Doi:10.1016/j.yebeh.2005.08.00

Epilepsy & Behavior 7 (2005) 539–542 Effects of levetiracetam on sleep in normal volunteers Carl W. Bazil a,*, Julianne Battista a, Robert C. Basner b a Department of Neurology, Columbia University College of Physicians and Surgeons, New York, NY, USA b Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA Received 13 June 2005; revised 1 August 2005; accepted 1 August 2005 Background. Epilepsy patients commonly suffer from sleep disturbances, and these can exacerbate memory dysfunction and seizures.
Sleep can be affected by seizures, independent sleep disorders, or anticonvulsant drugs. Levetiracetam is a novel anticonvulsant effectivefor the treatment of partial seizures. We studied the effects of levetiracetam (LEV) on sleep using polysomnography in normal subjects.
Methods. Subjects (aged 18–40) were screened for freedom from sleep disorders, excessive daytime sleepiness, and depression. Screen- ing overnight polysomnography was performed, followed by baseline polysomnography. Subjects were randomized to placebo or LEV,titrated to 1000 mg twice daily over 9 days. Polysomnography was repeated on Treatment Day 28. Differences between baseline andtreatment in the drug and placebo groups were compared using single-factor ANOVA.
Results. Seventeen subjects were enrolled; 14 completed the study (8 placebo, 6 LEV). All subjects who remained on LEV were able to tolerate the target dose. There were no significant differences between the placebo and drug groups with respect to baseline sleep char-acteristics. When baseline polysomnography was compared with treatment polysomnography, there were no differences in the change insleep efficiency, sleep latency, total sleep time, REM latency, or percentages of REM, stage 1, stage 2, or slow wave sleep. There was anincrease in the number of awakenings in the drug group that was significant compared with placebo.
Conclusion. These results suggest that LEV does not have major effects on sleep structure.
Ó 2005 Elsevier Inc. All rights reserved.
Keywords: Sleep; Polysomnography; Anticonvulsant drugs; Levetiracetam sleep, which can be responsible for the intractability of epi-lepsy in some patients.
Sleep disturbance and daytime drowsiness are common Potential causes of sleep disturbance include inadequate in epilepsy patients . Although our society tends to ac- sleep hygiene, coexisting sleep disorders, and circadian cept poor sleep as the norm, it can result in considerable rhythm disturbances Seizures themselves can disrupt impairment of daytime functioning, even in normal indi- sleep, and even daytime seizures have been shown to dis- viduals. In patients with epilepsy, the consequences are rupt the following nightÕs sleep Anticonvulsant drugs potentially more severe. Inadequate sleep can exacerbate and the vagus nerve stimulation can also alter sleep, in both the drowsiness and memory dysfunction common to these positive and negative ways, and these effects are indepen- individuals, and can contribute to intractable seizures dent of their anticonvulsant actions . Although there Even more concerning is the potential for a cycle of sleep are several studies of older anticonvulsants, relatively little disruption, worsening seizures, and further impairment of is known about the effects of the newest anticonvulsantdrugs on sleep .
Levetiracetam is an anticonvulsant drug effective for the treatment of partial seizures. Sleep complaints are not list- * Corresponding author. Present address: The Neurological Institute, ed among the common side effects We studied the ef- 710 West 168th Street, New York, NY 10032, USA. Fax: +1 212 305 1450.
fects of levetiracetam on sleep using normal subjects to 1525-5050/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.yebeh.2005.08.001 C.W. Bazil et al. / Epilepsy & Behavior 7 (2005) 539–542 isolate the effects of the drug itself from its effects on ment or placebo. Sleep latency, total sleep time, sleep effi- ciency, and time in each sleep stage (as a percentage oftotal sleep time) were calculated. Awakenings were defined as at least one epoch scored as awake after a sleep period;arousals were defined as a shift to higher EEG frequencies Normal subjects between the ages of 18 and 40 were during a sleep epoch without progression to full wakeful- recruited from the community. Informed consent was ob- ness, according to the criteria of the American Sleep Disor- tained before any study-related assessments were performed.
ders Association Differences between baseline and Because numerous anticonvulsants have been shown to af- treatment were calculated, and drug was compared with fect the percentage of REM sleep this was chosen placebo using single-factor ANOVA. Polysomnograms as the primary outcome variable. On the basis of previous were all scored by the same blinded investigator.
studies in patients with epilepsy we estimated that it Blood was taken for measurement of serum LEV to ver- was necessary to assign at least five subjects to each treat- ment arm to detect a difference in REM sleep percentage; atotal of 16 were targeted (8 per treatment group) to allow for dropouts. Secondary outcome variables included per-centages of stage 1, stage 2, and slow wave sleep; sleep effi- A total of 17 subjects met the aforementioned criteria ciency; and numbers of arousals and awakenings. With the and were enrolled in the study. One subject (randomized use of numbers similar to those in the above study, effects to LEV) dropped out after three doses of study medication on stage 1 sleep (with phenytoin and valproate) and slow due to agitation; another subject dropped out due to unre- wave sleep (with gabapentin) were seen; therefore, changes lated illness after randomization but before the second in at least some secondary variables, if similar in magnitude polysomnogram. A third subject (randomized to LEV) had to changes caused by other AEDs, could be expected with inadequate polysomnography due to technical failure. This this sample size. Subjects were initially screened by a neurol- left 14 subjects available for evaluation. Eight had been ogist by structured interview to ensure that they were free of randomized to placebo, and six to LEV. All subjects who sleep disorders and not taking any medication except occa- remained on LEV were able to tolerate the target dose of sional nonsteroidal anti-inflammatory agents or oral contra- 2000 mg/day, and were tested while taking this dose. The ceptives. Subjects also were screened for excessive daytime characteristics of the subjects are summarized in sleepiness with the Epworth sleepiness scale, and for depres- All subjects taking drug had measurable LEV levels sion using the Beck Depression Inventory. Women of child- (range, 11–42; mean ± SD, 24 ± 5). Results are outlined bearing potential could not be pregnant when entering the in . There were no significant differences between trial, and were instructed in the use of adequate birth control those taking placebo and drug with respect to baseline (oral contraceptive or barrier) throughout the trial. Urine sleep characteristics. When baseline polysomnography pregnancy tests were administered prior to treatment with was compared with treatment polysomnography, there drug or placebo. No caffeine was allowed after noon on days were no differences in the change in sleep efficiency, sleep latency, REM latency, total sleep time, or percentages of Subjects without signs of sleep disorder, significant day- REM, stage 1, stage 2, or slow wave sleep. There was an time sleepiness, or depression and who signed an informed increase in the number of awakenings (defined as a period consent were scheduled for screening overnight polysom- of at least one epoch of wakefulness after sleep onset) in the nography in the laboratory. So long as no significant sleep drug group that was significant compared with placebo disorder was seen, the subjects were randomized to drug or (P < 0.05). Arousals were also increased; however, this placebo, and the following night, a baseline study was per- did not reach statistical significance.
formed for comparison to treatment arms of the study.
Subjects were then given levetiracetam (LEV) or placebo, initially at a dose of 250 mg twice daily, increasing to500 mg twice daily after 3 days if tolerated, then 750 mg These results suggest that LEV does not have major ef- twice daily after 3 more days, then 1000 mg twice daily fects on sleep structure. There was, however, a significant after 3 more days (total of 9 days of titration). Subjects increase in the number of awakenings in subjects taking were contacted weekly during the treatment, but instructed LEV; this is of questionable clinical significance as awaken- to call immediately if they experienced side effects. If the ings were brief and there was no overall difference in sleep side effects were unacceptable, the titration rate could be efficiency. The clinical significance of increased awakenings slowed; however, the subject remained in the study so long could be further assessed by direct measurement of as he or she could tolerate at least 500 mg twice daily by 5 drowsiness using subjective (Epworth sleepiness scales) or days prior to the next polysomnogram. The daily dose of objective (multiple sleep latency testing) tests in patients 2000 mg was chosen because it represents the median rec- chronically treated with LEV. This study enrolled a rela- ommended dose and the median dose in the pivotal trials tively small number of subjects; it could be that more subtle . Polysomnography was repeated on Day 28 of treat- changes in sleep (less than seen with other agents) would C.W. Bazil et al. / Epilepsy & Behavior 7 (2005) 539–542 a SWS, slow wave sleep; TST, total sleep time; SE, sleep efficiency.
b P < 0.05 for drug versus placebo, baseline—treatment.
become evident in a larger group. These results differ some- what from those of another study, in which single-doseLEV was studied as monotherapy in normal volunteers This study, although small, suggests that levetiracetam and as add-on (to carbamazepine) therapy in subjects with appears to have no clinically significant effects on sleep epilepsy These authors found no effect on sleep effi- structure. The results are consistent with the clinical ciency or amount of slow wave or REM sleep in either impression that most subjects taking this medication do group; they saw no difference in the number of awakenings not commonly complain of drowsiness or sleep problems.
but did find increased REM latency and stage 2 sleep. Our A larger study is needed to determine the possibility of study used a higher dose (2000 mg/day, compared with more subtle changes associated with this medication.
1000 mg for the Bell study) and a longer treatment period(28 days compared with a single dose); this could be partly responsible for the observed differences.
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