Clinical Neurophysiology 111, Suppl.

2 (2000) S115±S119
www.elsevier.com/locate/clinph

Effect of antiepileptic drugs on sleep

Fabio Placidi a,b,*, Anna Scalise a, Maria Grazia Marciani a,b, Andrea Romigi a,b,
Marina Diomedi a, Gian Luigi Gigli c
a
Clinica Neurologica, UniversitaÁ Tor Vergata, Roma, Italy
b
IRCCS Clinica S. Lucia, Roma, Italy
c
Divisione Neurologica, Ospedale S. Maria della Misericordia, Udine, Italy

Abstract
The interactions between sleep and epilepsy are well known. A nodal point of the relationship between sleep and epilepsy is represented by
pharmacological treatment. Sleep disturbances such as drowsiness are among the most frequent side effects of treatment with antiepileptic
drugs, since they can deeply modify both sleep architecture and the sleep-wake cycle. Severe daytime somnolence affects patients' activities
and it may facilitate the occurrence of seizures. These considerations underline the importance of antiepileptic drugs having anticonvulsant
properties that do not negatively in¯uence sleep and daytime somnolence. In this paper we review some relevant aspects of the effects of
antiepileptic drugs on sleep. q 2000 Elsevier Science Ireland Ltd. All rights reserved.
Keywords: Antiepileptic drugs; Sleep; Epilepsy; Polysomnography

1. Introduction In epileptic patients, the relationship between sleep and

The ideal antiepileptic drug (AED) would be a substance
able to abolish seizures without side effects. Unfortunately,
none of the current AEDs ful®ls these requirements. In fact,
one major limit of AEDs is the presence of side effects,
which sometimes may compromise the quality of life of
epileptic patients more than the seizures. Common side
effects are gastrointestinal, dermatological and neurologi-
cal. In particular, sleep-wake cycle is affected by AEDs
(Declerck and Wauquier, 1991; Sammaritano and Sherwin,
2000). Despite their large use, the in¯uence of AEDs on
sleep has not been extensively investigated so far. It is
almost impossible to study these drugs in a healthy popula-
tion, in which the effects of epilepsy on sleep are absent. It is
not ethically acceptable to evaluate the effects of long-term
treatment with AEDs in healthy human subjects; on the
other hand, it is dangerous to discontinue AEDs in the
epileptic patients. For these reasons, some investigations
are limited by the fact that these studies did not include
healthy control subjects, or new referrals or comparison
between baseline, acute and chronic conditions, or patients
in monotherapy, or polysomnographic recordings, or homo-
genous samples for age, seizure frequency and typology.
* Corresponding author. Clinica Neurologica, Dipartimento di Neuros-
cienze, UniversitaÁ di Roma Tor Vergata, Via O. Raimondo 8, 00173 Roma,
Italy. Tel.: 139-06-5914436; fax: 139-06-5922086.
E-mail address: fbplacidi@libero.it (F. Placidi).
1388-2457/00/$ - see front matter q 2000 Elsevier Science Ireland Ltd. All rights reserved.
PII: S 1388-245 7(00)00411-9
pharmacological treatment is further affected by the pre-
existence of seizures and interictal epileptiform EEG
abnormalities, that are able to alter the sleep structure per
se (Janz, 1974; Degen and Niedermayer, 1984). Ictal and
interictal epileptic events interfere with sleep structure,
which appears altered by frequent awakenings, by increase
in the number of stage shifts, increase in Stage 1 (S1) and
Stage 2 (S2), reduction of REM sleep and of slow wave
sleep (SWS), increase in sleep onset latency and REM
latency (Broughton, 1984; Touchon et al., 1991). Recently,
several new AEDs have been introduced having minor side
effects compared with the traditional drugs. However, most
studies have investigated the effects of traditional AEDs on
sleep, whereas reports regarding the effects of new antic-
onvulsants are very few. On the basis of literature and our
investigations we summarized the relevant ®ndings of the
effects of AEDs on sleep.
1.1. Phenobarbital (PHB)
Phenobarbital belongs to the class of barbiturates and it
has been the ®rst anticonvulsant used in the clinical practice
since 1912. The mechanism of action of PHB is the
enhancement of chloride ion ¯ux by prolonging the mean
opening time of the channel linked to a speci®c binding site
of GABAa receptor (Meldrum, 1996). In animal studies
(Hinman and Okamoto, 1984; Wauquier et al., 1986) as
well as in humans (Wolf et al., 1984) PHB reduces REM
CLINPH 1041
S116 F. Placidi et al. / Clinical Neurophysiology 111, Suppl. 2 (2000) S115±S119
sleep, sleep latency, the number of awakenings and it
provokes increase in NREM sleep, namely S2, and increase
in sleep spindles (Johnson, 1982).
1.2. Phenythoin (PHT)
Pheythoin is a hydantoin derivative, whose main mechan-
ism of action consist of the inhibition of voltage-gated and
use-dependent sodium channels (Meldrum, 1996; Lang et
al., 1993). This property is responsible for its ef®cacy in
preventing sustained repetitive ®ring, which leads to the
spread of epileptic discharge. The effects of PHT on sleep
structure are characterized by reduction of sleep ef®ciency,
decrease in sleep latency, decrease in S1 and S2, light
decrease in REM sleep, increase or no effect on SWS and
increase in wakefulness (Wolf et al., 1984; Declerck and
Wauquier, 1991). Some authors (Wolf et al., 1985; Roder-
Wanner et al., 1988) have distinguished short-term from
long-term effects: acute effects were characterized by
decrease in sleep onset latency, decrease in S1 and S2,
whereas SWS was increased and REM sleep unchanged;
long-term effects consisted of increase in S1 and S2,
decrease in SWS, and REM sleep remained unmodi®ed.
1.3. Valproic acid (VPA)
Valproate exhibits a number of mechanisms of action
including the inhibition of GABA-degrading enzymes
(GABA-T and succinic semialdehyde dehydrogenase), the
blockade of voltage-gated sodium channels, and the reduc-
tion of low threshold calcium currents (Meldrum, 1996;
Kelly et al., 1990). Most studies show minor or no effects
on sleep architecture together to a stabilization of sleep
cycles (Roder-Wanner and Wolf, 1981; Declerck and
Wauquier, 1991; Manni et al., 1993a,b).
1.4. Carbamazepine (CBZ)
It is an iminostilbene and is the ®rst-choice drug in the
treatment of partial seizures with or without secondary
generalization. This drug exerts its anticonvulsant effect
by inhibiting voltage-gated sodium channels (Lang et al.,
1993; Meldrum, 1996). Several studies describe the effects
of CBZ on sleep in both animals and humans (epileptic
patients and healthy volunteers). Increase in S1, increase
in total sleep time (TST), decrease in REM sleep and
decrease of awakenings have been described after acute
administration of CBZ in cats (Gigli et al., 1988). A similar
decrease in REM sleep has been described after acute CBZ
treatment also in kindled cats (Gigli and Gotman, 1992). In
healthy humans, the short-term effects of CBZ can be
summarized as follows: improvement of sleep continuity
and sleep ef®ciency, increase in SWS, decrease in REM
sleep percentage and REM sleep density, increase in
daytime somnolence (Yang et al., 1989; Riemann et al.,
1993; Gann et al., 1994; Gigli et al., 1997).
In epileptic patients, the ®ndings regarding chronic treat-
ment are controversial: Touchon et al. (1987) reported an
increase in sleep stability with respect to basal condition. In
contrast, Manni et al. (1990), comparing epileptic patients
vs. normal control subjects, found an increase in sleep
instability associated with REM sleep decrease and increase
in REM sleep onset latency. Bonanni et al. (1995) documen-
ted a decrease in daytime somnolence in the shift from
polytherapy to CBZ monotherapy. In a recent study that
we carried out in temporal lobe epileptic patients, the
short-term effects of CBZ-CR were characterized by reduc-
tion and fragmentation of REM sleep and increase in the
number of stage shifts (Gigli et al., 1997). The acute effects
of the drug were partially reversed after chronic use, and no
signi®cant difference was found when basal condition was
compared with chronic follow up. NREM sleep was not
signi®cantly affected, as demonstrated both by macro- and
microstructural analysis. We concluded that CBZ-CR
disrupts REM sleep, but only after acute administration;
chronic CBZ-CR therapy does not cause relevant modi®ca-
tions of nocturnal sleep and daytime somnolence.
1.5. Ethosuximide (ES)
This is a succimide derivative speci®cally indicated for
the treatment of absence seizures. ES selectively reduces
low-threshold calcium currents in thalamic neurons (Coulter
et al., 1989). This drug seems to reduce SWS, to increase
REM sleep, S1 and wake after sleep onset (WASO) (Roder-
Wanner and Wolf, 1981; Wolf et al., 1985; Declerck and
Wauquier, 1991).
1.6. Benzodiazepines (BDZ)
A large number of compounds belongs to this group of
substances, all having anxiolytic, sedative muscle relaxing
and also anticonvulsant effects. Their mechanism of action
is linked to the enhancement of synaptic inhibition by
increasing the opening frequency of GABAa receptor-
coupled chloride channels where they bind to a speci®c
modulatory site. Some of these molecules are utilized in
the treatment of status epilepticus (i.e. Lorazepam, Diaze-
pam, Clonazepam); however, they are often used as add-on
therapy in drug resistant seizures (i.e. Clobazam, Clonaze-
pam). Most reports in literature are in agreement regarding
their effects on sleep architecture: decrease in sleep onset
latency, decrease in SWS, increase in S2, increase in REM
sleep onset latency, sometimes associated to REM sleep
reduction, decrease in number and duration of awakenings
and arousals; ®nally, an increase in spindle density has also
been reported (Johnson, 1982; Nicholson et al., 1989;
Declerck and Wauquier, 1991; Kales et al., 1991; Sammar-
itano and Sherwin, 2000).
1.7. Vigabatrin (VGB)
This drug is an irreversible inhibitor of GABA-T,
increases GABA concentration in human brain and inhibits
 F. Placidi et al. / Clinical Neurophysiology 111, Suppl. 2 (2000) S115±S119
GABA uptake (Meldrum, 1996). Bonanni et al. (1997)
found that chronic VGB add-on therapy did not modify
nocturnal polysomnographic sleep measures and daytime
somnolence in epileptic patients receiving CBZ. Recently,
in a study by Raol and Meti (2000) chronic VGB-treated
kindled rats showed an increase in TST due to an increase
in light slow-wave sleep stage with a decrease in wakeful-
ness.
1.8. Gabapentin (GBP)
GBP is a gamma-aminobutyric acid analogue. Its
mechanism of action has not been clari®ed yet, but its
®nal effects seem to consist of an enhancement of GABA
inhibition and a modulation of glutamate synthesis (Taylor
et al., 1998). Previous studies on the effects of GBP ther-
apy on sleep are very few: two studies showed an improve-
ment in subjective measures of sleep interference
associated with postherpetic neuralgia and painful diabetic
neuropathy (Rowbotham et al., 1998; Backonja et al.,
1998). A polysomnographic study performed on healthy
volunteers who underwent GBP therapy reported an
increase in SWS related to an increase in serotonine plasma
levels (Rao et al., 1988). In addition, GBP was recently
found to be of bene®t in controlling the leg discomfort
associated with Restless Leg Syndrome (RLS) (Ehremberg,
2000; Adler, 1997). Recently, we have studied the effects
of chronic GBP therapy on nocturnal sleep in drug-resistant
epileptic patients (Placidi et al., 2000a): we observed an
increase in REM sleep and SWS, associated with a reduc-
tion in the number of awakenings and Stage 1. The
increase in REM sleep did not correlate with changes in
seizure frequency.
1.9. Lamotrigine (LTG)
Lamotrigine [3,5-diamino-6-(2,3 dichloro-phenyl)-1,2,4-
triazine] has an anticonvulsant pro®le similar to that of
phenytoin and carbamazepine, but structurally unrelated
to them (Lang et al., 1993). The drug also potently inhibits
the presynaptic release of glutamate evoked by activation
of voltage-dependent sodium channels (Leach et al., 1995;
Macdonald and Green®eld, 1997) without acting directly
on the N-methyl-d-aspartate receptors. Bertorelli et al.
(1996) reported an increase in wakefulness during the
light phase and a reduction in REM sleep during the dark
phase in rats after acute LTG treatment. A retrospective
study showed that 6.4% of patients (7/109) treated with
LTG therapy complained of insomnia (Sadler, 1999).
Recently, we have studied the long term effects of add-
on LTG therapy on nocturnal sleep and daytime somno-
lence in drug-resistant epileptic patients (Placidi et al.,
2000b): we observed an increase in REM sleep, a reduction
in the number of entries into REM and stage shifts, a
decrease in SWS. The increase in REM sleep did not corre-
late to the reduction of the interictal spiking rate. Other
S117
sleep parameters and daytime somnolence were unmodi-
®ed.
1.10. Felbamate (FBM)
This drug is a dicarbamate used in the control of seizures
in Lennox±Gastatut Syndrome; it has been found to inter-
act with neurotransmission mediated by excitatory aminoa-
cids (De Sarro et al., 1994). Little or no effects on sleep
have been observed in a polysomnographic study carried
out in rats (Bertorelli et al., 1996); however, this drug has
been reported to induce insomnia in epileptic patients
during both acute and chronic intake (Leppik, 1995; Ketter
et al., 1996).
1.11. Topiramate (TPM) and Tiagabine (TGB)
The mechanism of action of TPM is complex: inhibition
of voltage-gated sodium channels, antagonism of kainate/
AMPA glutamate receptor, increase of human brain GABA
concentration and positive modulatory effect on a novel
type of GABAa receptor (Meldrum, 1996; Kuzniecky et
al., 1998). Tiagabine increases GABA concentrations by
inhibiting the reuptake of this neurotransmitter (Meldrum,
1996).
No polysomnographic studies are available for these
drugs.
2. Discussion
Sleep and epilepsy have reciprocal effects (Janz, 1974;
Degen and Niedermayer, 1984), since sleep is a strong
modulator of epileptic activity. Epileptic events may occur
with different distribution across the sleep stages
(Passouant, 1982). NREM sleep is apparently a permissive
stage for the expression of partial or generalized paroxysmal
events (Sammaritano et al., 1991; Baldy-Moulinier et al.,
1984). On the other hand, REM sleep causes an inhibition of
seizures and a circumscription of spatial distribution of
epileptic discharges (Sammaritano et al., 1991; Montplaisir
et al., 1987). Moreover, sleep instability, i.e. phase shifts,
transitions to waking and arousals, increases the frequency
of ictal and interictal epileptic phenomena (HalaÁsz, 1984)
which, in turn, can alter the sleep-waking cycle and sleep
architecture (Janz, 1974; Degen and Niedermayer, 1984).
The resulting sleep deprivation may induce further seizures
(Rowan et al., 1982).
AEDs are able to modify the frequency and course of
epileptic phenomena and the sleep architecture by acting
at both levels (Wolf et al., 1984; Declerck and Wauquier,
1991; Sammaritano and Sherwin, 2000). Drowsiness is one
of the most frequent side effects of AEDs (Collaborative
Group for the Study of Epilepsy, 1986). Severe daytime
somnolence not only adversely affects patients' activities
by impairing cognitive performance, but it may facilitate
the occurrence of seizures and be associated with injury
S118 F. Placidi et al. / Clinical Neurophysiology 111, Suppl. 2 (2000) S115±S119
and fatality. These considerations underline the importance
of the utilization of AEDs having anticonvulsant properties
that do not negatively in¯uence sleep and daytime somno-
lence.
From this review of the literature it appears that some
AEDs have detrimental effects on sleep, whereas others
seem to have stabilizing sleep effects. The problem is to
establish if this stabilization of sleep is a direct effect of
the intake of these anticonvulsants or rather the consequence
of the improvement of the epileptic condition. In fact, it
should be reminded that also AEDs producing negative
changes on sleep can improve its quality through the reduc-
tion of ictal and interictal events. On the basis of the results
given by literature and our own investigations, we think that
at least some AEDs are able to directly act on sleep. For
example, in our studies regarding the effects of LTG and
GBP on nocturnal sleep, an important result was represented
by the increase in REM sleep, which did not correlate with
the reduction in interictal spiking rate and the change in
seizure frequency (Placidi et al., 2000a,b). It is possible
that the stabilization of sleep and the improvement of
sleep pattern is the result of both direct and indirect effects
of the AEDs, mediated by the suppression of ictal and inter-
ictal epileptic phenomena. On the other hand, it is also
possible that the improvement of sleep pattern will contri-
bute to a better control of seizures. The recent introduction
of new AEDs having minor side effects and multiple
mechanisms of action, including the enhancement of the
gabaergic system, could be helpful in seizure control by
means the stabilization of sleep pattern.
In conclusion, the correct use of AEDs, the preference for
monotherapy, the choice of AEDs having minor interfer-
ences with sleep, the administration of the minimal effective
dosage, the attention to the time hours of administration, can
lead to a relevant improvement of nocturnal sleep and
daytime somnolence in epileptic patients, thus improving
their quality of life.
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