrawal.36,37
The ability of benzodiazepines
and certain anticonvulsants to
substitute for the GABA-enhanc-
ing effects of ethanol probably
accounts for their effectiveness in
suppressing acute symptoms of
alcohol withdrawal.56
Anticonvulsants’ neuroprotective
effects may also occur by potentia-
tion of GABAergic inhibitory path-
ways. Valproic acid, for example,
has multiple GABAergic actions. It
appears to mediate GABA-±
receptor activity, decrease GABA
catabolism, and increase GABA
release.44 The anticonvulsant topi-
ramate, recently shown to
decrease relapse in previous heavy
drinking, also has GABAergic
actions.57 Similarly, the anticonvul-
sant gabapentin is an amino acid
structurally related to GABA.
Although it neither adheres to the
GABA receptor nor modulates
GABA functioning, it may indirect-
ly interact with the GABA trans-
porter and increase GABA levels
in a dose-related manner.58,59 Its
mechanism of action remains elu-
sive, but inhibition of a neuronal
calcium channel (presumably L-
type) and potentiation of GABA
synthesis may play a role.60
While the effects of anticonvul-
sants on GABA may vary, it has
been postulated that anticonvul-
sants may inhibit alcohol withdraw-
al kindling by potentiating GABA-±
receptor activity.61,62 Specifically,
enhancement of GABAergic inhibi-
tion is thought to protect neurons
during insults, which induces exces-
sive neuronal depolarization. Of
interest, however, is the discovery
that medications targeting alcohol
withdrawal may have differential
effects on acute versus long-term
effects of alcohol withdrawal.63
Efforts to determine whether
GABAergic modulators can prevent
28 Psychiatry 2005 [ M A Y ]
or blunt the development of sensi-
tized CNS hyperexcitability during a
subsequent withdrawal episode are
underway. At least two animal stud-
ies have evaluated the effects of
benzodiazepines in attenuating CNS
hyperexcitability associated with
multiple cycles of ethanol with-
drawal.12,13 These studies have
employed a mouse model sensitive
to the effects of multiple cycles of
ethanol withdrawal. This experi-
mental model consists of exposing
mice to continuous or chronic inter-
mittent ethanol treatment (CIE)
followed by various withdrawal pat-
terns. For instance, one group may
receive four cycles of 16 hours of
ethanol exposure separated by
eight hours of withdrawal periods.
The second group may receive a
single 16-hour exposure period
while a third group consists of
ethanol-naïve controls. The pres-
ence, frequency, and severity of
seizures or epileptiform abnormali-
ties on EEG are compared among
these groups and the effects of vari-
ous medications on seizures during
acute and repeated withdrawal can
be evaluated.
In one study employing this
model, lorazepam attenuated the
development and expression of sen-
sitized handling-induced convul-
sions (HIC) during the acute with-
drawal phase and initial subsequent
unmedicated withdrawals in a dose-
dependent fashion.12 At later points,
however, lorazepam exacerbated
the development and expression of
sensitized seizures.
Another study of similar design
showed that diazepam suppressed
acute withdrawal symptoms, but
when administered during intermit-
tent withdrawal did not alter
seizure sensitivity during a subse-
quent unmedicated withdrawal.13
Together, these findings suggest
that suppression of acute withdraw-
al symptoms by benzodiazepines
may either not prevent or worsen
seizures resulting from repeated
exposures to ethanol withdrawal.12,13
Similar animal studies employing
anticonvulsants that interfere with
GABAergic systems combined with
clinical studies evaluating the effica-
cy of such medications on the treat-
ment of alcohol withdrawal may
improve understanding of the kin-
dling-GABAergic relationship.
Advancements in the field could be
expected if both antikindling and
improvement of acute symptoms
could be demonstrated for these
medications.
ANTICONVULSANTS FOR
ALCOHOL WITHDRAWAL
Carbamazepine (CBZ) is the
most studied anticonvulsant for the
treatment of alcohol withdraw-
al.17–20,65 It has been shown to be
superior to placebo and comparable
to benzodiazepines in improving
symptoms of mild to moderate alco-
hol withdrawal.18–20,64 In addition, at
least two double-blind trials support
its utility in comparison to other
sedative-hypnotic drugs (clomethia-
zole and tiapride) in ameliorating
withdrawal symptoms.17,65 In a few
of these studies, CBZ has also
shown beneficial effects on pro-
tracted withdrawal symptoms, such
as sleep disturbances, anxiety, and
psychological distress.18,64,66
Because alcohol-dependent indi-
viduals often have protracted with-
drawal symptoms, which may con-
tribute to relapse shortly after
detoxification, these post-detoxifi-
cation benefits may be of clinical
value. Indeed, at least two placebo-
controlled studies suggest that CBZ
may reduce some alcohol use in
alcohol-dependent patients in the
post-withdrawal period.20,67 One of
these trials (n=136) compared
lorazepam and carbamazepine for
the outpatient treatment of moder-
ate alcohol withdrawal and drinking
behaviors in the immediate post-
detoxification period.20 Patients
received either CBZ (600–800mg)
or lorazepam (6–8mg) on the first
day and were tapered to either
200mg of CBZ or 2mg of lorazepam
over a five-day period. Although
both CBZ and lorazepam caused a
comparable decrease in alcohol
withdrawal symptoms, CBZ was
superior to lorazepam in reducing
post-treatment drinking, particular-
ly among patients with multiple
withdrawal episodes. In this study,
the relative risk of having a first
drink was at least three times more
likely in lorazepam-treated patients
than in those receiving CBZ.
Despite these potential advantages,
the use of carbamazepine is limited
due to hematological and hepatic
toxicities, in addition to multiple
drug interactions.
Oxcarbamazepine, a newly
improved derivative of CBZ,
appears to have significantly less
hepatotoxicity and less drug inter-
actions.68 It may also have neuropro-
tective effects that need to be
examined in the context of alcohol
withdrawal.14
Preliminary studies suggest that
various formulations of the anticon-
Carbamazepine is the most studied anticonvulsant for the treatment
of alcohol withdrawl...[and] has been shown to be superior to
placebo and comparable to benzodiazepines in improving symptoms
of mild to moderate alcohol withdrawal.
vulsant valproate can modify the
course of alcohol withdrawal.62,69,70 In
one such study, 400 patients were
randomly assigned to either val-
proic acid plus conventional treat-
ment or conventional treatment
alone.69 Patients receiving adjunc-
tive valproic acid demonstrated a
faster decline in symptoms and
required less conventional treat-
ment. More recently, researchers
evaluated the efficacy of divalproex
sodium for alcohol withdrawal and
relapse prevention in an open-label
study.70 Sixteen patients in mild to
moderate alcohol withdrawal were
randomly assigned to receive ben-
zodiazepine detoxification, dival-
proex sodium detoxification, or
divalproex sodium detoxification
with maintenance. Symptom reduc-
tion occurred more rapidly in the
patients on divalproex sodium than
in the patients treated with benzo-
diazepines. In a double-blind, con-
trolled, seven-day study (n=36),
researchers evaluated the adjunc-
tive use of divalproex sodium to a
benzodiazepine in the treatment of
moderate alcohol withdrawal.62
Thirty-six patients in moderate
alcohol withdrawal were random-
ized to receive either divalproex
sodium (500mg TID) or placebo. All
patients received a dose of
oxazepam (30mg) at the time they
first received the study medication
and additional oxazepam in accor-
dance with a standard, symptom
triggered detoxification protocol.
Divalproex sodium-treated patients
required significantly less oxazepam
than placebo-treated patients. In
addition, the progression of with-
drawal severity was significantly
less among patients treated with
divalproex sodium. Although repli-
cation is required, these pilot stud-
ies suggest that both formulations
of valproate may alter the course of
alcohol withdrawal by decreasing its
severity. In addition, two small pilot
studies suggest that divalproex
sodium may decrease measures of
heavy drinking in alcohol-depend-
ent patients.70,71
Finally, the anticonvulsant
gabapentin has also been studied
for the treatment of alcohol with-
drawal states. It is reported that
gabapentin’s protective effects
against convulsant and anxiogenic
dimensions of alcohol withdrawal
syndrome in rodents.72
Subsequently, Myrick, et al., used
gabapentin in six alcohol-dependent
patients experiencing mild to mod-
erate alcohol withdrawal for a peri-
od of five days.73 Gabapentin was
both effective and well-tolerated in
these subjects. Bonnet, et al.,
reported its potential value as an
adjunct to chlormethiazole in treat-
ing four alcohol-dependent patients
undergoing detoxification.74
Gabapentin was found to be an
effective treatment for insomnia
associated with alcohol dependence
in 15 detoxified patients at average
doses of 600mg/d (range
200–1,500mg/d). In general, each
patient showed improvements in
the sleep pattern questionnaire.75
Voris, et al., conducted a retro-
spective chart review in 49 inpa-
tient (18) and outpatient (31) vet-
erans receiving gabapentin for mild
to moderate alcohol withdrawal.76
Gabapentin dosing in general was
400mg three times a day for three
days, 400mg twice a day for two
days and 400mg once a day for one
day. This report indicated the
potential efficacy of gabapentin for
mild to moderate alcohol withdraw-
al. Controlled trials are currently
being conducted to determine if
indeed gabapentin is useful in mild
to moderate alcohol withdrawal
treated in outpatient settings. In
sum, most available studies support
the efficacy of CBZ in the treatment
of mild to moderate alcohol with-
drawal. Similarly, preliminary trials
suggest the positive effects of vari-
ous valproate formulations and
gabapentin on the course of alcohol
withdrawal. Oxcarbamazepine, a
derivative of CBZ, has not yet been
studied and may yield favorable
results.
CONCLUSION
The kindling concept has
increasingly challenged current
notions of the optimal management
of alcohol withdrawal. Novel thera-
peutic approaches focus not only on
[MAY] Psychiatry 2005 29

symptom reduction, but also on
prevention of cumulative neurotox-
icity and progression of clinical
severity associated with multiple
withdrawal episodes. While it is
unclear if early pharmacological
interventions can slow this process,
putative neuroprotective effects of
anticonvulsants may influence alco-
hol withdrawal induced neurotoxic-
ity. Animal models designed to
study neurobiological changes
associated with multiple cycles of
alcohol withdrawal may clarify the
molecular basis of kindling.
Perhaps the use of anticonvulsants
as pharmacological probes in these
models may help determine if anti-
convulsants can halt the progres-
sion of withdrawal severity associ-
While it is unclear if early pharmacological interventions can slow this
process, putative neuroprotective effects of
anticonvulsants may influence alcohol withdrawal-induced
neurotoxicity.
ated with multiple alcohol with-
drawal episodes.
Thus far, clinical studies evaluat-
ing anticonvulsants for alcohol
withdrawal have focused on carba-
mazepine, which has the strongest
empirical basis supporting its use.
Carbamazepine has also shown
beneficial effects on both protract-
ed withdrawal and in reducing
alcohol consumption measures in
the immediate post-detoxification
period. Although not studied, the
anticonvulsant oxcarbazepine is a
likely candidate for examination
based on pharmacological similari-
ties with carbamazepine and its
potential neuroprotective effects.
Pilot studies of both valproic acid
and gabapentin have shown that
these anticonvulsants may truly
improve the course of alcohol with-
drawal. To date however, large
scale double-blind placebo-con-
trolled trials are lacking and more
information on the efficacy, safety,
30 Psychiatry 2005 [ M A Y ]
and neuromechanisms of these
medications are needed.
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